Current Topics in Behavioral Neurosciences 67

Josh M. Cisler
Kevin M. Crombie
Thomas G. Adams Editors

Exercise
and Mental
Health
Current Topics in Behavioral Neurosciences

Volume 67

Series Editors
Bart A. Ellenbroek, School of Psychology, Victoria University of Wellington,
Wellington, New Zealand
Thomas R. E. Barnes, Division of Psychiatry, Imperial College London, London,
UK
Susan L. Andersen, Harvard Medical School, Boston, MA, USA
Martin P. Paulus, Laureate Institute for Brain Research, Tulsa, OK, USA
Jocelien Olivier , GELIFES, University of Groningen, Groningen, The
Netherlands
Current Topics in Behavioral Neurosciences provides critical and comprehensive
discussions of the most significant areas of behavioral neuroscience research, written
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valled reference source. Each volume will be made available in both print and
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delivery, and sophisticated cross-species behavioral assessments, it is now possible
to study behavior relevant to psychiatric and neurological diseases and disorders on
the physiological level. The Behavioral Neurosciences series focuses on transla-
tional medicine and cutting-edge technologies. Preclinical and clinical trials for the
development of new diagnostics and therapeutics as well as prevention efforts are
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especially in psychiatric disorders.

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School of Psychology, Victoria University of Wellington, Wellington,
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Josh M. Cisler • Kevin M. Crombie •
Thomas G. Adams
Editors

Exercise and Mental Health

Editors
Josh M. Cisler Kevin M. Crombie
Department of Psychiatry and Behavioral Department of Kinesiology
Sciences, Dell Medical School The University of Alabama
The University of Texas at Austin Tuscaloosa, AL, USA
Austin, TX, USA

Thomas G. Adams
Department of Psychiatry
Yale University
New Haven, CT, USA

ISSN 1866-3370 ISSN 1866-3389 (electronic)

Current Topics in Behavioral Neurosciences
ISBN 978-3-031-68976-5 ISBN 978-3-031-68977-2 (eBook)
https://doi.org/10.1007/978-3-031-68977-2

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Preface

The goal of this volume is to provide a comprehensive overview of the emerging

science regarding the impact of physical activity and exercise on constructs related to
mental health. Towards this goal, the volume is divided into three sections. The first
section describes basic research on the effects of exercise on physiological systems
and health. This section provides foundational definitions of exercise and physical
activity, an overview of physiological systems engaged during exercise, and basic
neurophysiological processes by which exercise enhances resilience towards the
general negative effects of stress. This section of basic research on exercise and
associated neurophysiology serves as a foundation for understanding of the basic
processes and mechanisms by which exercise influences constructs related to mental
health.
Subsequently, the second section discusses laboratory studies of the impact of
exercise on mood and cognition. This section explores different facets of mood and
cognition that serve as basic mechanisms for understanding the pathophysiology and
treatment of mental health disorders. As an example, our chapter on the impact of
exercise on fear and safety learning describes how fear extinction is a foundational
process for understanding the psychological treatment of exposure therapy. Delin-
eating whether, and how, exercise impacts fear extinction then provides a basic
science foundation for understanding whether, and how, exercise might be helpful in
the treatment of disordered fear and anxiety. Similarly, the chapter discussing the
impact of exercise on acute affect and mood provides a foundational understanding
for the prescription of exercise in the treatment of mood disorders. Overall, the
critical review of basic laboratory studies investigating acute impacts of exercise on
various aspects of cognition, learning, memory, and mood and affect fosters an
understanding of constructs essential for understanding how exercise can be used to
target and treat symptoms of mental health disorders.
Upon establishing a foundation of basic neurophysiology and mechanisms of
mood and cognition engaged through exercise, section three describes the use of
exercise in the prevention, treatment, and pathophysiology of mental health

v
vi Preface

disorders. There are interesting bidirectional relationships between physical activity

and mental health symptoms for most mental health disorders. For example, certain
clinical symptoms may be a determinant of alterations in physical activity and
exercise (e.g., depression reducing overall activity levels). Reciprocally, physical
activity and exercise can directly impact certain clinical symptoms (e.g., an acute
bout of moderate intensity exercise improving depressed mood and anhedonia). The
use of exercise as either an adjunct to existing evidence-based treatments or as a
stand-alone treatment is accordingly accumulating a promising supporting body of
data.
It is our hope that this volume is interesting and informative for those working in
the intersection of exercise physiology, exercise psychology, and mental health
pathophysiology and treatment. We are grateful to all of the authors and contributors
whose hard work has resulted in this volume, which we hope will contribute to
further integration of exercise science into the fields of mental health research and
treatment.

Austin, TX, USA Josh M. Cisler

Tuscaloosa, AL, USA Kevin M. Crombie
New Haven, CT, USA Thomas G. Adams
Contents

Part I Basic Research on Effects of Exercise on Physiological Systems

and Health
Foundations of Exercise and Physical Activity Research . . . . . . . . . . . . 3
Angelique G. Brellenthin and Zoe Sirotiak
Applied Physical Activity Epidemiology: Relationship of Physical
Activity and Exercise Exposures with Health Outcomes . . . . . . . . . . . . . 23
Jessica (Jess) S. Gorzelitz
Multiple Sex- and Circuit-Specific Mechanisms Underlie
Exercise-Induced Stress Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Margaret K. Tanner, Simone M. Mellert, Isabella P. Fallon,
Michael V. Baratta, and Benjamin N. Greenwood
Exercise and Neuroendocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Anthony C. Hackney

Part II Exercise and Laboratory Studies of Mood and Cognition

Exercise and Acute Cognitive Enhancement . . . . . . . . . . . . . . . . . . . . . . 79
Jennifer L. Etnier, Samuel W. Kibildis, and Samantha L. DuBois
Exercise and Acute Affect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Steven J. Petruzzello and Jonathan R. North
Exercise and Fear and Safety Learning . . . . . . . . . . . . . . . . . . . . . . . . . 125
Ameera Azar, Troy Hubert, Thomas G. Adams, Josh M. Cisler,
and Kevin M. Crombie
Exercise and Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Michele Schmitter and Janna Nonja Vrijsen

vii
viii Contents

Part III Exercise and Clinical Symptoms and Treatment

Exercise for the Prevention and Treatment of Depression . . . . . . . . . . . 157
Brandon L. Alderman, Hannah M. Perdue, and Amber H. Sarwani
Exercise and Smoking Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Lorra Garey, Jessica M. Thai, Michael J. Zvolensky, and Jasper A. J. Smits
Exercise and Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Kevin M. Crombie and Patrick J. O’Connor
Adaptive and Maladaptive Exercise in Eating Disorders . . . . . . . . . . . . 223
Katherine Schaumberg, Lauren Pictor, and Max Frank
Exercise and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Laura M. Kinsman, Holden J. Norrie, Geoffrey S. Rachor,
and Gordon J. G. Asmundson
Exercise and Protection from Age-Related Cognitive Decline . . . . . . . . . 263
J. Carson Smith, Daniel D. Callow, Gabriel S. Pena, Yash Kommula,
Naomi Arnold-Nedimala, Junyeon Won, and Kristy A. Nielson
Physical Activity and Fatigue Symptoms: Neurotypical Adults and
People with Chronic Multisymptom Illnesses . . . . . . . . . . . . . . . . . . . . . 281
Alex Boruch, Grace Branchaw, Patrick J. O’Connor, and Dane B. Cook
Influence of Regular Physical Activity on Sleep . . . . . . . . . . . . . . . . . . . 309
Melissa J. McGranahan and Patrick J. O’Connor
Exercise Training for Chronic Pain: Available Evidence, Current
Recommendations, and Potential Mechanisms . . . . . . . . . . . . . . . . . . . . 329
Jacob V. Ninneman, Gunnar A. Roberge, Aaron J. Stegner,
and Dane B. Cook
Exercise and Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Fabiola González, Olga Montoya, and Simon Rosenbaum
The Placebo Effect in Exercise and Mental Health Research . . . . . . . . . 381
John S. Raglin and Jacob B. Lindheimer
 Part I
Basic Research on Effects of Exercise
on Physiological Systems and Health
Foundations of Exercise and Physical
Activity Research

Angelique G. Brellenthin and Zoe Sirotiak

Contents
1 Origins of Physical Activity Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2 Physical Activity Terms and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1 Physical Activity, Exercise, and Fitness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2 Parameters of Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.3 Acute Exercise and Exercise Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3 Physical Activity Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1 Supervised Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.2 Unsupervised Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4 Study Designs in Physical Activity Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4.1 Cross-Sectional . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4.2 Case–Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4.3 Cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4.4 Randomized Controlled Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.5 Systematic Review and Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.6 Qualitative Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Abstract While recognition of the link between physical activity and mental health
dates back nearly two millennia, the academic study of physical activity is a
relatively young discipline emerging over the last 50 years. This chapter provides
an overview of key terms and measurement techniques in physical activity, exercise,
and mental health research. The most common study designs in physical activity
research include cross-sectional, cohort, randomized controlled trials, systematic
reviews, and meta-analytic studies. Examples from the literature as well as the
advantages and disadvantages of various methodological approaches are discussed
throughout the chapter in the context of mental health research.

A. G. Brellenthin (✉) and Z. Sirotiak

Department of Kinesiology, Iowa State University, Ames, IA, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 3

Curr Topics Behav Neurosci (2024) 67: 3–22
https://doi.org/10.1007/7854_2024_488
Published Online: 31 July 2024
4 A. G. Brellenthin and Z. Sirotiak

Keywords Exercise · Measurement · Physical activity · Study design

1 Origins of Physical Activity Research

The relationship between physical activity and mental health has been acknowl-
edged since antiquity. In 600 BCE, a physician in India named Susruta advised his
patients to take moderate exercise every day to not only strengthen the body but also
“reduce senility” (Tipton 2014). However, it was not until the epidemiological
transition of the twentieth century, which marked a long-term shift in “mortality
and disease patterns whereby pandemics of infection [were] gradually displaced by
degenerative and man-made diseases as the chief form of morbidity and primary
cause of death,” that scientific and systematic efforts to quantify the health effects of
physical activity truly began (Omran 2005). The introduction of a series of highly
effective vaccines and antibiotics beginning in the 1930s contributed to reduced
mortality from infectious disease (McKinlay and McKinlay 1977). Reductions in
death from infectious diseases and the resulting increase in lifespan led to growing
concerns regarding the high rates of death from heart disease, a chronic disease that
could be neither prevented nor treated through traditional biomedical approaches.
Dr. Jeremy Morris first proposed the link between physical activity and chronic
disease prevention in his 1953 Lancet paper, “Coronary Heart-Disease and Physical
Activity of Work” (Morris et al. 1953). Morris found that among 31,000 male
employees of the London Transport system, bus drivers, who sat for the majority
of their work shifts, had higher rates of heart attack than bus conductors, who mostly
walked and climbed stairs during their shifts (Morris et al. 1953). Morris’s seminal
findings gave way to a line of inquiry into the associations of physical activity with a
wide range of chronic diseases, including many psychological disorders, for which
there were few medical treatments at the time. This body of research was summa-
rized in the first physical activity recommendations put forth by the Centers for
Disease Control and Prevention and the American College of Sports Medicine in
1995. They advised that adults should accumulate ≥30 min of moderate-intensity
aerobic physical activity on most, preferably all, days of the week due to the
associations between physical activity and the reduced risk of chronic diseases
including anxiety and depression (Pate et al. 1995). The United States Department
of Health and Human Services has since updated the Physical Activity Guidelines for
Americans in 2008 and 2018 as physical activity research expands into new topical
areas and as significant methodological advancements in the instruments and
approaches used to measure physical activity and mental health-related outcomes
have emerged (Physical Activity Guidelines for Americans 2018). The following
sections will provide an overview of key terms and definitions, measurement
considerations, and study designs commonly used in physical activity, exercise,
and mental health research.
Foundations of Exercise and Physical Activity Research 5

2 Physical Activity Terms and Definitions

2.1 Physical Activity, Exercise, and Fitness

The Physical Activity Guidelines for Americans contains the following specific and
standardized definitions for the conceptualization and measurement of physical
activity and exercise (Physical Activity Guidelines for Americans 2018). Physical
activity refers to “any bodily movement produced by the contraction of skeletal
muscle that increases energy expenditure above a basal level.” By this definition,
physical activity encompasses a wide range of activities from sitting and watching
television to a maximal effort sprint to catch a bus. Physical activity occurs through-
out the day, including any movement that takes place in work and home settings or
as part of recreation or transportation. Exercise is a form of physical activity that is
“planned, structured, repetitive, and performed with the goal of improving health or
fitness.” Exercise is always classified as physical activity, but physical activity is not
necessarily exercise. Physical fitness is the “ability to carry out daily tasks with vigor
and alertness, without undue fatigue, and with ample energy to enjoy leisure-time
pursuits and respond to emergencies.” There are many types of physical fitness such
as cardiorespiratory fitness, muscular strength, and flexibility. Cardiorespiratory
fitness, which represents the body’s capacity to use oxygen, is the most commonly
assessed type of fitness and serves as a strong predictor of a wide variety of health
outcomes (Ross et al. 2016).

2.2 Parameters of Physical Activity

Physical activity is prescribed and measured according to the parameters of fre-

quency, intensity, and time (Physical Activity Guidelines for Americans 2018).
Frequency is how often a person engages in a certain type of activity, often on a
“per week” basis. Intensity describes the level of effort needed to perform an activity.
This can be defined in terms of “absolute” intensity or “relative” intensity. Absolute
intensity is often quantified with metabolic equivalents (METs). One MET is
equivalent to an individual’s resting metabolic rate or the amount of energy
expended while sitting quietly (Physical Activity Guidelines for Americans 2018).
Brisk walking has an approximate MET value of 4, meaning the metabolic effort
required to walk briskly is about 4 times the metabolic effort required to sit quietly.
The Compendium of Physical Activities is an important research tool that was
created to ensure consistency in determining the intensity levels of hundreds of
activities (Ainsworth et al. 2011). On an absolute scale, aerobic activities are
commonly categorized as sedentary (≤1.5 METs), light (1.6 to 2.9 METs), moderate
(3.0 to 5.9 METs), or vigorous (≥6.0 METs) intensity (Physical Activity Guidelines
for Americans 2018). Relative intensity allows for physical effort to be quantified
relative to individual differences (e.g., baseline muscular strength or baseline
6 A. G. Brellenthin and Z. Sirotiak

cardiorespiratory fitness), and it is often used to prescribe exercise in recreational,

clinical, and research settings. Common units used to assess relative intensity
include the percentage of maximal heart rate (% HRmax), maximal oxygen uptake
(% VO2max), or 1-repetition max (% 1RM) as well as ratings of perceived exertion
(RPE) (Riebe 2018; Scherr et al. 2013). For example, an activity that requires a
sustained heart rate between 64 and 76% of HRmax is considered a moderate-
intensity activity. A vigorous-intensity activity is between 77 and 95% HRmax
(Riebe 2018). If HRmax is unknown, it can be estimated using the eq. 207-(0.7 × age
in years) (Gellish et al. 2007). Time or duration is simply how long a person
performs an activity in a given session (e.g., 30 min or 1 h). Frequency, intensity,
and time are multiplied together to calculate an overall volume or dose of physical
activity.
Physical activity is also classified in terms of its modality or type. The Physical
Activity Guidelines for Americans provide specific recommendations listed in
Table 1 for the two most prevalent modes of physical activity: aerobic physical
activity and muscle-strengthening physical activity (Physical Activity Guidelines for
Americans 2018). Aerobic physical activity, also known as endurance or cardio
activity, involves the sustained rhythmic movement of the body’s large muscles.
Aerobic physical activity includes brisk walking, running, swimming, and bicycling.
The guidelines recommend that adults perform at least 150 min (time) per week
(frequency) of moderate-intensity (intensity) aerobic physical activity or 75 min per
week of vigorous-intensity physical activity or an equivalent combination of mod-
erate- and vigorous-intensity physical activity per week. This level of physical
activity is associated with substantial mental health benefits including decreases in
depressed mood and anxiety symptoms and increases in cognitive function, sleep
quality, and quality of life (Physical Activity Guidelines Advisory Committee
Scientific Report 2018). This volume of aerobic physical activity could be achieved
in one session (e.g., a weekend pickup basketball game) or several sessions per week

Table 1 Physical activity guidelines for Americans

• Adults should move more and sit less throughout the day. Some physical activity is better
than none
• For substantial physical and mental health benefits, adults should do at least 150 to 300 min
a week of moderate-intensity, or 75 to 150 min a week of vigorous-intensity aerobic physical
activity, or an equivalent combination of moderate- and vigorous-intensity aerobic activity
• Additional physical health benefits may be gained by engaging in physical activity beyond
the equivalent of 300 min of moderate-intensity aerobic activity a week. There is limited evidence
on the association between high amounts of physical activity and mental health outcomes
• Adults should also do muscle-strengthening activities of a moderate or greater intensity that
involve all major muscle groups on 2 or more days a week for additional health benefits
Adapted from: 2018 Physical Activity Guidelines Advisory Committee. 2018 Physical Activity
Guidelines Advisory Committee Scientific Report and the U.S. Department of Health and Human
Services. Physical Activity Guidelines for Americans, 2nd edition. Washington, DC: U.S.
Washington, DC: U.S. Department of Health and Human Services, 2018 (Physical Activity
Guidelines for Americans 2018; Physical Activity Guidelines Advisory Committee Scientific
Report 2018)
Foundations of Exercise and Physical Activity Research 7

(e.g., a 30-min walk during one’s lunch break 5 days per week) (O’Donovan et al.
2017). Individuals can be categorized according to the dose of aerobic physical
activity that they regularly achieve. “Inactive” individuals do not engage in any
moderate-to-vigorous activity; “insufficiently active” individuals do some but less
than the recommended 150 min per week of moderate-to-vigorous intensity activity;
“active” individuals engage in 150–300 min per week; and “highly active” individ-
uals exceed 300 min per week of moderate-to-vigorous intensity aerobic activity
(Physical Activity Guidelines for Americans 2018).
Muscle-strengthening physical activity focuses on activities that enhance skeletal
muscle strength, power, endurance, and mass (Physical Activity Guidelines for
Americans 2018). Examples of such activities include strength training, weight
lifting, and resistance training as well as heavy gardening or lifting heavy loads in
occupational or household tasks. The guidelines recommend that adults perform
≥2 days per week of muscle-strengthening physical activity including movements
that strengthen the large muscle groups of the upper and lower body. The Physical
Activity Guidelines for Americans do not provide specific guidance regarding the
intensity or duration of muscle-strengthening activities at this time; however, the
American College of Sports Medicine recommends that healthy adults train each
major muscle group for 2–4 sets with 8–12 repetitions per set to improve general
muscular fitness (Riebe 2018). While aerobic and muscle-strengthening physical
activities are by far the most commonly measured and prescribed activities in mental
health research, sedentary behavior, light-intensity physical activity, and mind–body
physical activities (e.g., yoga, Tai Chi) are emerging areas of research.

2.3 Acute Exercise and Exercise Training

Physical activity’s effects on mental health have been researched predominantly in

relation to acute or chronic exercise rather than incidental (non-exercise,
non-purposeful) or lifestyle-embedded (housework, transportation) physical activ-
ity. However, stemming from the increased availability of activity monitors to
accurately capture these types of activities, there is growing investigation into the
effects of incidental and lifestyle-embedded physical activity on mental health
(Tremblay et al. 2007). Acute exercise is a single bout of exercise performed at a
specific intensity, duration, and modality. In the case of muscle-strengthening
physical activity, it may also be described by the number of sets and repetitions
performed of specific exercises. Acute exercise studies may measure outcomes
before, during, and after the exercise bout and are particularly useful for mechanistic
investigation of transient outcomes such as mood, affect, pain sensitivity, and some
aspects of cognition. Exercise training or “chronic exercise” is repeated bouts of
acute exercise over a period of time such as several weeks or months. Exercise
training studies are designed to determine the accumulated effects of exercise on
mental health, particularly on clinically-relevant outcomes such as remission rates.
Many studies investigate acute and chronic effects of exercise in the same protocol.
8 A. G. Brellenthin and Z. Sirotiak

For example, changes in brain-derived neurotrophic factor (BDNF) in response to

acute aerobic exercise may be examined to help understand long-term changes in
hippocampal volume or memory in response to exercise training (Knaepen et al.
2010; Erickson et al. 2011).

3 Physical Activity Measurement

3.1 Supervised Physical Activity

Physical activity is measured through a variety of approaches, and selection of the

best approach often depends on the research question, study design, and available
resources. In physical activity and exercise studies, physical activity may be super-
vised, unsupervised, or a combination of unsupervised and supervised. In supervised
studies, participants perform acute or chronic exercise in the presence of researchers.
Researchers collect exercise performance data such as time, intensity (e.g., heart rate
or ratings of perceived exertion), estimated energy expenditure, or weight lifted.
Supervised exercise studies also provide direct data on exercise adherence (how
many exercise sessions attended out of how many assigned), compliance (when
participants attended, how much of the exercise dose was performed out of how
much was prescribed), and attrition (patterns of participant dropout from the exercise
intervention over time). While the exact operational definitions of adherence, com-
pliance, and attrition may vary between studies, these data help researchers draw
more balanced conclusions regarding both the efficacy (i.e., how well an interven-
tion works under ideal circumstances) and effectiveness (i.e., how well an interven-
tion works in the “real world”) of an exercise intervention for mental health
outcomes. For example, one clinical trial of aerobic exercise versus pharmacother-
apy on major depression reported similar remission rates among supervised aerobic
exercise and sertraline therapy groups, yet 20% of supervised exercise patients
dropped out of the study compared to 14% of sertraline patients (Blumenthal et al.
2007). Therefore, the similar efficacy of the two treatments on remission rates must
be considered alongside the higher dropout and possibly reduced effectiveness of
exercise. It is also generally recommended that supervised exercise interventions
periodically (e.g., at baseline and follow-up) collect data on unsupervised physical
activity from all participants (e.g., control groups and exercise groups).
Unsupervised activity occurring outside the laboratory setting should be assessed
to account for potential differential patterns and exposures of physical activity
between experimental groups that might confound the results.

3.2 Unsupervised Physical Activity

Much of our foundational knowledge regarding the health outcomes associated with
physical activity comes, somewhat paradoxically, from observational studies of
Foundations of Exercise and Physical Activity Research 9

unsupervised (i.e., unobserved) physical activity. These studies have participants

recall their recent physical activity behaviors in a questionnaire or wear an activity
monitor during their daily activities for a certain period of time to measure
unsupervised physical activity. Regardless of the measurement approach, physical
activity is not directly witnessed by the study team.
Assessment of unsupervised physical activity can be either objective or subjec-
tive. Objective measures include activity monitors such as pedometers and acceler-
ometers as well as gold standard, criterion measures like indirect calorimetry and
doubly-labeled water. As their name implies, objective measures tend to produce
more unbiased measures of physical activity as they do not rely on participant recall.
However, they are not completely bias-free either, since researchers processing these
data must make decisions that might affect the findings. For example, many studies
ask participants to wear an accelerometer continuously for 7 days to measure weekly
physical activity. The participant may forget to wear the monitor for certain periods
of time, wear it improperly, or remove it during bathing. The researcher must
carefully review the raw data and make decisions about what is considered valid
wear time and whether they have enough data to get a reasonably accurate summary
of the participant’s physical activity behaviors. Even after collecting sufficient data,
researchers must further select cut-points for the accelerometer-generated activity
counts that categorize physical activity into different intensities (e.g., sleeping versus
sitting versus light-intensity activity, etc.). The selection of cut-points can affect
results dramatically, yet cut-points are not always consistent between studies and
may differ depending on the study population (e.g., children, older adults) (Watson
et al. 2014; Kim et al. 2012).
Subjective measures are at the other end of the physical activity measurement
spectrum. Subjective measures are based on participant self-report of physical
activity in the form of a physical activity interview, diary or log, or a questionnaire.
Questionnaires are particularly inexpensive and convenient, but they are prone to
poor validity as they rely on participants to accurately and honestly report past
physical activity behaviors, which may not be suitable in some clinical populations
(e.g., patients with mild cognitive impairment). Short recall surveys are the most
popular type of questionnaire. These surveys typically consist of 10 or fewer
questions and capture recent physical activity behaviors within the past week or
month. They more accurately capture structured exercise rather than incidental daily
physical activity since participants may be able to remember and therefore report
exercise to a greater extent than other types of physical activity (Colley et al. 2018).
These surveys are useful in categorizing individuals based on their activity levels,
such as “inactive” or “active” according to the physical activity guidelines. They are
also useful for ranking participants by their physical activity levels relative to other
participants in the sample, which is often used to examine dose-response relation-
ships between physical activity and the outcome of interest. The International
Physical Activity Questionnaire-Short Form (IPAQ-SF) is one of the most widely
used short recall surveys having undergone extensive reliability and validity testing
in a variety of populations. The IPAQ-SF consists of seven questions and assesses
vigorous-intensity activity, moderate-intensity activity, walking, and sitting. The
10 A. G. Brellenthin and Z. Sirotiak

Fig. 1 Tools for measuring

unsupervised physical
activity. Adapted from
Fig. 5A in Welk,
G. Morrow, J. Saint-
Maurice, P. Measures
Registry User Guide:
Individual Physical Activity.
Washington (DC): National
Collaborative on Childhood
Obesity Research, January
2017 (Welk et al. 2017)

IPAQ-SF is a free resource with a standardized data processing and scoring protocol
allowing findings based on the IPAQ to be compared across a wide array of studies
(Sjostrom et al. 2005).
In general, objective measures tend to be more accurate than subjective measures.
However, objective measures also tend to be more time- and resource-intensive, so
they are not the most practical option for many research studies. Furthermore, while
an approach like doubly-labeled water may be the most valid method to assess total
energy expenditure, information on energy expenditure, without accompanying
information on actual physical activity behaviors during the measurement period,
does not translate well into practical public health recommendations for physical
activity. Therefore, many studies use a combination of assessment tools, such as a
pedometer paired with a physical activity diary, to capture physical activity. These
approaches are relatively inexpensive and scalable for large sample sizes, while also
providing important information on physical activity context and setting, which may
be critical factors in mental health research. Finally, objective measures are currently
limited in that they are only able to measure aerobic physical activity. Quantification
of time spent in muscle-strengthening or mind–body activities can only be assessed
through direct supervision or self-report. Methods to measure unsupervised physical
activity are summarized in Fig. 1.
In addition to physical activity behaviors, cardiorespiratory fitness and muscular
strength are sometimes measured as proxies for recent participation in aerobic and
muscle-strengthening physical activity. People who are more physically active
generally have higher physical fitness than their less active counterparts. Changes
in cardiorespiratory fitness or muscular strength are also often included in aerobic or
resistance exercise training trials as secondary outcomes since these fitness param-
eters are partially reflective of trial fidelity. Among previously untrained participants,
exercise groups should generally show a mean improvement in physical fitness
compared to control groups if the exercise intervention was delivered as intended.
When using physical fitness measures as proxies for recent physical activity, how-
ever, it is crucial to account for other factors that heavily influence fitness like age,
sex, medications, and genetics (Lee et al. 2010). It is also well documented that
cardiorespiratory fitness responses to exercise programs are highly variable, and not
Foundations of Exercise and Physical Activity Research 11

everyone who begins an aerobic exercise program will meaningfully improve their
cardiorespiratory fitness, despite high adherence and compliance to the exercise
protocol (Ross et al. 2019). The choice of the most suitable physical activity
assessment method depends on various research priorities, including study size,
target population, research objectives, and outcome measures.

4 Study Designs in Physical Activity Research

4.1 Cross-Sectional

Cross-sectional studies are observational studies wherein physical activity behaviors

and other variables of interest are assessed without experimental manipulation, and
they are the most common study design in physical activity research. Cross-sectional
designs collect data at a single time point. For instance, a single questionnaire may
include items that ask participants to report current or past (e.g., past week, past
month) physical activity as well as items querying the mental health outcome of
interest (e.g., current diagnosis or symptom questionnaire).
A study by Harvey et al. (2010) provides an example of a cross-sectional study.
This study included over 40,000 participants who completed questionnaires on
physical activity and anxiety and depression symptoms. Participants were asked to
rate how often they performed light- and high-intensity leisure time and occupational
physical activity. They also completed The Hospital Anxiety and Depression Scale
to measure depression and anxiety symptoms over the past 2 weeks. The researchers
found an inverse relationship between leisure-time physical activity and depression
symptoms, with a significant linear trend ( p < 0.001) for both light- and high-
intensity leisure-time activity. No significant relationship was found between work-
place activity and depression or anxiety (linear trend p-values: anxiety = 0.81;
depression = 0.16). Those engaging in leisure-time activity are less likely to report
symptoms of depression, leading the authors to speculate that social support and
engagement may be contributing to mental health among those engaging in activity
during leisure (Harvey et al. 2023).
There are several advantages of cross-sectional studies. These studies can be
relatively resource-efficient compared to other study designs, as data is only col-
lected at one time. Relatedly, these studies often allow a larger sample size, enhanc-
ing the statistical power and generalizability of results. Large, diverse samples also
make it possible to efficiently examine relationships between physical activity and
mental health outcomes in different sociodemographic groups (e.g., gender, race,
age, income), which is useful for public health surveillance and identification of
inequities and potential targets for physical activity promotion efforts.
However, there are disadvantages to consider. Cross-sectional studies do not
allow for causal determination as variables are measured simultaneously, and it is
impossible to determine the temporal sequence of events. Using Harvey et al. (2010)
as an example, it could be reasoned that experiencing more depressive symptoms
12 A. G. Brellenthin and Z. Sirotiak

could cause low physical activity participation just as easily as low physical activity
participation could cause depressive symptoms (Harvey et al. 2023). There are
several sources of potential bias in cross-sectional designs. Many physical activity
and mental health questionnaires ask participants to recall their behaviors or symp-
toms over the past few weeks or months, which is prone to recall bias. Response bias
must also be considered, such as the participant answering in a way that they think
may please the researcher or providing socially acceptable answers. While cross-
sectional studies do not involve manipulating an independent variable, demand
characteristics can still be present, in which participants change their reporting or
behavior due to being in a study. Cross-sectional studies often attempt to generalize
to a population, but selection bias, which occurs when participants are not randomly
selected from the population, can limit generalizability. All research studies but
especially physical activity studies are vulnerable to healthy response bias whereby
research participants, even if randomly selected, are nonetheless volunteers who are
likely to be healthier and more active than the general population, which further
limits generalizability (Craig et al. 2009).

4.2 Case–Control

Case–control studies are an observational research design in which individuals with

a particular health outcome (cases) are compared to individuals without this health
outcome (controls). These studies are usually retrospective and consider exposure
history between groups to identify associations between specific exposures like
physical activity and the development of a health outcome. Ideally, the cases and
controls are similar in all attributes except the health outcome, minimizing
confounding factors that may influence associations.
Werneck et al. (2020) performed a cross-sectional study of 60,000 adults in
Brazil, investigating the relationship between severe mental illnesses, such as
schizophrenia, and lifestyle behaviors, such as leisure-time physical activity, tobacco
use, and consumption of alcohol. The researchers identified cases of severe mental
illness by physician diagnosis. Participants self-reported their engagement in leisure-
time physical activity over the past 3 months. Using logistic regression analysis, the
researchers found that schizophrenia was associated with lower odds of physical
activity in the prior 3 months. The authors concluded that lifestyle factors, including
leisure-time physical activity, could be targeted in prevention efforts in the context of
severe mental illness (Werneck et al. 2020).
The main advantage of case–control studies is to investigate rare outcomes like
schizophrenia. Compared to the large samples needed in other study designs to
identify sufficient cases of a rare outcome, investigators using a case–control design
can directly recruit participants with the outcome of interest. Case–control designs
often involve retrospective data, which can save on resources involved in collecting
data. Multiple exposures can be assessed simultaneously, allowing one study to
evaluate many contributing factors. Like in Werneck et al. the associations between
Foundations of Exercise and Physical Activity Research 13

physical activity and the outcome can be examined in relation to other lifestyle
variables such as tobacco or alcohol use (Werneck et al. 2020). In addition, case–
control studies often require one contact point with participants, lessening time and
resource commitment.
However, there are also disadvantages to case–control studies. Like a cross-
sectional design, case–control studies may rely heavily on participant recall, poten-
tially going back several decades, allowing reporting and recall bias to affect results.
Relying on participant recall is overtly problematic for some mental health condi-
tions such as dementia. Even with mental disorders that do not affect memory or
other cognitive functions, participants recently diagnosed with a rare medical con-
dition may recall their past behaviors differently than someone without a diagnosis.
Obtaining medical records, while more objective, may not be readily accessible and
may present ethical considerations. In addition, selection bias is an important
consideration, as finding a representative sample in rare conditions can be particu-
larly difficult. Selection bias is also a concern when identifying control group
participants. Control group participants should be representative of the population
from which the cases were obtained, not necessarily from the general population.
Since differences in the exposure histories of the control group and the general
population are unknown, case–control studies, which compare exposures between
controls and cases only, may produce associations that are not reflective of the true
relationship between physical activity and the outcome. Temporal uncertainty also
limits interpretability. Not only are past exposures recalled at the same time as other
data are collected (similar to a cross-sectional study), but the recall period (e.g., past
5 years, past 20 years, lifetime) may not capture the time period between all the
possible exposures and disease progression.

4.3 Cohort

Prospective cohort studies are another type of observational study design that
recruits and follows a cohort, or group of individuals, over a specific period.
Whereas case–control studies focus primarily on identifying the outcome (i.e.,
cases) and then examining the outcome in relation to a wide variety of potential
exposures, prospective cohort studies focus primarily on the exposure and then
examine the exposure in relation to a wide variety of outcomes over time. In physical
activity research, this method also allows for determining a population attributable
fraction for physical activity or the fraction of cases of a disease or disorder that
could be prevented if each participant engaged in physical activity.
Harvey et al. (2018) analyzed data from the Health Study of Nord-Trøndelag
County (HUNT Study), a prospective cohort study in rural Norway. In this study,
over 33,000 adults without mental health disorders at baseline were followed for
11 years. Participants reported the frequency and duration of aerobic exercise at
baseline, and depression and anxiety symptoms were assessed at follow-up using
The Hospital Anxiety and Depression Scale. Physical activity was associated with a
14 A. G. Brellenthin and Z. Sirotiak

reduced odds of depression at follow-up, though they noted no associations between

physical activity and anxiety. The authors also calculated a population attributable
fraction, estimating that 12% of cases of depression could have been prevented if
each participant had engaged in 1 h of physical activity per week (Harvey et al.
2018).
Compared to other observational research designs, prospective cohort studies are
advantageous in that they provide a temporal event sequence. Participants without
the outcome of interest at baseline are followed until they either develop the outcome
or until the latest study contact. Recall bias is less of a concern with prospective
cohort designs as the exposure is measured before an outcome occurs. Likewise,
exposures can often be assessed with more detail and accuracy in prospective cohort
studies compared to other forms of observational research. Prospective cohort
studies can be especially helpful for investigating conditions that develop slowly
over time, as both the exposure and disease progression can be measured at many
time points if resources allow. In addition, these studies can help calculate incidence
rates or the probability that an individual will be diagnosed with a condition within a
given period. Like case–control studies, several exposures can be measured simul-
taneously, saving time and resources.
However, there are disadvantages to a prospective cohort design. Like other
designs, prospective cohort studies are limited in generalizability by the degree to
which their sample represents the larger population. These studies can require
significant time and resources, as participants must be tracked over time, potentially
with multiple follow-up visits. Similarly, participant attrition and loss to follow-up
are important considerations in a prospective cohort design. If the characteristics of
those who drop out significantly differ from those who remain in the study, bias can
result. This is particularly true for cohorts assessing physical activity and mental
health. Participants who remain in a cohort over many years are generally healthier,
both physically and mentally, and more active than participants who are lost to
follow-up (Mein et al. 2012). Confounding variables, or spurious variables that can
affect the relationship between the main variables of interest, can also be a concern in
prospective cohort studies. Finally, while temporal sequence can be established,
causal connections cannot.

4.4 Randomized Controlled Trial

Randomized controlled trials (RCTs) are considered the gold-standard study design
for determining causality. Researchers frequently use RCTs to evaluate the effec-
tiveness of exercise interventions on mental health outcomes. Randomization is a
key feature of RCTs, with participants randomized to either a treatment or a control
group. The outcome of interest is measured before and after the trial, and changes in
the outcome between the treatment and control groups are analyzed.
A study by Blumenthal et al. (2007) provides an example RCT in their investi-
gation of the effect of aerobic exercise, pharmacotherapy, or a placebo control on
Foundations of Exercise and Physical Activity Research 15

depressive symptoms in individuals diagnosed with major depression. In this study,

202 adults with a major depressive disorder diagnosis were randomized to four
conditions: supervised group aerobic exercise, home-based aerobic exercise, antide-
pressant medication, or a placebo pill. Each intervention lasted 16 weeks, after which
each participant completed a clinical interview for depression to assess remission.
Forty-one percent of participants achieved depression remission, with the two
exercise interventions and pharmacotherapy group having greater remission rates
than the placebo group. Remission rates by group (aerobic exercise group results
combined) are shown in Fig. 2. The authors concluded that aerobic exercise and
pharmacotherapy were similarly effective in reducing depression among those with
major depressive disorder, offering exercise as an efficacious alternative to pharma-
ceutical approaches (Blumenthal et al. 2007).
Like observational studies, RCTs provide their own set of advantages and
disadvantages. Perhaps the most significant advantage of an RCT design is the
ability to determine causality. Randomizing participants allows researchers to bal-
ance measured and unmeasured confounding variables between groups, reducing the
likelihood that any observed effects are due to these other factors. However, RCTs
present limitations and challenges as well. These studies can require significant time
and resources both for the research team and participants. In addition, achieving high
exercise adherence rates can be difficult, particularly over a long study duration.
Blinding is another hallmark feature of RCTs, yet appropriate blinding can be
notably challenging, if not impossible, in the context of exercise and mental health.
Participants in an exercise intervention cannot be blinded to their condition as
participants in a drug trial might be. While exercise and mental health RCTs may
involve blinding the researcher collecting data, performing analyses, and drawing
conclusions, participants cannot be blinded to their exercise group. Expectation bias,

70
Remission rate (% of sample)

60

50

40

30

20

10

0
Aerobic exercise Medication Placebo

Fig. 2 Remission rates of major depressive disorder by group in Blumenthal et al. (2007). Adapted
from Fig. 3 in Blumenthal JA, Babyak MA, Doraiswamy PM, Watkins L, Hoffman BM, Barbour
KA, Herman S, Craighead WE, Brosse AL, Waugh R, Hinderliter A, Sherwood A. Exercise and
pharmacotherapy in the treatment of major depressive disorder. Psychosom Med. 2007;69 (7):
587–96. doi: https://doi.org/10.1097/PSY.0b013e318148c19a
16 A. G. Brellenthin and Z. Sirotiak

or when an individual’s expectations about a treatment affect their perceptions and

behaviors, can be a concern in exercise and mental health trials. Participants may
enter an exercise RCT believing that exercise positively impacts mental health,
which can contribute to an exaggerated mental health improvement in the exercise
group.
Some studies have attempted to address the issue of blinding and outcome
expectations by using placebo-control groups (see Chapter “Psychedelics and
Drug Checking” for comprehensive overview). Placebos are interventions that
offer no expected therapeutic benefit, and they are particularly important when
blinding is not possible. Theoretically, placebo groups allow isolation of the effect
of the treatment, subtracting the influence of a participant’s expectations due to being
in a study or being offered a treatment. The placebo effect has been suggested to
account for approximately half of the observed psychological benefits of exercise
(Lindheimer et al. 2015). In the previously mentioned study by Blumenthal and
colleagues, the remission rate of the placebo group was 75% of the remission rate
observed among the active treatment groups (Fig. 2) (Blumenthal et al. 2007). This
study also used a placebo pill, a convenient and routine approach, since another
experimental group was receiving active medication. Though for exercise trials
without a medication comparison group, it can be difficult to develop an appropriate
placebo control or comparison condition. Relaxation, social activities, and very
low-intensity exercise have been used frequently as placebo conditions in exercise
and mental health trials (Lindheimer et al. 2015). However, there is substantial
heterogeneity in placebo conditions across trials, and many placebos have unclear
associations with the outcome, making it difficult to compare these conditions to
each other and to the exercise treatment of interest. Ideally, exercise and control
groups would be equivalent in every way except the intervention, but this can be
difficult to implement in practice. Participants in control conditions may change their
exercise or lifestyle habits, and any group could be impacted by poor adherence,
affecting the study results. There are also ethical considerations in selecting com-
parison or control groups, as it is ethically problematic to withhold potentially
beneficial treatment from comparison or control groups in patients with mental
illness.
Conducting an exercise RCT with sufficient power to find differences between
groups can also be challenging. Supervised exercise RCTs are particularly labor-,
time-, and resource-intensive trials. Thus, most exercise RCTs are relatively small
(N < 100) (Abt et al. 2020) compared to typical pharmaceutical trials that might
enroll thousands of patients. Furthermore, the effect sizes for exercise on various
mental health outcomes can be quite modest, especially after considering placebo
effects in comparison groups (Lindheimer et al. 2015). The combination of modest
effect sizes and small sample sizes in the exercise science field has led some
researchers to conclude that the average power to detect true effects in exercise
RCTs is between 40–50% (Mesquida et al. 2022). This means that roughly one out
of two studies should report null findings. Yet, over 70% of published studies report
that their primary hypothesis was supported by their findings (Büttner et al. 2020).
Thus, there are serious concerns of the methodological quality and bias in reporting
for much of the existent literature. It should be noted, however, that this problem is
Foundations of Exercise and Physical Activity Research 17

not unique to exercise science, and traditional reporting and publication practices are
under scrutiny and revision in many scientific fields.

4.5 Systematic Review and Meta-Analysis

Systematic reviews and meta-analyses are summaries of the literature generated after
following explicit methodology to comprehensively search, critique, and synthesize
together individual studies. A systematic review is a structured review and summary
of existing literature on a specific topic or research area. These reviews follow a
sequence of forming a research question, identifying relevant literature, assessing the
quality of that literature, summarizing evidence based on the accumulation of
literature, and interpreting these findings (Khan et al. 2003). The review aims to
provide a thorough overview of the current literature on a specific topic. Often
combined with a systematic review, a meta-analysis is a statistical method combin-
ing data from multiple studies evaluating the same research topic. Relevant data are
extracted from the original studies, leading to overall effect size and statistical
significance calculations. Meta-analyses offer greater statistical power than individ-
ual studies, theoretically leading to a more comprehensive and conclusive assess-
ment of the effects of exercise on mental health.
Stubbs et al. (2017) evaluated literature describing the anxiety-reducing effects of
exercise among individuals with anxiety and stress-related disorders. The authors
analyzed six RCTs, including a total of 262 adults. The combined data suggested that
exercise significantly reduces anxiety symptoms for those with anxiety or stress-
related disorders compared to control conditions (standardized mean difference = -
0.582; p = 0.02) (Stubbs et al. 2017). Meta-analyses provide several advantages,
including increasing the sample size leading to increased statistical power to detect
differences that exist. More precise effect sizes can be measured with meta-analyses
compared to individual studies, and bias in one study may be lessened by including
other studies. Systematic reviews and meta-analyses are limited by the quality of the
studies they evaluate. Publication bias and the availability of databases and publi-
cations also limit these analyses. Articles written in English also receive publication
advantages and are more likely to be included in systematic reviews and meta-
analyses (Morrison et al. 2012). The heterogeneity of available studies can also
provide challenges and difficulty incorporating different measures of variables may
limit the ability to combine datasets.

4.6 Qualitative Studies

Qualitative research is an important but less common approach for studying physical
activity and mental health. Qualitative work allows for assessing the subjective
realities and the lived experience of individuals and groups, analyzing identity,
18 A. G. Brellenthin and Z. Sirotiak

perspectives, and meaning. Qualitative research may allow the identification of

beliefs, motivations, and experiences that impact one’s perception of physical
activity, mental health, and associations between the constructs. Qualitative methods
include observation, fieldwork, focus groups, and in-depth interviews. Analysis
often involves the identification of common themes, as well as the consideration
of findings in the context of existing literature, offering insights related to participant
perception and personal impact that are not found with quantitative approaches.
Mixed-methods research or combining quantitative and qualitative data analysis in
one research project can be a strong research design as it combines the strengths of
quantitative and qualitative research and allows for integrated understanding of
multiple sources of data.
Mason and Holt (2012) conducted a review of qualitative literature investigating
physical activity among those with mental health difficulties. The authors found
common concepts noted across articles, noting several themes: social interaction and
support, feeling safe, improved symptoms, a sense of meaning, purpose and achieve-
ment, identity, and the role of others in the physical activity experience (Mason and
Holt, 2012). Qualitative research can offer powerful improvements in understanding,
allowing participants to offer their lived experiences and subsequent knowledge
rather than being limited to selecting pre-determined options on a survey. Qualitative
research allows for participant voice and involvement in the research process, an
important consideration in working with individuals living with mental health issues,
conditions long associated with stigma and lack of autonomy among patients
(Palinkas 2014). Qualitative research can also help develop hypotheses that can
then be tested with follow-up quantitative or mixed-methods studies. Figure 3 pro-
vides an overview of the types of study designs used in physical activity and mental
health research.

5 Summary

This chapter provided an overview of the key concepts and methods used in the
study of physical activity and mental health. While there is no perfect or universal
approach to examine physical activity and mental health, there are several tools and
study designs, each with their own advantages and disadvantages that can be used
effectively to conduct rigorous research and generate impactful findings to improve
the lives of individuals living with mental illness. Chapters in Sects. 2 and 3 of this
volume will present findings from studies that used a variety of these approaches to
improve our understanding of: (1) the acute effects of exercise on mood, affect, and
cognition, and (2) the acute and chronic effects of physical activity and exercise on
preventing and treating mental health disorders including depression, anxiety, eating
disorders, cognitive impairment, substance use, schizophrenia, pain, and fatigue.
 Were ≥2 groups compared? Was there random allocaon ≥2 groups ?

↔ Outcome ← Outcome → Outcome

Foundations of Exercise and Physical Activity Research

Fig. 3 Flow chart of study designs in physical activity and mental health research
19
20 A. G. Brellenthin and Z. Sirotiak

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Applied Physical Activity Epidemiology:
Relationship of Physical Activity
and Exercise Exposures with Health
Outcomes

Jessica (Jess) S. Gorzelitz

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2 Mortality Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.1 Observational Studies with Physical Activity and Mortality Risk . . . . . . . . . . . . . . . . . . . . 25
2.2 Modality and Type of Physical Activity on Mortality Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3 Disease Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1 Type 2 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.2 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.3 Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4 Mental Health Outcomes: Anxiety and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.1 Physical Activity as Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.2 Physical Activity as Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5 Tradeoffs and Limitations of Observational Designs in Physical Activity
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Abstract There is consistent, strong evidence that both physical activity and exer-
cise lowers risk of many diseases, yet the way physical activity and exercise are
measured varies substantially. Physical activity epidemiologists use observational
designs (such as cohort or case-control studies) to examine the relationship of
physical activity exposures and outcomes including mortality, or disease-specific
such as incident type 2 diabetes mellitus, cancer, cardiovascular disease, anxiety, or
depression. These same observational designs can be used to examine the associa-
tions of prevalent disease in reducing symptom burden in those who are physically
active compared to those who are not, specifically examining anxiety and

J. (J). S. Gorzelitz (✉)

Department of Health and Human Physiology, College of Liberal Arts and Sciences, University
of Iowa, Iowa City, IA, USA
Department of Obstetrics and Gynecology, Carver College of Medicine, Holden
Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 23

Curr Topics Behav Neurosci (2024) 67: 23–36
https://doi.org/10.1007/7854_2024_489
Published Online: 31 July 2024
24 J. (J). S. Gorzelitz

depression. There is great statistical power and often large sample sizes in physical
activity epidemiologic studies with valid and reliable assessment tools but known
limitations such as measurement error or social desirability bias. Overall, physical
activity epidemiology can be a useful tool to understand the influence of exercise and
physical activity on risk of disease. In this chapter, we will explore the strength,
consistency, and sources of evidence primarily using a physical activity
epidemiology lens.

Keywords Exercise · Exposure · Mortality · Outcome · Physical activity ·

Physical activity epidemiology · Prevention · Treatment

1 Introduction

Understanding the association of physical activity with health outcomes is critical to

understanding population health, exercise prescription, and how to use exercise in a
therapeutic capacity. The discipline of physical activity epidemiology provides us
with the ability to measure these associations in different populations and with
various outcomes. Physical activity epidemiology allows for the population-level
assessment of physical activity (including exercise) to understand the distribution
and determinants of the behavior, and to understand the relationships between
physical activity participation and disease/health outcomes. The previous chapter
has provided an overview of this field including exposure and outcome assessment
definitions. We will build on that introduction in this chapter to examine the
influence of exercise and physical activity on risk of disease.

2 Mortality Outcomes

Death, or mortality as an outcome, is one of the critical outcomes in epidemiology.

Mortality outcomes are often a strong endpoint as individuals will only experience
this outcome once, which is both necessary and sufficient. Prospective cohort
designs are ideal for assessing the association between exposures and mortality
outcomes. Many cohort studies capture baseline or serial assessments of demo-
graphic and health behaviors over a period and follow individuals up for years or
decades to assess who developed what outcomes. Mortality data can be collected
from the National Death Index (NDI), Social Security Administration’s death
information, death certificates, or other registries. Depending on the data source,
some mortality data also includes causes of death. Having specific attributable
causes of death can be used analytically to go beyond all-cause mortality. Frequent
mortality outcomes include cardiovascular disease (CVD)-specific deaths and
cancer-related specific deaths. Given the population level of CVD and cancer,
Applied Physical Activity Epidemiology: Relationship of Physical. . . 25

these outcomes are quite common with the high population burden of disease.
Depending on the research question and the type of association to be studied with
a given mortality outcome, physical activity (PA) epidemiology researchers can use
previously collected exposures of physical activity to measure the associations.
Through this chapter, we will discuss the relationship between PA and mortality,
PA and physical disease outcomes, and PA and mental health outcomes. The chapter
will finally describe benefits and limitations focused on observational designs, and
ways to use and understand the physical activity epidemiologic literature.

2.1 Observational Studies with Physical Activity

and Mortality Risk

When measuring mortality as an outcome, physical activity should be measured as

the exposure which has occurred prior to the outcome of death. Some major cohort
studies such as the Aerobic Center Longitudinal Study (ACLS) or the Nurses’ Health
Study have measured different constructs related to physical activity. ACLS has
measured fitness, which is a consequence of exercise training, as the exposure to
understand the relationship between fitness and mortality which is favorable (Barry
et al. 2014). As discussed in subsequent sections, this fitness association has
similarly been observed for all-cause, CVD, and cancer-specific mortality.
Larger cohort studies will often use global assessments of physical activity
(Global Physical Activity Questionnaire-GPAQ, International Physical Activity
Questionnaire-IPAQ) for population-level assessment. These instruments capture
self-reported intensity and duration of typically aerobic physical activity. These
exposures can then be expressed in mean hours per week of activity, or frequently
aggregated into Metabolic Equivalents of Task (MET) levels per week. Many cohort
studies have found a similar positive association between physical activity measures
and all mortality outcomes (Brown and Gilmore 2019; Gorzelitz et al. 2022a, b;
Hupin et al. 2015; Paffenbarger et al. 1993; Watts et al. 2022; Nocon et al. 2008;
Blond et al. 2020; Friedenreich et al. 2020).
The National Health and Nutrition Examination Survey (NHANES) uses accel-
erometers (which provide a population-based device measurement of activity
precision) and has also found similar associations between different PA exposures
and mortality, with researchers finding accelerometer-measured physical activity
associated with reduced mortality risk (Fishman et al. 2016; Schmid et al. 2015) as
well as self-reported aerobic and muscle-strengthening exercises similarly associated
with reduced mortality (Zhao et al. 2014; Navaneethan et al. 2014).
26 J. (J). S. Gorzelitz

2.2 Modality and Type of Physical Activity on Mortality Risk

Most of physical activity epidemiology has historically focused on overall physical

activity or aerobic exercise as an exposure, with limited interest and evidence on
muscle-strengthening activities (Bennie et al. 2020). Per the 2018 Physical Activity
Guidelines Advisory Committee (PAGAC) reports, all adults (including older adults
above the age of 65) should participate in muscle-strengthening activities on two or
more days per week (Committee PAGA 2018). Muscle-strengthening activities
(MSA), including resistance exercise, strength training, weightlifting, and body
weight exercises, made it into the guidelines based on the amount and quality of
the evidence and health-promoting benefits of the activity. Comparatively, there is
far less evidence on the associations of MSA on mortality outcomes often due to
limited (if any) epidemiologic or survey assessments of MSA. Recently more
research has emphasized the mortality benefits of MSA, finding positive mortality
associations for weightlifting and all MSA following a J-shaped curve, suggesting
that moderate levels of MSA are associated with reductions in risk but high levels of
MSA are associated with an increased risk (Shailendra et al. 2022; Saeidifard et al.
2019). There is even new evidence of the unique and additive benefits of
weightlifting in older adults, with researchers finding mortality reductions for
weightlifting alone or in combination with aerobic exercise (Gorzelitz et al. 2022c).

3 Disease Outcomes

Like mortality as an outcome, disease outcomes can also be measured in prospective

cohort designs. Observational study designs can be used to study the role of physical
activity to determine if physical activity is associated with prevention of certain
diseases, in this section using examples of cancer, diabetes, and heart disease.
Additionally, observational designs commonly used in physical activity epidemiol-
ogy can be used to determine if physical activity is associated with improved
treatment or outcomes (treatment efficacy, tertiary prevention). This chapter will
primarily focus on the associations of physical activity in preventing disease as
primary prevention, with a brief mention of how physical activity can be used as
treatment in populations already diagnosed with disease.

3.1 Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, or high blood

sugar, which is the primary clinical manifestation of this disease. T2DM incidence
and prevalence rates are continuing to rise due to a multitude of factors (increasing
age, poor diet, high sedentary behavior, low physical activity, other metabolic
Applied Physical Activity Epidemiology: Relationship of Physical. . . 27

dysfunctions). The American Diabetes Association has published their position

statement on physical activity/exercise and diabetes with recommendations for
people with type 2 diabetes, in addition to less commonly examined outcomes,
including T1DM, gestational diabetes mellitus, and prediabetes (Colberg et al.
2016).
LaMonte and colleagues have summarized the evidence on the role of physical
activity and fitness in primary prevention of diabetes. In this narrative review, the
authors summarize many primary literature studies and describe that the evidence
base is only approximately 30 years old. Researchers report consistent observational
literature from large cohort studies including the Iowa Women’s Health Study,
Nurses’ Health Study, Women’s Health Study, and the Women’s Health Initiative
Observational Study. These different studies have all yielded similar conclusions
about the dose-response relationship between self-reported physical activity levels
and lowered incident risk of T2DM (LaMonte et al. 2005). Other observational
studies like the ACLS longitudinal cohort similarly found a significantly lowered
risk of new T2DM with higher levels of cardiorespiratory fitness (LaMonte et al.
2005).

3.2 Cancer

Cancer is often considered a disease of the old, and as our population continues to
age, we are expected to have more cancer diagnoses than ever before. One of the
challenges with studying physical activity and cancer prevention is the latent and
long-term etiology of the disease. Given that older adults are at higher risk of
developing cancer, is important to study individuals at an age where they are
cancer-free if wanting to measure the association of PA and risk of cancer. Not all
cancers have similar etiology, which further complicates the study. For example,
testicular cancer is most common in young, college-aged males where multiple
myeloma is most common in adults above age 70 (Siegel et al. 2023). Therefore,
when studying the association of PA with cancer prevention, most researchers will
use large prospective study designs that enroll adults with long follow-up periods.
The American College of Sports Medicine convened an International
Multidisciplinary Roundtable on Exercise and Cancer in March 2018, with one of
the subsquent publications led by Dr. Alpa Patel. This expert roundtable conducted a
thematic review and meta-analysis of previous studies reporting on the association of
physical activity and risk of cancer. In this report, researchers were able to examine
multiple cancer outcomes and concluded that physical activity was indeed associated
with lowered risks of breast, colon, endometrial, kidney, bladder, esophageal, and
stomach cancers. The one exception in that report was melanoma, a malignant form
of skin cancer, which was found to have a positive risk association with physical
activity (Patel et al. 2019). Since those who are physically active are more likely to
do outdoor activities in sunlight such as outdoor biking, running, walking, or other
outdoor recreation, it is speculated that sun exposure during active time is
28 J. (J). S. Gorzelitz

responsible for this positive risk association. This seminal report provides strong
evidence for the role of physical activity in preventing certain types of cancer,
however this report is limited in the inferences able to be made. These studies
provide evidence on the association and not the causal relationship between physical
activity and cancer, especially knowing that there are highly heterogenous etiologies
of different types of cancer. One of the criteria for causality is biological plausibility,
and each of the seven identified sites has different biological pathways by which
physical activity could influence the etiologic pathways of carcinogenesis. It is
important to note that the goal of these types of studies is not to establish a causal
relationship or to determine the biological pathway, but rather to summarize the
evidence and inform public health and healthcare-related recommendations for
individuals to lower their risk of cancer.
For adults with a cancer diagnosis, there is similar evidence on the benefits of
physical activity and exercise in improving eight commonly reported symptoms by
cancer survivors including low health-related quality of life, cancer-related fatigue,
anxiety, depression, lymphedema, low bone quality, poor physical function, and
sleep impairments (Campbell et al. 2019).

3.3 Cardiovascular Disease

Exercise and physical activity are both established preventive factors for atheroscle-
rotic cardiovascular disease. A statement from the Council on Clinical Cardiology
and the Council on Nutrition, Physical Activity, and Metabolism summarizes the
evidence and provides a position statement firmly in favor of both exercise and
physical activity behaviors (Thompson et al. 2003). Similar to the evidence bases for
diabetes and cancer, many volumes of observational research have consistently
shown an inverse protective relationship between physical activity and incident
cardiovascular disease (Arnett et al. 2019; Archer and Blair 2011; Haennel and
Lemire 2002; Alves et al. 2016; Wahid et al. 2016). While there has been strong
mechanistic literature to understand the etiologic process of the disease in terms of
exactly how exercise and physical activity impacts the vascular, observational
research allows for comparisons of active vs inactive individuals to provide
population-level inferences of the preventive benefit for physical activity (Lee
et al. 1997; Blair and Jackson 2001). Similar research has been done for fitness,
revealing the highest levels of cardiorespiratory fitness associated with lowered risk
of cardiovascular disease (Al-Mallah et al. 2018; Ozemek et al. 2018). Recent
Cochrane systematic reviews have revealed the benefits of cardiac rehabilitation, a
form of structured exercise following a CVD incident or diagnosis, to be beneficial
for assisting with treatment and lowered mortality in coronary heart disease ((Dibben
et al. 2021) as well for adults with heart failure (Long et al. 2019).
Applied Physical Activity Epidemiology: Relationship of Physical. . . 29

4 Mental Health Outcomes: Anxiety and Depression

Mental health outcomes can similarly be studied using physical activity epidemiol-
ogy approaches to examine the association of PA with prevention of mental health
issues or with the efficacy of treatment for those who have a diagnosed condition.
Approximately 40 million adults (~19%) in the United States experience anxiety
disorders each year, with an estimated 31% of US adults experiencing an anxiety
disorder at some point in their lives (Kessler et al. 2004). Women have been more
likely to experience an anxiety disorder than men, however these estimates are
imperfect and perhaps subject to bias for reporting (Beesdo et al. 2010). Estimates
for major depressive disorder reveal that 6.7% of adults (8% of women and 5% of
men) had at least one major depressive episode in the past year impacting an
estimated 17 million US adults. Approximately 20% of all adults are likely to
experience at least one bout of depression in their lifetime (Kessler et al. 2004).
Estimates for both anxiety and depression are measured at the population level,
which, like all other study tools, have known limitations in their measurement
abilities. These limitations are described at the end of the chapter.

4.1 Physical Activity as Primary Prevention

Studies examining relationships of physical activity and exercise on disease out-

comes will often assume a person is disease-free at exposure assessment and then
assess later risk of developing an outcome. Studying those who are free from disease
without any indications of clinical precursors on reducing risk of developing the
outcome is primary prevention.

4.1.1 Anxiety

In prospective cohort studies, where participants are free from disease at baseline,
physical activity has been associated with lower prevalence of major anxiety disor-
ders. Data from the National Comorbidity Survey have revealed that those who
report regular physical activity have lower adjusted odds of agoraphobia (36–48%
lower), social phobia (35–42% lower), specific phobias (22–32% lower), general-
ized anxiety disorder (24–42% lower), and panic attacks (27–41% lower) (Goodwin
2003). Much work has been published addressing the potential mechanisms of this
relationship elsewhere, and that is beyond the scope of this chapter. This association
of lowered risk with physical activity and risk of incident anxiety symptoms/disorder
is consistent (see Chapter “Traumatic Psychedelic Experiences”).
30 J. (J). S. Gorzelitz

4.1.2 Depression

Just as with anxiety, so too can PA epidemiology designs help us to understand the
relationship between physical activity and the prevention of depression. In a sys-
tematic review and meta-analysis of over 111 reports representing over three million
adults, researchers found that overall, there was 25–37% lower odds of depressive
symptoms among physically active individuals compared to physically inactive
individuals. After adjustment for potential confounders, there was still 18–25%
lower odds of depressive symptoms in active individuals, when compared to inactive
individuals (Dishman et al. 2021). Of note, this meta-analysis included original
studies of adolescents, adults and older adults form 11 countries in five continents,
providing strong evidence for the role of physical activity in preventing depression.
In addition to the measures of self-reported PA levels as a measure of activity,
researchers can also test the consequences of regular physical activity and exercise
by using measures of fitness in association with mental health outcomes.
Researchers were able to conduct a prospective study measuring cardiorespiratory
fitness and depressive symptoms over time. Participants had their fitness measured at
enrollment and incidence rates of new depressive symptoms were measured over
time. Researchers found a risk reduction of 31% in men and 44% in women for those
who had moderate levels of cardiorespiratory fitness. For those with the highest
levels of cardiorespiratory fitness, the risk reduction was 51% in men and 54% in
women. This prospective study combines some of the strongest and objective
measures of fitness coupled with the prospective design allowing for the temporal
association to see which came first – the inactivity or the depression (Sui et al. 2009).
Overall, the evidence base is quite extensive illustrating the role of exercise in
preventing depression (see Chapter “Management of ‘Challenging Experiences’
and ‘Bad Trips’ in Psychedelic-assisted Therapy and Recreational Use”).

4.2 Physical Activity as Treatment

Oftentimes physical activity epidemiology designs allow for a simple exposure

outcome relationship with one measure of exposure. There are examples of certain
studies and designs that have used repeated measures or longitudinal designs to
examine how changes in physical activity or exercise behaviors are associated with
changes or reductions to disease status or progression.

4.2.1 Mortality

The Harvard Alumni Study began as a prospective cohort study that has since
included multiple longitudinal assessments of participants, making it an ideal data
source to examine changes in physical activity over time on disease risk.
Applied Physical Activity Epidemiology: Relationship of Physical. . . 31

Paffenbarger et al. in 1993 found that men who increased their moderate to vigorous
intensity physical activity (MVPA) was associated with a 23% lowered risk of
mortality, and for those men who maintained their already high levels of MVPA
was also associated with a 41% lowered risk of CVD-specific mortality
(Paffenbarger et al. 1993). When comparing these similar changes in physical
activity in women, Gregg et al. found that in a sample of ~9,000 women aged
65 years or older, those who increased their physical activity over time had 48%
lower risk of all-cause mortality, and those women who were active and remained
active had a 36% lowered risk of all-cause mortality (Gregg et al. 2003).
Fitness, whether cardiovascular or muscular, is often the consequence of training
or repeated, intentional exposures to exercise to improve physiological function. The
Aerobic Center Longitudinal Study is one of the unique epidemiologic studies as
researchers there will measure participant fitness as an exposure to examine out-
comes over time. With these repeated exposures over time, researchers can quantify
the effect of changing one’s fitness on their risk of disease. One seminal contribution
was Blair et al. (1995) publication examining over 9,000 men aged 20–82 at baseline
with fitness tests and 5 years of follow-up to examine the role of changing fitness
profiles on mortality. Men who were initially categorized as unfit at baseline, but
then became fit at the five-year follow-up had a 44% reduction in mortality. Men
who were fit at both assessments had a 67% lowered risk of mortality, and those men
who were fit initially but still improved their fitness measures at follow-up had a 28%
lower risk of mortality when compared to men who went from unfit to fit (Blair et al.
1995).
Early studies in physical activity epidemiology were almost exclusively focused
on men, which is certainly not the whole picture nor is it generalizable to human
health. Additional studies have replicated these findings in women, older adults, and
individuals with racial and ethnic diversity (Gregg et al. 2003; Mok et al. 2019;
Talbot et al. 2007; Imboden et al. 2019; Braun 1970).

4.2.2 Anxiety

Understanding the role of PA for treatment in those who have already been diag-
nosed with anxiety is similarly consistent. The 2018 Physical Activity Guidelines for
Americans state that there is strong evidence that physical activity reduces anxiety
symptoms in those with anxiety disorders (Committee PAGA 2018). Reviews have
varied in conclusions specifically on whether exercise is either better than or no
different from or not as effective as other treatments (see Chapter “Traumatic
Psychedelic Experiences” for a comprehensive overview).

4.2.3 Depression

While physical activity is strongly associated with the prevention of depression, less
is known about the role of exercise in treating those with clinical depression. A meta-
analysis of 14 randomized controlled trials found that chronic exercise reduced
32 J. (J). S. Gorzelitz

depression symptoms by 1.1 standard deviations. This meta-analysis included stud-

ies with participants as having depression diagnosed via any method and also
included any severity of depression, but notably most of the studies found in this
review enrolled non-clinical participants which limits generalizability of findings
(Lawlor and Hopker 2001). More recent reviews of reviews have similarly con-
cluded that exercise can appropriately be recommended for depression in combina-
tion with other treatments (Daley 2008). Newer randomized studies have been
conducted to examine the dose and viability of physical activity as a treatment for
depression. The DOSE study randomly assigned participants aged 20–45 to one of
four exercise treatments or to an exercise placebo control of stretching and flexibil-
ity. Exercise treatments varied by energy expenditure (low dose, public health dose)
and frequency (3 vs. 5 days per week). Researchers found a 47% reduction in
depressive symptoms following 12 weeks of exercise for those in the public health
dose group (independent of weekly frequency) (Dunn et al. 2005). The SMILE study
was a prospective, randomized controlled trial with 202 adults. Individuals were
randomly assigned to one of four conditions including supervised group exercise,
home-based exercise, anti-depressant medication, and placebo group. Researchers
found that the aerobic exercise groups were as effective as drug treatments for those
adults aged 40+ with diagnosed major depressive disorder (Blumenthal et al. 2021).
Finally, the TREAD study found that exercise was a viable treatment for adults aged
18–75 with MDD that did not respond to drug treatment (Trivedi et al. 2011),
leading to clinical guidelines for prescription and dosing of exercise/PA as treatment
for adults with MDD (Rethorst and Trivedi 2013). These results from multiple, high
quality randomized controlled trials suggest that exercise may be a viable alternative
treatment for Major Depressive Disorder (see Chapter “Management of ‘Challenging
Experiences’ and ‘Bad Trips’ in Psychedelic-assisted Therapy and Recreational Use”
for a comprehensive overview).

5 Tradeoffs and Limitations of Observational Designs

in Physical Activity Epidemiology

While there are many benefits to using large population-based research and PA
epidemiology methods to assess the aforementioned relationships between PA and
various health outcomes (e.g., mortality, cancer, CVD, T2D, depression, anxiety),
there are also known limitations. Most large, population-based cohort studies will
rely on self-report for these outcomes. Self-report is the most efficient and least
invasive (with respect to privacy) for the participant; however, it is prone to
measurement error including artifacts of social desirability bias and participant
outcomes expectations (Brenner and DeLamater 2014; Motl et al. 2005).
Furthermore, when assessing mental health conditions, it’s incredibly important
to use validated, reliable tools for the given population. This is a key research design
consideration that will pay dividends for many individuals. In addition to having a
validated assessment tool, it is important to determine if the outcome is symptoms of
Applied Physical Activity Epidemiology: Relationship of Physical. . . 33

a condition or a diagnosis of the condition. The former can be captured on tools like
the Center for Epidemiologic Studies Depression Scale (CES-D); however, the latter
will require confirmation on the part of the participant that indeed there is a
diagnosis. Some researchers will ask about certain medications to confirm or assess
the severity of illness in that it may require medication treatment. Furthermore,
anxiety and depression are often recurring or chronic conditions, as compared to
heart disease or diabetes, and thus the temporal sequence and relationship can be
challenging. Oftentimes researchers will want a hard timeline of the relationship
between these components, and that is simply very challenging to do given the
nature of these conditions.
For research contexts, it is important to consider symptoms (vs. diagnoses);
treated vs. untreated (medication/CBT/therapy/combination); assessment timing
(relative to symptom burden); and finally, state vs. trait anxiety or depression.
These considerations will be more fully explored in future chapters of this textbook
(see Chapters “Classification and Differential Diagnoses of Psychedelic-related
Crises and Disorders” and “Traumatic Psychedelic Experiences”), specifically
exploring experimental designs.
Finally, a major limitation of this type of epidemiologic research is the population
reach. Individuals who volunteer for and participate in this type of research are often
times WEIRD: Western, Educated, Industrialized, Rich, and Democratic (WEIRD)
(Schulz et al. 2018; Hendriks et al. 2019). While there is nothing inherently wrong
with any of these characteristics, these attributes do not represent the full entirety of
our populations (Muthukrishna et al. 2020). Furthermore, research studies are often
prone to the healthy adherer effect and any given population we study will be
inherently healthier than those who do not agree to participate in exercise studies
(Shrank et al. 2011; Ladova et al. 2014). Any of our inferences for any study are only
as good as those who are recruited, we cannot extrapolate beyond the sample
characteristics.

6 Conclusion

There are known tradeoffs when using epidemiologic designs versus experimental
studies. Observational designs generally allow for larger sample sizes, and often can
include longer-term follow-up with longitudinal or prospective designs. These large
sample sizes will often require certain types of measurement tools, such as self-
report or standardized, validated questionnaires. These tools have limitations includ-
ing measurement error, recall bias in certain contexts, and social desirability bias.
These are important considerations depending on the disease or outcome studied.
Historically there has been a stigma against certain conditions including certain
mental health conditions, some of these stigmas may be persistent in certain
populations or age groups. Subsequent chapters will address experimental designs
and more clinical utility for assessing these conditions and more. Overall, physical
activity epidemiology can be a useful tool to understand the influence of exercise and
physical activity on risk of disease.
34 J. (J). S. Gorzelitz

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Multiple Sex- and Circuit-Specific
Mechanisms Underlie Exercise-Induced
Stress Resistance

Margaret K. Tanner, Simone M. Mellert, Isabella P. Fallon,

Michael V. Baratta, and Benjamin N. Greenwood

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
2 Sex Differences in Exercise-Induced Stress Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.1 Limitations of Clinical Studies on Exercise-Induced Stress Resistance . . . . . . . . . . . . . . 39
2.2 Considerations for the Use of Pre-Clinical Models to Study Sex Differences
in Exercise-Induced Stress Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.3 Exercise-Induced Stress Resistance Is Sex Divergent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
2.4 Sex Differences in Exercise-Induced Stress Resistance Resemble Sex Differences
in Other Exercise Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
2.5 Potential Mechanisms Underlying Sex Differences in Exercise-Induced Stress
Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3 A Conceptual Framework for Mechanisms Underlying Exercise-Induced Stress Resistance
Includes the Development and Expression of Stress Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4 The Development of Stress Resistance from Exercise Involves Molecular Mediators,
Neural Circuits, and Exercise Signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
5 Multiple Mechanisms Underly the Expression of Exercise-Induced Stress Resistance . . . . 46
5.1 Non-specific Effects of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
5.2 The Role of the Hypothalamic-Pituitary-Adrenal Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.3 Constraint over Stress-Induced Activity of Dorsal Raphe Nucleus Serotonergic
Neurons Is One Mechanism Underlying the Expression of Stress Resistance from
Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.4 The Role of Inputs to the Dorsal Raphe Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
5.5 The Role of Exercise Adaptations Within Dorsal Raphe Nucleus 5-HT Neurons . . . 52
5.6 The Role of Exercise Adaptations Within Dorsal Raphe Nucleus Efferent Circuits . 52

M. K. Tanner and B. N. Greenwood (✉)

Department of Psychology, University of Colorado Denver, Denver, CO, USA
e-mail: [email protected]
S. M. Mellert
Department of Integrative Biology, University of Colorado Denver, Denver, CO, USA
I. P. Fallon
Department of Neurobiology, Duke University School of Medicine, Durham, NC, USA
M. V. Baratta
Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO,
USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 37

Curr Topics Behav Neurosci (2024) 67: 37–60
https://doi.org/10.1007/7854_2024_490
Published Online: 31 July 2024
38 M. K. Tanner et al.

6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Abstract Prior physical activity reduces the risk of future stress-related mental
health disorders including depression, anxiety, and post-traumatic stress disorder.
Rodents allowed to engage in voluntary wheel running are similarly protected from
behavioral consequences of stress. The present review summarizes current knowl-
edge on mechanisms underlying exercise-induced stress resistance. A conceptual
framework involving the development (during exercise) and expression (during
stress) of stress resistance from exercise is proposed. During the development of
stress resistance, adaptations involving multiple exercise signals and molecular
mediators occur within neural circuits orchestrating various components of the stress
response, which then respond differently to stress during the expression of stress
resistance. Recent data indicate that the development and expression of stress
resistance from exercise involve multiple independent mechanisms that depend on
sex, stressor severity, and behavioral outcome. Recent insight into the role of the
prefrontal cortex in exercise-induced stress resistance illustrates these multiple
mechanisms. This knowledge has important implications for the design of future
experiments aimed at identifying the mechanisms underlying exercise-induced stress
resistance.

Keywords Anxiety · Physical activity · Serotonin · Sex differences · Wheel running

1 Introduction

Exposure to stress is a primary contributing factor to the development of mental

health disorders such as depression, anxiety, and post-traumatic stress disorder.
These stress-related mental health disorders are the most common mental health
disorders in the world, accounting for 7% of the global burden of disease and 19% of
all years lived with disability (Rehm and Shield 2019). In 2019, depression disorders
were the second and anxiety disorders the eighth leading contributor to years lived
with disability (Ferrari et al. 2022). Understanding factors that can facilitate the
prevention (stress resistance) and recovery from (stress resilience) the effects of
stress on mental health is thus of utmost importance.
Stress resistance and resilience factors include experiential factors over which we
have some degree of control. One experiential factor that both enables protection
against, and facilitates recovery from, stress-related disorders is physical activity.
Indeed, sedentary behavior is recognized as a leading risk factor for development of
future stress-related mental health disorders, whereas a history of physical activity
reduces this risk (Chekroud et al. 2018; Laird et al. 2023; Harvey et al. 2018).
Additionally, physical activity, alone or in combination with traditional behavioral
or pharmacological treatments, can aid in the recovery from stress-related disorders
(Heissel et al. 2023; Hegberg et al. 2019; Bjorkman and Ekblom 2022; Stonerock
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 39

et al. 2015). A handful of pharmaceutical treatment options with varying degrees of

efficacy are employed for the treatment of existing stress-related disorders (Cipriani
et al. 2018). However, no drugs are currently available to reduce the risk of
development of future stress-related mental health disorders. Therefore, the ability
of physical activity to provide protection against the future onset of these disorders
(here simply referred to as stress resistance) is of particular importance.
Understanding the features of, and mechanisms underlying, exercise-induced
stress resistance could potentially inform strategies to maximize the stress-protective
potential of physical activity and reveal circuit and/or molecular targets for novel
prophylactic pharmaceuticals (exercise mimetics). With these objectives in mind,
this review discusses current knowledge and issues pertaining to the mechanisms by
which physical activity enables stress resistance. First, we discuss the understudied
aspect of sex differences in exercise-induced stress resistance and the intriguing
possibility that females are more responsive than males to stress resistance from
exercise. Next, we present a conceptual framework for the study of exercise-induced
stress resistance which includes the development (during exercise) and expression
(during stress) of stress resistance. Applying this framework to our model system of
acute inescapable stress clarifies the involvement of exercise signals, molecular
mediators, and circuit adaptations to exercise-induced stress resistance. Finally,
recent insights into sex- and circuit-determinants of exercise-induced stress resis-
tance support the notion that exercise recruits multiple, independent, stress resistance
mechanisms which act in parallel to enable protection from stress. These topics are
presented with an eye toward limitations of current experimental approaches and
ideas to guide future research.

2 Sex Differences in Exercise-Induced Stress Resistance

Women are more likely than men to suffer from stress-related mental health disor-
ders (Pavlidi et al. 2023; Steel et al. 2014). Additionally, some stress resistance
factors (Fallon et al. 2020) and pharmacological treatment strategies (Bigos et al.
2009) are reported to work better in males compared to females. Given the recent
emphasis on prevention (Insel and Scolnick 2006; Simmons et al. 2021), it is
particularly relevant that physical activity is a readily available and inexpensive
stress prophylactic strategy for both sexes. Understanding potential sex differences
in exercise-induced stress resistance could inform the implementation of physical
activity programs designed to optimize benefits for a particular sex.

2.1 Limitations of Clinical Studies on Exercise-Induced

Stress Resistance

Longitudinal studies including both female and male subjects indicate that exercise
can reduce the risk for development of future stress-related disorders in both sexes.
40 M. K. Tanner et al.

For example, Pearce and colleagues recently estimated that achieving the
recommended minimum amount of weekly physical activity reduces the risk of
developing future depression in both sexes by an impressive 25% (Pearce et al.
2022). However, the duration, frequency, or intensity of physical activity required to
enable stress resistance, or the magnitude of the protective effect of exercise against a
stressor of a given severity, could differ between the sexes in subtle ways that are
difficult to detect in longitudinal studies. Intervention studies that assign groups of
people to exercise and stress conditions could, in theory, be designed to detect
potential sex differences. Clinical intervention studies, however, are limited to the
use of relatively mild stressors, since it is unethical to expose people to the types of
stressors that lead to stress-related mental health disorders. Characteristics of resis-
tance to the effects of mild stress could differ from those of severe stress, so it cannot
be assumed that results of intervention studies using mild stressors resemble what
would be found in response to severe stress. Intervention studies can more readily be
designed to detect potential sex differences in therapeutic effects of exercise, by
assigning groups of humans with stress-related mental health disorders to exercise
groups. However, mechanisms underlying therapeutic exercise are not necessarily
the same as those of prophylactic exercise. These are some of the reasons why our
understanding of sex differences in exercise-induced stress resistance remains
limited.

2.2 Considerations for the Use of Pre-Clinical Models

to Study Sex Differences in Exercise-Induced Stress
Resistance

Given the limitations of clinical studies, preclinical models could be particularly

useful in the study of sex differences in stress resistance. Preclinical models allow
groups of rodents to be assigned to sedentary or exercise conditions, followed by
exposure to no stress or a laboratory stressor resulting in behaviors resembling
symptoms of stress-related mental health disorders. Acute, rather than chronic, stress
models are advantageous here, as the exercise intervention can be precisely timed to
occur prior to stress administration. It is difficult to differentiate effects of physical
activity on stress resistance vs. recovery in studies that allow animals to continue
exercising during chronic stress exposure.
There are various ways, both voluntary and involuntary, to increase the physical
activity status of rodents. Since removing the control over aspects of one’s environ-
ment is aversive (Leotti et al. 2010), chronic stress produced by forced exercise
could overshadow potential stress-protective effects. Voluntary physical activity
paradigms are thus most appropriate. Voluntary physical activity paradigms are
easily employed in the laboratory, as rodents demonstrate robust spontaneous
wheel running behavior on wheels placed in their cages (voluntary wheel running;
VWR). An additional benefit of preclinical studies is that they allow the
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 41

measurement and manipulation of factors potentially involved in exercise-induced

stress resistance, and so are useful for identification of underlying mechanisms.
An important, and often overlooked, consideration in the design of experiments
aimed at determining sex differences in exercise-induced stress resistance is that the
experiments need to be designed to statistically compare female and male subjects.
Designs that simply include subjects of both sexes and determine effects of exercise
in each sex separately are insufficient for determination of sex differences. Designs
allowing interactions between sex and exercise to be compared statistically are
necessary (Garcia-Sifuentes and Maney 2021). Additional factors such as housing
conditions, breeding history, estrous phase, controlling for handling and potential
stress effects of estrous phase monitoring, and hormonal status should also be
considered (Becker et al. 2005).

2.3 Exercise-Induced Stress Resistance Is Sex Divergent

We have been using an acute, inescapable stress (IS) model, to study sex difference
in exercise-induced stress resistance. The IS procedure involves restraining rats in
tubes and delivering a series of 100 unpredictable, inescapable electric shocks to the
tail. IS produces behaviors in rats that resemble symptoms of stress-related mental
health disorders, including anxiety-like social avoidance, exaggerated fear-like
potentiated shock-elicited freezing, and depression-like deficits in shuttle box escape
(Christianson et al. 2008; Maier and Watkins 2005). Importantly, the behavioral
consequences of IS are dependent on the uncontrollability of the stressor and do not
occur if shocks of equal duration and intensity can be terminated by the subject
(Christianson et al. 2008; Maier and Watkins 2005).
We and others have previously reported that long-term VWR (e.g., 4–6 weeks)
prevents anxiety-, fear-, and depression-like behavioral consequences of IS in adult
male (Dishman 1997; Dishman et al. 1997; Duman et al. 2008; Greenwood et al.
2003a, 2012a) and female (Tanner et al. 2019) rats. We have also observed a
potential sex difference in the duration of VWR required to enable stress resistance;
whereby 3 weeks of VWR prevents IS-induced social avoidance and exaggerated
fear in females (Fallon et al. 2020), but fails to prevent IS-induced exaggerated fear
or the shuttle box escape deficit in males (the effects of 3 weeks of VWR on
IS-induced social avoidance in males was not assessed; (Greenwood et al. 2005a)).
These time course studies, however, were performed in different laboratories, years
apart, and did not allow statistical comparison of the effects of exercise between
sexes.
To determine if sex differences in exercise-induced stress resistance exist, we
recently allowed adult (age-matched), female and male Sprague-Dawley rats volun-
tary access to in-cage running wheels for either 3 or 6 weeks prior to exposure to a
single session of IS. As expected, 6 weeks of VWR prevented IS-induced social
42 M. K. Tanner et al.

avoidance and exaggerated fear in both sexes. Confirming prior work with females
and males separately, we observed a sex difference in exercise-induced stress
resistance, whereby 3 weeks of VWR prevented IS-induced exaggerated fear in
females, but not in males. Surprisingly, however, 3 weeks of VWR did protect males
from IS-induced social avoidance (Tanner et al. 2023).
This study reveals that long-term physical activity may be equally effective at
enabling stress resistance in females and males, but the duration of physical activity
required to enable stress resistance differs between the sexes in a stress outcome-
dependent manner. A similar duration of physical activity seems to enable protection
against anxiety-like consequences of stress between sexes, whereas exaggerated
fear-like effects of stress seem to be more readily prevented by physical activity in
females compared to males. Physical activity also seems to reduce depression-like
behavior more readily in female mice than males. Both VWR (Elias et al. 2023) and
treadmill training (Munive et al. 2016; Naghibi et al. 2021) have been reported to
reduce immobility time in the tail suspension test in female, but not male, mice.
If these preclinical data apply to humans, they suggest that women at risk for
mental health disorders should prioritize physical activity as a prophylactic strategy.
Unfortunately, this sex difference will be difficult to confirm in humans, given the
difficulty in performing clinical intervention studies on stress resistance. One longi-
tudinal study following more than 100,000 adults over 3 years did find a sex
difference like that observed in rodents. Kim et al. (2019) found that transitioning
from a sedentary lifestyle to a physically active one reduced the incidence of new
depression within a year in women, but not in men (Kim et al. 2019).

2.4 Sex Differences in Exercise-Induced Stress Resistance

Resemble Sex Differences in Other Exercise Effects

The observation that females are more responsive than males to exercise-induced
stress resistance does not seem to be an anomaly among sex differences in response
to exercise. Physical activity can improve cognitive function more readily in female
than in male rats and humans (Wang et al. 2015; Colcombe and Kramer 2003; Barha
et al. 2017a; Barha and Liu-Ambrose 2018) and can reduce the risk for dementia to a
greater extent in women than in men (Hogervorst et al. 2012; Laurin et al. 2001). A
similar sex difference is found in studies examining the impact of physical activity
on drug-seeking behaviors (Cosgrove et al. 2002; Lespine and Tirelli 2018;
Smethells et al. 2020; Gallego et al. 2015), hypoalgesia (Rice et al. 2019), and
mood (McDowell et al. 2016). Although conflicting reports exist (Peterson et al.
2014; Szuhany et al. 2015), growing evidence indicates that females are generally
more responsive to the behavioral effects of physical activity than males. However,
these effects may partly depend on exercise type (Barha et al. 2017a, b).
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 43

2.5 Potential Mechanisms Underlying Sex Differences

in Exercise-Induced Stress Resistance

Relatively little work has explored whether mechanisms underlying exercise-

induced stress resistance are sex divergent. Observed sex differences in the effects
of physical activity on hippocampal microglial activation (Kohman et al. 2013),
hippocampal neurotrophic factors (Naghibi et al. 2021; Uysal et al. 2015), and
hippocampal volume (Varma et al. 2015) could all contribute to sex differences in
exercise-induced stress resistance. Two factors that stand out as potentially driving
sex differences in exercise effects, including stress resistance, are sex differences in
exercise behavior and ovarian hormones.
Female rats run greater distances and faster speeds than males (Basso and Morrell
2017; Eikelboom and Mills 1988). Additionally, ovarian hormones during early life
could alter the development of the female brain rendering it more susceptible to
exercise effects (organizational effects). Alternatively, ovarian hormones during
adulthood could interact with exercise, altering the way in which exercise impacts
the brain (activational effects).
Sex differences in VWR behavior are dependent on activational effects of ovarian
hormones (Gentry and Wade 1976; Slonaker 1924), particularly estrogen (Gorzek
et al. 2007), thus the involvement of sex differences in VWR behavior and
activational effects of ovarian hormones in mediating sex differences in exercise-
induced stress resistance can be simultaneously tested by removing ovarian hor-
mones. We removed ovaries from adult, female rats, and observed that female VWR
behavior now resembled that of males (Tanner et al. 2023). Interestingly, despite the
elimination of the female pattern of VWR and the absence of activational effects of
ovarian hormones during exercise, 3 weeks of VWR still produced rapid protective
effects against both IS-induced social avoidance and exaggerated fear (Tanner et al.
2023).
Whether ovarian hormones are similarly unnecessary for other sex differences in
response to exercise is unknown. It does seem that ovarian hormones are not
required for exercise to impact brain and behavior in females, in general. For
example, VWR rapidly upregulates BDNF gene expression (Berchtold et al. 2001)
and cell proliferation (Jin et al. 2008) in the hippocampus of ovariectomized female
rats, and both VWR and treadmill training have been reported to protect ovariecto-
mized rats from impairments in cognition produced by sleep deprivation (Saadati
et al. 2015; Rajizadeh et al. 2020). Future work will be needed to determine
mechanisms underlying sex differences in exercise-induced stress resistance. Since
very little research on sex differences in underlying mechanisms has been com-
pleted, the following section on mechanisms focuses on work done in males.
44 M. K. Tanner et al.

3 A Conceptual Framework for Mechanisms Underlying

Exercise-Induced Stress Resistance Includes
the Development and Expression of Stress Resistance

A conceptual framework to aid in consideration of the variety of mechanisms

underlying exercise-induced stress resistance is provided in Fig. 1. For physical
activity to alter the brain and behavioral response to stress, physical activity must
produce experience-dependent plasticity prior to stressor exposure which then
allows the physically active organism to respond to the stressor differently than it
would if it were sedentary. Mechanisms of exercise-induced stress resistance can,
therefore, be thought of in terms of those mechanisms underlying the development of
exercise-induced stress resistance (i.e., during exercise prior to stress) and the
expression of exercise-induced stress resistance (i.e., during stress after a period of
physical activity).

Fig. 1 A conceptual framework for exercise-induced stress resistance involves the development
and expression of stress resistance. During the development of stress resistance (left, blue box),
neural circuits governing physical activity motivation, planning, execution, and reinforcement
determine the extent to which the organism engages in physical activity. Repeated physical activity
triggers exercise signals, either derived from peripheral organs and/or motor/motivation circuits
themselves, which communicate the experience of physical activity to brain stress-responsive
circuits responsible for stress-induced behavioral outcomes. Exercise signals converge on molec-
ular mediators which produce experience-dependent plasticity within these circuits. During the
expression of stress resistance (right, red box), stress circuits altered by prior physical activity now
respond to stressful events in a manner that is protective against stress-induced behavioral outcomes
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 45

4 The Development of Stress Resistance from Exercise

Involves Molecular Mediators, Neural Circuits,
and Exercise Signals

As we saw with the protective effects of VWR against the behavioral consequences
of IS, stress resistance from exercise develops over time with repeated exercise. The
development of stress resistance from exercise refers to exercise-induced physiolog-
ical adaptations occurring during exercise which mediate the later expression of
stress resistance. The molecular mediators of these adaptations, the circuits in which
these adaptations occur, and the signals through which exercise initiates these
adaptations are all critical to the development of stress resistance (Fig. 1).
Physical activity status of the organism modulates many aspects of physiology,
including central gene expression (Loughridge et al. 2013; Tong et al. 2001),
alterations in neurotransmitter systems (Dishman 1997; Greenwood 2019; Green-
wood and Fleshner 2011; Petzinger et al. 2015), synaptic plasticity (Cotman et al.
2007; de Sousa Fernandes et al. 2020), proliferation and survival of adult-born
neurons (Vivar et al. 2013; van Praag 2008), and brain structure (Wilckens et al.
2021; Chen et al. 2020). Despite these many exercise adaptations, identifying which,
if any, of these are causally related to stress resistance is challenging. The types of
experiments required to determine causation are especially difficult to perform with
long-term exercise studies. Loss-of-function experiments require candidate mecha-
nistic factors to be altered in physically active organisms for the entire duration of the
exercise period (during the development of stress resistance), but not during expo-
sure to stress (during the expression of stress resistance). Similarly, gain-of-function
experiments require factors to be increased for a long period of time prior to, but not
during, stress. Compounding the issue is the possibility that physical activity utilizes
several different mechanisms acting in parallel to enable stress resistance. For
example, several molecular mediators could drive the experience-dependent neural
plasticity required for stress resistance. Likely candidates include brain-derived
neurotrophic factor (Duman et al. 2008; Cotman et al. 2007), mammalian target of
rapamycin (Lloyd et al. 2017; Moya et al. 2020), and delta-FosB (Mul et al. 2018;
Werme et al. 2002). Additionally, several exercise signals derived from peripheral
organs (e.g., muscle, fat, liver, gut) or the brain itself (e.g., from circuits directly
governing voluntary exercise) could be responsible for communicating the experi-
ence of exercise to these molecular mediators. Irisin (Islam et al. 2021), IL-6
(Severinsen and Pedersen 2020), and lactate (Xue et al. 2022), for example, have
been shown to be important for periphery-to-brain communication during exercise.
Since physical activity most obviously involves the movement of skeletal muscle,
it is not surprising that research efforts aimed at identifying factors responsible for
communicating the experience of exercise to the brain circuits underlying behavioral
effects of exercise (referred to here as exercise signals) have been focused on signals
released from muscle or other peripheral organs. We must keep in mind, however,
that these signals could also come from within the brain itself. Potential sources of
central exercise signals include neural circuits involved in the motivation for
46 M. K. Tanner et al.

physical activity, and/or the planning, performance, and/or reinforcing effects of

physical activity. Our understanding of these circuits has been growing in recent
years (Tanner et al. 2022; Dohnalova et al. 2022). Interestingly, there is evidence that
circuits governing voluntary exercise vary by sex (Tanner et al. 2022). It is therefore
plausible that sex differences in central signals could drive sex differences in the
development of exercise-induced stress resistance.

5 Multiple Mechanisms Underly the Expression

of Exercise-Induced Stress Resistance

The expression of stress resistance from exercise occurs during the discrete
timepoint of stressor exposure. The changes in the brain established during the
development of stress resistance enable stress-reactive neural circuitry orchestrating
neurochemical, behavioral, and physiological stress responses to react differently
during stress than they would if the organism were sedentary (Fig. 1). Results of
recent experiments reveal a common take-home message: there are multiple mech-
anisms mediating the expression of stress resistance from exercise. These mecha-
nisms can vary depending on sex, stressor severity, duration of prior exercise, and
behavioral outcome. The multiple stress resistance mechanisms also seem to act in
parallel to enable the expression of stress resistance from exercise. This is perhaps
not surprising, given the wide variety of physiological and neural systems impacted
by exercise.

5.1 Non-specific Effects of Exercise

In addition to changes in specific stress-responsive systems, non-specific effects of

exercise, such as altered pain sensitivity or locomotor activity, could contribute to
the expression of stress resistance from exercise. VWR can reduce pain sensitivity,
raising the possibility that VWR could reduce sensitivity to stressors such as electric
shock. VWR, however, does not alter sensitivity to shock in mice (Duman et al.
2008) or rats (Tanner et al. 2023), nor does it globally blunt stress responses to
electric shock stressors, as would be expected if VWR reduced shock sensitivity. For
example, VWR has no effect on IS-induced increases in corticosterone (Tanner et al.
2023; Fleshner 2000; Speaker et al. 2014), plasma cytokines (Speaker et al. 2014), or
cFos in several stress-responsive brain regions (Greenwood et al. 2003b, 2005a).
Regarding altered pain sensitivity contributing to protection against the behavioral
effects of IS specifically, IS itself produces massive analgesia (Maier et al. 1982) that
begins early during IS treatment (Maier and Keith 1987). Importantly, the behavioral
sequelae of IS occur whether or not these antinociceptive effects of IS are present,
indicating that IS outcomes are independent of pain sensitivity (MacLennan et al.
1982; Hemingway and Reigle 1987).
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 47

Animal models of stress-related mental health disorders often depend on subjects

engaging in locomotor activity, whereby general increases in movement could be
mistaken for anxiolytic or antidepressant effects. This raises the possibility that
potential effects of VWR on locomotor activity could contribute to the observed
behavioral effects. IS reduces locomotor activity during exposure to a novel envi-
ronment for at least 48 h following IS, but VWR has no impact on this stress-induced
reduction in locomotor activity in either sex (Tanner et al. 2023). This observation
suggests that the stress-protective effect of VWR against IS outcomes is not attrib-
utable to alterations in locomotor activity. Future research utilizing different animal
models should consider how these factors and others (such as increased fitness)
contribute to the behavioral effects of exercise in that model.

5.2 The Role of the Hypothalamic-Pituitary-Adrenal Axis

Physical activity blunts the response of the hypothalamic-pituitary-adrenal (HPA)

axis to stress (see (Nowacka-Chmielewska et al. 2022) for a recent review). Given
the link between HPA activity and stress-related mental health disorders (Sapolsky
2000; McEwen et al. 2015), it is easy to conceptualize how constraint over stress-
induced activity of the HPA axis could contribute to stress resistance from exercise.
However, severely stressful events are more likely to precipitate the formation of
stress-related disorders than mild stressors, and the impact of VWR on the HPA axis
seems to be limited to mild-moderate stressors (Campeau et al. 2010). VWR, for
example, fails to attenuate the HPA response to IS in either sex (Tanner et al. 2023;
Fleshner 2000; Speaker et al. 2014). Attenuation of HPA responses could, therefore,
contribute to exercise-induced resistance to the effects of relatively mild stressors,
but protective effects of exercise against behavioral consequences of more severe
stressors likely involve mechanisms other than blunting of the HPA axis. These data
demonstrate that mechanisms underlying the expression of stress resistance from
exercise can vary depending on stressor severity.

5.3 Constraint over Stress-Induced Activity of Dorsal Raphe

Nucleus Serotonergic Neurons Is One Mechanism
Underlying the Expression of Stress Resistance from
Exercise

Since VWR prevents the anxiety- and depression-like consequences of acute expo-
sure to severe, inescapable stressors, such as IS, it is of particular interest to consider
the mechanisms involved in this effect. One of the benefits of using the IS model is
that the neural circuits mediating the behavioral consequences of IS have been well-
defined. Briefly, brain regions involved in processing specific aspects of IS,
48 M. K. Tanner et al.

including the locus coeruleus (LC), lateral habenula, and bed nucleus of the stria
terminalis (BNST), have converging excitatory inputs to the dorsal raphe nucleus
(DRN). Activity of these inputs during severe stressors drives the activity of DRN
serotonergic (5-HT) neurons, measured both by cFos (Grahn et al. 1999) and
extracellular 5-HT released into the DRN from DRN axon collaterals (Maswood
et al. 1998). The excessive extracellular 5-HT in the DRN during IS desensitizes
inhibitory somatodendritic 5-HT1A autoreceptors, leaving DRN 5-HT neurons in a
sensitized state (Rozeske et al. 2011). Sensitized DRN 5-HT neurons now respond to
future mild stressors with excessive 5-HT release in DRN projection sites. Among
these DRN projection sites are the basolateral amygdala (Amat et al. 1998), where
sensitized 5-HT release produced by prior IS leads to anxiety-like (Christianson et al.
2010) and exaggerated fear-like (potentiated shock-elicited freezing) behavior
(Strong et al. 2011), and the dorsal striatum, where sensitized 5-HT release produces
depression-like behavior, such as the shuttle box escape deficit (Strong et al. 2011).
In addition to being necessary and sufficient for the behavioral consequences of IS
(Maier and Watkins 2005), increased 5-HT activity in the DRN is also involved in
the anxiety- and depression-like consequences of social defeat (Hammack et al.
2012; Amat et al. 2010). Moreover, manipulations that prevent the behavioral out-
comes of IS, including behavioral control over the stressor (Amat et al. 2006),
prophylactic ketamine (Amat et al. 2016), dominance rank (Coleman et al. 2023),
and 6 weeks of VWR (Greenwood and Fleshner 2011), all prevent IS-induced DRN
hyperactivity and sensitization.
In adult, male rats, 6 weeks of VWR attenuates IS-induced expression of the
neural activation marker cFos within DRN 5-HT neurons (Greenwood et al. 2003a),
indicating that 6 weeks of VWR prevents the excessive activation of DRN 5-HT
neurons that occurs during IS. Six weeks of VWR also prevents IS-induced sensi-
tization of extracellular 5-HT in the DS in response to a few foot shocks, assessed
with microdialysis (Clark et al. 2015). These data suggest that the expression of
stress resistance from 6 weeks of VWR involves the prevention of stress-induced
hyperactivity and subsequent sensitization of DRN 5-HT neurons, at least in males.
An increase in central 5-HT is thought to contribute to central fatigue (Davis and
Bailey 1997). Constraint over DRN 5-HT activity could thus be a training adaptation
that evolved to help delay fatigue during exercise. Whether DRN constraint is
involved in the expression of stress resistance from exercise in females is a critical
unanswered question.
Understanding how exercise comes to constrain the DRN 5-HT response to
severe stressors could reveal novel insights into mechanisms underlying the devel-
opment and expression of exercise-induced stress resistance. Two possibilities seem
most plausible. First, exercise could alter inputs to the DRN that regulate 5-HT
activity during stress. Second, exercise could produce adaptations within DRN 5-HT
neurons themselves which alter their response to stress. There is evidence that
exercise does both, as outlined below. Additionally, exercise modifies the response
of DRN efferent circuits mediating specific behavioral consequences of IS to 5-HT
and/or stress. Multiple independent mechanisms involving the 5-HT system thus
seem to contribute to the expression of stress resistance from exercise (Fig. 2).
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 49

Fig. 2 Circuit-specific determinants of exercise-induced stress resistance. Repeated physical

activity initiates the development of the stress-resistant brain by acting on at least 3 unique neural
substrates, each of which could be sufficient for the expression of stress resistance: (1) Repeated
physical activity potentiates activity of inhibitory inputs to the dorsal raphe nucleus (DRN; dotted
line) and potentially reduces activity of excitatory DRN inputs (solid lines) during stress.
(2) Repeated physical activity alters factors intrinsic to DRN serotonergic (5-HT) neurons that
influence their response to stress. (3) Repeated physical activity produces adaptations within DRN
efferent circuits that are the proximal mediators of behavioral-specific stress outcomes. These
stress-protective mechanisms develop at different rates during exercise, depending on sex and
circuit-specific behavioral outcome

5.4 The Role of Inputs to the Dorsal Raphe Nucleus

One means by which exercise could attenuate the DRN 5-HT response to stress is by
modifying the activity during stress of brain structures with modulatory control over
DRN 5-HT neurons. VWR could, for example, attenuate excitatory drive or increase
inhibitory drive to DRN 5-HT neurons from afferent structures during IS. Numerous
DRN afferent structures are sensitive to physical activity and are thus prime candi-
dates for exercise-induced modulation of DRN activity, as discussed previously
(Greenwood 2019; Greenwood and Fleshner 2008, 2011; Nicastro and Greenwood
2016). Exercise produces a hyperdopaminergic state within midbrain-striatal path-
ways which we have argued simultaneously contributes to both a more positive
outlook on stress and DRN constraint in physically active compared to sedentary
organisms (Greenwood 2019). The medial prefrontal cortex (PFC) also stands out
due to its established role in stress resistance and resilience (Maier et al. 2006).
Based on our prior data, it was thought that the PFC was not involved in stress
resistance from exercise (Christianson and Greenwood 2014; Greenwood et al.
2013). However, here we present new data which provides an updated view on the
role of the PFC in exercise-induced stress resistance.
The PFC has an inhibitory influence over DRN 5-HT activity, mediated through a
glutamatergic projection from the medial PFC to the DRN, where PFC glutamatergic
50 M. K. Tanner et al.

terminals synapse on GABAergic neurons which inhibit 5-HT neural activity (Amat
et al. 2005). Physical activity induces neuroplasticity in the PFC and enhances PFC
function in both humans (Erickson and Kramer 2009; Soshi et al. 2021) and animals
(Dong et al. 2018; Brockett et al. 2015). Given the established sensitivity of the PFC
to exercise and the ability of the PFC to inhibit the DRN during IS, we sought to
determine whether the PFC is necessary for the expression of exercise-induced stress
resistance. After 3 weeks of wheel access to establish habitual VWR, male rats
received sham surgery or bilateral lesions of the medial PFC, where DRN-projecting
neurons are located. Rats ran an additional 3 weeks following surgery, for a total of
6 weeks of VWR, prior to exposure to no stress or IS. The idea was that if the PFC-
to-DRN pathway inhibits the DRN during IS in VWR rats, then removing this
inhibitory influence over DRN activity would prevent the expression of stress
resistance and would restore the behavioral consequences of IS in previously
physically active rats. To our surprise, PFC lesions had absolutely no effect on
exercise-induced stress resistance. Six weeks of VWR still protected male rats from
the behavioral consequences of IS despite PFC lesions (Greenwood et al. 2013).
These data indicate that the PFC is not necessary for the expression of exercise-
induced stress resistance. But does this negative experimental result mean that
physical activity does not utilize the PFC or the PFC-to-DRN pathway for stress
resistance at all? A limitation of lesion and inactivation studies is that if negative
results are found, it cannot be assumed that the inhibited region or circuit is not
utilized for stress resistance in an intact animal. Indeed, if multiple independent
mechanisms act in parallel to enable stress resistance from exercise, then inhibiting
one should have no impact on another and stress resistance should remain intact. If
multiple neural circuits contribute to DRN constraint during stress in previously
physically active animals, the only way to know whether a certain circuit contributes
to DRN constraint is to measure its activity during stress.
We designed an experiment to determine whether prior exercise recruits the PFC-
to-DRN circuit during stress (Fig. 3a). Red fluorescent retro-beads were injected into
the DRN of male rats (Fig. 3c). These beads reveal DRN-projecting PFC neurons by
traveling retrograde from axon terminals in the DRN to cell bodies of origin in DRN
afferent structures. After 6 weeks of sedentary or VWR conditions, rats were
exposed to IS and cFos was quantified in DRN-projecting PFC neurons with
immunohistochemistry (Fig. 3b; n = 6/group). We found that 6 weeks of VWR
increased the percentage of DRN-projecting PFC neurons expressing cFos following
IS (unpaired t-test p < 0.0001; Fig. 3d).
These data provide an updated view on the role of the PFC in exercise-induced
stress resistance. VWR does indeed recruit the PFC-to-DRN inhibitory circuit during
stress, which likely contributes to DRN inhibition (Fig. 3e). However, since VWR
still enables stress resistance even in the absence of the PFC, this activity is not
necessary for stress resistance from exercise and exercise must utilize an additional
mechanism that can enable stress resistance in the absence of the PFC (Fig. 3f).
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 51

Fig. 3 Prior physical activity recruits a prefrontal cortex (PFC)-to-dorsal raphe nucleus (DRN)
pathway during inescapable stress. (a) Experimental timeline. Rats received red retro-beads in the
DRN prior to 6 weeks of sedentary (Sed) or voluntary wheel running (VWR) conditions. All rats
were exposed to inescapable tail shock stress and then euthanized 90 min later. PFC was processed
for cFos immunohistochemistry (IHC) and the % of DRN-projecting PFC neurons containing cFos
was quantified. (b) cFos (green) expression within DRN-projecting PFC neurons (red). Arrows
point to DRN-projecting neurons expressing cFos. Distance noted is relative to Bregma. Scale
bar = 200 μm. (c) Injection site of red retro-beads in the DRN. Distance noted is relative to Bregma.
Scale bar = 200 μm. (d) Relative to Sed rats, prior VWR increased cFos expression within
DRN-projecting PFC neurons during inescapable stress. ***p < 0.0001. (e) Cartoon illustrating
that VWR rats with intact PFC utilize the PFC-to-DRN pathway during stress. (f) In PFC-lesioned
rats, VWR rats no longer utilize the PFC-to-DRN pathway but are still protected from stress through
an alternative mechanism. This illustrates that multiple mechanisms are involved in the expression
of exercise-induced stress resistance. Figure created in BioRender. Brain images adapted from the
rat brain atlas of Paxinos and Watson (Paxinos and Watson 1998)
52 M. K. Tanner et al.

5.5 The Role of Exercise Adaptations Within Dorsal Raphe

Nucleus 5-HT Neurons

Another possible way in which prior physical activity could attenuate activity of
DRN 5-HT neurons during stress is by impacting DRN 5-HT neurons directly
(during the development of stress resistance), altering factors intrinsic to 5-HT
neurons which modulate their response to stress (during the expression of stress
resistance; Fig. 2). Reported adaptations within DRN 5-HT neurons in response to
VWR, such as increased 5-HT content in the DRN and DRN projection sites
(Dishman 1997; Dishman et al. 1997) and altered gene expression within DRN
5-HT neurons (Loughridge et al. 2013), are consistent with this possibility. For
example, VWR increases mRNA coding for the 5-HT1A inhibitory autoreceptor in
the DRN in male rats (Greenwood et al. 2003a). An increase in 5-HT1A
autoinhibition could help constrain the DRN 5-HT response to stress. This mecha-
nism may only contribute to stress resistance after long-term VWR in males, since
6 weeks, but not 3 weeks, of VWR increases 5-HT1A mRNA (Greenwood et al.
2005b). Other DRN adaptations occur more rapidly (Greenwood et al. 2005b).
Future work should determine if similar intrinsic changes in DRN 5-HT neurons
occur in females and clarify whether these adaptations contribute to DRN constraint
during stress in both sexes.

5.6 The Role of Exercise Adaptations Within Dorsal Raphe

Nucleus Efferent Circuits

Constraint over stress-induced activity of DRN 5-HT neurons, either via modulation
of the activity of DRN inputs or adaptations within DRN 5-HT neurons, is one
potential mechanism underlying the expression of stress resistance from long-term
exercise. However, it doesn’t appear to be the only one. In male rats, 3 weeks of
VWR does not attenuate the activity of DRN 5-HT neurons during IS, as 6 weeks
does (Greenwood et al. 2005a). How then, does 3 weeks of VWR prevent IS-induced
social avoidance in males?
IS-induced social avoidance depends on IS-induced sensitization of 5-HT release
in the amygdala (Christianson et al. 2010). Since 3 weeks of VWR fails to constrain
the DRN response to IS, 3 weeks of VWR could instead be preventing IS-induced
social avoidance by acting on DRN efferent circuits that mediate the anxiety-like
consequences of sensitized 5-HT release. The BNST is implicated in anxiety
(Walker et al. 2003), and stress-induced social avoidance involves a circuit from
the amygdala to the BNST (Vantrease et al. 2022). Three weeks of VWR does not
alter cFos in response to IS in the amygdala (Greenwood et al. 2005a), but it does
alter gene expression (Fox et al. 2023) and the cFos response to IS (Greenwood et al.
2005a) in the BNST. Anxiogenic effects in a fear-potentiated startle paradigm
Multiple Sex- and Circuit-Specific Mechanisms Underlie Exercise-Induced. . . 53

produced by 2 weeks of VWR were recently shown to be mediated by a reduction in

5-HT2C receptor expression in the BNST (Fox et al. 2023).
Together, these data are consistent with the possibility that rapid exercise-induced
adaptations in the BNST could lead to protection from social avoidance and other
anxiety-like behaviors, despite a failure of 3 weeks of VWR to prevent IS-induced
sensitization of the DRN. Of course, longer-duration physical activity could also
produce adaptations within DRN efferent circuits that underly fear- and depression-
like effects of stress. Indeed, 6 weeks of VWR reduces the expression and sensitivity
of 5-HT2C receptors in the amygdala and dorsal striatum (Greenwood et al. 2012b).
Since the behavioral consequences of IS are dependent on 5-HT2C receptor signaling
in these regions (Christianson et al. 2010; Strong et al. 2009, 2011), the expression of
stress resistance induced by a long duration of prior physical activity could involve
both DRN constraint and resistance to the post-synaptic effects of 5-HT in DRN
projection sites mediating specific IS-induced behaviors. This prior work was done
in males. Whether physical activity produces neural adaptations in DRN projection
sites in females is currently unknown and should be addressed in future studies.

6 Conclusions

Physical activity enables robust protection against behavioral effects of stress,

including stress-related mental health disorders in humans and anxiety-, fear-, and
depression-like behaviors in animals. Mechanisms underlying stress resistance from
exercise can be thought of in terms of those driving the development of stress
resistance (during exercise) and those driving its expression (during stress). The
development of stress resistance involves multiple exercise signals and molecular
mediators and varies depending on sex and behavioral outcome. The expression of
stress resistance from exercise similarly involves multiple independent mechanisms
acting in parallel, as is demonstrated by the role of the PFC in exercise-induced stress
resistance. This knowledge has important implications for the design and interpre-
tation of causal experiments aimed at identifying underlying mechanisms. The
inescapable stress model in rodents reveals a key role of DRN constraint in medi-
ating exercise-induced stress resistance, but the specific involvement of exercise
adaptations within DRN inputs, within the DRN itself, and within DRN projection
sites require further clarification. Much of our knowledge of the mechanisms
underlying exercise-induced stress resistance comes from work using male subjects.
The recent realization that female rodents are more responsive than males to
exercise-induced stress resistance highlights the need to expand our mechanistic
knowledge in females. Whether this sex difference extends to humans is a critical
unanswered question, but regardless of the answer, identifying the mechanisms
driving this sex difference could reveal novel targets that could be harnessed by
both sexes to bolster the stress-protective impact of exercise.
54 M. K. Tanner et al.

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Exercise and Neuroendocrinology

Anthony C. Hackney

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
2 Hormonal Roles: Physiology of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
3 Hormonal Exercise Response Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
3.1 Phase I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.2 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.3 Phase III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.4 HERM Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4 Recovery from Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5 Mechanisms of Hormonal Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6 Sex and Exercise Endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
6.1 Menstrual Cycle and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
6.2 Women Versus Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
7 Neuroendocrine Dysfunction with Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Abstract The intent of this chapter is to provide a basic overview and explanation
of the neuroendocrine system responses to an exercise session in healthy adults.
Specifically, the physiologic mechanisms for inducing the hormonal responses of
this system and the scope of such responses are addressed. Additionally, factors that
augment or attenuate exercise hormonal responses are presented as well as issues
related to sex differences, and exercise-related hormonal dysfunction.

Keywords Endocrines · Homeostasis · Hormones · Physical Activity · Stress

A. C. Hackney (✉)
University of North Carolina, Chapel Hill, NC, USA,
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 61

Curr Topics Behav Neurosci (2024) 67: 61–76
https://doi.org/10.1007/7854_2024_491
Published Online: 23 July 2024
62 A. C. Hackney

1 Introduction

Public health and medical research support the benefit of regular physical activity to
aid the overall health of well-being of people (Surgeon General Report 1996).
Recommendations for the quantity and quality of such physical activity have been
developed by leading health agencies such as the World Health Organization
(WHO) and the American College of Sports Medicine (Bull et al. 2020). To this
end, exercise scientists continue to pursue and understand the physiological changes
associated with the multitude of physical activities that the human body can perform.
This is critical as the adaptive processes (physiological mechanisms) and time course
for such responses need to be fully elucidated in order to optimize the health and
performance benefits of women and men.
Along these lines, many scientists interested in the physiology of exercise
recognize the critical roles of the hormonal responses by the neuroendocrine system
to the physical stress of exercise. This is a logical pursuit due to the critical roles
hormones play in bringing about homeostatic adjustments in many bodily systems to
allow coping with the demands of any stressful activity, such as an exercise session
(Johnson et al. 1992). The hormonal reactions to exercise occur in order to bring
about and aid in inducing appropriate cardiovascular-respiratory adjustments (e.g.,
the hormones, norepinephrine, epinephrine), accelerating energy metabolism (e.g.,
growth hormone, cortisol), and maintaining proper thermoregulation accommoda-
tions (e.g., aldosterone). In addition, some physiological changes occur which can be
classified as stress-reactive responses (e.g., immunological changes) which may not
physiologically aid directly in the exercise session but are a consequence of the
activity (Hackney 2006).
The endocrine system’s release of hormones works via a stimulus-response
model. Specifically, some form of humoral, neural, or hormonal stimuli (primarily
within the blood) provokes an endocrine gland to produce and secrete its hormone
(s) in the circulatory system. In turn, the circulating hormones invoke changes in
target tissues to allow for accommodations to the original stimulus (Nussey and
Whitehead 2001). The regulation of circulating hormones revolves around feedback
loops, which are chiefly of a negative feedback type (Nussey and Whitehead 2001).
A classic illustration of this would be when a person eats, this raises blood glucose,
which provokes pancreatic insulin release, which then in turn promotes target tissue
(e.g., skeletal muscle) update of glucose from the blood.
This chapter intends to present an overview of the sequence of events that bring
about the multi-faceted changes in circulating hormones in reaction to an exercise
session. It is recognized that entire volumes have been written concerning this topic
but herein space limitations dictate a truncated discussion of the topic. For that
reason, this dialogue is delimited to hormonal responses found in healthy, mature
adults who are not overweight/obese and prior to experiencing either menopause or
andropause. Furthermore, in the context of this discussion, relative to sex the focus
herein is on cis-gender men and women. Therefore, the terms female and male are
used as adjectives, and man/men and woman/women as nouns.
Exercise and Neuroendocrinology 63

2 Hormonal Roles: Physiology of Exercise

Figure 1 presents a schematic illustration of the physiological consequences of the

hormonal responses to an exercise session. Noticeably, there are wide-ranging
effects of hormones, and without their appropriate response (i.e., neuroendocrine
activity) the ability of an exerciser, whether recreational or a competitive athlete, to
perform physical exercise would be severely compromised and sub-optimal.
Furthermore, in examining Fig. 1, it is important to recognize that there are
several critical factors that determine the magnitude of the change in the circulating
hormone levels during a specific exercise session (i.e., not all exercise is the same in
effect on the neuroendocrine system). These factors are: (1) the intensity at which the
exercise is performed, (2) the duration for which the exercise is performed, (3) the
modality involved in doing the exercise (e.g., running vs. lifting-weights), (4) the
ambient environment that the exercise is performed in (hot vs. cold weather), and
(5) the physical fitness level of the person performing the exercise, in the sense of,
are they a novice or experienced and considered “trained” (Borer 2003; Galbo 1983;
McMurray and Hackney 2000; Viru and Viru 2001).
Relative to the first, in nearly a universal fashion, the greater the intensity of an
exercise session the larger the magnitude of the hormonal change in the circulation.
And, in the case of some hormones, for example, cortisol and growth hormone, until
a critical threshold of exercise intensity is reached (~50–60% of maximal intensity)
there are only slight changes in circulating levels. Secondly, prolonging the duration

Fig. 1 The roles that the neuroendocrine system plays via hormones to bring about the physiolog-
ical adjustments to allow exercise in humans. Abbreviations: ATP = adenosine triphosphate (i.e.,
the energy currency of the body), CHO = carbohydrate, H2O = water, HR = heart rate. Red arrows
indicate factors that invoke and amplify neuroendocrine hormonal changes/responses
64 A. C. Hackney

of an exercise session typically has a similar effect to augment the magnitude of the
hormonal change. The mechanism for these gradual increases seems to be a combi-
nation of events influencing the hormone levels, such as blood hemoconcentration,
increased hormonal production and reduced metabolic clearance of hormones from
the blood (Hackney 2006). However, in some circumstances, excessive duration can
actually have the opposite effect, and hormonal levels have been reported to be
reduced (Galbo 1983; Galbo et al. 1977) (N.B., what defines “excessive duration” is
relative to the level of training an individual has undergone). Examples of hormones
that can be reduced in such scenarios are testosterone and thyroid-stimulating
hormone (Galbo et al. 1977; Opstad and Aakvaag 1981). Relative to this last
point, the specific level of duration to invoke reductions is an issue of some debate
as this phenomenon is not well studied. As to exercise modality, this can be a
complicated factor to characterize, as issues such as muscle mass involvement
(e.g., lifting weights with only upper body muscularity versus only the lower
body), the dynamic versus static movement pattern aspects of the muscular contrac-
tile process, and the body position (sitting down, upright, supine) can all play
modifying roles to affect hormones (Athanasiou et al. 2023). Similarly, the ambient
environment can drastically modify responses. For example, exercising in hot,
humid weather can exacerbate the thermoregulatory responses of individuals (i.e.,
greater body core temperature increases), which leads to a substantially greater
magnitude of hormonal changes (Cross et al. 1996). Interestingly, becoming
dehydrated while exercising mimics the physiological responses of a hot environ-
ment, even if the ambient temperature is comfortable and thermoneutral (Costill
et al. 1981). Along these same lines, exercising in water can impact thermoregulation
influences as water immersion results in an enhanced conductive heat transfer in or
out of the body depending upon the water temperature. Furthermore, with water
immersion, the influence of the external hydrostatic forces of the water changes fluid
distributions and dynamics in the body and as such hormonal responses. Finally, the
greater the level of physical fitness an individual exhibits, typically the less the
magnitude of the hormonal response to an exercise session. With increases in an
individual’s physical fitness level, there is a greater degree of sensitivity within the
neuroendocrine system and target tissue receptor responsiveness due to increased
receptor expression (Goodman 2002; Hackney and Lane 2015); hence, less hormone
is necessary to invoke needed physiological accommodations.

3 Hormonal Exercise Response Model

As already noted, there is a multitude of hormone changes in a single exercise

session, primarily increased circulating blood levels (N.B., although typically insulin
becomes decreased during an exercise session). Many of these hormonal responses
are not independent of one another but are highly interrelated and interdependent. To
illustrate this point, what is termed the Hormonal Exercise Response Model (HERM)
is presented herein. Essentially, this model describes how the hormonal responses to
Exercise and Neuroendocrinology 65

most exercise sessions can be organized into a series of three interactive phases
which invoke either differing responses or amplification of ongoing responses
(Hackney and Lane 2015).

3.1 Phase I

The first phase of this model deals with the hormonal response immediately at the
onset of exercise, with these responses taking just seconds to occur. These responses
revolve around the increased sympathetic nervous system activation that occurs with
the onset of bodily motion. This increased sympathetic nervous system activity can
also be a result of anticipation of the ensuing exercise—which is most certainly the
case in sports competition scenarios. This increased sympathetic nervous system
activity results in catecholamines (norepinephrine and epinephrine) released at target
tissues directly, as well as elevations in circulating catecholamines (specifically
norepinephrine) from so-called sympathetic “spillover” effects (Luger et al. 1988).
This effect is further amplified by the sympathetic connection to the adrenal
medullary gland which in turn adds to the circulating catecholamine (epinephrine
release via medulla is greater than norepinephrine) response. Simultaneous with
these sympathetic-adrenal medullary actions, pancreatic insulin secretion begins to
be inhibited, while glucagon secretion becomes stimulated, the latter resulting
mobilization of glucose for liver glycogen stores and fatty acid from adipocytes.
This entire process involves a feed-forward mechanism of the central nervous
system to drive these initial responses, although the events are also modified by
peripheral afferent neural input from sensory receptors, in particular, those of
skeletal muscle once movement commences (Luger et al. 1988; Hackney et al.
2011; Sutton et al. 1968).

3.2 Phase II

The intermediate or secondary phase takes slightly longer to develop but is still
typically very fast beginning usually in much less than a minute from the onset of
exercise. In this stage, the hypothalamus begins the process of releasing hormones
such as thyrotropin-releasing factor, corticotrophin-releasing factor (i.e., CRF; see
Table 1 for standard neuroendocrine abbreviations), and growth hormone-releasing
factor in an attempt to provoke changes at the anterior pituitary gland to stimulate the
release of specific hormones from this endocrine gland. As the pituitary begins to
respond to the hypothalamic stimulus there is the release of the various “trophic
hormones” from it into circulation. These hormones in turn begin to affect their
specific peripheral target endocrine glands to stimulate additional hormonal release.
One of the most rapidly acting elements in this cascade of events is the
hypothalamic-pituitary-adrenal cortical interaction where CRF brings about
66 A. C. Hackney

Table 1 Hormone (hormone-like agents) abbreviations utilized in neuroendocrinology. Note that

some hormones have more than one abbreviation, as well as more than one proper name. N.B.,
hormone abbreviations are not standardized within the scientific literature, as such, what is
presented is the most commonly cited term(s) used for specific hormones. This list is not exhaustive
but focuses on the hormones most prevalent in exercise-related research
Abbreviation Hormone
ACTH Adrenocorticotropic hormone
ALD Aldosterone
ADH Antidiuretic hormone
Arginine vasopressin
AMH Anti-Müllerian hormone
CCKCCK-PZ Cholecystokinin
CRH Corticotropin-releasing hormone
CRF Corticotropin-releasing factor
C Cortisol
CT Calcitonin
DHEA Dehydroepiandrosterone
DHEA-S Dehydroepiandrosterone-sulfate
E Epinephrine
Epi Noradrenaline
EPO Erythropoietin
E2 Estradiol-β-17
FSH Follicle-stimulating hormone
GHRL Ghrelin
GH Growth hormone
GIP Glucose-dependent insulinotropic polypeptide
GHIH Growth hormone-inhibiting hormone
GLP-1 Glucagon-like peptide 1
GnRH Gonadotropin-releasing hormone
GHRH Growth hormone-releasing hormone
hCG Human chorionic gonadotropin
IGF-1 Insulin-like growth factor-1
IL-6 Interleukin-6
LH Luteinizing hormone
MSH Melanocyte-stimulating hormone
NE Norepinephrine
NEpi Noradrenaline
OT Oxytocin
P4 Progesterone
17-OHP 17-Hydroxyprogesterone
PIH Prolactin-inhibiting hormone
PRH Prolactin-releasing hormone
PRL Prolactin
PTH Parathyroid hormone
Parathormone
PYY Peptide YY
(continued)
Exercise and Neuroendocrinology 67

Table 1 (continued)
Abbreviation Hormone
SS Somatostatin
SST
SOM
T Testosterone
Testo
T3 Triiodothyronine
T4 Thyroxine
Tetraiodothyronine
TRH Thyrotropin-releasing hormone
TRF Thyrotropin-releasing factor
TSH Thyroid-stimulating hormone

adrenocorticotrophic hormone release and that in turn ultimately brings about

cortisol release from the adrenal cortex. The duration of this phase is highly variable,
being dependent on the intensity of the exercise session and the overall physical
fitness level of the individual who is exercising, the phase length being prolonged the
greater the exercise intensity and, or the lower the fitness level of the individual
(Borer 2003; Galbo 1983; Luger et al. 1987; Deuster et al. 1989).

3.3 Phase III

As an exercise session is continued (i.e., extending the duration) there is a transition

beyond the intermediate phase into the third phase of response which is a more
prolonged state of responsiveness. In this third phase, the responses of the
sympathetic-adrenal axis are augmented by other hormones from the anterior and
posterior pituitary (e.g., growth hormone, prolactin, antidiuretic hormone) and the
peripheral endocrine glands subordinated to pituitary regulation (such as testoster-
one, thyroxine, triiodothyronine, insulin-like growth factor-1 [i.e., hepatic release of
insulin-like growth factor-1 (IGF-1) into blood; muscle release of mechano-growth
factor, a local IGF-1 variant]). As fluids shift from the vascular space and total body
water stores are compromised due to sweating for heat dissipation and inter-
compartmental fluid movement, the renin-angiotensin-aldosterone system (RAAS)
is activated (inducing vasoconstrictive actions and water resorption action at the
kidney). Additionally, during this phase, the skeletal muscle begins to release select
cytokines (e.g., interleukin-6 [IL-6]), hormonal-like agents, into the circulation
which affect other hormones to be released (e.g., cortisol) which can have actions
to signal energy substrate mobilization and well as immune response (Borer 2003).
Phases I and II of the model propose that neural factors are the primary stimuli
regulating the hormonal responses to exercise; however, in the third phase of the
model, there is an ever-increasing influence of the humoral and hormonal factors that
regulate the overall responses due to the changes in the internal milieu. This shifting
68 A. C. Hackney

of primary regulatory factors allows an increasing reliance upon feedback rather than
a feed-forward control mechanism to determine the magnitude of the hormonal
response. The influence of humoral and hormonal stimuli in modulating hormonal
levels is magnified as the exercise duration is extended and energy substrate avail-
ability issues cause shifts in energy fuel usage (i.e., decreased carbohydrate
increased lipid), or hydration issues affecting the blood volume (i.e.,
hemoconcentration and, or dehydration) begin compromising the thermoregulatory
ability and leading to greater heat storage within the body affecting hormonal
responses (e.g., increased heat storage increased norepinephrine, and epinephrine
release). Interestingly, the core temperature changes with exercise (and also via
ambient environment amplification) result in an exceedingly greater hormonal
response for several key endocrine agents (Borer 2003; Galbo 1983; Galbo et al.
1977; Luger et al. 1987; Daly et al. 2005).

3.4 HERM Synopsis

In summary, the proposed HERM model consists of: Phase I – an immediate phase
primarily driven by neural mechanism, Phase II – the intermediate phase involves
neural and pituitary mechanisms controlling responses, and Phase III – the humoral-
based adjustment phase involving principally more slow-acting pituitary mecha-
nisms. The model, while not perfectly inclusive of all hormonal responses, does
provide an organized framework for the endocrine responses to exercise activities
and helps to illustrate the highly interactive complexity of these responses. Further-
more, the HERM model gives the context for the sequence of changes and the
direction of change. However, it is important for scientists studying exercise hor-
monal responses to recognize that the intensity and duration of the exercise sessions
are critical factors in determining the magnitude of the hormonal change response
observed. The objective of this model is to provide a conceptual framework to aid
scientists in understanding the endocrine responses and reactivity to the stress of an
exercise session.

4 Recovery from Exercise

Findings from many research studies suggest the neuroendocrine response to an

acute exercise session appears very transient in nature and rebounds during the
recovery from exercise. That is, the hormonal levels return to baseline or slightly
below basal values relatively rapidly within 1 to 2 h (i.e., the latter being a biphasic
response event within the negative feedback regulatory system) (Goodman 2002).
The exception to these findings is when the exercise is highly demanding such as a
competitive event or exercising to exhaustion (Galbo 1983; Galbo et al. 1977). In
Exercise and Neuroendocrinology 69

such scenarios the recovery of the hormonal levels to normal, resting points can take
several days (Anderson et al. 2016).
Interestingly, it has been reported that if athletes performed two intense training
sessions (>75% maximal aerobic capacity [VO2max]) in a single day, their circulat-
ing cortisol levels were significantly depressed at night compared to daytime basal
levels. Furthermore, the more intense these day-time exercise sessions (i.e., higher
intensity of workload), the greater the magnitude of the night-time suppression
observed (Viru et al. 2007). While not typical in exercise programs, such exercise
training practices are something that does occur in the training regimes of elite
athletes (McKay et al. 2022).

5 Mechanisms of Hormonal Responses

The physiological mechanisms by which hormone levels (i.e., concentrations) in the

blood change during exercise are due to three factors: 1) alterations in circulatory
vascular fluid content, 2) rate of hormonal metabolic clearance, and 3) glandular
production/secretion responses. It is important to recognize that blood concentration
changes (increases) with exercise are not always due to the increased endocrine
gland secretion (N.B., a common belief; (Viru 1985)) (Borer 2003; McMurray and
Hackney 2000; Viru and Viru 2001).
Circulatory vascular fluid content alterations are a result of plasma fluid moving
into or out of the vascular spaces. Throughout an exercise session, it is common for
plasma volume “shifts” to occur, specifically a loss of plasma fluid, resulting in
hemoconcentration (increased levels) of any substance trapped within the blood
vessel. This would apply to large molecular weight hormones or hormones bound to
large molecular weight carrier proteins (e.g., >20,000 Da, but capillaries
[glomerular vs. systemic] vary on this point) (Kaufman and Lamster 2002; Renkin
1986). For example, in a 30-to 90-min exercise session of moderate intensity
(~50–60% of maximum) a 10–15% hemoconcentration effect of the blood could
be expected (Van Beaumont 1973; Dill and Costill 1974). This plasma volume
reduction is exacerbated if the ambient environment condition creates a greater
thermal load invoking a heavy sweating response and, or an individual does not
consume adequate fluids during exercise in an attempt to maintain hydration (Costill
et al. 1981). Conversely, during the recovery from exercise (when ample fluids are
consumed) there tends to be a rebound effect and fluid moves into the vascular space
to cause a hemodilution effect on substances such as hormones (Borer 2003;
McMurray and Hackney 2000; Viru and Viru 2001; Hackney and Viru 2008).
The rate of metabolic clearance of a hormone is a physiologic concept concerned
with hormone removal from the blood. Hormones are “taken up” by receptor
mechanisms at their target tissues which can implement physiological actions at
the tissue, what are termed downstream events (Goodman 2002). Additionally,
though, some clearance is through the degradation–deactivation removal process
at non-target tissues such as hepatocytes, or via renal filtration and clearance.
70 A. C. Hackney

Increases and/or decreases in the rate of metabolic clearance can consequentially

impact blood hormonal concentration dramatically (Cadoux-Hudson et al. 1985).
Glandular secretion involves the endocrine gland producing the hormone in
response to a stimulus and the gland secreting more of the hormone in the circulatory
system. This usually results in increases in blood concentration levels, but it is
possible for the rate of secretory increases and the rate of metabolic clearance
removal to match one another (Goodman 2002; Widmaier 1992). In such a case as
this, the concentration of the hormone in the blood does not seem to increase but the
turnover has, and the target tissues are being presented with greater amounts of the
hormone (Goodman 2002).
Regrettably, it is a prevalent belief that if hormonal levels increase in the blood,
then the physiological actions of that hormone are going to be activated (e.g.,
increased ["] cortisol → " catabolism). This is a gross oversimplification of endo-
crinological events concerning hormones. Indeed, hormonal concentration in the
blood is a key fundamental determinant of activation of physiological actions, but
not the only one; that is, in order for a hormone to initiate and activate a physiolog-
ical process in target tissue there must be:
(a) Adequate numbers of target tissue cells expressing functional receptors for the
hormone.
(b) Adequate numbers of functional receptors on the cells of target tissue.
(c) A high-affinity level of the receptors on the cells for the hormone.
(d) Sufficient post-receptor amplification mechanisms within the cells (Goodman
2002; Widmaier 1992).
This last point is extremely critical and can be influenced by the behavior and
actions of the exerciser. For example, if anabolism is to be initiated in the target
tissue, not only does an anabolic hormone need to be present, but adequate amounts
of amino acids must be consumed in the diet and be available for cellular mecha-
nisms (biochemical pathways, enzymes) to utilize in specific protein synthesis
processes. These downstream amplification mechanisms are essential for a positive
adaptation to occur in skeletal muscle, arguably the most critical tissue–organ
affecting exercise capacity (Brooks et al. 2004; Hackney and Constantini 2020).
Hormonal assessment has traditionally been collected on blood specimens
(plasma or serum). Contemporary technology has allowed saliva to be used as part
of the evaluation of endocrine function with exercise. The factors that affect drug
availability in saliva are generally true also for salivary hormones. Most hormones
enter saliva by passive diffusion across the acinar cells. Most of these hormones are
lipid-soluble (i.e., steroids). Small polar molecules do not readily diffuse across cells
and instead enter saliva through the tight junctions between cells (i.e., ultrafiltration;
Quissell 1993). The molecular weight cut-off for ultrafiltration is 100–200 Da. This
relatively small molecular size prevents many hormones from entering saliva from
serum by means of ultrafiltration. In addition, active transport does not appear to
facilitate hormone transfer into saliva (Vining and McGinley 1986).
Exercise and Neuroendocrinology 71

6 Sex and Exercise Endocrinology

6.1 Menstrual Cycle and Pregnancy

Adult men and women share a multitude of physiological similarities in how their
bodies function. Yet there are specific neuroendocrine differences that result in vast
hormonal differences between the sexes. Most obviously a majority of these hor-
monal differences revolve around the reproductive systems in men compared to
women. Women of reproductive age have a highly dynamic system for ensuring
menstrual cycle hormonal changes to allow uterine and follicle development. The
menstrual cycle can be divided into various phases based on the reproductive
hormonal change. This consists of a repeating pattern of menses to start the follicular
phase, followed by ovulation which leads into the luteal phase (Elliott-Sale et al.
2021). Evidence supports that the phase of the menstrual cycle influences to some
degree the magnitude of hormonal responses to an exercise session. For example,
during the luteal phase of the cycle, growth hormone and cortisol responses can be
elevated over that of the follicular (Hackney 2021; Bunt 1990), while the exercise-
induced suppression of ghrelin is blunted (Moniz et al. 2023). However, these
menstrual cycle phase effects on the hormonal responses to exercise are not univer-
sally reported (Kanaley et al. 1992a, b), which may relate in some instances to the
quality of the science being conducted on the menstrual cycle and exercise in women
(Elliott-Sale et al. 2021).
An in-depth discussion of the impact of pregnancy on the neuroendocrine system
is beyond the scope of this chapter. Nonetheless, it is important to mention, even if in
brief. As the mother goes through gestation, reproductive hormones such as
estradiol-β-17 and progesterone gradually increase to super-physiological levels as
do some non-reproductive hormones (Kumar and Magon 2012). While there is
growing research on the safety and efficacy of exercise during pregnancy, there is
limited work on exercise hormonal responses in pregnant women (ACOG 2015).
Interestingly it was reported from a study that cortisol and prolactin (two highly
reactive stress hormones) did not significantly change with maximal exercise to
volitional fatigue at 35 weeks of pregnancy. However, in this study, the resting levels
of these hormones were many-fold higher than non-pregnancy levels (Hackney et al.
1993). The authors speculated this might have represented some type of “physio-
logical ceiling effect” (i.e., resting levels of the hormones were at near maximal
glandular secretion and hence when stressed with exercise there was a limited ability
for further production).

6.2 Women Versus Men

Additionally, when comparing the sexes directly it is notable that women typically
have higher resting levels of growth hormone, estradiol-β-17, progesterone, luteinizing
hormone follicle stimulating hormone, androstenedione, IGF-1, prolactin, and leptin
72 A. C. Hackney

than men (Rifai 2018; Clinical Laboratory Reference Values 2019; Bunt et al. 1986;
Pincus et al. 1996). Conversely, women have lower testosterone levels than men.
However, it should be noted these differences can be influenced by age, menstrual
cycle phase-status, and, or if hormonal contraceptive is being used by a woman (Lucis
and Lucis 1972; Gardner and Shoback 2018).
These initial hormone differences (just noted) in a resting state can result in
exercise response changes differing if men and women are directly compared
(Rifai 2018; Clinical Laboratory Reference Values 2019; Vislocky et al. 2008).
Interestingly, there are scenarios where no pre-exercise resting differences existed
between the sexes; however, during and at post-exercise hormone response differ-
ences develop (e.g., norepinephrine and epinephrine) (Horton et al. 1998). The
causality of this occurrence is unclear but may related to muscle mass size differ-
ences between the sexes, or muscle fiber type variations, and/or cardiovascular
system disparities (e.g., in general women have smaller hearts, less blood volume,
and cardiac output than men) (Huxley 2007).
Currently, the quantity and extent of exercise neuroendocrinology research on
women is lacking. This is regrettable as women represent 50% of the population of
the world and their engagement in exercise and sport is growing exponentially and
shows no signs of abatement, and as such there deserves to be more robust research
on female exercise physiology (Cowley et al. 2021; Laxdal 2023).

7 Neuroendocrine Dysfunction with Exercise

It has been well established that excessive exercise training, or even appropriate
training without adequate nutritional caloric intake results in neuroendocrine dys-
function (Stellingwerff et al. 2021). Most prominent in these effects are disruptions
to reproductive hormones resulting in lower resting levels of testosterone,
estradiol-β-17, progesterone, luteinizing hormone, and follicle-stimulating hormone
in both sexes (Borer 2003; Hackney 2017). These resting changes are not limited to
just reproductive hormones as triiodothyronine has been found to be reduced as has
leptin, while cortisol, prolactin, and growth hormone are elevated. The changes also
manifest as altered exercise responses for some hormones (Meeusen et al. 2010),
which can disrupt energy metabolism regulation as well as the adaptive response to
exercise training (Hackney 2006; Stellingwerff et al. 2021). This entire area of
research regrettably is understudied and is limited in application and practicality as
published papers tend to be underpowered or are case studies.

8 Conclusions

The neuroendocrine system is highly responsive to stress, and the hormonal changes
it evokes are means to accommodate and adjust (deal with) the disruption of
homeostasis brought on by stress exposure. Physical exercise is a stressor to the
Exercise and Neuroendocrinology 73

human body (Hackney 2006). In many connotations, the term stress is viewed or
interpreted as negative, however, exposure to exercise, in a repeated fashion has
been shown to be beneficial and lead to many positive health outcomes (Surgeon
General Report 1996; Brooks et al. 2004). Hence, not all stress exposure is bad and
within realms that the body can cope with and adapt to.
The hormonal changes induced by exercise are multi-faceted and bring about
diverse changes principally in energy metabolism, cardiovascular-respiratory param-
eters, and thermoregulatory temperature control as homeostatic adjustment
responses. The physiological changes in these systems allow humans to perform a
variety of exercise forms (modalities) across a spectrum of intensity efforts, and in
varying environments.
The neuroendocrine system shows a great deal of plasticity and is able to adapt to
the stress of repetitive exercise exposure. These adaptations allow for a more
sensitive response to physical exercise sessions, and more tightly regulated accom-
modations in the physiological systems being controlled. The result of which is an
improved exercise capacity and tolerance. The system, however, is not perfect and
can be compromised in functionality and subsequent physiological effects by poor
exercise approaches (e.g., too much) or dietary nutrition inadequacies (Mountjoy
et al. 2023). This said, the neuroendocrine system is remarkable in its ability to allow
us to change our physiological systems so we as humans can perform exercise.

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 Part II
Exercise and Laboratory Studies of
Mood and Cognition
Exercise and Acute Cognitive Enhancement

Jennifer L. Etnier , Samuel W. Kibildis, and Samantha L. DuBois

Contents
1 Introduction and Chapter Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
2 Historical Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
3 Acute Exercise and Executive Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4 Acute Exercise and Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
5 The Influence of Acute Exercise Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
6 Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
7 Why Study Exercise and Acute Cognitive Enhancement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Abstract Substantial research has explored the effects of a single session of exer-
cise on cognitive performance. Meta-analytic reviews provide summary statistics
relative to these effects when the cognitive task is performed while exercising and
when performed after exercise. When performed concomitantly the effects of exer-
cise are typically small or negative with the exception of moderate effects for speed
of cognitive performance during moderate intensity exercise. When cognitive per-
formance is assessed following the cessation of exercise, the effects are typically
positive. When considering the effects following exercise, most studies have focused
on executive function and episodic memory as the cognitive outcomes of interest
with meta-analyses supporting small-to-moderate benefits. When potential modera-
tors related to exercise parameters or participants characteristics are examined,
results suggest that 20 minutes of moderate to vigorous intensity exercise consis-
tently benefits performance with larger effects evident for executive function tasks
with higher cognitive demands, for long-term memory tasks when exercise is
performed prior to information encoding, and when considering individuals with
lower initial cognitive performance levels. These observed benefits are likely due to
the impacts acute exercise can have on physiological arousal, brain function, and
brain neurotrophic factors. Advancements in our understanding of the potential of a

J. L. Etnier (✉), S. W. Kibildis, and S. L. DuBois

Department of Kinesiology, University of North Carolina Greensboro, Greensboro, NC, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 79

Curr Topics Behav Neurosci (2024) 67: 79–102
https://doi.org/10.1007/7854_2024_492
Published Online: 31 August 2024
80 J. L. Etnier et al.

single session of exercise to benefit cognitive performance are important for exercise
prescription and to inform chronic exercise programs designed to benefit cognition.

Keywords Cognitive Performance · Executive Function · Memory ·

Physical Activity

1 Introduction and Chapter Overview

As discussed in the previous chapters, exercise has been shown to impact neuro-
transmitters, neuroendocrinology, and neurocircuitry. These impacts in the central
nervous system have the potential to influence cognitive performance in both the
short-term (acute) and the long-term (chronic). Cognitive performance is defined as
the performance of tasks that require mental action or brain activity and that
demonstrate proficiency in a variety of mental processes such as attention, executive
function, information processing, memory, and perception. In this chapter, we focus
on the effects of exercise on acute cognitive performance and look at cognitive
domains that have been consistently explored in the literature.
In the published literature on acute exercise and cognitive performance, the
cognitive domain that has received the most empirical attention is executive func-
tion. Executive function is defined as a higher order cognitive process that regulates
more basic cognitive functions and emotions toward goal-directed behavior. Several
cognitive abilities commonly included under the umbrella of executive function
include inhibition, planning, set shifting, and working memory. Inhibition is the
ability to restrain impulses and behaviors. Planning is defined as the ability to choose
the necessary actions and perform those actions in the correct order to achieve a goal.
Set shifting (sometimes referred to as cognitive flexibility) refers to the ability to
switch mental focus to adapt to changing situations. And lastly, working memory is
the ability to temporarily hold and manipulate a limited amount of information in
mind. This ability to actively manipulate information to meet task goals is what
characterizes working memory as an executive function ability and distinguishes it
from the other forms of memory we will review in this chapter. The research interest
in the effects of acute exercise on executive function probably reflects the perception
that exercise-induced effects on these higher order cognitive abilities are likely to
have the greatest impact on overall cognitive performance.
In addition to executive function, memory is another cognitive domain that has
recently received substantial attention in the acute exercise and cognition literature.
Memory is a broad cognitive construct that encompasses our ability to encode
(initially learn), consolidate (stabilize learned information into long-term memory),
and retrieve (access at a later time) information. Given the wide variety of informa-
tion we encounter on a daily basis, memory is often classified into different subtypes
according to the nature of the information involved. For example, episodic memory
is the ability to remember details of specific events and experiences (e.g., what you
Exercise and Acute Cognitive Enhancement 81

ate for dinner last night). In contrast, semantic memory refers to the ability to
remember general knowledge, concepts, and facts (e.g., your date of birth). And
finally, procedural memory is the ability to unconsciously remember information
necessary to perform different actions and skills (e.g., how to ride a bike). In addition
to classification according to the type of information to be remembered, memory is
also frequently classified according to the length of time the information needs to be
retained. Short-term memory typically refers to the retention of information for a few
seconds or 1–2 min after information encoding. In contrast, long-term memory is
characterized by the retention of information for longer periods of time, usually
several minutes, hours, or even days. The effect of acute exercise on memory
performance is particularly interesting because exercise-induced benefits may be
observed following an extended period of time after exercise cessation. In other
words, although most research suggests that the effects of acute exercise on overall
cognitive performance tend to be relatively transient (Chang et al. 2012a), evidence
also suggests that the effects on memory specifically may be more enduring with
larger effects reported for long-term memory than for short-term memory (Roig et al.
2013).
Due to the attention the cognitive domains of executive function and memory
have received in the acute exercise literature, this chapter will focus on the effects of
acute exercise on these cognitive abilities following the cessation of exercise. We
will set the stage with a brief historical overview of research investigating the effects
of acute exercise on overall cognitive performance. Then, we will transition to a
discussion of the effects of acute exercise on executive function and memory
specifically. We will examine meta-analytic reviews (quantitative reviews that
allow for the assessment of standardized measures of an effect which are called
effect sizes) assessing the effects of acute exercise on these cognitive abilities and
provide exemplars to demonstrate the types of empirical studies conducted in these
areas. We will also discuss the exercise parameters that may influence the overall
effect of acute exercise on executive function and memory, as well as the mecha-
nisms that may underlie the relationship between acute exercise and these cognitive
abilities. Finally, we will conclude the chapter with a consideration of the practical
implications of acute exercise-induced benefits to executive function and memory
and why continuing to study the effects of acute exercise is important for achieving
the long-term goal of developing precise chronic exercise recommendations that
maximize the benefits of exercise to cognitive performance.

2 Historical Overview

From a historical perspective, there has been interest in the potential effects of acute
exercise on cognitive performance for almost a century. Early studies were focused
on understanding the relationship between muscle tension and mental performance
efficiency with the earliest work looking at how performance of a mental task
influenced performance of a muscular tension task. Subsequent research then flipped
82 J. L. Etnier et al.

the question by exploring how performance of a muscular tension task influenced

mental task performance. For example, Bills (1927) published a study examining the
effects of a handgrip dynamometer task on addition, associative memory (i.e.,
remembering the relationship between unrelated items), and perception performance
when these cognitive tasks were performed during the handgrip exercise. A similar
protocol was used in many of the early exercise and cognition studies (Bills 1927;
Bills and Stauffacher 1937; Courts 1939; Stauffacher 1937) in that they focused on
cognitive performance during very brief, high-intensity anaerobic exercises. Scien-
tists during this time were interested in identifying the optimal intensity of the
exercise, understanding the role of the demands of the cognitive task, and exploring
the influence of the fatigue level of participants. Since that early research, scientists
have begun to explore how other types of acute exercise with a wide range of
durations and intensities affect cognitive performance. They have continued to
explore how exercise affects cognitive performance when exercise and cognitive
tasks are performed simultaneously and have expanded the question to assess
cognitive performance following the cessation of exercise.
Meta-analytic reviews of this literature generally show that the effects of acute
exercise on cognitive performance during exercise are relatively small (Chang et al.
2012a) or negative (Lambourne and Tomporowski 2010; Loprinzi et al. 2019;
McMorris and Hale 2012). However, when studies are limited to those that measure
speed of cognitive performance during moderate intensity exercise, McMorris and
Hale do report a moderate benefit (effect size, ES = 0.48). These overall findings
may be explained by the reticular-activating hypofrontality model (Dietrich and
Audiffren 2011) which posits that during exercise, resources in the central nervous
system are prioritized to support the physical demands of the exercise itself thus
limiting the resources available for cognitive processing. According to this model,
performance on frontal-lobe dependent tasks (also referred to as explicit tasks which
include measures of executive function) is expected to be hindered when simulta-
neously completed with exercise. By contrast, performance on tasks that are not
frontal-lobe dependent (also referred to as implicit tasks which include speed of
performance measures for simple tasks) is expected to benefit from exercise due to
an exercise-induced release of catecholamines. Further discussion of the effects of
acute exercise on cognitive performance assessed during exercise is beyond the
scope of this chapter. Instead, we will focus on cognitive performance assessed
following the cessation of an acute bout of exercise.
Meta-analytic reviews focused on the effects of acute exercise on cognitive
performance following the cessation of the exercise bout are relatively consistent
in reporting small benefits (Chang et al. 2012a; Roig et al. 2013; Lambourne and
Tomporowski 2010; Loprinzi et al. 2019; McMorris and Hale 2012; Oberste et al.
2019), with the average effect size ranging from 0.10 to 0.52. Given that numerous
meta-analytic reviews have provided summary statistics relative to the effects of a
single bout of exercise on cognitive performance, Chang et al. (in press) conducted
an umbrella review of this literature (a meta-review of systematic reviews and meta-
analyses) and reported an overall effect size of 0.31. Examination of moderators
indicated that the largest effects were evident when cognitive performance was
Exercise and Acute Cognitive Enhancement 83

assessed following the cessation of exercise (ES = 0.30) as compared to during

exercise (ES = 0.03) and when either executive function (ES = 0.34) or attention
(ES = 0.34) was assessed. Effects for memory were also significant and positive
with an average effect size of 0.22.

3 Acute Exercise and Executive Function

The effect of acute exercise on executive function is a topic of significant interest in

the exercise and cognition literature. Evidence suggests that executive function
follows a common developmental pattern, as it emerges within the first few years
of life, strengthens throughout childhood and adolescence (Best and Miller 2010),
peaks in adulthood, and then declines with advancing age due to normal cognitive
aging or disease-related cognitive deficits, such as mild cognitive impairment or
Alzheimer’s disease (Buckner 2004; Kirova et al. 2015) (see Fig. 1).
The various cognitive processes involved in executive function can be assessed
with a wide range of cognitive tasks. Performance on many of these tasks can be
measured with both time-dependent (e.g., response time) and accuracy (e.g., number
of correct responses) scores to provide multiple estimates of executive functioning.
Interestingly, in some cases researchers will assess accuracy simply to ensure that
participants aren’t sacrificing speed for accuracy. Once they establish that accuracy
is maintained at a high level, they then present speed of performance data as the
primary outcome. In the acute exercise and cognition literature, researchers have
largely used measures of working memory and inhibition (Ishihara et al. 2021;
Moreau and Chou 2019) (e.g., Stroop Test) but have also been interested in assessing
set shifting (e.g., Wisconsin Card Sorting Test) and planning (e.g., Tower of
London Task).
Chang and colleagues conducted a study that serves as a useful exemplar of the
methodology commonly used in the acute exercise and executive function literature.

Fig. 1 Theoretical
depiction of the relationship
between age and executive
function ability
84 J. L. Etnier et al.

Fig. 2 The Tower of London Task requires the participant to move 3 beads on pegs from a starting
state (right) to a goal state (left) in a specified number of moves (2 moves in this example). The
tallest peg can hold all 3 beads, the middle peg can hold 2 beads, and the shortest peg can hold
1 bead. Only one bead can be moved at a time, and only the top bead on a peg can be moved

In this study, 42 young adults performed the Tower of London Task before and after
either cycling for 30 min at moderate intensity or reading exercise materials for the
same amount of time. During the Tower of London Task, participants are asked to
move beads on pegs from a starting state to a goal state in a prescribed number of
moves. The tallest peg can hold 3 beads, the middle peg can hold 2 beads, and the
shortest peg can only hold 1 bead. Only the top bead on a peg can be moved and
beads must be moved one at a time (see Fig. 2). Results showed that the acute
exercise group improved their performance on the Tower of London test from pre- to
post-exercise, while the reading group exhibited no change in performance.
The Stroop Test (Stroop 1935) and Wisconsin Card Sorting Test (WCST; Heaton
et al. (1993)) are widely used measures of executive function in the acute exercise
and cognition literature (Etnier and Chang 2009). When performing the Stroop Test,
participants are instructed to name colors as quickly as possible in three different
conditions. The Stroop Word condition displays color names written in black ink and
the participant must read the color name. The Stroop Color condition displays colors
in rectangles and the participant must identify the color. The Stroop Color-Word
condition displays color names printed in a different color of ink and the participant
must identify the color of ink. The Stroop Color-Word condition is considered a
measure of inhibition because the participant has to inhibit the prepotent response of
reading the color name.
The WCST is primarily a measure of set shifting but is also thought to reflect
inhibition, working memory, and selective attention (Miyake et al. 2000). During the
WCST, participants are required to sort 128 response cards based on one of three
characteristics (i.e., color, form, or number) present on 4 stimulus cards (see Fig. 3).
The experimenter provides feedback to the participants to let them know if their
response is correct or incorrect as they try to determine the characteristic of the card
Exercise and Acute Cognitive Enhancement 85

Fig. 3 The WCST includes 4 stimulus cards and 128 response cards to be sorted based on three
characteristics (i.e., color, form, or number)

being used for sorting (the sorting characteristic). The sorting characteristic changes
after every 10 responses.
In an acute exercise and executive function study conducted by Chang et al.
(2012b), researchers administered both the Stroop Test and the WCST to 40 children
with attention-deficit hyperactivity disorder (ADHD), a common neurobehavioral
disorder that is associated with deficiencies in executive function (Semrud-Clikeman
et al. 2008). Participants completed the Stroop and WCST both before and after
either running for 30 min at moderate intensity or sitting to watch a video about
exercise for the same amount of time. Results showed that the acute exercise group
exhibited greater improvements in pre- to post-condition performance on the Stroop
Color-Word condition and WCST compared to the seated rest group.
Interest in the effects of acute exercise on executive function and the large number
of studies conducted in this area have made it a topic worthy of meta-analytic review.
In an early meta-analysis examining the effects of acute exercise on cognitive
performance, Chang et al. (2012a) found a positive effect of acute exercise on
executive function during exercise (ES = 0.26), immediately following exercise
(ES = 0.19), and after a delay following exercise (ES = 0.17). It is worth noting that
this positive effect of acute exercise on executive function during exercise is
different from the effect of acute exercise on overall cognitive performance during
exercise which suggests that executive function is positively impacted regardless of
the timing of the exercise bout. Since this meta-analysis, three additional meta-
86 J. L. Etnier et al.

analyses have examined the effects of acute exercise on executive function specif-
ically (Ishihara et al. 2021; Moreau and Chou 2019; Ludyga et al. 2016).
In 2016, Ludyga et al. (2016) conducted a meta-analytic review of the literature
investigating the effects of moderate intensity acute aerobic exercise on executive
function, including both time-dependent and accuracy measures of set shifting,
inhibition, and working memory. Since executive function has been shown to
change across the lifespan, the moderating role of age in the acute exercise and
executive function relationship was examined. Age was categorized into four
groups: preadolescent children (6–12 years old), adolescents (13–17 years old),
young adults (18–35 years old), and older adults (50+ years old). The age range of
36–49 years old was not included as there were no empirical studies investigating the
effects of acute exercise on executive function for this age group. The moderating
role of fitness was also examined, as cross-sectional evidence has consistently shown
that higher levels of fitness are associated with better performance on executive
function tasks (Hillman et al. 2005; Huang et al. 2015). Fitness was categorized
according to maximal oxygen uptake (VO2max) into three groups: low-, average-,
and high-fit. The researchers included 40 studies and found that acute exercise had a
positive effect on both time-dependent (ES = 0.35) and accuracy (ES = 0.22)
measures of executive function. The specific executive function task used and the
fitness level of participants were not found to be significant moderators. However,
age was found to be a significant moderator but only for time-dependent measures of
executive function, such that older adults (ES = 0.67) and preadolescent children
(ES = 0.54) demonstrated the largest benefits from acute exercise. The effect was
small in young adults (ES = 0.20) and nonsignificant in adolescents.
While the meta-analysis conducted by Ludyga et al. (2016) specifically examined
moderate intensity acute exercise, Moreau and Chou (2019) conducted a meta-
analytic review of the effects of high-intensity acute exercise on executive function.
The authors chose to focus on high-intensity exercise because they argued that
shorter, high-intensity exercise may have the potential to help address the inactivity
crisis as it is more efficient and engaging than longer duration, lower-intensity
exercise while still conferring health benefits comparable to traditional longer
duration exercise. In this meta-analytic review, the researchers included over 1,100
participants from 28 studies comparing the effects of high-intensity exercise to low-
to-moderate intensity exercise and seated rest. A significant positive effect was
found for high-intensity acute exercise compared to seated rest (ES = 0.34), but
not compared to low-to-moderate intensity exercise (ES = 0.07). This lack of a
difference between the effects for high-intensity and low-to-moderate intensity
exercise suggests that acute exercise may benefit executive function regardless of
exercise intensity. The potential moderating role of exercise intensity will be
discussed in greater detail later in this chapter.
In a more recent meta-analysis, Ishihara et al. (2021) adopted a slightly different
approach and conducted a meta-analysis of individual participant data regarding the
effects of acute aerobic exercise on executive function. By using individual partic-
ipant data, as compared to a traditional meta-analysis based on comparisons among
studies, they were able to investigate how differences in baseline cognitive
Exercise and Acute Cognitive Enhancement 87

performance may impact the effects of acute exercise. Previous evidence demon-
strates that acute exercise may be more beneficial for individuals with worse
performance at baseline (Drollette et al. 2014). Furthermore, they assessed how
executive function task demands influenced the relationship between acute exercise
and executive function by grouping tasks as either high- or low-demand. They
hypothesized that acute exercise would confer greater benefits to higher-demand
executive function tasks. Like Ludyga et al. (2016), both time-dependent and
accuracy measures were considered in this review. Results demonstrated that acute
exercise improved response time, with greater improvements in response time
observed for tasks that placed higher demands on executive function and for
individuals with slower baseline response times. Additionally, while the main effect
of acute exercise on accuracy was not significant, the interaction between acute
exercise and baseline accuracy was significant, with greater improvements in accu-
racy after acute exercise observed for participants with lower accuracy at baseline.
Thus, performance at baseline was a significant moderator of the effect of acute
exercise on both time-dependent and accuracy measures of executive function. This
finding suggests that acute exercise may serve to improve executive function in those
most in need of that improvement.
Summarily, researchers have used a wide variety of tasks to assess the effects of
acute exercise on executive function in varying populations. Overall, the evidence
indicates that acute aerobic exercise can benefit various aspects of executive func-
tion. This acute exercise-induced benefit may be greatest for performance on tasks
that place higher demands on executive function (Ishihara et al. 2021) and for
individuals with lower levels of baseline executive function (Ishihara et al. 2021;
Ludyga et al. 2016). As such, future investigations may seek to explore the effects of
exercise in populations with weaker executive function abilities (e.g., children, older
adults, ADHD) and continue to investigate variables related to exercise and cogni-
tion that could moderate the effect of acute exercise on executive function.

4 Acute Exercise and Memory

As previously discussed, memory has received substantial attention in the acute

exercise and cognition literature in recent years. Specifically, research has primarily
focused on how a single session of exercise affects short- and long-term episodic
memory. As a reminder, episodic memory is the ability to remember details of
specific events or experiences, including contextual, temporal, spatial, and emotional
information about a past event/experience. For example, the ability to remember the
details of your 10th birthday party (where it was, what you did, who was there, a gift
you received, etc.) is an example of long-term episodic memory. In this chapter, we
consider episodic memory by describing meta-analytic reviews of this literature and
providing exemplars of studies exploring how the timing of the bout of exercise
relative to encoding and consolidation may influence the observed effects.
88 J. L. Etnier et al.

Additional information about exercise and memory can be found in Chapter “Exer-
cise and Memory” which considers memory more broadly.
A wide range of cognitive tasks have been used in the literature to assess the
effects of acute exercise on episodic memory. These tasks have employed a variety
of stimuli, including visual (e.g., objects and faces), auditory (e.g., words and
numbers), and spatial (e.g., locations and routes) information. One of the most
common episodic memory tasks used in the acute exercise literature is a word-list
learning paradigm, like the Rey Auditory Verbal Learning Test (de Sousa et al.
2012) or the California Verbal Learning Test (Delis et al. 1987). During these word-
list learning tasks, participants are exposed to a list of unrelated words (usually
15–20 words) and then immediately asked to recall as many words as they can
remember to assess short-term episodic memory. The list of words is then repeated
and recalled multiple times to measure learning with repeated exposure. Sometimes
participants are then exposed to a second list of unrelated words to assess proactive
(i.e., memory for previous information impairing learning of new information) and
retroactive (i.e., new information impairing memory for previously learned infor-
mation) interference. Finally, to measure long-term episodic memory, participants
can also be asked to recall the original list of words after a delay period of 15 min,
30 min, 24 h, or longer. In addition to word-list learning paradigms like this, other
common assessments of episodic memory found in the acute exercise literature
include visual object recognition tasks, number sequence tasks, and short story
learning tasks.
The results of early studies suggested that acute exercise had null or minimal
effects on memory performance when performance was assessed following a single
session of exercise (Etnier et al. 1997; Tomporowski 2003). Similarly, the meta-
analytic review conducted by Chang et al. (2012a) also found nonsignificant effects
of acute exercise on memory performance both immediately following exercise
(ES = 0.05) and after a delay following exercise (ES = -0.03). However, when
performance was classified according to the specific type of memory measure used,
acute exercise was found to have small to moderate positive effects on free recall
(ES = 0.49) and visual short-term memory (ES = 0.23) following exercise. This
meta-analysis therefore provided evidence that the effects of acute exercise on
memory are not domain general but vary based on the specific type of memory
ability being assessed.
In a more recent meta-analytic review, Roig et al. (2013) examined data from
22 studies exclusively focused on memory (episodic and semantic). Acute aerobic
exercise was shown to have an overall small positive effect on the memory of
healthy adults (ES = 0.22). When broken down by retention interval, acute exercise
was found to have a small positive effect on short-term memory (ES = 0.26) and a
moderate positive effect on long-term memory (ES = 0.52). This finding of a more
robust effect of acute exercise on long-term memory is particularly interesting
because it suggests that the benefits of acute aerobic exercise to memory are not
transient but can be relatively long-lasting. Unlike other cognitive abilities that see
the benefits of acute exercise dissipate after a few minutes (e.g., attention, executive
Exercise and Acute Cognitive Enhancement 89

Fig. 4 Schematic of the protocol typically used in studies examining the timing of acute exercise
relative to episodic memory encoding, consolidation, and recall. These studies frequently include
three conditions: acute exercise prior to information encoding, acute exercise after information
encoding during memory consolidation, and no exercise. The parameters of the acute exercise bout
can be manipulated to examine how different modalities, durations, and intensities of exercise
impact episodic memory performance. The delay between information encoding and recall can also
be varied to explore the durability of acute exercise effects on episodic memory

function, and processing speed), the benefits of acute exercise to memory may
persist even after an extended period of time has passed since exercise cessation.
It has been hypothesized that the durable effects of acute exercise on memory
exist because acute exercise confers benefits to both the initial encoding of infor-
mation and the ongoing memory consolidation process that continues after encoding
has finished. A substantial body of research has been conducted to test this hypoth-
esis by manipulating the timing of acute exercise relative to information encoding,
memory consolidation, and information recall. For example, in a study conducted by
Labban and Etnier (2011), young adults were randomly assigned to one of three
conditions: acute exercise prior to encoding a short story, acute exercise after
encoding a short story, or no exercise. Figure 4 depicts the protocol for these
conditions and the timing of exercise relative to encoding, consolidation, and recall.
Results showed that the young adults in the exercise prior to encoding group had
significantly better story recall 35 min after exposure to the story compared to the
young adults in the no-exercise group. No differences in story recall were found
between the exercise prior to encoding group and exercise after encoding group as
well as between the exercise after encoding group and the no-exercise group. This
finding therefore provides preliminary evidence suggesting that acute exercise
facilitates the greatest improvement in episodic memory when performed prior to
encoding and consolidation rather than during the consolidation process.
Continuing this line of research investigating the timing of acute exercise relative
to information encoding and memory consolidation, Labban and Etnier (2018) next
examined how acute exercise prior to encoding, acute exercise after encoding, and
90 J. L. Etnier et al.

no exercise impacted the word-list recall of younger adults 60-min and 24 h after
exposure to the list of words. In this study, the researchers implemented a within-
subjects design, whereby every participant completed each of the three exercise
conditions. Additionally, the implementation of a 60-min delay following exposure
to the to-be-remembered information provided adequate time for exercise comple-
tion and recovery prior to word recall so the effects of acute exercise on memory
consolidation could be better isolated from the potential confound of acute exercise
effects on information retrieval. Similar to the results of the previously discussed
study, the acute exercise prior to encoding condition had significantly better word
recall at the 60-min and 24 h delay intervals compared to the no-exercise condition.
No significant differences were found between the acute exercise prior to encoding
and acute exercise after encoding conditions, as well as between the acute exercise
after encoding and no-exercise conditions. This study therefore provided further
evidence that acute exercise benefits to episodic memory are greatest when exercise
is performed prior to information encoding. Furthermore, it also showed that acute
exercise benefits to long-term episodic memory can be observed for up to 24 h
following information exposure.
With numerous studies having been conducted to investigate how the timing of
acute exercise relative to encoding and consolidation affects episodic memory
performance, a meta-analytic review of the literature was conducted by Loprinzi
et al. (2019). Loprinzi et al. reported that acute exercise prior to information
encoding (ES = 0.11), during early consolidation (ES = 0.47), and during late
consolidation (ED = 1.05) enhanced episodic memory performance. In contrast,
acute exercise performed during information encoding had a negative effect on
episodic memory performance (ES = -0.12). While these summary statistics are
inconsistent with the results of the two previously discussed empirical studies that
found acute exercise prior to information encoding conferred the greatest benefit to
episodic memory, it is worth noting that this meta-analysis identified several vari-
ables that may moderate the temporal effects of acute exercise on episodic memory,
including age, exercise intensity, and retention interval (short-term or long-term
memory). For example, a significant positive effect for acute exercise prior to
information encoding was found for long-term memory (ES = 0.19) but not for
short-term memory (ES = -0.01). The temporal relationship between acute exercise
and episodic memory therefore appears to be influenced by complex interactions
between participant characteristics, exercise parameters, and features of the specific
memory task used.
To date, the vast majority of acute exercise and episodic memory studies have
been conducted with younger adults, with far fewer studies focusing on children and
older adults. However, children and older adults are potentially important target
populations for acute exercise studies due to the developing and declining nature of
their episodic memory abilities, respectively. In children, whose episodic memory
abilities are still developing as they mature, acute exercise may confer greater
benefits. Preliminary evidence is promising, as acute aerobic exercise has been
shown to benefit the word-list recall of preadolescent children (Etnier et al. 2014;
Pesce et al. 2009). In the study conducted by Pesce et al. (2009), children aged
Exercise and Acute Cognitive Enhancement 91

11–12 years completed a word-list recall task following three experimental condi-
tions: a physical education class involving aerobic circuit training, a physical
education class involving team games, and a no-exercise control condition. Results
showed that word recall immediately after exposure was higher following the team
games compared to the control condition, but word recall after a 12-min delay was
higher following both team games and aerobic circuit training compared to the
control condition. These findings suggest that acute exercise performed during
physical education classes may facilitate better episodic memory performance in
preadolescent students. Furthermore, the cognitive and social demands of the acute
exercise bout (i.e., team games versus aerobic circuit training) may also influence
acute exercise-induced benefits for children’s episodic memory performance.
In contrast to children whose episodic memory abilities are still developing, older
adults experience a decline in episodic memory as part of the normal cognitive aging
process. Acute exercise may therefore confer greater benefits to older adults by
reducing the severity of this age-related decline to preserve or even improve their
episodic memory abilities. Thus far, the preliminary evidence is positive as acute
aerobic exercise has been shown to benefit the word-list recall (Etnier et al. 2021)
and visual-image recall (Segal et al. 2012) of older adults. Using a similar experi-
mental design to the previously discussed Labban and Etnier study conducted with
younger adults, Etnier et al. (2021) examined how acute exercise prior to encoding,
acute exercise after encoding, and no exercise influenced older adults’ performance
on a word-list learning paradigm where word recall occurred immediately after
exposure and 24 h later. Results showed that in the acute exercise prior to encoding
condition, older adults had significantly better immediate recall compared to the
acute exercise after encoding and no-exercise conditions. For 24-h recall, word
recall was significantly better in the acute exercise prior to encoding condition than
the after encoding condition, which in turn was significantly better than the
no-exercise condition. The authors concluded that the benefits observed for acute
exercise performed after encoding were significant in this study, but not in their
previous studies, because of the deleterious effect of aging on episodic memory
performance.
Collectively, the existing body of research demonstrates that acute aerobic
exercise can benefit certain aspects of episodic memory, especially when performed
prior to information encoding and when recall occurs after a delay period. However,
more research across the lifespan is needed so we can better understand how acute
exercise affects the episodic memory of specific age groups, especially children and
older adults. In addition to age, specific exercise parameters (e.g., modality, duration,
and intensity) have also been shown to influence the effect acute exercise has on
episodic memory and other cognitive abilities, including executive function. We will
therefore now turn our attention to the research examining the moderating effects of
these exercise parameters on the acute exercise and cognitive performance
relationship.
92 J. L. Etnier et al.

5 The Influence of Acute Exercise Parameters

Although the previously discussed empirical studies and meta-analytic reviews

provide some insights about relevant moderators of the acute exercise and cognitive
performance relationship, we will focus on moderating variables that are relevant to
the exercise experience itself. When considering the effects of acute exercise on
cognitive performance, important parameters that should be considered include the
exercise modality (i.e., type of exercise), intensity (e.g., light, moderate, vigorous),
and duration (e.g., 10 min, 30 min).
Exercise modality is a relatively complex construct because of the various ways
in which exercise type can be categorized. For example, meta-analytic reviewers
have coded exercise modality to allow for comparisons between aerobic, anaerobic,
muscular resistance, combination exercise, and accelerometer-based reports of phys-
ical activity (Chang et al. 2012a), aerobic versus cognitively-engaging exercise
(de Greeff et al. 2018), and aerobic versus resistance exercise (Oberste et al.
2021). Results from these reviews must be interpreted cautiously because of the
overlap between exercise types and other relevant parameters like exercise duration
and intensity. Furthermore, since the vast majority of the research has focused on
aerobic exercise (e.g., 92% of effects in Chang et al.; 83% of effects in de Greeff
et al.; 77% of effects in Oberste et al. 2021), it is likely that the results for all other
types of exercise are unreliable due to the small number of studies. Overall, when
limited to studies focused only on aerobic exercise, findings are consistent with the
overall conclusions drawn from meta-analytic reviews regarding small to moderate
benefits of acute exercise on cognitive performance (Chang et al. 2012a; de Greeff
et al. 2018; Oberste et al. 2021; Chueh et al. 2022).
Taking a somewhat unique approach to the definition of exercise type,
Lambourne and Tomporowski (2010) made comparisons between the effects of
ergometer cycling and treadmill running on cognitive performance following exer-
cise. Results showed that while both modes of exercise yielded small benefits,
effects were larger for cycling than for treadmill running. The authors attributed
this difference to the potentially larger attentional demands required to sustain a
prescribed pace and maintain balance while running on a treadmill compared to the
lesser attentional demands required to cycle on a stationary ergometer. Subse-
quently, when examining the effects of acute exercise on episodic memory specif-
ically, Loprinzi et al. (2019) also compared effect sizes between ergometer cycling
and treadmill-based walking or running. When exercise was performed prior to
information encoding, memory benefits were evident for studies that implemented
cycling (ES = 0.46) but not for studies that used treadmill walking or running.
Similarly, when exercise was performed in the early stages of memory consolida-
tion, the authors found that benefits were only evident for studies using cycling
(ES = 1.17) but not for studies examining treadmill walking or running. When
exercise was performed in the late stages of memory consolidation, there were no
effects for cycling, but treadmill walking or running resulted in a large benefit
(ES = 1.31). To the best of our knowledge, there is currently no published empirical
Exercise and Acute Cognitive Enhancement 93

study that has directly compared the effects of treadmill exercise to cycling exercise
on acute cognitive performance. In fact, to expand upon this point, there are
relatively few studies that have directly compared the cognitive benefits of acute
exercise relative to exercise modality (Hung et al. 2020). This lack of direct
comparisons between different modes of exercise is important because of the
challenge of basing conclusions on summary statistics. That is, findings across
meta-analytic reviews are somewhat limited because they can only be examined at
the levels identified as relevant by the reviewers and because they cannot account for
third order variables (e.g., exercise duration, exercise intensity, cognitive domain)
that might offer alternative explanations of the findings. Additional theory-driven
research in this area would therefore be of benefit as we continue to work toward the
goal of being able to prescribe exercise as a means of improving cognitive
performance.
Like exercise mode, relatively little attention has been paid to understanding the
potential dose-response relationship between exercise duration and cognitive per-
formance. Meta-analytic reviews can again provide us with summary information.
Chang et al. (2012a) categorized acute exercise duration as 0–10, 11–20, and
>20 min and found positive effects only for exercise of 11–20 min or >20 min.
Specific to studies looking at memory, Loprinzi and colleagues (2019) compared
effects for short (<20 min), medium (20–40 min), and long (>40 min) acute exercise
durations and reported that effects were only significant and positive for long
duration exercise performed during the early memory consolidation period. By
contrast, Roig and colleagues (2013) reported that effects for short-term memory
were largest when exercise duration was <20 min while the effects for long-term
memory were best when exercise was <20 min or 20–40 min. Specific to executive
function tasks, Moreau and Chou (2019) categorized duration as 0–5, 6–10, 11–20,
and >20 min and found no significant differences as a function of acute exercise
duration. These contrasting findings are perplexing and again emphasize the chal-
lenge of using summary statistics to answer questions about moderating variables.
When summarized across meta-analytic reviews, the umbrella review conducted by
Chang et al. (in press) reported that benefits were evident for exercise performed for
more than 20 min (ES = 0.28) and exercise performed for less than 20 min
(ES = 0.20). This summary finding suggests that benefits are generally evident for
acute exercise regardless of exercise duration.
Given the aforementioned limitations of using summary data to inform our
understanding of the dose-response relationship between exercise duration and
cognitive outcomes, empirical studies are important to allow for a direct comparison
across levels within a single study. Chang et al. (2015) conducted a series of studies
comparing the effects of no exercise with exercising at moderate intensity for 10, 20,
or 45 min. In a sample of young men (20–22 years), Chang et al. showed that both
speed of performance and accuracy on the congruent and incongruent trials of the
Stroop Test were significantly better after 20 min of exercise compared to all other
durations of exercise. In a sample of late middle-aged adults (55–65 years), Chang
et al. (2019) found that response times on the congruent, neutral, and incongruent
trials of the Stroop Test were best after 20 min of exercise. Chen et al. (2018)
94 J. L. Etnier et al.

conducted a similar study with late middle-aged adults and reported that 20 min of
exercise resulted in the best performance on a different measure of executive
function (task switching). Overall, these findings are consistent in suggesting that
when considering 10, 20, or 45 min of moderate intensity exercise, beneficial effects
for executive function are greatest after 20 min of exercise.
The final exercise parameter we will discuss is exercise intensity. Exercise
intensity has been extensively studied with numerous empirical studies comparing
performance across intensity levels and many meta-analytic reviews considering
intensity as a moderator. Results from meta-analytic reviews suggest that intensity
moderates the observed effects of acute exercise on cognitive performance. Across
all cognitive outcomes, Chang et al. (2012a) found that only very light, light, and
moderate intensity exercise resulted in small positive benefits for cognitive perfor-
mance performed immediately after exercise. However, when cognitive performance
was assessed after a delay following exercise cessation, benefits were observed for
light, moderate, hard, and very hard intensity exercise. These findings are intriguing
because they may indicate that when cognitive performance is performed immedi-
ately after exercise, a lower-intensity exercise is recommended, but that for more
enduring effects, higher intensity exercise is better. Focusing on studies examining
memory performance, Roig et al. (2013) reported that effects for short-term memory
were best at low intensity. They also found that intensity did not impact long-term
memory. By contrast, in their meta-analytic review that was also focused on
memory, Loprinzi et al. (2019) found that vigorous intensity exercise resulted in
the largest memory benefits for exercise performed prior to encoding (ES = 0.54)
and during early consolidation (ES = 1.09). It is difficult to compare these findings
to those of the meta-analysis conducted by Roig and colleagues because the analyses
weren’t conducted separately for short- and long-term memory. However, if most of
the studies included in the Loprinzi et al. review were looking at long-term memory,
then these results would be consistent. In a meta-analysis looking at the executive
function performance of children following acute exercise, Moreau and Chou (2019)
found that effects for both lower-intensity and high-intensity exercise were
beneficial.
Results from the Chang et al. (in press) umbrella review suggest that there is no
significant difference in effect sizes as a function of intensity. However, despite the
lack of significance of this finding, an examination of the effect sizes suggests that
there might be something of an inverted-U relationship between intensity and
performance with the largest effects evident at an intensity described as moderate
to vigorous (ES = 0.57). On either side of this intensity level, effects were smaller:
ES = 0.28 for moderate intensity, ES = 0.24 for vigorous to maximal intensity, and
ES = 0.10 for very light to light intensity exercise. Again, these summary findings
across meta-analytic reviews are somewhat limited because they can only be exam-
ined at the levels identified as relevant by the reviewers and because they cannot
account for third order variables (e.g., exercise duration, exercise intensity, cognitive
domain) that might offer alternative explanations of the findings. That is, for
example, if most of the studies performed at moderate to vigorous intensity also
measured executive function while the studies at other intensity levels measured
Exercise and Acute Cognitive Enhancement 95

information processing, the findings that we are attributing to intensity could actu-
ally be reflective of the cognitive domain assessed rather than intensity per se.
To address the limitations of using summary data from meta-analytic reviews, it is
important to also consider empirical studies in which intensity level was manipulated
within a single study so that the inferences can be directly linked to intensity level
per se and not to other variables. Chang and Etnier (2009) conducted a study that
explored the effects of exercise intensity of resistance exercise on cognitive perfor-
mance on two tasks that assess different cognitive domains. They randomly assigned
young adults to either no exercise or 40%, 70%, or 100% of 10-repetition maximal
effort on six resistance exercises. Following the treatment condition, participants
performed the Stroop Test and the Paced Auditory Serial Addition Task (PASAT).
The PASAT is a task that requires participants to calculate the sum of every pair of
single digit numbers as they are read in a single list. So, for example, as a string of
numbers are read, they would say aloud the sum of the first and second number, they
would then hear the third number and have to say the sum of the second and third
number, they would then hear the fourth number and have to say the sum of the third
and fourth number, and so on. This is a very challenging task that assesses attention
and working memory. Results from this study showed that there was a significant
linear relationship between exercise intensity and performance on the Stroop neutral
condition and a significant curvilinear relationship for the Stroop incongruent
condition. For the PASAT, the relationship was curvilinear and explained increas-
ingly more of the variance as the task difficulty increased. These findings are
fascinating because they suggest that the relationship between intensity and perfor-
mance may be task-specific with more simple measures of information processing
benefiting from higher intensity levels of exercise while more complex measures that
require executive function benefit most from moderate intensity exercise.
It is actually very challenging to study exercise intensity or exercise duration in
isolation because the two so naturally go together in real-world exercise activities. In
other words, if people are exercising at a high intensity, they typically only exercise
for a short period of time. By contrast, if exercising at a low intensity, they are able to
exercise for a longer period of time. For this reason, in an important extension to this
literature, Chang et al. (2023) conducted a study in which they held exercise volume
constant to test the effects of bouts of acute exercise that differed in terms of both
intensity and duration. Older adults carrying a genetic risk factor for Alzheimer’s
disease (the epsilon 4 allele of apolipoprotein E) were asked to perform the Tower of
London task (a measure of executive function) following four treatment conditions.
The treatment conditions were rest for 30 min, lower-intensity exercise for 40 min,
moderate intensity exercise for 30 min, or higher intensity exercise for 16 min.
Results showed that performance was better for all exercise conditions relative to the
control condition and there was no difference in performance between the exercise
conditions. This study is intriguing because the focus was on exercise volume rather
than looking at intensity with duration held constant or duration with intensity held
constant.
96 J. L. Etnier et al.

6 Mechanisms

While empirical studies and meta-analyses have provided consistent evidence of

acute exercise-induced benefits to cognitive performance, less is known about the
mechanisms underlying this relationship. To date, several potential mechanisms
have been proposed, including both psychological and biological changes following
a single session of exercise. From a psychological perspective, acute exercise may
enhance arousal to facilitate better cognitive performance (Audiffren 2009;
McGaugh 2006). According to the Inverted-U Hypothesis initially applied to the
relationship between exercise and cognitive performance by Davey (1973), exercise
can induce small to large changes in arousal that can then positively or negatively
impact cognitive performance. Exercise at low intensities may not increase arousal
enough to enhance cognition. However, high-intensity exercise may stimulate too
much arousal and be detrimental to cognitive performance. Moderate intensity
exercise is therefore predicted to stimulate the optimal amount of arousal to enhance
cognitive functioning. As was previously discussed, this hypothesis is somewhat
supported by evidence from an umbrella review (Chang et al. (in press)).
Regarding executive function, the effect of acute exercise on neural activation has
been extensively examined using electroencephalogram (EEG). EEG is a neuroim-
aging technique that measures electrical signals produced by the brain on the scalp in
real time. Given the distance between the sites producing the signals and where the
signals are measured on the scalp, EEG may be limited with regard to spatial
resolution, but the technique has strong temporal resolution. Specifically, most of
this research has used event-related potentials (ERPs), which represent the electrical
activity of large groups of neurons that can be broken down into time-locked
components. ERPs are used to assess the electrical activity of the brain in preparation
for, or in response to, a stimulus or response (Coles et al. 1990). When exploring the
relationship between acute exercise and executive function, the most well-studied
ERP component is P3 (also known as P300). This is a positive-going deflection that
occurs approximately 300 ms after the presentation of a stimulus with a topograph-
ical maximum over the parietal region (Polich and Kok 1995). The P3 is thought to
represent the allocation of attentional resources during stimulus engagement (Polich
2007). Meta-analytic reviews show that acute exercise leads to decreased P3 latency
and increased P3 amplitude, with this increase in P3 amplitude associated with better
executive function (Kao et al. 2022; Martínez et al. 2023). The nature of the P3
component and the changes observed following acute exercise suggest that acute
exercise may improve the allocation of attentional resources which subsequently
leads to improvements on executive function tasks. Other ERP components that have
been assessed in the acute exercise and executive function literature include N2 (also
known as N200, which is thought to relate to inhibition), contingent negative
variation (CNV), and N450. Results for these other components are less conclusive,
though there is some evidence of acute exercise effects on N2 and N450 (Chang et al.
2017). Ultimately, ERP evidence supports an acute exercise effect on neural
Exercise and Acute Cognitive Enhancement 97

activation that relates to improvements in executive function, and researchers con-

tinue to use ERPs to explore the nuances of the acute exercise and cognition
relationship.
In the acute exercise and episodic memory literature, acute exercise has been
proposed to stimulate several physiological changes that benefit the underlying
neural processes that give rise to our episodic memory abilities. For example,
previous research has shown that acute aerobic exercise can increase levels of
brain-derived neurotrophic factor (BDNF), a protein that plays an important role in
regulating and maintaining several different neural processes that enable learning
and memory (Dinoff et al. 2017; Szuhany et al. 2015). Additionally, a neuroimaging
technique known as functional magnetic resonance imaging (fMRI) has been used to
investigate how acute aerobic exercise influences neural activation during episodic
memory tasks. fMRI is a noninvasive technique that indirectly measures neural
activity by detecting changes in blood flow to different brain regions in response
to changes in neural activity. This change in blood flow at the site of neural activity
produces a signal (i.e., the blood oxygen level-dependent signal) that can be mea-
sured with fMRI to provide insight into different aspects of brain function during
cognitive tasks. In a study conducted by Slutsky-Ganesh et al. (2020) using fMRI,
acute aerobic exercise performed both before and after encoding was shown to
improve the word-list recall of younger adults and reduce neural activation in
brain regions that support memory processing, including the lingual gyrus which
plays a role in the encoding of visual memories as well as the superior temporal
gyrus and planum temporale which are involved in auditory processing and lan-
guage. This reduction in neural activation coupled with improved memory perfor-
mance suggests that acute aerobic exercise may enhance younger adults’ neural
efficiency during episodic memory tasks. Acute aerobic exercise may therefore
induce rapid physiological adaptations that enhance the neural processes underlying
episodic memory.

7 Why Study Exercise and Acute Cognitive Enhancement

Thus far, we believe this review has demonstrated that engaging in a single session
of exercise can benefit cognitive performance following exercise cessation. Meta-
analytic reviews and empirical studies have shown that this acute exercise-induced
benefit extends to specific aspects of both executive function and episodic memory
performance. Research has also identified several moderating variables that can
influence the effect acute exercise has on cognitive performance, including the
exercise parameters of modality, duration, and intensity. Furthermore, we have
briefly discussed some of the potential mechanisms through which acute exercise
may enhance cognitive performance. However, at this point in the chapter you may
be asking yourself, “Why is understanding the effects of acute exercise on cognitive
performance important?”. This is an excellent question!
98 J. L. Etnier et al.

First, understanding the effects of acute exercise on cognitive performance has

important practical implications for improving our performance on everyday tasks
that require cognitive processing. For example, young adults in college are fre-
quently required to take exams to assess their learning. If we consider the results of
the previously discussed Labban and Etnier (2018) study that examined the effects of
acute exercise on young adults’ long-term episodic memory, then it might be
beneficial for young adults to exercise prior to studying for an exam in order to
enhance their memory for the studied information 24 h later. Similarly, the findings
of the study conducted by Pesce et al. (2009) with elementary school children
suggest that incorporating exercise sessions into the school day (e.g., physical
education classes, recess time, movement breaks) can enhance children’s learning
and memory. Research examining the effects of afterschool exercise programs has
also shown that acute exercise can improve children’s performance on executive
function tasks and mathematics assessments, as well as benefit certain markers of
brain function (Davis et al. 2011; Hillman et al. 2014). Acute exercise-induced
benefits to episodic memory and executive function may therefore have positive
implications for the academic performance of children and young adults.
The practical applications of acute exercise enhancements to cognitive perfor-
mance do not just include students in academic settings but can also be extended to
the daily functioning of the rapidly expanding older adult population. As will be
discussed in more detail in a later chapter focused on exercise and age-related
cognitive declines (see Chapter “Exercise and Protection from Age-Related Cogni-
tive Decline”), older adults are susceptible to declines in cognitive performance as
part of the normal aging process. However, if we consider the results of the study
conducted by Etnier et al. (2021), acute exercise may be a useful strategy for
mitigating some of the normal age-related declines in episodic memory experienced
by older adults. Engaging in acute exercise may therefore help older adults better
perform everyday tasks that require episodic memory (e.g., remembering items on a
grocery list, remembering the location of their parked car). Recent investigations
have also found a positive effect of both acute aerobic and resistance exercise on the
executive function performance of older adults with mild cognitive impairment (Tsai
et al. 2018). Acute exercise-induced enhancements to older adults’ cognitive perfor-
mance therefore have important implications for the maintenance of daily function-
ing and overall quality of life.
In addition to these everyday practical applications, examining the effects of
acute exercise on cognitive performance is also critical to achieving the long-term
goal of being able to prescribe chronic exercise as a strategy for improving cognitive
performance. The physiological changes that accompany a single session of exercise
may be the building blocks for the chronic exercise-induced brain changes that
facilitate long-term benefits to cognitive performance (El-Sayes et al. 2019). Study-
ing the effects of acute exercise can therefore further our understanding of the
mechanisms through which chronic exercise confers enduring benefits to cognitive
performance. Furthermore, acute exercise studies allow us to examine which exer-
cise parameters are optimal for enhancing specific aspects of cognitive performance.
Subsequently, we can begin to develop precise exercise recommendations that
Exercise and Acute Cognitive Enhancement 99

maximize the benefits of chronic exercise for cognitive performance. For example,
meta-analytic reviews (Chang et al. 2012a; Roig et al. 2013) and empirical studies
(Etnier et al. 2021; Callow et al. 2022) suggest that 20 min of moderate intensity
aerobic exercise may be optimal for eliciting acute exercise-induced benefits to the
episodic memory of older adults. Chronic aerobic exercise interventions aimed at
improving the everyday memory function of older adults may therefore want to
design exercise programs that encourage older adults to engage in 20 min bouts of
moderate intensity aerobic exercise several days per week. However, before we can
achieve this long-term goal of prescribing precise chronic exercise programs to
enhance cognitive performance, more research examining moderating variables
and underlying mechanisms of the acute exercise-induced cognitive enhancements
is needed.

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Exercise and Acute Affect

Steven J. Petruzzello and Jonathan R. North

Contents
1 Issues of Conceptualization: Affect, Emotions, or Moods? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2 Categorical Versus Dimensional Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3 Issues of Measurement: Generalized or Specific? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3.1 Generalized Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3.2 Exercise-Specific Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
4 Temporal Dynamics of Affective Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5 Research on Affective Responses to Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.1 “Real World,” Free-Living Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.2 Before- and After-Exercise Affective Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.3 In-Task Exercise Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6 Making a Place for Genetic Contributions to Affective Responding . . . . . . . . . . . . . . . . . . . . . . 118
7 What About High-Intensity Interval Exercise/Training (HIIE/HIIT)? . . . . . . . . . . . . . . . . . . . . . 119
8 Where To From Here? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Abstract The study of the affective impact of physical activity and exercise has a
long and fraught history. In this chapter we outline some of the longstanding issues,
in the hopes that research moving forward will be more mindful of these.
Included are: (a) what we are actually trying to assess; (b) measurement issues;
(c) the timing of affective measurement; (d) research that highlights what we know
and don’t know; and (e) suggestions for moving forward.

Keywords Ecological Momentary Assessment · Genetics · Measurement ·

Temporal Dynamics

If you are in a bad mood, go for a walk. If you are still in a bad mood, go for another walk.
Attributed to Hippocrates

S. J. Petruzzello (✉) and J. R. North

Department of Kinesiology and Community Health, University of Illinois at Urbana-
Champaign, Urbana, IL, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 103
Curr Topics Behav Neurosci (2024) 67: 103–124
https://doi.org/10.1007/7854_2024_493
Published Online: 31 July 2024
104 S. J. Petruzzello and J. R. North

According to Ekkekakis and Brand (2019), the question “How does exercise
make people feel?” led to the development of the field of study known as exercise
psychology in the 1960s. The vast majority of that early research focused on
examining whether exercise led to reductions in negative emotions, namely anxiety
and depression. While there was nothing inherently wrong with this line of inquiry,
particularly considering the prevalence of such mental-health problems, this
approach was also rather limiting as there is potentially much more than people
might feel as a result of exercise or, more broadly, physical activity. For example,
one of the most consistently reported effects from exercise, even at lower intensities,
is an increased feeling of energy. Robert Thayer referred to this phenomenon as the
“energizing effect” of exercise (Thayer 2001), paradoxical in that expending energy
could leave one feeling more energetic. What follows is an overview of some of the
major issues in studying the impact of physical activity and exercise on affect along
with a brief overview of the literature and recommendations for future research in
this domain.

1 Issues of Conceptualization: Affect, Emotions, or Moods?

The literature examining feeling states associated with physical activity and exercise
has been messy and confusing, in large part because of the equating of the terms
affect, emotion, and mood. An uninformed reading of studies would lead one to
believe that these terms all refer to the same thing (see 3, 4), which of course they do
not. While affect, emotion, and mood are all feeling states and are related to one
another, each has important differences from the others. These terms, and the
constructs they represent, are distinct and should not be used as if they were
synonyms. Indeed, an entire volume has been devoted to this very issue because
of its importance and should be required reading for those working in this area
(Ekkekakis 2013).
Emotions (e.g., fear, guilt, pride) are brief states of feeling that are not always
present. Importantly, an emotion is elicited following an appraisal where something
(e.g., object, person, or event) is judged to either directly impact or have the potential
to impact, an individual’s well-being (Lazarus 1991). As such, an emotion is an
immediate, often fairly intense but short-lived, response to some stimulus (Scherer
2005) (e.g., an exam elicits anxiety, winning the lottery elicits joy, completing a
challenging workout elicits a sense of accomplishment) that requires some level of
cognitive input. Simply put, emotions occur following a cognitive evaluation ascrib-
ing a level of meaning to an occurrence.
Moods (e.g., irritation, cheerfulness) are also feeling states and, like emotions,
have a cognitive basis, and can augment or impede goal-directed behavior. While
moods are present most of the time, they are different from emotions in at least three
important ways:
Exercise and Acute Affect 105

1. While emotions are usually brief, moods typically occur over a longer time frame,
lasting for hours or days (Nowlis and Nowlis 1956).
2. Whereas the cause of an emotion is often identifiable, the cause of a mood is
sometimes unable to be determined (Morris 1992).
3. The intensity and variability of emotions are greater than moods (Nowlis and
Nowlis 1956).
Affect is the most basic element of all feeling states and is always present (Russell
and Barrett 1999). Distinguished from emotions and moods, affect is a general
“valenced” response (i.e., good–bad, positive–negative, pleasure–displeasure). As
such, affect subsumes all emotions and moods. Affect is considered more basic than
emotion in that it is evolutionarily more primitive and does not require any cognitive
input (Russell 2003). The primitive nature of affect is adaptive, much like a reflex.
Consider that an immediate response to pain – that it is unpleasant – does not require
any cognitive input to feel unpleasant. A valenced response is an affect, but only
becomes an emotion or a mood once some level of cognitive elaboration takes place
(Ekkekakis and Petruzzello 2000).
It could be argued that prior to 2000, the vast majority of what was examined
regarding the impact of exercise on feeling states was exclusively about emotions
and moods (e.g., anxiety, depression). The implicit assumption was that exercise
could potentially reduce anxiety or depression but wouldn’t have an impact on any
other affective states (e.g., exercise would not improve perceptions of energy,
increase feelings of relaxation, or minimize a sense of fatigue). Very little work
had taken a broader perspective to first determine if such a focus on specific feeling
states was even warranted. That began to change when the focus of research went
from discrete states (i.e., a categorical approach) to a perspective that could theoret-
ically capture a broader range of affective states (i.e., a dimensional approach). The
dimensional approach assumes that affective states are interrelated and can be
accurately captured by a small number of dimensions (as few as two), thereby
providing a more encompassing picture of the affective dynamics occurring as a
result of a bout of exercise. With as few as two dimensions (e.g., valence, activation),
a bout of exercise might be shown to result in increased energy during and imme-
diately upon completion of, and increased relaxation during the recovery from, the
activity.

2 Categorical Versus Dimensional Approaches

We, and others, argued at the time that dimensional models provide an opportunity
to study affective phenomena in a more desirable manner (see Biddle and Mutrie
(2001); Ekkekakis and Petruzzello (2002)). Even earlier, Gauvin and Brawley
(1993) noted the utility of the dimensional approach to examining affect in the
exercise domain:
106 S. J. Petruzzello and J. R. North

[The dimensional] approach seems better suited to the understanding of exercise and affect
because the models stemming from it are intended to be broad, encompassing conceptual-
izations of affective experience. Because the affective experience that accompanies exercise
has not been thoroughly described, a model of affect that has a wider breadth is more likely
to capture the essence of exercise induced affect than a model that, at the outset, limits the
focus of investigation to specific emotions. (p. 152)

The model adopted and still primarily being used is the 2-dimensional circumplex
model of affect (Ekkekakis and Petruzzello 1999, 2002; Russell 1980, 1997).
Essentially, the model posits that the orthogonal dimensions of affective valence
(pleasure–displeasure) and activation (low–high) can be used to capture affect
through the various combinations of the dimensions. What results are 4 quadrants:
pleasant–activated (e.g., excited, enthusiastic, energetic); pleasant–unactivated (e.g.,
relaxed, calm, tranquil); unpleasant–unactivated (e.g., tired, fatigued, bored); and
unpleasant–activated (e.g., anxious, tense, nervous). As such, the circumplex model
provides a more general representation of affect and is able to capture both positive
and negative affective states. Furthermore, the dimensions of valence and activation
can each be assessed with a single-item measure, thus allowing for more frequent
assessment as well as assessments before, during, and after exercise.

3 Issues of Measurement: Generalized or Specific?

There is a plethora of measures available for assessing affective states, including

more generalized measures and supposedly “exercise-specific” measures.

3.1 Generalized Measures

Measures of mood, emotion, or affect that are not specific to any particular context
are considered “general” measures. The most used measures in the exercise literature
include the Profile of Mood States (POMS), the Positive and Negative Affect
Schedule (PANAS), and the Activation–Deactivation Adjective Check List
(AD ACL). Of course, this does not include the State-Trait Anxiety Inventory or
the Beck Depression Inventory, but these are not included here because they are
specific to anxiety and depression, not affect more generally.
Profile of Mood States The POMS (McNair et al. 1971) is one of the most
frequently used questionnaires in the exercise (and sport for that matter) psychology
literature. It was originally developed for use in psychiatric populations, particularly
military veterans with anxiety or post-traumatic stress disorder (and formerly known
as the Psychiatric Outpatient Mood Scale). Despite being designed to capture feeling
states relevant in assessing the effects of psychotropic drugs, the POMS has been
routinely used to examine mood changes in response to various exercise
Exercise and Acute Affect 107

manipulations for nearly 40 years. The POMS, comprised of a 65-item adjective

rating scale, yields scores on six different mood subscales. Five of the subscales
assess negative moods (tension–anxiety, depression–dejection, anger–hostility,
fatigue–inertia, and confusion–bewilderment) with only one assessing positive
mood (vigor–activity).
Each of the 65 adjectives (e.g., exhausted, alert, terrified, ready to go, miserable,
tense, confused, uneasy, fatigued) is rated on a 5-point scale ranging from 0 (not at
all) to 4 (extremely), according to how the individual feels. The instructions given
for making the assessments (i.e., response set) can be varied so that the respondent
reflects on how they feel “right now,” “today,” “over the past week,” “over the past
month,” “over the past year,” or even “over a lifetime.” While it is not designed for a
specific context, a problem with the POMS is that it only assesses six distinct mood
states. Its use in an exercise study thereby implicitly assumes that one or more of the
six mood states measured are influenced by an exercise manipulation. Of course,
these six states likely do not reflect the entire domain of mood. Furthermore, the
POMS is problematic because of its length. Thus, assessing mood multiple times in a
single exercise session creates participant burden. Even though shorter and alterna-
tive versions are available, they remain limited in the range of moods that they assess
(see Ekkekakis (2013) for a detailed critique).
Positive and Negative Affect Schedule The PANAS (Watson et al. 1988) is
another relatively popular measure of feeling states in the exercise domain. Much
shorter than the POMS, this 20-item questionnaire was developed to capture the
two-dimensional (positive affect, negative affect) model proposed by Watson and
Tellegen (1985). It therefore assesses two orthogonal (i.e., conceptually indepen-
dent) dimensions: positive affect (PA; enthusiastic, alert) and negative affect (NA;
anger, disgust). Respondents, according to how they feel, rate each of the 20 adjec-
tives (e.g., interested, distressed, excited, jittery, ashamed) along a 5-point scale,
ranging from 1 (very slightly or not at all) to 5 (extremely). Response sets range from
“you feel this way right now, that is, at the present moment” to “you generally feel
this way, that is, how you feel on average.” Although the PANAS provides a broader
capture of potential feeling states than the POMS, it only assesses the high-activation
ends of PA (e.g., excitement, enthusiasm) and NA (e.g., nervousness, fright), but not
the low-activation ends (e.g., PA: relaxation, calmness; NA: sadness, tiredness).
Watson and Clark created a modified version, the PANAS-X (Watson and Clark
1994) to capture each dimension more fully, but the revised measure has been
infrequently used in the exercise literature.
Activation–Deactivation Adjective Check List (AD ACL) Thayer (1986, 1989)
created the AD ACL, using a theoretical framework incorporating two bipolar
dimensions of activation and arousal (see Fig. 1). The dimension of Energetic
Arousal (EA) is designed to capture feelings ranging from energy, vigor, and
liveliness to feelings of fatigue and tiredness. An important distinction for the
exercise domain is that Thayer proposed EA to reflect changes in gross physical
activity. The second dimension referred to as Tense Arousal (TA) is designed to
capture feelings ranging from subjective tension to placidity, quietness, and stillness.
108 S. J. Petruzzello and J. R. North

Fig. 1 The circumplex model of affect. (Adapted from (Ekkekakis and Petruzzello 2002))

The two dimensions were thought to vary as a function of energy expenditure.

Specifically, Thayer proposed they would be positively related (i.e., EA and TA
both either increase or decrease) from low to moderate levels and negatively related
from moderate to high levels of energy expenditure (i.e., EA increases, TA
decreases). The AD ACL is the 20-item measure developed to capture the various
feeling states characterized in the 2-dimensional model. Respondents rate the way
they are feeling using a 4-point scale ranging from “definitely feel” to “definitely do
not feel.” The resultant scoring provides values for both EA and TA, along with the
component subscales of Energy and Tiredness (i.e., EA dimension) and Tension and
Calmness (i.e., TA dimension). Given its more complete capture of possible feeling
states, it is puzzling why this measure has not been used more frequently by exercise
researchers.
Feeling Scale Finally, the FS (Hardy and Rejeski 1989) is a single-item measure of
valence or hedonic tone (good–bad/pleasant–unpleasant). In this regard, it is much
like a visual analog scale. While it is often thought to be an “exercise-specific”
measure, it is hardly context-specific. Responses are made along an 11-point con-
tinuum ranging from -5 (very bad) to +5 (very good), with 0 as a neutral midpoint.
It was designed for use as an in-task (e.g., during exercise) measure of affective
valence and has been used extensively in studies examining affect during acute
exercise bouts.
Exercise and Acute Affect 109

3.2 Exercise-Specific Measures

There was a movement in the early 1990s that led to the development of several
“exercise-specific” self-report measures of feeling states. This was driven by two
major concerns with existing general self-report instruments: (1) measures like the
POMS and the PANAS were not sensitive enough to exercise stimuli, containing
irrelevant items or items that were often unchanged as a result of exercise manipu-
lations; and (2) exercise has unique and distinct properties that available measures
failed to detect. In other words, the argument was made that feeling states (i.e.,
affect) are changed in the exercise context in ways that are distinct from other
contexts.1 Out of this dissatisfaction, three multi-item scales – the Exercise-induced
Feeling Inventory (EFI), Subjective Exercise Experiences Scale (SEES), and Phys-
ical Activity Affect Scale (PAAS) – and one single-item scale – Feeling Scale (FS) –
were developed.
Exercise-Induced Feeling Inventory The EFI (Gauvin and Rejeski 1993) was
developed as a 12-item measure of exercise-induced feeling states, composed of
four subscales (positive engagement, revitalization, physical exhaustion, and tran-
quility). Each of these subscales was thought to represent the affective experience
associated with exercise that was not adequately captured with existing instruments.
These subscales are supposedly analogous to enthusiasm, energy, fatigue, and
calmness (Gauvin and Spence 1998).
Subjective Exercise Experiences Scale The SEES (McAuley and Courneya 1994)
was also developed as a 12-item measure of the subjective experiences unique to
exercise (with supposed attention to the positive dimensions of affect resulting from
exercise), comprised of three subscales (positive well-being, psychological distress,
and fatigue). Psychological well-being is analogous to positive affect, whereas
psychological distress is analogous to negative affect. An extensive discussion of
the numerous issues inherent in both the EFI and the SEES is available in separate
articles by Ekkekakis and Petruzzello (2001a, b).
Physical Activity Affect Scale Lox et al. (2000), attempting to exploit the “unique”
aspects of the EFI and the SEES while simultaneously reducing the overlap between
them, developed the PAAS, another 12-item exercise-specific measure consisting of
the four EFI subscales and the psychological distress subscale of the SEES. The
PAAS has not been used extensively in the literature to this point.
A shortcoming of these exercise-specific scales is the fact that each was devel-
oped in the absence of any theoretical framework (see Ekkekakis and Petruzzello
(2000, 2001a, b) for extensive critiques). Interestingly enough, neither the EFI,
SEES, nor PAAS has actually addressed, in any substantive manner, the two

1
It is worth noting that no evidence was (or has been) shown that exercise has such distinct, unique
properties. As such, the already existing affect measures should work well in assessing any affective
changes occurring as a result of exercise.
110 S. J. Petruzzello and J. R. North

concerns (see above) that led to their development. What these instruments have
done, more than anything else, is create additional confusion and messiness in an
already messy area of research. Ekkekakis has gone to great lengths to highlight the
importance in deciding on the most appropriate affect measure to use in their
research (see (Ekkekakis 2013)).

4 Temporal Dynamics of Affective Responses

Timing when affective responses are measured is particularly important, not only for
understanding the temporal dynamics of affective responses to exercise but also for
examining whether any consistent dose–response effects may occur. As Ekkekakis
and Brand noted (Ekkekakis and Brand 2019), timing of affective assessments in
much of the research was restricted to before and after an acute bout of exercise due
to the cumbersome nature of the oft-used multi-item measures. Systematic investi-
gation of affect is now more routinely done before, during, and after a bout of
exercise.
As has now been shown repeatedly, the affect experienced during an exercise
bout may be rather different from what is seen if only before- and after-exercise
assessments are made. As shown in Fig. 2, if only before- and after-exercise
responses were assessed (Path A), the assumption would be that the exercise resulted
in an increasingly more pleasant affective state. However, Path B and Path C show
that the same exercise, for 2 different people (or potentially even the same person on
different days), yields much different affective responses during the activity, even

Fig. 2 Potentially divergent patterns of affective dynamics to the same exercise bout
Exercise and Acute Affect 111

though the affective state at the end and during recovery is the same. This clearly has
important implications for exercise prescription. An individual with an affective
pattern revealed in Path B (i.e., decreasing pleasantness/increasing unpleasantness),
even with the rebound seen afterward, might be less likely to do such an activity
again. As Emmons and Diener (1986) showed, time spent engaging in various
activities is predicted by how people feel when doing them. And of course, Williams
et al. (2008) showed that even a small increase in pleasantness during treadmill
walking predicted increased time spent being active 6 and 12 months later. The post-
activity pleasant feelings might not be enough to “override” the unpleasant feelings
experienced during the activity.
All told, the “methodological platform” for guiding the study of affective
responses to exercise, originally outlined by Ekkekakis and Petruzzello (1999) and
reiterated numerous times since (e.g., (Ekkekakis et al. 2011)), has been nicely
encapsulated by Ekkekakis and Brand (2019). In sum, they note that such investi-
gations should: (1) utilize a dimensional approach (e.g., affect circumplex); (2) make
repeated affective assessments (i.e., before, during, and after); (3) examine patterns
of variation as well as group level changes; and (4) standardize the intensity of the
exercise itself with more individualized metabolic landmarks (e.g., ventilatory
threshold).

5 Research on Affective Responses to Exercise

5.1 “Real World,” Free-Living Responses

As noted at the outset, physical activity and acute bouts of exercise have long been
believed to create a “feel better” effect. However, there has been a growing recog-
nition of the fact that physical activity and exercise do not always result in pleasant
feelings (Ekkekakis and Brand 2019; Dunton et al. 2023). Indeed, for some people
(e.g., sedentary, highly deconditioned individuals) and for some types of physical
activity (e.g., high intensity), physical activity and exercise can result in rather
unpleasant feelings (e.g., (Ekkekakis et al. 2011; Ekkekakis and Lind 2006)). With
increasing access to technology that is both mobile and wearable, investigators have
leveraged such technological advances to study affective responses to physical
activity “in the wild,” that is, in response to everyday physical activity experiences
people have outside of controlled laboratory environments (Dunton 2017; Liao et al.
2015). This methodology, called experience sampling or ecological momentary
assessment (EMA), often pairs accelerometers with smartphones to capture an
individual’s experiences (e.g., affective states, context, perceptions) at various
times during their normal daily routines, including before, during, and after physical
activity. Many of these studies use a variation of random prompting schemes, what
Dunton et al. (2016) describe as interval-contingent sampling [i.e., prompts given at
preset times (e.g., daily at 8:00 a.m., 4:00 p.m.), signal-contingent sampling (i.e.,
prompts randomly throughout the day), or event-contingent sampling [i.e.,
112 S. J. Petruzzello and J. R. North

individual is tasked with completing survey during or following a predetermined

behavior (e.g., bout of physical activity)]. A more recent strategy, context-sensitive
EMA (CS-EMA) automatically prompts the individual to respond based on infor-
mation from a smartphone or other devices or sensors (e.g., accelerometer), allowing
collection of information related to specific behaviors (e.g., exercise, sedentariness)
within specific contexts (Dunton et al. 2016). For example, if the accelerometer
indicated a certain level of movement, a prompt would be sent to the smartphone
requesting a response from the participant. As noted by Dunton et al. (2023), such
“emerging technologies pose incredible opportunities for real-time, real-world inter-
ventions to enhance how one feels while engaging in physical activity or to boost the
effects of those affective states on future behavior.”
An initial review (Liao et al. 2015) analyzed the early research utilizing EMA to
study the relationships between affect and physical activity within a relatively short
time frame from the physical activity stimulus itself. The review included studies
where (a) affective states and subsequent physical activity were examined and
(b) affective states following physical activity were studied. Liao et al. concluded
that when positive affective states were reported, there was a greater likelihood of
engaging in physical activity within the following several hours; negative affective
states appeared unrelated to subsequent physical activity. Additional studies from
this review examined affective states following physical activity, with Liao et al.
concluding that higher positive affect (e.g., greater feelings of energy) generally
occurred for the subsequent several hours. Reductions in negative affect following
physical activity were not consistently seen in these studies.
Perhaps more than anyone else, Genevieve Dunton and her team have pioneered
EMA research examining physical activity and affect. Building from the 2015
review, Liao et al. (2017a) conducted an EMA study with a relatively large sample
(N = 110) of non-active adults (~40 years old; engaged in <150 min·week-1 of
physical activity). Both light (LPA) and moderate-to-vigorous (MVPA) physical
activity were captured via accelerometry, with random smartphone prompts
(8 prompts within a 15.5 h time period for 4 consecutive days) to assess affective
states [e.g., positive affect, negative affect, energy, and fatigue; “how __________
(happy/stressed/sad/cheerful/angry/tired/calm/energetic/tense) were you feeling?”]
experienced just prior to the prompt. More MVPA took place within the 15 min
following responses indicating greater positive affect coupled with lower negative
affect and fatigue. Greater amounts of LPA and MVPA were related to higher
feelings of energy for up to 30 min following the activity. In a separate study,
Liao et al. (2017b) assessed current physical activity level and affect (e.g., happy,
stress, energetic, tired) as well as MVPA 6 and 12 months later. Using random
prompting across 4 days, they were able to examine reported affect (via EMA
prompts) at times when participants reported performing physical activity (e.g.,
exercise, sports, walking), as well as the extent to which these affective responses
during activity were associated with MVPA (via accelerometry) measured 6 and
12 months later. They showed that those who reported feeling energetic during
physical activity were performing more daily MVPA 6 and 12 months later. In
addition, less negative affect (assessed as anxious, stressed, angry, depressed) during
Exercise and Acute Affect 113

physical activity was associated with more daily MVPA minutes 12 months later.
They interpreted this as reflecting an increase of 91 min per week of MVPA
12 months later for every decrease of 1 standard deviation in negative affect during
physical activity. Dunton et al. (2023), in discussing this work, proposed that a
reduction of ~1/3 standard deviation in negative affect (as assessed in the Liao study
(Liao et al. 2017b)) would result in 30 more min/week of MVPA, the equivalent of
~200 min/week in overall physical activity (including light intensity). This is again
more evidence of the importance of the affective response during physical activity
and its impact on future physical activity behavior. As Liao et al. (2015) stated
“Knowledge gained from this topic could offer valuable insights for promoting daily
physical activity adoption and maintenance in non-clinical populations.” (p. 1).
Reichert et al. (2017) sought to differentiate physical activity in the form of
exercise from non-exercise physical activity (NEA; walking to the bus stop) and
whether there was any differential relationship with affect (which they incorrectly
refer to as “mood”). A sample of adults (N = 93, 23.4 years, 62% female) wore an
accelerometer and were prompted over a 7-day recording period to report their
affective states (well–unwell; content–discontent; full energy–without energy;
awake–tired; relaxed–tense; calm–agitated) using a visual analog scale format
(score of 0–100) and a sophisticated sampling scheme. Prompts were triggered
based on location (using GPS information), at fixed times (8:00 a.m., 10:20 p.m.),
and every 40–100 min throughout the day. Reichert et al. reported that exercise
activity resulted in increased valence (i.e., greater pleasantness) and calmness,
whereas NEA increased perceptions of energy and wakefulness but decreased
calmness. They noted that it may be worthwhile to distinguish between exercise
activity and NEA as they seemingly have different impacts on affect.
As Dunton noted in her 2017 paper, a limitation of EMA is that it is a time-
intensive methodology (Dunton 2017). It is also an invasive methodology. However,
it has the potential to not only reveal more within-person variability than more
traditional laboratory-based approaches, but to also better account for dynamic
change. All of this could assist in better explaining and predicting physical activity
and its effects, something existing theories have not done particularly well to date.
Next, we turn to the more traditional approach to studying affective responses to
exercise. The emphasis is on research that examined varying levels of exercise
intensity, duration, or their combination on affective responses. Separate sections
focus on research examining pre- and post-exercise affective responses and more
recent studies that also examine affective responses during exercise.

5.2 Before- and After-Exercise Affective Responses

Research, primarily in non-clinical samples, has generally shown that exercise

results in an increase in positively valenced affective states (e.g., energy; see Reed
and Buck (2009); Reed and Ones (2006) and Chapter “Psychedelic-associated
Affective and Anxiety Disorders”) and a reduction in negatively valenced affective
114 S. J. Petruzzello and J. R. North

states (e.g., tension). This is particularly the case when the exercise intensity is light
to moderate in nature (e.g., up to ~60–65% of maximal capacity) or is based on a
relative workload (e.g., %VO2peak). As intensities increase to higher levels, feelings
of fatigue are often increased. However, as Ekkekakis and Petruzzello (1999)
pointed out, fitness mediates this effect at the high intensity end of the continuum
when absolute intensities are used (i.e., less fit individuals experience significant
increases in fatigue); fitness has no effect on higher intensities that are relativized.
Another important factor in all of this is when the post-exercise measure is taken.
These more negatively valenced feeling states are usually only seen immediately
post-exercise, are often gone within 5 min after completion of the exercise bout, and
completely reversed thereafter (i.e., increased energy).
As alluded to earlier, an interesting effect of exercise on affect is the paradoxical
energizing effect. Perhaps the first study to demonstrate this effect showed that
10 min of brisk walking at a self-selected pace significantly elevated feelings of
energy for up to 120 min following the walk (Thayer 1987). As noted by Thayer
(2001), moderate amounts (both in duration and intensity) of aerobic exercise
usually energize the exerciser. Saklofske et al. (1992) also showed increased energy,
along with decreased tension (both assessed via the AD ACL), following walks of
4 and 10 min in duration. We have shown (Ekkekakis et al. 2000) in a series of
studies including more naturalistic as well as controlled laboratory settings that
10 to 15 min walking consistently resulted in increased activation and more positive
affective valence, essentially reflecting increased energy and decreased tension
(using the AD ACL, FS, FAS). The typical finding is that positive affect tends to
increase from pre- to post-exercise following exercise intensities that are more
moderate in nature (Reed and Ones 2006; Reed 2013). Stated another way, posi-
tively valenced affective states (e.g., energy, vigor, exhilaration) are increased,
whereas negatively valenced affective states (e.g., fatigue, tension) are either
reduced or unchanged, following moderate-intensity aerobic exercise (see also
Reed and Ones (2006); Reed (2013)). Immediately following high-intensity exer-
cise, negative affective states are often increased while positive affective states are
decreased (e.g., (Acevedo et al. 1994)), especially in individuals who are less fit. It
isn’t unusual to see, in more fit individuals, that positive affect may be improved
following high-intensity exercise (see (Ekkekakis and Petruzzello 1999)).
Backhouse et al. (2007) suggested that this might just as likely reflect the relief
that the exercise bout is over.
Of course, there are numerous studies that have assessed feeling states before and
after exercise using measures that have already been described as problematic for
various reasons (e.g., POMS, PANAS). This is a potentially defensible position
when the sample being examined has a psychiatric diagnosis (e.g., (Brellenthin et al.
2021; Crombie et al. 2018, 2019, 2021; Meyer et al. 2016)). However, given the
explicit focus of the current chapter, these studies are cited for the interested reader,
but are not discussed in the context of affective responses to exercise.
Exercise and Acute Affect 115

5.3 In-Task Exercise Responses

One of the greatest conundrums for the field is the fact that exercise generally makes
people feel better once they have finished. This should result in more people
exercising, but that is not the case (see, for example, Backhouse et al. (2007)). As
Thayer (2001) put it, “The extensive evidence about the value of exercise should
have the gyms packed, the running tracks crowded, and the sidewalks filled with
throngs of people walking. But they aren’t” (p. 32). We now know that it may very
well be that even though people feel better after exercise, how they feel during
exercise may be part of the problem. The work of Emmons and Diener (1986) nicely
pointed out that the affect experienced during an activity is a good predictor of future
engagement in that activity. As postulated by hedonic theory (Ekkekakis 2009;
Kahneman 1999; Williams 2008), a person is not likely to continue an activity that
is not fun to do or isn’t enjoyable. Despite the abundance of research examining pre-
to post-exercise changes in affect, studies examining “in-task” affective responses
have been rare, although that has been changing (see Ekkekakis et al. (2011)).
One reason for the change has been the development and use of single-item or
very brief multi-item self-report scales for measuring affect. This has made the
assessment of affect during exercise more viable. The Feeling Scale has been
extensively used in such investigations, often being coupled with a measure of
arousal/activation (e.g., Felt Arousal Scale; (Svebak and Murgatroyd 1985)) to
allow a dimensional assessment of affect. The replicable finding, routinely shown
in a variety of samples and across various types of exercise (e.g., (Ekkekakis et al.
2011; Benjamin et al. 2012; Sheppard and Parfitt 2008a, b); see Ekkekakis (2013)),
from this research is that, as exercise intensity increases, affect becomes progres-
sively less positive/more negative (as measured by the FS) and more activated
(as assessed by the FAS). It is also worth noting that, while use of single-item scales
has been criticized, there is a growing body of literature showing them to be valid
and reliable measures (Allen et al. 2022).
Another important issue in the study of affective responses has been the “pre-
scription” of exercise intensity. Traditionally, the intensity of an exercise bout has
been determined as a percentage of some maximal value (e.g., heart rate or maximal/
peak aerobic capacity). Assigning an exercise intensity as a percentage of this
maximal capacity has been thought to relativize the workload so that two people
with different maximal capacities end up exercising at similar metabolic levels. This
assumption has been demonstrated to be inaccurate, with individuals exercising at
the same relative workload having very dissimilar metabolic responses (Ekkekakis
and Petruzzello 1999; Katch et al. 1978). For example, exercise at a “moderate”
intensity (e.g., 60% VO2peak) leaves some individuals working almost exclusively
aerobically, while others may need a significant degree of anaerobic metabolism to
complete the same workload. It has been demonstrated that as the degree of reliance
on anaerobic metabolism increases (e.g., as shown in increasing levels of blood
lactate), affective valence gets progressively less positive/more negative (Ekkekakis
et al. 2011).
116 S. J. Petruzzello and J. R. North

A much more useful metabolic landmark in the study of exercise intensity effects
is the lactate threshold (Ekkekakis 2003), that point where blood lactate concentra-
tions increase faster than the rate it can be removed from the blood. As a result of this
excess lactate, anaerobic energy systems are increasingly utilized during exercise.
The ventilatory threshold (VT), a less invasive approximation of the lactate
threshold, thus also reflects the shift to increasingly anaerobic metabolism as exer-
cise intensity progresses during exercise. Research using the lactate or ventilatory
threshold as a basis for prescribing exercise intensity has yielded much more
consistent and coherent results. For example, Parfitt, Rose, and Burgess (Parfitt
et al. 2006) showed that exercising for 20 min at an intensity above the lactate
threshold resulted in significantly greater negative affect than exercising for 20 min
either below the lactate threshold or at a self-selected intensity. Interestingly, partic-
ipant’s self-selected intensity was very similar to the intensity that corresponded to
the lactate threshold.
A final issue in examining affective responses is the potential that individual
differences can have in such responses to exercise. The “nomothetic” approach (i.e.,
responses averaged across individuals) has been the predominant approach but could
very easily obscure critical differences in inter-individual affective responses
between (Ekkekakis 2005). An “ideographic” approach (i.e., responses examined
at the individual level for differences) can reveal distinctions in affective responses
that are missed with a nomothetic approach. For example, Van Landuyt and col-
leagues (Van Landuyt et al. 2000) demonstrated that a 30-min bout of moderate-
intensity (60% VO2peak) cycling resulted in essentially no change in FS ratings.
However, the lack of change was due to nearly half (48%) of the participants
reporting an increase in affective valence (greater pleasantness), 35% reporting a
decrease in affective valence (less pleasantness), with the remainder (~17%)
reporting no change. The lack of change at the group level masked the variability
in affective response. This is a useful demonstration that even at exercise intensities
considered moderate in nature, affective responses are not necessarily positive,
likely because a third of the individuals were exercising above their VT. This is
despite the fact that the pre- to post-exercise changes are generally positive (see also
(Ekkekakis et al. 2000)).
An interesting example of research examining the intensity-affect link was done
by Zenko et al. (2016). In this work, they assigned participants to an exercise session
where intensity was gradually: (a) increased over the 15-min bout, ending with the
intensity being 120% of the workload corresponding to the ventilatory threshold, or
(b) gradually decreased, starting at 120% of the ventilatory threshold and decreasing
from there. As expected, when intensity was “ramped up,” the vast majority of
participants (77%) reported decreased pleasantness/increased unpleasantness
whereas when the intensity was “ramped down,” most participants (83%) reported
increased pleasantness/decreased unpleasantness. Zenko et al. thus demonstrated
that a positive slope of pleasure (i.e., from the ramped down protocol) resulted in
more pleasantness and enjoyment post-exercise as well as more positive remem-
bered pleasure and forecasted pleasure for future exercise as much as a week later.
Exercise and Acute Affect 117

Given the previous discussion, it is worth noting what has been delineated
regarding the spectrum of exercise intensity and affective responses. Ekkekakis
(2005) has conceptualized this idea very nicely within the Dual-Mode Model.
Essentially, when exercise is done at intensities below the lactate/ventilatory thresh-
old, affective responses tend to be fairly homogeneous and pleasant (i.e., nearly
everyone feels good at such intensities). When the intensity is increased to a level
proximal to the lactate/ventilatory threshold, affective responses may be pleasant or
unpleasant and are quite variable (i.e., some feel pleasant, some unpleasant, some
indifferent). Finally, as exercise intensity exceeds the lactate/ventilatory threshold,
homogeneity of affective responding is the norm again, except now it is primarily
unpleasant (i.e., nearly everyone feels less pleasant/more unpleasant).
While less studied than aerobic forms of exercise, resistance exercise has received
some attention regarding its affective impact. Like the research discussed above, as
the intensity of the resistance exercise increases, affective valence becomes increas-
ingly less positive/more negative. For example, Focht et al. (2015) showed that
intensities based on 40% of an individual’s 1-repetition maximum (1-RM) and self-
selected intensity (which approximated 57% 1-RM) yielded primarily increased
affective valence, whereas 70% 1-RM showed a progressive decline in valence.
Greene and Petruzzello (2015) showed a similar finding. Whereas the same protocol
performed at 100% 10-RM (keeping in mind that a 10-RM approximates ~70–75%
of a person’s 1-RM, thus 100% 10-RM is about 70% 1-RM) resulted in a decreasing
valence response, 70% of an individual’s 10-RM (a more moderate-intensity stim-
ulus) yielded stable and somewhat increasing affective valence across a bout
consisting of 3 sets of 10 repetitions of 7 different resistance exercises. While only
a partial picture, resistance exercise seems to result in a similar pattern of affective
responses as aerobic forms of exercise.
To summarize, affect becomes increasingly less positive/more negative as the
intensity of exercise increases. Moderate-intensity exercise, when accounting for the
lactate or ventilatory threshold, tends to yield more positive affective changes.
However, it is critically important to account for individual difference factors
(Ekkekakis 2013; Ekkekakis et al. 2011). To date, exercise duration has received
relatively little systematic attention, but it seems that as duration progresses, affec-
tive valence seems to follow an intensity-dependent pattern, often tending to
decrease (i.e., become less pleasant; (Ekkekakis and Petruzzello 1999)). It is worth
noting that when it comes to exercise duration, it doesn’t seem to have much of an
impact on subsequent adherence (Rhodes et al. 2009).
118 S. J. Petruzzello and J. R. North

6 Making a Place for Genetic Contributions to Affective

Responding

Since at least 2007, a case has been made for the potential influence of genetics on
affective responses to exercise (Bryan et al. 2007; de Geus and Moor 2008). In their
paper, de Geus and De Moor argued that genetics may contribute significantly to the
variability in acute affective responses, specifically that there might be individual
differences in genetic sensitivity. A major point of their argument is that genetics
influences the pleasant/unpleasant impact that exercise has. Specifically, their
hypothesis is that for the regular exerciser, the pleasant (i.e., appetitive) effects are
amplified whereas for the non-exerciser the unpleasant (i.e., aversive) effects hold
sway. While there have not been many investigations of these propositions, there has
been some promising work. In a study involving primarily twin pairs, Schutte et al.
(2017) examined affective responses to submaximal and maximal exercise tests on
both a cycle ergometer and treadmill, using the FS to assess affect during the
exercise and the AD ACL to examine affect post-exercise.
The basic premise of the study by Schutte et al. (2017) was to examine the extent
of heritability in affective responses during and following a bout of exercise. The
submaximal exercise sessions involved 4 incremental increases in the workload,
with each stage lasting 5 min (20 min total). Not surprisingly, FS responses
decreased with increasing workloads (i.e., intensity), then rebounded during the
5-min post-exercise recovery period. For the AD ACL, Energy increased while
Calmness and Tiredness decreased during the recovery period. To address the
main hypothesis, the heritability estimate (i.e., the proportion of the affective
response accounted for by the genetic contribution) for FS was 15%. For Energy
and Calmness, heritability estimates ranged from 19 to 37%. Those who engaged in
more regular exercise also had more positive/less negative affective responses.
Huppertz et al. (2014), from a sample of 5,095 18–50 year old twins and their
siblings, showed a genetic link between enjoyment (or lack thereof) of physical
activity and weekly time spent engaging in voluntary exercise, with heritability
estimates of 44–47%. de Geus (2023), drawing from a variety of brain research in
animals and humans, notes that there appears to be a strong convergence on brain
circuitry involved in the rewards:punishment of engaging in physical activity and
actually engaging in exercise. One example comes from the work of Flack et al.
(2019), where they demonstrated a genetic contribution to the ability to tolerate
exercise intensity, the relative reinforcement value of exercise, and the amount of
moderate-to-vigorous physical activity individuals engaged in.
Exercise and Acute Affect 119

7 What About High-Intensity Interval Exercise/Training

(HIIE/HIIT)?

With what has been presented so far, it becomes somewhat difficult to understand
why HIIT has become such a popular exercise modality. It has been clearly
established that as intensity increases, especially at levels beyond the lactate/venti-
latory threshold, affective valence declines and becomes increasingly less pleasant/
more unpleasant. Yet, HIIT has been a yearly top 10 fitness trend since 2014
(Thompson 2023). Such workouts involve repeated intervals of all-out/nearly all-out
effort (i.e., high-intensity), interspersed with periods of rest or recovery (very low
effort). These work:recovery scenarios vary greatly, from the “classic” Tabata-style
([20 s:10 s] × 8), to those more commonly used in research settings
([60 s:60 s] × 10), and any other variation imaginable. While often promoted as a
“time-efficient strategy” for physical activity, time-use surveys have shown large
increases in discretionary time in Western countries (e.g., +4–5 h per day in the
USA, 1965–2003), most of which has not been allocated to exercise or physical
activity (Sturm and Cohen 2019). Research examining affect and enjoyment to HIIT
protocols usually compares HIIE to moderate-intensity continuous exercise (MICE),
often reporting no difference following or that HIIE results in more negative valence
during the activity. Enjoyment, reported following the exercise has ended, is often
similar between HIIE and MICE.
So, if HIIT (or HIIE) is a supposedly enjoyable form of exercise, do people stick
with it? Stork et al. (2018) compared affective (via FS) and enjoyment responses in a
group of inactive adults (~21 years old) to 3 different cycling protocols: (a) moder-
ate-intensity continuous exercise (MICT), entailing 45 min of cycling at ~70–75%
HRmax (50 min total including warm-up and cool-down); (b) HIIT, comprised of
10 bouts of 60-s at ~85–90% interspersed with 60-s of rest, both done a total of
10 times (24 min total); and (c) sprint interval training (SIT), which involved 320-s
“all-out” sprints with 2-min of rest between each (10 min total). Predictably, affect
(via FS) declined slightly across the MICT session, and much more so during HIIT
and SIT. Interestingly, enjoyment was rated similarly across all 3 sessions. The key
piece of information was, when activity behavior tracked over the next month, MICT
was chosen almost twice as frequently (6.1 times) as HIIT (3.5 times) and far more
often than SIT (1.4 times). This highlights, again, that how people feel during an
exercise activity is potentially an important piece of the adherence puzzle (Williams
et al. 2008, 2012). There seems to be plenty of unanswered questions surrounding
the affective impact that HIIT has on the individual exerciser. The interested reader
can learn much more about the “extraordinary claims” that have been made regard-
ing HIIT and where these claims almost always come up short (Ekkekakis and
Biddle 2023; Ekkekakis and Tiller 2022; Ekkekakis et al. 2023).
120 S. J. Petruzzello and J. R. North

8 Where To From Here?

It should be obvious that physical activity and exercise is a pleasant experience for
some and an unpleasant experience for others. These affective experiences during
the activity have been shown to predict future exercise behavior (e.g., (Williams
2008; Williams et al. 2012; Dunton et al. 2020)). An interesting avenue that research
is beginning to pursue is to better identify, via assessment, and then modify affective
responses in an effort to determine if this might be a viable intervention strategy
(Dunton et al. 2023). One such approach that seems to have promise involves
creating associations between physical activity and pleasure through the use of
smart phones (Conroy and Kim 2021). This particular study showed that when users
were exposed to ~2 min per day of these conditioned associations, this was further
associated with increased amounts of physical activity over the course of 8 weeks.
As alluded to throughout this chapter, there remains a need to systematically
examine plausible mechanisms to explain both the positive and negative affective
responses to physical activity and exercise as well as accounting for individual
differences. This could include the examination of cognitive constructs drawn
from relevant theory (e.g., perceived autonomy), exploration of biological mediators
(e.g., endocannabinoids, brain activation, temperature), how somatosensory and
cognitive factors interact at various exercise intensities, and continued investigation
of genetic contributions to affective responses.
There is also a need to more carefully and systematically examine activity
modalities beyond what are typically aerobic in nature. More attention is needed
regarding resistance exercise and high-intensity interval exercise, especially with
respect to the timing of affective measurement. It also bears repeating that choice of
affective measure is crucially important, with measures that allow assessment of
valence and activation seemingly providing the best capture of the possible affective
space.
The road ahead appears to hold a great deal of promise for better understanding
the impact that exercise has on affect and the impact such affective responses have
on physical activity behavior. Borrowing once again from Schutte et al. (2017),
some people associate exercise and physical activity with pleasantness and experi-
ence it as such. Unfortunately, others associate exercise with unpleasantness.
Coupled with the recommendations from Dunton et al. (2023), individualizing the
exercise “prescription” to highlight the positive aspects and reduce the aversive
aspects to the extent possible seems a fruitful intervention approach.

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Exercise and Fear and Safety Learning

Ameera Azar, Troy Hubert, Thomas G. Adams, Josh M. Cisler,

and Kevin M. Crombie

Contents
1 Clinical Relevance for Examining the Effects of Exercise on Fear Conditioning
and Extinction Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
2 Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2.1 Chronic Exercise Prior to Fear Conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.2 Acute Exercise Before, During, or After Fear Extinction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3 Human Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
4 Potential Mechanisms for Exercise-Induced Enhancement of Extinction Learning
and Recall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
5 Future Directions for Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

A. Azar
Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell
Medical School, Austin, TX, USA
Department of Neuroscience, The University of Texas at Austin, Austin, TX, USA
T. Hubert
Department of Psychology, University of Kentucky, Lexington, KY, UK
T. G. Adams
Department of Psychology, University of Kentucky, Lexington, KY, UK
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
J. M. Cisler
Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell
Medical School, Austin, TX, USA
Institute for Early Life Adversity Research, The University of Texas at Austin Dell Medical
School, Austin, TX, USA
K. M. Crombie (✉)
Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell
Medical School, Austin, TX, USA
Department of Kinesiology, The University of Alabama, Tuscaloosa, AL, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 125
Curr Topics Behav Neurosci (2024) 67: 125–140
https://doi.org/10.1007/7854_2024_494
Published Online: 23 July 2024
126 A. Azar et al.

Abstract Fear conditioning paradigms have been studied for over 100 years and are
of great interest to the behavioral and clinical sciences given that several safety
learning processes (e.g., extinction learning and recall) are thought to be fundamen-
tal to the success of exposure-based therapies for anxiety and related disorders. This
chapter provides an overview of preclinical and clinical investigations that examined
the effects of exercise on initial fear acquisition, fear extinction learning and
consolidation, and return of fear outcomes. This chapter highlights the collective
body of evidence suggesting that exercise administered after extinction learning
enhances the consolidation and subsequent recall of extinction memories to a greater
extent than exercise administered prior to extinction learning. This suggests that the
addition of exercise after exposure therapy sessions may improve treatment out-
comes for people with anxiety and related disorders. Potential mechanisms are
discussed in addition to suggestions for future research to improve our understand-
ing of the effects of exercise on fear conditioning and extinction outcomes.

Keywords Behavioral tagging · Exposure therapy · Extinction recall ·

Fear conditioning · Fear extinction · Memory encoding · Memory retrieval ·
Posttraumatic stress disorder

1 Clinical Relevance for Examining the Effects of Exercise

on Fear Conditioning and Extinction Outcomes

Fear learning and memory processes are commonly studied with laboratory-based
paradigms that assess fear acquisition, extinction, and recall (see Fig. 1). Fear
learning and memory have long been a topic of interest among behavioral scientists,
neuroscientists, and mental health professionals. In addition to improving our
fundamental knowledge of these processes, there has also been a surge of interest
in incorporating our understanding of fear learning and memory processes to
enhance treatments for mental health disorders (Fullana et al. 2020). Exposure-
based psychotherapies are some of the most common and efficacious treatment
options for individuals with anxiety disorders, obsessive-compulsive disorder
(OCD), or posttraumatic stress disorder (PTSD). These therapies are believed to
rely heavily on the principles of fear extinction and extinction recall (Rothbaum and
Davis 2003) (see Fig. 1). For example, trauma exposure can be considered a
conditioning event whereby the traumatic event (e.g., car accident) serves as an
unconditioned stimulus (US) and associated details (e.g., sound of screeching tires)
serve as conditioned stimuli (CS+). Re-exposure to trauma-related details (CS+)
then provokes conditioned threat responses (e.g., increased anxiety and
re-traumatization expectancies). As part of therapy, the patient is gradually
reintroduced and repeatedly exposed to components of the fear memory (i.e.,
trauma-related stimuli) in a safe context. This process mimics fear extinction pro-
cesses (extinction learning, consolidation, and recall) and is thought to weaken the
Exercise and Fear and Safety Learning 127

Fig. 1 Overview of a typical human lab-based fear conditioning paradigm assessing fear acquisi-
tion (a), extinction (b), and extinction recall (c). During fear acquisition (a), participants learn to
associate the presentation of a given stimulus (CS+; depicted here as a triangle) with the occurrence
of an aversive outcome (US; depicted here as an electric shock), presented in an acquisition context
(depicted here as a green background). During fear extinction (b), the conditioned stimuli (CS+ and
CS-) are presented in the extinction context (depicted here as an orange background), and aversive
outcomes no longer follow presentation of the CS+. During the fear extinction recall phase (c)
participants are presented both conditioned stimuli (CS+ and CS-) in both the acquisition and
extinction contexts, without any aversive outcomes administered. The extinction recall phase often
involves two runs, with an experimental procedure (e.g., single electric shock) administered in
between runs in order to promote reinstatement. During the fear extinction recall phase, researcher
can assess fear responding (often via physiological and cognitive indices) to assess several relevant
return of fear outcomes (e.g., spontaneous recovery, context renewal, and reinstatement). This
figure was adapted from a figure included in a recent review by Crombie et al. (2023a)

predictive value of the CS+ to elicit distress and a conditioned threat response.
Essentially, learned inhibition of the fear memory is accomplished following the
acquisition and consolidation of new “safety” learning (Fullana et al. 2020;
Rothbaum and Davis 2003; Cisler et al. 2014; Craske et al. 2008a; Crombie et al.
2021a).
Unfortunately, even when successful fear extinction learning occurs, original
fears are likely to return (Quirk and Mueller 2008). For example, increased fear
responding following adequate extinction learning can occur following the passage
of time (i.e., spontaneous recovery), after the presentation of context cues of the
original trauma (i.e., context renewal), or upon re-exposure to the unconditioned
stimulus that directly contributed to the initial fear acquisition (i.e., reinstatement)
(Crombie et al. 2021b) (Fig. 2). It has been demonstrated that the return of fear can
be a critical barrier to the successful treatment of anxiety and related disorders (e.g.,
PTSD and OCD) with therapeutic exposure (Craske et al. 2008a, 2014). It has also
been demonstrated that greater reductions in distress between subsequent exposure
therapy sessions and decreased return of fear between sessions are predictive of
greater overall treatment response (Craske et al. 2008b). These findings suggest that
128 A. Azar et al.

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Fig. 2 General depiction of animal and human fear conditioning paradigm involving administra-
tion of exercise following extinction learning and subsequent effects on return of fear outcomes

enhanced extinction learning consolidation and greater retrieval of inhibitory safety

learning are important therapeutic targets for enhancing the efficacy of exposure-
based therapy. Given this, it makes sense for researchers to use fear conditioning
paradigms to develop means for enhancing several of these fear and safety learning
and memory processes to improve the efficacy of exposure-based therapies.
Fear conditioning paradigms have been well-established and studied for over
100 years (Fullana et al. 2020; Bach et al. 2023; Lonsdorf et al. 2017; Vervliet and
Boddez 2020). Recently, researchers have investigated manipulating different
aspects of extinction learning to improve understanding of potential adjunct treat-
ments for exposure-based therapies (e.g., enhanced consolidation of extinction
learning and extinction recall). The vast majority of such investigations have been
pharmacological (e.g., D-cycloserine, methylene blue, yohimbine) (Ebrahimi et al.
2020; Inslicht et al. 2021; Smits et al. 2013, 2014; Zoellner et al. 2017). However,
there has also been a recent interest in examining the potential role of exercise, given
that it generally results in a small but significant cognitive enhancing effect and
engages multiple neural systems thought to play an important role in fear and safety
learning processes (Tanner et al. 2018; Crombie et al. 2023a). The proceeding
sections of this chapter will provide a brief overview of the preclinical (animal)
and clinical (human) studies that have shaped our current understanding, followed
by a synopsis of potential mechanisms responsible for exercise-induced enhance-
ment of extinction learning and recall, and finally, suggestions for future research.

2 Animal Studies

Most early investigations examining the effects of exercise on fear conditioning

outcomes were conducted in mice and rats. Although slightly different paradigms
and protocols have been used, the collective body of evidence has primarily exam-
ined: 1) the effect of chronic exercise (i.e., wheel running) before fear conditioning
on subsequent fear acquisition, fear extinction learning, extinction recall, and return
Exercise and Fear and Safety Learning 129

of fear outcomes (e.g., spontaneous recovery, context renewal, reinstatement), and 2)

the effect of acute exercise (i.e., wheel running) before, during, or after fear extinc-
tion on subsequent fear extinction learning, extinction recall, and return of fear
outcomes. The following section provides a summary of some of the seminal
findings in each of these domains. For a comprehensive overview, see Tanner
et al.’s review out of Benjamin Greenwood’s lab at the University of Colorado at
Denver (Tanner et al. 2018).

2.1 Chronic Exercise Prior to Fear Conditioning

Studies conducted to date suggest that chronic wheel running of a sufficient duration
prior to contextual fear conditioning enhances the initial acquisition of the fear
memory (Burghardt et al. 2006; Falls et al. 2010; Greenwood et al. 2009; Van
Hoomissen et al. 2004). The effect of chronic wheel running enhancing the initial
fear acquisition has been demonstrated in male mice and rats with wheel running
access ranging from 2 to 8 weeks (Burghardt et al. 2006; Falls et al. 2010;
Greenwood et al. 2009; Van Hoomissen et al. 2004), with 1 week having null effects
(Greenwood et al. 2009). There is also evidence to suggest that chronic wheel
running in male rats before fear conditioning contributes to delayed extinction
learning and impaired extinction recall during subsequent extinction recall phases
(Greenwood et al. 2009). However, Tanner et al. speculated that the delayed within-
session extinction observed following chronic exercise is likely due to exercise’s
effect on strengthening the initial encoding of the fear memory as opposed to
impairing extinction mechanisms (Tanner et al. 2018). This hypothesis is supported
by findings that suggest that chronic wheel running by male rats does not impair
initial fear extinction learning in protocols that assess fear extinction learning
immediately after a fear acquisition protocol (Greenwood et al. 2003, 2005),
which suggests that chronic exercise delays extinction learning only when there is
an opportunity for exercise to boost consolidation of the original fear memory
(Tanner et al. 2018). In contrast to the number of investigations conducted examin-
ing the effects of chronic wheel running prior to fear acquisition, there has only been
one investigation conducted that examined the influence of chronic wheel running
after fear acquisition on subsequent fear extinction learning (Greenwood et al. 2009).
In this study, Greenwood et al. provided male rats with 1 or 6 weeks of wheel
running access and found that neither condition influenced fear extinction learning
(Greenwood et al. 2009).

2.2 Acute Exercise Before, During, or After Fear Extinction

Several studies examined the effect of acute exercise before, during, or after fear
extinction on initial fear extinction learning, extinction recall, and fear relapse. An
130 A. Azar et al.

early investigation in this area reported that 3 h of wheel running access prior to or
immediately following fear extinction learning contributed to improved extinction
recall (24 h later) among male rats, compared to male rats with locked running
wheels or with wheel access delayed until 6 h after extinction learning sessions
(Siette et al. 2014). Additionally, Jacquart et al. reported that 30-min of wheel access
1 or 2 h prior to fear extinction, or 3 h of wheel access immediately prior to fear
extinction, did not influence initial fear extinction learning or return of fear (extinc-
tion consolidation) in male rats (Jacquart et al. 2017).
Male rats provided with running wheel access during a cued fear extinction
training session exhibited lower fear responses during an extinction recall test
(1 week later) compared to male rats that were provided with running wheel access
prior to fear extinction (Mika et al. 2015). In line with this finding, acute access to
running wheels after a contextual fear extinction session and an extinction retention
test (24 h later; i.e., a proximal memory test that also served as an additional
extinction training session) contributed to enhanced extinction recall in male rats
when tested 10 days later (Bouchet et al. 2017). Although wheel running did not
influence the consolidation of fear extinction learning or return of fear outcomes in
female rats, both male and female rats that ran more during the fear extinction
learning consolidation phase exhibited stronger extinction memories during the
extinction recall and return of fear tests (Bouchet et al. 2017). Similarly, Crombie
et al. demonstrated in male wild-type mice (but not cannabinoid type-1 receptor
knockout mice) that voluntary running wheel access in between extinction training
sessions (daily training for 4 days) resulted in significantly less (moderate to large
effects) freezing during tests of extinction retention compared to mice that were
housed with locked running wheels. Additionally, this study revealed that there were
moderate to strong relationships between the number of wheel running revolutions
and freezing time during extinction training sessions, indicating that mice that ran
more in between extinction training sessions exhibited less freezing during subse-
quent sessions (Crombie et al. 2018). However, a limitation of this study was that
mice were provided with unlimited access from immediately after a given extinction
training session ended until immediately before the next extinction training ses-
sion (24h later).
Collectively, these findings led researchers from several recent reviews to con-
clude that the timing of exercise in relation to fear extinction is highly relevant, such
that exercise during or shortly after extinction training limits the return of fear to a
greater extent than if administered prior to extinction training (Tanner et al. 2018;
Crombie et al. 2023a). The conclusions from these reviews were also supported via
meta-analytic evidence that demonstrated that the timing of exercise administration
was a significant moderator in determining whether exercise enhances extinction
processes among rodents (Roquet and Monfils 2018). Additional preclinical research
examining sex differences is warranted. The collective body of evidence suggests
that the pro-extinction effect of exercise may be blunted, but not abated, in female
rats. Additional research is needed, but it may be the case that female rats need to
engage in a greater volume of exercise in order to achieve comparable pro-extinction
effects as male rats (Bouchet et al. 2017).
Exercise and Fear and Safety Learning 131

3 Human Studies

More recently, investigations into the effects of aerobic exercise on fear conditioning
outcomes have been conducted in humans with and without psychiatric disorders. In
contrast to the preclinical body of evidence, early exercise and fear conditioning
investigations in human populations have solely examined the effects of exercise
administered after fear extinction learning on subsequent extinction recall. This is in
large part because the preclinical investigations preceded the clinical investigations,
and therefore human studies were primarily designed based on the collective body of
knowledge from the animal studies.
Keyan and Bryant conducted the first human trial among a sample of adult men
and women (mean age = 20.64 ± 3.18) without a psychiatric disorder and reported
that 20-min of stationary cycling (cycling at maximal resistance while still
maintaining a cadence of 60–70 rpm [RPMs]) following an extinction training
session contributed to significantly lower fear-potentiated startle to CS+ stimuli
(24 h later) compared to participants from a light-intensity aerobic exercise control
group (20-min of cycling with no resistance while maintaining a cadence of 60–70
RPMs) (Keyan and Bryant 2019). This was also the first human study to examine
potential neurobiological mechanisms – as the authors reported that the beneficial
effect of exercise was moderated by the presence of the BDNF Val66Met polymor-
phism (Keyan and Bryant 2019). Although this was a seminal study, one limitation
of this investigation was that the researchers implemented a 2-day design, during
which fear acquisition and fear extinction occurred on day 1, with extinction recall
tests occurring on day 2. As a result, it is difficult to determine if the aerobic exercise
group exhibited reduced fear responding during extinction recall tests due to the
effects of exercise on the consolidation of fear conditioning or extinction (Keyan and
Bryant 2019).
More recently, a study among women (mean age = 30.88 ± 7.15) with PTSD
stemming from interpersonal violence (i.e., physical and/or sexual assault) reported
that individuals that engaged in 30-min of moderate-intensity aerobic exercise
(70–75% age-adjusted maximum heart rate [MHR] on a treadmill) after extinction
learning exhibited significantly lower threat expectancy ratings to conditioned
stimuli during a delayed (24 h later) reinstatement test compared to individuals
that were administered 30-min of a light-intensity aerobic exercise control condition
(Crombie et al. 2021b). Importantly, exercise did not appear to affect spontaneous
recovery or context renewal and did not affect skin conductance responses during
return of fear testing. A follow-up report indicated that the effect of aerobic exercise
on threat expectancy ratings during reinstatement was statistically mediated by
exercise-induced increases in circulating brain-derived neurotrophic factor
(BDNF) and N-arachidonoylethanolamine (i.e., Anandamide, AEA), but not
homovanillic acid (HVA) or 2-arachidonoylglycerol (2-AG) (Crombie et al.
2021c). Importantly, this study implemented a three-day design during which fear
acquisition, fear extinction, and fear extinction recall phases occurred on separate
days, with all study visits occurring at the same time of day (1800 CST) for all
132 A. Azar et al.

participants (Crombie et al. 2021b). Additionally, researchers examined the effects

of aerobic exercise on fear extinction recall using a 3-day category-based protocol
(i.e., images of tools and animals used as conditioned stimuli). Results revealed that
women without a clinical diagnosis (mean age = 33.00 ± 9.82) that were adminis-
tered 30-min of moderate-intensity aerobic exercise (i.e., 70–75% MHR on a
stationary cycle while maintaining a cadence of 60–70 RPMs) after extinction
learning exhibited reduced threat expectancy ratings during delayed (24 h after
extinction learning) tests of fear recall compared to individuals that were adminis-
tered 30-min of light-intensity aerobic exercise (i.e., less than 50% MHR on a
stationary cycle) (Crombie et al. 2023b).
Most recently, a 3-day study was conducted among 60 healthy, young men (mean
age = 24.30 ± 4.40) to determine whether a single bout of vigorous-intensity aerobic
exercise (20-min of running at 85% heart rate reserve) administered after an extinc-
tion training session enhanced physiological indices (skin conductance and
pupillometry) of extinction memory retrieval during delayed (24 h after extinction
session) spontaneous recovery and reinstatement tests (Jentsch et al. 2023). This
study also tested if vigorous-intensity exercise influenced the generalization of safety
learning to two novel, but perceptually similar, stimuli. Contrary to their hypothesis,
the researchers reported that the exercise group exhibited impaired extinction mem-
ory retrieval during spontaneous recovery, as evident via stronger differential skin
conductance and pupillary responses to the original conditioned stimuli and the
novel stimuli, compared to the control group (Jentsch et al. 2023). Importantly, the
authors note that although participants exhibited a slight decrease in differential
conditioned fear responses throughout the extinction training session, there was still
evidence of inadequate extinction at the end of the extinction session (i.e., higher
ratings to CS+ compared to CS-). This led the researchers to suggest that exercise
administered after unsuccessful or incomplete fear extinction may have boosted the
consolidation of the original fear memory trace, which was evident via greater
physiological responses during the return of fear tests (Jentsch et al. 2023). These
results are in contrast to the aforementioned trials which administered moderate-
intensity aerobic exercise (i.e., different exercise stimulus) in women (i.e., different
sex examined) and reported either an exercise-enhancing effect on limiting physio-
logical indices of return of fear outcomes (Keyan and Bryant 2019) or no difference
in physiological indices between exercise and control groups (Crombie et al. 2021b,
2023b). Unfortunately, the Jentsch et al. trial did not assess cognitive indices of
return of fear outcomes, which was the outcome that yielded significant effects in the
Crombie et al. studies (Crombie et al. 2021b, 2023b). Ultimately, this study suggests
that adequate and complete extinction memory formation may be a prerequisite for
vigorous-intensity aerobic exercise to enhance extinction memory retrieval in regu-
larly healthy men (Jentsch et al. 2023). This hypothesis will need to be tested in
future studies.
Collectively, the human studies are promising and warrant further consideration.
Although the findings from the majority of investigations suggest an exercise-
enhancing effect (Crombie et al. 2021b, 2023b; Keyan and Bryant 2019), the
findings are nuanced, which may be due to different population characteristics
Exercise and Fear and Safety Learning 133

(i.e., PTSD vs control), paradigm characteristics (i.e., standard fear conditioning vs

category-based fear conditioning protocol), or exercise intensity parameters (i.e.,
moderate-intensity vs vigorous-intensity aerobic exercise). For instance, the study in
women with PTSD revealed an exercise-enhancing effect during a reinstatement test
(Crombie et al. 2021b), which was in contrast to the study in women without a
clinical diagnosis (Crombie et al. 2023b), which found an exercise-enhancing effect
during both extinction recall tests. Given that these studies used slightly different
fear conditioning paradigms, the researchers from these studies speculated that it
may be the case that aerobic exercise only influences threat expectancy ratings in
women with PTSD after a reactivation event occurs, or perhaps women with PTSD
may also exhibit reduced threat expectancy ratings prior to a reactivation event
(similar to women without PTSD) if category-based fear conditioning protocols
are administered (Crombie et al. 2023b). Exercise intensity may also play an
important role as the studies (Crombie et al. 2021b, 2023b; Keyan and Bryant
2019) that reported a beneficial effect of exercise on return of fear outcomes
administered moderate-intensity aerobic exercise, whereas the one study that did
not report a beneficial effect administered vigorous-intensity aerobic exercise
(Jentsch et al. 2023).
In addition to fear conditioning protocols, there have also been several recent
attempts in humans to examine the effects of exercise on exposure therapy or therapy
analogue outcomes (Jacquart et al. 2017; Bryant et al. 2023; Voorendonk et al. 2022;
Weisman and Rodebaugh 2020; Young-McCaughan et al. 2022; Bischoff et al.
2018). As alluded to earlier, this makes intuitive sense because much of the research
examining the relationship between exercise and fear conditioning is being
conducted to improve our understanding of the potential utility of exercise as an
adjunct/augmentative strategy to enhance the efficacy of psychotherapies (e.g.,
exposure-based therapy) for clinical anxiety and PTSD populations. Given that
this chapter focuses exclusively on fear conditioning outcomes, we refer the reader
to a recent comprehensive review that discusses the results of these investigations
(Crombie et al. 2023a). In brief, the findings from the few studies in this domain have
been mixed, which highlights the importance for future studies to incorporate
experimental designs and methods based on the prior lab-based fear conditioning
and extinction protocols (Crombie et al. 2023a).

4 Potential Mechanisms for Exercise-Induced

Enhancement of Extinction Learning and Recall

Given that enhanced consolidation of extinction learning and subsequent retrieval of

said learning is thought to be an important therapeutic target for exposure-based
therapies, it is important to briefly consider some plausible mechanisms that may be
at least partially responsible for the exercise-induced enhancement of extinction
learning and recall. Although a comprehensive overview of plausible mechanisms is
beyond the scope of this chapter (see (Crombie et al. 2023a)), it is important to
briefly describe a few interwoven, synergistic mechanisms (see Fig. 3).
134 A. Azar et al.

One potential mechanism involves the behavioral tagging hypothesis (Crombie

et al. 2023a; Dunsmoor et al. 2022; de Carvalho et al. 2013, 2014), which is an
extension of the synaptic tagging and capture process (Frey and Morris 1997). The
behavioral tagging hypothesis postulates that some behavioral experiences result in
the synthesis of plasticity-related products that can get captured by a “synaptic tag”
set by some recently completed “weak” learning experience, thereby contributing to
enhanced long-term memory formation; said otherwise, plasticity-related proteins/
neuromodulatory factors released in close proximity to initial memory encoding can
lead to greater long-term memory consolidation (Crombie et al. 2021c, 2023a;
Dunsmoor et al. 2022; de Carvalho et al. 2013, 2014; Ritchey et al. 2016). Based
on this notion, it may be the case that aerobic exercise performed in conjunction with
extinction learning serves as a behavioral event that increases plasticity-related
products, which then get captured by the initial LTP tag set during extinction
learning, thereby contributing to greater enhancement of extinction learning
(Crombie et al. 2021c, 2023a). Although more research in humans is needed, recent
research from a clinical study among women with PTSD offered support for this
hypothesis as greater exercise-induced increases in AEA and BDNF were found to
mediate the relationship between aerobic exercise and enhanced cognitive indices of
extinction recall (Crombie et al. 2021c).
Another potential mechanism involves exercise-induced enhancement of pattern
separation, and more broadly, episodic memory (Crombie et al. 2023a). Engaging

A
PRPs get captured by
learning tags at tagged
synapses

Administration
Extinction
of Aerobic
Training
Learning tags are Exercise Increase of PRPs
set at synapses (e.g., AEA, BDNF, PRPs strengthen the synapses
dopamine) and allow for enhanced long-term
memory formation and extinction
recall, including discrimination of
similar but different stimuli
B

Synapse strength remains the

Administration same post-extinction training,
Extinction resulting in no enhancement of
of Aerobic
Training memory consolidation or
Learning tags are Exercise No increase of PRPs
set at synapses extinction recall

Fig. 3 Overview of hypothesized synergistic mechanisms involved in exercise-induced enhanced

consolidation of extinction learning and enhanced recall. This figure was adapted from a figure
included in a recent review by Crombie and colleagues (Crombie et al. 2023a). When extinction
learning occurs, a tag is set at hippocampal synapses. If aerobic exercise is administered during the
post-consolidation window, exercise-induced increases in plasticity-related products (PRPs) get
captured by the tag, which then strengthens the tagged synapses, resulting in enhanced long-term
memory consolidation (see panel a). If aerobic exercise is not administered in the post-extinction
consolidation window, enhanced long-term memory consolidation is less likely to occur (see panel
b)
Exercise and Fear and Safety Learning 135

with every detail in the environment is ultimately impossible for humans, and
therefore details are analyzed based on importance and relevance. Humans’ ability
to retain and retrieve specific details about important events is advantageous for
future decision-making (i.e., catalog information for future retrieval). For example,
someone with PTSD may want to recall particular details about the event (or about
information covered in therapy) to adequately differentiate between safe and threat-
ening contexts in similar and dissimilar contexts. This process of distinguishing
similar experiences to keep stored memories separate from one another is otherwise
known as pattern separation. Individuals with PTSD often have considerable diffi-
culty with pattern separation, which is why a significant portion of exposure-based
psychotherapy focuses on forming new safety memories to inhibit the initial trauma
memory. This method also helps individuals with PTSD learn to discern a safe
contextual environment from a threatening one and to further limit avoidance
behaviors and reduce symptomology (Crombie et al. 2023a). In other words, greater
pattern separation is thought to be beneficial for adults with PTSD.
Although this is a relatively new area of investigation, initial human evidence
suggests that aerobic exercise is capable of improving pattern separation and epi-
sodic memory in adults (Crombie et al. 2023a; Déry et al. 2013; Suwabe et al. 2017,
2018; Marin Bosch et al. 2020; van Dongen et al. 2016). For instance, participants
administered an acute bout of aerobic exercise (35-min of submaximal interval
training on stationary cycling) after a declarative memory task, exhibited greater
retention of picture-location associations and increased hippocampal pattern simi-
larity for correct responses (48 h later) compared to a no-exercise control condition
(van Dongen et al. 2016). Additionally, an acute bout of aerobic exercise and greater
baseline aerobic fitness are associated with enhanced pattern separation during a
mnemonic discrimination task (Déry et al. 2013; Suwabe et al. 2017, 2018). Several
animal studies also revealed that wheel running enhanced discrimination between
distinct, but similar, stimuli and contexts (Greenwood et al. 2009; Bolz et al. 2015;
Creer et al. 2010; Wu et al. 2015; Islam et al. 2021). Collectively, these results
provide initial support to suggest that perhaps exercise enhances extinction learning
via its effects on pattern separation. In other words, aerobic exercise may be effective
because it enhances an individual’s ability to correctly discriminate similar but
importantly different stimuli (e.g., CS+ in acquisition context vs CS+ in the extinc-
tion context). In addition to offering an explanation for the aforementioned lab
studies, it is plausible that this may prove to be a mechanism by which incorporating
exercise into exposure-based therapy sessions may help individuals distinguish
between distinct safety and threat cues as they navigate their environment outside
of the clinical setting (Crombie et al. 2023a).

5 Future Directions for Clinical Trials

There is much work to be done to improve our understanding of the effect of exercise
on fear conditioning outcomes, and ultimately to improve our understanding of the
potential for incorporating exercise with exposure-based therapies to improve
136 A. Azar et al.

clinical outcomes for individuals with anxiety disorders and PTSD. For example,
future clinical trials need to continue to systematically examine the precise exercise
parameters needed to enhance relevant outcomes of interest (e.g., enhanced extinc-
tion recall). For instance, 3 of the 4 human trials that reported a beneficial effect of
exercise on return of fear outcomes administered moderate-intensity aerobic exercise
(Crombie et al. 2021b, 2023b; Keyan and Bryant 2019), whereas the one investiga-
tion that did not report a beneficial effect administered vigorous-intensity exercise
(Jentsch et al. 2023). Exercise intensity was not the only major difference between
these investigations, but nonetheless, the differential findings highlight that further
attention be devoted to teasing out the potential relevance of exercise intensity.
Relatedly, future investigations should continue to assess and report pertinent
information about the exercise stimulus administered as part of the study (e.g.,
duration of exercise bout, exercise intensity, and methods for assessing intensity),
in addition to the timing of the exercise bout in relation to the fear conditioning
protocol (e.g., prior to or following extinction learning) (Crombie et al. 2023a).
Future research should also continue to examine potential sex differences. Much of
our understanding from preclinical studies is derived from studies involving male
rodents (Tanner et al. 2018). Among human studies conducted to date, one study has
examined men and women (Keyan and Bryant 2019), two have assessed only
women (Crombie et al. 2021b, 2023b), and one has assessed only men (Jentsch
et al. 2023). Additionally, future clinical trials should examine individuals with
psychiatric disorders, for which we may expect to see the biggest effect, and who
are arguably the most important populations of interest from a clinical perspective
(Crombie et al. 2023a). To date, there has only been one trial among individuals with
PTSD (Crombie et al. 2021b).
It is also important for future trials to improve our understanding of potential
mechanisms that contribute to an exercise-enhancing effect on extinction learning in
some cases. For instance, the collection of peripheral biomarkers prior to and
following exercise may help determine relevant systems involved (or not involved)
in the cognitive enhancing effects of exercise (Crombie et al. 2023a). Relatedly,
when possible, researchers should expand our understanding beyond peripheral
biomarkers by having participants complete fear conditioning protocols while in
the MRI environment. Incorporating modern advances in functional neuroimaging
should significantly improve our understanding of potential neural mechanisms
responsible for enhanced extinction memory consolidation (Crombie et al. 2023a).
Additionally, beyond extinction learning specific mechanisms, future research
should also consider including other relevant outcomes that may mediate or moder-
ate effects, such as participant’s physical activity and exercise history, motivation for
physical activity/exercise, and potential expectancy/placebo effects (Lindheimer
et al. 2020) (see Chap. 19: The Placebo Effect in Exercise and Mental Health
Research).
Lastly, future investigations should consider examining: 1) other exercise modal-
ities beyond aerobic exercise (e.g., resistance training), 2) paradigms that use
generalized stimuli (perhaps trauma-related) as conditioned stimuli, and 3) the effect
of exercise on the return of fear outcomes beyond 24 h (Crombie et al. 2023a).
Exercise and Fear and Safety Learning 137

Additionally, although it is more demanding from a data collection perspective,

future research investigations should utilize 3-day fear conditioning paradigms
where fear acquisition, fear extinction, and extinction recall/return of fear outcomes
are assessed on separate days. As alluded to earlier, doing so allows researchers to
more clearly define the impact of exercise on the consolidation of extinction learning
compared to 2-day designs where acquisition and extinction phases occur on the
same day (Crombie et al. 2023a).

6 Conclusion

Overall, this chapter provided an overview of animal and human studies that
administered exercise (or provided wheel running access in the case of animal
studies) at different phases of fear conditioning and extinction paradigms to examine
subsequent effects of exercise on initial fear acquisition, fear extinction learning,
extinction recall, and return of fear outcomes (e.g., spontaneous recovery, context
renewal, reinstatement). As discussed, enhanced extinction learning consolidation
and greater retrieval of inhibitory safety learning are important therapeutic targets for
enhancing the efficacy of exposure-based therapies among adults with anxiety and
related disorders. Importantly, the collective body of evidence to date suggests that
exercise administered after extinction learning enhances the consolidation and
subsequent recall of extinction memories, but these effects may be moderated by
biological sex and exercise parameters (e.g., intensity). This chapter also highlighted
that there is much work to be done to improve our understanding of the relationship
between exercise and enhanced consolidation of extinction learning; research is
needed to characterize mechanisms, sex differences, and to optimize exercise
parameters. Despite the need for additional research, initial investigations discussed
in this chapter suggest that there may be potential for precisely timed exercise to play
an important augmentative role in enhancing exposure-based therapies for anxiety
and related disorders.

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Exercise and Memory

Michele Schmitter and Janna Nonja Vrijsen

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2 What Is Memory? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
3 Exercise and Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
3.1 Biological Effects of Exercise Underlying Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
3.2 Exercise Protocols as Moderator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
3.3 Different Populations as Moderator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
4 Exercise on Different Memory Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
4.1 Working Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
4.2 Procedural Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
4.3 Semantic Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4.4 Episodic Memory: Neutral and Emotional Recall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4.5 Episodic Memory: Autobiographical Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
4.6 Episodic Memory: Pattern Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
5 Relevance and Promise of Exercise to Improve Memory Functioning . . . . . . . . . . . . . . . . . . . . 150
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

Abstract Our memory is crucial to our daily functioning, our identity, and how we
interact with the world around us. Maintaining memory functioning is therefore
important in many ways. Exercise positively affects our memory. Even a single
exercise session can directly boost different memory types, including working,
procedural, and episodic memory. Due to these benefits, exercise has great potential
as an intervention in different settings, such as schools or rehabilitation centers, and

M. Schmitter (✉)
Behavioural Science Institute, Radboud University Nijmegen and Depression Expertise Center,
Pro Persona Mental Health Care, Nijmegen, The Netherlands
e-mail: [email protected]
J. N. Vrijsen
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud
University Medical Center, Nijmegen, The Netherlands
Depression Expertise Center, Pro Persona Mental Health Care, Nijmegen, The Netherlands
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 141
Curr Topics Behav Neurosci (2024) 67: 141–154
https://doi.org/10.1007/7854_2024_495
Published Online: 31 July 2024
142 M. Schmitter and J. N. Vrijsen

as a prevention strategy. In this chapter, we first give an overview of what memory is

and why it is so relevant to our mental health. Next, we briefly discuss how, for
whom, and under which circumstances exercise improves memory functioning.
Then, we will summarize the literature of experimental studies investigating the
direct effect of exercise on different memory types, while acknowledging current
limitations and potential future directions. Finally, we briefly highlight the potential
of exercise as intervention to preserve and improve memory.

Keywords Exercise · Memory · Mental health

1 Introduction

I often go on a run to clear my head. When I am brooding over something and notice
that negative memories keep popping up, a run always helps. After running, I feel
good, I can focus so much better, the negative memories become less potent, and I
seem to glide through my tasks with more ease. Why is that? In addition to the direct
effect on mood and affect (see Chapters “Exercise and Acute Affect and Mood
States”), exercise also affects the functioning of our memory. This is very interesting
both from a theoretical and mental health perspective. Understanding how and under
which conditions exercise enhances memory – including memory processes related
to mental health problems – gives insight in the cognitive and behavioral mecha-
nisms of exercise. This in turn allows us to translate the findings from experimental
research into prevention strategies and mental health care solutions. In this chapter,
we start by briefly introducing relevant memory processes. This is followed by
presenting experimental work on the effect of exercise on both “cold” (i.e.,
non-emotional) and “warm” (i.e., emotional) memory processes. Here we will
briefly touch upon the clinical potential of the memory benefits for exercise, with
a focus on mental health solutions. The evidence for the effect of exercise on
memory is based mainly on aerobic or endurance exercise, although the clinical
value and mechanisms of other types of exercise (i.e., strength, balance, flexibility)
are gaining interest.

2 What Is Memory?

Take care of all your memories. For you cannot relive them. – Bob Dylan

Thinking back to our vacation or the precious moments we spent with our friends
and families can enlighten us in difficult times and help maintain our mental well-
being. They shape us as a person and how we perceive the world around
us. Memories are therefore crucial to cherish and preserve. The formation of a
memory can be divided into different phases, as well as different types of memory.
Exercise and Memory 143

When new information enters the human system, it does so via working memory
(WM). It is an essential component of our daily life as we rely on it constantly to
perform many tasks throughout the day. WM is the ability to temporarily store and
manipulate information and in turn comprises multiple processes including mainte-
nance, updating, attending to, inhibiting, and encoding of information. The latter is
what we could approach as the first phase of memory: most information is removed
from WM, but a limited portion flows on to be encoded and consolidated (or: stored)
in long-term memory. From long-term memory, information can be retrieved (i.e.,
brought to conscious memory) and re-consolidated again (or: re-worked based on
relevant new/contextual information).
Long-term memory again comprises different subtypes of memory. In relation to
exercise research, procedural memory (PM), semantic memory (SM) and episodic
memory (EM) are important. PM refers to memory of how to complete tasks, for
example how to ride a bike or make a cup of coffee. It enables us to perform a variety
of everyday activities. SM is where information gets its meaning. This can include
factual information (e.g., what a car is) and the emotional meaning of a memory.
Within EM, a distinction should be made between recall of nonpersonal infor-
mation, as, for example, words one can learn during a computer task and later on
recall, and autobiographical information. Autobiographical memory refers to recol-
lections of our personal history and is unique to a person, e.g., where we parked our
car in the morning, or that great road trip we took last summer. A mechanism
necessary for unique episodic memories is called pattern separation. Pattern sepa-
ration is the neurocomputational process that allows the brain to distinguish between
similar experiences. An example of pattern separation is when we meet new people
and try to remember their names and faces to avoid confusion. Overall, memory
processes are essential to our daily functioning (without it we cannot do anything)
and our conception of ourselves and the world around us. What affects these central
memory processes and phases – including exercise – is hence incredibly valuable to
understand.

3 Exercise and Memory

3.1 Biological Effects of Exercise Underlying Memory

Exercise has been found to have numerous biological effects on the brain (see
Chapters “Exercise, Neurocircuitry, and Neurotransmitter Systems”, “Exercise and
Stress Resilience” and “Exercise and Neuroendocrinology and Immunology”),
which enhance neuroplasticity in the prefrontal cortex (PFC) and the hippocampus;
areas that subserve memory functioning. A single exercise session triggers several
neuroplasticity-enhancing mechanisms (e.g., long-term potentiation [LTP], release
of brain-derived neurotrophic factor [BDNF]), and on a regular basis these effects
accumulate and induce structural and functional changes in the brain. Consistent
with the improved functioning of the hippocampus and PFC, recent reviews
144 M. Schmitter and J. N. Vrijsen

conclude that acute exercise bouts (see Chapter “Exercise and Acute Cognitive
Enhancement”) and regular exercise benefit memory (Loprinzi et al. 2018; Roig
et al. 2013).

3.2 Exercise Protocols as Moderator

The relations between exercise and memory are complex, and various studies also
report null or adverse effects (Roig et al. 2013). For instance, it has been suggested
that the effect of an acute exercise bout on the outcome of a memory task depends on
the timing of exercise as different phases of memory formation might be affected
differently by exercise (e.g., Roig et al. 2016; Loprinzi et al. 2019). Mechanistically,
exercise prior to encoding may improve memory through the direct facilitation of
LTP, while exercise during consolidation may enhance the stabilization of the
memory trace through the exercise-induced increase in neurotrophins. Several
studies showed that an exercise bout before encoding and during early and late
consolidation can enhance memory functioning (Loprinzi et al. 2019).
The benefit of exercise depends on the intensity of the exercise and the type of
memory assessed. For example, low-intensity exercise prior to encoding is beneficial
to WM, whereas high-intensity exercise before encoding enhances EM (Loprinzi
2018). Similarly, the duration of the exercise bout can affect memory functioning:
Shorter bouts (<40 min) seem to be more favorable than longer durations, possibly
due to exercise-induced fatigue (Roig et al. 2013; Crush and Loprinzi 2017). In
summary, the variation in exercise protocols complicates comparisons between
studies and impedes the determination of the right amount of exercise to improve
memory functioning. Standardization of exercise paradigms would facilitate a more
effective leverage of each exercise study (Basso and Suzuki 2017).

3.3 Different Populations as Moderator

The effect of exercise on memory may also depend on the population under study.
For example, several studies suggest that while exercise has the potential to enhance
memory function, the extent of these gains appears to depend on baseline fitness
levels. Specifically, individuals with lower fitness levels tend to experience more
memory improvements after exercise (e.g., Roig et al. 2013; Pena et al. 2022).
Likewise, sex assigned at birth (i.e., differential results for males and females for
different aspects of executive functioning, (Barha et al. 2019)) and age may moder-
ate the effect of exercise (i.e., younger adults show greater memory improvements
after an exercise session (Roig et al. 2013)). While this effect regarding age is of
interest from a developmental perspective, this result does not imply that exercise is
not effective for older adults. Stute et al. (2020), for example, showed that a
moderate-intensity exercise bout (15 min; cycling at 50% VO2max) directly improves
Exercise and Memory 145

WM performance in older adults (<64 years). However, more studies are needed
that focus specifically on the direct effect of exercise on older adults. Regular
exercise, on the other hand, has been intensively studied as a tool to postpone
cognitive decline in the aging population (e.g., Blondell et al. 2014; Sofi et al.
2011; see Chapter “Exercise and Cognitive / Age-Related Decline”). Similarly,
chronic exercise gained interest as an intervention for specific populations with
memory problems such as dementia (e.g., Huang et al. 2022), post-stroke (e.g.,
Yang and Wang 2021), Parkinson’s disease (PD) (e.g., Murray et al. 2014), depres-
sion (e.g., Morres et al. 2019; see Chapter “Exercise and Depression”), anxiety (e.g.,
Bartley et al. 2013; see Chapter “Exercise and Anxiety”), and posttraumatic stress
disorder (e.g., Crombie et al. 2023a; see Chapter “Exercise and PTSD”). However, it
should be noted that although most of these patients are troubled with varying types
of specific memory problems, exercise can affect the broad spectrum of memory
types and, thus, work differently for different (combinations of) mental and somatic
conditions. In the following, we will therefore summarize the effects of exercise on
different memory types and focus on experimental studies using acute exercise bouts
to improve memory functioning in healthy and patient populations.

4 Exercise on Different Memory Types

4.1 Working Memory

WM is vital for our daily functioning and WM impairment affects our mental health.
Hence, it is of functional and clinical interest to improve WM functioning among
those with WM impairment. While a recent meta-analysis of randomized controlled
trials showed that chronic exercise has a small, positive effect on WM in cognitively
and physically healthy participants, results for single exercise sessions are less
consistent (Rathore and Lom 2017). According to this meta-analysis, acute exercise
does not directly improve WM in healthy participants (Rathore and Lom 2017).
However, the studies included in the analysis of acute exercise were very heteroge-
neous, which limits the interpretation of the results. A crucial factor that affects the
impact of exercise is the test used to assess WM. Different WM tasks (e.g., n-back
task, digit span test, and Sternberg task) tap into different components of WM, which
can lead to differential results. To illustrate, Gothe et al. (2013) did not find
superiority for moderate-intensity exercise (20 min; treadmill at 60–70% of esti-
mated maximal heart rate; MHR) compared to yoga or resting in improving WM
assessed with the n-back task. In comparison, Pontifex et al. (2009) showed that
acute treadmill exercise (30 min; 60–70% VO2max) compared to resistance training
(three sets of 8–12 repetitions at 80% of their one-repetition maximum) improved
reaction time during the Sternberg test. Similar results are also found in clinical
populations. Moriya et al. (2016), for example, investigated the effect of moderate-
intensity exercise (15 min; cycling at 40% VO2max) on WM in post-stroke patients
with the Sternberg task and found positive results. In contrast, Meyer et al. (2022)
146 M. Schmitter and J. N. Vrijsen

did not find superiority for cycling (30 min; perceived exertion (RPE) of 13)
compared to rest in improving WM measured with the 2-back task in depressed
patients.
A WM-based process involved in the onset and maintenance of depression and
anxiety disorders is rumination. Rumination is defined as the repetitive replay of
negative information (Nolen-Hoeksema et al. 2008) and is related to deficits in
inhibition, shifting, and updating of WM. Although previous research showed that
chronic exercise appears to diminish rumination (Craft 2005) and that an acute
exercise bout (30 min; cycling at 60–70% MHR) can attenuate the effect of rumi-
nation after a stressor (Bernstein and McNally 2017, 2018), no direct decrease in
rumination after moderate-intensity exercise (30 min; cycling at 70% MHR) has
been observed (Schmitter et al. 2023). In conclusion, the results on the direct effect
of exercise on WM are mixed and depend on the test used to assess WM. More
research is warranted to identify which processes within the WM domain are
affected by exercise.

4.2 Procedural Memory

Studies investigating the effect of exercise on PM usually use motor skill learning as
an outcome. For example, Roig et al. (2012) showed that for healthy individuals,
15 min of intervallic cycling at high intensity (2 min of warm-up at 75 W, followed
by 3 × 3 min blocks of high intensity, interspersed with 3 × 2 min blocks of low
intensity at 50 W in between; where high-intensity workload was adjusted to each
subject’s VO2peak), prior to and after practicing a visuomotor accuracy-tracking task,
improved retention of the motor skill more than resting. Especially high-intensity
exercise seems to benefit PM (Thomas et al. 2016), although this kind of intensity
may not be feasible in rehabilitation centers where exercise could be implemented to
improve motor skill learning. However, initial evidence suggests that moderate-
intensity cycling before or after a motor skill task is sufficient to improve retention in
patients with PD ((Steib et al. 2018); where exercise intensity was based on 60–70%
VO2max; (Wanner et al. 2021); where exercise intensity was based on ≥60 rpm
[RPM] and Wmax) and presymptomatic and early manifest Huntington’s disease
(HD) ((Andrews et al. 2023); where exercise intensity was based on 50–55% of heart
rate reserve; HRR). Overall, clinical trials demonstrated so far that exercise is an
effective strategy for symptom management in patients with neurodegenerative
diseases (e.g., Mak et al. 2017). Although the effect of exercise on PM specifically
has not been extensively investigated, the results so far are promising as well. Future
studies would benefit from larger samples and extensive randomized controlled trials
(RCT) that include motor skill learning as an outcome.
Exercise and Memory 147

4.3 Semantic Memory

Though under-investigated (Loprinzi 2019), from a biological viewpoint it is plau-

sible that acute exercise improves SM. For example, Won et al. (2019) investigated
brain activation during a semantic memory task after exercise (30 min; cycling at
RPE 15; vs rest), with aid of functional magnetic resonance imaging (fMRI), in a
counter-balanced within-subject design, including healthy older adults. The authors
found significantly greater brain activation during the task after exercise (vs rest), in
the brain regions implicated in semantic memory (i.e., middle frontal, inferior
temporal, middle temporal, fusiform gyri, and bilateral hippocampus) (Won et al.
2019). To the best of our knowledge, only one experimental study (Day and Loprinzi
2019) has specifically investigated the effect of acute exercise (15 min; treadmill at
70% MHR; vs rest) on general SM in healthy participants. In this study, participants
were instructed to recall words from two specific categories (i.e., animals and
vegetables). Exercise, however, did not result in more correct recall. Yet, chronic
exercise (12 weeks, spinning three times per week, gradually increased in intensity
and duration) was found to improve SM in older adults (<65 years) more than the
control condition (Nocera et al. 2015). More studies are needed to draw conclusions
about the (lack of) acute effects of exercise on SM.

4.4 Episodic Memory: Neutral and Emotional Recall

A meta-analysis (Loprinzi et al. 2019) showed that acute exercise before encoding or
during consolidation can enhance EM. Most of the studies included in this meta-
analysis used word-recall paradigms, indicating that an exercise bout can directly
improve neutral, episodic memories. Less is known about the impact of exercise on
emotional memories that evoke a strong emotional reaction. To illustrate, Keyan and
Bryant (2017) invited healthy participants to the laboratory where they first watched
a car accident film to trigger an emotional state, and then exercised at high intensity
(stepping exercise based on the Karvonen formula: 50–85% (MHR – Rest HR) + Rest
HR where MHR was estimated using an age calculated formula (220 beats per
minute – age)) or walked for 10 min. The authors found that participants in the
exercise condition reported more intrusive memories 2 days later (Keyan and Bryant
2017). However, these results have not been replicated so far. In a series of
laboratory studies, Loprinzi et al. (2022) showed that acute exercise of different
intensities did not affect emotional memory performance in healthy participants,
using the same car accident film as Keyan and Bryan (2017). Crombie et al. (2023b)
examined the effect of exercise on fear-related memory after extinction learning in
healthy females. Participants first completed a fear acquisition training and then on
the next day a fear extinction training followed by moderate-intensity exercise
(30 min; cycling at 70–75% MHR) or low-intensity exercise (40–50% MHR). The
next day, the participants returned to the lab for a fear recall test. The authors found
148 M. Schmitter and J. N. Vrijsen

that moderate-intensity exercise had a beneficial effect on memory for items learned
during extinction training. Regarding the inconsistency of study results, more studies
are needed to better understand how exercise affects the encoding and (re)-
consolidation of emotional memories.

4.5 Episodic Memory: Autobiographical Memory

Another part of EM is autobiographical memory. Day and Loprinzi (2019) investi-

gated the effect of acute exercise (15 min; treadmill at 70% MHR) on autobiograph-
ical recall, in which participants had to recall as many personal memories as possible
from their childhood and adolescence. No differences were found between exercise
and rest conditions. In MDD, autobiographical memories tend to be overly general,
lacking details about place and time (Gotlib and Joormann 2010). Schmitter et al.
(2023) assessed whether an acute exercise bout (30 min; cycling at 70% MHR) after
a negative mood induction can improve the amount of detail in autobiographical
memories in healthy participants but did not detect any differences between exercise
and rest. In summary, exercise can directly improve the recall of neutral material, but
the effect of exercise on emotional and autobiographical memories is less understood
and needs further investigation.

4.6 Episodic Memory: Pattern Separation

Pattern separation is hypothesized to strongly depend upon hippocampal function, a

canonically important brain region where different types of information are inte-
grated to form a unique long-term memory. If pattern separation is impaired,
mnemonic discrimination is poor. Importantly, here the term “discrimination” refers
to the behavioral measure of the neural process. Mnemonic discrimination is often
assessed with object recognition tasks (e.g., Mnemonic Similarity Task; MST). For
example, participants are shown everyday objects during encoding and then asked to
identify each object as “old,” “new,” or “similar” during recognition. Other discrim-
ination tasks use variations in spatial information of previously seen objects or in the
temporal lag between events. Discrimination difficulties arise as part of aging, but
are also found in psychological disorders such as anxiety or depression (Leal and
Yassa 2018). In anxiety disorders, poor pattern separation may manifest as fear
generalization (Bernstein et al. 2021; Lange et al. 2017), where patients feel anxious
in reaction to stimuli (e.g., physical sensations in panic disorder or social situations
in social anxiety disorder) that resemble a past, threatening experience. Better
discrimination between past events and similar, but different, new events may help
reduce anxious responses to the similar new events, which is also the goal of
exposure-based therapy (see Chapter “Exercise and Fear Learning and Extinction”).
In depression, pattern separation is diminished for neutral information, but enhanced
Exercise and Memory 149

for negative information (Yassa and Stark 2011). Impaired pattern separation may
result in a blurring of negative and neutral information, leading to a greater likeli-
hood of interpreting ambiguous information in a negative way (Yassa and Stark
2011), in line with a depressotypic negative memory bias (e.g., Everaert et al. 2022).
Because exercise improves hippocampal functioning (e.g., Kandola et al. 2016),
it is plausible that exercise exerts an effect on pattern separation. Initial evidence
derived from studies with healthy, young adults (Déry et al. 2013; Suwabe et al.
2017, 2018) supports this assumption. For example, Suwabe et al. (2017) examined
the effect of acute moderate-intensity exercise (10 min; cycling at 50% VO2max; vs
rest) on pattern separation assessed with the mnemonic discrimination task and
found that the exercise condition showed better separation between highly similar
items. Nauer et al. (2020) investigated whether regular exercise can also attenuate
the age-related decline in mnemonic discrimination and found positive results.
Comparably, Callow et al. (2022) showed in a paradigm that moderate-intensity
cycling (13–15 RPE) directly elicited better mnemonic discrimination in older
adults. Similarly, in a follow-up study, the authors found evidence for better
discrimination after acute moderate exercise (30 min; RPE 15), using a counter-
balanced design. Mnemonic discrimination after acute exercise (vs rest) was better
among those participants with lower baseline fitness (Pena et al. 2022). To the best of
our knowledge, no study directly investigated the effect of exercise on mnemonic
discrimination in patients with anxiety or depression. Yet, compelling evidence
shows that exercise is an effective treatment for both disorders (e.g., Morres et al.
2019; Stubbs et al. 2017). For anxiety disorders, the exercise-induced discrimination
improvements may contribute to improved fear extinction learning (see
Chapter “Exercise and Fear Learning and Extinction”) and therefore, impact the
anxiolytic effect of exercise. In depression, improving pattern separation through
exercise may help reduce the negative memory bias, which is also a goal of
cognitive-behavioral therapy for depression. Schmitter et al. (2023) examined this
idea in an experimental setting. Interestingly, the authors found that aerobic exercise
(30 min; cycling at 70% MHR) resulted in more negative memory bias than rest,
among healthy participants with higher levels of rumination. From this study, it
seems that a single exercise session is not sufficient to improve negative memory
bias or possibly mnemonic discrimination. In conclusion, exercise seems to benefit
pattern separation in the hippocampus which enables us to discriminate between
similar experiences and might be reduced in psychological disorders and the aging
population. Although the initial results with healthy participants are promising,
future laboratory studies are needed to test the effect of exercise directly on mne-
monic discrimination in clinical populations. Collectively, we have shown so far that
exercise may directly benefit different types of memory in different populations,
although results are mixed and future research warranted. In the following, we will
briefly discuss the relevance and promise of implementing exercise in daily life and
clinical settings.
150 M. Schmitter and J. N. Vrijsen

5 Relevance and Promise of Exercise to Improve Memory

Functioning

Our memory enables us to perform simple activities every day, to learn and under-
stand, and to interact with the world around us. Therefore, maintaining and improv-
ing memory functioning is crucial in many ways. Because regular exercise positively
affects our memory, it offers several opportunities as intervention and prevention
program. For example, exercise in the school setting may directly boost the learning
ability of children. Similarly, it can delay the onset of memory loss in populations at
risk for dementia and prevent developing emotional disorders such as depression or
anxiety.
Furthermore, acute exercise has the potential to directly improve treatment out-
comes in clinical settings. Cognitive and physical therapies depend on the patient’s
learning and memory capacity. Because a single exercise session directly improves
memory of cognitive and motor skills, strategically timing exercise in close prox-
imity to therapy sessions could augment clinical outcomes of therapy. This concept
has also been termed “exercise priming” (Moriarty et al. 2019). Exercise priming in
practice involves acute exercise stimulation prior to or directly after treatment. For
example, exercise before cognitive behavioral therapy for patients with anxiety and
depression or before physical therapy for patients with HD or PD. We believe that
exercise priming holds great promise as a simple and effective way to enhance the
outcomes of cognitive-behavioral and physical therapies, partly due to exercise’s
impact on memory processes. By capitalizing on the immediate benefits of acute
exercise, patients may experience faster recovery. With ongoing research in this
area, exercise priming may become a valuable addition to a range of therapeutic
approaches for a variety of conditions.

6 Conclusion

Exercise is a simple and safe intervention that may protect our memory function and
promote our mental well-being. Therefore, it is crucial to prioritize the implemen-
tation of exercise in both our daily life and clinical settings. However, despite the
recognized benefits, there is much to discover about the exact memory-based effects
and mechanisms of change of exercise. Open question are: The exact domains of
memory impacted by exercise, the precise mechanisms by which exercise influences
memory, the most effective exercise protocols, and whether there exists a perfor-
mance threshold beyond which exercise ceases to yield additional gains. Of course,
all these factors are interactive (e.g., the ideal exercise protocols and performance
thresholds likely vary for specific memory domains). Through thoughtful research
programs and translational endeavors, we can move further toward in-depth under-
standing of the exercise-memory link, in turn contributing to mental health
promotion.
Exercise and Memory 151

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 Part III
Exercise and Clinical Symptoms
and Treatment
Exercise for the Prevention and Treatment
of Depression

Brandon L. Alderman, Hannah M. Perdue, and Amber H. Sarwani

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
2 Conventional Treatments for Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
3 Exercise in the Management of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
3.1 Exercise and Physical Activity for the Prevention of Depression . . . . . . . . . . . . . . . . . . . 161
3.2 Exercise and Physical Activity for the Treatment of Depression . . . . . . . . . . . . . . . . . . . . 163
4 Symptoms of Depression Undermine Exercise Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
5 Tailored Exercise Prescriptions for Depression Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

Abstract Depression is among the world’s leading causes of disability and

accounts for a significant loss of life. Despite large investments in research for
antidepressants and psychotherapies, non-response, partial response, and small
effects remain significant problems. Exercise and physical activity are two lifestyle
behaviors that have been studied for well over half a century for the prevention and
treatment of depression. The aim of this chapter is to summarize the current evidence
base supporting the efficacy of exercise and physical activity in the prevention and
treatment of depression, including evidence supporting exercise as a monotherapy
and adjunct to antidepressant medication and psychotherapies. We conclude the
chapter by outlining challenges to prescribing exercise for depression and general
recommendations for encouraging behavioral adoption for individuals suffering
from depression.

Keywords Behavioral Intervention · Depression · Exercise · Lifestyle Physical

Activity · Mental Health

B. L. Alderman (✉), H. M. Perdue, and A. H. Sarwani

Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 157
Curr Topics Behav Neurosci (2024) 67: 157–176
https://doi.org/10.1007/7854_2024_496
Published Online: 24 July 2024
158 B. L. Alderman et al.

1 Introduction

Depression is a common, debilitating, and often recurrent disease characterized by

persistent feelings of sadness, worthlessness, and a lack of interest or pleasure in
previously enjoyable or rewarding activities. Clinical depression, or major depres-
sive disorder (MDD), goes well beyond the normal vicissitudes of life and can
significantly impair a person’s social, occupational, and overall well-being. Glob-
ally, more than 300 million people suffer from depression, and it is recognized as a
leading cause of avoidable suffering worldwide (World Health Organization 2017).
It is estimated that over 20 million adults in the United States will have at least one
major depressive episode during their lifetime, a figure that represents over 8% of all
US adults (Brody et al. 2018). The prevalence rate of major depression is higher
among females compared to males and is highest among individuals aged 18–25
years and for those who report being two or more races (13.9%) (Substance Abuse
and Mental Health Services Administration 2021). Although there are different types
of depressive disorders, clinical depression, or MDD is often just referred to as
“depression.”
Depression is formally diagnosed using the Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (American Psychiatric Association 2013). Diagnos-
tic criteria include the presence of at least one of the two cardinal symptoms of a
depressed mood and diminished interest or pleasure in previously enjoyable activ-
ities (i.e., anhedonia). Additional symptoms of depression include a significant
change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or
retardation, fatigue or loss of energy, feelings of worthlessness or excessive/inap-
propriate guilt, difficulty thinking and concentrating, and thoughts of death or
suicide. To be diagnosed with depression, an individual must experience five or
more of these symptoms for more than 2 weeks, which cause significant emotional
distress or impair normal day-to-day functioning (World Health Organization 2017;
American Psychiatric Association 2013). Depression is characterized by pronounced
heterogeneity. Estimates indicate that at least 227 and possibly up to 681 different
combinations of symptoms may result in a formal diagnosis of depression (Fried and
Nesse 2015). In addition, people may suffer from more minor or subsyndromal
depression or dysthymic disorder, which can significantly impair one’s quality of life
(Judd et al. 1994; Baune et al. 2009). At the extremes, depression is associated with
an increased risk for numerous chronic health conditions (Moussavi et al. 2007) and
death by suicide, particularly among adolescents and young adults (Orsolini et al.
2020).
The exact causes of depression remain unknown; it likely results from a combi-
nation of genetic, biological, and psychological vulnerability factors. Therefore,
depression is a common but poorly understood health condition with imprecise
causal origins. Depression is also highly comorbid with other mental health condi-
tions. For instance, nearly three-quarters of all people who meet criteria for depres-
sion during their lifetime will also meet criteria for another psychiatric disorder,
including anxiety and substance use disorders (DeRubeis et al. 2008). In the United
Exercise for the Prevention and Treatment of Depression 159

States, the economic burden of depression increased by 21.5% from 2000 to 2010
(from $173.2 billion to $210.5 billion, inflation-adjusted dollars), with approxi-
mately 45% attributable to direct costs, 5% to suicide-related costs, and 50% to
workplace costs (Greenberg et al. 2015). Over this same time period, the proportion
of adults who received treatment for depression remained stable, suggesting a critical
need for effective approaches to prevent and treat depression.

2 Conventional Treatments for Depression

Conventional treatments for depression typically consist of antidepressant medica-

tions or psychotherapy. The most commonly prescribed antidepressants include
selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine,
paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (e.g.,
venlafaxine and desvenlafaxine), and norepinephrine and dopamine reuptake inhib-
itors (e.g., bupropion) (Luo et al. 2020; Milea et al. 2010). The primary mechanism
of action of these medications involves inhibiting the transporters responsible for the
reuptake of these brain monoamine neurotransmitters into presynaptic neurons,
increasing their availability and thereby enhancing neurotransmission (Feighner
1999). This evidence led, in part, to the notion that these neurotransmitters play a
significant role in the etiopathogenesis of depression (i.e., that depression is caused
by low levels of serotonin, norepinephrine, or dopamine in the central nervous
system) (Artigas et al. 2002). Although the monoamine hypothesis of depression
provides a plausible neurobiological explanation for the actions of antidepressants,
this mechanism does not provide a complete explanation for the etiology of depres-
sion (Jesulola et al. 2018; Hirschfeld 2000). Rather, it is likely that a combination of
biological, psychological, and social hypotheses (e.g., genetic vulnerability, child-
hood experiences, hormonal imbalances, major life events, and low socioeconomic
status) will help to explain this heterogeneous and etiologically complex disorder.
Although antidepressants are effective for many people, they are not consistently
beneficial. A review of four meta-analyses of efficacy trials submitted to the US
Food and Drug Administration and findings from the Sequenced Treatment Alter-
natives to Relieve Depression (STAR*D) trial, the largest open trial of antidepres-
sant effectiveness ever conducted, concluded that antidepressants are only
marginally efficacious compared to placebos (Pigott et al. 2010). In addition to
their questionable efficacy, antidepressant medications can be costly (Arnaud et al.
2021) and are often associated with unpleasant or intolerable side effects (e.g.,
nausea, constipation, weight gain, upset stomach, sexual dysfunction, headache,
drowsiness, and difficulty sleeping, among other side effects) (Cascade et al. 2009;
Wang et al. 2018). The stigma and fear of dependency associated with taking
antidepressant medications also preclude many individuals from seeking or continu-
ing treatment (Mechanic 2002; Castaldelli-Maia et al. 2011). Although thousands of
clinical trials have been conducted to examine the efficacy of antidepressant medi-
cations, many of these trials have been limited to 8–12 weeks. This short duration of
160 B. L. Alderman et al.

clinical trials limits our understanding of the potential consequences of long-term

antidepressant use. In a mixed methods study, patients reported that antidepressants
improved their depression episodes and symptoms, yet many reported concerns
about withdrawal and adverse emotional effects, such as feeling emotionally numb
and addicted (Cartwright et al. 2016). In addition, some patients expressed a need for
more information about the potential long-term risks of antidepressants and infor-
mation and support to discontinue their use. Some evidence suggests that using
psychotherapy while tapering from antidepressants may be a successful approach to
prevent relapse, with an effect comparable to continuing medication use (Breedvelt
et al. 2021).
Like antidepressant medications, hundreds of randomized controlled trials
(RCTs) have examined the efficacy of psychological treatments for depression.
Psychological therapies, including cognitive behavioral therapy (CBT), work by
helping individuals learn to recognize and change negative thought patterns and
behaviors to better cope with stressful life events and challenging situations. Other
types of psychological therapies for depression include interpersonal psychotherapy,
problem-solving therapy, and behavioral activation. These treatments have demon-
strated comparable efficacy to antidepressant medications for reducing depression,
and some studies suggest the benefits may be longer-lasting (Cuijpers and Gentili
2017). However, like antidepressants, response rates to psychotherapies vary widely,
with ranges of 38–87% reported for depressive and anxiety disorders relative to care-
as-usual, waitlist, and pill placebo control groups (Cuijpers et al. 2021). Unfortu-
nately, the public health impact of psychotherapy is limited by factors such as the
costs, availability of trained therapists, and perceived inconvenience of traveling to
weekly face-to-face sessions (Thase et al. 2020). Furthermore, the findings surround-
ing the benefit of psychotherapies reported in the research literature have been
considerably overestimated, likely due to publication bias, sub-optimal quality of
experimental trials, and the use of “nocebo” waiting list control groups, which may
result in negative effects relative to the use of care-as-usual or pill placebo compar-
ison groups (Cuijpers et al. 2016). The efficacy of psychological treatments may also
depend on the quality of the practitioner (Stubbe 2018), the nature of the intervention
(e.g., face-to-face, group-based, and Internet delivered) (Kambeitz-Ilankovic et al.
2022), and individual preferences (Steidtmann et al. 2012). Regardless, psychother-
apy, like antidepressants, is effective for many people, helping them to manage their
depressive symptoms (Cuijpers et al. 2013).
The availability of antidepressant medications and psychotherapy has increased
markedly over the past three decades (Kovich et al. 2023). However, the general
population prevalence of depression has not decreased over the same period of time
(Ormel et al. 2022). This “treatment-prevalence paradox” has raised fundamental
questions about the treatment of depression, including how to tailor the most
effective treatment for each patient (i.e., personalized medicine) (Ormel et al.
2022). Despite an array of antidepressant and psychotherapy options, there is
currently no empirically validated approach to match patients to optimal treatments,
and many patients go on to develop treatment-resistant depression over time. As a
Exercise for the Prevention and Treatment of Depression 161

result, clinical treatment for depression remains largely based on trial and error and
the preferences of the primary care provider.

3 Exercise in the Management of Depression

Arguments for the use of alternative treatments for depression often include the
unpleasant side effects of antidepressant medications (Cascade et al. 2009; Wang
et al. 2018), costs of treatment (Arnaud et al. 2021), and difficulty accessing
in-person treatment (Mohr et al. 2010) along with the limited efficacy of existing
treatments. However, alternative treatment approaches for depression warrant the
same level of evaluation as conventional treatments. Research conducted over the
past 50 years supports a clinically meaningful impact of exercise and physical
activity for the prevention and treatment of depression (Meyer and Schuch 2018;
Blumenthal and Rozanski 2023; Cooney et al. 2013; Martinsen 1990). Although
early cross-sectional and intervention studies focused on cardiorespiratory fitness
and exercise per se (North et al. 1990; Greist et al. 1979), more recent studies have
broadened the focus to include lifestyle physical activity, defined as any bodily
movement produced by skeletal muscles that results in an increase in energy
expenditure and includes recreational, occupational, or household-based physical
activities that can be accumulated throughout the day (Caspersen et al. 1985; Farris
and Abrantes 2020). Although exercise and physical activity have been recognized
as important lifestyle behaviors for millenia (Tipton 2014), the seminal studies
conducted by William P. Morgan in the late 1960s and early 1970s helped to
bring contemporary scientific attention to the potential for exercise to prevent and
treat depression. Morgan found that patients with depression tended to have lower
cardiovascular fitness and physical capacity compared to their non-depressed coun-
terparts (Morgan 1969, 1970). Since these early studies, there have been a large
number of cross-sectional and epidemiological studies that support the utility of
exercise as a stand-alone or adjunctive treatment for depression (Blumenthal and
Rozanski 2023). There have also been an increasing number of RCTs conducted to
compare exercise and physical activity to usual care, placebo controls, or established
therapies in treating depression (Blumenthal and Rozanski 2023). Below, we present
the evidence supporting the role of exercise and physical activity in the prevention
and treatment of depression.

3.1 Exercise and Physical Activity for the Prevention

of Depression

The potential for exercise and physical activity to prevent depression has been
examined in numerous cross-sectional and prospective epidemiological studies. In
162 B. L. Alderman et al.

one of the earliest cross-sectional studies, Farmer and colleagues (Farmer et al. 1988)
examined the relationship between self-reported physical activity and depressive
symptoms among 1,900 healthy adults between the ages of 25 and 77 years from the
Epidemiologic Follow-up Study (1982–1984) to the first National Health and
Nutrition Examination Survey (NHANES I). There was an almost twofold increase
in the odds of experiencing increased depressive symptoms among individuals who
reported little-to-no physical activity compared to those engaging in moderate or
high activity. Goodwin (2003) similarly examined the association between self-
reported physical activity and depression among 5,877 Americans aged between
15 and 54 years who participated in the National Comorbidity Survey (1990–1992),
a nationally representative survey to better understand the prevalence, risk factors,
and consequences of psychiatric morbidity and comorbidity. Physical activity was
assessed using a single item that asked, “How often do you get physical exercise –
either in your job or in a recreational activity?” with response choices of regularly,
occasionally, rarely, and never. Depression status was confirmed using a structured
interview (the World Health Organization Composite International Diagnostic Inter-
view). Individuals who reported no regular physical activity were more likely to be
depressed relative to those who reported regular physical activity engagement. The
findings also suggested a potential dose-response relationship: depression was least
prevalent among individuals who regularly engaged in physical activity (8.2%)
compared to those who occasionally (11.6%), rarely (15.6%), or never (16.8%)
engaged in physical activity. Interestingly, Goodwin noted that the observed asso-
ciation between physical activity and depression could be explained through reverse
causation, with depression leading to less physical activity. The temporal nature of
the relationship between physical activity and depression (i.e., does physical inac-
tivity precede an increase in depressive symptoms, or vice versa) can be tested
through prospective epidemiological studies.
In a prospective cohort study, Gudmundsson et al. (2015) examined the relation-
ship between physical activity and depressive symptoms among 676 women
followed over a period of 32 years (1974–2005, with follow-up assessments
conducted in 1992, 2000, and 2005). The repeated assessments allowed the inves-
tigators to test the directionality of the relationship between physical activity and the
symptom burden of depression. In 1974 at baseline, women who engaged in lower
levels of physical activity also reported greater depressive symptoms. Across time, a
decrease in physical activity was also associated with higher depression scores. In
support of the reverse causality pathway mentioned by Goodwin (2003), higher
depression scores at earlier assessments predicted lower levels of physical activity at
subsequent examinations, but not vice versa. However, many additional prospective
studies have been conducted to help answer the temporality question.
Mammen and Faulkner (2013) reviewed the available published prospective
longitudinal studies to determine whether physical activity is protective against the
onset of depression. A total of 25 of the 30 reviewed studies found a significant
inverse relationship between baseline physical activity levels and subsequent depres-
sion, suggesting that physical activity can prevent the onset of depression. They also
reported that engaging in as little as 10–29 min of daily physical activity could
Exercise for the Prevention and Treatment of Depression 163

reduce the subsequent risk for depression by approximately 10%. Dishman et al.
(2021) conducted a review and meta-regression analysis of 111 studies, including
more than three million people, to determine whether the odds of depression vary
according to the amount of physical activity or change in physical activity exposure
across time. This evidence is important for clinical practice and for satisfying
minimal criteria (e.g., strength of association, consistency, temporal sequence, and
dose–response) in observational studies for a possible causal association between
physical activity and depression. Lower odds for depression were associated with:
(World Health Organization 2017) moderate-to-vigorous physical activity in line
with public health guidelines; and (Brody et al. 2018) increases in physical activity
across time.
Choi et al. (2019) examined physical activity and depression data from the UK
Biobank Study to test the causal pathway between physical activity and depression.
Using a Mendelian randomization approach, they reported that for each 1 SD unit
increase in accelerometer-based physical activity there was a 26% reduction in risk
for developing depression. This 1 SD increase in physical activity was equivalent to
replacing sedentary time (e.g., sitting) with 15 min of vigorous physical activity,
60 min of moderate activity, or a combination of light and vigorous activities. No
associations were observed between the pathway from depression to physical activ-
ity, providing support for the causal pathway of physical activity reducing the
likelihood of depression. There is also evidence suggesting a potential dose–
response relationship between physical activity and future depression. A review of
15 studies comprising 191,130 participants revealed an inverse dose–response
association between physical activity and depression (Pearce et al. 2022). Relative
to adults not reporting any activity, those who accumulated half of the recommended
volume of physical activity had an 18% lower risk of depression while adults who
accumulated the recommended volume of physical activity per week (equivalent to
2.5 h/week of brisk walking) had a 25% lower risk of depression. Based on an
estimate, if less active adults achieved current physical activity recommendations,
11.5% of depression cases could be prevented. Although it is possible that the
relationship between physical activity and depression is bidirectional in nature
(Stavrakakis et al. 2012), the findings from these reviews support lifestyle physical
activity for the prevention of depression and depressive symptoms.

3.2 Exercise and Physical Activity for the Treatment

of Depression

The use of exercise as a treatment for depression has gained considerable traction, as
evidenced by the inclusion of exercise in recent depression and mood disorder
treatment guidelines published by the American Psychiatric Association (Rethorst
and Trivedi 2013), the Canadian Network for Mood and Anxiety Treatments
(Ravindran et al. 2016), and the Royal Australian and New Zealand College of
164 B. L. Alderman et al.

Psychiatrists (Malhi et al. 2015). However, despite this recognition, the American
Psychiatric Association’s clinical guidelines included the statement, “...if a patient
with mild depression wishes to try exercise alone for several weeks as a first
intervention, there is little to argue against it...” (Gelenberg 2010 (p. 30)). This
statement, from one of the largest psychiatric organizations in the world, seems
incompatible with the available research evidence on the use of exercise as a
therapeutic lifestyle intervention for depression. Moreover, patients who may have
the most to benefit from exercise (e.g., those who present with higher depressive
symptoms, are inactive, or have comorbid health conditions) may be relatively
uninformed about the benefits of exercise or less inclined to try exercise as a first-
line therapy for depression. One way to provide convincing evidence for the
therapeutic potential of exercise for depression is from gold standard RCTs.
In an early RCT, Blumenthal et al. (1999) randomized 156 adults with depression
who were 50 years of age and older to a 4-month treatment of aerobic exercise,
standard antidepressant treatment with sertraline, or a combination of aerobic exer-
cise plus sertraline. For the exercise program, participants attended three supervised
sessions per week in a group setting and were prescribed walking or jogging at 70%–
85% of heart rate reserve (HRR), a range of vigorous intensity that accounts for the
difference between maximal and resting heart rate. Although patients receiving
sertraline monotherapy exhibited the fastest initial response relative to the exercise
alone and combined treatment groups, all three groups showed comparable reduction
in depressive symptoms by the end of the 16-week intervention. The rates of
participants who no longer met criteria for depression (i.e., remission) were 60.4%
in the exercise group, 65.5% in the medication group, and 68.8% in the combined
treatment group. These findings suggest comparable improvements in depressive
symptoms and remission from depression from exercise and antidepressant medica-
tion, even among patients with more severe depression.
Six months following the intervention, Babyak et al. (2000) found that individ-
uals assigned to the exercise monotherapy group had significantly lower rates of
depression (30%) compared to the sertraline (50%) or combined treatment (55%)
groups, suggesting that exercise monotherapy may help to decrease depression
relapse. During the follow-up period, physical activity levels were also associated
with lower depressive symptoms, while the use of antidepressant medications was
not associated with depression. Blumenthal and Rozanski (2023) noted that several
questions remained following this initial RCT, including whether the improvements
were the result of a placebo effect, spontaneous remission, or demand characteristics
inherent to the study (e.g., expectation of benefit or the increased attention provided
to participants by the study staff). Because participants exercised in a group setting,
it is also possible that enhanced social support further enhanced the antidepressant
benefits of exercise. To address these questions, Blumenthal et al. (2007) random-
ized 202 participants with depression to the following groups for 16 weeks: (a) super-
vised group exercise, (b) home-based aerobic exercise, (c) antidepressant medication
(sertraline, 50–200 mg daily), or (d) a placebo pill. At end of treatment, 41% of the
patients achieved remission, and all active treatment groups had greater remission
rates compared to the placebo pill group (45% for supervised exercise, 40% for
Exercise for the Prevention and Treatment of Depression 165

home-based exercise, and 47% for those receiving medication, compared with only
31% who received the pill placebo). Exercise had comparable efficacy to antide-
pressant medication, and both exercise and medication tended to be better than the
placebo group. These two RCTs helped to establish the efficacy of exercise as a
stand-alone and adjunctive treatment for depression, with comparable effects to
antidepressant medications.
In addition to the question of overall efficacy, several issues remain to be studied
within the context of treating depression with exercise and physical activity. For
instance, prescribing exercise remains a challenging endeavor due in part to the
number of program variables involved (e.g., frequency, intensity, and duration of
exercise sessions as well as treatment length) and the type of exercise performed. For
instance, although the early research evidence was primarily focused on aerobic
forms of exercise, more recent studies—including RCTs—are beginning to focus on
resistance exercise (Gordon et al. 2018; O’Sullivan et al. 2023). Gordon and
colleagues conducted a meta-analysis of published RCTs and found that resistance
exercise training programs were associated with a significant reduction in depressive
symptoms, regardless of study participants’ characteristics (age, sex, and health
status) or features of the exercise stimulus (program duration, session duration,
intensity, frequency, or total prescribed volume). Given the rising popularity of
resistance exercise, particularly among younger adults who are at higher risk for
depression (Mojtabai et al. 2016), these findings are promising for tailoring exercise
prescriptions while considering individual preferences toward exercise.
Establishing the optimal or minimal dose of physical activity to produce health
benefits has been a focus of scientific interest since the early 2000s (Kesaniemi et al.
2001). At the time, aerobic exercise training for 6–12 weeks was believed to be
consistently associated with a reduction in depressive symptoms of a magnitude
comparable to that observed following treatment with antidepressants; however, the
evidence base at the time was insufficient to support a dose–response relationship
between physical activity and depression. Indeed, an umbrella review of systematic
reviews showed that exercise interventions that last ≤12 weeks have an effect size of
0.84, but this antidepressant response drops to 0.46 for exercise interventions lasting
12–23 weeks and further drops to 0.28 for exercise interventions lasting ≥24 weeks
(Singh et al. 2023a). It is important to determine whether the initial antidepressant
response from exercise can be sustained over time and whether exercise program
variables (frequency, intensity, duration) moderate the long-term antidepressant
response.
Dunn et al. (2005) randomized 80 adults aged 20–45 years diagnosed with mild-
to-moderate depression to one of four aerobic exercise treatment groups that varied
in total energy expenditure (7.0 kcal/kg/week or 17.5 kcal/kg/week) and frequency
(3 days/week or 5 days/week) or to a control group that performed light stretching
exercises 3 days/week for 15 to 20 min per session. The findings from this clinical
trial supported a dose–response effect given that the public health dose of exercise
(17.5 kcal/kg/week) led to significantly lower depression scores on the Hamilton
Rating Scale for Depression (HRSD) compared to the low dose (7.0 kcal/kg/week)
and stretching control groups. However, it is noteworthy that both the low-dose
166 B. L. Alderman et al.

exercise and stretching exercise groups also led to significant reductions in depres-
sion scores. Further, the antidepressant response and remission rates following the
public health dose are comparable to those observed following antidepressant
medication and CBT. These findings suggest that the public health dose of exercise
is likely to result in a significant and clinically meaningful reduction in depressive
symptoms. Current recommendations suggest that adults should do at least
150–300 min per week of moderate intensity, or 75–150 min per week of
vigorous-intensity aerobic physical activity, or an equivalent combination of mod-
erate- and vigorous-intensity aerobic activity spread throughout the week. Adults
should also do muscle-strengthening activities of at least moderate intensity that
includes all major muscle groups on 2 or more days per week.
Pearce et al. (2022) reviewed the dose–response association between physical
activity and incidence of depression among 15 studies, involving 191,130 partici-
pants. An inverse curvilinear association was observed, with steeper gradients at
lower volumes of physical activity. Relative to those adults not reporting any
activity, those accumulating half the recommended volume of physical activity
(approximately 75 min of moderate-intensity activity per week) had an 18% lower
risk of depression, while those who engaged in the recommended amount of physical
activity (150 min of moderate-intensity activity per week) had 25% lower risk, with
diminishing benefits beyond that exposure level. The greatest differences in risk for
depression were observed between those who were totally sedentary versus those
who were engaging in low doses of physical activity. At a population level, this
suggests that moving people from being completely sedentary to engaging in low
levels of physical activity may have a significant impact on the overall burden of
depression. At present, the available evidence suggests that the USDHHS physical
activity recommendations (Piercy et al. 2018) may be used as an initial prescription
for depression and should be modified based on physical activity history and
individual preferences.
One important consideration for treatment guidelines is that exercise may be an
effective adjunct treatment to antidepressant medication and psychotherapies (Meyer
et al. 2022). For instance, Legrand and Neff (2016) evaluated the effects of a short
add-on aerobic exercise intervention in hospitalized patients with severe depression
being treated with antidepressant medication (and no other form of therapy) for less
than 2 weeks. Thirty-five participants were randomly assigned to aerobic exercise
(n = 14), placebo exercise (stretching) (n = 11), or to a no-intervention control
group (n = 10) for 10 days. The aerobic exercise group consisted of 30 min of daily
brisk walking or jogging outdoors at 65–75% of age-predicted maximal heart rate
and the stretching group consisted of 30 min of stretching per day for 10 consecutive
days. Intent-to-treat analysis showed significant improvements in depression sever-
ity for both the aerobic exercise and stretching groups compared to the control group.
However, aerobic exercise led to a significantly larger reduction in depressive
symptoms from pre- to post-intervention compared to the control (Cohen’s d = -
1.39) group although the reductions relative to the stretching group (Cohen’s d = -
1.06) did not reach significance ( p = 0.082). This study provides further support for
the acceptability and safety of exercise, as well as its utility as an adjunctive
treatment, even among patients with more severe forms of depression.
Exercise for the Prevention and Treatment of Depression 167

A Cochrane review reported a small effect favoring exercise compared to a

no-treatment control in reducing depression, although no significant differences
were reported between exercise and psychological or pharmacological interventions
(Cooney et al. 2013). Although the clinical value of this systematic review and meta-
analysis has been questioned (Honey 2015), exercise was found to improve numer-
ous aspects of physical health, including cardiorespiratory fitness, body mass index,
and heart rate variability. Further, there are far fewer side effects associated with
exercise and patients with depression who have been randomized to exercise in
RCTs are significantly less likely to drop out compared to participants who were
allocated to the control arms in these trials (Stubbs et al. 2016). Exercise is also much
more accessible and cost-effective in comparison to both antidepressant medications
and psychotherapy (Singh et al. 2023b), making it a feasible option for patients with
depression. While antidepressants and psychotherapy remain important treatments in
the toolbox for depression, the available evidence supports the efficacy of exercise as a
monotherapy or add on to traditional treatments. However, fewer adverse side effects
and the accompanying physical health benefits may make exercise a preferable option.

4 Symptoms of Depression Undermine Exercise Behavior

Despite the numerous neurobiological benefits associated with exercise (Dishman

et al. 2006), it is important to recognize that symptoms of depression may undermine
exercise motivation. For instance, common affective symptoms of depression
include depressed mood, fatigue, and a lack of motivation or initiative (apathy).
Further, one of the core symptoms of depression (anhedonia) involves the loss of
enjoyment or interest in hobbies and activities that were once viewed as pleasurable.
These affective symptoms, combined with negative cognitions and reward system
dysfunction in depression (Admon and Pizzagalli 2015), may contribute to exercise
avoidance and intolerance (Glowacki et al. 2017). Firth et al. (Firth et al. 2016)
examined motivating factors and barriers to exercise in 12 independent studies of
6,431 psychiatric patients and found that 91% of people with serious mental illness
endorsed “improving health” as a reason to exercise, particularly for “losing weight”
(83% of patients), “improving mood” (81%), and “reducing stress” (78%). However,
low mood and high stress were identified as the most prominent barriers to exercise
(61%), followed by “lack of support” (50%). In a scoping review (Glowacki et al.
2017), low mood, lack of energy, and being too tired were the most commonly
reported barriers to physical activity among adults with depression, whereas being
stressed, boredom, and lack of enjoyment were also frequently reported barriers. The
authors highlighted that these emotional barriers are not typically addressed by
traditional theories of behavior change (e.g., Theory of Planned Behavior, Self-
Determination Theory, and Self-Efficacy Theory) and may be overlooked when
trying to promote physical activity among adults with depression. Future behavior
change research should specifically target these emotional barriers when attempting
to help individuals with depression in adopting and maintaining physical activity and
exercise.
168 B. L. Alderman et al.

Exercise has proven to be a challenging and difficult health behavior for most
individuals to engage in, and this is particularly so for patients with depression. The
approach to incorporating exercise into a depression treatment plan should prioritize
ways to overcome common barriers to participation while considering motivating
factors identified in the research literature (Busch et al. 2016). First, when it comes to
developing an initial exercise prescription, the USDHHS guidelines of 150 min of
moderate-intensity physical activity and 2 days per week of muscle-strengthening
activity should be used as a starting point. This general prescription can be tailored
based on the current activity level, physical capacity, and goals and exercise
preferences of the individual. Patients should be counseled to begin slowly and
choose an enjoyable and preferred form of physical activity. Individuals with
depression have reported that walking is their most preferred form of exercise,
followed by weightlifting, yoga, and dance (Busch et al. 2016). Men preferred
weightlifting marginally more than women did, while women preferred yoga sig-
nificantly more than men. It may be useful to initially focus on the frequency of
physical activity, for instance, by setting a goal of three exercise sessions per week at
a comfortable pace for a manageable length of time (e.g., 10 min). Once the patient
becomes confident and comfortable with exercise frequency, then duration and
intensity of exercise can be gradually increased (Craft and Perna 2004). The goal
should be to establish a regular physical activity routine rather than being overly
concerned about meeting an exercise dose (intensity and duration) for symptom
reduction. Also, focusing on frequency may help to establish a behavioral habit and
routine while addressing any symptoms that are serving as barriers to adherence.
Next, increasing the duration of exercise may help to build endurance and exercise
tolerance. Finally, increasing the intensity of the exercise can be effective for
increasing cardiorespiratory fitness, reaching specific health goals, improving qual-
ity of life, and decreasing depression. Increasing exercise intensity too quickly,
however, may lead to burnout, injury, reduced self-efficacy, or exercise
nonadherence (Vetter and Symonds 2010). Therefore, it should not be the primary
focus of exercise treatment until an individual has established the habit (i.e., fre-
quency) and tolerance (i.e., duration) for regular physical activity. It is also important
for clinical exercise specialists and health providers to provide basic education, give
realistic expectations, and outline timelines for an anticipated antidepressant
response (e.g., 4–6 weeks).

5 Tailored Exercise Prescriptions for Depression

Management

Despite substantial evidence supporting the use of exercise in the treatment of

depression, previous studies have not provided a clear indication of a standard or
tailored dose of exercise for promoting antidepressant effects. Exercise benefits
numerous aspects of physical and mental health, but the motivational effort required
to adopt and maintain a regular exercise routine can quickly become overwhelming
to depressed patients. It is therefore important to make exercise recommendations on
Exercise for the Prevention and Treatment of Depression 169

Table 1 Exercise prescription for depression

Frequency (days/ Duration
Program stage week) Intensity (min) Mode
Initial stage (weeks 3–4 Low to moderate 20–30 Walking, light
1–4) aerobic
Middle stage 4–5 Moderate 30–45 Aerobic, light
(weeks 5–8) resistance
Later stage (weeks 5 Moderate-to- 30–60 Aerobic,
9–12) vigorous resistance

Table 2 An evidence-informed approach to increase exercise motivation and adherence

Before prescribing exercise
1. Provide brief psychoeducation about the recommended physical activity guidelines and benefits
of exercise for mental health
2. Question patients about their current activity level and preferences
3. Perform motivational interviewing and question patients about their personal barriers and
facilitators to exercise
4. Explain therapeutic expectations and realistic timelines for the exercise treatment plan
Prescribing exercise
1. Start low and go slow: Emphasize starting with lower intensity and duration, gradually
increasing over time to prevent negative exercise experiences
2. Use an individualized approach tailored to the patient’s abilities, preferences, and tolerance
levels
3. Discuss strategies to increase adherence, including goal-setting, incorporating enjoyable
activities, and social support
4. Acknowledge the potential impact of depressive symptoms on motivation and adherence.
Encourage small, manageable steps and consider the use of incentives to aid in achieving goals
During the exercise program
1. Regularly monitor patient progress and mood responses to exercise
2. Adjust the prescription according to individual progress and preferences
3. Periodically assess depressive symptoms and provide feedback about progress

an individual level when possible, accounting for personal differences in exercise

history, preferences, barriers, and facilitators. Acute bouts of exercise have been
shown to be effective for depression management, and it is possible that the
antidepressant response to chronic exercise is the result of daily symptom manage-
ment through individual bouts of activity (Meyer et al. 2016). Like any clinical
prescription, treatment with exercise should include the following key elements:
(1) type or mode of exercise; (2) frequency and duration of exercise sessions; and
(3) exercise intensity. Given the importance of behavioral adherence, additional key
elements to include are: (4) duration of the intervention; and (5) psychoeducation
about motivating factors, barriers, and monitoring of adherence (Rethorst and
Trivedi 2013). These elements provide the core structure for an exercise prescription,
while specific recommendations can then be individually tailored. An example
exercise prescription plan for depression is summarized in Table 1. An interventional
approach to addressing barriers to exercise and improving behavioral adherence to
exercise is described in Table 2.
170 B. L. Alderman et al.

6 Conclusion

Depression is a prevalent and disabling disease and has become the leading cause of
avoidable suffering worldwide. Clinically, depression is characterized by feelings of
sadness and helplessness, loss of pleasure (anhedonia), and lack of motivation.
Antidepressant medications and psychological therapies are effective treatments
for some patients with depression; however, non-response, partial response, and
small effects remain significant problems. Additionally, these treatments are associ-
ated with several barriers and many people with depression either never seek
treatment or gravitate exclusively to medications (Beshai et al. 2019), which pose
considerable side effects (Cascade et al. 2009; Wang et al. 2018). Exercise and
physical activity are lifestyle behaviors that can be used to prevent and treat
depression. Cross-sectional and prospective epidemiological studies indicate that
engaging in regular physical activity is associated with a lowered risk of developing
depression. Several large-scale RCTs have provided evidence for efficacy of exer-
cise in treating depression, with effects that are comparable to those typically
observed for antidepressant medications and psychotherapy. Systematic reviews
and meta-analyses indicate that aerobic and resistance exercise training results in
moderate-to-large reductions in depressive symptoms, and exercise can be used as
an adjunct to antidepressants and psychotherapy. Although several organizations
dedicated to psychiatric care, including the American Psychiatric Association and
National Institute of Mental Health, have not specifically endorsed the use of
exercise as a treatment for depression, statements from these organizations highlight
the use of exercise as an “effective, cost-effective treatment for depression” and that
“exercise helps keep your psyche fit.” This is promising, considering the decades of
research supporting the effects of exercise on depression. By incorporating some of
the recommendations outlined in this chapter, we believe that exercise can be
incorporated as an effective behavioral monotherapy or adjunctive treatment to
advance treatment for depression.

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Exercise and Smoking Cessation

Lorra Garey, Jessica M. Thai, Michael J. Zvolensky, and Jasper A. J. Smits

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
2 Smoking and Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
3 Exercise Interventions for Smoking Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
4 Mechanisms of Exercise Interventions for Smoking Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
5 Special Populations of Exercise Interventions for Smoking Cessation . . . . . . . . . . . . . . . . . . . . 186
6 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Abstract Smoking is a public health crisis, leading to a multitude of health com-

plications. Exercise is associated with numerous health benefits and is accepted by
health professionals and smokers as a potentially effective smoking cessation aid.
This chapter discusses the extant literature on the relation between exercise and
smoking, including cross-sectional studies, experiments, and randomized clinical
trials. There is robust evidence for exercise’s efficacy in reducing cigarette craving,
tobacco withdrawal symptoms, and negative affect. Further, exercise-based

L. Garey (✉)
Department of Psychology, University of Houston, Houston, TX, USA
HEALTH Institute, University of Houston, Houston, TX, USA
e-mail: [email protected]
J. M. Thai
Department of Psychology, University of Houston, Houston, TX, USA
M. J. Zvolensky
Department of Psychology, University of Houston, Houston, TX, USA
HEALTH Institute, University of Houston, Houston, TX, USA
Department of Behavioral Science, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA
J. A. J. Smits
Department of Psychology, The University of Texas at Austin, Austin, TX, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 177
Curr Topics Behav Neurosci (2024) 67: 177–198
https://doi.org/10.1007/7854_2024_497
Published Online: 2 August 2024
178 L. Garey et al.

interventions appear to boost short-term abstinence yet may fall short of facilitating
long-term abstinence. Methodological limitations of extant work are reviewed. We
conclude with a discussion of the next steps in this line of work to fine-tune exercise
interventions and their application for smoking cessation.

1 Introduction

According to the World Health Organization (WHO), tobacco use kills more than
eight million people each year, with more than seven million of these deaths due to
direct tobacco use, and about 1.2 million due to non-smokers being exposed to
second-hand smoke (World Health Organization 2022). Additionally, smoking can
lead to the development of chronic diseases, including cardiovascular disease,
respiratory diseases, and cancer, as well as other health issues such as infertility,
premature aging, and oral health problems (Bonnie et al. 2015).
Smoking cessation is the process of quitting smoking, and it is essential for
improving health outcomes for smokers (Centers for Disease Control Prevention
2020). There are several efficacious approaches to smoking cessation, including
pharmacological interventions (e.g., nicotine replacement therapy, bupropion, and
varenicline) and behavioral interventions (e.g., counseling and support groups;
García-Gómez et al. 2019). Although these interventions can be efficacious, many
smokers struggle to quit smoking. Indeed, most established interventions are asso-
ciated with relatively low short-term abstinence rates (15–35%), and long-term
(≥6 months) abstinence rates rarely exceed 20–25%, even with the gold standard
combination of psychotherapy and pharmacotherapy for smoking cessation (Simons
et al. 2010). Accordingly, the most recent guidelines for clinical practice on treating
tobacco dependence indicate a need for innovative, potent strategies for smoking
cessation (Fiore et al. 2008).
Physical activity and exercise are known to have numerous health benefits,
including reducing the risk of developing chronic diseases, improving mental health
and well-being, and increasing overall longevity (Penedo and Dahn 2005). There-
fore, it is unsurprising that exercise interventions have been considered as a possible
aid in smoking cessation efforts. Indeed, exercise is routinely recommended as a
cessation aid by smoking professionals (Everson et al. 2010) and is endorsed by the
current Clinical Practice Guideline for Treating Tobacco Use and Dependence (Fiore
et al. 2008). Many smokers themselves identify exercise as a potentially useful
quitting strategy (Everson-Hock et al. 2010).
In this chapter, we will review the relation between smoking and exercise and
exercise interventions for smoking cessation. We will also discuss putative mecha-
nisms of exercise interventions for smoking cessation and special populations to
consider regarding exercise interventions for smoking cessation. We will conclude
the chapter by discussing future directions.
Exercise and Smoking Cessation 179

2 Smoking and Physical Activity

Extensive evidence has highlighted an inverse relation between smoking and phys-
ical activity (Boutelle et al. 2000; Picavet et al. 2011). Indeed, smoking is known to
have several adverse effects on physical fitness and exercise capacity (Conway and
Cronan 1992). Nicotine found in cigarettes acts as a vasoconstrictor, leading to
reduced blood flow to muscles and other tissues (Benowitz and Burbank 2016) and
reduced exercise capacity (McAllister et al. 1995). Smoking is also known to lower
lung function, leading to a decreased ability to perform physical activities requiring
exertion (Tantisuwat and Thaveeratitham 2014; Mohamed Abdelaal and Mohamed
Mousa 2022). Smokers also have a higher risk of developing cardiovascular disease,
which can further reduce exercise capacity (US Department of Health Human
Services 2010). In part, these adverse health effects likely contribute to lower
exercise rates among smokers relative to the general population (Furlanetto et al.
2014; Kaczynski et al. 2008).
Smoking can negatively impact one’s ability and desire to exercise. Those
persons who can overcome these challenges report better motivational and behav-
ioral outcomes related to quitting smoking. Specifically, among smokers, being
physically active has been positively associated with the intention to quit (Frith
and Loprinzi 2018), initiating a quit attempt (DeRuiter et al. 2008; Gauthier et al.
2012; Haddock et al. 2000), confidence in maintaining smoking abstinence (King
et al. 1996), smoking cessation (Abrantes et al. 2009; Derby et al. 1994; Loprinzi and
Walker 2016; Paavola et al. 2001; Sedgwick et al. 1988), and reduced likelihood of
smoking relapse (Emery et al. 2014). In part, the positive effect of exercise on
smoking urges (Haasova et al. 2013; Abrantes et al. 2018; Kunicki et al. 2022;
Roberts et al. 2012; Bock et al. 1999; Ussher et al. 2001; Daniel et al. 2004; Taylor
et al. 2005) and withdrawal (Ruslan et al. 2023; Ussher et al. 2019) may contribute to
these relations and help promote cessation. Indeed, recent work found that even an
acute bout of exercise reduced smoking urges in both men and women smokers
during an acute state of abstinence (Allen et al. 2018). Further, exercise engagement
prior to quitting has been shown to relate to changes in smoking behavior and
perception of use among women, including decreased puff duration, smoking
satisfaction, psychological reward, enjoyment of respiratory tract sensations, crav-
ing, and increased puff flow (De Jesus and Prapavessis 2018). Taken together, there
is evidence supporting the benefits of exercise as a component of tobacco depen-
dence treatments. It should be highlighted that being physically active is associated
with numerous health benefits on its own (Penedo and Dahn 2005) and can promote
the health of the smoker even if cessation is not attempted or achieved (Ferrucci et al.
1999; Auer et al. 2014; Ussher et al. 2003; Bock et al. 2012). Nevertheless, the
combination of smoking cessation and regular physical activity, relative to each
behavior on its own, has the potential to lead to more significant health improve-
ments among current smokers.
180 L. Garey et al.

3 Exercise Interventions for Smoking Cessation

Exercise interventions for smoking cessation employ physical activity and exercise
to promote smoking cessation. Several types of exercise approaches have been tested
in the context of exercise interventions for smoking cessation. The most used
approaches utilize aerobic exercise (i.e., cardiovascular based), resistance exercise
(i.e., weight training), or a combination of the two (Whiteley et al. 2012). Exercise
interventions for smoking cessation also have been tested in various formats, such as
supervised exercise programs, home-based exercise programs, or a combination of
both (Taylor et al. 1988). Additionally, exercise interventions have been studied as
standalone smoking cessation interventions or as adjunct interventions that are
provided in combination with traditional smoking cessation approaches (i.e., behav-
ioral therapy and/or pharmacotherapy; (Chen et al. 2022; Prapavessis et al. 2007;
Marcus et al. 2005).
The overall potential for exercise as a standalone treatment or adjunct treatment to
standard smoking cessation has been summarized by a recent Cochrane review (see
Ussher et al. 2019). This review focused on 21 (total number of participants = 6,607)
studies that included an exercise intervention (with exercise alone or as an add-on)
for smoking cessation. The outcome of interest was self-reported and biochemically
verified abstinence at the final follow-up, ranging from 6 to 16 months post-quit.
Based on the review, the authors concluded that there is limited supporting evidence
that exercise in conjunction with smoking cessation support increased quit rates
relative to smoking cessation support alone when measured at distal follow-ups.
Indeed, only one study demonstrated a significant difference in smoking cessation at
the 6-month follow-up among those who received an exercise intervention (but
confounded by severity of sensitivity to somatic symptoms; Smits et al. 2016) and
only one study supported a significant benefit of exercise at the 1-year follow-up
(Marcus et al. 1999). Another recent meta-analysis found that yoga, in combination
with standard smoking cessation treatment, was the only exercise type that increased
the likelihood of smoking cessation (Klinsophon et al. 2017). This inference,
however, was based on a single study.
Several notable explanations can be offered to explain the lack of findings among
most studies (Ussher et al. 2019). First, several studies were underpowered to detect
effects (Taylor et al. 1988; Abrantes et al. 2014; Hill 1985; Marcus et al. 1995; Patten
et al. 2016; Russell et al. 1988; Vickers et al. 2009; Whiteley et al. 2007). Second,
differences in methodology across studies, including timing and intensity of the
smoking cessation and exercise programs offered, could impact the findings. Third,
the review included studies that reported smoking cessation outcomes, but the
operationalization of cessation differed across studies, which may have biased
results. Fourth, the comparison group differed across studies, with some being
more robust than others. Finally, adherence may have influenced findings. Indeed,
some work indicated stronger adherence to the exercise condition, whereas other
trials reported lower adherence or limited data on adherence. This is an important
consideration, as several studies suggest that the degree of adherence to exercise
Exercise and Smoking Cessation 181

programs is integral to the observed outcomes (Whiteley et al. 2012, 2007). Thus,
although the review by Ussher et al. (2019) provides limited support for exercise
interventions to assist with smoking cessation, these data must be considered in the
context of the limitations and inconsistencies across the studies included.
It is possible that the efficacy of exercise interventions for smoking cessation may
be specific to certain subgroups of smokers, exercise interventions, or their combi-
nations. Indeed, recent studies have found promising support for exercise interven-
tions to promote smoking cessation, particularly among specific populations. For
example, Smits et al. (2021) conducted a randomized controlled trial in which they
randomized 150 daily smokers with high anxiety sensitivity who were interested in
quitting to (a) standard smoking cessation treatment through the Texas Tobacco
Quitline, which consists of a 5-session counseling package, combined with nicotine
replacement therapy and high-intensity aerobic exercise (60–85% of heart rate
reserve) or (b) the same standard smoking cessation treatment through the Texas
Tobacco Quitline with nicotine replacement therapy and low-intensity aerobic
exercise (20–40% of heart rate reserve). The trial consisted of a 15-week intervention
period and, importantly, was conducted in a community center (i.e., YMCA).
Participants met with their personal trainers during the first week to complete three
training sessions, establish an exercise training schedule, and set their target quit day
for week 6. The next 14 weeks consisted of one supervised and two non-supervised
exercise training sessions each week. Participants were connected to the Texas
Tobacco Quitline in week 3 and were provided nicotine replacement therapy in
weeks 6 through 14. The authors found that point prevalence abstinence was
significantly higher at the 6-month follow-up in the high-intensity group relative to
the low-intensity group (27.6% vs. 14.8%). This data highlights the potential of a
supervised, high-intensity exercise program integrated into a community center to
promote smoking cessation among smokers with elevated anxiety sensitivity.
Stockton et al. (2023) also conducted a study of an exercise-based intervention for
smoking cessation protocol in the YCMA. Daily smokers (N = 392) interested in
quitting were randomized into one of two study conditions: (1) a physical activity
intervention consisting of an individualized exercise plan containing moderate and
vigorous intensity exercise, with supervised activity sessions and behavioral
counseling and supportive contacts during the post-cessation maintenance phase,
or (2) a wellness intervention with curriculum surrounding multiple dimensions of
wellness and health (e.g., healthy eating, injury reduction, and avoidance). The target
quit date was set to week 3 after the intervention was initiated, and the treatment
lasted for 7 weeks. Participants in the physical activity intervention participated in
16 face-to-face physical activity/cessation sessions, 11 telephone activity/cessation
sessions, and received 11 supportive mailings (i.e., supportive contacts to boost
adherence). The physical activity intervention consisted of supervised leisure exer-
cises, “lifestyle activities” (i.e., manual labor that is performed in day-to-day life),
and short bouts (>10 min) of exercise to manage urges and cravings. Participants
started off engaging in physical activity three times per week. They gradually
increased the frequency until they reached five to six times per week (i.e.,
150–180 min of exercise per week). Participants achieved the weekly goal by
182 L. Garey et al.

engaging in any combination of the different exercises. Participants in the wellness

intervention participated in 8 face-to-face wellness/cessation sessions, 12 telephone
wellness/cessation sessions, and received 18 follow-up mailings. Participants in both
treatments received nicotine replacement therapy in the form of transdermal nicotine
patches and behavioral smoking cessation counseling. The Social Cognitive Theory
informed all behavioral counseling to increase self-efficacy and address barriers to
cessation. Biochemical verification of smoking was collected at 7 weeks, 6 months,
and 1 year. The physical activity intervention did not result in a higher abstinence
rate compared to the wellness intervention (19.6% and 25.4% at 7 weeks, 15.1% and
16.6% at 6 months, and 14.1% and 17.1% at 12 months, respectively). Despite the
community-based physical activity intervention not improving long-term quit rates,
the program was found to be acceptable among individuals interested in quitting
smoking. Interestingly, unlike Smits et al. (2021), who enrolled smokers with high
anxiety sensitivity, Stockton enrolled a general sample of smokers. Thus, consider-
ing the findings by Smits et al. (2021), community-based exercise interventions for
smoking cessation may be most effective among emotionally vulnerable subgroups
of the larger smoking population, such as those with elevated sensitivity to anxiety-
related symptoms commonly experienced during exercise and withdrawal.
Another study (Abrantes et al. 2018) documented the effects of aerobic exercise
on smoking abstinence through negative affect reduction. Female (N = 57)
low-active daily smokers were randomized to either a group-based moderate-inten-
sity aerobic exercise intervention or a health-education intervention. An exercise
physiologist guided aerobic exercise to ensure moderate-intensity exercises
(55–69% of age-predicted maximal heart rate). Based on fitness level and progress,
weekly exercises were decided collaboratively between the exercise physiologist
and the participant. Exercise sessions gradually increased in duration throughout the
weeks. The aerobic exercises offered to participants included ellipticals, treadmills,
and recumbent bicycles. Exercise sessions started as 15-min sessions each week and
gradually increased to 40-min sessions by week 12 (51.7% of participants reached
40 min). Participants were also prescribed home-based exercises that would take
place 2–4 additional times per week, with a goal of achieving 150 min of exercise per
week. Home-based exercises were reported by the participant using self-monitored
logs. The health-education intervention consisted of weekly 45–60-min health-
education sessions that covered health topics (i.e., oral and sleep hygiene) but did
not discuss physical activity. The information was conveyed through handouts,
in-group exercises, lectures, and Internet resources. Both interventions were
12 weeks in length, and the target quit day was set to week 5. Standard cognitive-
behavioral smoking cessation treatment (Abrams and Niaura 2003) was delivered to
both groups via telephone starting at week 1 and continued throughout the interven-
tion period. In addition to cognitive-behavioral smoking cessation treatment, both
groups received nicotine replacement therapy in the form of transdermal patches
beginning on the quit day. To avoid multiple onsets of behavioral changes that could
affect outcomes (King et al. 1996), exercise was initiated 1 month prior to the quit
day. The wellness group was not instructed to engage in any new behaviors prior to
the quit day. Beginning at week 5, biochemical verification of smoking was collected
Exercise and Smoking Cessation 183

at each weekly session until week 12. Among smokers, Abrantes et al. (2018) found
a statistically significant ( p = 0.0019) difference in pre- to post-cessation decreases
in anxiety among those in the aerobic exercise intervention compared to those in the
health-education intervention after an exercise session. Those in the aerobic exercise
intervention also reported a statistically significant ( p = 0.025) reduction in cravings
at the 8-week follow-up period compared to those in the health-education interven-
tion. Though this study did not find statistically significant differences in smoking
cessation rates between groups, the findings suggest that aerobic exercise sessions
prior to a quit date aid in alleviating anxiety and, in turn, could decrease fear and
avoidance of arousal sensations (Smits et al. 2011), which are common and impact-
ful barriers to cessation (Lasser et al. 2000; Piper et al. 2010).
Similarly, Bock et al. (2019) conducted a randomized clinical trial using yoga as a
complementary therapy for adult smokers wanting to quit. Yoga was chosen over
other types of exercise because it has been shown to improve mood and reduce stress
through asanas (Yoga postures) and pranayama (breathing exercises; (Li and Gold-
smith 2012; Shahab et al. 2013). Yoga has also been shown to enhance mindfulness,
with increases in mindfulness associated with reductions in nicotine withdrawal,
improvement in coping with cravings, and increases in cognitive deliberations
required to avoid smoking (Gard et al. 2012; Ussher et al. 2006; McClernon et al.
2004). The study looked at 227 daily smokers and consisted of an 8-week yoga or
general wellness program. Both groups had participants meeting for a 1-h weekly
group-based smoking cessation counseling session using cognitive-behavior ther-
apy, which was scheduled after their respective wellness or yoga class. The Social
Cognitive Theory informed smoking cessation counseling. The quit date was sched-
uled for week 4. The type of Yoga practiced throughout the intervention was Iyengar
Yoga (Iyengar 2007) due to its emphasis on posture (asanas) and the use of props to
reduce injury and facilitate learning. Participants in the yoga intervention attended
yoga classes twice weekly for 8 weeks. Certified Iyengar instructors would select a
pattern of asanas appropriate for beginners and teach them during class. The classes
consisted of 5 min of breathing exercises and seated medication, followed by 45 min
of asanas, and concluded with 10 min of closing postures and a final set of seated
meditation. To encourage continued practice, participants were given one free class
voucher for weeks 9 through 20 after the 8-week intervention. The wellness group
consisted of 1-h twice-weekly classes consisting of videos and lectures on health
topics (i.e., oral and sleep hygiene). At the end of the 8 weeks, participants were sent
health and wellness materials during weeks 9–20. In both interventions, participants
completed and mailed in a monthly log to report either their yoga practice or health
behaviors. Follow-ups were completed at 3- and 6 months. Results indicated that
Iyengar Yoga was feasible and acceptable among smokers based on the strong
attendance and retention rates at the 6-month follow-up (94.7% for both intervention
groups). Participants in the Yoga group were also more likely to quit compared to
those in the wellness group (46.9% vs. 17.4%, respectively), and lighter smokers
were also over twice as likely to quit smoking if they were engaging in Yoga. The
results highlight the potential of Yoga as a smoking cessation aid and may partic-
ularly be more beneficial for light smokers.
184 L. Garey et al.

Onkcen et al. (2020) recently completed a trial among 301 postmenopausal

women. Researchers were particularly interested in this group, given that postmen-
opausal women who smoke are at a much greater risk than their nonsmoking female
counterparts to develop osteoporosis and fractures (Health UDo, Services H 2004;
Alberg et al. 2014), cardiovascular disease, chronic obstructive lung disease, and
cancer (Health UDo, Services H 2004). The study compared the effectiveness of a
smoking cessation program with an aerobic and strength-based, moderate exercise
(i.e., 50–69% of maximum heart rate) program to an identical smoking cessation
program combined with a relaxation program as a comparison condition. The
intervention lasted 6 months, and participants were followed up for a year post-
intervention. Participants received varenicline, a smoking cessation pharmacological
agent, during the first 12 weeks of the treatment. The study contained 3 phases:
(1) Phase I included smoking cessation counseling with varenicline for 4 weeks,
(2) Phase II included supervised exercise or relaxation two times per week with
varenicline for 8 weeks, and (3) Phase III included supervised exercise or relaxation
every week for 8 weeks and then every other week for 4 weeks. Quit day was set for
the second week in phase I. In phase I, 1.5-h long supervised sessions were
conducted weekly and introduced exercise and relaxation depending on the inter-
vention group. Smoking cessation was emphasized to both groups during these
sessions. The exercise condition was introduced to supervised isometric exercises,
contract/relax exercises, breathing and stretching exercises, proper clothing to wear
during exercise, hydration during exercise, and the Borg scale to determine the
intensity of the exercises. The relaxation group was introduced to different relaxation
techniques. Both groups were encouraged to practice what they had learned at home.
In phase II, 1.5-h long sessions were conducted twice weekly and focused more on
exercise and relaxation. Participants in the exercise intervention began a supervised
1-h twice weekly aerobic and strength training program, totaling up to 180 min of
moderate exercise per week. The sessions for participants in the relaxation interven-
tion followed a similar schedule and focused on breathing techniques and muscle
relaxation. In phase III, 1-h sessions on exercise and relaxation were conducted
every week for 8 weeks and then every other week for 4 weeks. Follow-ups occurred
at 3-, 6-, 9-, and 12 months to assess smoking status. Exercise testing was conducted
3-, 6-, 9-, and 15 months after the quit date. Findings did not support the exercise
intervention, compared to relaxation, to increase end-of-treatment prolonged absti-
nence (i.e., abstinence at the end of 60 weeks). There were no statistically significant
effects observed in the exercise condition at 4 weeks (Wald χ 2 = 1.85; df = 292;
p = 0.18) or for prolonged abstinence (Wald χ 2 = 0.08, df = 292, p > 0.78). In part,
the use of varenicline by participants in both conditions may have contributed to the
non-significant effects. Further, as relaxation techniques exert a positive effect on
negative affect and mood (Ng and Jeffery 2003), participants in the control group
may have received an alternative yet equally effective treatment as those in the
exercise-based treatment. Notably, the exercise intervention was associated with
reduced cigarettes per day during the treatment period. Thus, this study suggests that
continued exercise may relate to reduced smoking behavior but not result in cessa-
tion among postmenopausal women.
Exercise and Smoking Cessation 185

There is increased recognition that long-term (> 6 months) abstinence following

a quit attempt is low (Stead et al. 2016). Focusing on such distal outcomes may mask
the potential of exercise interventions to assist smoking cessation. Indeed, of the
articles reviewed by Ussher et al. (2019), when considering abstinence at end-of-
treatment or more proximal follow-up assessments, evidence was more favorable to
exercise conditions, with several trials demonstrating significantly higher abstinence
rates in an exercise condition relative to a control (Bock et al. 2012; Smits et al.
2016; Marcus et al. 1991, 1999; Patten et al. 2016; Thompson et al. 2015; Martin
et al. 1997). Further, a recent meta-analytic review by Santos et al. (2021) found that
aerobic exercise was better than usual care in promoting smoking cessation in the
short-term (11 trials, risk ratio 0.79; 95% confidence interval, 0.66–0.94) but not in
the medium- or long-term (i.e., after engaging in exercise, smoking cessation was
achieved for a short period of time but did not last). Other reviews have found similar
findings (Chen et al. 2022). Based on these collective data, exercise interventions for
smoking cessation are efficacious at promoting cessation in the short-term. Including
booster sessions to promote sustained effects of an exercise intervention on cessation
following the end-of-treatment may be beneficial.

4 Mechanisms of Exercise Interventions for Smoking

Cessation

Identifying treatment mechanisms may aid the efforts to optimize interventions

(Kazdin 2007). At a biological level, aerobic exercise induces an increase in plasma
β-endorphins (De Meirleir et al. 1986). This is important in the context of smoking
cessation as higher levels of β-endorphin have been found to be associated with
lesser smoking relapse after cessation (Shaw and al'Absi 2008). Yet, this may vary as
a function of exercise regime, given that increases in β-endorphin depend on the
intensity and duration of the exercise (Goldfarb et al. 1990). Other work has
suggested that specific neurobiological mechanisms may be relevant to the effect
of exercise at particular stages of addiction. For example, during drug use initiation
and withdrawal, the efficacy of exercise may be related to its ability to facilitate
dopaminergic transmission. Once addiction develops, its efficacy may be explained
by its effects on glutamatergic and dopaminergic signaling and reverse drug-induced
changes in chromatin via epigenetic interactions with brain-derived neurotrophic
factor (BDNF) in the reward pathway (Lynch et al. 2013). A recent review of the
neural mechanisms unpinning the effects of exercise on smoking-related processes
and behavior also suggested that exercise leads to increased serum dopamine levels,
which partially replaces the rewarding effect of smoking and reduces the desire to
smoke in smokers (Ni et al. 2022). Although such work indicates a biological
mechanism, additional research is needed to isolate the precise neurobiological
factors and identify the conditions under which specific mechanisms may be
engaged to their full potential.
186 L. Garey et al.

Several studies also indicate that the effect of exercise on cognitive-affective

processes may help explain how exercise affects smoking cessation. As noted above,
exercise leads to reductions in smoking craving and nicotine withdrawal symptom
severity and increases in positive affect and decreases in negative affect (Haasova
et al. 2013, 2014; Roberts et al. 2012; Taylor and Katomeri 2007). These changes are
essential, given increases in negative affect (Burgess et al. 2002; Piasecki et al. 2000;
Kang and Lee 2010; Boden et al. 2010), decreases in positive affect (Cook et al.
2004; Lerman et al. 2002), and more severe craving and withdrawal symptoms are
consistently associated with poorer cessation outcomes (Xian et al. 2003; Killen and
Fortmann 1997; Allen et al. 2008; Kahler et al. 2002; Kenford et al. 1994; Brnstrm
et al. 2010). In an effort to fully understand the potential for mood as a mechanism of
exercise intervention efficacy on smoking cessation outcomes, Zvolensky et al.
(2018) conducted a secondary analysis using data collected by Smits et al. (2016)
to examine anxiety sensitivity and dysphoria (sadness; Covinsky et al. 2014) as
unique explanatory mechanisms for the intervention effect on smoking cessation.
Findings indicated that both anxiety sensitivity and dysphoria explained the effect of
the exercise intervention on abstinence among smokers with high anxiety sensitivity.
These two mechanisms may be particularly relevant to exercise treatment
responsivity given that by exercising, participants may learn how to manage uncom-
fortable physical sensations better, thereby promoting reduced anxiety sensitivity
and promoting cessation. Further, extensive evidence has highlighted the benefits of
exercise on depression (Ross et al. 2023). As dysphoria is a cardinal feature of
depression (Kovacs and Yaroslavsky 2014), these data indicate that exercise influ-
ences specific components of depression to promote cessation. There is a need for
more research to understand how other aspects of depression, such as anhedonia
(loss of interest in usually pleasurable activities; Covinsky et al. 2014), may be
impacted by an exercise intervention to promote smoking cessation. Taken together,
through its acute effect on craving and affect, including such affective vulnerability
processes as anxiety sensitivity and dysphoria, aerobic exercise may play an impor-
tant role in smokers’ quit attempts.

5 Special Populations of Exercise Interventions

for Smoking Cessation

Women also represent a unique group of smokers who may be apt for exercise-based
smoking cessation trials. Although men are more likely to be smokers than women
(20.6% vs. 12.8%; Creamer et al. 2019), the gender gap in smoking rates has closed
considerably over the past 50 years, and some studies show that women have more
difficulty quitting and remaining abstinent (for a review, see Smith et al. 2016).
Weight control is a leading reason for smoking among women (Saarni et al. 2004)
and may pose a barrier to cessation among women smokers (Berg et al. 2008; Levine
et al. 2010). Weight gain has been observed in individuals who quit; however,
Exercise and Smoking Cessation 187

women gain more weight than men (O'Hara et al. 1998; Williamson et al. 1991;
Pisinger and Jorgensen 2007). Weight gain following cessation is related to relapse
among women but not men, suggesting that a weight control component (e.g.,
physical activity) should be included in smoking cessation interventions for
women (Kuo et al. 2022). Additionally, evidence has indicated that for postmeno-
pausal women, in particular, smoking provides a weight control benefit. As a result,
postmenopausal women are at a higher risk for relapse than premenopausal women
(Caan et al. 1996; Copeland et al. 2006). Pregnancy is also an ideal time for cessation
and is a preventable cause of poor health outcomes for both mother and child
(Fingerhut et al. 1990; Linke et al. 2013). Moderate-intensity exercise has already
been recommended to improve pregnant women’s health (Obstetricians ACo, Gyne-
cologists 2003; Bell and Dooley 2006). It presents another option for pregnant
smokers who are reluctant to use nicotine replacement therapy (Ussher and West
2003) or fear post-cessation or postpartum weight gain (Pomerleau et al. 2000). A
survey by Ussher et al. (2004) found that pregnant smokers are interested in personal
exercise plans for smoking cessation, with 44% of participants expressing interest,
and two studies have already demonstrated the feasibility of an exercise intervention
for pregnant women (Ussher et al. 2008). Although exercise interventions for
smoking cessation have enrolled both men and women, a high percentage of trials
have enrolled only women (Bock et al. 2012; Whiteley et al. 2012; Prapavessis et al.
2007; Marcus et al. 1991, 1995, 1999, 2005; Russell et al. 1988; Vickers et al. 2009;
Williams et al. 2010; Chaney and Sheriff 2008; Jung et al. 2010; Ussher et al. 2012;
Kinnunen et al. 2008), as exercise theoretically targets weight-related barriers for
women. Among women, acute bouts of exercise have been found to temporarily
reduce cigarette cravings and withdrawal symptoms (Haasova et al. 2013; Taylor
et al. 2007). Taken together, exercise interventions may alleviate weight and health
concerns related to smoking cessation among women.
Individuals who experience elevated psychological distress or meet the criteria
for a mental health disorder represent another group who may benefit from exercise
interventions for smoking cessation. Extensive work has highlighted that regular
physical activity is related to better mental health outcomes and that exercise
interventions are effective at improving mental health conditions among those who
struggle with such symptoms or syndromes (Smith and Merwin 2021). Smokers are
more likely to experience elevated psychological distress (Jamal et al. 2018) and
meet the criteria for a mental health disorder relative to the general population (Smith
and Merwin 2021). Indeed, adults with anxiety and depressive symptoms also report
a higher smoking prevalence (35.8%) compared with adults without such symptoms
(14.7%; Jamal et al. 2018). Such data are concerning as smokers who experience
mental health concerns have more difficulty quitting than those without mental
health problems (Lê Cook et al. 2014). As such, an exercise intervention plus a
smoking cessation program may benefit these individuals by (1) engaging neuro-
mechanistic functions associated with improved mental health and (2) subsequently
reducing mental health distress that promotes relapse. This has served as the
theoretical foundation for several studies on exercise intervention for smoking
cessation among those with mental health concerns. Specifically, based on a meta-
188 L. Garey et al.

analysis of 6 studies and 296 participants (see Schöttl et al. (2022) for review),
evidence suggests that exercise interventions benefit smoking cessation in individ-
uals with mental illness; however, results were not statistically significant at the
6-month follow-up, suggesting a short-term effect. Thus, there may be potential for
physical activity interventions to support cessation among this group, but additional
refinement is needed to improve efficacy and maintenance.

6 Future Directions

There is no consistency in “best methods” to prescribe an exercise intervention for

smoking cessation. Across studies, there are considerable methodological differ-
ences regarding exercise modality, dose (i.e., duration and frequency), intensity (i.e.,
low, moderative and vigorous), and modality of implementation (i.e., supervised or
unsupervised; Ussher et al. 2019). The design considerations within these areas have
the potential to impact efficacy. Furthermore, there is considerable inconsistency for
when to initiate the exercise intervention to support cessation. Specifically, some
studies start the exercise intervention before the quit date (Whiteley et al. 2012;
Prapavessis et al. 2007; Marcus et al. 1991, 1995, 1999, 2005; Smits et al. 2016;
Abrantes et al. 2014; Patten et al. 2016; Kinnunen et al. 2008; Bernard et al. 2015;
Bize et al. 2010; Prapavessis et al. 2016; Ussher et al. 2015), others begin on the quit
date (Hill 1985; Martin et al. 1997; Ciccolo et al. 2011), and others initiate the
exercise intervention after the quit date (Taylor et al. 1988; Russell et al. 1988;
Hassandra et al. 2017; Maddison et al. 2014). There has been limited evidence
suggesting that initiating exercise prior to a quit date is more efficacious; however,
results have been mixed, and the effect of exercise on a self-initiated quit attempt has
not been explored (Ussher et al. 2019). Thus, additional work is needed to parse the
potential influence of specifics of an exercise program on cessation outcomes,
particularly considering the potential mediational effects via changes in
β-endorphin depending on the exercise regime. To achieve this goal, it may be
fruitful for researchers to look at the study design of recently reported trials that
found promising findings and conduct a dismantling study to isolate the precise
aspects related to improved smoking cessation outcomes. Specifically, it may be
prudent to look at the timing, i.e., whether the exercise is initiated pre-quit, at the
same time as a quit attempt, or post-quit attempt. It may be interesting to explore
whether the time between a quit attempt and initiation of exercise influences
successful abstinence. Additionally, research could be usefully directed at different
intensities or types of exercise, such as isometric versus aerobic exercises.
As this area of work continues to develop, researchers are urged to include
smokers from racial or ethnic minority backgrounds. There is little to no under-
standing of how individuals from diverse racial or ethnic backgrounds may respond
to exercise treatment for smoking cessation. The lack of diversity among participants
enrolled in published trials on exercise for smoking cessation has contributed to this
limitation in scientific knowledge. Indeed, nearly all published work on exercise as
Exercise and Smoking Cessation 189

an aid to promote smoking cessation has been conducted with predominantly

Non-Hispanic White samples (Ussher et al. 2019). Of note, one recently completed
small-scale pilot trial for an exercise intervention to improve smoking cessation
specifically targeted Black women (Williams et al. 2021). Although the data did not
support differences in cessation between the exercise and a control group, the
exercise intervention was deemed feasible and acceptable and resulted in high
retention. Yet, a notable limitation was that exercise adherence was low, suggesting
the need for procedural refinement to engage this group actively. Given the
established, significant smoking-related health disparities that exist across racial
and ethnic minority groups (Sakuma et al. 2021), targeted efforts are needed to
examine the potential benefit, generalizability of findings, and protocol regimen for
an exercise program to assist with smoking cessation among racial and ethnic
minority groups.
Persons living with HIV (PLWH) are another unique group of smokers who may
benefit from exercise-based smoking cessation treatment. Smoking rates are signif-
icantly higher among PLWH relative to the general population (33.6% vs. 12.5%;
(Frazier et al. 2018; Cornelius et al. 2023). HIV infection also increases the suscep-
tibility to the harmful effects of smoking (Calvo et al. 2015). For example, compared
to uninfected smokers, PLWH who smoke are more likely to develop respiratory
complications and disease than smokers without HIV (Reddy et al. 2017; Depp et al.
2016). Further, emerging evidence suggests that smoking contributes to more years
of life lost than HIV-related illnesses among HIV-infected smokers when HIV is
properly managed (Reddy et al. 2016). Notably, previous work has highlighted the
benefits of exercise among PLWH (Jaggers and Hand 2016; Bopp et al. 2003;
Heissel et al. 2019; O'Brien et al. 2010). Specifically, exercise helps with HIV and
ART side effect symptom management, improves mental health, and leads to
increased quality of life among PLWH. Yet, there has been limited work on
exercise-based smoking cessation treatments among PLWH (Ledgerwood and
Yskes 2016). Further work is encouraged to evaluate such smoking interventions
among this group.
Electronic cigarette use (i.e., vaping) has quickly become a popular alternative to
combustible cigarette smoking (Dutra et al. 2017). Electronic cigarette use has been
associated with higher smoking cessation rates (Tackett et al. 2015; Rahman et al.
2015). However, recent studies have shown that vaping may cause similar detri-
mental effects to the lung and cardiovascular system as combustible cigarettes
(Darabseh et al. 2020, 2021; Li et al. 2020). A recent meta-analysis by Darabseh
et al. (2022) on the effects of aerobic exercise on vaping and smoking cessation
found that there have been no clinical trials conducted on aerobic exercise and
vaping cessation. Consequently, the effect of exercise on vaping cessation is rela-
tively unknown. Vaping and smoking cessation have barrier overlaps, such as stress
reduction as a reason for use (Sanchez et al. 2021). As such, exercise-based smoking
cessation interventions targeted toward stress reduction may prove fruitful for
vaping cessation (Abrantes et al. 2018; Smits et al. 2021). However, with vaping
cessation, there are new barriers to consider, such as the enjoyment of flavors (i.e.,
e-liquids), convenience and discreetness, and lack of self-awareness regarding
190 L. Garey et al.

vaping behavior (Sanchez et al. 2021). Barriers such as e-liquid flavors may be
targeted directly with exercise, as previous studies have shown that human taste
preferences change after exercise (Horio and Kawamura 1998). Additionally, Helen
et al. (2018) found that vaping behavior changes between different e-liquids, such as
the amount of puffs and puff duration, can affect nicotine intake. Vaping and
smoking consist of many overlapping components and barriers. Future studies
should explore the implications of exercise-based treatments for vaping cessation.
Evidence is relatively robust for the end-of-treatment and short-term benefits of
an exercise intervention on smoking cessation outcomes; however, the long-term
effects of exercise on smoking cessation are limited. Indeed, data indicate that these
benefits fade without continued intervention. Future research may consider the
potential of ‘booster sessions’ related to the exercise intervention to promote
sustained effects. Booster sessions have been shown to help maintain both smoking
abstinence and exercise following treatment (Metz et al. 2007; Fleig et al. 2013).
Yet, this work has not been applied to an exercise-based smoking cessation program.
As continued efforts to develop a programmatic method for prescriptive exercise
interventions for smoking cessation continue to be refined, research is needed to
understand the clinical utility of booster sessions focused on continued exercise and
smoking cessation to promote, maintain, or re-initiate cessation.

7 Summary

This chapter reviewed the extensive literature on smoking cessation and exercise,
discussing different exercise interventions, mechanisms of exercise interventions,
special populations of exercise interventions, and discusses future directions of
exercise and smoking cessation. A vast literature showcases the inverse relationship
between smoking and physical activity and that engagement in exercise can lead to
long-lasting health improvements irrespective of successful cessation. Although
smoking is a serious health concern, smoking cessation interventions have shown
little success in prolonged abstinence rates, indicating a need for more potent and
lasting strategies. Exercise smoking cessation interventions have been shown to be
efficacious for short-term abstinence, indicating a need for more potent and lasting
exercise strategies.

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Exercise and Anxiety

Kevin M. Crombie and Patrick J. O’Connor

Contents
1 Overview of Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
2 Acute Effects of Exercise on State Anxiety in Individuals With and Without Anxiety
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
3 Physical Activity and Exercise and the Risk for Developing Anxiety Symptoms
or Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
4 Physical Activity and Exercise Interventions in Individuals Without an Anxiety
Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
5 Physical Activity and Exercise in the Treatment of Anxiety Disorders . . . . . . . . . . . . . . . . . . . 210
5.1 Effectiveness of Exercise Training Only (or Waitlist Control) . . . . . . . . . . . . . . . . . . . . . . 211
5.2 Effectiveness of Exercise Training in Comparison to Other Treatments . . . . . . . . . . . . 212
6 Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

Abstract Anxiety disorders are among the most commonly diagnosed mental
health disorders in the United States – affecting over 40 million adults per year.
Although anxiety disorders are commonly treated via psychotherapy and/or phar-
macotherapy, there is also accumulating evidence to suggest that physical activity
and exercise may play an important role in prevention and treatment. This chapter
provides an extensive overview of literature examining the effects of physical
activity, acute bouts of exercise, and chronic exercise training on several anxiety
outcomes, primarily in adults. The collective evidence to date suggests that: (1) an
acute bout of aerobic or resistance exercise generally results in reductions in state
anxiety among adults with and without clinical anxiety disorders, (2) greater levels
of physical activity are associated with fewer anxiety symptoms and a reduced

K. M. Crombie (✉)
Department of Kinesiology, The University of Alabama, Tuscaloosa, AL, USA
Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell
Medical School, Austin, TX, USA
e-mail: [email protected]
P. J. O’Connor
Department of Kinesiology, University of Georgia, Athens, GA, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 199
Curr Topics Behav Neurosci (2024) 67: 199–222
https://doi.org/10.1007/7854_2024_498
Published Online: 31 July 2024
200 K. M. Crombie and P. J. O’Connor

likelihood of developing an anxiety disorder, (3) exercise training (aerobic and

resistance) appears to reduce general anxiety symptoms in adults without a clinical
anxiety disorder and adults with a chronic illness (e.g., cardiovascular disease) and
may reduce disorder-specific symptoms of anxiety in adults with a clinical anxiety
disorder. Although the collective body of evidence is promising, there is a need for
additional well-designed and adequately powered randomized controlled trials,
especially among adults with clinical anxiety disorders.

Keywords State anxiety · Clinical anxiety disorders · Acute anxiolytic effects ·

Anxiety symptoms · Exercise training · Physical activity · Generalized anxiety
disorder (GAD) · Panic disorder · Social anxiety disorder · Specific phobias ·
Obsessive compulsive disorder (OCD) · Posttraumatic stress disorder (PTSD)

1 Overview of Anxiety

Anxiety is a psychobiological state characterized by anticipatory cognitive, behav-

ioral, and affective changes in response to uncertainty about a future event or
potential threat (Grupe and Nitschke 2013). It is normal for individuals to experience
occasional anxiety as they navigate life. This general transient fluctuation in anxiety
is often referred to as state anxiety (i.e., how anxious one feels at a given moment).
Some individuals are also more prone to appraise and respond to many situations
with elevated levels of anxiety, which is often referred to as trait-anxiety (i.e., how
anxious one generally feels) (Endler and Kocovski 2001; Spielberger 1966). In
addition to state and trait anxiety, there are several types of anxiety disorders that
individuals can develop when specific anxiety symptoms persist or worsen over a
significant period of time and cause clinically significant impairment or distress
(American Psychiatric Association 2013). Anxiety disorders all share some common
affective and physiological features. However, each category of disordered anxiety
differs based of the objects or situations that induce symptoms, and there is consid-
erable variability in frequency and severity of symptoms between and within
disorders (see Table 1).
Anxiety disorders are consistently among the most commonly diagnosed mental
health disorders in the United States, affecting over 40 million adults per year
(approximately 20% of US adult population). In fact, data from the National
Comorbidity Survey Replication (NCS-R) study among American adults
(N = 9,282) suggest that up to 30% of US adults meet criteria for one or more
anxiety disorder(s) at some point during their lifetime (Blumenthal et al. 2021;
Kessler et al. 2005; Stonerock et al. 2015). Prevalence rates for anxiety disorders
are generally higher in women compared to men (McLean et al. 2011), with NCS-R
data revealing past-year year prevalence rates of any anxiety disorder of 23.4% for
women compared to 14.3% in men (Kessler et al. 2005). Anxiety disorders are most
commonly treated with psychotherapy (e.g., cognitive behavioral therapy, CBT) or
pharmacotherapies, including, but not limited to, selective serotonin reuptake
Exercise and Anxiety 201

Table 1 General overview of prevalence, sex differences, primary characteristics, and basic
diagnostic criteria for clinical anxiety disorders
Clinical
anxiety Primary characteristics/basic
disorders Prevalence Sex differences diagnostic criteria
Generalized Affects 6.8 million Women are two Excessive anxiety and worry that
anxiety adults (3.1% of US times as likely to be occurs more days than not for at
disorder population) affected as men least 6 months, about a number of
events or activities (e.g., work or
school performance) that is
accompanied by at least three of
the following symptoms: Restless
or feeling keyed up or on edge,
being easily fatigued, difficulty
concentrating or mind going blank,
irritability, muscle tension, and
sleep disturbance (difficulty falling
or staying asleep or restless
unsatisfying sleep)
Panic disorder Affects six million Women are two Panic attacks involve abrupt surge
adults (2.7% of US times as likely to be of intense fear or intense discom-
population) affected as men fort that reaches a peak within
minutes and during which time
four or more of the following
symptoms occur: accelerated heart
rate, sweating, trembling or shak-
ing, sensations of shortness of
breath, feeling of choking, chest
pain or discomfort, nausea or
abdominal distress, feeling dizzy/
lightheaded/faint, derealization or
depersonalization, fear of losing
control, fear of dying, paresthesia,
or chills and hot flushes. Panic
disorder involves recurrent and
unexpected panic attacks, with at
least one panic attack followed by
1 month or more of either persis-
tent concern about additional
attacks or their consequences
and/or a significant maladaptive
change in behavior related to the
attacks
Social anxiety Affects 15 million No significant sex Marked fear or anxiety about one
disorder adults (7.1% of US differences or more social situations in which
population) the individual is exposed to possi-
ble scrutiny by others (e.g., social
interactions, being observed, and
performing in front of others). The
social situations almost always
provoke fear or anxiety and are
(continued)
202 K. M. Crombie and P. J. O’Connor

Table 1 (continued)
Clinical
anxiety Primary characteristics/basic
disorders Prevalence Sex differences diagnostic criteria
avoided or endured with intense
fear or anxiety. The fear or anxiety
is out of proportion to the actual
threat posed by the social situation
and to the sociocultural context.
The fear, anxiety, or avoidance
causes clinically significant dis-
tress or impairment in social,
occupational, or other important
areas of functioning for at least
6 months or more
Specific Affects 19.3 mil- Women are two Marked fear or anxiety about a
phobias lion adults (9.1% times as likely to be specific object or situation (e.g.,
of US population) affected as men flying, heights, animals, receiving
an injection, seeing blood). The
phobic object or situation almost
always provokes immediate fear or
anxiety and is actively avoided or
endured with intense fear or anxi-
ety. The fear or anxiety is out of
proportion to the actual danger
posed by the specific object or sit-
uation and to the sociocultural
context. The fear, anxiety, or
avoidance causes clinically signif-
icant distress or impairment in
social, occupational, or other
important areas of functioning and
is persistent (usually lasting
6 months or more)
Obsessive Affects 2.5 million Women are three Presence of obsessions, compul-
compulsive adults (1.2% of the times as likely to be sions, or both. The obsessions or
disorder* population) affected as men compulsions are time consuming
(e.g., take more than 1 h per day) or
cause clinically significant distress
or impairment in social, occupa-
tional, or other important areas of
functioning. Obsessions refer to
recurrent and persistent thoughts,
urges, or images that are experi-
enced, at some time during the
disturbance, as intrusive and
unwanted, and that in most indi-
viduals cause marked anxiety or
distress. The individual attempts to
ignore or suppress such thoughts,
urges, or images or to neutralize
them with some thought or action
(continued)
Exercise and Anxiety 203

Table 1 (continued)
Clinical
anxiety Primary characteristics/basic
disorders Prevalence Sex differences diagnostic criteria
(i.e., by performing a compulsion).
Compulsions refer to repetitive
behaviors (e.g., hand washing,
ordering checking) or mental acts
(e.g., praying, counting, repeating
words silently) that the person
feels driven to perform in response
to an obsession or according to the
rules that must be applied rigidly.
The behaviors or mental acts are
aimed at preventing or reducing
distress or preventing some
dreaded event or situation. How-
ever, these behaviors or mental
acts either are not connected in a
realistic way with what they are
designed to neutralize or prevent or
are clearly excessive
Posttraumatic Affects 7.7 million Women are five The primary characteristics of
stress adults (3.6% of the times more likely to PTSD include reexperiencing
disorder* population) be affected as men symptoms, avoidance of trauma-
related stimuli, negative alterations
in cognitions and mood, and alter-
ations in arousal and reactivity – all
of which must cause significant
impairment for at least 1 month
following exposure to a traumatic
event or multiple traumatic events
(actual or threatened death, serious
injury, or sexual violence)
Note. Information reported in the table was obtained from the National Institute of Mental Health
and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision
(DSM-5-TR). Posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) are
no longer classified as anxiety disorders (denoted *), but given that they were categorized as anxiety
disorders up until the release of the DSM-V TR, they are still often discussed alongside anxiety
disorders. As a result, studies examining individuals with OCD are discussed in this chapter, as well
as some studies that examined individuals with PTSD (e.g., meta-analyses that grouped all anxiety
disorders together and as a result included participants with PTSD). Please see Chap. 13 for a
comprehensive overview of PTSD studies

inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or benzo-

diazepines (Baldwin et al. 2014; Carpenter et al. 2018). Despite high efficacy rates
for commonly administered treatments, less than 40% of adults with an anxiety
disorder seek treatment (Herring 2018; Kroenke et al. 2007). This is unfortunate as
anxiety is also a risk factor for several other adverse outcomes, such as lower health-
related quality of life and increased risk of all-cause mortality and chronic health
conditions, especially cardiovascular disease (Blumenthal et al. 2021; Stonerock
204 K. M. Crombie and P. J. O’Connor

et al. 2015; Allgulander 2016; Emdin et al. 2016; Roy-Byrne et al. 2008). In fact,
individuals with an anxiety disorder are over 50% more likely to develop cardio-
vascular disease compared to those without an anxiety disorder (Batelaan et al. 2016;
Kandola et al. 2018).
There has been a continued effort to incorporate physical activity and exercise
with treatments for anxiety, in part as a result of the relationship between poorer
physical health and anxiety. Given that none of the conventional treatments for
anxiety (psychotherapy and/or pharmacotherapy) directly address physical health
concerns, incorporating exercise into a comprehensive treatment plan makes intui-
tive sense. Moreover, there is also evidence to suggest that (1) acute bouts of
exercise often reduce state anxiety in individuals with and without clinical anxiety
disorders, (2) greater levels of regular physical activity are associated with fewer
anxiety symptoms and lowered risk of developing a clinical anxiety disorder, and
(3) exercise interventions may reduce general anxiety symptoms and anxiety
disorder-specific symptoms among individuals with and without a clinical anxiety
disorder. The following sections will present a brief overview of the evidence that
forms the basis of these claims.

2 Acute Effects of Exercise on State Anxiety in Individuals

With and Without Anxiety Disorders

The majority of early investigations into the anxiolytic effects of acute aerobic
exercise examined individuals without a clinical diagnosis of an anxiety disorder.
Small, but statistically significant, transient reductions in state anxiety (approxi-
mately 1/6–1/2 standard deviation) following acute bouts of aerobic exercise (com-
pared to control conditions) have been consistently demonstrated in several
quantitative reviews and meta-analyses (Ensari et al. 2015; McDonald and Hodgdon
1991; Petruzzello 2012; Petruzzello et al. 1991; Landers and Petruzzello 1994). One
review quantified this change as approximately a 7.7–15.4% reduction in state
anxiety scores (based on state anxiety norms from the commonly used State Trait
Anxiety Inventory [STAI]) (Herring 2018). Results from some of the earliest
investigations suggested that an acute bout of moderate-intensity aerobic exercise
is as effective at reducing state anxiety as meditation (Bahrke and Morgan 1978) and
quiet-rest (Bahrke and Morgan 1978; Breus and O’Connor 1998; Motl et al. 2004;
Smith et al. 2002), with the duration of anxiolytic effects favoring exercise compared
to the other aforementioned modalities. Reductions in state anxiety following aero-
bic exercise typically occur anywhere from 5- to 30-min post-exercise, with effects
persisting up to 2 h in some instances (Raglin and Wilson 1996). There is evidence
that a single session of yoga reduces feelings of anxiety, but the evidence that other
mindful exercise modes, such as Tai Chi and Qigong, reduce anxiety is limited by
the small number of studies conducted to date (Ray and O’Connor 2023; Yin et al.
2021). Additional research is needed to confirm if exercise training augments
Exercise and Anxiety 205

reductions in state anxiety among those with elevated anxiety or a diagnosed anxiety
disorder (Lucibello et al. 2019).
It should be noted that a few experiments among adults without a clinical anxiety
disorder have reported no change or an increase in state anxiety following an acute
bout of aerobic exercise (Raglin and Wilson 1996; Broman-Fulks et al. 2015;
Crombie et al. 2018; Koltyn et al. 1998; O’Connor et al. 1995). While this may
seem contradictory to the aforementioned findings, methodological issues may
explain these effects. For instance, the majority of trials reporting unchanged levels
of state anxiety after exercise often tested individuals with baseline anxiety levels
well-below normative values (Broman-Fulks et al. 2015; Crombie et al. 2018).
Additionally, the trials that resulted in transient increases in state anxiety either
administered a maximal exercise test (Koltyn et al. 1998; O’Connor et al. 1995) or
more vigorous-intensity exercise (Raglin and Wilson 1996). It is important to note
that increases in state anxiety following vigorous intensity aerobic exercise are
typically only present when assessed shortly after the exercise bout, with reductions
eventually occurring when assessed after a delay. For instance, a prior investigation
revealed that state anxiety was increased 5 min following completion of a 20-min
cycling bout at 70% VO2 peak but decreased 60- and 120-min post-exercise (Raglin
and Wilson 1996). This was in contrast to the less intense exercise conditions (40%
and 60% VO2 peak) for which reductions in anxiety were observed at all time points
(Raglin and Wilson 1996).
Investigations examining the anxiolytic effect of aerobic exercise among clinical
populations have lagged a bit. The delay is thought (in part) to be a result of
misconceived interpretation of findings from a study published in the New England
Journal of Medicine in 1967 (Pitts and McClure1967). In this study, 93% of
participants with an anxiety disorder experienced a panic attack following infusion
of sodium DL-lactate, which was not the case following glucose injection (Pitts and
McClure 1967). Given that exercise increases lactate, this led many researchers and
clinicians to speculate that individuals with anxiety disorders should avoid exercis-
ing. However, several rebuttals to this study (Grosz and Farmer 1972; Morgan 1979)
suggested that the authors made an erroneous conclusion given that an acute bout of
aerobic exercise is vastly different from acute lactate infusion. For example, infused
lactate results in metabolic alkalosis and hyperventilation whereas exercise-induced
elevations in lactate result in metabolic acidosis (Tappy et al. 1996). Furthermore,
O’Connor et al. reviewed 15 exercise studies among patients with panic disorder
(n = 420) and found that there were only 5 instances of panic attacks following
444 acute exercise bouts (O’Connor et al. 2000). O’Connor later demonstrated that
not only was it safe for individuals with panic disorder to exercise, but these patients
exhibit significant reductions in state anxiety following acute bouts of moderate- or
high-intensity aerobic exercise compared to quiet-rest (O’Connor 2022). Addition-
ally, Knapen et al. reported significant reductions in state anxiety following 20 min
of prescribed (50% heart rate reserve) or preferred and preferred (self-selected
intensity) aerobic exercise in a noncontrolled trial of men (n = 19) and women
(n = 29) with one or more clinically diagnosed anxiety disorders (Knapen et al.
2009). More recently, investigations reported large reductions (d = 0.98) in state
206 K. M. Crombie and P. J. O’Connor

anxiety following an acute bout of moderate-intensity aerobic exercise (70–75%

MHR) in adults with posttraumatic stress disorder (PTSD) (Crombie et al. 2018,
2019) and moderate reductions in state anxiety 10 and 30 min (hedges g = 0.59,
g = 0.61, respectively) following an acute bout of moderate-intensity aerobic
exercise (rating of 13 on Borg’s Ratings of Perceived Exertion scale) compared to
quiet-rest in adult women with major depressive disorder (Perkins et al. 2023). It
should be noted that PTSD is no longer classified as an anxiety disorder in the
DSM-V (Crombie et al. 2023a) but is discussed here given that it was previously
categorized as an anxiety disorder and given that the dedicated chapter on PTSD
focused on effects beyond state anxiety (see Chap. 13: Exercise and PTSD).
Overall, reductions in state anxiety following an acute bout of aerobic exercise are
generally larger among individuals with a clinical anxiety disorder or higher levels of
state anxiety compared to those without an anxiety disorder or those exhibiting lower
levels of state anxiety. However, this is likely due (at least partially) to floor effects
among individuals without a clinical anxiety disorder (Ensari et al. 2015). There is
also evidence to suggest that an acute bout of aerobic exercise and greater habitual
levels of physical activity contribute to reduced reactivity to stressors and anxiety-
and fear-provoking stimuli (Broman-Fulks et al. 2015; Crombie et al. 2021; Esquivel
et al. 2002, 2008; Rejeski et al. 1992; Smits et al. 2009, 2011; Ströhle et al. 2005,
2009). The reader is referred to Chap. 3: Multiple Sex- and Circuit-Specific Mech-
anisms Underlie Exercise-Induced Stress Resistance for a comprehensive overview
of this literature.
An acute bout of resistance training (e.g., weightlifting) has also been shown to
reduce state anxiety in nonclinical adults, although several investigations have
revealed a delayed-onset effect (Focht and Koltyn 1999; O’Connor et al. 1993;
Bartholomew and Linder 1998; Bibeau et al. 2010). Similar to aerobic exercise, the
anxiolytic effect of resistance exercise is typically greater for individuals with higher
baseline levels of state and trait-anxiety (Hale and Raglin 2002). One of the earliest
investigations found no significant effect of weight training on state anxiety when
assessed shortly after training (Raglin et al. 1993). Broman-Fulks et al. reported no
significant change in state anxiety scores when assessed 5 min following an acute
resistance exercise session (Broman-Fulks et al. 2015). However, as noted above,
mean baseline state anxiety values for this study were well below normative values
(Broman-Fulks et al. 2015). A recent investigation also reported nonsignificant
reductions in state anxiety in untrained young adults (n = 62) when assessed
10 min after acute resistance exercise sessions administered as part of a resistance
exercise training program (Gordon et al. 2022). However, several investigations
found that reductions in state anxiety occur after weight training when assessed
15–30 min after exercise (Bartholomew and Linder 1998; Bibeau et al. 2010) and in
some cases up to 90–180 min post-exercise (Focht and Koltyn 1999; O’Connor et al.
1993). It is worth nothing that a prior investigation reported reductions in state
anxiety after only a 10-min delay, although participants in this study were collegiate
athletes administered a combination of aerobic exercise (30 min of cycling at 70%
heart rate reserve) and resistance training (6–8 sets of 8–10 repetitions targeting
upper and lower body muscles in a 30-min period) (Hale et al. 2002). Relatedly, a
Exercise and Anxiety 207

recent narrative review concluded that vigorous (e.g., high-intensity) resistance

exercise worsens acute anxiety symptoms (Cavarretta et al. 2019). However, this
conclusion warrants further examination. Although state anxiety has been reported
to increase shortly after (5 and 15 min after) completing 20 min of high-intensity
resistance exercise training (75–85% 1RM) (Bartholomew and Linder 1998), other
investigations have reported significant reductions in state anxiety 20 and 40 min
following high-intensity (80–85% 1RM) and moderate-intensity (50–55% 1RM)
resistance exercise sessions with varying (short and long) rest periods in between
sets (Bibeau et al. 2010).

3 Physical Activity and Exercise and the Risk

for Developing Anxiety Symptoms or Anxiety Disorders

Relationships between physical activity/exercise and anxiety symptoms have been

thoroughly investigated. Several large cross-sectional and population-based studies
have demonstrated that higher rates of physical activity are associated with less
severe anxiety symptoms (De Moor et al. 2006; Goodwin 2003; Stephens 1988;
Strine et al. 2008; Ströhle et al. 2007; Thorsen et al. 2005). One of the earliest cross-
sectional survey studies found that more active individuals (i.e., those who self-
reported they expended five or more kilocalories/kilogram of body weight per day
during leisure time physical activities) reported fewer symptoms of anxiety com-
pared to less active individuals (i.e., those who self-reported they expended fewer
than 2 kcal/kg of body weight per day during leisure time physical activities)
(Stephens 1988). Additionally, Renee Goodwin examined self-report data from a
nationally representative sample of Americans (n = 5,877) between the ages of
18 and 54 and found that individuals who regularly exercised had lower rates
(OR = 0.64–0.78) of a past year diagnosis of agoraphobia, social anxiety, specific
phobias, panic disorder, and generalized disorder. All of these effects, other than the
generalized anxiety disorder effect, held after controlling for age, sex, race, marital
status, education, income, and comorbid physical conditions and mental health
disorders (Goodwin 2003). More broadly, World Health Survey data among indi-
viduals from 46 low- and middle-income countries (n = 237,023) revealed that low
levels of physical activity are significantly associated with greater anxiety symptoms
alone (OR = 1.37, 95% CI = 1.23–1.53) and comorbid anxiety and depression
symptoms (OR = 1.75; 95% CI–1.52 to 2.01). In this study, self-reported low
physical activity (obtained via short form of the International Physical Activity
Questionnaire (Craig et al. 2003)) was defined as meeting one or more of the
following criteria: (1) three days of vigorous activity of at least 20 min per day,
(2) five days of moderate-intensity activity or walking at least 30 min per day
(minimum of 10-min bouts), or (3) five days of any combination of walking,
moderate-intensity, or vigorous-intensity activities achieving at least
600 MET-minutes per week (Ma et al. 2023). Additionally, the researchers of this
208 K. M. Crombie and P. J. O’Connor

study created a four-category variable for anxiety and depression categories

(no anxiety, no depression, depression without anxiety, anxiety without depression,
anxiety and depression) (Ma et al. 2023).
A significant limitation with the aforementioned cross-sectional studies is that
they do not address temporal relationships and therefore cannot establish causality.
However, evidence from prospective cohort studies can improve causal inferences
by examining physical activity/exercise levels prior to the onset of an anxiety
disorder. As a result, prospective cohort studies provide some insight into whether
exercise may offer protection against the development of anxiety disorders. In one
such investigation, Ströhle et al. examined a cohort (N = 2,548) of adolescent and
young adults (aged 14–24) and found that individuals that self-reported that they
engaged in regular physical exercise were 48% less likely (OR = 0.52, 95%
CI = 0.37–0.74) to be diagnosed with any anxiety disorder over a four-year
follow-up period, compared to those who self-reported that they were inactive
(Ströhle et al. 2007). Several other prospective cohort studies conducted outside
the United States have also demonstrated that regular participation in physical
activity is associated with a 25–57% reduction in the risk of developing an anxiety
disorder (Beard et al. 2007; Jonsdottir et al. 2010; McDowell et al. 2018; Sanchez-
Villegas et al. 2008). For instance, meeting physical activity guidelines (based on
self-report) compared to not meeting physical activity guidelines was associated
with 57% reduced odds (OR = 0.43; 95% CI = 0.19–0.99) of developing general-
ized anxiety disorder over a two-year period in adult men and women (n = 3,950)
that participated in The Irish Longitudinal Study on Ageing (McDowell et al. 2018).
Lastly, participants in an endurance snow ski race in Sweden (n = 197,685, median
age of 36 years, 38% women) were 60% less likely to develop an anxiety disorder
during the >20-year follow-up when compared to nonskiers (Svensson et al. 2021).
McDowell et al. conducted a systematic review and meta-analysis of prospective
cohort studies that examined relationships between physical activity/exercise and
self-reported anxiety symptoms, a diagnosis of any anxiety disorder, and a diagnosis
of generalized anxiety disorder (McDowell et al. 2019). Twenty-four studies were
reviewed for the systematic review (median follow-up of 4.75 years), and 13 studies
were included in the meta-analysis. The researchers found that the odds of elevated
anxiety symptoms (OR = 0.87, 95% CI = 0.77–0.99), any anxiety disorder diag-
nosis (OR = 0.66, 95% CI = 0.54–0.82), and generalized anxiety disorder
(OR = 0.54, 95% CI = 0.32–0.92) were significantly lower for those that were
physically active compared to those who were not (McDowell et al. 2019). Another
meta-analysis published in that same year (n = 69,037 participants from 11 cohorts)
similarly reported that greater levels of physical activity significantly reduced the
incidence of anxiety symptoms (OR = 0.74; 95% CI = 0.63–0.89) or anxiety
disorders (OR = 0.75; 95% CI = 0.61–0.92) over a 3.5-year follow-up period
compared to those with lower levels of physical activity (Schuch et al. 2019). The
researchers also reported that those who reported accumulating at least 150 min of
moderate- to vigorous-intensity physical activity had reduced odds of developing
anxiety symptoms (OR = 0.71, 95% CI = 0.54, 0.94) over time compared to those
who did not meet the aforementioned activity threshold (Schuch et al. 2019).
Exercise and Anxiety 209

Although the collective body of evidence suggests that engaging in physical

activity offers protection against increased anxiety symptoms and the development
of anxiety disorder(s), our understanding of this relationship could be strengthened
by using device-based measures of physical activity (e.g., accelerometers) to cor-
roborate the commonly administered self-report measures. Future research should
also consider assessing cardiorespiratory fitness, as some investigations have
reported that greater cardiorespiratory fitness is associated with a lower risk of
developing a clinical anxiety disorder (Baumeister et al. 2017; Kandola et al.
2019; Nyberg et al. 2018), while others have not (Kandola et al. 2019; Shigdel
et al. 2019).

4 Physical Activity and Exercise Interventions

in Individuals Without an Anxiety Disorder

Evidence has demonstrated that exercise training (aerobic and resistance) signifi-
cantly reduces (small to moderate effect size reduction) anxiety symptoms among
adults without a clinical anxiety disorder (Petruzzello et al. 1991; Conn 2010;
Gordon et al. 2018; Long and van Stavel 1995; Rebar et al. 2015; Wipfli et al.
2008). Small to large effect size reductions in anxiety have also been reported among
children and adolescents (Petruzzello et al. 1991; Wipfli et al. 2008; Ahn and
Fedewa 2011; Calfas and Taylor 1994; Larun et al. 2006). Several recent meta-
analyses have also demonstrated that exercise training contributes to reductions in
anxiety symptoms (small to moderate effects) among adults with comorbid chronic
disease and illnesses, particularly among individuals with cardiovascular disease and
fibromyalgia (Herring et al. 2010; Kugler et al. 1994; McDowell et al. 2017; Rossy
et al. 1999). For instance, Matthew Herring, Pat O’Connor, and Rod Dishman
conducted an extensive review of over 40 exercise training randomized controlled
trials (with 75 effects) and found a small but significant reduction in anxiety
symptoms (mean effect size Δ = 0.29) across all chronically-ill patient groups,
with small to moderate reductions across each of the individual groups, including
multiple sclerosis (mean effect size Δ = 0.19), cancer (mean effect size Δ = 0.19),
fibromyalgia (mean effect size Δ = 0.29), chronic pain (mean effect size Δ = 0.30),
cardiovascular disease (mean effect size Δ = 0.32), chronic obstructive pulmonary
disease (mean effect size Δ = 0.40), and others (mean effect size Δ = 0.47) (Herring
et al. 2010). Importantly, meta-regression analyses revealed that the largest effects
were found for exercise training programs that involved at least 30-min exercise
bouts and lasted at least 12 weeks long, with a time frame of anxiety assessment of
more than 1 week in the past (Herring 2018; Herring et al. 2010).
In addition to aerobic exercise, a recent meta-analysis reported a small but
significant reduction (mean effect size Δ = 0.31) in anxiety symptoms following
participation in resistance exercise training interventions (Gordon et al. 2017). This
effect is comparable to several previously published meta-analyses that reported
210 K. M. Crombie and P. J. O’Connor

reductions in anxiety symptoms among adults without a clinical anxiety disorder

following aerobic exercise interventions (Wipfli et al. 2008; Herring et al. 2010;
Herring et al. 2014a). In contrast to meta-analytic evidence in chronically ill patients
(Herring et al. 2010), the effects were not moderated based on intervention length,
time frame of anxiety assessment, and exercise bout duration (in addition to age, sex,
and control condition). Although the aforementioned meta-analysis (Gordon et al.
2018) analyzed 31 effects from 16 different randomized controlled trials, only one of
the trials examined individuals with a clinical anxiety disorder diagnosis (general-
ized anxiety disorder), highlighting the need for further investigations of the anxi-
olytic effect of resistance training in clinical populations. At least three randomized
controlled trials tested the short-term influence of yoga compared to relaxation and
found large mean benefits favoring the yoga interventions (Cramer et al. 2018).
Several quantitative reviews have also concluded that exercise training reduces
anxiety symptoms in individuals with elevated anxiety symptoms (compared to
normative data) but not necessarily with a clinical anxiety disorder diagnosis
(Petruzzello et al. 1991; Wipfli et al. 2008; Aylett et al. 2018). Several of these
investigations examined adults with high levels of anxiety sensitivity (i.e., fear of
anxiety-related sensations), which plays a role in the etiology and maintenance of
panic attacks and panic disorder (Broman-Fulks and Storey 2008; Ehlers 1995;
Schmidt et al. 2006). For instance, Smits et al. randomly assigned adult men and
women with elevated levels of anxiety sensitivity to either a two-week aerobic
exercise intervention (six, 20-min treadmill sessions at 70% MHR), a two-week
exercise plus cognitive restructuring intervention, or a waitlist control condition.
Results revealed that both exercise conditions resulted in significant reductions in
anxiety sensitivity and general anxiety symptoms (measured via Beck Anxiety
Inventory) at 1 and 3 weeks after the intervention compared to the waitlist control
condition (Smits et al. 2008). Another study published in that same year among men
and women undergraduates (n = 24) with elevated levels of anxiety sensitivity
reported a significant reduction in self-reported fears of anxiety sensations (i.e.,
anxiety sensitivity) immediately after and one-week following six, 20-min treadmill
sessions at 60–90% MHR over a two-week period, compared to a waitlist control
condition (Broman-Fulks and Storey 2008).

5 Physical Activity and Exercise in the Treatment

of Anxiety Disorders

Several recent reviews and meta-analyses concluded that exercise training appears to
be an effective stand-alone and adjunct treatment for adults with clinical anxiety
disorders (Wipfli et al. 2008; Herring et al. 2014a; Aylett et al. 2018; Asmundson
et al. 2013; Jayakody et al. 2014; Ramos-Sanchez et al. 2021; Stubbs et al. 2017). In
fact, one of the most recent meta-analyses examined the influence of exercise
training in adults (n = 262) with an anxiety disorder (and PTSD) from six
Exercise and Anxiety 211

randomized controlled trials (Broocks et al. 1998; Gaudlitz et al. 2015; Herring et al.
2012; Merom et al. 2008; Powers et al. 2015; Rosenbaum et al. 2015) and found a
significant, moderate effect size improvement in anxiety symptoms (Stubbs et al.
2017). It should be noted that there was considerable variability in the magnitude of
the effect among studies included in this meta-analysis (Stubbs et al. 2017), with
standardized mean differences ranging from 0.012 (Gaudlitz et al. 2015) to 1.418
(Broocks et al. 1998) for anxiety disorders and up to 2.648 for a study among adults
with PTSD (Powers et al. 2015). Similarly, a recent random-effect meta-analysis of
13 randomized controlled trials (consisting of 376 adults with an anxiety disorder or
PTSD randomly assigned to an exercise condition and 355 adults with an anxiety
disorder or PTSD randomly assigned to a control condition) found that exercise
interventions resulted in a small, but statistically significant effect (standardized
mean difference = -0.425) reduction in anxiety symptoms compared to a control
condition (Ramos-Sanchez et al. 2021).

5.1 Effectiveness of Exercise Training Only (or Waitlist

Control)

Egil Martinsen and colleagues conducted some of the earliest investigations exam-
ining the effect of exercise training on anxiety symptoms in individuals with an
anxiety disorder. One of their first investigations was a noncontrolled trial that found
significant reductions in anxiety symptoms for adults (n = 44) with a clinical anxiety
disorder (except for social phobia) following an exercise intervention consisting of
walking or jogging five times a week (60 min per session) for a duration of 8 weeks
(Martinsen et al. 1989b). A second noncontrolled investigation revealed significant
(and comparable) reductions in anxiety following random assignment to either an
aerobic or nonaerobic exercise intervention, both of which involved three sessions a
week (60 min per session) for 8 weeks. Importantly, aerobic capacity was assessed as
part of this intervention, which revealed that reductions in anxiety occurred inde-
pendently of changes in aerobic capacity (Martinsen et al. 1989a). Similarly, another
noncontrolled early study among inpatients (n = 52) reported significant (and
comparable) reductions in anxiety for up to 6 months following 8 weeks of either
walking or jogging (Sexton et al. 1989).
There have been a few recent studies that examined the effect of exercise training
on anxiety symptoms among individuals with a specific anxiety disorder. For
instance, Herring et al. compared the effect of 6 weeks of resistance exercise training
(two sessions per week of lower body weightlifting at 50% of 1RM, which
progressed by 5% weekly) to 6 weeks of aerobic exercise training (two weekly
sessions per week) and a waitlist control condition on generalized anxiety disorder
symptoms and remission in women (n = 30) with a clinically confirmed diagnosis of
generalized anxiety disorder (Herring et al. 2012). A strength of this study was that
researchers selected cycling to match the primary muscle groups engaged during the
212 K. M. Crombie and P. J. O’Connor

resistance exercise intervention, along with matching for the work completed during
the sessions and the actual time engaged in exercise (as opposed to simply matching
for the duration of the exercise session [e.g., including rest periods]). Results
revealed that remission rates were higher following resistance exercise training
(60% remission) and aerobic exercise training (40% remission) compared to the
weight-list control (30% remission). Additionally, in comparison to the waitlist
control condition, the exercise training groups exhibited significant reductions in
worry symptoms (hallmark of generalized anxiety disorder) and moderate reductions
in trait-anxiety (among other secondary outcomes including depression, feeling of
energy and fatigue, and pain) (Herring et al. 2012). Although not directly compared
as part of this study, the reported remission rates for the exercise groups were
comparable to other commonly administered treatments (e.g., pharmacotherapies,
psychotherapies, relaxation therapy) for generalized anxiety disorder (Chessick et al.
2006; Hackett et al. 2003; Hofmann et al. 2010, 2012; Springer et al. 2018). In
addition to generalized anxiety disorder, a noncontrolled aerobic exercise trial
among adults with obsessive compulsive disorder (OCD) resulted in a mean reduc-
tion in OCD symptoms (obtained via Yale-Brown Obsessive Compulsive Scale)
from the severe to moderate range for the 11 out of 16 individuals that completed the
intervention (Lancer et al. 2007). It should be noted that OCD (along with PTSD) is
no longer classified as an anxiety disorder in the DSM-V but is discussed here given
that it was previously categorized as an anxiety disorder and there is not a dedicated
chapter on OCD (which is the case for PTSD; see Chap. 13: Exercise and PTSD).

5.2 Effectiveness of Exercise Training in Comparison

to Other Treatments

Several investigations among adults with varying anxiety disorders have also exam-
ined the effect of exercise training in conjunction with or in comparison to other
treatment modalities. The strongest research designs have been implemented in
investigations examining adults with panic disorder. Broocks et al. examined anxiety
symptoms among adults with a clinical diagnosis of moderate-to-severe panic
disorder (with or without agoraphobia) following random assignment to either an
aerobic exercise intervention (3–4 weekly sessions of walking or running a four-mile
route for 10 weeks), antidepressant medication (112.5 mg daily dose of a tricyclic
antidepressant [clomipramine]), or placebo (Broocks et al. 1998). Although the
antidepressant treatment contributed to quicker reductions in anxiety symptoms,
both the exercise and medications groups exhibited a significant reduction (large
effect size reductions) in anxiety symptoms compared to placebo (Broocks et al.
1998). A separate randomized controlled trial implemented a slightly different
design in which adults with panic disorder (n = 75) were randomized to either
10 weeks of (1) aerobic exercise and antidepressant medication (40 mg daily dose of
a selective serotonin reuptake inhibitor [paroxetine]), (2) aerobic exercise and
Exercise and Anxiety 213

placebo, (3) relaxation and antidepressant medication (as described above), or

(4) relaxation and placebo (Wedekind et al. 2010). Results revealed that all four
groups exhibited significant reductions (large effect size improvements) in self-
report and clinician-administered assessments, which in part suggests that antide-
pressant medication did not enhance the efficacy of exercise in reducing anxiety
symptoms (Wedekind et al. 2010).
In addition to medication, a few trials among adults with panic disorder have also
compared the effects of aerobic exercise to cognitive behavioral therapy. Hovland
et al. reported that a 12-week group-based multicomponent (cardiorespiratory fitness
and muscular strength) exercise intervention (3 sessions per week) resulted in
significant and comparable reductions in anxiety compared to 12 weeks of CBT
(one session per week) in a sample of adult men and women (n = 36; 81% women)
with panic disorder (Hovland et al. 2013). In a separate trial (Gaudlitz et al. 2015),
researchers found that an aerobic exercise intervention (three weekly sessions of
treadmill running at 70% VO2 max) in conjunction with CBT resulted in significant
and similar reductions in anxiety symptoms compared to a control (very-low-
intensity flexibility training) and CBT condition in adults with panic disorder
(n = 47). However, there was a moderate effect size difference favoring the exercise
group at a seven-month follow-up. Unfortunately, it is difficult to draw strong
conclusions from this study as there was no control group in this trial and due to
the fact that physical activity and/or exercise levels were not assessed during the
follow-up period (Gaudlitz et al. 2015).
In addition to panic disorder, there have been a few exercise trials conducted in
adults with OCD. The first trial conducted was a quasi-experimental pilot study that
reported large reductions (d = 1.69) in OCD symptoms after the intervention and
6-months later for participants (n = 15) after they completed a 12-week aerobic
exercise intervention (3–4 sessions per week of 20–40 min of moderate-intensity
aerobic exercise). Importantly, all of the participants in this study previously
received at least 12 weeks of either pharmacotherapy or psychotherapy and had
not experienced a significant remission of symptoms (Brown et al. 2007). Relatedly,
another uncontrolled small pilot study (n = 11) reported large improvements
(d = 2.55) in OCD symptoms following a 12-week aerobic exercise intervention
administered in conjunction with CBT (Rector et al. 2015). The exercise intervention
for this pilot study (Rector et al. 2015) consisted of three weekly sessions at 40–60%
MHR for 15–30 min for 4 weeks and progressed to 60–80% MHR for 30–45 min for
an additional 8 weeks. More recently, Ana Abrantes and colleagues conducted a
randomized controlled trial that examined the efficacy of a 12-week aerobic exercise
intervention in comparison to 12 weeks of health education sessions among phys-
ically inactive adults (n = 56) currently receiving treatment for OCD with either
pharmacotherapy or CBT (Abrantes et al. 2017). The aerobic exercise intervention
consisted of a weekly supervised moderate-intensity session on either a treadmill,
elliptical machine, or recumbent cycle (participant’s choice). Participants were also
encouraged to exercise on their own in between weekly sessions, building up to a
goal of obtaining 150 min of moderate-intensity aerobic exercise per week. Results
revealed that both groups exhibited significant reductions in anxiety and
214 K. M. Crombie and P. J. O’Connor

OCD-specific symptom severity at posttreatment, with no significant differences

between groups (exercise group d = 1.16; health education d = 0.63). However,
there was a trend toward greater treatment response (i.e., at least a 35% reduction in
symptoms from baseline) among participants in the aerobic exercise group. Specif-
ically, 30.4% of participants from the aerobic exercise group exhibited a 35%
reduction in symptom severity from baseline (i.e., treatment responders), which
was in contrast to the health education condition, in which only two individuals
(7.7%) exhibited such a response (Abrantes et al. 2017).
There have been even fewer investigations among individuals with a primary
diagnosis of social anxiety disorder. One such trial found moderate reductions in
anxiety symptoms among unmedicated patients (n = 56) following random assign-
ment to either 8 weeks of an aerobic exercise intervention (two individual and one
group-based exercise session per week) or a mindfulness-based stress reduction
condition (a weekly 150-min group class, a 1-day retreat, and daily practice)
(Jazaieri et al. 2012). These reported anxiety reductions were comparable between
groups as evident via nonsignificant group differences (Jazaieri et al. 2012). Lastly,
prescription of a home-based aerobic exercise program that included 30-min bouts of
moderate-intensity walking with a goal of 150 min per week, in addition to
8–10 weeks of group-based CBT among adults with a diagnosis of social anxiety
disorder, generalized anxiety disorder, or panic disorder, resulted in significant, large
reductions in anxiety symptoms compared to a CBT-only condition (Merom et al.
2008).
More recently, researchers at the Duke University Medical Center conducted a
randomized controlled trial in which adult men and women (n = 128) with coronary
heart disease and a diagnosed anxiety disorder (any disorder, 73% of sample) or high
levels of anxiety (Hospital Anxiety and Depression-Anxiety Subscale [HADS-A]
score of 8 or higher) were randomly assigned to receive an aerobic exercise
intervention, escitalopram (up to 20 mg per day), or a placebo (Blumenthal et al.
2021). The 12-week aerobic exercise intervention consisted of three weekly super-
vised moderate-intensity aerobic exercise sessions (35 min at 70–85% heart rate
reserve) of either walking, cycling, or jogging. Researchers found that the exercise
intervention and escitalopram significantly reduced anxiety symptoms (HADS-A
scores) to a greater degree than the placebo group, with greater reductions reported
for the escitalopram group (Blumenthal et al. 2021). Additionally, participants from
the exercise and medication groups exhibited significantly lower state anxiety scores
compared to the placebo group at posttreatment. Interestingly, weekly reductions in
state anxiety occurred most rapidly in the escitalopram group; reductions primarily
occurred in the last 6 weeks for the exercise group (Blumenthal et al. 2021).
However, a follow-up study with 94% of the original sample revealed that partici-
pants from the escitalopram group exhibited greater reductions in anxiety scores
(HADS-A) at a six-month follow-up compared to both the exercise and placebo
conditions (Blumenthal et al. 2022).
Exercise and Anxiety 215

6 Conclusions and Future Directions

To date, the collective evidence suggests that (1) acute bouts of aerobic or resistance
exercise generally results in small reductions in state anxiety among adults with and
without clinical anxiety disorders, (2) greater levels of physical activity are associ-
ated with fewer anxiety symptoms and reduced likelihood of developing an anxiety
disorder, (3) exercise training (aerobic and resistance) appears to reduce general
anxiety symptoms in adults without a clinical anxiety disorder, including adults with
a chronic illness (e.g., cardiovascular disease), and often reduces anxiety disorder-
specific symptoms and general anxiety in adults with a clinical anxiety disorder.
Continued research efforts are needed to provide further insight into the potential
role for exercise as an affordable and easily accessible treatment modality for
individuals with clinical anxiety disorders. Our current understanding of the rela-
tionship between physical activity, exercise, and anxiety is restricted by several
common methodological limitations often found in the literature (e.g., cross-
sectional designs, small sample sizes, lack of long-term follow-up and/or monitoring
of activity levels during follow-up periods). There is also an urgent need for
additional well-designed and adequately powered randomized controlled trials,
especially among individuals (including children and adolescents) with clinical
anxiety disorders. Such trials will help to improve our understanding of the efficacy
of exercise of varying modalities, intensities, and doses as a potential treatment for
anxiety. Additionally, it is important for future research to continue to examine
potential and plausible mechanisms that may be at least partially responsible for the
anxiolytic effects of acute and chronic exercise. Several mechanisms have been
proposed in the literature (and discussed in several other chapters in this series),
including but not limited to improvements in self-efficacy (Katula et al. 1999), self-
esteem (Herring 2018; Herring et al. 2014b), adaptations to relevant neurotransmit-
ter/neuromodulatory systems and signaling (e.g., GABA, norepinephrine, serotonin,
dopamine, endocannabinoid) (Dishman 1997; Dishman et al. 2006; Dishman and
O’Connor 2009; Greenwood et al. 2011; Greenwood and Fleshner 2011; Crombie
et al. 2023b), and expectancy and/or placebo effects (see Chap. 19: The Placebo
Effect in Exercise and Mental Health Research) (Herring et al. 2023; Lindheimer
et al. 2015, 2020a, b).

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Adaptive and Maladaptive Exercise
in Eating Disorders

Katherine Schaumberg, Lauren Pictor, and Max Frank

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
1.1 Defining and Understanding Maladaptive Exercise in Eating Disorders . . . . . . . . . . . . 224
1.2 Defining and Understanding Adaptive Exercise in Eating Disorders . . . . . . . . . . . . . . . . 227
2 The Biobehavioral Underpinnings of Maladaptive Exercise in Eating Disorders . . . . . . . . . 229
2.1 Biological Reinforcement of Maladaptive Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
2.2 Behavioral Reinforcement of Maladaptive Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
2.3 Potential Genetic Underpinnings of Maladaptive Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3 Advancing an Understanding of Maladaptive Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
4 Exercise in Eating Disorder Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
4.1 Reducing Maladaptive Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
4.2 Promoting Adaptive Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

Abstract While exercise is generally associated with positive health outcomes, in

the context of eating disorders, exercise has high potential to become maladaptive.
Maladaptive exercise is compelled or compulsive in nature for the purposes of
weight and shape control or to obtain/avoid other eating disorder-relevant conse-
quences. A transdiagnostic eating disorder feature with moderate-to-high preva-
lence across restrictive- and bulimic-spectrum eating disorders, maladaptive
exercise is often associated with negative mental and physical health sequalae.
Several proposed threat- and reward-related biobehavioral mechanisms may initi-
ate or perpetuate maladaptive exercise. While exercise is generally contraindicated
during periods of acute medical concern, adaptive forms of exercise are also
present among those with eating disorders, and facilitation of adaptive exercise
has potential to promote physical and mental health benefits during eating disorder

K. Schaumberg (✉), L. Pictor, and M. Frank

Department of Psychiatry, University of Wisconsin, Madison, WI, USA
e-mail: [email protected]; [email protected]; [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 223
Curr Topics Behav Neurosci (2024) 67: 223–240
https://doi.org/10.1007/7854_2024_499
Published Online: 24 July 2024
224 K. Schaumberg et al.

recovery. Detailed assessment and targeted interventions are needed to address the
clinical conundrum of how and when to integrate exercise into eating disorder
treatment.

Keywords Anorexia Nervosa · Bulimia Nervosa · Eating Disorders · Maladaptive

Exercise

1 Introduction

Exercise (i.e., planned, structured physical activity carried out to improve one or
more fitness domains) is commonly associated with positive mental health outcomes
(Deslandes et al. 2009; Vankim and Nelson 2013; Chekroud et al. 2018) and is
increasingly prescribed as a component of mental health treatment (Herring et al.
2010; Carek et al. 2011). However, within the context of an eating disorder, exercise
presents a mental health paradox, as it also has high potential to become a maladap-
tive behavior with compulsive qualities, which can interfere with both quality of life
and eating disorder recovery (Davis and Kaptein 2006; Shroff et al. 2006; Cook et al.
2014; Davis et al. 1997). Priorities for exercise-related research in the context of
eating disorders include clarifying when and for whom exercise is
adaptive vs. maladaptive along with designing interventions that promote adaptive
exercise in eating disorder recovery while mitigating risk for maladaptive use.

1.1 Defining and Understanding Maladaptive Exercise

in Eating Disorders

Exercise-related research in eating disorders has historically focused on character-

izing and understanding maladaptive forms of exercise that can arise during an active
eating disorder. While maladaptive qualities of exercise may arise with any form or
type of exercise, and a growing literature notes the presentation of maladaptive
forms of resistance training that are common among boys and men with eating
disorders (Griffiths et al. 2015; Martenstyn et al. 2021; Murray et al. 2013), the most
commonly reported type of maladaptive exercise is aerobic (Nagata et al. 2017).
Defining maladaptive exercise has led to substantial debate and myriad terminology,
including compulsive exercise, obligatory exercise, compensatory exercise, exercise
addiction, excessive exercise, and driven exercise. We use the term “maladaptive
exercise” to refer to exercise which, broadly defined, fits into any of these categories
and note that definitions of these terms and their measurement components overlap
substantially (see Table 1).
Studies that have examined multiple definitions simultaneously find substantial
overlap in endorsement of compulsive and addictive exercise, with compensatory
exercise, which refers to exercise that occurs specifically to counteract the effects of
Adaptive and Maladaptive Exercise in Eating Disorders 225

Table 1 Maladaptive exercise constructs

Cognitive Affective Behavioral Example assessment
Construct features features features items
Compensatory NA Reduces feel- Occurs after “Have you exercised as a
exercise ings of guilt overeating or means of controlling
about overeating binge eating your weight, altering
your shape or amount of
fat, or burning off calo-
ries?” (Fairburn and
Bèglin 1994)
“Have you ever used
[exercise] to compensate
for episodes of binge
eating or over eating?”
(Thornton et al. 2018)
Compulsive Weight/shape Mood improve- Exercise “I follow a set routine for
exercise and/or affect ment rigidity my exercise sessions”
regulation Guilt if missed Rule-driven (Meyer et al. 2016)
motivation Lack of enjoy- behavior
ment (habit)
Avoidance of
negative affect
Excessive Weight/shape NA Daily or “I exercise more than
exercise motivation almost daily, 3 days per week”
1 h or more (Steffen and Brehm
1999)
“I spend most of my free
time exercising”
(Hausenblas and Downs
2002)
Driven Weight/shape Feeling “com- Interferes How many times have
exercise and/or affect pelled” or with life you exercised in a
regulation “driven” to activities “driven” or “compul-
motivation complete sive” way as a means of
exercise controlling your weight,
shape, or amount of fat or
to burn off calories?
(Fairburn and Bèglin
1994)
Exercise Weight/shape Needing to Exercising “I continually increase
addiction and/or affect exercise more to more than my exercise intensity to
regulation produce a simi- intended achieve the desired
motivation lar effect over Inability to effects/benefits”
time reduce (Hausenblas and Downs
Interferes 2002)
with life “I exercise despite per-
activities sistent physical prob-
lems” (Hausenblas and
Downs 2002)
(continued)
226 K. Schaumberg et al.

Table 1 (continued)
Cognitive Affective Behavioral Example assessment
Construct features features features items
Obligatory Preoccupation Intense negative Exercise “If I miss an exercise
exercise with exercise affect when rigidity session, I will try and
unable to Rule-driven make up for it when I
exercise behavior next exercise (Meyer
(habit) et al. 2016)”
Continued “I will engage in other
exercise forms of exercise if I am
despite nega- unable to engage in my
tive usual form of exercise”
consequences (Steffen and Brehm
1999)
“Sometimes, I find that
my mind wanders to
thoughts about exercis-
ing” (Pasman and
Thompson 1988)

overeating or binge eating, showing some distinction from other maladaptive exer-
cise definitions (Holland et al. 2014; Scharmer et al. 2020). Though some debate
persists regarding an optimal definition of maladaptive exercise, consistent evidence
indicates that some individuals, can adaptively exercise at very high levels, without
negative consequence (Juwono et al. 2022). Among athlete samples (e.g., ultramar-
athon runners and other competitive runners, elite dancers, competitive body
builders, triathletes, and other mixed groups of athletes), exercise addiction or
dependence was estimated between 3% and 42% (Juwono et al. 2022). Further,
individuals may experience negative sequalae of maladaptive exercise even when
exercise is present at moderate levels (Adkins and Keel 2005; Young et al. 2017).
For example, average metabolic equivalents (METS) per week was weakly associ-
ated with compulsive exercise in a sample of adolescents (r = 0.15) (Goodwin et al.
2011), and time spent in driven exercise on the eating disorder examination ques-
tionnaire (EDEQ) was moderately associated (r = 0.42) with compulsive exercise
total score in a clinical sample of individuals with eating disorders (Young et al.
2017). Further, a study of university students found no difference in self-reported
exercise mins/week among those who reported high levels of appearance motivation
(M = 241.44, SD = 217.75 min), vs. those who reported no appearance motivations
for exercise (M = 299.29, SD = 277.42 min); however, those who reported high
appearance motivations for exercise reported significantly higher levels of eating
pathology (Adkins and Keel 2005). Defining features that are common across
maladaptive exercise constructs include a problematic psychological relationship
with exercise (e.g., exercise feels driven or compulsive, feelings of guilt when
missing exercise, overreliance on exercise to manage affect and/or concerns about
shape and weight) along with life interfering symptoms (e.g., inability to reduce
exercise, exercising despite illness or injury, exercise routines interfering with work,
school, or social functioning).
Adaptive and Maladaptive Exercise in Eating Disorders 227

Maladaptive exercise occurs transdiagnostically across eating disorders but at

somewhat varying rates based on eating disorder presentation (Davis and Kaptein
2006; Shroff et al. 2006; Cook et al. 2014; Davis et al. 1997). Definitional compo-
nents of specific eating disorders and estimations of maladaptive exercise prevalence
within these subpopulations is presented in Table 2.
Overall rates of maladaptive exercise are highest among individuals with
anorexia nervosa (AN) followed by bulimia nervosa (BN) and other specified
feeding or eating disorder (OSFED); however, maladaptive exercise is also present
among individuals with BED. Little research has investigated whether maladaptive
exercise presents in those with avoidant/restrictive food intake disorder. Other
disorder-relevant characteristics and demographic factors associated with increased
risk for maladaptive exercise include lower body mass index reached during illness,
lower novelty, higher levels of persistence (Shroff et al. 2006), suicidal behavior
(Smith et al. 2013), obsessive-compulsive traits and symptoms (Davis and Kaptein
2006; Shroff et al. 2006), higher levels of anxiety (Shroff et al. 2006; Holtkamp et al.
2004), perfectionism (Shroff et al. 2006), body dissatisfaction (Brewerton et al.
1995), reward dependence (Dalle Grave et al. 2008), dietary restraint (Dalle Grave
et al. 2008; Holtkamp et al. 2004), and anhedonia (Davis and Woodside 2002).
When present in an eating disorder, maladaptive exercise is associated with poor
treatment outcome, prognosis, and quality of life (Dalle Grave et al. 2008), along
with hypoleptinemia (Holtkamp et al. 2003, 2006). Further, among epidemiological
samples, maladaptive exercise is prospectively associated with eating disorder
symptom severity, and eating disorder cognitions in middle adolescence are associ-
ated with greater odds of engaging in maladaptive exercise across adolescence and
young adulthood (Schaumberg et al. 2022, 2023). Additionally, while the current
chapter focuses on exercise in the context of eating disorders, it is also relevant to
note that exercise can develop maladaptive qualities outside of eating disorders,
which may present similar treatment challenges. Some work on the construct of
exercise addiction, for instance, distinguishes between primary exercise addiction,
which includes addictive qualities but occurs outside of a co-occurring mental health
condition, and secondary exercise addiction, which occurs secondary to a mental
health condition, most often an eating disorder (Cook et al. 2014). The odds ratio for
exercise addiction in populations with vs. without indicated eating disorders has
been estimated at 3.71, indicating substantial increased risk for maladaptive exercise
among those with an eating disorder (Trott et al. 2021).

1.2 Defining and Understanding Adaptive Exercise in Eating

Disorders

While most research on exercise in eating disorders has focused on maladaptive

forms of exercise, it is well established that exercise can promote positive mental
health outcomes, including among those with eating disorders. In the context of
228 K. Schaumberg et al.

Table 2 Maladaptive exercise prevalence estimates across eating disorders

Maladaptive exercise prevalence
estimate during active eating
Eating disorder Basic definitional components disorders
Anorexia nervosa Significant restriction of energy Adult: 38–80% (Shroff et al. 2006;
(AN) intake, resulting in low body weight, Brewerton et al. 1995); AN with
intense fear of gaining weight, and a purging subtype has demonstrated
distorted body image. AN primarily a higher prevalence of maladaptive
affects adolescents and young adults exercise than other AN subtypes
and is most prevalent in females (Shroff et al. 2006)
Adolescent: 23–80% (Davis et al.
1997; Stiles-Shields et al. 2011)
Bulimia nervosa Recurrent episodes of binging Adult: 23–51% (Shroff et al. 2006;
(BN) followed by compensatory behav- Brewerton et al. 1995; Monell et al.
iors (e.g., self-induced vomiting and 2018)
laxative misuse). Individuals with Adolescent: ~66% (Stiles-Shields
BN have a preoccupation with body et al. 2015)
shape and weight and may experi-
ence feelings of guilt and loss of
control
Binge eating disor- Recurrent episodes of consuming Adult: 13–43% (Monell et al.
der (BED) large amounts of food in a short 2018; Lampe et al. 2021)
period accompanied by a sense of Adolescent: No current estimates
loss of control and marked distress.
Unlike BN, individuals with binge
eating disorder do not engage in
compensatory behaviors
Atypical AN Similar to AN, with significant Adult: No current estimates
weight loss and restrictive eating Adolescent: 73% (Sawyer et al.
behaviors, but individuals may 2016)
maintain a weight within or above
the normal range. Despite not meet-
ing the low weight criteria of typical
anorexia nervosa, individuals with
atypical anorexia nervosa experi-
ence similar psychological and
physical consequences to those with
AN
Other specified A diagnosis used when an individ- Adult: 21–55% (Shroff et al. 2006;
feeding and eating ual presents with significant eating Monell et al. 2018; Dalle Grave
disorders (OSFED) disorder symptoms that do not meet et al. 2008)
the full criteria. OSFED encom- Adolescent: ~17% (Machado et al.
passes a range of eating disorder 2007)
presentations, such as subthreshold
BN, BED, and purging disorder
Avoidant/restrictive Persistent avoidance or restriction of Current research does not support
food intake disorder food intake, often driven by sensory the presentation of maladaptive
(ARFID) sensitivity, lack of interest in eating, exercise with ARFID (Nakai et al.
or fear of negative consequences. 2017)
Unlike other eating disorders, indi-
viduals with ARFID do not neces-
sarily have body image concerns or
a desire for weight loss
Adaptive and Maladaptive Exercise in Eating Disorders 229

eating disorder treatment, structured, adaptive exercise (i.e., exercise that is

noncompensatory and not motivated by intention to control shape or weight) has
the potential to promote muscle health, prevent loss of bone density, enhance
cognitive functioning and self-regulation skills, and facilitate social engagement
and mood regulation. Further, as mood and anxiety disorders are highly comorbid
with eating disorders (Bühren et al. 2014), exercise may improve outcomes for these
comorbid conditions (Carek et al. 2011; Asmundson et al. 2013; Heyman et al.
2012). Some research has successfully distinguished adaptive from maladaptive
exercise engagement in individuals with eating disorders. For example, among
adults with binge-spectrum eating disorders, ecological momentary assessment pro-
tocols have identified that these individuals report a mix of maladaptive and
nonmaladaptive exercise bouts, with some individuals reporting exclusively mal-
adaptive exercise, others reporting exclusively nonmaladaptive exercise, and others
reporting both types of exercise (Lampe et al. 2021). Further, among this sample,
nonmaladaptive exercise promoted positive affect after an exercise bout, while
maladaptive exercise did not (Lampe et al. 2023a), suggesting potential specificity
of adaptive exercise in promoting positive affect among those with eating disorders.
Outside of the exercise behavior itself, participation in sports has the potential to
exacerbate eating disorder risk (Atkinson 2011; Martinsen and Sundgot-Borgen
2013) but may also facilitate social skills and connection, motivation for recovery,
and support identity development outside of an eating disorder. Overall, research
supports that (1) not all exercise behavior among individuals with eating disorders is
maladaptive and (2) inclusion of intervention components that promote adaptive
exercise, while largely untested, holds promise for facilitating eating disorder
recovery.

2 The Biobehavioral Underpinnings of Maladaptive

Exercise in Eating Disorders

2.1 Biological Reinforcement of Maladaptive Exercise

Models of maladaptive exercise propose that, for individuals with eating disorders,
overengagement of biological reward and threat, which are mediated by cognitive
processes, may lead to exercise that is habitual and compulsive (Davis and Kaptein
2006; Shroff et al. 2006; Cook et al. 2014; Adams 2009; Adams and Kirkby 2002;
Bamber et al. 2003; Bratland Sanda et al. 2011; Davis and Claridge 1998; Guarda
et al. 2015; Herring et al. 2014; Lichtenstein et al. 2017). Rodent research has
specifically identified a model, the “activity-based anorexia” (ABA) model, in
which free access to voluntary exercise during a period of low food availability
can trigger an anorexia-like syndrome. Changes in leptin, a hormone that modulates
reward circuitry, is specifically noted to predict hyperactivity in the ABA model
(Holtkamp et al. 2003; Holtkamp et al. 2006). In addition to research supporting
leptin as a mechanism of action in the ABA model (Hillebrand et al. 2008), exercise
230 K. Schaumberg et al.

has demonstrated an association with reduced plasma leptin post-exercise in a small

sample with AN but not in healthy control women (Dostalova et al. 2007). Further,
plasma leptin levels have been associated with maladaptive exercise (Ehrlich et al.
2009) and serum leptin with motor restlessness (Holtkamp et al. 2006) in AN
samples. Further investigations of the ABA model suggest mesolimbic activity,
and related dopamine signaling regulates exercise behavior (Foldi et al. 2017a, b)
and that disrupting these processes can impact wheel running activity (Klenotich
et al. 2015; Verhagen et al. 2009). As with the preponderance of female (vs. male)
humans who present with AN, female adolescent mice are particularly susceptible to
experiencing ABA (Chowdhury et al. 2015). From an evolutionary perspective,
ABA mechanisms may include that exercise reward is heightened during periods
of starvation to motivate foraging (Adan et al. 2010) or that exercise may increase
body temperature when metabolism drops due to starvation (Hillebrand et al. 2005).
Altogether, the ABA model supports that food restriction and hyperactivity may
drive one another and that rewarding aspects of exercise may entrench anorexia-like
behaviors in rodents, with translational implications.

2.2 Behavioral Reinforcement of Maladaptive Exercise

Behavioral reinforcement and observations of exercise effects among individuals

with EDs further support both reward- and threat-related mechanisms as relevant to
the onset and maintenance of maladaptive exercise. Exercise may be a particularly
salient reward for individuals with eating disorders due to the positive affect
experienced in response to exercise coupled with a Western cultural contextualiza-
tion which supports high valuation of exercise behavior (Coniglio et al. 2022). For
example, a study using ecological momentary assessment in a population of indi-
viduals with AN found that, over the course of a week, physical activity level
predicted positive affect and positive affect also predicted physical activity within
the same hour and within the next hour (Karr et al. 2017). Behavioral research that
has examined willingness to work for exercise among individuals with AN addi-
tionally found that individuals with greater commitment to exercise worked harder
on a progressive-ratio computer task for the opportunity to exercise as compared to
those with less commitment to exercise, a finding that persisted after patients were
weight restored. Further, a sample of individuals recovered from AN demonstrated
more motivation to work for exercise in a behavioral task compared to healthy
controls, even when dopamine was depleted (O’Hara et al. 2016). Together, findings
highlight (1) a high reward value of exercise reflective of willingness to work for
exercise among those with AN and (2) variability among the reinforcement value of
exercise which is potentially reflective of risk for maladaptive exercise (Klein et al.
2010).
In addition to its rewarding effects, exercise also demonstrates substantial poten-
tial impact related to reduction of negative affect in the context of eating disorders.
Initial experience sampling studies support the notion that a primary function of
Adaptive and Maladaptive Exercise in Eating Disorders 231

maladaptive exercise includes reducing momentary negative affect and weight-

related fears – for example, individuals with EDs report reductions in negative affect
post-exercise (Engel et al. 2013; Kolar et al. 2020; Reichert et al. 2020). Among
those with binge-spectrum eating disorders, negative affect is likely to occur imme-
diately prior to exercise episodes characterized by feeling driven and intended to
influence shape/weight (Lampe et al. 2023b). Further, the most central ED fears in a
network analysis study predicted excessive exercise (but not other ED behaviors) at
a two-month follow-up (Levinson and Williams 2020), suggesting potential impor-
tance of negative reinforcement patterns to maladaptive exercise maintenance.

2.3 Potential Genetic Underpinnings of Maladaptive Exercise

Both twin and molecular genetic studies indicate that exercise propensity is both
variable and heritable (Herring et al. 2014; de Geus et al. 2014; Klimentidis et al.
2018; Flack et al. 2019), and accelerometer-assessed physical activity in a sample of
adults in midlife demonstrates a positive genetic correlation with AN (rg = 0.17)
(Anorexia Nervosa Genetics Initiative, Eating Disorders Working Group of the
Psychiatric Genomics Consortium et al. 2019). Thus, individuals who are genetically
at risk for eating disorders, and more specifically AN, may also be prone to
experiencing high levels of reinforcement from exercise behavior. As previously
mentioned, not all individuals with eating disorders engage in maladaptive exercise;
thus, a relevant question in identifying those at highest risk for maladaptive exercise
includes distinguishing what factors, beyond eating disorder risk itself, coincide with
engagement in maladaptive exercise. At a phenotypic level, both compulsive and
addictive traits and symptoms associate with maladaptive exercise among individ-
uals with EDs (Davis and Kaptein 2006; Shroff et al. 2006). Genetic findings further
the narrative that risk for obsessive-compulsive disorder may be specifically related
to maladaptive exercise. In a large, epidemiological sample of youth, for instance,
maladaptive exercise was the only eating disorder behavior predicted by both an
obsessive-compulsive and an anorexia nervosa polygenic risk score (Yilmaz et al.
2022). Overall, genetic links between obsessive compulsive disorder, anorexia
nervosa, and physical activity suggest that some shared genetic liability among
these traits may influence the degree to which exercise behavior is experienced as
reinforcing. At extreme levels or in the context of an active eating disorder, a
tendency to experience exercise as a potent modulator of affective experience may
lead to exercise patterns which are rigid, compulsive, and maladaptive.

3 Advancing an Understanding of Maladaptive Exercise

Figure 1 presents a model of maladaptive exercise, based on the literature reviewed

above. Overall, biobehavioral theories contend that maladaptive exercise may serve
varying primary functions, to increase positive affect (reward) and decrease negative
232 K. Schaumberg et al.

Risk Factors Behavior Outcome

Rewarding Effects
Genetic
Psychological Biological Impacts
Obsessive Compulsive
Positive Affect eCB
Disorder Leptin
Sense of Control
Physical Activity BDNF
Anorexia Nervosa
Exercise Moderators
Psychological Trait-based Sensitivity to Exercise as a
Perfectionism Pharmacological Agent, Physical Fitness,
Cognitive Expectancies
Rigidity
Weight/Shape Concern
Anhedonia Threat Reduction Effects
Psychological Biological Impacts
Sociodemographic Negative Affect Cortisol
Body Dissatisfaction
Female Fear of Weight Gain
Adolescent
Societal view of exercise
as pro-health/thinness

Fig. 1 A model of maladaptive exercise in the context of eating disorders. Note: This model of
maladaptive exercise is based on the literature reviewed in Sect. 2. Biobehavioral theories contend
that maladaptive exercise may serve varying primary functions, to increase positive affect (reward)
and decrease negative affect (negative reinforcement), or as a rigid and compulsive (habitual)
behavior. These potential functions of exercise implicate divergent neurobiological mechanisms
in the development and maintenance of maladaptive exercise, which may vary across individuals,
vary within individuals across time, and/or co-occur in a single behavioral instance. eCB,
endocannabinoids; BDNF, brain-derived neurotrophic factor. Evidence for impacts of exercise on
biological variables are reviewed in-depth throughout several chapters of this volume. Briefly, and
with a focus on eating disorder-relevant effects: BDNF, expression in the mesolimbic reward
system is altered in the rodent model of AN after wheel running (Ho et al. 2016). In humans,
BNDF impacts hippocampal functioning: relating to reward sensations, emotions, and mood
(Kumar et al. 2019; Severinsen and Pedersen 2020). Cortisol: elevated cortisol is consistently
associated with threat processing, including in samples of individuals with anorexia nervosa
(Guarda et al. 2015). In patients with AN show blunted reactivity to social stressors (Schmalbach
et al. 2020). eCB: Exercise-induced increases in eCBs are associated with central mood state
improvements in human clinical and nonclinical populations (Brellenthin et al. 2017; Crombie
et al. 2018, 2021; Meyer et al. 2019) and reductions in anxiety and fear ratings during a threat task
(Crombie et al. 2021). Leptin: Acute exercise associated with reduced plasma leptin postexercise in
a small sample with AN but not in healthy control women. Plasma leptin levels show association
with driven exercise (Ehrlich et al. 2009) and serum leptin with motor restlessness (Holtkamp et al.
2006) in AN

affect (negative reinforcement), or as a rigid and compulsive (habitual) behavior.

These potential functions of exercise implicate divergent neurobiological mecha-
nisms in the development and maintenance of maladaptive exercise, which may vary
across individuals, vary within individuals across time, or co-occur in a single
behavioral instance. At present, we do not fully understand mechanistic factors
that contribute to the variability in presence vs. absence of maladaptive exercise
among those with eating disorders—why some individuals present with maladaptive
exercise and others do not or how and why exercise serves various functions among
those with eating disorders. Greater attunement to moderators across levels of
Adaptive and Maladaptive Exercise in Eating Disorders 233

analysis (genetics, preexercise biomarker availability, exercise training status, exer-

cise expectancies, neural circuitry differences, eating disorder illness factors) will
clarify accounts of exercise-related risk across individuals. Further, differential
functions of exercise impact treatment outcomes. Ultimately, improved understand-
ing of varying maladaptive exercise maintenance factors – and how to reduce them –
may better guide treatment programs.

4 Exercise in Eating Disorder Treatment

4.1 Reducing Maladaptive Exercise

There are growing calls for action within the eating disorder field (Cook et al. 2016;
Cook and Leininger 2017; Hay et al. 2018; Hausenblas et al. 2008) to address
exercise in eating disorder treatment. Maladaptive exercise patterns often present
early in the course of an ED (Davis et al. 1997; Achamrah et al. 2016) and can mark
poor treatment prognosis, suggesting that intervention strategies that directly address
this symptom are essential. The most dominant treatments for eating disorders do not
have specific guidance related to targeting maladaptive exercise: enhanced cognitive
behavioral therapy (CBT-E), for instance, notes that exercise should be monitored
and the patient should be educated about its potential effects, stating that “Unless the
exercising has other functions than weight control, it generally decreases during the
course of CBT-E as patients become less concerned about their eating, shape and
weight,” and encouragement to use more general affect management strategies to
address exercise which primarily functions to reduce negative affect (Fairburn
2008). In more controlled settings (e.g., family-based treatment, residential and
inpatient treatment facilities), exercise is often minimized during weight restoration
(Lock and Le Grange 2015). Ultimately, a failure to adequately assess and address
exercise behavior in treatment can pose risk to patients by perpetuating suboptimal
treatment. Even if access to exercise is substantially reduced in acute treatment
settings, these settings represent only a first phase of recovery for the subset of
patients who access this care. Patients in free-living environments are navigating
ongoing choices about when, whether, and how much to exercise at different points
during eating disorder recovery, often with little empirical guidance. Intervention
development which is targeted toward maladaptive exercise is underway, specifi-
cally a cognitive-behavioral based intervention for those with restrictive eating
disorders (compulsive exercise activity therapy, LEAP) (Hay et al. 2018). As models
of maladaptive exercise are further tested and refined, treatment development can
include investigation of the ways that psychological agents (e.g., exposure and
response prevention, distress tolerance) and exercise dose (e.g., frequency, type,
intensity, and duration) might be optimally incorporated into eating disorder treat-
ment and how prescriptions may be effectively tailored based on the function of
exercise for individual patients along with their exercise-related history and risk.
234 K. Schaumberg et al.

4.2 Promoting Adaptive Exercise

Ultimately, a goal of eating disorder recovery includes a return to adaptive exercise.

In addition to myriad benefits of adaptive exercise engagement for more general
physical and mental health, adaptive exercise also holds potential to be used as a tool
for improving eating disorder-specific symptoms, including reducing driven exercise
behaviors, drive for thinness, binge eating frequency, compensatory behaviors, and
body dissatisfaction (Lampe et al. 2022; Mathisen et al. 2020; Vancampfort et al.
2017). Nascent research investigating potential exercise-targeted interventions in
eating disorders include an intervention for binge eating and bulimia which incor-
porates psychoeducation, supervised exercise, and recommendations for healthy
exercise engagement (Mathisen et al. 2018, 2020), which could support increases
in adaptive exercise. Research on standard cognitive behavioral therapy for those
with binge-spectrum disorders indicates that there is no effect of this therapy on
adaptive exercise (Wons et al. 2023), highlighting the potential for novel interven-
tions to specifically target adaptive exercise with greater potency. Further, at present,
exercise professionals are rarely integrated into eating disorder treatment teams;
however, there may be great benefit for incorporating such professionals in eating
disorder treatment, particularly for patients who have significant history of maladap-
tive exercise and those who aim to engage in high levels of adaptive exercise as they
progress in ED recovery (e.g., athletes). Ultimately, a recovery goal could include
return to adaptive activity that includes a psychologically flexible relationship with
exercise and may even be at high levels for some individuals.

5 Conclusion

Exercise poses a complex challenge in the realm of mental health and the treatment
of eating disorders, presenting a paradox and clinical dilemma (Moola et al. 2013;
Mathisen et al. 2023). During the course of an eating disorder, maladaptive exercise
patterns may develop and be reinforced when intertwined with obsessive-
compulsive traits and preoccupation with weight and shape (Coniglio et al. 2022).
Maladaptive exercise is a prevalent symptom of eating disorders, and effective
intervention and treatment approaches that address exercise-related issues are still
under development. While the presentation of maladaptive exercise in eating disor-
ders is common, exercise also has high potential to contribute to positive mental
well-being and may even aid recovery (Vancampfort et al. 2013, 2014). Current
evidence indicates that exercise can have beneficial effects when incorporated
thoughtfully into eating disorder treatment (Vancampfort et al. 2013, 2014; Rosa-
Caldwell et al. 2023). Suggested guidelines include employing a team of experts and
monitoring medical status; screening for exercise-related psychopathology; creating
a written contract, including psychoeducation and focusing on positive reinforce-
ment in exercise programming with debriefs after exercise sessions; and developing
Adaptive and Maladaptive Exercise in Eating Disorders 235

a graduated set of recommendations that starts slow and is tailored to the individual
(Cook et al. 2016). In addition, careful assessment and differentiation between
adaptive and maladaptive exercise may be relevant to supporting more adaptive
exercise over time (Wons et al. 2023). Moving forward, close attention to the
functions of maladaptive exercise, such as mood regulation and compensatory
functions, may improve precision of interventions which aim to reduce maladaptive
and increase adaptive exercise engagement.

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Exercise and PTSD

Laura M. Kinsman, Holden J. Norrie, Geoffrey S. Rachor,

and Gordon J. G. Asmundson

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
2 PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
2.1 What Is PTSD? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
2.2 Established PTSD Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
2.3 The Role of Exercise in Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
3 Exercise and Mental Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
3.1 Psychological Impacts of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
3.2 Physiological Impacts of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
4 Exercise and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
4.1 Overview of General Research Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
4.2 Randomized Controlled Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

Abstract Evidence indicating that exercise benefits mental health symptoms across
a range of mental health diagnoses spans decades of scientific literature; however,
fewer studies have examined the impact of exercise on posttraumatic stress disorder
(PTSD). Exercise is an accessible, cost-effective, and scalable treatment option that
has the potential to improve both physiological and psychological symptoms among
individuals with PTSD. The purpose of this chapter is to review empirical literature
on the role of exercise in the treatment of PTSD. Researchers have demonstrated that
exercise improves PTSD symptoms as both a stand-alone treatment and as an
adjunct to cognitive behavioral and trauma-focused therapies. Additional research
is needed to clarify mechanisms that account for the impacts of exercise on PTSD
and to identify which components of exercise (e.g., type of exercise, dose, intensity,
frequency) are the most beneficial.

Keywords posttraumatic stress disorder · exercise · physical activity

L. M. Kinsman, H. J. Norrie, G. S. Rachor, and G. J. G. Asmundson (✉)

Department of Psychology, University of Regina, Regina, SK, Canada
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 241
Curr Topics Behav Neurosci (2024) 67: 241–262
https://doi.org/10.1007/7854_2024_500
Published Online: 8 August 2024
242 L. M. Kinsman et al.

1 Introduction

The physiological and psychological benefits of exercise in treating various mood-

and anxiety-related disorders are well documented across the scientific literature.
There is a growing interest in documenting the benefits of exercise among individ-
uals with posttraumatic stress disorder (PTSD). The purpose of the current chapter is
to review the empirical literature on the role of exercise in the treatment of PTSD. An
overview of the research evidence for treating PTSD with exercise is provided,
including recommended types of exercise, dose, intensity, and frequency. The
chapter concludes with recommendations for further research efforts in elucidating
the role of exercise in the treatment of PTSD.

2 PTSD
2.1 What Is PTSD?

PTSD is characterized by the sudden or delayed onset of psychological distress

following exposure to one or more traumatic events (American Psychiatric Associ-
ation 2022). Approximately 70.4% of individuals worldwide have experienced at
least one traumatic event in their lifetime (Benjet et al. 2016; Kessler et al. 2017a).
Interpersonal violence (e.g., sexual violence, physical violence) is among the most
common potentially traumatic experiences, while the unexpected death of a loved
one is among the greatest risk factors for developing PTSD (Kessler et al. 2017b).
Approximately 6.8% of the adult population in the United States experience PTSD
in their lifetime (American Psychiatric Association 2022). The risk of developing
PTSD is elevated among females, veterans, active military members, public safety
personnel (e.g., correctional officers, firefighters, paramedics, police), and survivors
of sexual violence or traumatic injury (American Psychiatric Association 2022).
PTSD often cooccurs with other disorders, including depressive, bipolar, anxiety,
substance use disorders, and chronic pain conditions (e.g., migraine, back pain,
arthritis, and fibromyalgia). For example, 25% (N = 1761) of Canadian Forces
personnel who met diagnostic criteria for PTSD also reported chronic pain condi-
tions (Vun et al. 2018). Moreover, individuals who are diagnosed with PTSD and a
co-occurring disorder are more likely than those with PTSD alone to develop more
severe comorbid symptoms, impairments, and suicide attempts and completions
(Walter et al. 2018).

2.2 Established PTSD Treatments

Several evidence-based psychological and pharmacological interventions are avail-

able for treating PTSD, of which cognitive behavioral therapies (CBT) are regarded
Exercise and PTSD 243

as the gold standard (Clinical practice guideline for the treatment of posttraumatic
stress disorder (PTSD) in adults: (501872017-001) 2017; Schnurr 2017). Trauma-
focused CBT, including cognitive therapy, cognitive processing therapy, and
prolonged exposure (PE), exhibits short- and long-term efficacy in reducing symp-
toms of PTSD and is strongly recommended by the American Psychological Asso-
ciation (APA) (Clinical practice guideline for the treatment of posttraumatic stress
disorder (PTSD) in adults: (501872017-001) 2017; Schnurr 2017; Asmundson et al.
2019; Bradley et al. 2005; Cusack et al. 2016; Kline et al. 2018; Olthuis et al. 2016;
Van Etten and Taylor 1998; Watkins et al. 2018). Researchers have identified –
using meta-analyses – that treatment gains may be sustained up to 20 months
posttreatment (Kline et al. 2018). However, challenges such as treatment
nonresponse, residual symptoms, and attrition may reduce positive treatment out-
comes (Fonzo et al. 2020; Larsen et al. 2019; Najavits 2015; Koek et al. 2016;
Schottenbauer et al. 2008). The APA also conditionally recommends psychological
therapies such as brief eclectic therapy, eye movement and desensitization and
reprocessing therapy, narrative exposure therapy, and pharmacological treatments
such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin
norepinephrine reuptake inhibitors (Clinical practice guideline for the treatment of
posttraumatic stress disorder (PTSD) in adults: (501872017-001) 2017; Brady et al.
2000; Lindauer et al. 2005; Marshall et al. 2001; Schauer et al. 2011; Shapiro 2007).
Additional research is necessary to determine the efficacy of conditionally
recommended treatments among different populations.
Treatment planning and delivery may be influenced by factors such as access to
services, stigma regarding mental health services utilization, and client preferences
(Chen et al. 2013; Markowitz et al. 2016). For example, stigma regarding accessing
mental health treatment may prevent individuals from seeking treatment for PTSD
(Wade et al. 2015), in which case alternative treatment options such as pharmaco-
logical interventions may be considered or used in conjunction with psychotherapy.
However, pharmacological treatments may confer adverse outcomes that are not
associated with psychotherapeutic interventions (e.g., sexual dysfunction, insomnia)
(Edinoff et al. 2021). The positive effects of pharmacological treatments may also be
diminished following discontinuation of treatment, whereas treatment gains follow-
ing trauma-focused psychotherapies generally remain stable following treatment
completion (Kline et al. 2018).

2.3 The Role of Exercise in Treatment

As noted above, limited access to first-line treatments, stigmatization associated with

utilizing mental health services, and side effects associated with pharmacotherapy
may pose significant barriers to effective PTSD treatment. Conversely, while not
entirely free from barriers, exercise is generally not associated with stigma or
adverse side effects and tends to be lower in cost (Hegberg et al. 2019); however,
limited financial resources may still pose a barrier to engaging in exercise (e.g.,
244 L. M. Kinsman et al.

purchasing a gym membership or exercise equipment). Other barriers to exercise

may include time constraints, low motivation, and reduced self-efficacy (Hegberg
et al. 2019; Zen et al. 2012).
Exercise interventions have the potential to improve both psychological and
physical sequelae associated with PTSD, which are explored further in subsequent
sections of the chapter. Researchers have identified an association between PTSD
and physiological changes that adversely impact multiple organ systems (e.g.,
central nervous system, autoimmune and inflammatory, neuroendocrine, metabolic,
and cardiovascular disorders) (Koenen et al. 2017; McFarlane et al. 2017; Pacella
et al. 2013; Qureshi et al. 2009; Ryder et al. 2018). Indeed, individuals with PTSD
are at risk for poor health outcomes such as cardiovascular disease, diabetes,
hypertension, metabolic syndrome, pain, and stroke (Asmundson et al. 2002;
Boscarino 2004; Burg and Soufer 2016; Goodwin and Davidson 2005; Rosman
et al. 2019; Rosenbaum et al. 2015a; Sareen et al. 2005). Researchers have suggested
the potential for exercise to improve hypothalamic-pituitary axis (HPA) functioning
and reduce inflammatory markers as a rationale for implementing exercise interven-
tions for PTSD, as improvements in HPA functioning and inflammation may lead to
improved stress response (e.g., reduced cortisol) and sleep regulation (Hegberg et al.
2019; de Kloet et al. 2006; Santos et al. 2007). Given the potential for exercise to
improve physiological and psychological functioning among individuals with
PTSD, exercise is a promising treatment option for PTSD, if not at least an adjunct
to psychotherapy. Physical health conditions may also increase risk for the onset of
PTSD symptoms (Carmassi et al. 2020), suggesting that exercise may also
prevent PTSD.

3 Exercise and Mental Health

3.1 Psychological Impacts of Exercise

A well-documented short-term psychological benefit of exercise is improved over

time following engaging in exercise (Guérin et al. 2013; Reed and Buck 2009). A
meta-analysis of 158 lab-based studies identified an increase in positive affect (e.g.,
energy, joy, pleasant mood, vigor) following acute aerobic exercise with a medium
effect size (d = 0.47) (Reed and Ones 2006). The benefits of exercise on positive
affect also extend to naturalistic field-based studies, as evidenced by a systematic
review that found enhanced positive affect and feelings of vitality following physical
exercise (Liao et al. 2015). Factors associated with greater increases in positive affect
following exercise interventions include more negative baseline preexercise affect,
lower intensity exercise, durations of exercise spanning 7–35 min, and low to
moderately intense doses of exercise (Reed and Ones 2006). These findings were
corroborated by a study of individuals in a weight training class who were randomly
assigned to one of four conditions of resistance exercise with varying intensity and
rest time (i.e., low-intensity and long rest time, low-intensity and short rest time,
Exercise and PTSD 245

high-intensity and long rest time, high-intensity and short rest-time) or a no-exercise
control (Bibeau et al. 2010). Positive affect improved significantly among all
exercise conditions, with the largest increase in positive affect observed in the
group who exercised at a low intensity for a long period of time (Bibeau et al.
2010). Exercise enjoyment also impacts affective states, with one study finding that
greater enhancement in affect was reporting following individuals engaging in their
most preferred compared to their least preferred form of exercise (Lane et al. 2005).
Studies have also shown that individuals with PTSD reported increased positive
affect after engaging in moderate-intensity aerobic exercise (Crombie et al. 2018,
2019, 2021a, b).
Researchers have also demonstrated that negative affect (e.g., anxiety, stress)
decreases following exercise (Basso and Suzuki 2017; Petruzzello et al. 1991). A
meta-analysis of 16 randomized controlled trials determined that acute bouts of
exercise can produce reductions in self-reported state anxiety with a small but
statistically significant effect size (Ensari et al. 2015). Researchers have identified
that reductions in negative affect persist for up to 24 h postexercise (Reed and Ones
2006; Basso and Suzuki 2017; Petruzzello et al. 1991; Ensari et al. 2015; Maroulakis
and Zervas 1993; Raglin and Morgan 1987). One form of exercise that is associated
with worsened negative affect is high-intensity interval training (HIIT), a type of
exercise consisting of brief, intermittent bouts of exercise followed by periods of rest
or reduced activity (Karlsen et al. 2017). HIIT may have a negative impact on affect
by enhancing the experience of negative emotions and perceptions of physical
exertion, as well as decreasing feelings of pleasure (Hall et al. 2020; Jung et al.
2014; Kilpatrick et al. 2007; Parfitt et al. 2006; Saanijoki et al. 2015). Researchers
speculate that negative feelings following HIIT may be attributed to the strong link
between exercise intensity and adverse emotions (Saanijoki et al. 2015; Ekkekakis
2003; Oliveira et al. 2013). However, in a study where eight males were randomly
assigned to complete either HIIT running or moderate-intensity continuous running,
researchers demonstrated that HIIT running was rated as more enjoyable than
moderate intensity running (Bartlett et al. 2011).
Accumulating evidence demonstrates that exercise improves mental health
through reduced symptoms of anxiety among individuals with and without an
anxiety disorder diagnosis (Asmundson et al. 2013; Bartley et al. 2013; Herring
2018; Herring et al. 2014; Jayakody et al. 2014; Ramos-Sanchez et al. 2021;
Stonerock et al. 2015; Stubbs et al. 2017). In a recent meta-analysis of 13 randomized
controlled trials, researchers confirmed that exercise is efficacious in reducing
anxiety symptoms (e.g., worry, nervousness) with a small-medium effect size
compared to control groups (SMD = -0.43 among individuals with anxiety and
related disorders) (Ramos-Sanchez et al. 2021). Both aerobic exercise and resistance
training have received the most empirical support for reducing anxiety symptoms;
however, other forms of low-intensity exercise such as tai chi, walking, and yoga
have also been associated with lowered anxiety (Asmundson et al. 2013; Ramos-
Sanchez et al. 2021).
246 L. M. Kinsman et al.

3.2 Physiological Impacts of Exercise

Past research indicates that changes in psychological states are associated with
changes in measures of immunity and inflammation (Weisse 1992). More specifi-
cally, psychological states like depression and stress are correlated to decreases in
immune system response (Herbert and Cohen 1993a, b), and meta-analytic findings
indicate that depression may be associated with inflammation (Zorrilla et al. 2001).
Studies also show that anxiety is associated with increased inflammation, leading to
a higher risk of developing inflammatory disease (O'Donovan et al. 2010). The
increase in inflammation due to anxiety is theorized to be related to HPA activation,
as the states of anxiety are significantly associated with the inflammatory markers
interleukin-6 (IL-6) and high sensitivity C-reactive protein (hs-CRP) and decreased
cortisol (O'Donovan et al. 2010). Individuals with increased levels of inflammatory
cytokines are also more likely to develop PTSD, and the increased inflammatory
response is theorized to influence health declines indirectly related to PTSD (Gill
et al. 2009).
Researchers have suggested that the enhancing effects of exercise on cognition
and mood are mediated by brain-derived neurotrophic factor (BDNF) (Szuhany et al.
2015). Past studies have shown that BDNF is correlated with increases in
neurogenesis, potentiation of neurons, and dendrite maintenance and development
(Szuhany et al. 2015). In studies examining the impact of exercise and depression in
rats, exercise was shown to lessen the decrease of BDNF mRNA expression in
comparison to the nonexercise group, 24 h after the chronic unpredictable stress was
discontinued (Zheng et al. 2006). Levels of cortisol in the nonexercise group were
also observed to be higher in comparison to the exercise group. These results suggest
that exercise may lead to more flexible HPA responses to stress and a faster return to
baseline levels of cortisol following chronic unpredictable stress (Zheng et al. 2006).
Additionally, the group of rats that exercised exhibited less depressive behaviors.
Exercise has also been noted as an effective method for increasing
endocannabinoids, dopamine, and levels of serotonin, similar to SSRIs (Desai
et al. 2022; Wipfli et al. 2011; Crombie et al. 2021c; Heyman et al. 2012). The
endocannabinoid system exists within the central nervous system and is involved in
synaptic plasticity and several biological processes (e.g., cognition, eating, inflam-
mation, metabolism, pain, reproduction) (Desai et al. 2022; Zou and Kumar 2018).
Recent studies have shown that aerobic exercise maintains and increases circulating
concentrations of endocannabinoids (Desai et al. 2022). The increase in
endocannabinoids has also been associated with increases in BDNF, which, in
turn, further supports cognitive enhancement and reductions in depression (Crombie
et al. 2021c; Heyman et al. 2012). In a study comparing the effects of exercise and
static stretching in a seven-week intervention, participants who were assigned to the
exercise group were found to have lower levels of depression and decreased levels of
serum serotonin in comparison to the stretching group (Wipfli et al. 2011). These
results mimic similar results to using pharmaceutical interventions like SSRIs
(Hughes et al. 1996). Researchers have hypothesized that the effectiveness of
Exercise and PTSD 247

antidepressants is partly based on increases in dopaminergic synapses (Muscat et al.

1992). In animal studies examining the influence of exercise on dopaminergic
circuits, researchers found that regular exercise increased endurance and plasticity
within dopaminergic neurocircuits (Wipfli et al. 2011). In turn, results showed that
the aerobic exercise group was found to synthesize monoamine dopamine faster than
the sedentary group.
The HPA is responsible for regulating physiological reactions to stress through
the secretion of corticotrophin-releasing hormone (CRH) (Hegberg et al. 2019).
Secretion of CRH stimulates the pituitary gland to release adrenocorticotropic
hormone (ACTH) in response to stress. Previous research has shown that individuals
diagnosed with PTSD have increases in CRH and excessive HPA axis activation
(Daskalakis et al. 2016). Frequent aerobic exercise has been shown to be an effective
method for normalizing the HPA (Childs and de Wit 2014). More specifically,
moderate to vigorous physical activity is a more efficient intensity for normalizing
the HPA in comparison to low-intensity aerobic exercise (Hill et al. 2008). Exercise
has also been noted as an effective method for decreasing pro-inflammatory
responses (i.e., interleukin-1, IL-6) that are associated with PTSD (Archer et al.
2011; Passos et al. 2015). Specifically, studies utilizing moderate to vigorous aerobic
exercise interventions have shown that regular aerobic exercise decreases
pro-inflammatory responses, leading to an increased quality of sleep and decreased
symptoms of PTSD (Santos et al. 2007; Archer et al. 2011).

4 Exercise and PTSD

4.1 Overview of General Research Findings

Researchers have identified associations between exercise behaviors and reduced

PTSD symptoms via observational, cross-sectional research (Hegberg et al. 2019;
Vancampfort et al. 2017; Whitworth et al. 2019a; b). One study of American
Veterans (N = 38,883, 77% of male), 96% of whom did not have PTSD at baseline,
found that participants who engaged in vigorous exercise (≥20 min, two or more
times per week), but not light- or moderate-intensity exercise, had significantly
reduced odds of developing new PTSD symptoms (OR 50.58, [95% CI: 0.49,
0.70]) or reporting persistent PTSD symptoms at 3–5-year follow-ups (OR 50.59,
[95% CI: 0.42, 0.83]) (LeardMann et al. 2011). An additional cross-sectional study
of American Veterans identified a U-shaped association between self-reported
exercise frequency and probable PTSD (N = 2,832, 90% male) (Adams et al.
2020). Veterans with probable PTSD were more likely to report no exercise or
exercising daily and were less likely to report exercising 1–6 days a week compared
to those without probable PTSD. Indeed, exercising three or more days a week was
associated with approximately 49% lower odds of probable PTSD compared to
exercising less than 3 days per week [95% CI: 0.21, 0.70). No exercise was
associated with more severe emotional numbing symptoms and less severe anxious
248 L. M. Kinsman et al.

arousal symptoms than those who exercised 1–6 days a week, while daily exercise
was associated with greater severity of reexperiencing symptoms compared with
participants who exercised 1–6 days per week. A recent follow-up study of Amer-
ican Veterans replicated these findings (N = 3,875, 9.4% women), showing that self-
reported moderate levels of physical activity were associated with the lowest like-
lihood of probable PTSD (3.8% adjusted probability), whereas greater levels of
physical activity were associated with the highest likelihood of screening positive for
PTSD (7.8% adjusted probability) (Adams et al. 2022). Intrusion symptoms (e.g.,
nightmares) and anhedonia symptoms were associated with significantly lower
probability of reporting moderate physical activity. Moreover, researchers using a
national sample of American Veterans (N = 501,161, 95.9% male) found that the
odds of reporting no regular exercise were the highest among Veterans with PTSD
(OR = 1.26, [95% CI: 1.20, 1.32), as well as schizophrenia and bipolar disorder
compared to Veterans without these diagnoses (Chwastiak et al. 2011). Another
study of male Croatian Veterans (N = 478, 269 with PTSD as determined using the
diagnostic criteria of the International Classification of Diseases, 10th revision,
209 without PTSD) found that 27.9% of Veterans with PTSD reported engaging
in any exercise compared to 48.8% of Veterans without PTSD (Kozaric-Kovacic
et al. 2009).
Researchers have also examined associations between exercise and PTSD symp-
toms among community samples. A longitudinal investigation of community-
recruited adults who screened positive for self-reported PTSD symptoms
(N = 182, 72% female) found that strenuous-intensity exercise (e.g., vigorous
running or cycling) was associated with reduced avoidance, numbing, and
hyperarousal symptoms at a three-month follow-up (Whitworth et al. 2017). How-
ever, reporting both strenuous and moderate (e.g., nonexhaustive sports, jogging, or
weight training) intensity exercise was only associated with reduced avoidance/
numbing symptoms. A significant association between exercise and reduced PTSD
symptoms at three-month follow-up did not emerge among participants who only
reported engaging in moderate-intensity exercise (Whitworth et al. 2017). A cross-
sectional study investigated the association between exercise intensity (i.e., light,
moderate, vigorous) and posttraumatic stress symptom cluster severity (i.e.,
reexperiencing, avoidance/numbing, and hyperarousal) in a nonclinical
community-based sample exposed to a DSM-IV PTSD Criterion A traumatic life-
time event (N = 108, 54.6% female) (Harte et al. 2015). Results showed a signif-
icant, inverse association between self-reported vigorous-intensity exercise, but not
light- or moderate-intensity exercise, and PTSD hyperarousal symptom severity
after adjusting for gender and lifetime number of trauma exposures (Harte et al.
2015). However, vigorous-intensity exercise uniquely accounted for a small portion
of the variance in hyperarousal symptoms (4%). No significant associations emerged
between exercise of any intensity and reexperiencing or avoidance/numbing symp-
tom clusters. As this was a nonclinical sample that did not endorse comorbid mental
health disorders, these findings may not generalize to those with more severe PTSD
symptoms and comorbid psychopathology (Harte et al. 2015).
Exercise and PTSD 249

Other researchers have failed to find an association between exercise and PTSD
symptoms. One study of American Veterans completing a 90-day rehabilitation
program for PTSD (N = 346, 81% male) found that PTSD symptoms were not
associated with exercise (i.e., participants rated how frequently they engaged in
exercise on a scale ranging from not at all to every day) but that higher levels of
exercise were associated with lower levels of depressive symptoms and higher sleep
quality. Additionally, decreased depressive symptoms and improved sleep quality
were each associated with reduced suicide risk (Davidson et al. 2013). Another study
of males with combat-related PTSD (N = 55) did not find a significant difference in
the severity of PTSD symptoms between participants who reported regular physical
activity versus those who were not active (Arnson et al. 2007). A study of Veterans
(N = 76, 82% male) found a significant association between engagement in exercise
at baseline (i.e., light, moderate, vigorous) and improved sleep quality at one-year
follow-up but failed to find a significant relationship between exercise engagement at
baseline and PTSD symptoms at one-year follow-up (Bosch et al. 2017). Similarly, a
study of Veterans (N = 239, 91.1% male) did not observe a significant main effect of
physical activity on PTSD symptom severity but found that exercise moderated the
relationship between PTSD and pain, with participants who reported being active
and endorsing high levels of pain severity or interference reporting less PTSD
symptoms (Bourn et al. 2016).
Due to the cross-sectional nature of these studies, causal inferences cannot be
made (e.g., those with lower PTSD symptoms may exercise more frequently or
vigorously) (Hegberg et al. 2019). The use of self-report questionnaires may also
influence results due to the high potential for inaccurate reporting or misunderstand-
ing questions (Hegberg et al. 2019). As previously described, other observational
studies have failed to identify a significant relationship between exercise and PTSD
symptomatology (Davidson et al. 2013; Arnson et al. 2007; Bosch et al. 2017; Bourn
et al. 2016), but this may be attributed to methodological limitations (Hegberg et al.
2019; Harte et al. 2015). For example, some studies measured exercise with a single-
item questionnaire or variable, which does not allow for assessment of frequency,
intensity, duration, and type of exercise and may not accurately reflect how exercise
impacts PTSD symptoms (Hegberg et al. 2019).

4.2 Randomized Controlled Trials

Uncontrolled studies offered initial support for exercise as an effective intervention

for PTSD. For example, one study with a small sample (N = 9) of adults with PTSD
found that PTSD symptoms, anxiety, and depression reduced following a 12-week
aerobic exercise program (Manger and Motta 2005). In another study, adolescent
females (N = 15) completed an eight-week aerobic exercise program (three 20-min
weekly exercise sessions) (Newman and Motta 2007). Results indicated that PTSD,
depression, and anxiety were significantly reduced from pre- to postintervention and
treatment gains remained at one-month follow-up. More recently, researchers
250 L. M. Kinsman et al.

evaluated a 12-week moderate-intensity exercise program (i.e., brisk walking) in a

sample of Veteran women (N = 16) and found significant improvements in PTSD
and depression symptoms by the end of the intervention (Shivakumar et al. 2017).
However, the aforementioned findings may only be considered preliminary due to
the lack of control groups, unblinded assessors, and small sample sizes.
A small but growing number of randomized controlled trials have investigated the
impact of exercise interventions on PTSD symptoms across a variety of settings,
populations, and exercise modalities (Björkman and Ekblom 2022). For example, a
sample of American Veterans (N = 47, 81% male) were randomized to receive an
integrative exercise program (3-h group sessions of aerobic and resistance training
combined with mindfulness-based practices for 12 weeks) or a waitlist control
condition (Goldstein et al. 2018). Participants in the integrative exercise group
displayed greater reductions in PTSD symptom severity (d = 0.90) and greater
improvements in psychological quality of life (d = 0.53). Analyses of PTSD
symptom clusters also indicated that symptoms of hyperarousal were significantly
more reduced among the integrative exercise conditions compared to the control
group (d = 0.80). While there was a moderate effect of improvement in symptoms of
reexperiencing and avoidance/numbing that favored the integrative exercise group,
these effects did not reach statistical significance. Another study examined the
impact of cycling on PTSD symptoms (Fetzner and Asmundson 2015). Adults
with PTSD or subsyndromal PTSD (N = 33, 76% female) were assigned into
three groups with varying attentional focus: (1) attention to somatic arousal (i.e.,
participants were promoted to direct their attention to the interoceptive effects of
exercise), (2) distraction from somatic arousal (i.e., participants watched a nature
documentary), and (3) exercise with no distractions or interceptive prompts. Reduc-
tions in PTSD symptoms and anxiety were observed among all groups, with large
effect sizes, indicating that aerobic exercise has a therapeutic effect on PTSD and
PTSD-related symptoms regardless of attentional focus. However, it is necessary to
note that this study did not employ a nonexercise control group. A study using the
same data found that greater reductions in PTSD symptoms were observed among
participants with lower levels of baseline fitness, suggesting that individuals with
lower fitness may experience greater benefits from aerobic exercise (LeBouthillier
et al. 2016).
Studies have also examined the impact of resistance training on PTSD symptoms
(Whitworth et al. 2019a, b). Researchers randomly assigned 30 (73.3% female)
nontreatment-seeking, urban-dwelling adults who screened positive for PTSD to a
three-week resistance exercise intervention or a time-matched control condition
(Whitworth et al. 2019a). Total self-reported PTSD scores at follow-up did not
significantly differ between groups; however, large effect sizes for avoidance
(d = 1.26) and hyperarousal symptoms (d = 0.90), sleep quality (d = 1.31), and
hazardous alcohol use (d = 0.99) were observed at follow-up between the interven-
tion group compared to the control group. Significant differences did not emerge
between groups for posttraumatic intrusions or mood and cognitive symptoms. In a
separate study, researchers randomized community-dwelling adults with probable
PTSD (N = 22, 82% women) to complete a three-week, nine-session resistance
Exercise and PTSD 251

exercise training intervention or a time-matched attention control (Whitworth et al.

2019b). Results indicated that the intervention group reported significantly improved
sleep quality (d = -0.93), sleep latency (i.e., the length of time it takes an individual
to fall asleep; d = -1.61), and reduced anxiety (d = -0.68) compared to the control
group; however, both groups reported similar beneficial effects on PTSD and
depression symptoms. Nonsignificant effects of resistance training on overall
PTSD severity may be explained by low statistical power, or it may also be that
resistance training only has beneficial effects on certain PTSD symptom clusters
(e.g., hyperarousal).
Randomized controlled trials designed to determine whether yoga improves
PTSD symptoms have produced mixed findings (Cramer et al. 2018; Kysar-Moon
et al. 2021; van der Kolk et al. 2014; Davis et al. 2020). One study randomized
women with treatment-resistant PTSD (N = 64) to participate in weekly trauma-
informed hatha yoga or supportive women’s health education classes for 10 weeks
(van der Kolk et al. 2014). Both groups improved in terms of reduction in PTSD
diagnostic status; however, the improvement of the yoga group (d = 1.07) was
significantly greater than the control group (d = 0.66). Moreover, both groups
improved from pretreatment to the mid-treatment point, but only the yoga group
maintained gains at post-treatment, suggesting yoga may offer more durable benefits
than a women’s health education class. Another study (N = 209, 66% male) found
that participants who completed a 16-week yoga intervention reported significantly
greater reductions in PTSD symptom severity compared with participants in a
wellness program (i.e., walking, health education) at posttreatment (d = 0.43), but
that these improvements were not sustained at seven-month follow-up (van der Kolk
et al. 2014). Contrarily, other research has found marginally significant to no effects
of yoga on PTSD and depression symptoms in a sample of women (Kysar-Moon
et al. 2021).
In addition to examining the impact of exercise as a stand-alone treatment for
PTSD, researchers have assessed how adding exercise to trauma-focused therapy
impacts treatment outcomes and have identified mixed findings (see (Crombie et al.
2023) for a full review). One pilot study with a small sample (N = 9) randomized
participants with PTSD to receive either 12 weeks of PE alone or PE plus a 30-min
session of moderate-intensity treadmill exercise prior to each PE session (Powers
et al. 2015). Individuals in the PE plus exercise group exhibited improvements in
PTSD symptoms (d = 2.65); however, significance tests were not used to directly
compare changes in PTSD symptoms between groups due to the small sample size.
A recent study of adults with PTSD (N = 130, 61% women) randomly assigned
participants to receive either nine weekly sessions of PE with aerobic exercise or PE
with passive stretching (Bryant et al. 2023). Participants in the PE with aerobic
exercise group exhibited greater reductions in PTSD scores compared to those in the
PE with stretching group at the six-month follow-up (d = 0.6). An additional
randomized controlled trial compared the effectiveness of physical activity added
to an intensive trauma-focused treatment (i.e., daily PE, EMDR, and
psychoeducation) for PTSD with nonphysical control activities (e.g., crafting activ-
ities with paint, clay, and crochet) (Voorendonk et al. 2023). Significant decreases in
252 L. M. Kinsman et al.

both clinician and self-reported PTSD symptoms were observed among both condi-
tions with large effect sizes (pre- to posttreatment: d = 2.28, pretreatment to -month
follow-up: d = 2.20), but significant differences between conditions were not found.
Further, 80.0% of participants in the physical activity condition and 82.7% of
participants in the control condition no longer met diagnostic criteria for PTSD at
posttreatment (Voorendonk et al. 2023).
Another randomized controlled trial examined the impact of exercise added to
treatment as usual for PTSD (Rosenbaum et al. 2015b). Participants (N = 81) were
randomly assigned to receive either usual care (i.e., psychotherapy, pharmaceutical
interventions, group therapy) or exercise (i.e., resistance training and walking) in
addition to usual care. Participants in the exercise group showed significant reduc-
tions in PTSD symptoms compared with the usual care group, with a medium effect
size (MD = -5.4, partial eta squared = 0.07, [95% CI: -13.7 to -0.60]). Partic-
ipants in the intervention group also reported greater improvements in depressive
symptoms, sleep quality, and sedentary time than those in the usual care group.
Other studies have failed to find evidence that treatment outcomes are improved
by the addition of exercise protocols (Nordbrandt et al. 2020; Young-McCaughan
et al. 2022). A recent study of active duty service members (N = 72) with clinically
significant PTSD symptoms investigated the impact of adding aerobic exercise to
imaginal exposure for PTSD (Young-McCaughan et al. 2022). Participants were
randomly assigned to one of four conditions: exercise only, imaginal exposure only,
imaginal exposure plus exercise, and a self-care control condition. Participants
exercised five times a week for 8 weeks and chose which type of exercise they
would do to keep their heart rate above 60% of their individual heart rate reserve for
20–25 min, with the majority of participants electing to run outside or on a treadmill.
While PTSD symptom severity decreased from pre- to postintervention with large
effect sizes among all three experimental conditions, there were no significant
differences between the experimental conditions, suggesting that adding aerobic
exercise before completing an imaginal exposure protocol may not confer additional
benefits than imaginal exposure alone. However, this study is limited by the lack of a
true control condition, as participants assigned to the self-care control group may
have participated in exercise, online self-help, or other interventions that may have
targeted PTSD symptoms. Participants were also instructed to engage in their
preferred form of aerobic exercise at >60% of their individually determined heart
rate reserve for 20–25 min but did not provide data on exercise intensity (e.g., heart
rate), which may have had an impact on participants’ physiological response to
exercise and treatment outcomes. This finding also stands in contrast to previous
research findings that found exercise augmented PTSD treatment outcomes (Bryant
et al. 2023). Another study randomized refugees with PTSD (N = 318, 53% women)
to one of three groups: (1) basic body awareness therapy, (2) individual mixed
physical activity for 1 h per week for 20 weeks plus treatment as usual, or (3) treat-
ment as usual (Nordbrandt et al. 2020). Reductions in PTSD symptoms were
observed among all groups with no significant group differences, indicating that
adding basic body awareness therapy or mixed physical activity did not augment
treatment as usual.
Exercise and PTSD 253

Researchers have also examined how exercise may impact PTSD symptoms in
older adults. One pilot trial randomly assigned older adult Veterans (N = 54, 90.7%
male) to a supervised exercise condition (i.e., aerobic, strength training, balance, and
flexibility exercises) or a waitlist condition (Hall et al. 2020). The authors reported
what appears to be clinically meaningful reductions in PTSD symptoms (i.e.,
negative cognitions and mood, reexperiencing) among the exercise condition; how-
ever, the effects were not statistically significant. Worsened PTSD symptoms were
also observed among a significant minority of participants in both groups,
suggesting that additional research is needed to investigate individual variability in
response to exercise protocols among older adults (Hall et al. 2020).
Results from meta-analyses have found additional support for exercise interven-
tions reducing PTSD symptoms (Stubbs et al. 2017; Björkman and Ekblom 2022;
Rosenbaum et al. 2015c). A recent meta-analysis of 11 randomized controlled trials
(N = 605) examining the impact of exercise on PTSD symptoms found a small to
medium effect size of exercise on PTSD symptom severity relative to control
conditions (ES 0.29 [95% CI: 0.10, 0.49]) (Björkman and Ekblom 2022). A small
but significant effect of exercise on depression symptoms (ES 0.20, [95% CI: 0.01,
0.38]) and a moderate effect of exercise on sleep symptoms were also identified
(ES 0.51, [95% CI: 0.29 to 0.73]). Additionally, moderate effects were found for the
effect of exercise on substance use (alcohol and drugs combined; ES 0.52, [95% CI:
0.06, 0.98]) and quality of life (ES 0.51, [95% CI: 0.34, 0.69]). Contrary to previous
meta-analytic findings (Stubbs et al. 2017), exercise was not found to have a
significant effect on anxiety symptoms (ES = 0.18, [95% CI: -0.15 to 0.51]).
Evidence for publication bias was not detected. Treatment moderators such as
volume of exercise (i.e., >20 h in total vs. ≤20 h in total), dose of training (i.e.,
high or low), type of exercise (e.g., aerobic exercise, resistance training), and type of
trauma (e.g., military trauma) were also examined. The effect of exercise on PTSD
symptoms was more robust when exercise interventions consisted of more than 20 h
of exercise, indicating that greater amounts of exercise may be more beneficial.
Exercise type, training dose, and type of trauma did not influence treatment effects.
In sum, these results suggest that exercise can be a beneficial addition to PTSD
treatment, and larger amounts of exercise may be more beneficial. Adverse effects or
negative experiences associated with engaging in exercise were not reported,
confirming the feasibility of exercise interventions for PTSD. Additional research
is needed to elucidate which type of exercise is most effective at reducing PTSD
symptoms. Studies investigating the impact of exercise on PTSD are limited by
factors such as small sample sizes and lack of follow-up data (Björkman and Ekblom
2022; Rosenbaum et al. 2015c). Many studies have also been conducted using
homogenous samples (e.g., Veterans) or convenience samples, which limits gener-
alization to the general population. Additionally, some studies included restrictions
of age, ethnicity, and gender, which may also reduce generalizability to other
demographics with PTSD. Several studies did not include a nonexercise control
group, which may influence outcomes and limit the conclusions that can be drawn.
Researchers have suggested that other aspects of participating in exercise, such as
254 L. M. Kinsman et al.

social support or receiving increased attention, may contribute to decreases in PTSD

symptoms (Voorendonk et al. 2023).

5 Summary and Conclusions

Exercise is recognized to exert a beneficial effect on physiological and psychological

symptoms across several mood- and anxiety-related disorders. Research to date
indicates that various forms of exercise (i.e., aerobic, resistance training) effectively
reduce symptoms of PTSD when applied as a stand-alone intervention or adjunct to
cognitive behavioral and trauma-focused therapies. Evidence further indicates that
greater amounts of exercise may produce greater benefits. Cross-sectional, observa-
tional studies suggest that moderate levels of exercise are associated with a lower
likelihood of probable PTSD compared to low and high levels of exercise. Longi-
tudinal findings indicated that strenuous/vigorous-intensity exercise is associated
with greater reductions in PTSD symptoms than moderate- and low-intensity exer-
cise. Associations between exercise and PTSD symptom clusters have been mixed in
cross-sectional and longitudinal studies.
More research is needed to clarify which dose, intensity, and type of exercise are
most effective at improving PTSD symptoms and to elucidate which prescriptions of
exercise interventions are most effective for different types of trauma. Studies using
larger, more diverse sample sizes are also needed, as is additional research investi-
gating mediators and mechanisms that are responsible for the therapeutic effects of
exercise on PTSD symptoms. Notwithstanding, the available evidence indicates that
exercise is an accessible, cost-effective, and scalable treatment option that has the
potential to improve both physiological and psychological symptoms among indi-
viduals with PTSD.

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ijms19030833
Exercise and Protection from Age-Related
Cognitive Decline

J. Carson Smith, Daniel D. Callow, Gabriel S. Pena, Yash Kommula,

Naomi Arnold-Nedimala, Junyeon Won, and Kristy A. Nielson

Contents
1 Significance and Impact of Age-Related Cognitive Decline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
1.1 Definitions: PA, Cardiorespiratory Fitness, and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
1.2 Definitions: Cognitive Domains, Age-Related Cognitive Decline, and Mild
Cognitive Impairment (Leading to Alzheimer’s Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
2 Leisure-Time PA and Protection from Age-Related Cognitive Decline . . . . . . . . . . . . . . . . . . . 267
3 Cardiorespiratory Fitness and Protection from Age-Related Cognitive Decline . . . . . . . . . . . 268
3.1 Exercise Training in Healthy Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
3.2 Exercise Training in MCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
4 Neuroimaging Evidence for Cognitive Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5 Potential Mechanisms from Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
6 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

Abstract In this chapter, we review the cross-sectional evidence in healthy human

subjects for physical activity and cardiorespiratory fitness to offer neuroprotection
and moderate cognitive decline in older age. The role of exercise training on
cognition in healthy older adults and those diagnosed with mild cognitive impair-
ment (MCI) is also discussed, including the evidence from neuroimaging studies that
document changes to brain structure and function after a period of exercise training
and improved fitness. Finally, in reference to animal models, the potential neuro-
physiological mechanisms for physical activity and exercise to impact human brain
health are highlighted.

J. Carson Smith (✉), D. D. Callow, G. S. Pena, Y. Kommula, and N. Arnold-Nedimala

University of Maryland, College Park, MD, USA
e-mail: [email protected]
J. Won
Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas,
TX, USA
K. A. Nielson
Marquette University, Milwaukee, WI, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 263
Curr Topics Behav Neurosci (2024) 67: 263–280
https://doi.org/10.1007/7854_2024_501
Published Online: 31 July 2024
264 J. Carson Smith et al.

Keywords Aging · Brain Health · Cardiorespiratory Fitness · Cognition · Executive

Function · Memory · Neuroimaging · Physical Activity

1 Significance and Impact of Age-Related Cognitive Decline

The prevalence of age-related cognitive impairment among older adults in the USA
is estimated to be over 20%, and approximately 6.7 million people over the age of
65 have been diagnosed with Alzheimer’s disease (AD) in the USA. Women have
nearly twice the incidence of AD compared to men, and African Americans are at
greater risk than European Americans. With an aging US population, cognitive
impairment and AD constitute alarming public health problems. For example, the
number of older adults with AD is expected to increase to over 13 million by 2060.
The brunt of the burden and cost for cognitive impairment and AD overwhelmingly
falls on caregivers, who experience increased stress and mental health concerns, and
expend untold financial and physical resources, which have been estimated at over
$330 billion in annual unpaid wage (Alzheimer’s Association 2023).
Modifiable lifestyle behaviors such as exercise and leisure-time physical activity
(PA), which even modestly delay the onset of cognitive impairment or help maintain
cognitive function in older adults at greater risk, could slow the development of AD
and have a major public health impact (Woodard et al. 2012). For example, from
data collected in the ABC Health Study from 2,509 well-functioning older adults,
those who maintained weekly moderate-to-vigorous PA had a 31% lower odds of
cognitive decline over a period of 8 years (Yaffe et al. 2009). Moreover, it has been
further estimated that physical inactivity is attributable to 13% of AD cases world-
wide and nearly 21% of AD cases in the USA. If physical inactivity rates were
reduced by 25%, this could result in a prevention of nearly one million cases of AD
worldwide and over 230,000 cases in the USA (Barnes and Yaffe 2011). Indeed,
physical exercise training (exercise training) has received considerable attention as
an intervention (Geda et al. 2010; Kramer et al. 2006; Lautenschlager et al. 2008;
Smith et al. 2013a), primarily because it has relatively few side effects, a key factor
in implementing a treatment in a population with comorbid conditions (ACSM 2006;
IOM 2015). A physically active lifestyle and greater cardiorespiratory fitness has
long been associated with reduced all-cause mortality (Samitz et al. 2011) and also
with reduced mortality attributable to dementia (Liu et al. 2012).

1.1 Definitions: PA, Cardiorespiratory Fitness, and Exercise

Although PA, cardiorespiratory fitness (CRF), and exercise represent distinct con-
structs, they are often used interchangeably in the literature. First, PA refers to any
kind of skeletal muscle-related bodily movements that increase energy expenditure
Exercise and Protection from Age-Related Cognitive Decline 265

above resting energy expenditure (Caspersen et al. 1985). PA includes leisure time
activities as well as structured health-related activities. Self-report questionnaire or
actigraphy are widely used to measure amount of PA (see Chapter “Introduction”).
CRF is cardiovascular ability to supply and utilize oxygen to large muscle groups
during dynamic PA of moderate-to-vigorous intensity for prolonged periods of time
(Caspersen et al. 1985). The integrated functions of musculoskeletal, respiratory, and
cardiovascular systems constitute the level of CRF. It has been well documented that
higher CRF is associated with lower risk of cardiovascular disease, all-cause mor-
tality, and improvement in other health outcomes (Samitz et al. 2011; Blair et al.
1989; Paffenbarger Jr. et al. 1986). The gold standard method to assess CRF is to
measure the maximal rate of oxygen consumption (VO2max) using open circuit
spirometry. VO2max reflects the highest rate of oxygen uptake that an individual
can attain during sustained exercise and is typically defined as a plateau of oxygen
consumption despite increased work rate that is combined with attainment of other
criteria for maximal effort (such as a near maximal subjective rating of perceived
exertion, heart rate near age-predicted maximum, respiratory exchange ratio greater
than 1.0) and represents maximal aerobic capacity. For physically inactive older
participants or those with known cardiovascular disease, a modified submaximal test
is often used due to safety concerns. Although regular participation in moderate-to-
vigorous aerobic exercise largely influences VO2max, there are other factors (e.g.,
training status, age, and sex) that may moderate VO2max, which also are strongly
influenced by genetic inheritance (Bouchard et al. 2011). Thus, it is imperative to
factor in these potential moderators into the analyses to investigate the associations
with CRF.
Exercise is a specific subtype of PA comprising planned and structured PA to
enhance physical fitness or health. Aerobic exercise (also referred to as cardiovas-
cular exercise) refers to planned and structured large-muscle dynamic activity that
engages the cardiovascular system, such as walking, running, swimming, or cycling
(ACSM 2006; Caspersen et al. 1985). While resistance exercise (also referred to as
strength training or weight lifting) also involves the cardiovascular system, it is
distinguished by providing resistance to concentric or eccentric contractions of
specific muscle groups, usually repeated for a limited number of repetitions and
sets of repetitions in order to increase strength or ability to produce force (ACSM
2006; Caspersen et al. 1985). In clinical research, acute exercise is a single bout of
exercise typically administered using cycle ergometer or treadmill or resistance
exercise (e.g., a single session of cardiovascular exercise for 10–60 min) and then
undergo experimental conditions at various timepoints (immediately to minutes to
several hours) afterward. Exercise training refers to repeated participation in exercise
for a certain period. Most exercise training studies are conducted for ≥3 months, and
participants typically undergo experimental conditions at baseline and
postintervention. Randomized controlled trials are commonly used in exercise
training investigations. It is common for randomized controlled trials to randomize
participants into either aerobic exercise or nonaerobic exercise control (e.g., balance,
stretching, and toning) groups. See Chapter “Introduction” for a comprehensive
overview of key physical activity and exercise-related definitions and concepts.
266 J. Carson Smith et al.

1.2 Definitions: Cognitive Domains, Age-Related Cognitive

Decline, and Mild Cognitive Impairment (Leading
to Alzheimer’s Disease)

Cognitive functioning includes an array of mental faculties that encompass experi-

ence of the world around and within and the acquisition of knowledge, skills, and
understanding, with maximum speed and accuracy. The major domains of cognition
include sensory-perceptual processing, mental and motor speed, attention, learning,
memory, language, reasoning, problem-solving, and executive functioning. Memory
generally encompasses a wide array of encoding and retrieval functions including
knowledge and facts (i.e., semantic memory), temporally specific information and
experiences (i.e., episodic memory), skills (i.e., procedural memory), and uncon-
scious/automated learning (i.e., implicit memory). Executive functioning is an
umbrella term encompassing high-level (i.e., “fluid”) cognitive skills including
attentional and inhibitory control, cognitive flexibility, and working memory (i.e.,
holding, updating, and manipulating information in current consciousness).
Cognitive functions develop capacity and efficiency throughout development into
the second decade, followed by incremental but continuous decline in most cognitive
domains thereafter (McArdle et al. 2002). Although the degree and trajectory of
change vary by domain, both cross-sectional and longitudinal data show this general,
modest pattern of decline (Salthouse 2019; Singh-Manoux et al. 2012). Importantly,
there are also spared cognitive domains in aging, such as in low-load and
nondeclarative (e.g., implicit, procedural) memory tasks, naming, and the acquisi-
tion and retrieval of vocabulary and general knowledge (Salthouse 2019; Cohen
et al. 2019; Zec et al. 2005). Distinctions between sparing and decline often go
unnoticed until much later in life and decline may be offset by growth in expertise
and skills into later life (Haaland et al. 2003). However, there is clear evidence that
cognitive functions that require effortful and/or time-sensitive processing peak in
younger adulthood and decline quite consistently throughout the rest of life
(Salthouse 2019). Additionally, older adults have more difficulty ignoring irrelevant
information, solving problems, learning new things, and most especially retrieving
previously learned information (Craik and Salthouse 2007). There are multiple
theories that attempt to explain cognitive aging processes, ranging from single-
process, all-cause theories that rely on behavioral findings (e.g., processing speed,
inhibitory deficit, binding in memory) to the most contemporary models that explain
cognitive decline and resilience in terms of neural changes and individual adaptation
to those changes (e.g., compensation, scaffolding) (Dennis et al. 2020). Adaptation
to change and areas of cognitive sparing are given less attention in the literature, but
they are of particular importance as they demonstrate that functional cognitive
decline is not an inevitable consequence of aging and that cognitive plasticity can
be leveraged for targeted interventions that can protect and enhance functioning into
old age.
Cognitive impairment, as distinguished from age-related cognitive decline, is
typically considered performance that is more than 1.5 standard deviations below
Exercise and Protection from Age-Related Cognitive Decline 267

the normative mean for the domain assessed (Petersen and Morris 2005). Dementia
is a heterogenous major neurocognitive disorder that is characterized by a significant
impairment and progressive decline of function in multiple cognitive domains,
including attention, memory, processing speed, and executive function, and the
disruption of normal activities of daily living (American Psychiatric Association
2022). AD, characterized by widespread, progressive brain atrophy and beta-
amyloid and tau neuropathology, is by far the most prevalent form of dementia
(Alzheimer’s Association 2023). Juxtaposed between typical age-related cognitive
decline and AD-related cognitive impairment is a “preclinical,” transitional phase
termed “mild cognitive impairment” (MCI). While 1–2% of healthy elders progress
to dementia annually, 10–15% of those diagnosed with MCI will do so (Peltz et al.
2011). As such, this transitional MCI stage is an ideal, perhaps crucial time to initiate
interventions to slow or reverse the dementia process.
MCI is currently characterized by cognitive complaints (by the individual or
informant) accompanied by verified cognitive impairment in one or more cognitive
domains that is not severe enough to meet the criteria for dementia and intact
independence of daily activities (Albert et al. 2011). Various subtypes exist, most
simply those that categorize MCI by amnestic or nonamnestic and by single or
multiple domains of impairment. Episodic memory is commonly impaired, particu-
larly in those who later convert to AD (Albert et al. 2011), as is executive functioning
(Corbo and Casagrande 2022). The threshold for impairment in MCI, by definition
less precise than in dementia because deficits are mild, is typically 1–1.5 standard
deviations below the age- and education-corrected norms (Albert et al. 2011). In
addition, MCI does not necessarily progress as consistently as it does in dementia.
Instead, there is sometimes “reversion” over time, where impairment resolves or
improves for a time before declining again (Malek-Ahmadi 2016).

2 Leisure-Time PA and Protection from Age-Related

Cognitive Decline

Including regular PA as part of a healthy lifestyle offers numerous health-related

benefits to include disease prevention, maintenance of independence, and improved
quality of life particularly in older adults (Lautenschlager et al. 2008; Sun et al.
2013). In the USA, approximately 10% of premature mortality and an annual
healthcare cost of an estimated $117 billion are associated with inadequate PA
(Piercy et al. 2018). A large-scale, eight-year longitudinal study found that a
moderate amount of additional daily PA (as little as 15 min) decreased mortality
rates by 4% (Sun et al. 2013). The PA Guidelines for Americans recommends adults
to engage in 150–300 min a week of moderate-intensity or 75–150 min a week of
vigorous-intensity aerobic PA or an equivalent combination of moderate- and
vigorous-intensity aerobic activity, including muscle-strengthening activities on
two or more days a week (Piercy et al. 2018). Additionally, older adults should do
268 J. Carson Smith et al.

multicomponent PA that includes balance training as well as aerobic and muscle-

strengthening activities.
In recent years, focus on the impact of leisure-time PA in reducing risk for
age-related cognitive decline in older adults has become an emerging area of
research (Smith et al. 2013b). For example, a population-based case-control longi-
tudinal study from the Mayo Clinic Study of Aging investigated the association
between PA and risk of the development of MCI in older adults. They found that
engagement in moderate intensity PA at any frequency greater than zero days per
week in midlife (at ages 50–65 years) and late-life (70–89 years, less than 1 year
prior to the cognitive assessment) was associated with an approximately 40% and
30% reduction, respectively, in risk for a diagnosis of MCI (Geda et al. 2010). The
largest protective effect at midlife was found for moderate PA at a frequency of
5–6 days per week, which provided a 60% reduction in risk for MCI after age 70.
The findings from this study suggest that at midlife, and even later in life, frequent
engagement in PA may help to preserve cognitive abilities and may provide protec-
tion from the onset of MCI. In another longitudinal study, 3,903 dementia-free older
adults (age 55+) were followed in Ebersberg, Bavaria, for 2 years. Those who
engaged in moderate (<3 times per week) or high levels (≥ 3 times per week) of
PA had significantly reduced odds for developing incident cognitive impairment at
follow-up compared to those who did not engage in PA (Etgen et al. 2010). In a
1,740-person study of healthy, cognitively intact older adults (age 65+), with a mean
follow-up of 6.2 years, the incidence rate of dementia was 13.0 per 1,000 person-
years for those who were physically active greater than or equal to 3 times per week
compared with a rate of 19.7 per 1,000-person years for those who exercised less
than 3 times per week (Larson et al. 2006). Moreover, the risk reduction associated
with PA was greatest in those who were less physically active at baseline.
In summary, leisure time PA is associated with lower incidence of cognitive
decline. These findings support the adoption of PA for older adults as a method to
attenuate the rate of cognitive decline with age, even when the adoption of an active
lifestyle begins mid- to late-life or with a history of very little leisure-time PA. These
hypothesized associations are depicted in Fig. 1. Note, however, that it is not
possible to determine if these associations are linear with age or have a greater or
lesser slope at younger or older ages. Moreover, very little is known regarding the
comparative effectiveness of different modes and intensities of PA/exercise in
relation to cognitive outcomes or symptoms of AD.

3 Cardiorespiratory Fitness and Protection from

Age-Related Cognitive Decline

CRF, a facet of cardiovascular health, has been positively correlated with better
overall and domain-specific cognitive function in healthy older adults (Pentikainen
et al. 2019). A meta-analysis of 18 aerobic fitness training studies reveals that CRF in
Exercise and Protection from Age-Related Cognitive Decline 269

Fig. 1 Hypothesized associations between PA and the trajectory of cognitive decline, with
protective effects even when started in late life

healthy older adults may bolster executive function most strongly, when compared
to other key cognitive functions such as processing speed, visuospatial processing,
and effortful-controlled processes that, unlike executive functions, can become
automatic without need of constant mediation by a central executor over time
(Colcombe and Kramer 2003). Cross-sectional studies consistently support that
higher VO2max is related to better executive functioning, as assessed by tasks such
as the Wisconsin Card Sorting Test, the Trail-Making Tests (part B), and the Stroop
task (Gauthier et al. 2015). Meanwhile, longitudinal research examining cognitive
function has identified that higher baseline VO2max in older adults is positively
associated with better executive function 6 years later (Barnes et al. 2003). Although
the mechanism of fitness benefits on executive function in healthy aging is
unconfirmed, recent research suggests that higher global neural efficiency and
lower local neural efficiency might play a role (Kawagoe et al. 2017; Callow and
Smith 2023). Higher global efficiency reflects that the whole brain is more well
integrated, whereas lower local efficiency implies that the brain is less well func-
tionally segregated.
CRF has also frequently been associated with memory in healthy aging. For
instance, one study has supported that high-fit older adults outperform low-fit older
adults on episodic memory tasks such as the face-name memory task (Hayes et al.
2016). A study considering the Rey Auditory Verbal Learning Test as the episodic
memory outcome measure, however, showed that CRF was associated with Rey
270 J. Carson Smith et al.

Auditory Verbal Learning Test performance in older men but not older women
(Dougherty et al. 2017). Still, this study revealed a significant correlation between
CRF in older women and hippocampal volume, which is encouraging given the
classically noted relationship between the hippocampus and episodic memory
(Squire and Wixted 2011). The degree of sex specificity in the relationship between
fitness and episodic memory should be clarified in future research. Other forms of
memory such as working memory have also correlated with CRF in healthy older
adults, as research supports that CRF increase across a five-year moderate aerobic
exercise training is positively associated with better working memory performance
as assessed by the Digit Span Backwards test (Sokolowski et al. 2021). Working
memory, such as visual or verbal working memory, is vital for processing and using
limited information to support everyday reasoning, comprehension, and problem-
solving, among other processes.
Like executive function and memory, language function is considered integral for
older adults’ functional independence. Challenges with communication can burden
older adults during routine life activities, such as interaction with community,
caregivers, and healthcare professionals. One study showed that after a 12-week
spin cycling intervention in healthy, previously sedentary older adults, improvement
in estimated VO2max was correlated positively with increase in semantic fluency
(Nocera et al. 2015). Similarly, higher aerobic fitness levels have been found to
associate with decreased likelihood of tip-of-the-tongue states in healthy older
adults, even when the effect of age is controlled (Segaert et al. 2018). Tip-of-the-
tongue states represent a common cognitive difficulty in healthy older adults and
occur when a speaker knows the desired word but is unable to produce it. One study
assessing language function with the Boston Naming Test also supported that greater
estimated cardiorespiratory fitness in healthy older adults is correlated with better
language function, as well as functions within other cognitive domains (Velazquez-
Diaz et al. 2023).
CRF in healthy older adults has also been associated with other vital cognitive
processes, including processing speed, pattern separation, and visuospatial reasoning
(Sokolowski et al. 2021; Espana-Irla et al. 2021). Apart from increased efficiency of
neural networks, other candidate mechanisms may entail preservation of brain
regions key for cognitive function. For instance, one study found that the relation-
ship between CRF and executive function task performance was mediated by
volume of regions within the prefrontal cortex (Weinstein et al. 2012). It may also
be that better CRF improves sleep or attenuates the effects of poor sleep (Kuhn and
Heisz 2022). Indeed, sleep quality declines with aging (Mander et al. 2017; Moraes
et al. 2014), and worsened sleep quality is associated with poor cognition (Lim et al.
2012) and accelerated cognitive decline (Altena et al. 2010).

3.1 Exercise Training in Healthy Older Adults

In humans, aerobic exercise training interventions have been associated with better
cognitive function in healthy older adults (Kramer et al. 2006). In a meta-analysis
Exercise and Protection from Age-Related Cognitive Decline 271

from 18 randomized-controlled trials, exercise interventions (cardiovascular exer-

cise, resistance exercise, or combined cardiovascular and resistance exercise) had a
significant effect on multiple domains of cognitive function compared to a
nonexercise control condition, including executive function, controlled processing,
visuospatial performance, processing speed, and episodic and short-term memory
(Colcombe and Kramer 2003). Moreover, in their meta-analysis, these effects were
shown to be larger in studies with a greater proportion of women, in participants
greater than 65 years old (compared to ages 55–65), when the intervention lasts at
least 6 months and when it consists of a combination of cardiovascular and resistance
exercise training (Colcombe and Kramer 2003). Notably, the effects did not depend
on the duration of each individual exercise session (up to 60 min long). Subsequent
research has also indicated that one of the most consistent effects of exercise training
compared with other types of interventions is improved processing speed (e.g.,
simple reaction time or other timed tasks, such as Trail-Making part A) (Callow
and Smith 2023). Improved processing speed also positively impacts performance in
other cognitive domains, particularly in executive function. The other finding among
healthy older adults after exercise training compared to any other type of active
intervention is improved immediate recall verbal memory performance (Angevaren
et al. 2008). However, research has been less consistent regarding effects in other
domains, including visual and auditory attention and visual memory (Young et al.
2015).

3.2 Exercise Training in MCI

Despite the efforts of the medical and research communities, there is insufficient
evidence to support the use of pharmaceutical agents or dietary supplements to
prevent cognitive decline or AD (Daviglus et al. 2010). Even the most recently
FDA-approved medication, lecanemab, has been shown to only modestly attenuate
(but not prevent) the rate of cognitive decline in patients diagnosed with early
Alzheimer’s disease (van Dyck et al. 2023), an effect that may or may not be
clinically meaningful (Valenzuela and Pascual-Leone 2023; Zeng et al. 2023; Qiao
et al. 2023), Antiamyloid infusions, including lecanemab, also have potential
adverse and life-threatening side effects, particularly among those who are at
increased genetic risk for AD (Qiao et al. 2023; Cummings et al. 2023). This has
stimulated efforts to identify preclinical biomarkers to predict future cognitive
decline and AD more effectively and to facilitate targeted intervention and preven-
tion trials. One approach is to initiate trials at a much earlier stage of disease
progression to slow or delay disease progression once a diagnosis of MCI due to
AD has been determined.
Results from the Fitness for the Ageing Brain Study, a randomized trial of older
adults with subjective memory complaints showed improved scores on the
Alzheimer Disease Assessment Scale-Cognitive subscale in those assigned to a
home-based PA program compared to the usual care condition (Lautenschlager
272 J. Carson Smith et al.

et al. 2008). Another six-month randomized clinical trial in 33 adults diagnosed with
MCI compared aerobic exercise training to a stretching control group (Baker et al.
2010). They found that exercise training resulted in significant improvement on
verbal fluency, with the strongest effects for category fluency, an index of semantic
memory retrieval. In the Mental Activity and Exercise trial (Barnes et al. 2013),
older adults with cognitive complaints did 12 weeks of exercise plus mental activity
or control conditions, and all groups improved on a composite index of cognition,
which suggests that the effects of exercise may not be independent from other
cognitively and/or socially stimulating interventions. Another study reported
increased efficiency of semantic memory activation and improved verbal learning
after 12 weeks of walking exercise (Smith et al. 2013a). Relatedly, another study
showed that 6 months of aerobic exercise in women 70–80 years old with subjective
memory complaints resulted in stable hippocampal volume compared to hippocam-
pal atrophy measured in a control group that performed balance and toning exercise
(Ten Brinke et al. 2015). While there is evidence for the efficacy of exercise to
modestly improve cognition, it is unknown if exercise training among individuals
diagnosed with MCI leads to a reduced incidence of, or progression to,
AD. Accordingly, there is a need to conduct an exercise clinical trial earlier in the
disease process among those who are at greatest risk, including those with increased
genetic risk.

4 Neuroimaging Evidence for Cognitive Aging

Magnetic resonance imaging (MRI) has been crucial in understanding the effect of
exercise on the brain and cognition in older adults. The importance of brain imaging
has grown with technological advancements in the development and implementation
of various MRI approaches, which researchers now use to investigate numerous
structural and functional changes in the brain that may result from exercise inter-
ventions and facilitate healthy cognitive aging. For example, structural MRI
approaches suggest that exercise may reduce age-related atrophy of brain structures
essential for higher-order cognitive processes, such as memory and executive func-
tion. Additionally, perfusion MRI suggests that exercise can influence cognitive
aging by altering levels of brain tissue perfusion with blood, oxygen, and essential
nutrients. Thus, neuroimaging provides a noninvasive means of investigating neu-
roanatomical and neurophysiological changes in the human brain that may account
for improvements in cognitive function previously documented by PA and exercise
interventions.
Structural MRI provided some of the first evidence for the effects of exercise on
cognitive aging in humans by observing how exercise might alter the relative size
and trajectories of different brain regions with age, particularly gray matter tissue.
Changes in brain volume are well characterized throughout healthy and pathological
aging and suggest that the majority of cortical and subcortical gray matter tissue
begins to shrink in mid-adulthood, with atrophy hastening in older age. Notably, the
Exercise and Protection from Age-Related Cognitive Decline 273

prefrontal cortex and the hippocampus are specific gray matter brain regions that
consistently shrink approximately 1–2% a year in older age, with more rapid
declines experienced after the onset of cognitive impairment. Given that these two
structures are critical for memory and executive function, their rapid deterioration in
older age may be related to the often pronounced declines in fluid cognitive abilities
associated with aging (O'Shea et al. 2016).
Two foundational exercise intervention studies (Colcombe et al. 2006; Erickson
et al. 2011) found cardiorespiratory fitness improvements from a six-month and
one-year exercise training program in healthy older adults led to increases in frontal
lobe and anterior hippocampal gray matter volume. Consistent with these early
findings, recent observational studies suggested that PA levels and CRF are related
to preserved gray matter volume in older adults, particularly in the frontal lobes and
hippocampus (Koblinsky et al. 2021). Notably the benefits of PA and fitness for gray
matter preservation may be most pronounced for those genetically predisposed to
cognitive impairment and hippocampal deterioration. Specifically, higher PA levels
can ameliorate the negative effect of the Apolipoprotein-E ε4 allele – a genetic
polymorphism associated with AD risk – on hippocampal atrophy in old age (Fraser
et al. 2022; Smith et al. 2014). However, many randomized controlled trials for
exercise interventions conducted in the last decade fail to establish that exercise
training can increase gray matter or hippocampal volume. For example, a meta-
analysis of exercise intervention randomized controlled trials in adults only noted a
retention of left hippocampal volume but not bilateral volume (Firth et al. 2018).
Meanwhile, a recent meta-analysis of 14 exercise randomized controlled trials
focusing exclusively on older adults found that exercise training was not associated
with differences in gray matter volume compared to control conditions (Gogniat
et al. 2021). Several potential reasons exist for inconsistencies in the reported
relationships between exercise and gray matter volume, providing a framework
and direction for future studies. Thus, future studies should differentiate between
exercise responders and nonresponders by reporting changes in fitness and consider
potential moderating factors. Additional MRI-based measures of brain tissue integ-
rity and microstructure can proceed volumetric decline and thus should be explored
within the context of exercise and cognitive aging (Callow et al. 2021). High-
resolution structural imaging approaches focusing on the hippocampus are needed,
as animal and recent human studies indicate the benefits of exercise training and
fitness for cognitive aging may be specific to the preservation and integration of new
neurons in particular hippocampal subfields (Duzel et al. 2016; Frodl et al. 2020).
Finally, future studies must determine what cognitive domains and processes
exercise-related preservation of gray matter tissue specifically mediates.
Researchers have also used perfusion MRI approaches to discern the cerebrovas-
cular effects of exercise on cognitive aging. Notably, aging is often associated with
cardiovascular dysfunction, which may contribute to consistent age-related declines
in gray matter cerebral blood flow (CBF) (Leidhin et al. 2021; Tarumi and Zhang
2018). Additionally, longitudinal studies have linked age-related CBF declines to
poorer fluid cognitive abilities such as executive function and processing speed
(Staffaroni et al. 2019). Given the strong ties between exercise and cardiovascular
274 J. Carson Smith et al.

health, understanding exercise and PA’s effects on CBF in older adults may provide
additional insight into how exercise may promote healthy cognitive aging.
Cross-sectional studies suggest that a sedentary lifestyle is associated with
reduced resting cerebral perfusion in the frontal lobe. In contrast, greater light and
moderate intensity PA levels have a positive, dose-dependent association with
resting frontal lobe perfusion in older adults (Zlatar et al. 2019). Meanwhile, a
small study of ten masters athletes found that 10 days of exercise cessation was
associated with a decline in resting hippocampal CBF (Alfini et al. 2016). Further-
more, a within-subject 8-week fully supervised personalized and progressive aerobic
exercise training program on a cycle ergometer in 17 older sedentary individuals
found that in addition to improved CRF and executive functioning, exercise training
was associated with higher resting CBF in the frontal lobe but lower resting CBF in
the medial temporal lobe (Kleinloog et al. 2019). Finally, a 12-week progressive
walking aerobic exercise intervention in healthy older adults and those with MCI
found that exercise ameliorated elevated insular CBF at baseline in those with MCI
and increased CBF in the cingulate cortex of the healthy older adults (Alfini et al.
2019). Both groups of older adults also saw improvements in executive function and
memory following the intervention (Alfini et al. 2019). Notably, a lack of exercise
intervention randomized controlled trials with adequate sample sizes, proper control
groups, and that specifically test for relationships between exercise-induced CBF
changes and cognition in older adults makes it challenging to interpret how exercise
may affect CBF and cognitive aging. However, limited evidence indicates that these
relationships may depend on individual factors, the specific brain regions evaluated,
and the cognitive tasks analyzed.
In summary, greater PA, CRF, and exercise training programs appear to influence
the trajectory of age-related changes across various structural and physiological
neuroimaging domains and mechanisms. However, there is a notable lack of well-
designed exercise intervention randomized controlled trials in older adults that test
for exercise-induced MRI-based changes and subsequently link these changes to
alterations in cognitive performance. Future studies must target this gap to improve
our understanding of how these various neurophysiological mechanisms mediate the
positive relationship between exercise and healthy cognitive aging.

5 Potential Mechanisms from Animal Models

The molecular mechanisms behind exercise-related neuroprotection are challenging

to address in humans given that circulating peripheral biomarkers do not always
reflect the neural milieu (Calverley et al. 2020). Nevertheless, animal models of
biological and pathological aging suggest that exercise is neuroprotective through
the upregulation of neurotrophins and growth factors that, over time, promote the
proliferation and differentiation of quiescent adult neural stem cells in a process
Exercise and Protection from Age-Related Cognitive Decline 275

termed adult neurogenesis (Cotman et al. 2007). In the context of human health,
animal studies have shown that adult neurogenesis takes place in the subgranular
zone of the dentate gyrus in the hippocampus, a subcortical structure that is partic-
ularly susceptible to neurodegeneration and pathologies such as AD (Henneman
et al. 2009). As such, understanding how exercise may lead to adult neurogenesis is a
promising way to delay cognitive decline and neurodegeneration.
Neurotrophins are growth factors widely expressed throughout the central ner-
vous system that play fundamental roles in neural plasticity and the development and
maintenance of neurons (Noble et al. 2011). Among these, brain-derived
neurotrophic factor (BDNF) has been shown to regulate adult neurogenesis and be
upregulated in response to aerobic exercise (Cotman et al. 2007). In this context,
aerobic exercise acutely upregulates mRNA levels of BDNF’s high-affinity receptor
TrkB as well as mRNA levels for proteins that facilitate neurotransmitter release and
synaptic plasticity such as synapsin I (Gomez-Pinilla et al. 2002). Moreover, aerobic
exercise increases phosphorylation of BDNF-related signal transduction pathways
such as the MAPK ERK 1/MAPK ERK 2 pathway as well as the upregulation of
transcription factors such as cyclic AMP response element that aid neuroplasticity
(Gomez-Pinilla et al. 2002). Insulin growth factor 1 (IGF-1) and vascular endothelial
growth factor (VEGF) are additional growth factors that play key roles in the
neuroprotective benefits of aerobic exercise (Cotman et al. 2007). IGF-1 is a growth
factor that is essential for cellular growth and metabolism, and it is intracellular
signaling cascades that have been implicated in neurogenesis and cognitive health
(Frater et al. 2018; Pardo et al. 2018). For example, in aging rats, IGF-1 upregulation
is accompanied by higher expression of genes involved in synaptic plasticity such as
synaptophysin-like protein 2 concomitant to improved performance in spatial mem-
ory tasks (Pardo et al. 2018). Importantly, exercise has been noted to upregulate the
secretion of IGF-1 by neurons and peripheral tissues such as the skeletal muscle and
liver (Cotman et al. 2007). This upregulation in central and circulating IGF-1 is
associated with higher IGF-1 uptake by brain hippocampal neurons and synergistic
interactions with BDNF that facilitate long-term potentiation and neuroplasticity via
the activation of cellular signaling pathways such as MAPK (Cotman et al. 2007).
Lastly, VEGF is an angiogenic growth factor that is upregulated by aerobic exercise,
and VEGF in the brain may serve as an important regulator of adult neurogenesis via
VEGF2/Filk-1 receptor signaling and subsequent phosphorylation of cell survival
mediators such as PI3K/AKT1 (Fabel et al. 2003; Cao et al. 2004). Thus, although
not exclusive, neurotrophins and growth factors are among the most well-
documented molecular mechanisms by which PA and exercise can benefit long-
term brain and cognitive health. It is important to note here, however, that this is a
growing field of research, and recent evidence suggest that the molecular mediators
of exercise-related neuroprotection may also involve proteins secreted from periph-
eral tissues such as skeletal muscle. Thus, there is continued need to employ animal
models that can clarify the complex molecular neuroprotective responses
upregulated during and following exercise.
276 J. Carson Smith et al.

6 Summary and Conclusions

Leisure-time PA, greater cardiorespiratory fitness, and exercise training interven-

tions all have been associated with attenuation of age-related cognitive decline.
These associations have been manifest in neurocognitive test performance outcomes,
particularly executive function and cognitive processing speed, as well as indices of
neural function and structure derived from MRI scans. There is some evidence that
the protective effects of exercise and PA on cognition are greater among females, but
additional research is needed due to the tendency for these studies to include more
females than males. While there currently is no evidence to suggest that the cognitive
benefits of PA do not extend to people from all racial and ethnic backgrounds,
additional research with more diverse samples is needed. The complex mechanistic
causes for these neuroprotective effects have not been conclusively demonstrated but
likely involve neurotrophic pathways that stimulate growth and/or protection for
neural atrophy within and between neural networks. Additional research in humans
using cutting-edge neuroimaging methods will also help to demonstrate whether or
not acute and chronic exercise modifies the neural networks that govern multiple
cognitive domains and provide the type of mechanistic findings that may help to
establish and promote evidence-based prescription of exercise and PA for protection
against age-related cognitive decline.

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Physical Activity and Fatigue Symptoms:
Neurotypical Adults and People
with Chronic Multisymptom Illnesses

Alex Boruch, Grace Branchaw, Patrick J. O’Connor, and Dane B. Cook

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2 Acute Physical Activity and Fatigue Symptoms in Neurotypical Adults . . . . . . . . . . . . . . . . . . 285
2.1 Summary of Acute Studies with Neurotypical Participants . . . . . . . . . . . . . . . . . . . . . . . . . . 285
2.2 Evidence Regarding Plausible Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
3 Acute Physical Activity and Fatigue Symptoms: ME/CFS, GWI, and Long-COVID . . . . 288
3.1 Summary of Acute Studies: E.g., Extent of Post-Exertional Malaise . . . . . . . . . . . . . . . 288
3.2 Evidence Regarding Plausible Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
4 Chronic Physical Activity and Fatigue Symptoms in Neurotypical Adults . . . . . . . . . . . . . . . . 294
4.1 Summary of Chronic Exercise Training Studies with Neurotypical Participants . . . 294
4.2 Evidence Regarding Plausible Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
5 Chronic Physical Activity and Fatigue Symptoms: ME/CFS, GWI, and Long-COVID . . 296
5.1 Summary of Chronic Exercise Training Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
5.2 Evidence Regarding Plausible Mechanisms of Chronic Exercise and Fatigue
in Atypical Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

Abstract For neurotypical adults, a single bout of low-to-moderate intensity phys-

ical activity usually transiently improves feelings of energy. Similar bouts of exer-
cise have the opposite effect of increased feelings of fatigue when performed by
samples with chronic multisymptom illnesses (CMIs) such as Long-COVID, Gulf
War Illness (GWI), or Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS). The short-term adoption of regular moderate intensity physical activity
(typical experiments are 1 to 6 months) among neurotypical adults results in small-
to-moderate improvements in self-reported feelings of fatigue, energy, and vitality.

A. Boruch, G. Branchaw, and D. B. Cook (✉)

Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
Department of Kinesiology, University of Wisconsin–Madison, Madison, WI, USA
e-mail: [email protected]
P. J. O’Connor
Department of Kinesiology, University of Georgia, Athens, GA, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 281
Curr Topics Behav Neurosci (2024) 67: 281–308
https://doi.org/10.1007/7854_2024_502
Published Online: 23 July 2024
282 A. Boruch et al.

Small improvements in these feelings, or no change at all, occur for CMIs, but
limited data precludes strong conclusions. The mechanisms of exercise effects on
fatigue, whether acute or chronic, are poorly understood but likely involve multiple
neural circuits and associated transmitters. For CMIs, the mechanisms of acute
worsening of fatigue with exercise may be driven by the yet unknown pathophys-
iological mechanisms of the disease (perhaps involving brain, immune and auto-
nomic system dysfunction, and their interactions). Likewise, fatigue improvements
may depend on whether chronic physical activity is a disease-modifying treatment.

Keywords Energy · Exercise · Post-exertional malaise

1 Introduction

The primary purpose of this chapter is to overview research that has examined
relationships between physical activity and symptoms of fatigue. The information
in this chapter is preceded by background about fatigue, information about its
measurement, and comments about the scope and impact of the problem of fatigue.
Subsequent sub-sections focus on both acute and chronic physical activity in both
neurotypical adults and atypical adults such as those with diseases that are defined by
chronic fatigue and associated symptoms.
The Oxford English Dictionary provides a definition of the noun fatigue, dating
back to the seventeenth century, as “lassitude or weariness resulting from either
bodily or mental exertion” (Proffitt 2023). Much has been learned about fatigue since
that time, especially about moderators of fatigue. For instance, factors such as one’s
genetics (Wang et al. 2017), acute drug use, including caffeine, modafinil, and
methylphenidate (Qu et al. 2016; Ward-Ritacco et al. 2021), and environmental
exposures such as bright light (Xiao et al. 2022) or viral pathogens (Islam et al. 2020)
can moderate fatigue even though these variables are independent of physical or
mental exertion.
Fatigue has multiple complex meanings. This chapter will focus on feelings of
fatigue, which is synonymous with symptoms of fatigue. There is evidence that
symptoms of fatigue have small-to-moderate negative relationships with feelings of
energy yet are independent from feelings of energy (Boolani et al. 2019; Loy et al.
2018). Feelings of fatigue can covary with fatigue induced by skeletal muscle actions
(Monroe et al. 2016). This is because high intensity or long duration exercise
produces both feelings of fatigue and a transient reduction in the ability to produce
power output. The criterion measure of symptoms of fatigue is self-reported feelings,
often assessed with reference to the duration, frequency, or intensity of such feelings.
There are dozens of measures of fatigue symptoms that have been used by
researchers and clinicians. Most of these measures have been supported by at least
one study providing at least one type of evidence to support the validity of the scores
as a measure of fatigue (O'Connor 2004). The most widely used measures of fatigue
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 283

symptoms, however, have thousands of references providing comprehensive sup-

portive evidence for the validity of the measure (e.g., fatigue and vigor scales of the
Profile of Mood States questionnaire; vitality scale of the SF-36 health survey)
(Curran et al. 1995; Ware 2000). The National Institutes of Health supported the
development of the Patient Reported Outcomes Measurement Information System
(PROMIS®) which includes a measure of fatigue symptoms (Cella et al. 2016).
PROMIS, based on Item Response Theory, uses a computer adaptive approach to
determine fatigue levels. One key under-appreciated assessment issue is that some
measures focus solely on the concept of fatigue (e.g., State Trait Energy and Fatigue
Scales) (Boolani and Manierre 2019) while other measurement tools aim to simul-
taneously assess both fatigue and aspects of the affective, behavioral and/or cogni-
tive consequences of fatigue (e.g., European Organization for Research and
Treatment of Cancer – Quality of Life Questionnaire) (Aaronson et al. 1993).
While this latter approach has the advantage of more comprehensively surveying
fatigue-related experiences, it also has the potential disadvantage of introducing
substantial construct-irrelevant variance into scores, which adds error to the measure
of fatigue (Eignor 2013).
The prevalence of fatigue symptoms is not adequately represented by a single
number but depends on several factors including the group studied, such as a
community sample compared to samples with a chronic illness. The timeframe
(e.g., point prevalence versus lifetime prevalence) and how fatigue is defined (e.g.,
elevated symptoms above a cut point versus meeting criteria for a diagnosis of a
fatigue disorder) are also critical factors in determining prevalence of fatigue symp-
toms. For example, in 2017, the prevalence of prior month persistent fatigue was
reported as 13.6% for the Japanese general population (Aritake et al. 2015). Eight
years later a comprehensive worldwide review of studies from population-based
samples identified 76 data points from investigations that measured general fatigue
of less than six months duration or of an unspecified duration (i.e., not specified as
chronic or lifetime) primarily using the Chalder Fatigue Scale. The prevalence of
fatigue in adults was 20.4% (with a 95% Confidence Interval (CI) of 16.7–25.0). In
the same review, the prevalence of chronic fatigue (fatigue lasting more than
6 months) in adults was 10.1% (95% CI, 8.2–12.5) (Yoon et al. 2023).
The prevalence of fatigue is typically higher in those characterized by a medical
illness compared to community samples. A meta-analysis of 129 studies of over
71,000 individuals, primarily residing in Western countries, found that the preva-
lence of fatigue was 49% among cancer patients based on symptom scores elevated
above cut-offs on multiple measures of fatigue and primarily 3 months after treat-
ment (Al Maqbali et al. 2021). The prevalence of usual or prior month fatigue was
46% in a sample of 458 non-hospitalized adults with a positive polymerase chain
reaction test for COVID-19 in the prior 1.5 to 6 months (Stavem et al. 2021). The
prevalence of fatigue, using various time frames, has been reported in meta-analyses
to be elevated on average for multiple types of chronic illnesses, including post-
stroke (48%), multiple sclerosis (36.5% to 78%), irritable bowel syndrome (47%),
and many others (D’Silva et al. 2022; Oliva Ramirez et al. 2021; Alghamdi et al.
2021). Also, the odds of severe fatigue increases as the number of chronic conditions
284 A. Boruch et al.

increases; in one study, the odds of severe fatigue was 1.6 (95% CI,1.5–1.7) in those
with one chronic condition and the odds increased to 5.5 (95% CI, 4.5–6.7) for those
with four chronic conditions (Goërtz et al. 2021). When strict diagnostic criteria are
used, such as with the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) (Regier et al. 2013), the prevalence of fatigue is typically lower.
For example, a systematic review of epidemiological studies of Myalgic Encepha-
lomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe identified only a few
studies, two of adults and one of adolescents (Estévez-López et al. 2020). This
research reported that the prevalence of ME/CFS ranged from 0.1% to 2.2%
(Estévez-López et al. 2020). A separate review of ME/CFS studies with broader
inclusion criteria reported a mean prevalence of 1.4 (± 1.6%) based on data from
46 studies that involved over one million participants (Lim et al. 2020a). Gulf War
illness (GWI), a disease involving multiple and diverse symptoms similar to
ME/CFS, has been estimated to affect ~30% of the nearly 700,000 Veterans
deployed to the Persian Gulf War (United States Department of Veterans Affairs
2008). Based on the make-up of active-duty U.S. military personnel and those
deployed to the Persian Gulf (~7% women), GWI affects mainly men who were
deployed during Operations Dessert Shield and Storm. The global prevalence of
post-acute sequelae of SARS CoV-2 infection (i.e., Long-COVID) has been esti-
mated at 43% (95% CI: 39% to 46%) based on data from 41 studies that involved
over one million COVID-19 positive patients. Among the symptoms assessed,
fatigue was the most prevalent with an estimate of 23% (95% CI: 17% to 30%)
(Chen et al. 2022).
Regardless of the timeframe, the prevalence of fatigue is usually higher in
samples of women compared to men (Stavem et al. 2021; Reeves et al. 2007;
Friedberg et al. 2015). A recent study found that the odds of suffering from fatigue
was 1.4 (95% CI, 1.3–1.6) times higher for women than men and this magnitude of
group difference is generally consistent with other studies. Elevated symptoms of
fatigue are associated with an increased risk of mortality; for example, a 20-year
prospective population study of more than 18,000 European men and women from
40 to 79 years found a 1.4 (95% CI, 1.25–1.56) times greater probability of death
during the follow-up period compared to those reporting low fatigue symptoms
(Basu et al. 2016).
The healthcare, societal, personal, and financial costs of fatigue are substantial.
The economic impact of ME/CFS in the United States alone has been estimated to be
36 to 51 billion dollars annually (Jason and Mirin 2021). The economic impact of
Long-COVID has yet to be fully determined, although a recent update estimated that
the total costs (i.e., healthcare costs, lost wages, reduced quality of life) were
upwards of $3.7 trillion, an increase from the previous estimate of $2.6 trillion
(Cutler 2022). Affordable and accessible techniques with few adverse side effects to
improve fatigue symptoms, such as engagement in physical activity, could have a
considerable, positive public health impact.
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 285

2 Acute Physical Activity and Fatigue Symptoms

in Neurotypical Adults

2.1 Summary of Acute Studies with Neurotypical Participants

Most of the investigations into the effect of a single bout of exercise on feelings of
energy and fatigue have tested college students before and after performing a single
cycle ergometry session for about 20 to 40 min. These exercise bouts are usually in a
laboratory setting with comparisons made to a seated control condition involving
either little cognitive activity (quiet rest) or a range of cognitive engagements such as
coloring, playing videos, or listening to a lecture (Cooper et al. 2022; Arent et al.
2007). A meta-analysis of studies of this type found that low-to-moderate intensity
aerobic type exercise typically results in transient increases in feelings of energy
with a standardized mean effect of 0.47 (95% CI, 0.39–0.56) (Loy et al. 2013). Other
experiments have examined the influence of weightlifting on feelings of energy and
fatigue and found similar results (Herring and O'Connor 2009; Bartholomew et al.
2005). When a sample of pregnant women reported symptoms before and after
24 separate low-to-moderate intensity weight lifting sessions, perceptions of phys-
ical and mental energy were consistently increased while perceptions of physical and
mental fatigue were consistently decreased (Ward-Ritacco et al. 2016). Overall, the
evidence suggests that low-to-moderate intensity acute exercise improves feelings of
energy and fatigue transiently for about 85% of individuals tested and across about
85% of workouts. The size of the effect is typically larger for measures of feelings of
energy compared to measures of feelings of fatigue.
There appears to be no single experiment in which intensity and duration have
been systematically manipulated for the purpose of examine interactions between
intensity and duration. Acute exercise intensity and duration both affect feelings of
energy and fatigue. A single bout of high intensity exercise can produce increased
feelings of fatigue and reduced feelings of energy. These changes appear to depend
on the relative exercise intensity such that greater fatigue is produced when the
intensity exceeds anaerobic threshold and approaches an individual’s peak capacity
(Monroe et al. 2016). Intensities above anaerobic threshold cannot be maintained,
consequently it is not possible to test long duration high intensity efforts through the
same range of durations that are possible with low intensity exercise which can be
endured longer (Yoshida 1984). Fatigue does not appear to accrue if the exercise
intensity is high but the duration is quite short, such as with a single bout of high
intensity cycling lasting 30 s or less (Monroe et al. 2016). However, competitive and
recreational exercisers who engage in single workouts that include multiple, repeated
near-maximal sprints, often from 30 s to several minutes duration, with short rest
periods do show large increases in feelings of fatigue (Costello et al. 2022). In
general, as the intensity is maintained at a high level and the total duration is
lengthened or the rest interval is reduced, there is an increased likelihood of elevated
feelings of fatigue. For example, studies comparing a bout of high intensity interval
exercise to a bout of moderate intensity continuous exercise find that there is lower
286 A. Boruch et al.

fatigue during the moderate intensity exercise (Greene et al. 2023). In popular
recreational and competitive events, such as a 5-K, 10-K, and 42-K runs, anecdotal
evidence supports that feelings of fatigue are elevated and gradually increase as the
duration of the activity lengthens if a high effort is maintained. Also, we hypothesize
the feelings of fatigue can take longer to return to the pre-exercise baseline level with
higher intensities and longer durations when a high effort is maintained as has been
shown with feelings of effort and pain during recovery (Cook et al. 1997).
Individual characteristics may moderate the influence of acute exercise on feel-
ings of energy and fatigue. Post-exercise improvements in feelings of energy and
fatigue were larger for females compared to males after a 30-min bout of vigorous
treadmill running compared to a quiet rest control condition (McDowell et al. 2016).
In a sample of patients with a depressive disorder, treadmill running for 25 min at a
moderate-to-high intensity increased feelings of fatigue 30-min post-exercise com-
pared to controls. The authors contended, if the findings are replicable and general-
izable, this mood shift could contribute to the known reduced physical activity levels
among depressed patients compared to controls (Weinstein et al. 2010). In contrast,
20 min of both moderate and preferred intensity cycling exercise reduced feelings of
fatigue at both 10- and 30-min post-exercise in women with major depressive
disorder (Meyer et al. 2019). Vigorous cycling for 20 min induced large increases
in feelings of energy compared to a sitting control condition in a sample of young
men characterized by elevated ADHD symptoms. The differences between exercise
and control were large when assessed 3-min post-exercise, moderate when assessed
40-min post-exercise, and small when assessed 75-min after exercise (Fritz and
O’Connor 2016). The findings above from single experiments above require repli-
cation before strong conclusions about individual characteristic moderators can be
drawn.
The potential moderating role of the environment on the extent to which acute
exercise influences feelings of energy and fatigue has been inadequately explored. A
recent review stated that definitive conclusions could not be drawn regarding the
effect of most countermeasures against mental fatigue, including exposures to
elements that might co-occur during exercise such as music or odors (Proost et al.
2022). Another example is whether exercising outdoors enhances the positive mood-
altering effects compared to indoor exercise. These comparisons are challenging to
interpret because of the multitude of outdoor elements that could influence feelings
of energy and fatigue (e.g., observers, traffic, safety concerns, pollution, noise,
variations in sunlight). To date, results from a limited number of studies have been
mixed with some showing approximately the same change in feelings of energy or
fatigue occurring after outdoor exercise compared to indoor exercise (Legrand et al.
2018; Focht 2009), while other studies finding small-to-moderate augmentation in
improvements in feelings of energy or fatigue following exercise performed out-
doors or indoors during bright light exposure (LaCaille et al. 2004; O'Brien and
O’Connor 2000).
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 287

2.2 Evidence Regarding Plausible Mechanisms

Relatively few studies have focused on the potential mechanisms by which a single
bout of exercise could influence feelings of fatigue; however, there is strong evi-
dence that acute exercise has widespread effects on the brain, which could support
exercise-induced changes in symptom states. Evidence from microdialysis studies
have revealed that acute exercise in rodents results in increased brain levels of
monoaminergic transmitters such as norepinephrine and dopamine (Meeusen et al.
2001), and some of these observations have been confirmed in humans using
radiolabeled non-invasive brain imaging techniques (Boecker and Drzezga 2016).
These findings are relevant, given that animal and human psychopharmacology
investigations suggest that feelings of energy and fatigue can change in response
to alterations in neural circuits involving monoamine, acetylcholine, and histamine
neurotransmission (Meeusen et al. 2001; Loy and O'Connor 2016; Stahl 2002).
Anatomically, there are diffuse norepinephrine, dopamine, acetylcholine, serotonin,
and histamine projections to the cortex that have been hypothesized to regulate
feelings of fatigue. Many other variables could be involved, including inhibitory
neurotransmitters such as gamma-aminobutyric acid (GABA), neurotrophic factors
such as brain-derived neurotrophic factor (BDNF), neuropeptides (endorphins,
galanin), gases (nitric oxide), and other signaling molecules (Dishman and O'Connor
2009; Basso and Suzuki 2017).
Several investigations have explored relationships between exercise-induced
changes in brain electrocortical signals and changes in feelings of fatigue
(Petruzzello et al. 2001; Woo et al. 2009). One of these experiments examined
acute exercise across weeks 1, 3, and 6 of a 6-week training program in a sample
of young adults with elevated symptoms of fatigue. Fatigue symptoms were
improved after low intensity exercise on weeks 3 and 6 while feelings of energy
were improved at all three measurement periods. About 50% of the improvement in
feelings of energy with acute exercise was accounted for by changes in EEG in the
theta frequency range measured in the posterior part of the brain (Dishman et al.
2010).
One approach to understanding the potential role of specific neurotransmitters in
causing exercise-induced changes in fatigue symptoms is to administer drugs that
specifically target neurotransmitters of interest. One experiment had female partic-
ipants consume doxepin, a drug that blocks histamine H1 receptors, prior to cycling
at a low intensity for 30 min. On a separate occasion, the participants consumed a
placebo prior to an identical exercise bout. Feelings of energy changed similarly in
both conditions while mental fatigue increased only for the doxepin condition. It was
concluded that exercise-induced changes in brain histamine binding play a role in
post-exercise changes in feelings of fatigue but not energy (Loy and O'Connor
2016).
Neuromodulators also could play a role in causing exercise-induced changes in
feelings of fatigue. The endocannabinoid system is a large network of chemical
signals and receptors that is involved in the regulation of many bodily functions,
288 A. Boruch et al.

including sleep, pain, immune responses, and mood (Zou and Kumar 2018; Raichlen
et al. 2012; Brellenthin et al. 2017; Crombie et al. 2018). At least one investigation
has implicated endocannabinoids in positive improvements in feelings of fatigue
after exercise. This study reported improvements in feelings of fatigue 10 to 30 min
after a single bout of cycling exercise at a moderate and self-selected preferred
intensity were significantly associated with changes in serum endocannabinoid
levels in a sample of depressed women (Meyer et al. 2019). A separate study
among people with post-traumatic stress disorder and elevated depression symptoms
failed to find a significant relationship between endocannabinoids and fatigue
(Botsford et al. 2023).
Improvements in self-reported feelings of fatigue after a single session of exercise
might be partly a placebo response (Szabo 2013) (see Chapter 19: “The Placebo
Effect in Exercise and Mental Health Research” for comprehensive overview). This
idea has been tested experimentally at least once (Lindheimer et al. 2017a). Partic-
ipants completed very low intensity exercise for 25 min on a semi-recumbent cycle
ergometer. Active cycling was compared to passive cycling (the “exercise placebo”)
in which equipment moved participants legs for them. Some participants were told
by a research confederate prior to exercise about the expected psychological benefits
of acute exercise while others were not. Active cyclists told about the benefits of
exercise showed larger improvements in feelings of energy after exercise compared
to the active cyclists not given this information. Also, the improvements in feelings
of energy after exercise were smaller after the placebo condition despite the condi-
tions being matched on energy expenditure. While these effects were not statistically
significant, arguably because of the low exercise intensity (35%), the findings
support pursuing further research aimed at understanding fatigue symptom improve-
ments after acute exercise as partially placebo responses.

3 Acute Physical Activity and Fatigue Symptoms: ME/CFS,

GWI, and Long-COVID

3.1 Summary of Acute Studies: E.g., Extent

of Post-Exertional Malaise

When fatigue is the defining feature of a disease, the relationships between physical
activity and fatigue feelings change. Unlike the fatigue reducing and energy enhanc-
ing potential of acute exercise in neurotypical adults, fatigue is more often worsened
along with other disease defining symptoms including pain, concentration/memory
(i.e., brain fog), and unrefreshing sleep. This is the case for diseases such as
ME/CFS, GWI, and Long-COVID (Chu et al. 2018; Khan et al. 2004; Nehme
et al. 2023; Thaweethai et al. 2023). Collectively, ME/CFS, GWI, and Long-
COVID can be broadly considered as chronic multisymptom illnesses (CMIs)
(Fukuda et al. 1998), although the heterogeneity within and between these distinct
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 289

diagnostic entities is high and each disease has unique case definitions (Thaweethai
et al. 2023; Carruthers et al. 2003; Fukuda et al. 1994; Clayton 2015; Shine et al.
2014; Steele 2000).
The phenomenon of symptom worsening (e.g., increased fatigue) consequent to
physical and/or mental challenge has been termed post-exertional malaise (PEM)
(Clayton 2015) and is considered a cardinal feature of CMIs (Clayton 2015; Steele
2000; Brown and Jason 2020; Davis et al. 2021; Fappiano and Baraniuk 2020).
Although no consensus definition has been agreed upon, PEM is characterized by
symptom exacerbation across a host of domains (e.g., fatigue, pain, cognition)
following physical and/or mental exertion and is considered one of the most inca-
pacitating aspects of these diseases. The presence of PEM is required for a diagnosis
of ME/CFS, but not for either GWI or Long-COVID. Patient-based survey data
indicate that between 78% and 99% (143/144) of people with ME/CFS experience
symptom worsening triggered by physical exertion (Chu et al. 2018; Holtzman et al.
2019). Fatigue was the most frequently reported symptom (88%–94%), followed by
poor concentration, difficulty thinking, poor memory, and cognitive exhaustion
(63%–90%), sleep disturbance/unrefreshing sleep (68%–81%), muscle pain (69%–
74%), and flu-like symptoms (58%–59%). The onset of symptoms has been reported
to vary between hours and weeks, with the most frequent symptom onset time being
1–2 days (Holtzman et al. 2019). Prevalence of PEM in other CMIs is comparable to
ME/CFS, ranging from 70%–96% in GWI (Khan et al. 2004; Fappiano and Baraniuk
2020) and 86% in Long-COVID (Davis et al. 2021), although characteristics of
symptom type (e.g., fatigue, pain, brain fog), onset, and duration are less well
understood.
When tested in controlled laboratory settings, the occurrence of fatigue worsening
after exercise in CMIs is more variable, although still the most common symptom
(Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis et al. 2015).
Measurement and design issues including symptom heterogeneity, limited measure-
ment of associated symptoms, poor control over quantification of the exercise
stimulus, symptom ceiling effects, and lack of control conditions have limited better
understanding of the impact of exercise of various types, severities, and durations on
PEM (Loy et al. 2016; Lindheimer et al. 2017b, 2020). Despite these limitations,
meta-analytic estimates indicate moderate-to-large effects (0.73; 95% CI:
0.24 to 1.23) of acute exercise on ratings of fatigue in ME/CFS (Loy et al. 2016);
effects that are opposite to that observed in non-ME/CFS conditions (Loy et al.
2013).
Acute exercise studies of PEM are typically conducted using case–control
designs where the CMI sample of interest (i.e., ME/CFS, GWI, & Long-COVID)
is compared to a control group. Symptom questionnaires (e.g., Fatigue Severity
Scale (FSS; (Krupp et al. 1989)), POMS (McNair et al. 1981), SF-36 (Ware 2000)
are administered at variable times (i.e., days to minutes) prior to exercise and then
again at variable times during (e.g., mid-point and peak) and after (i.e., immediately,
minutes, hours, days) exercise (Loy et al. 2016; Lindheimer et al. 2020). Most
studies use aerobic exercise on a cycle ergometer for a duration of 25–30 min at
70–75% of age-predicted maximal heart rate or heart rate reserve (HRR) for
290 A. Boruch et al.

submaximal exercise, or until volitional exhaustion for maximal exercise (Loy et al.
2016; Lindheimer et al. 2017b, 2020; Boruch et al. 2021). To date, this research has
been conducted in ME/CFS and GWI; however, exercise research for people with
Long-COVID is emerging (Durstenfeld et al. 2022; Joseph et al. 2021, 2023;
Mancini et al. 2021; Singh et al. 2022). Future studies that incorporate symptom
measurement before and after acute exercise in Long-COVID samples are needed.
Exercise intensity and duration have variable effects on fatigue in CMIs. Thirty
minutes of intermittent treadmill exercise (i.e., 3 min of exercise and 3 min of rest) at
a self-selected pace did not worsen fatigue in ME/CFS; however, this study did not
have a control group (Clapp et al. 1999). In contrast, both 30 min of treadmill
walking at 1-mph and serial six-minute walk tests have been shown to worsen
fatigue for ME/CFS but not controls (Peterson et al. 1994; Friedberg et al. 2023).
Prolonged increases in fatigue have been reported for acute exercise protocols
ranging from moderate-to-high intensity in both ME/CFS and GWI (Lindheimer
et al. 2017b, 2020; Boruch et al. 2021, 2023; Light et al. 2009, 2012; White et al.
2010; Meyer et al. 2013). Twenty-five minutes of combined leg- and arm-ergometry
at 70% maximal heart rate resulted in large fatigue increases at 30 min, 8-, 24- and
48-h post-exercise in ME/CFS compared to controls (White et al. 2010). Thirty
minutes of daytime cycling at 70% of HRR resulted induced large symptom
increases in GWI; however, the most frequently reported symptoms were sleep
related (i.e., “difficulty getting to sleep” and “unrefreshing sleep”: 18/43, 41.9%),
followed by musculoskeletal pain (9/43, 20.9%), headache (8/43, 18.6%), difficulty
with memory (4/43, 9.3%), fatigue (3/43 6.9%), and nausea (1/43, 2.3%) (Boruch
et al. 2021). Maximal exercise to volitional exhaustion has been reported to worsen
fatigue ranging from 24 h to over 10 days in ME/CFS (Lindheimer et al. 2017b;
Meyer et al. 2013; Bazelmans et al. 2005; Van Ness et al. 2010; Moore et al. 2023).
When two maximal exercise tests were conducted 24-h apart (i.e., 2-Day cardiopul-
monary exercise test (CPET)), ME/CFS participants reported greater symptom
exacerbation compared to controls and took an average of two weeks to recover
compared to two days for controls (Moore et al. 2023). A meta-analysis of PEM in
ME/CFS found that six out of seven studies showed that post-exercise fatigue
increases were larger in ME/CFS compared to healthy controls (Loy et al. 2016).
Significant univariate effect sizes were found for moderate (0.955; 95% CI:
0.795 to 1.115) and high (0.618; 95% CI: 0.305 to 0.931) intensity exercise, but
not light intensity exercise (0.081; 95% CI: -0.402 to 0.565). Fatigue differences
were found at a minimum of 4- and up to 96-h post-exercise suggestive of a delayed
and variable response.
The variability of PEM has been examined by a few studies. In ME/CFS, focus
group interviews involving 43 patients revealed PEM responses that covered six
categories (i.e., General, Cognitive, Neuromuscular Complaints, Sensory, Affect, &
Ear, Nose, Throat) and 24 symptoms. Exhaustion was the most reported symptom
response to exercise with variable onsets (2 to 48 h) and durations (up to 14 days)
(Stussman et al. 2020). One study comparing maximal and submaximal exercise
responses in ME/CFS found that pain, but not fatigue, was worsened at 24-h post
submaximal exercise (Lindheimer et al. 2017b). Maximal exercise symptom
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 291

responses differed from submaximal showing large increases in fatigue at 72 h, but

not 48 h, post-exercise. Moreover, dot-density plots indicated high within-group
variability for both maximal and submaximal symptom responses (Lindheimer et al.
2017b). Baseline symptom severity may also affect post-exertional fatigue. In
ME/CFS, symptom exacerbation following a 1- or 2-Day CPET test post-exercise
was related to baseline symptom severity (Stussman et al. 2020). Conversely,
recovery time following a 2-Day CPET test was not predicted by baseline symptom
severity (Moore et al. 2023). In GWI, multivariate modeling of PEM responses to
30 min of submaximal exercise at 70% of HRR did not show symptom worsening.
However, subgroup analyses involving only those Veterans who endorsed “feeling
unwell after physical exercise or exertion” at study intake revealed exacerbation of
pain- and GWI-related symptoms (Lindheimer et al. 2020). A follow-up study
reported that peak symptom responses for this group of Gulf War Veterans occurred
at 48 h post-exercise for most GWI participants yet ranged from 24 h to 7 days
(Boruch et al. 2021).
Sex differences in post-exertional fatigue ratings are currently understudied
primarily due to the make-up of the population’s studied (i.e., ME/CFS predomi-
nantly female, GWI predominantly male) and resultant difficulties in recruiting
adequate samples of both female and male participants. In one ME/CFS study, sex
differences in post-exercise fatigue and function following a 6-min walk test were
found only for female ME/CFS participants (Friedberg et al. 2023). There are
currently no studies investigating sex differences on post-exertional fatigue in
GWI, yet baseline symptoms are more variable and severe for female Veterans
compared to male Veterans (Dursa et al. 2019; Heboyan et al. 2019; Sullivan et al.
2020). Currently, there are no Long-COVID studies of PEM. A global meta-analysis
estimated pooled post-COVID-19 condition prevalence rates of 49% (95% CI: 35%
to 63%) for females and 37% (95% CI: 24% to 51%) for males (Chen et al. 2022).
These data suggest that future PEM research testing for potential sex differences in
Long-COVID may be more feasible than either ME/CFS or GWI.
Fatigue is one of many symptoms worsened with exercise in CMIs. Current data
suggest acute exercise fatigue responses vary as a function of exercise intensity and
duration, are highly variable with respect to symptom onset, intensity, and duration,
and are somewhat dependent on whether PEM is endorsed at study intake. Exper-
iments testing the consequences of different exercise doses and modes between male
and female participants and compared to non-exercise control conditions are needed.

3.2 Evidence Regarding Plausible Mechanisms

The biological mechanisms that underlie PEM are not well understood; however,
acute exercise has been used extensively to explore numerous physiological systems
and biological markers. Both maximal and submaximal exercise protocols have been
used to determine behavioral and physiological consequences of acute exercise
challenge. These studies have demonstrated symptom exacerbation of variable
292 A. Boruch et al.

intensity, type, and duration (White et al. 2010; Barhorst et al. 2021), inefficient/
impaired cardiopulmonary responses to acute exercise (Joseph et al. 2023; Cook
et al. 2022; Lindheimer et al. 2019), impaired pain regulation (Van Oosterwijck et al.
2010), altered immune function markers (e.g., cytokines, compliment c4, natural
killer cells) (Light et al. 2012; Meyer et al. 2013; Smylie et al. 2013; Moneghetti
et al. 2018); changes in gut microbiome interactions (Shukla et al. 2015), disruption
of metabolites (Baraniuk et al. 2021; Germain et al. 2020), and altered brain function
(Cook et al. 2017; Rayhan and Baraniuk 2021; Washington et al. 2020). It is clear
from these studies that exercise differentially influences multiple physiological
systems in CMIs. Although exercise has been used extensively to study disease
pathophysiology, few studies have directly tested the associations between the
physiological and behavioral manifestations of PEM. Thus, the extent that putative
biomarkers of disease cause symptom exacerbation is largely unknown.
Blood-based biomarkers including those involving immune, metabolic, viral, and
other agents have been tested in multiple CMI exercise studies, but with no clear
pattern. In response to a 25-min submaximal exercise test, ME/CFS participants
exhibited greater gene expression changes in leukocytes for metabolic detecting
receptors (ASIC3, P2X4, and P2X5), adrenergic function (⍺-2A, β-1, β-2, &
COMT), and immune function (IL-10, TLR4) compared to healthy controls (Light
et al. 2009). These differences were observed at 30-min, 8-h, 24-h, and 48-h post-
exercise and were significantly correlated with increased physical and mental
fatigue. Similarly, maximal exercise was found to increase adrenergic α-2A receptor
and nuclear receptor subfamily 3 (NR3C1) gene expression that were positively
correlated with post-exercise fatigue (Meyer et al. 2013). These results suggest post-
exertional fatigue may be associated with dysfunction of the hypothalamic-pituitary-
adrenal axis, abnormal immune or stress response, and alterations of peripheral
sensory signaling. Contrary to the results from ME/CFS samples, gene expression
to submaximal exercise for adrenergic, metabolic, and immune-related receptors was
found to decrease in GWI samples and was not predictive of post-exercise symptom
exacerbation (Boruch et al. 2023).
Two-Day CPET protocols have been used to study transcriptomic, virome, and
metabolomic composition/pathways (Bouquet et al. 2019; Germain et al. 2022). No
differentially expressed genes related to immune signaling in response to exercise
were found in ME/CFS compared to controls. Further, neither viral composition nor
number of reads were associated with PEM (Bouquet et al. 2019). Numerous
metabolite differences representing numerous pathways (e.g., fatty-acid metabolism,
glycolysis, glutamate synthesis, carnitine synthesis) were found post-exercise in
sample of 60 ME/CFS (45 female, 15 male) and 45 controls (30 female, 15 male);
however, relationships with PEM symptoms were not directly tested (Germain et al.
2022).
Abnormal cardiopulmonary responses to exercise have been found for ME/CFS,
GWI, and Long-COVID groups. These studies have found abnormal breathing
patterns (Mancini et al. 2021; Lindheimer et al. 2019; Alexander et al. 2023),
reduced ventilatory efficiency (Boruch et al. 2021; Joseph et al. 2023; Cook et al.
2022), impaired venous return and oxygen extraction (Joseph et al. 2021; Singh et al.
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 293

2022), and reduced exercise capacity (Durstenfeld et al. 2022; Lim et al. 2020b).
Moreover, 2-Day CPET protocols have revealed an inability of ME/CFS samples to
reproduce exercise outcomes such as power output at ventilatory threshold (Lim
et al. 2020b). These abnormal responses could help explain why exercise worsens
fatigue in CMIs; however, this has rarely been directly tested. One study of
submaximal exercise reported that neither symptom nor cardiopulmonary responses
during submaximal exercise were predictive of PEM in GWI (Boruch et al. 2021).
PEM was defined as the peak symptom change from baseline in the 7 days following
exercise. A general linear model including cumulative work (kJ), peak leg muscle
pain during exercise, the Physical Component Score of the Veterans R and 36-item
Health Survey, and the ventilatory equivalents for carbon dioxide (VE/VCO2) was
not predictive of symptom responses to exercise. Although the total model was not
predictive of PEM, both VE/VCO2 (Pearson r = 0.31, 95% CI = 0.01, 0.56,
p = 0.05) and leg muscle pain (Pearson r = 0.31, 95% CI = 0.01, 0.55, p < 0.05)
were significantly correlated with peak symptom responses.
Dysfunction of the gut microbiota has also been proposed to contribute to PEM.
Early studies reported baseline differences between ME/CFS and controls (Lakhan
and Kirchgessner 2010), with irritable bowel syndrome (IBS) being a common
comorbidity in ME/CFS (Riedl et al. 2008). Individuals with comorbid IBS and
ME/CFS were found to report more severe fatigue compared to ME/CFS but not IBS
(Lakhan and Kirchgessner 2010). The hypothesis that gut dysbiosis and bacterial
translocation could contribute to PEM was examined in a small sample of ME/CFS
(n = 10) and controls (n = 10) in response to maximal exercise (Shukla et al. 2015).
Enteric (gut) bacterial concentrations and makeups in both stool and blood samples
were measured before, 15 min, 48 and 72 h following exercise. ME/CFS showed
greater increases for both stool and blood enteric bacterial concentration and
makeups, which remained elevated at 72-h post-exercise suggestive of delayed
blood clearance (Shukla et al., 2015). This co-occurred with large changes in fatigue
over the same timeframe (i.e., 72-h post-exercise). These findings suggest the
exercise-induced translocation of enteric bacteria may trigger systemic inflammation
and fatigue worsening in ME/CFS.
Post-exercise worsening of fatigue could be emblematic of central nervous
system dysfunction. Both self-paced and submaximal exercise were found to
decrease pressure pain thresholds in ME/CFS compared to increases for controls
(Van Oosterwijck et al. 2010). Changes in pressure pain thresholds were signifi-
cantly and positively associated with fatigue changes. Functional brain responses
during fatiguing cognition have been shown to be associated with symptom wors-
ening in ME/CFS (Cook et al. 2017). ME/CFS patients and controls completed
symptom assessments and functional magnetic resonance imaging while performing
non-fatiguing (finger-tapping and simple number recognition) and fatiguing cogni-
tive tasks (paced auditory serial addition task). Testing occurred at baseline and 24 h
after 30 min of exercise at 70% of peak HR. Differential patterns of brain responses
to the fatiguing cognitive task were found and were characterized by greater activity
in bilateral hippocampus, left frontal, and cingulate cortices, and decreased activity
in superior and inferior parietal cortices for ME/CFS compared to controls. No
294 A. Boruch et al.

differential brain responses occurred during the non-fatiguing tasks. Symptoms and
cognitive performance worsened for ME/CFS but improved for controls.
Symptom worsening with physical exertion in CMIs is opposite to the normal
beneficial responses experienced by healthy people and therefore suggests physio-
logical dysregulation. Although numerous physiological systems are differentially
affected in ME/CFS, GWI, and Long-COVID, whether these differences cause
symptom exacerbation (i.e., fatigue and other symptoms) is unknown. Research
that determines whether select physiological systems are significantly predictive of
symptom worsening is needed to begin pinpointing the pathophysiology of PEM,
and perhaps CMIs. Moreover, efficacious treatments for CMIs, when discovered,
could aid this effort by testing whether treatment mechanisms and symptom
improvement reduce or eliminate PEM responses.

4 Chronic Physical Activity and Fatigue Symptoms

in Neurotypical Adults
4.1 Summary of Chronic Exercise Training Studies
with Neurotypical Participants

Numerous reviews have examined research aimed at understanding relationships

between regular physical activity and symptoms of fatigue and/or energy (Puetz
et al. 2006; Puetz 2006; O'Connor et al. 2010; O'Connor and Puetz 2005). Some of
these reviews have focused on patients with specific chronic conditions such as
arthritis (Rongen-van Dartel et al. 2015), cancer-related fatigue (Tomlinson et al.
2014), fibromyalgia (Estévez-López et al. 2020), multiple sclerosis (Pilutti et al.
2013; Razazian et al. 2020), or specific sub-types of cancers such as breast (Medeiros
Torres et al. 2022) or gynecologic cancer (Ma et al. 2023). Most of these reviews
show that exercise training results in small positive improvements in fatigue symp-
toms though there are some exceptions, often when the number of studies included is
relatively small (Paneroni et al. 2020). There are few experiments directly comparing
exercise training to an alternative method for potentially improving fatigue symp-
toms. One meta-analysis found that among cancer patients, regular exercise yielded
larger improvements than the pharmacological therapies tested. Moreover, the
exercise training effect on improving fatigue symptoms was equivalent to psycho-
logical treatments such as cognitive behavioral therapy (Mustian et al. 2017).
A meta-analysis published in 2022 represents a comprehensive review of ran-
domized controlled trials, which are considered the strongest type of evidence
(Wender et al. 2022). This investigation revealed that the influence of chronic
exercise on symptoms of fatigue and energy has been examined in at least 81 ran-
domized controlled trials. These experiments involved over 7000 participants who
were predominantly mid-aged (mean of 50 years old) women (~70%) with a variety
of health problems, most commonly cancer, heart disease, and neuropsychological
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 295

concerns such as multiple sclerosis or fibromyalgia. The exercise interventions were

typically about 3 months long and usually involved three sessions per week, each
lasting about 45 min. About 82% of the investigations involved moderate intensity
exercise bouts. About 36% of the investigations focused on aerobic exercise modes,
about 10% used yoga, about 20% focused on resistance training, and 32% used a
combination of both resistance and aerobic type exercise. Symptoms were catego-
rized into feelings of energy or fatigue as well as vitality, which combines energy
and fatigue questions into a single score, because the vitality scale of the SF-36
Health Survey was so frequently used as an outcome measure.
Across all of these trials, regular exercise resulted in moderate sized improve-
ments in vitality; the mean standardized effect size g equaled = 0.54 and the 95%
confidence interval did not overlap zero (0.40, 0.67). Regular exercise resulted in
smaller, statistically significant, increases in feelings of energy (g = 0.42; 95% CI of
0.25 to 0.58) and reductions in feelings of fatigue (g = -0.37; 95% CI of -0.52 to -
0.23). The authors concluded that “when groups adopt a moderate intensity exercise
training program while participating in a randomized trial, compared to controls, this
typically results in small-to-moderate average improvements in feelings of fatigue,
energy, and vitality” (Wender et al. 2022).
This comprehensive quantitative review identified several meaningful moderators
of the chronic exercise effects (Wender et al. 2022). For feelings of fatigue, larger
improvements were found for moderate compared to low intensity exercise as well
as for longer exercise sessions and greater weeks of exercise training. For feelings of
energy, larger improvements were found for moderate compared to low intensity
exercise as well as for resistance exercise mode whether performed alone or in
combination with aerobic exercise. For vitality, larger improvements were found for
low and high intensity compared to moderate intensity. The small number of high
and low intensity trials means that more data are needed before treating this finding
without caution. Also, for vitality, larger improvements were found for neurological/
psychological samples compared to samples with cancer. Larger improvements in
vitality also were found for exercise completed under supervision in a facility and
when resistance exercise was combined with aerobic exercise modes. In summary,
these observations are potentially useful for practitioners prescribing exercise pro-
grams to reduce symptoms of fatigue and enhance feelings of energy. To date,
demographic and clinical characteristics have not been found to moderate the effects
of exercise on fatigue (van Vulpen et al. 2020).

4.2 Evidence Regarding Plausible Mechanisms

There is a paucity of research testing specific mechanisms by which regular physical

activity plausibly could cause improvements in feelings of energy and fatigue.
Regular physical activity may cause adaptations in neural circuits that underlie
feelings of energy and/or fatigue (Salamone and Correa 2024). Also, regular phys-
ical activity may have positive effects on behavior, such as improved sleep (Kline
296 A. Boruch et al.

et al. 2021), or peripheral physiology, such as a favorable impact on hematocrit or

hemoglobin in cancer patients (Courneya et al. 2008), that might help to improve
fatigue or energy symptoms. Alternatively, because symptoms are self-reported
exercise-induced placebo responses cannot be ruled out, and one review estimated
that about half of the psychological response to exercise training appears to be
attributable to placebo responses (Lindheimer et al. 2015). The absence of better
data regarding mechanisms that could explain improvements in symptoms of energy
and fatigue after the adoption of regular physical activity performed by neurotypical
adults and patients with variety of medical illnesses is a major limitation in this
literature and represents the greatest need regarding research in this area going
forward.

5 Chronic Physical Activity and Fatigue Symptoms:

ME/CFS, GWI, and Long-COVID

5.1 Summary of Chronic Exercise Training Studies

The occurrence of PEM complicates using regular physical activity as a fatigue

treatment for CMIs. People with CMI report avoiding physical activity to limit
symptom worsening and this avoidance behavior, sometimes termed kinesiophobia,
has been shown to be associated with reduced self-reported physical activity in at
least one study (Nijs et al. 2004). Physical activity pacing, a process whereby the
person determines and adjusts the level of activity that they can tolerate without
exacerbating symptoms, has been proposed as one strategy to avoid PEM in
ME/CFS (Casson et al. 2022; Goudsmit et al. 2012). A meta-analysis of eleven
pacing studies in ME/CFS reported moderate (g = -0.52; 95% CI of -0.73, -0.32)
fatigue reductions (Casson et al. 2022). However, there is a paucity of pacing studies
involving GWI and Long-COVID. Notably, this approach differs from graded
exercise therapy (GET) studies where progression of the exercise training dose is
typical; although pauses in progression are common in CMI studies when symptom
worsening occurs. Regular physical activity research in CMIs largely almost uni-
formly uses the phrase graded exercise therapy (GET), and therefore this section will
adopt that terminology for consistency with the literature.
One early randomized controlled trial (RCTs) for people with ME/CFS compared
GET to flexibility training combined with relaxation therapy (Fulcher and White
1997). Twelve weeks of supervised exercise, prescribed at an intensity of 50%–60%
of individual maximum heart rate, significantly improved fatigue compared to
flexibility training plus relaxation therapy. Attrition due to symptom exacerbation
occurred for only one participant from each treatment. More than a decade later, a
meta-analysis compared the efficacy of GET and cognitive behavioral therapy
(CBT) for fatigue and other health-related outcomes in ME/CFS (Castell et al.
2011). A total of N = 21 studies (GET: N = 5 studies, sample size = 170; CBT:
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 297

N = 16 studies, sample size = 1457) included both fatigue and functional impair-
ment related outcomes. Both GET and CBT had small-to-moderate effects for
reducing fatigue (GET: g = 0.41, 95% CI = 0.06, 0.77; CBT: g = 0.36, 95%
CI = 0.25, 0.46) and functional impairment (GET: g = 0.39, 95% CI = 0.23,
0.56; CBT: g = 0.36, 95% CI = 0.26, 0.47). Heterogeneity was greater for GET
(I2 = 62) than CBT (I2 = 27), warranting the need for additional studies that examine
the characteristics of exercise that moderate fatigue and physical function in
ME/CFS. Eight years later a meta-analysis of exercise therapy for ME/CFS (i.e.,
GET) examined studies directly comparing GET to other therapies (Larun et al.
2019). Eight GET trials, involving 1518 participants, and other therapies ranging
from 12 to 26 weeks were included. Exercise intensities were variable across modes
(e.g., walking, swimming, dancing, and cycling). Studies compared GET primarily
to “passive” controls (n = 8 studies) but also to CBT (n = 3), adaptive pacing
(n = 1), and antidepressants (n = 1). Fatigue reductions (d = -0.66, 95% CI = -
1.01, -0.31) and physical function improvements (SF-36 physical functioning
subscale (scale range 0–100) difference of 13.1 points) favored GET compared to
the “passive” control conditions but not when compared to CBT or antidepressants
for which there was much less evidence. The lone active pacing study reported
reduced fatigue in favor of GET (1.99-point difference on the Chalder Fatigue Scale
(scale range 0–33)).
Using a four-arm RCT, one large ME/CFS trial (N = 641 participants) compared
the efficacy of three previously investigated treatment options (i.e., GET (n = 160),
CBT (n = 161), and specialist medical care (n = 160)) with a fourth arm of physical
activity pacing (n = 160) (White et al. 2011). At 52 weeks, all four treatment arms
reduced fatigue (Chalder Fatigue Scale), though only GET (3.2 points, 95%
CI = 1.7, 4.8) and CBT (3.4 points, 95% CI = 1.8, 5.0) resulted in significant
fatigue reductions compared to specialist medical care ( p < 0.05). Moreover, both
GET and CBT resulted in improved physical function (SF-36 GET: 9.4 points, 95%
CI = 4.4, 14.4; SF-36 CBT: 7.1 points, 95% CI = 2.0, 12.1). The synergistic effects
of physical activity and CBT have also been estimated to produce moderate-to-large
(g = 0.72, 95% CI = 0.51, 0.94) fatigue reductions and moderate (g = 0.43, 95%
CI = 0.22, 0.64) depression improvements in ME/CFS (Marques et al. 2015).
The impact of patient engagement was tested in one RCT (Powell et al. 2001).
The 12-week interventions consisted of: 1) a minimum intervention that included
three hours of consultation and GET explanation; 2) a telephone intervention that
included the minimum intervention, plus seven 30-min telephone consultations; and
3) a maximum intervention that included the minimum intervention plus seven
60-min in-person sessions. All three education-based treatment arms significantly
improved fatigue in ME/CFS compared to a standard medical treatment control
group. There were no significant differences between the intervention levels. These
results are consistent with meta-analytic data indicating that minimal contact inter-
ventions (e.g., those minimizing face-to-face contact with the provider) have large
effects (g = 0.96, 95% CI = 0.63, 1.28) on fatigue in ME/CFS samples (Marques
et al. 2015). Fatigue may be influenced by various combinations of the physical,
mental, and social demands of completing an exercise intervention. Moreover,
298 A. Boruch et al.

minimal contact interventions may be more economical options and alleviate bur-
dens (e.g., travel to and from appointments, scheduling conflicts, etc.) for both the
patient and provider. Finally, placebo and/or expectancy responses have not been
adequately studied in exercise training trials of CMIs. The placebo response was
reported to be low in ME/CFS by one review (Cho et al. 2005). This study
determined that among 28 RCTs, the pooled placebo response was 19.6%
(95% CI: 15.4, 23.7).
Exercise interventions have been less well studied in GWI and Long-COVID.
Two trials, one aerobic (Donta et al. 2003) and the other resistance exercise (Stegner
et al. 2021) have been tested in GWI. One large RCT (N = 1092 participants) of
Veterans with GWI investigated the efficacy of aerobic exercise training alone or as
an adjuvant treatment (e.g., in tandem with either CBT or usual standard of care
practices) for improving physical function and GWI symptoms. Participants com-
pleted one supervised exercise training session per week for 12 weeks at a self-
selected intensity. Participants were also instructed to exercise at home two to three
times per week throughout the intervention. Exercise alone and when combined with
CBT improved fatigue, cognitive and mental health outcomes compared to
usual care.
Sixteen weeks of resistance exercise training was found to be both safe and
effective at improving strength and overall illness perceptions in Gulf War Veterans
with widespread and chronic musculoskeletal pain (Stegner et al. 2021). However,
neither fatigue nor pain was found to improve over the course of the intervention or
at 6-month and 12-month follow-up periods. Despite the absence of symptom
improvements, moderate-to-large (g = 0.47 to 0.78) increases in both maximal
strength and training volume occurred. Moreover, there were no adverse events
related to the RET intervention and adherence to training was high (87%, 27.9/32
sessions).
The COVID-19 pandemic drastically affected physical activity as well as phys-
ical and mental health in countries across the world (Aritake et al. 2015). Qualitative
data based on semi-structured interviews of people with Long-COVID identified
prolonged and varied challenges for physical activity engagement including reduced
function, coping with brain fog, and fear of symptom exacerbation (Humphreys et al.
2021). We are aware of one exercise training intervention in Long-COVID compar-
ing 8 weeks of multicomponent (i.e., both aerobic and resistance) exercise to
standard rehabilitation and self-management recommendations of the World Health
Organization (Jimeno-Almazán et al. 2022). Participants performed three sets of
eight repetitions for squat, bench press, deadlift, and bench pull on two days per
week starting at 50% of their one repetition maximum. This was combined with
“moderate intensity variable training” ranging from 55% to 80% of heart rate
reserve. The third day consisted of “light intensity continuous training” for 60 min
at 65%–70% of heart rate reserve. Training progression was individualized and
based on participant tolerance. Compared to the self-management control group,
multicomponent exercise improved fatigue, quality of life, depression, cardiovascu-
lar fitness, and muscular strength. The fatigue improvements were large
(ηp2 = 0.15–0.23) and no adverse events were reported.
Physical Activity and Fatigue Symptoms: Neurotypical Adults and. . . 299

When considering physical activity for people with ME/CFS, clinicians face the
challenge of helping patients avoid the negative effects of acute exercise (e.g.,
symptom exacerbation), while moving them toward experiencing the health benefits
associated with a more physically active lifestyle. A logical approach is to develop
exercise prescriptions which strike a balance between minimizing symptom exacer-
bation and maximizing physical function; however, there is limited information on
the mode, duration, or intensity threshold at which this ideal balance occurs or
guidance on how to establish this threshold for individual patients. It is noteworthy
that organizations such as the American College of Sports Medicine, as part of their
Exercise is Medicine campaign (https://www.exerciseismedicine.org/), have created
exercise prescription materials for similar diseases such as Fibromyalgia (https://
www.exerciseismedicine.org/wp-content/uploads/2021/04/EIM_Rx-for-Health_
Fibromyalgia.pdf). These recommendations are logical in that they emphasize the
individualized nature of exercise prescription and focus on light activity and slow
intensity progression to minimize symptom exacerbation. More research is needed to
determine for whom physical activity is both tolerable and effective for reducing
symptoms, and for whom it may be contraindicated or unsafe.

5.2 Evidence Regarding Plausible Mechanisms of Chronic

Exercise and Fatigue in Atypical Adults

The mechanisms that underlie the small-to-moderate fatigue improvements with

exercise training in CMIs are unknown. Improvements in aerobic fitness and
strength (Fulcher and White 1997; Stegner et al. 2021) suggest that the broad
benefits of exercise training (e.g., more efficient cardiovascular function, increased
aerobic capacity, and improved metabolism) may facilitate fatigue improvements. It
is also plausible that exercise training, when appropriately structured, might posi-
tively affect multiple physiological systems (e.g., central, immune, autonomic, and
gut microbiome) that have been shown to be associated with CMIs. Such responses
might include adaptations to neural circuitry, peripheral and central inflammation,
heart rate, blood pressure, and brain blood flow regulation, and gene methylation.
However, these potential adaptations and their associations with feelings of fatigue
have not been tested.

6 Conclusion

In neurotypical adults and compared to a resting control condition, dozens of

experiments support that a single bout of low-to-moderate intensity exercise for
20 to 40 min almost always results in increased feelings of energy and common, but
less so, are concomitant reductions in feelings of fatigue. Larger effects might be
300 A. Boruch et al.

realized depending on the characteristics of the individual (e.g., presence of a

psychiatric disorder) and the environment (e.g., exercising outdoors with a partner).
High intensity and/or long duration exercise produces increased feelings of fatigue.
For atypical adults (i.e., CMIs), acute exercise under similar circumstances can
worsen fatigue and other associated symptoms. However, the exercise and symptom
responses are highly variable with respect to exercise type, intensity, and duration.
The mechanisms that underlie fatigue responses to acute exercise are not well
understood and are largely untested for chronic exercise training. It is likely that
multiple neural systems and their associated neurotransmitters interact to mediate
feelings of energy and fatigue. In CMIs, dysregulation among multiple physiological
systems, systemic inflammation, and skeletal muscle disuse issues could interact
such that a single bout of exercise produces acute symptom worsening. The small
number of RCT involving chronic physical activity have not reported acute symp-
tom exacerbation in ME/CFS, GWI, or Long-COVID samples, and none have tested
biological mechanisms of treatment responses. This suggests that acute exercise
effects of symptom worsening in CMI should not be uniformly conflated with
chronic exercise training which has not been shown to worsen symptoms. However,
extreme care should be taken when prescribing any physical activity in CMI and
should be tailored based on the individual’s disease status and physical functional
capacity.

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Influence of Regular Physical Activity
on Sleep

Melissa J. McGranahan and Patrick J. O’Connor

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
2 Effects of Regular Physical Activity on Sleep in Apparently Healthy Samples . . . . . . . . . . . 311
3 Effects of Regular Physical Activity on Sleep in People with Selected Sleep
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
4 Effects of Regular Physical Activity on Sleep in Patients with Selected Mental
Illnesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
5 Effects of Regular Physical Activity on Sleep in People with Selected Medical
Illnesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
6 Overtraining in Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
7 Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

Abstract Good sleep and adequate physical activity are essential to health. Yet,
large numbers of people are chronically deficient in sleep and physical activity.
About 1 in 3 Americans get less than 7 h of sleep per night and only 1 of 4 adults
regularly complete weekly physical activity in amounts recommended for good
health. This chapter reviews research that has examined relationships between
regular physical activity and sleep. The overall weight of evidence supports that
regular physical activity is associated with better sleep quality among healthy adults,
with epidemiological studies showing moderate-sized effects and more well-
controlled randomized controlled trial experiments often showing larger effects.
Large epidemiology studies suggest that the relationship between regular physical
activity and better sleep quality may partially mediate the well-established associa-
tions between physical activity and reduced risk of mortality, cardiovascular dis-
eases, and dementia. There is evidence that the completion of regular physical
activity also is associated with better sleep quality among those with certain sleep

M. J. McGranahan and P. J. O’Connor (✉)

Department of Kinesiology, University of Georgia, Athens, GA, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 309
Curr Topics Behav Neurosci (2024) 67: 309–328
https://doi.org/10.1007/7854_2024_503
Published Online: 31 July 2024
310 M. J. McGranahan and P. J. O’Connor

disorders (i.e., insomnia, obstructive sleep apnea, and restless legs syndrome),
mental health disorders (i.e., depression and posttraumatic stress disorder), and
medical illnesses (i.e., breast cancer survivors). The evidence is inadequate to
support that regular physical activity substantially improves sleep quality either
(i) in children, adolescents, and older adults, (ii) in those with cancers except for
breast cancer, (iii) in those with fibromyalgia, or (iv) among those with chronic
kidney disease. Also, there is inadequate evidence to conclude that sleep quality is
disrupted during weeks when competitive athletes engage in periods of overtraining.

Keywords Exercise · Sleep Initiation and Maintenance Disorders · Sleep Quality ·

Strength Training

1 Introduction

The primary purpose of this chapter is to provide an overview of research that has
examined the influence of regular physical activity on sleep.
Physical activity refers to any force produced by skeletal muscle action
(Caspersen et al. 1985). Physical activity is a complex exposure variable that can
meaningfully be categorized in multiple ways, including the purpose (e.g., occupa-
tional, transport, recreational, sport), frequency per week, the duration in minutes of
a single bout, and the intensity from low to maximal (often expressed relative to a
measure of an individual’s capacity such as a percentage of maximal strength or peak
aerobic capacity) (Beenackers et al. 2012). Regular physical activity (aka, chronic)
refers to daily activity bouts that are repeated regularly such as two, three, or five
times per week for multiple weeks (see Chapter “Introduction” for comprehensive
overview). Complicating physical activity as an exposure variable with regard to
sleep outcomes are factors that plausibly could interact with physical activity to
influence sleep such as time of day, or the time during a circadian phase, that the
activity occurs as well as if it occurs concomitantly with sunlight or heat exposure or
as part of competitive or non-competitive social interactions (Youngstedt et al. 2019,
2016).
There are large changes in sleep across the lifespan. Sleep duration generally
decreases from birth to the fifth decade of life and then increases around the age of
50. Clock time at sleep onset is earlier among children and older adults while the
delay of sleep onset into the early morning hours is most apparent around 20 years of
age (Su et al. 2022). Adequate amounts of physical activity and sleep are associated
with better health status while inadequate or excessive levels of physical activity and
sleep are associated with worse health status (Hale et al. 2020; Warburton and
Bredin 2017). Sleep disorders are more common among people who are unable to
engage in physical activity for extended periods of time either because of a
movement-related pathology (Lélis et al. 2016), an injury (Giannoccaro et al.
2013) or environmental restrictions such as during space flight (Pandi-Perumal and
Influence of Regular Physical Activity on Sleep 311

Gonfalone 2016). When sleep is prevented chronically, such as among individuals

with a rare genetic disorder that prevents sleep, it is fatal (Llorens et al. 2017).
Chronic short sleep, often defined as less than 6 h per night, is significantly
associated with obesity (mean relative risk of 1.38 and 95% Confidence Interval
[CI] 1.25, 1.53), type II diabetes (1.37, 95% CI 1.22, 1.53), heart disease (1.26, 95%
CI 1.15, 1.38), hypertension (1.17, 95% CI 1.09, 1.26), and mortality (1.12, 95% CI
1.08, 1.16) (Itani et al. 2017) as is chronic long sleep (> 9 h per night) with
associated increased risks established for stroke (1.46, 95% CI 1.26, 1.69), mortality
(1.39, 95% CI 1.31, 1.47), type II diabetes (1.26, 95% CI 1.11, 1.43), cardiovascular
disease (1.25, 95% CI 1.14, 1.37), and coronary heart disease (1.24, 95% CI 1.13,
1.37) (Jike et al. 2018). Regular physical activity reduces the risk of the medical
conditions listed above (see Chapter “Classification and Pharmacological Proper-
ties”) and a limited amount of evidence suggests that the associations between sleep
and mortality/adverse health outcomes are driven, in part, by physical inactivity.
Beyond the physical health problems associated with poor sleep, there are
consistent links between sleep and mental health during both stable historical periods
and especially stressful times driven by major social or economic upheavals. Psy-
chological and health threats, such as occurred during the COVID pandemic, were
associated with concomitant changes in physical activity, sleep, and mental health.
On average, participation in physical activity was reduced during the COVID
pandemic based on 57 worldwide studies of over 119,000 participants (Wunsch
et al. 2022). People not meeting physical activity guidelines reported worse loneli-
ness, depression, and stress which may have contributed to sleep problems (Meyer
et al. 2020). Fear of acquiring COVID was associated with greater anxiety and stress
which plausibly contributed to sleep problems (Alimoradi et al. 2022). Four of every
10 people reported a sleep problem during the pandemic with the prevalence highest
among infected patients, children and adolescents, and hospital workers (Jahrami
et al. 2022).
The next section will summarize research exploring the influence of regular
physical activity on sleep that has been conducted among samples without major
health problems. Subsequent sections will focus on the extent to which regular
physical activity alters sleep in samples suffering from selected physical or psychi-
atric illness.

2 Effects of Regular Physical Activity on Sleep

in Apparently Healthy Samples

In contrast to the common parental hope that children will fall asleep quickly and
stay asleep longer after a physically active day, the evidence shows that physical
activity is quite weakly associated with sleep duration in children aged 3 to 13
(r = 0.02; 95% CI -0.03, 0.07) based on a meta-analysis of 47 studies (Antczak
et al. 2020). A similar weak, non-significant relationship also was observed in
312 M. J. McGranahan and P. J. O’Connor

university students (averaged age between 18.9 and 23.1) based on a meta-analysis
of 29 studies involving data from 141,035 students (Memon et al. 2021). Results of
studies examining the effect of exercise on sleep are more mixed among samples of
older adults. Studies of older adults can be especially challenging because of the
frequent presence of co-morbid conditions that can influence sleep and the changes
in sleep that occur with normal aging, including advanced sleep timing, increased
wakefulness after sleep onset, less total sleep duration, decreased slow wave sleep,
and more daytime naps (Li et al. 2022). A review of 21 prospective studies of older
adults (aged >50 years) concluded that the most consistent risk factors for future
sleep disturbances were: female sex, depressed mood, and having a physical illness
while the evidence was less robust for low physical activity levels as a risk factor
(Smagula et al. 2016). In contrast, meta-analysis of 13 randomized controlled trials
with older adults (> 65 years old) showed small, significant improvements in sleep
quality after adopting a program of regular exercise (Solis-Navarro et al. 2023). This
small effect may be moderated by brain health given that a meta-analysis of
11 studies examining the influence of aerobic exercise on both cognitive function
and sleep in older adults (aged ≥60 years) with mild cognitive impairment found that
global cognitive function was improved but sleep was not (Ahn and Kim 2023).
Regular physical activity appears to be more consistently associated with sleep in
samples of adults; however, the magnitude of the effect appears to be small-to-
moderate (Atoui et al. 2021; Kline et al. 2021) and cross-sectional studies showing
better sleep among physically active people may reflect confounding variables such
as better health among the physically active (O’Connor and Wender 2021). In a
study of over 50,000 British older adults (aged ≥60 years old), self-reported physical
activity significantly moderated relationships between health-related quality of life
and sleep duration (Hu et al. 2022).
Much of the exercise and sleep literature has been based on self-reports of both
physical activity and sleep. There is more error in self-reports of sleep than more
objective measures such as polysomnography or activity-monitor derived assess-
ments (e.g., accelerometers), so it is perhaps not surprising that effects of exercise on
sleep are typically smaller with the more objective measures. The effects of regular
physical activity on sleep onset, total sleep time, and sleep efficiency are small when
sleep has been measured objectively such as via polysomnography or actigraphy
(Kline et al. 2021). In one analysis of over 3,000 adults aged 18 to 85 years from the
National Health and Nutrition Examination Survey (NHANES) study during a year
when participants wore an accelerometer on the hip to assess physical activity, after
controlling for several confounders including age, it was found that the relative risk
of excessive daytime sleepiness (an index of poor sleep) was reduced by a factor of
0.65 among those participants who met the U.S. federal government recommended
amount of physical activity for health (Loprinzi and Cardinal 2011). Information
providing a biological basis for potential relationships between physical activity and
sleep is unfortunately rare but it is important and needed for making a strong case
that physical activity per se meaningfully influences sleep. Thus, it is notable that
one genome-wide association study of over 91,000 adults aged 45 to 79 years whose
sleep and physical activity was documented from wearing a waist-worn
Influence of Regular Physical Activity on Sleep 313

accelerometer for one week found that as much as 18% of the variation in physical
activity and sleep duration might be accounted for by common central nervous
system genetic variations (Doherty et al. 2018).
The timing of exercise might influence sleep. Avoiding evening exercise so as to
not negatively impact sleep has long been generally recommended based on clinical
wisdom. The current evidence, based on 23 studies, supports the opposite; that is,
small benefits of late night exercise for sleep except for high intensity exercise
completed less than one hour prior to sleep which can lead to sleep disruptions
(Stutz et al. 2019). One small study with insomniacs used reading before bed as a
control condition and compared it to a separate night involving the completion of
30 min of moderate intensity treadmill exercise and 15 min of moderate muscle
strengthening exercise 2 h prior to bedtime. Large sleep disruptions were observed in
16% of the sample, leading to the conclusion that people with insomnia should be
cautious about completing a bout of moderate and higher intensity exercise within
two hours of bedtime (Youngstedt et al. 2021).
The short-term adoption of regular exercise (typically for a few months) by
groups of healthy adults (mean age of 42 years) results in large improvements in
self-reported sleep quality (the effect size is about ¾ standard deviation) based on a
meta-analysis of randomized controlled trials in predominantly community samples
without sleep complaints (Kredlow et al. 2015). One systematic review of 13 studies
focused on resistance exercise concluded that chronic strength training has
moderate-to-large benefits for sleep quality and noted that the magnitude of the
benefit appears to exceed the small-to-moderate improvement in sleep quality that
accrues from sleep medications (Kovacevic et al. 2018). The effects of resistance
exercise on the more objective sleep measures were small and inconsistent across the
studies.
There is a small body of evidence regarding relationships among physical
activity, sleep, and mortality and most of it has been limited to sleep duration and
focused on older adult samples. Early epidemiological research found a U-shaped
relationship between sleep duration and an increased risk of mortality, with reduced
risk of mortality associated with a sleep duration of about 7 h per night (Bellavia
et al. 2013; Youngstedt et al. 2017). The evidence is stronger for the negative effects
of sleep that is too long and prospective cohort studies support a J-shaped relation-
ship between sleep duration and mortality (Liu et al. 2017). For sleep durations
between 4 and 6 h, the relative risk of mortality ranged between 1.02 and 1.09 while
the relative risk ranged from 1.21 to 1.28 for a sleep duration of 10 or more hours per
night. One review of prospective cohort studies concluded that high levels of
physical activity plausibly could offset the increased risk of all-cause mortality
associated with short sleep duration while long sleep duration was associated with
increased mortality risk regardless of physical activity level (Duncan et al. 2023).
314 M. J. McGranahan and P. J. O’Connor

3 Effects of Regular Physical Activity on Sleep in People

with Selected Sleep Disorders

Insomnia – About 20% of adults occasionally have insomnia symptoms while about
10% suffer from an insomnia disorder (Morin and Jarrin 2022). Those with an
insomnia disorder have sleep problems for at least 3 months (Vahia 2013). They
often have difficulties falling asleep, waking up during sleep, and having trouble
going back to sleep, or they wake too early in the morning and are unable to get back
to sleep. This often leads to daytime symptoms such as feelings of low energy and
irritability as well as cognitive impairments such as problems with perceived or
objectively measured attention and memory (Wardle-Pinkston et al. 2019).
At least five experiments have tested the influence of regular physical activity on
sleep in adults with a diagnosed insomnia disorder. One study involved yoga
(Afonso et al. 2012), a second used Tai Chi (Irwin et al. 2014), and several
experiments involved aerobic exercise (Guilleminault et al. 1995; Hartescu et al.
2015; Reid et al. 2010). Four of the five experiments found significant improvements
in sleep quality after exercise, one experiment likely lacked the statistical power to
detect a true effect given there were only 10 participants in the exercise condition
(Kline et al. 2021; Guilleminault et al. 1995; Passos et al. 2012; Banno et al. 2018;
Yang et al. 2012).
The small body of research (<20 studies) examining the influence of exercise
training on sleep in samples with insomnia symptoms has been reviewed at least five
times (Kline et al. 2021; Passos et al. 2012; Banno et al. 2018; Yang et al. 2012;
Lowe et al. 2019). Despite the methodological limitations in the studies (e.g., small
samples), the consistency of the effect has led reviewers to conclude that there is a
moderate amount of evidence that physical activity reduces the severity of insomnia
among those with elevated insomnia symptoms.
Sleep apnea – Obstructive sleep apnea (OSA) results when the upper airway
collapses during sleep resulting in transient cessation or attenuation of ventilation.
By mid-age, OSA affects about 10% of men and 3% of women; yet, many people are
unaware they have the problem (Peppard et al. 2013). At least 14 randomized
controlled trial experiments have tested the influence of exercise training on some
aspect of OSA, typically the apnea-hypopnea index (AHI), sleep quality, or a
measure of daytime functioning (Kline et al. 2021). These investigations included
a variety of exercise modes including cycling, walking, resistance exercise, and Tai
Chi but there were not enough studies to test for moderator variables such as exercise
mode. Overall, the studies show that exercise training, in the absence of meaningful
loss of body mass, reduces OSA severity by a moderate amount (~0.5 standard
deviations, equating to a range of 4 to 13 fewer events per hour) compared to
controls (Kline et al. 2021; Aiello et al. 2016; Peng et al. 2022). Exercise training
is not as effective in reducing OSA severity as treatment with continuous positive
airway pressure (CPAP) or mandibular advancement devices but was more effective
in improving sleep quality (Iftikhar et al. 2014). Subsequent research with OSA
samples showed that exercise training improved sleep quality, daytime sleepiness
Influence of Regular Physical Activity on Sleep 315

and polysomnographic measures of sleep efficiency, sleep duration, and stage N3

sleep (Peng et al. 2022; Mendelson et al. 2018; Lins-Filho et al. 2020, 2023).
Restless legs syndrome – Restless legs syndrome (RLS) is an uncomfortable
feeling in the legs while awake that can disrupt sleep onset. Most people with RLS
also have periodic limb movements during sleep which reduce sleep continuity. RLS
is more common in women, during pregnancy and for those with chronic pain and
kidney disease. Randomized controlled trials consistently have found a reduced
severity of RLS symptoms in response to exercise training primarily involving
cycling but also including yoga, stretching, walking, resistance exercise, and a
mixture of modes (Aukerman et al. 2006; Mortazavi et al. 2013; Çoban et al.
2023; Giannaki et al. 2013). A meta-analysis of four randomized controlled trials
focused on patients undergoing hemodialysis and reported that the adoption of
regular exercise training induced moderate-to-large reductions in RLS symptoms
(Song et al. 2018).

4 Effects of Regular Physical Activity on Sleep in Patients

with Selected Mental Illnesses

Depression – Depression is characterized by a depressed mood or loss of interest/

pleasure in daily activities. Both insomnia and hypersomnia are symptoms included
in the diagnostic and statistical manual of mental disorders (DSM-5) criteria for
major depressive disorder (MDD). Insomnia symptoms in depression are more
common (85–88%) compared to hypersomnia (27–48%) (Yates et al. 2004;
Geoffroy et al. 2018). Both cross-sectional and longitudinal data support that poor
sleep quality increases the odds of elevated depression symptoms (Furihata et al.
2017; Pan et al. 2022). Sleep architecture features also may vary based on MDD
sub-types (Solelhac et al. 2023). In a notable meta-analysis (k = 17), patients with
MDD had significantly higher subjective sleep disturbances (Hedges’ g = 2.1, 95%
CI 1.72, 2.47) compared to healthy controls (Cox and Olatunji 2020).
Physical activity and exercise-based interventions improve depression symptoms
(Gordon et al. 2018) (see Chapter “Management of ‘Challenging Experiences’ and
‘Bad Trips’ in Psychedelic-assisted Therapy and Recreational Use”) and recent
studies suggest that the effects of physical activity on depressive symptoms may
be mediated through changes in sleep. In a cross-sectional study of 1,576 partici-
pants, higher levels of self-reported physical activity significantly predicted fewer
depression symptoms (β = -0.114). Mediation analysis indicated that sleep quality
accounted for 19% of the effect of physical activity on depressive symptoms
(Barham et al. 2022). In a similar analysis from the longitudinal Cardiovascular
Risk in Young Finns Study, physical activity was associated with better sleep quality
and lower depression symptoms, and sleep quality mediated the relation between
physical activity and depression symptoms (Kaseva et al. 2019). However, after
adjusting for baseline depressive symptoms, the mediation was no longer significant.
In a large study evaluating 402,290 participants in the U.K. Biobank study, the risk
316 M. J. McGranahan and P. J. O’Connor

of developing depressive disorder was lowest (hazard ratio = 0.39, 95% CI 0.33,
0.47) for individuals categorized as having healthy sleep (based on appropriate sleep
duration, fewer insomnia symptoms, and less snoring and daytime sleepiness) and
moderate-to-high levels of physical activity (Pan et al. 2022). However, whether
physical activity levels lowered the risk of developing depression in those with poor
sleep behavior was not evaluated (Pan et al. 2022).
Although the impact of exercise training on depression has been frequently
studied, only a smaller number of studies have included sleep quality metrics
(Gerber et al. 2019; Cheung and Lee 2018). In the most extensive meta-analysis
on the topic (n = 17), vigorous aerobic exercise, moderate aerobic exercise plus
treatment as usual (TAU), light strength training, and vigorous aerobic exercise plus
TAU all had a moderate effect on improving sleep quality compared to passive
controls. Large improvements in sleep quality based on effect size differences were
found for moderate aerobic plus health education, mind-body exercises plus TAU,
and vigorous strength training compared to passive control (Brupbacher et al. 2021).
When compared to TAU, mind-body plus TAU (standardized mean difference
(SMD) = -0.46, 95% CI -0.80, -0.12), and vigorous strength training
(SMD = -0.61, 95% CI -1.12, -0.10) were the only interventions to significantly
improve sleep quality (Brupbacher et al. 2021). This meta-analysis provides evi-
dence that exercise interventions have potential for improving sleep quality in
patients with diagnosed depression or those with elevated depressive symptoms.
However, what factors may moderate the anti-depressant effect were not evaluated
due to the low heterogeneity of the effects (I2 = 4.3%). In a sub-analysis, larger
improvements in sleep quality were observed in studies with patients with diagnosed
depressive disorder. Overall, the evidence suggests a beneficial effect of exercise
training on sleep quality for individuals with depression.
Posttraumatic stress disorder (PTSD) – PTSD is a condition that develops fol-
lowing exposure to a traumatic event. Sleep disturbances prior to and following
trauma exposure are associated with an elevated risk of developing PTSD (Neylan
et al. 2020; Pace-Schott et al. 2015). Nightmares related to the trauma, an impaired
ability to fall asleep, and frequent awakenings in the night are a part of two of the
four symptom clusters in the DSM-5 PTSD criteria (American Psychiatric Associ-
ation 2013). Self-reported sleep disturbances (e.g., nightmares, insomnia, restless
sleep) range from 70 to 92% in samples of individuals with PTSD (Ohayon and
Shapiro 2000; Seelig et al. 2010). Sleep disturbance often remains a residual
problem following treatment such as after standardized cognitive behavioral therapy
or exposure therapy (Brownlow et al. 2016; Taylor et al. 2020).
A few observational studies have evaluated the evidence between physical
activity and sleep in patients with PTSD. In a one-year prospective study
(n = 736), veterans who developed PTSD had significantly decreased physical
activity levels at the end of the study compared to veterans without PTSD (Talbot
et al. 2014). Poor sleep quality significantly mediated the relationship between
baseline PTSD and the lower physical activity levels one year later (Talbot et al.
2014). While this suggests that in samples with PTSD, sleep quality may be an
important predictor for physical activity levels, likewise increasing physical activity
Influence of Regular Physical Activity on Sleep 317

can have a beneficial impact on PTSD symptoms through improvements in sleep

quality. In a three-month long internet-based study of 182 individuals with probable
PTSD, higher exercise intensity was associated with decreases in common symp-
toms of PTSD such as hyperarousal, avoidance, and emotional numbing (Whitworth
et al. 2017). Additionally, the effects of physical activity on PTSD symptoms were
mediated by changes in sleep quality (β = -2.54) (Whitworth et al. 2017).
Currently, there are only a small number of high-quality studies evaluating the
effects of exercise training on sleep quality in patients with PTSD. In a meta-analysis
(k = 5) evaluating exercise training on sleep quality in patients with PTSD, the
overall effect size was small (Hedges’ d = -0.47, 95% CI -0.75, -0.18)
(McGranahan and O’Connor 2021). In a recent randomized controlled trial evaluat-
ing 8 sessions of various exercise activities compared to 8 sessions of creative tasks,
as adjunctive care during intensive trauma focused treatment, no significant differ-
ence in insomnia severity index occurred between the groups (Hedges’ d = -0.19,
CI -0.57, 0.19) (Voorendonk et al. 2023). There were several limitations to this
study: (1) a lack of reporting of exercise intensity, (2) the actual duration participants
were physically active was not measured, and (3) without a treatment alone com-
parison group, it is not possible to determine whether exercise or creative tasks had
an impact on insomnia symptoms. The overall evidence, while limited, suggests that
exercise training may help improve sleep for patients with PTSD. Whether exercise
training is superior to other treatments for sleep outcomes in adults PTSD requires
future well-designed studies.

5 Effects of Regular Physical Activity on Sleep in People

with Selected Medical Illnesses

Cancer – Early small studies suggested that yoga has promising beneficial effects on
sleep for cancer patients with insomnia and that the activity was well tolerated
(Mustian 2013). This stimulated additional research investigating the impact of
regular physical activity of various types on sleep in cancer survivors and this has
yielded mixed results. A quantitative review of 17 randomized trials found no
statistically significant effect of physical activity on subjective or objective measures
of sleep in cancer survivors (Mercier et al. 2017). Several other meta-analyses, each
with different inclusion and exclusion criteria, found small improvements in some
aspect of sleep, most often self-reported sleep quality (Fang et al. 2019; Kreutz et al.
2019). A smaller body of randomized trials (n = 6) tested the influence of regular
exercise on sleep problems among breast cancer survivors as assessed using the
PSQI (Yang et al. 2021). It was found that increased physical activity improved sleep
quality by a small mean difference (SMD = 0.22, 95% CI 0.04, 0.40) and there were
smaller non-significant effects on sleep duration, latency, efficiency, and daytime
functioning. A subsequent meta-analysis of 12 randomized controlled trials of the
influence of yoga on sleep quality among breast cancer survivors found a significant,
318 M. J. McGranahan and P. J. O’Connor

small mean improvement in sleep quality favoring yoga (SMD = -0.40, 95% CI -
0.71, -0.09) compared to control conditions (Zhu et al. 2023). Another meta-
analysis concluded that walking was more effective in improving sleep among
cancer survivors than was yoga (Tang et al. 2019). Finally, a meta-analysis using
individual patient data, which can be used to resolve study-level from individual-
level effects in randomized trials, found small decrease in sleep disturbances after
exercise but no effect on sleep quality even though sleep quality is the variable most
frequently improved with the adoption of regular physical activity (Bernard et al.
2019).
Cardiovascular Disease – It is well established that regular leisure-time physical
activity is associated with a reduced risk of cardiovascular disease; 70% of the
possible risk reduction occurs by engaging in 150 min of brisk walking per week
(Kraus et al. 2019). There is a U-shaped relationship between sleep duration and
increased risk of heart disease and stroke; for example, compared to 7 h of sleep both
6 h or less and 8 h or more are associated with an increased risk of heart disease and
stroke (Wang et al. 2022, 2016). The results of one large prospective cohort study of
502,616 adults based on self-reported physical activity concluded that the adverse
associations of sleep with cardiovascular disease mortality were exacerbated by low
levels of physical activity – suggesting synergistic effects of poor sleep and low
levels of physical activity (Huang et al. 2022a). A cross-sectional analysis of 5,312
suburbanites living near Shanghai, China, found that activity intensity, duration, and
frequency all significantly mediated the relationship between longer sleep duration
and increased risk of stroke (Liu et al. 2022).
Dementia – Emerging evidence suggests bidirectional relationships between
sleep disturbances and Alzheimer’s disease and other dementias. That is,
Alzheimer’s disease can cause sleep problems and sleep disruptions can contribute
to an increased risk of developing Alzheimer’s disease (Lucey 2020). A small
number of cross-sectional studies suggest that some of the negative effect of poor
sleep on cognition might be attenuated when people are adequately physically active
(Sewell et al. 2021). A similar small body of evidence suggests that the effects of
physical activity on improving sleep might mediate the improved cognition associ-
ated with regular physical activity (Won et al. 2019). One large cross-sectional study
(n = 431,924) examined relationships among sleep, physical activity, sedentary
behavior, and dementia risk. The lowest dementia risk (Relative risk = 0.59, 95% CI
0.50, 0.69) was found for those reporting 7 h of sleep per day as well as moderate-to-
high levels of leisure-time physical activity (LTPA) and low-to-moderate levels of
sedentary behavior compared to the reference group (longer or shorter sleep/low
LTPA/high sedentary behavior) (Huang et al. 2022b).
Fibromyalgia – Fibromyalgia (FM) is a disorder characterized by chronic wide-
spread pain. Other symptoms include fatigue, cognitive difficulties, and sleep-related
disruptions (Segura-Jiménez et al. 2015; Häuser et al. 2015). The estimated preva-
lence rate of FM in the United States ranges from 1.1 to 6.4% (Wolfe et al. 1995;
Vincent et al. 2013). Similar rates of FM have been reported in European countries,
specifically 1.4 to 3.7% (Branco et al. 2010). Prevalence rates of FM are higher in
Influence of Regular Physical Activity on Sleep 319

older compared to younger adults and in women compared to men (Branco et al.
2010; Jones et al. 2015).
Sleep related issues, including nonrestorative sleep and sleep disturbances, are
common in patients with FM. In a sample of 2,596 people with FM, nonrestorative
sleep was indicated as one of the top three most frequent symptoms, and sleep
problems were in the top three problems listed to exacerbate FM symptoms (Bennett
et al. 2007). Objective sleep metrics, as measured by polysomnography, indicate that
there are distinct differences in the sleep architecture of patients with FM compared
to healthy controls (Wu et al. 2017). Similarly, large differences in subjective sleep
quality, as measured via the Pittsburgh Sleep Quality index (PSQI), were observed
between patients with FM and healthy controls. Sleep was worse in patients with FM
compared to healthy controls based on global PSQI scores (Hedges’ g = 2.19, 95%
CI 1.58, 2.79) and sleep onset latency scores (Hedges’ g = 1.75, 95% CI 0.80, 2.70)
that were higher and lower sleep efficiency scores (Hedges’ g = - 1.08, 95% CI -
1.65, -0.51) (Wu et al. 2017).
Non-pharmacological interventions, such as physical activity, are currently
recommended to help manage FM symptoms (Macfarlane et al. 2017). A study of
409 women with FM found that individuals with greater light and total physical
activity minutes, assessed via wrist accelerometry, had significantly better PSQI
scores (Borges-Cosic et al. 2019). While statistically significant, whether the
changes were clinically meaningful is questionable because the raw change score
was small (~1.2 points).
A recent systematic review evaluating the effects of resistance training on sleep
quality in patients with FM stated that four of the six studies showed improvements
(Bastos et al. 2023). With the exception of one study (Jones et al. 2002), when the
effects sizes were calculated all were small (Hedges’ d ranging from -0.06, -0.57)
and the 95% CI’s crossed zero (Häkkinen et al. 2001; Bircan et al. 2008; Andrade
et al. 2017, 2019). The Jones et al. study showed large improvements (Hedges’
d = -3.73, 95% CI, -4.68, -2.78) with the sleep visual analog scale (VAS) item
from the Fibromyalgia Impact Questionnaire (FIQ). The sleep VAS item from the
FIQ asks participants about how they felt in the morning upon waking with anchors
of “felt tired” or “well-rested.” Andrade, Sieczkowska, and Vilarino 2019 showed a
moderate-sized improvement in the sleep VAS from the FIQ following four weeks
of resistance training (Hedges’ d = -0.65, 95% CI -1.25, -0.05), but no improve-
ment was found for PSQI scores (Hedges’ d = -0.06, 95% CI -0.64, 0.52,)
(Andrade et al. 2019). Resistance training may improve some aspects of sleep
quality, but more studies are needed to better understand which components of
sleep quality are most impacted when FM patients complete regular resistance
training.
One meta-analysis comparing usual care to exercise training (k = 14) in people
with FM found a small, significant effect of exercise training for improving sleep
quality (SMD = -0.17, 95% CI -0.32, -0.01) (Estévez-López et al. 2021). Studies
included in the analysis involved a wide range of exercise modalities including yoga,
qigong, tai chi, resistance training, and water aerobics. The length of the interven-
tions ranged from 7 to 21 weeks. Due to the lack of heterogeneity (I2 < 30%), a
320 M. J. McGranahan and P. J. O’Connor

moderation analysis was not conducted. In a secondary analysis of a small number of

mind–body interventions (e.g., tai chi, yoga, and qigong) compared to other exercise
interventions, large sized improvements in sleep quality were observed (k = 5,
SMD = - 0.80; 95% CI -1.57, -0.02) (Estévez-López et al. 2021). The available
evidence suggests the exercise training may improve sleep difficulties in patients
with FM. Understanding the variables that moderate these effects, and the specific
aspects of sleep quality which exercise may target, requires larger well-designed
studies that more fully capture and report different sleep quality metrics.
Kidney Disease – Compared to the general population, sleep disorders are more
prevalent in patients with chronic kidney disease and especially those with end-stage
renal disease (Maung et al. 2016). While the reasons for this are likely multi-
factorial, one hypothesis is that hyperactivity of the sympathetic nervous system
and decreased vagal tone contribute to sleep disruptions (Maung et al. 2016; Hildreth
2011). Well-established adaptations to regular exercise, including increased vagal
tone and reductions in sympathetic activity (Martinez Matthew et al. 2021), plausi-
bly could contribute to improved sleep by changing the autonomic imbalance that is
present among those with kidney disease. A meta-analysis of 4 experiments with a
total of 130 people with chronic kidney disease reported significant improvements in
sleep quality and a mean difference of about 5 points on the PSQI (Valera et al.
2023). A quantitative review of 20 randomized controlled trials involving
989 patients with chronic kidney disease found that the adoption of moderate
intensity aerobic exercise resulted in a small improvement in sleep quality
(SMD = -0.16) (Zhang et al. 2023). Large confidence intervals calculated in this
larger meta-analysis (CI range = - 0.62 to 0.31) indicated that the true effect of
exercise could either improve or worsen sleep quality (Zhang et al. 2023).

6 Overtraining in Athletes

Some endurance athletes periodically engage in a high volumes and intensities of

physical activity and at times this amount of physical activity is extreme. For
example, it was reported that the current male marathon world record holder,
Kevin Kiptum, ran about 186 miles per week for three weeks preceding the 2023
London marathon which he won in a time of 2 h, 1 min, and 25 s. It is unclear what
effect, if any, this level of physical activity had on Kiptum’s sleep. His coach,
Gervais Hakizimana, told a reporter that “All he does is run, eat and sleep”
(McAlister 2023).
If there is a dose-dependent relationship between physical activity and sleep, then
extremes of physical activity might result in very large changes in sleep. Only a few
small sample studies have measured sleep objectively using wrist actigraphy before
and during periods of intensified training. In these investigations generally small
decreases in sleep duration and sleep efficiency of 1.6 to 7.9% were reported
(Hausswirth et al. 2014; Killer et al. 2017; Schaal et al. 2015). The modest changes
in sleep suggest that extremes of physical activity do not necessarily lead to dramatic
Influence of Regular Physical Activity on Sleep 321

changes in sleep. If these findings are true, then they discount the hypothesis that one
purpose of sleep is for recovery from the prior day’s metabolic processes (Shapiro
1982). Reviewers have concluded that more research is needed to understand this
topic fully (Neil et al. 2021).

7 Conclusions and Future Directions

Overall, the evidence supports that regular physical activity is associated with better
sleep quality, among healthy adults (Kredlow et al. 2015), individuals with sleep
disorders (i.e., insomnia (Kline et al. 2021)), OSA (Aiello et al. 2016), and RLS
(Song et al. 2018), individuals with mental health disorders (i.e., depression
(Brupbacher et al. 2021)) and PTSD (McGranahan and O’Connor 2021), and
among people with certain medical illnesses (i.e., breast cancer survivors (Zhu
et al. 2023)). As well, evidence suggests that the positive benefit of physical activity
on disease prevention (i.e., decreased risks of all-cause mortality, cardiovascular
disease (Wang et al. 2022; Wang et al. 2016)), and dementia (Huang et al. 2022b)
and mental health (i.e., odds of developing depression (Pan et al. 2022; Barham et al.
2022)) may be mediated by improved sleep. The evidence is inadequate to support
that regular physical activity consistently improves sleep quality either (i) in chil-
dren, adolescents (Antczak et al. 2020) and older adults (Smagula et al. 2016), (ii) in
those with cancers (Mercier et al. 2017), (iii) those with fibromyalgia (Bastos et al.
2023; Estévez-López et al. 2021), or (iv) those with chronic kidney disease (Zhang
et al. 2023).
To date there are a limited number of trials that evaluated sleep objectively using
the gold standard of polysomnography. Notably, studies measuring sleep metrics
with polysomnography following exercise training have primarily been in older
adults (King et al. 2008), those with OSA (Lins-Filho et al. 2023), and patients
with insomnia (Ferreira et al. 2022). In many of the conditions discussed in the
chapter, the impact on polysomnography measured sleep has not been studied. The
specific aspects of sleep architecture that exercise may impact and how that relates to
the prevention of diseases and improvements in mental health should increasingly be
considered as vital to the health of our society. Due to advances in technology, the
quality and cost of at-home polysomnography are becoming more feasible and
increasingly should be incorporated into research aimed at understanding the rela-
tionship between physical activity and sleep. Moreover, data are emerging regarding
the accuracy of widely used smart watches to measure aspects of sleep (Roomkham
et al. 2019). Thus, it is likely that future large studies will provide useful objective
information about sleep and physical activity with this relatively inexpensive and
palatable technology.
The wide ranges in 95% confidence intervals in many of the studies suggest there
is a range of responses to the impact exercise training has on sleep. As stated in the
beginning of this chapter, physical activity is a complex exposure variable which
will require novel techniques to improve our understanding. One possible future
322 M. J. McGranahan and P. J. O’Connor

direction is to leverage large databases with sleep and physical activity measures and
implement machine-based learning algorithms to identify patterns and characteris-
tics in those who report improved sleep after increased participation in physical
activity. More studies are needed to understand aspects of physical activity that have
the largest impact on sleep and what moderates the response across different
conditions.
Another opportunity with regard to research design is the use of Mendelian
randomization. This approach allows for potential causal effects to be estimated
based on genetic variants previously associated with sleep and physical activity. One
study using this approach failed to find evidence that sleep duration was causally
related to the risk of cardiovascular disease while confirming that vigorous exercise
does decrease the risk (Zhuang et al. 2020). More studies, and associated insights,
are expected in the future using a Mendelian randomization design.

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Exercise Training for Chronic Pain:
Available Evidence, Current
Recommendations, and Potential
Mechanisms

Jacob V. Ninneman, Gunnar A. Roberge, Aaron J. Stegner,

and Dane B. Cook

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.1 Defining Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.2 Prevalence and Burden of Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1.3 Physical Activity and Exercise for the Prevention and Treatment of Chronic Pain . 332
2 Chronic Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
2.1 Exercise in Chronic Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
2.2 Guidelines for Exercise in Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
2.3 Potential Mechanism of Action in Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
3 Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
3.1 Exercise in Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
3.2 Guidelines for Exercise in Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
3.3 Potential Mechanism of Action in Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
4 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
4.1 Exercise in Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
4.2 Guidelines for Exercise in Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
4.3 Potential Mechanism of Action in Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
5 Chronic Cervical Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
5.1 Chronic Cervical Pain and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
5.2 Guidelines for Exercise in Chronic Cervical Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
5.3 Potential Mechanism of Action in Chronic Cervical Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
6 Chronic Widespread Pain and Fibromyalgia Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
6.1 Exercise for Chronic Widespread Pain and Fibromyalgia Syndrome . . . . . . . . . . . . . . . 345
6.2 Guidelines for Exercise in Chronic Widespread Pain and Fibromyalgia Syndrome 348
6.3 Potential Mechanism of Action in Chronic Widespread Pain and Fibromyalgia
Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
7 Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
7.1 Exercise in Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

J. V. Ninneman, G. A. Roberge, A. J. Stegner, and D. B. Cook (✉)

Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
Department of Kinesiology, University of Wisconsin–Madison, Madison, WI, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 329
Curr Topics Behav Neurosci (2024) 67: 329–366
https://doi.org/10.1007/7854_2024_504
Published Online: 10 August 2024
330 J. V. Ninneman et al.

7.2 Guidelines on Exercise for Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

7.3 Potential Mechanisms for Action in Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

Abstract Chronic pain conditions pose a significant global burden of disability,

with epidemiological data indicating a rising incidence. Exercise training is com-
monly recommended as a standalone or complementary approach for managing
various chronic pain conditions like low back pain, osteoarthritis, rheumatoid
arthritis, fibromyalgia syndrome, and neuropathic pain. Regardless of the specific
condition or underlying cause (e.g., autoimmune disease, chronic inflammation),
exercise training consistently leads to moderate to large reductions in pain. More-
over, exercise yields numerous benefits beyond pain alleviation, including small-to-
moderate improvements in disability, quality of life, and physical function. Despite
its efficacy, there is a lack of comprehensive research delineating the optimal
intensity, duration, and type of exercise for maximal benefits; however, evidence
suggests that sustained engagement in regular exercise or physical activity is neces-
sary to achieve and maintain reductions in both clinical pain intensity ratings and the
level that pain interferes with activities of daily living. Additionally, the precise
mechanisms through which exercise mitigates pain remain poorly understood and
likely vary based on the pathophysiological mechanisms underlying each condition.

Keywords Physical Activity · Inflammation · Guidelines

1 Introduction
1.1 Defining Chronic Pain

The International Association for the Study of Pain (IASP) defines pain as an
unpleasant sensory and emotional experience associated with, or resembling that
associated with, actual or potential tissue damage (Raja et al. 2020). Like any
perception, pain is an inherently subjective experience that is influenced by multiple
biological, psychological, social, and contextual factors. When pain persists or
recurs for longer than 3 months it is considered chronic. The World Health Organi-
zation recently collaborated with the IASP to develop a classification system for
chronic pain diagnoses in the 11th edition of International Classification of Diseases
(ICD-11) (International Classification of Diseases, Eleventh Revision 2019; Treede
et al. 2019). The ICD-11 divides chronic pain conditions into the following seven
subgroups: chronic primary pain (Nicholas et al. 2019), chronic cancer-related pain
(Bennett et al. 2019), chronic postsurgical or post-traumatic pain (Schug et al. 2019),
chronic secondary musculoskeletal pain (Perrot et al. 2019), chronic secondary
visceral pain (Aziz et al. 2019), chronic neuropathic pain (Scholz et al. 2019), and
chronic secondary headache or orofacial pain (Benoliel et al. 2019).
Exercise Training for Chronic Pain: Available Evidence,. . . 331

Chronic primary pain conditions are those whose symptoms are not better
accounted for by another condition and can be considered an independent disease.
The remaining subgroups are considered chronic secondary pain conditions in which
the pain experienced is initially regarded as a symptom of an underlying condition
such as cancer or osteoarthritis (OA). Contributing factors to pain in these conditions
may include injury, persistent inflammation, or diseases of the nervous system. It
should be noted that it is not always possible to delineate between primary and
secondary pain from the literature, as many musculoskeletal pain conditions get
grouped together by location (e.g., low back pain, LBP). The full details and nuances
of this classification system are beyond the scope of this chapter, but more informa-
tion can be found in the above citations and on the IASP website (https://www.iasp-
pain.org/advocacy/icd-11-pain-classification/). We will use the updated ICD-11
terminology throughout the chapter when feasible.

1.2 Prevalence and Burden of Chronic Pain

Chronic musculoskeletal pain (CMP) conditions are estimated to be the most

common cause of morbidity and disability worldwide (Rice et al. 2016; Vos et al.
2015). Point prevalence data indicate that chronic pain affects more than 100 million
Americans and is more common among females (34.3%) than males (26.7%;
(Johannes et al. 2010). In Europe, pain lasting for greater than 6 months affects
19% of people 18 years of age and older (Breivik et al. 2006). Low- and middle-
income countries are disproportionately affected with musculoskeletal pain rates of
26%, 39%, and 86% for the general population, the elderly, and workers, respec-
tively (Jackson et al. 2015). For most countries, LBP alone is estimated to be the
leading cause of years lived with disability (YLDs; e.g., 146 million YLDs estimated
in 2013) and the prevalence of several CMP conditions is on the rise (Rice et al.
2016; Vos et al. 2015). Overall, chronic LBP, chronic neck pain, migraine, and a
category designated as “other musculoskeletal disorders” are estimated as being
within the top ten causes of YLDs in every developed and developing country (Rice
et al. 2016; Vos et al. 2015).
The costs of chronic pain are staggering and current treatment standards are
suboptimal (Institute of Medicine (US) Committee on Advancing Pain Research,
Care, and Education 2011). In the United States of America, the economic impact
has been estimated to be between $560 and $650 billion annually in terms of
healthcare costs, prescription drug use, and loss of work productivity (Gaskin and
Richard 2012). By comparison, the costs of cardiovascular diseases, cancers, and
respiratory diseases were $309 billion, $243 billion, and $112 billion, respectively
(Gaskin and Richard 2012). Chronic pain is estimated to cost between 1.5% and
3.0% of the European Gross Domestic Product (Phillips 2006). The rising costs, low
quality of life (QoL), and rates of disability are an enduring public health crisis and
make clear that current approaches for treating chronic pain are lacking along several
fronts.
332 J. V. Ninneman et al.

1.3 Physical Activity and Exercise for the Prevention

and Treatment of Chronic Pain

In 2011, the National Academies of Sciences, Engineering, and Medicine published

a Consensus Study Report, titled Relieving Pain in America: A Blueprint for
Transforming Prevention, Care, Education, and Research (Institute of Medicine
(US) Committee on Advancing Pain Research, Care, and Education 2011). Recog-
nizing an urgent need and that pain is a public health problem, this report made
numerous recommendations focused on “transforming the way pain is understood,
assessed, treated, and prevented.” Recommendations focused on the need for better
pain measurement and reporting; population level strategies for prevention, treat-
ment, management, and research; development of person-centered treatments and
initiatives that reduce barriers to access; expansion and redesign of educational
programs; and increased federal investment in pain research. The report includes
the importance of physical activity for chronic pain prevention and the value of
exercise training and physical therapy as part of a multidisciplinary approach to
chronic pain management.
The reasons for the rising prevalence of chronic pain are not well understood but a
rapidly aging population, rising rates of obesity, and physical inactivity are
suggested as primary reasons (Rice et al. 2016). Physical inactivity is a risk factor
for developing CMP conditions. A retrospective longitudinal cohort study of young
adults (19–24 years) in Sweden reported that stress (Odds Ratio (OR) = 1.6; 95%
Confidence Interval (CI): 1.0, 2.4), non-restorative sleep (OR = 1.5; 95% CI: 1.0,
2.3), and physical inactivity (OR = 1.8; 95% CI: 1.1, 3.0) increased risk for
developing chronic pain 1 year, but not 4 years, after baseline (Lindell and
Grimby-Ekman 2022). Among Norwegian adults, exercising for more than 3 days
per week at a medium intensity reduced the risk of chronic widespread musculo-
skeletal complaints such as pain or stiffness (OR = 0.72; 95% CI: 0.59, 0.88) and
there was a 53% lower prevalence of chronic widespread musculoskeletal com-
plaints for those that “maintained a medium activity level” over the 11-year study
period (Holth et al. 2008). The relationship between chronic pain and physical
activity is bidirectional. People with widespread pain were found to be more likely
(relative risk ratio = 4.5; 95% CI: 3.2, 6.2) to report that their physical activity levels
were “less” or “much less” than their age-group peers (McBeth et al. 2010). Device-
measured physical activity and cardiopulmonary fitness have also been shown to be
lower among those with chronic pain (Duque et al. 2009; McLoughlin et al. 2011;
Pianosi et al. 2017; Smeets et al. 2006; Suárez et al. 2010; Zambolin et al. 2022) and
pain is a primary barrier to a physically active lifestyle (Vos et al. 2015; Boutevillain
et al. 2017; Clark 1999). Poor physical function combined with low levels of
physical activity and aerobic fitness in chronic pain patients suggest that exercise
interventions may aid in reducing the overall burden of chronic pain.
This chapter provides an overview of the strength of the evidence regarding
exercise treatment for chronic LBP, OA, rheumatoid arthritis (RA), chronic cervical
pain (CCP), chronic widespread pain (CWP), fibromyalgia syndrome (FMS), and
Exercise Training for Chronic Pain: Available Evidence,. . . 333

chronic neuropathic pain. Current recommendations regarding exercise prescription

are reviewed, and although limited, some of the proposed mechanisms for exercise’s
treatment effects are presented. The chapter concludes with a discussion of current
knowledge gaps and needs for future research. This chapter is not meant to be a
comprehensive review of exercise treatment for all chronic pain conditions, but
rather a representative overview of some of the most common chronic pain condi-
tions and thus should provide the reader with a general understanding for the current
state of the literature.

2 Chronic Low Back Pain

Presenting in the area between the lower edge of the ribs and the buttocks, LBP can
occur with or without accompanying sciatic nerve pain (i.e., pain radiating from the
lower back and down the legs). Chronic LBP can be classified as either a primary or
secondary musculoskeletal pain condition (often labeled non-specific or specific,
respectively). These conditions are defined by pain felt in the musculoskeletal tissues
(e.g., bones, joints, muscles, tendons) and are grouped by their location. Specific
LBP is considered a secondary chronic musculoskeletal pain associated with
spondylosis or after musculoskeletal injury (Perrot et al. 2019). Chronic secondary
LBP can result from issues such as spondylosis, musculoskeletal injury, tumors, or
neurologic conditions (e.g., Parkinson’s disease, multiple sclerosis) and comprises
5–15% of all chronic LBP cases (Hoy et al. 2010a). For secondary LBP, treatment
options are generally focused on the assumed root cause of the pain. LBP of any
kind, whether acute, subacute, or chronic, has a lifetime prevalence of ~40% and is a
leading cause of YLDs (Maher et al. 2017; Manchikanti et al. 2014). Most cases of
LBP resolve in less than 6 weeks, with only 5–10% of patients experiencing
persistent pain; however, it is also estimated that 24–33% of those with acute LBP
will have a recurrence within 12 months (Manchikanti et al. 2014). The incidence,
risk of recurrent episodes, and recovery rates for LBP are poorly understood due to a
lack of high-quality evidence (Costa et al. 2009; Da Silva et al. 2017). Treatment in
both recurrent and chronic LBP is focused on reducing pain symptoms and
preventing disability (Verkerk et al. 2012). Exercise is generally considered a
frontline treatment for chronic primary LBP and is recommended by most major
medical organizations (Oliveira et al. 2018).

2.1 Exercise in Chronic Low Back Pain

Exercise is a generally safe and efficacious intervention to reduce pain symptoms,

improve physical function, and avoid disability in chronic primary LBP. Multiple
modes of exercise (e.g., aerobic, resistance, yoga, Pilates, stabilization/coordination,
motor control therapy) have demonstrated significantly greater pain relief than usual
334 J. V. Ninneman et al.

care, with resistance and stabilization exercises often exhibiting the greatest benefits
(Hayden et al. 2005; Owen et al. 2020). A meta-analysis of 39 randomized controlled
trials (RCTs) reported a small general effect (Standard Mean Difference (SMD) = -
0.32, 95% CI: -0.44, -0.19) of exercise compared to usual care. Exploratory
subgroup analyses found that both stabilization (SMD = -0.47, 95% CI: -0.77,
-0.18) and resistance (SMD = -0.50, 95% CI: -0.77, -0.24) exercise had larger
effects, while aerobic (SMD = 0.04, 95% CI:-0.31, 0.39) and “combined”
(SMD = -0.16, 95% CI:-0.29, -0.04) exercise modalities had smaller effects
(Searle et al. 2015). A more recent network meta-analysis reported that Pilates,
McKenzie therapy (i.e., a physical therapy technique involving primarily spinal
extension and flexion exercises), and strengthening exercises were superior at
reducing pain intensity and functional limitations compared to minimal therapy
with clinically meaningful changes ranging from 15 to 19 points for pain (0–100
VAS) and 10 to 12 points for functional limitations (0–100 Disability Index;
(Hayden et al. 2021). Limited data suggest that pain reductions may last for up to
3 years following exercise therapy, and continued adherence to the exercise signif-
icantly reduced the likelihood of reporting disability due to pain (Cecchi et al. 2014;
Rasmussen-Barr et al. 2009). Multiple types of exercise have also been shown to
reduce the risk of work-related disability (Oesch et al. 2010). Although neither short-
term (4 weeks: OR = 0.80, 95% CI 0.51, 1.25) nor intermediate-term (6 months:
OR = 0.78, 95% CI 0.45, 1.34) effects were found, odds of disability were reduced
by 34% for longer-term follow-ups (1 year: OR = 0.66, 95% CI: 0.48, 0.92).
The optimal dose (e.g., duration, frequency, intensity) of exercise needed to
reduce various pain outcomes for chronic LBP patients has not been identified for
most types of exercise. A recent review of stabilization exercise therapy for LBP
recommended that patients should exercise for at least 20–30 min per session and
only 3–5 times per week, with the benefits for pain diminishing for larger doses
(Mueller and Niederer 2020). Importantly, exercise, particularly when supervised, is
safe for individuals with chronic primary LBP. Reports of adverse events are rare,
with a majority related to a transient increase in pain or stiffness (Hayden et al. 2005;
Saragiotto et al. 2016).

2.2 Guidelines for Exercise in Low Back Pain

Several medical organizations endorse regular exercise as a component of standard

care for acute and chronic LBP. The European Spine Journal releases periodic
reviews of clinical treatment guidelines. A recent review highlighted that all guide-
lines, across 14 different countries, recommend the use of exercise in treatment of
“non-specific” LBP–although the mode, intensity, and language used for prescrip-
tion were not consistent across organizations (Oliveira et al. 2018). The American
College of Physicians strongly recommends initial and continued
non-pharmacological treatment of chronic LBP with exercise. They further advise
Exercise Training for Chronic Pain: Available Evidence,. . . 335

that pharmacologic therapy should only be considered following an inadequate

response to non-pharmacologic options (Qaseem et al. 2017). The Academy of
Orthopedic Physical Therapy recommends the use of multimodal exercise interven-
tions as therapy for LBP. They have specifically endorsed trunk muscle strengthen-
ing exercises as well as endurance, aerobic, aquatic, and general exercise for both
acute and chronic LBP (George et al. 2021). The Departments of Veterans Affairs
and Defense jointly produced a clinical practice guideline for the treatment of LBP
and endorsed “structured, clinician-directed exercise” to manage pain and disability
but offered few specifics for an optimal program (VA/DoD Clinical Practice Guide-
line 2022). The American College of Sports Medicine (ACSM) recommends meet-
ing the public health guidelines for physical activity with a focus on resistance
exercise to help maintain good postural strength (American College of Sports
Medicine 2019). Multiple modes of exercise are beneficial for reducing pain,
improving physical function, and avoiding disability; treatment guidelines reflect
this evidence through their recommendations. Considering there is insufficient
evidence to support the optimal dose of exercise, clinical guidelines have stopped
short of recommending a specific duration, intensity, frequency, and length of
exercise for the treatment of chronic LBP.

2.3 Potential Mechanism of Action in Low Back Pain

Numerous mechanisms of how exercise can improve chronic primary LBP have
been proposed, but few have been directly tested. Thus, the mechanisms of why
exercise improves pain and physical function are largely unknown. Moreover, the
root cause of pain in non-specific LBP is not well characterized, and this makes
identifying a potential therapeutic target more challenging (Müller-Schwefe et al.
2017). The mechanisms most often discussed in chronic primary LBP research
involve neuromuscular adaptations that occur during exercise training such as
increased activation and strengthening of lower back musculature, increasing flex-
ibility, and improved lumbar kinematics and proprioception (Wun et al. 2021).
However, exercise interventions focusing on neuromuscular adaptions resulting
from motor control exercises and spinal manipulation have generally failed to see
any meaningful associations between changes in strength, flexibility, or control of
lumbar movement and changes in pain (Steiger et al. 2012; Taulaniemi et al. 2019).
Psychosocial (e.g., improvements in fear avoidance, pain catastrophizing), neuro-
physiological (e.g., neuroplastic changes in brain activation), and cardiometabolic
factors have all similarly been theorized to partially explain the benefits of exercise,
without much supportive data (Wun et al. 2021; Roussel et al. 2013). There is a need
for trials that directly test hypothesized mechanisms of chronic LBP–i.e., whether
the resulting changes in pain are mediated by a theoretical biological or biomechan-
ical adaptation.
336 J. V. Ninneman et al.

One randomized, double-blind, placebo-controlled cross-over study directly

tested whether endogenous opioid function may partially explain pain improvements
resulting from exercise training (n = 38, 55.3% female) compared to usual activity
(n = 44, 65.9% female) in chronic LBP (Bruehl et al. 2020). The exercise interven-
tion consisted of 30-min sessions of aerobic exercise training three times per week
for 6 weeks at an intensity ranging from 70–85% of heart rate reserve. Endogenous
opioid activity was operationalized as the difference in heat pain ratings in response
to thermally evoked pain tolerance testing following the administration of naloxone
or placebo infusions, with greater differences (i.e., higher pain ratings under nalox-
one compared to placebo) indicative of greater endogenous opioid activity. Aerobic
exercise training resulted in meaningful changes in clinical pain ratings for 40.5% of
the exercise training group compared to 27.3% of controls and pain interference
ratings (PROMIS Interference) were moderately (Cohen’s d = 0.53) improved.
Endogenous opioid activity was found to increase from pre- to post-intervention,
but only for the female participants in the exercise condition. Greater increases in
endogenous opioid activity were associated with greater improvements in clinical
pain ratings and higher exercise doses (i.e., greater average minutes in the target
heart rate zone). These results suggest that pain improvements in chronic LBP from
aerobic exercise training may be partially mediated by improvements in endogenous
opioid activity for a subset of patients.

3 Osteoarthritis

OA is a common form of arthritis and one of the most common causes of joint
disorders. When OA is accompanied by significant pain symptoms, it can include an
additional diagnosis of chronic secondary musculoskeletal pain (Nicholas et al.
2019; Perrot et al. 2019). This condition is characterized by the degeneration of
cartilage in the joint space and inflammation of the synovial fluid surrounding the
joint. The prevalence of OA varies greatly based on the body location, geographic
location, and method of diagnosis (Pereira et al. 2011). Point prevalence estimates of
knee OA range from 16–28%, hip OA estimates range from 10–25%, and rates of
hand OA range from 7–26% (Vina and Kwoh 2018; Johnson and Hunter 2014). The
prevalence of OA is related to modifiable (e.g., muscular strength, a history of joint
injury) and non-modifiable risk factors, with age being one of the strongest pre-
dictors of OA (Shane Anderson and Loeser 2010). The symptoms associated with
OA include pain, joint stiffness, joint instability, reduced function, and when pain
persists, psychological distress (Hunter et al. 2008; Wieland et al. 2005). Moreover,
OA can lead to difficulties with mobility, completing activities of daily living, and
decreases in overall QoL (Clynes et al. 2019). Exercise is commonly recommended
with the goal of reducing pain, joint stiffness, and body weight, while increasing
flexibility and muscular strength around the joint (Holden et al. 2021).
Exercise Training for Chronic Pain: Available Evidence,. . . 337

3.1 Exercise in Osteoarthritis

As detailed below, the beneficial effects of exercise on OA pain have been well
documented by multiple meta-analyses. Pain (assessed using various measures of
pain intensity and impact) is reduced in OA immediately following exercise inter-
ventions and there is moderate evidence for pain reductions in the short-term (2–-
6 months) post-intervention (Fransen et al. 2015a; Raposo et al. 2021; Wellsandt and
Golightly 2018). OA pain is generally reduced by a moderate to large degree
immediately following an exercise intervention (SMD range: 0.49–1.20), resulting
in, on average, a decrease of 12 points on a 100-point scale (Fransen et al. 2015a).
Notably, the magnitude of the effect of exercise on pain is greater than commonly
prescribed pharmacologic treatments (e.g., acetaminophen, naproxen, celecoxib,
etc., compared to an oral placebo; Hedges’ g range: 0.18–0.33) and is similar to
the most effective pharmacologic interventions (interarticular hyaluronic acid, com-
pared to an oral placebo (Hedges’ g = 0.63; (Bannuru et al. 2015; Beaudart et al.
2020). Similar to pain, physical function is improved with exercise by a moderate
degree (SMD range: 0.44–0.52), and these effects are consistently larger than
reported for pharmacological treatments (SMD range: 0.18–0.40; (Fransen et al.
2015a; Raposo et al. 2021; Wellsandt and Golightly 2018). Exercise has a small, but
consistent, impact on QoL in patients with OA (SMD range: 0.15–0.44; (Fransen
et al. 2015a; Raposo et al. 2021; Wellsandt and Golightly 2018).
The benefits of exercise are not isolated to a certain mode; several types of
exercise (e.g., aerobic, resistance, Pilates, yoga, tai chi) have been shown to be
beneficial in OA. Meta-analytic data demonstrate only small differences in the
magnitude of improvement of pain outcomes among aerobic, resistance, and perfor-
mance exercise (SMD: 0.67, 95% CI: 0.39, 0.94; 0.62, 95% CI: 0.45, 0.79; 0.48,
95% CI: 0.11, 0.85, respectively; (Juhl et al. 2014). This same review also reported a
lack of evidence to support that engaging in multiple types of exercise yields greater
benefits. Trials incorporating a combination of exercise types were not as effective
(SMD = 0.16, 95% CI: -0.04, 0.37) compared to more concentrated prescriptions
focusing on a singular type of exercise (SMD = 0.61, 95% CI: 0.48, 0.75). One trial
comparing non-weight-bearing quadriceps strengthening exercises to functional
exercises reported that pain and physical function were significantly improved
following 12 weeks of exercise in both groups, with no significant difference in
the magnitude of improvement (Bennell et al. 2020). Further, the benefits of exercise
can be realized in a variety of settings (e.g., home-based, class-based, or individu-
ally), with greater pain reductions occurring with individually-based interventions
(Fransen et al. 2015b). The benefits of exercise on pain persisting beyond 6 months
post-intervention are less consistent; however, it is unclear from the cited literature
whether participants maintained the same level of activity during the follow-up.
Consistent participation in an exercise program is likely necessary to maintain the
therapeutic benefits of exercise on OA pain (Marks 2012).
338 J. V. Ninneman et al.

3.2 Guidelines for Exercise in Osteoarthritis

According to current clinical guidelines, exercise is the most consistently

recommended frontline treatment for OA (Conley et al. 2023). The most recent set
of American College of Rheumatology (ACR) guidelines strongly recommend the
use of exercise for the treatment of knee, hip, and hand OA, but does not set forth
specific recommendations (Kolasinski et al. 2020). Non-specific recommendations
are primarily the result of two factors: the lack of sufficient evidence for a universally
efficacious prescription and the beneficial effects of multiple exercise types, fre-
quencies, and doses. The European Alliance of Associations for Rheumatology
(EULAR) recommends physical activity and weight loss, if overweight, as an
integral part of standard care for OA (Fernandes et al. 2013; Kloppenburg et al.
2019; Rausch Osthoff et al. 2018). The National Institute for Health and Care
Excellence (NICE) states that exercise should be offered based on needs (e.g.,
local muscle strengthening or general aerobic fitness) and combined with an educa-
tional program or behavioral change approaches (NICE 2022). The NICE guidelines
also state, “doing regular and consistent exercise, even though this may initially
cause pain or discomfort, will be beneficial for their joints and that long-term
adherence to an exercise plan increases its benefits by reducing pain and increasing
functioning and quality of life” (NICE 2022). The Ottawa Panel clinical practice
guidelines recommend the use of progressive aerobic and strength training programs
to best treat OA (Brosseau et al. 2017a,b). The ACSM similarly recommends a
general exercise program, matching the general population recommendations, to
improve pain and function in OA. Although the specific frequency, intensity, time,
and type parameters for the most effective exercise intervention have not been
defined, exercise in some form is consistently recommended in the treatment of OA.

3.3 Potential Mechanism of Action in Osteoarthritis

Exercise elicits a systemic anti-inflammatory response, that may partially explain the
hypoalgesic effects of exercise in conditions characterized by chronic inflammation
(i.e., OA, RA). Acute exercise stimulates the release of Interleukin (IL)-6 from
contracting skeletal muscle (Pedersen et al. 2001). IL-6 is often considered a
pro-inflammatory cytokine; however, when released via muscle contraction, it can
act as a myokine, producing local and systemic anti-inflammatory effects through
the downregulation of other pro-inflammatory cytokines (e.g., tumor necrosis factor
α, C-reactive protein) and upregulation of anti-inflammatory cytokines (e.g., IL-10;
(Benatti and Pedersen 2015; Metsios and Kitas 2018). Exercise also stimulates the
release of cortisol and catecholamines, reduces the amount of pro-inflammatory
monocytes in the blood, and downregulates the expression of toll-like receptors,
all of which have anti-inflammatory effects (Gleeson et al. 2011). These acute
Exercise Training for Chronic Pain: Available Evidence,. . . 339

benefits may accumulate over time, resulting in the chronic reduction of inflamma-
tion levels and consequently, reduced pain.
The mechanisms by which exercise specifically benefits OA are not well charac-
terized, but there are several theories with modest levels of support. Cartilage, bone,
and synovium release pro-inflammatory signaling molecules in OA, generating and
maintaining a pro-inflammatory state in the affected joints (Berenbaum 2013) and
the evidence suggests these inflammatory signals contribute to the pain experienced
in OA (O’Neill and Felson 2018). Conversely, the established anti-inflammatory
effects of exercise, as described above, may act to reduce pain post-exertion
(Gleeson et al. 2011). Exercise may mitigate OA pain by suppressing inflammation
through the promotion of an anti-inflammatory state and a decrease in the levels of
circulating pro-inflammatory signaling molecules (Griffin et al. 2012; Lu et al.
2021). However, support for this hypothesis derives primarily from research
employing animal models of OA (e.g., treadmill exercise of mice following a high
fat diet or pharmacological injections into the intra-articular space). Studies designed
to test and confirm this mechanism in humans with OA have been mixed, with only a
modest number of studies (30%) reporting a decrease in circulating biomarkers and
the majority of studies (63%) reporting no change following an exercise intervention
(Bricca et al. 2019). Muscular strength and range-of-motion adaptations from
strength training have also been investigated as potential mediators for pain
improvements following exercise training (Zeng et al. 2021). Multiple RCTs have
found significant strength benefits, and when restricting analyses to studies that have
found benefits on pain, over 70% of the trials reported significant strength increases.
Moreover, one trial reported that strength gains were significantly associated with
reductions in pain and disability (Bartholdy et al. 2017). Brain activity in response to
experimental pain stimuli and resting connectivity may also be altered in response to
an exercise program in OA, but more research is needed to understand whether and
how these brain adaptations translate to changes in pain regulation and perception
(Liu et al. 2019; Öztürk et al. 2021).

4 Rheumatoid Arthritis

RA is a chronic autoimmune inflammatory disease that can affect many body

systems, but most commonly impacts musculoskeletal joints leading to pain, joint
stiffness, impaired range of motion, fatigue, and difficulty with activities of daily
living (Aletaha et al. 2010; Arnett et al. 1988). Chronic pain symptoms associated
with RA are diagnosed as secondary musculoskeletal pain (Nicholas et al. 2019;
Perrot et al. 2019). RA can have profound effects on the synovial joints, causing
damage through the erosion of bony surfaces and degradation of cartilage. This dual
impact contributes to the progression of joint destruction and may result in severe
disability. Moreover, the consequences of RA extend beyond joint damage, as the
condition can impact other organ systems and is associated with an increased risk of
premature mortality (Van Der Woude and Van Der Helm-van Mil 2018). It is
340 J. V. Ninneman et al.

estimated that RA affects approximately 0.24% of the global population, with the
prevalence rate for women being roughly twice that for men. However, rates vary
greatly by geographical location (Van Der Woude and Van Der Helm-van Mil 2018;
Cross et al. 2014). Individuals with RA are less physically active than healthy
individuals, as quantified by both self-report and device-based measures (Verhoeven
et al. 2016). Pain and fatigue are consistently reported as the greatest barriers to
physical activity participation in this patient population followed by reduced mobil-
ity/functional ability, stiffness, and lack of knowledge pertaining to the design and
potential benefits of exercise programs for RA (Verhoeven et al. 2016; Veldhuijzen
Van Zanten et al. 2015). Further, those with RA who report high levels of sedentary
behavior are more likely to report worse symptoms and disability than those who are
physically active (Henchoz et al. 2012).

4.1 Exercise in Rheumatoid Arthritis

Exercise is a crucial component in the non-pharmacological management of RA. It is

safe, complements the primary pharmacological treatments like disease-modifying
antirheumatic drugs, and offers multiple additional benefits, including, but not
limited to, pain reduction. Both regular aerobic and resistance exercise are safe for
RA patients and reduce pain by a moderate degree (SMD range: 0.31–0.61) and
reduce the amount of swollen and tender joints (i.e., “disease activity”) by a small-to-
moderate degree (SMD range: 0.14–0.69; (Baillet et al. 2010; Wen and Chai 2021;
Ye et al. 2022). Exercise also reduces fatigue by a small degree (SMD ~0.35;
(Cramp et al. 2013; Kelley et al. 2018). Function, as assessed through the Health
Assessment Questionnaire, consistently shows a modest improvement (mean differ-
ences (MD) range: 0.22–0.30) following both aerobic and resistance exercise train-
ing (Ye et al. 2022; Baillet et al. 2012). Few direct comparisons of the effectiveness
of resistance and aerobic exercise have been conducted in RA patients. However, the
magnitude of changes reported in the cited literature for each exercise modality are
comparable (Juhl et al. 2014).
The characteristics of exercise training that may impact the beneficial effects of
exercise for RA pain have not yet been determined. Two meta-analyses, one
focusing on aerobic exercise and the other on resistance exercise, reported that
different exercise parameters, such as session duration, training program duration,
frequency, and intensity, did not consistently influence the exercise responses
(Baillet et al. 2010, 2012). Few studies have directly tested how these parameters
affect outcomes. One early trial compared 12 weeks of either high (i.e., weight-
bearing activities including knee-bends, step-ups, and fast walking) or low intensity
(i.e., non-weight-bearing range of motion and isometric) exercise and did not report
significant differences for pain, function (i.e., self-reported and timed walk and stair
tests), disease activity, or inflammation (Van Den Ende et al. 1996). It is unclear if
similar benefits occur when exercise treatment is delivered at home or under expert
supervision (Baillet et al. 2010, 2012). Emerging evidence has demonstrated that
Exercise Training for Chronic Pain: Available Evidence,. . . 341

aquatic exercise may provide similar benefits for disease activity while reducing the
likelihood of exacerbating joint pain and swelling (Siqueira et al. 2017). It remains
unclear what mode, duration, frequency, or intensity of exercise is required to
optimize clinical improvements in pain, physical function, and QoL in those
with RA.

4.2 Guidelines for Exercise in Rheumatoid Arthritis

The existing treatment guidelines for RA from multiple organizations list pharma-
cological interventions as a first-line treatment and support the use of general
exercise as an adjunct therapy. The 2022 ACR guidelines for the treatment of RA
strongly recommend consistent engagement in exercise, with the specific prescrip-
tion to be individually tailored based on capabilities, disease trajectory, and comor-
bid conditions. The ACR guidelines also conditionally recommend engagement in
aerobic, aquatic, and mind-body exercise. The conditional recommendations are
attributed to the low certainty of evidence stemming from the small sample sizes
of included studies, the presence of serious biases (e.g., a lack of participant
blinding, uncertainty about assessor blinding), a recognition of varying patient
preferences for different types of exercise, and various obstacles (e.g., cost, access
to facilities) that often prevent RA patients from regularly engaging in those types of
exercise (England et al. 2023). The 2018 NICE guidelines for the treatment of RA
encourage regular exercise and recommend the use of physiotherapy (i.e., strength-
ening, general fitness, stretching, and proprioceptive exercises) to improve general
fitness. In addition, exercises intended to enhance joint flexibility, increase muscle
strength, and manage functional impairments (e.g., pain or dysfunction in the hands)
are also recommended. The NICE guidelines, however, do not go into any greater
detail on the optimal dose, intensity, or duration of exercise to achieve these out-
comes (Allen et al. 2018). The Ottawa Panel stated, “good evidence exists. . . that
therapeutic exercise including functional strengthening and low- or high-intensity
exercises, should be included as an intervention for patients with RA. Therapeutic
exercises reduce pain while improving periarticular muscle force, aerobic capacity,
and joint mobility” (Ottawa Panel Evidence 2004). The 2018 EULAR guidelines do
not provide specific prescriptions for exercise but do recommend patients with
inflammatory arthritis, including RA, perform enough physical activity to meet
public health guidelines (Rausch Osthoff et al. 2018). The ACSM also recommends
that RA patients attempt to meet the physical activity guidelines for healthy adults,
although they advise avoiding vigorous exercise during symptom flare-ups; avoiding
vigorous, highly repetitive activities; and to expect some discomfort, but not pain,
after workouts.
342 J. V. Ninneman et al.

4.3 Potential Mechanism of Action in Rheumatoid Arthritis

Pharmacologic therapies primarily alleviate RA disease activity by targeting inflam-

mation through various proposed mechanistic pathways. Elevated levels of periph-
eral inflammation are believed to amplify nociceptive signaling, serving as a key
factor driving pain symptoms in RA (Guo et al. 2018). The most widely reported
mechanism of action for RA drugs is through the increased release of adenosine into
the extracellular space leading to lower levels of inflammation (Friedman and
Cronstein 2019). Due to the widespread nature of RA disease activity (e.g., circu-
lating inflammatory biochemicals), other potential mechanisms for disease modifi-
cation and pain relief include decreased leukocyte recruitment, decreased bone
degeneration, and reduced spinal and supraspinal nociceptive signaling (Borea
et al. 2018). Further, there is evidence that pharmacologic treatment can act directly
on immune cells to reduce pro-inflammatory cytokine production. The benefits of
exercise training for RA may be partially related to its anti-inflammatory properties,
detailed above (Walsh and McWilliams 2012).
The cytokine response following acute resistance exercise is similar between RA
and otherwise healthy controls (Pereira Nunes Pinto et al. 2017). Both aerobic and
resistance exercise training in RA have been shown to decrease inflammation and
circulating pro-inflammatory cytokines by a moderate to large effect (Wen and Chai
2021; Azeez et al. 2020). Regular exercise can reduce visceral fat, which in turn may
slow the release of pro-inflammatory cytokines, as adipose tissue is a potent IL-6
secretor (Metsios et al. 2015, 2020). Although reductions in body fat and increases in
lean mass are consistently observed in RA following resistance exercise trials, the
impact of aerobic exercise on body composition in RA is still inadequately under-
stood (Yekini and Grace 2023). Exercise has many other beneficial effects for
patients with RA, including reducing risk factors for cardiovascular disease, decreas-
ing risk of falls, and improving mental health (Cooney et al. 2011; Rongen-van
Dartel et al. 2015; Sul et al. 2020). Trials that establish the optimal dose, intensity,
and mode of exercise for clinical benefits, while testing associations with inflamma-
tory mediators of disease and pain symptoms, are needed to advance exercise
prescription for this patient population.

5 Chronic Cervical Pain

Cervical (i.e., neck) pain occurs in the upper back region, defined superiorly by the
superior nuchal line and laterally/inferiorly by the spine of the scapula (Guzman
et al. 2009). CCP can be considered either a primary or secondary musculoskeletal
pain condition, commonly referred to as non-specific or specific, respectively.
Common causes of secondary cervical pain may include whiplash or other soft
tissue injury, tumors, or RA (Nicholas et al. 2019). It is estimated that nearly half
of all adults will encounter neck pain at some juncture in their lives, with women
Exercise Training for Chronic Pain: Available Evidence,. . . 343

experiencing it at higher rates than men (Fejer et al. 2006; Hoy et al. 2010b). The
hypothesis that weak or easily fatigued neck musculature serves as a potential
underlying cause of primary CCP has been proposed, leading to the suggestion of
exercise as a potential treatment.

5.1 Chronic Cervical Pain and Exercise

Exercise has been shown to be effective at reducing pain, decreasing disability, and
increasing QoL in CCP (Bertozzi et al. 2013; O’Riordan et al. 2014). Most studies
have assessed the effectiveness of various forms of neck strengthening and/or
stretching, primarily considering the localized nature of the painful region and the
underlying muscular weakness. Resistance exercise reduces pain and disability by a
moderate to large effect size (Hedges g range: 0.53–1.53, and 0.39–0.75, respec-
tively) in the short to intermediate term (0–6 months post-intervention; (Bertozzi
et al. 2013; De Zoete et al. 2021). The magnitude of pain and disability reductions is
similar to that achieved with cognitive behavioral therapy (Monticone et al. 2015).
When exercise and cognitive behavioral therapy are directly compared, exercise
produces a more rapid improvement in pain, with benefits occurring as early as
4 weeks into an exercise program (Vonk et al. 2009). Few studies have focused on
aerobic exercise in isolation but have found generally positive effects on pain and
disability (Paraskevopoulos et al. 2023). Adding aerobic exercise to a neck-
strengthening program resulted in greater improvements in pain, disability, and
function than the neck-strengthening program alone (Daher et al. 2020). One
meta-analysis reviewed the existing exercise trials to determine the optimal fre-
quency, intensity, time, and type of an exercise program for CCP. This review
reported that an exercise program should consist of three multimodal training
sessions per week, each 30–45 min in duration, at an individually tailored intensity
for the best results (O’Riordan et al. 2014).

5.2 Guidelines for Exercise in Chronic Cervical Pain

The American Physical Therapy Association recommends, on a moderate evidence

base, that clinicians should consider coordination, strengthening, and endurance
exercises to reduce neck pain (Blanpied et al. 2017). They also recommend the
use of stretching, nerve mobilization, and thoracic mobilization and manipulation to
reduce pain and disability. Clinical practice guidelines published in the Journal of
Manipulative and Physiological Therapeutics and the European Spine Journal
recommended the use of supervised strengthening exercises alone or as part of a
multimodal treatment plan that also includes stretching and joint manipulation for
primary CCP (Bussières et al. 2016; Côté et al. 2016). However, in a review of 17
European clinical treatment guidelines, only six included specific guidelines for the
344 J. V. Ninneman et al.

treatment of CCP, and among these, only three recommended exercise for CCP
(Corp et al. 2021).

5.3 Potential Mechanism of Action in Chronic Cervical Pain

Two main mechanisms have been proposed to explain why exercise can reduce
cervical pain. One mechanism is that strength training of the neck muscles increases
both muscular strength and endurance (Andersen et al. 2011; Ylinen et al. 2006)
thereby improving cervical postural control (Chung and Jeong 2018). Greater
strength and endurance of the neck musculature could allow for better head and
neck control throughout the day and less cervical lordosis (i.e., spinal compression),
thereby leading to less pain. Notably, one trial compared stretching exercises to
strengthening coupled with stretching exercises and reported no differences in pain
upon completion of the 12-month training program (Häkkinen et al. 2008). How-
ever, the strength and stretching group did not demonstrate consistent strength
improvements relative to the stretching group and this may explain the lack of
differences in pain outcomes between the two groups. Alternatively, exercise can
influence the central processing and modulation of pain, providing an additional
explanation for the pain-relieving benefits (Heredia-Rizo et al. 2019; Rittig-
Rasmussen et al. 2014)

6 Chronic Widespread Pain and Fibromyalgia Syndrome

CWP is a primary pain condition with diffuse pain in at least four of five body
regions (i.e., axial spine, above and below the waist, both sides of the body) and is
associated with significant emotional distress and/or functional disability (Interna-
tional Classification of Diseases, Eleventh Revision 2019; Nicholas et al. 2019).
FMS is a form of CWP associated with concomitant fatigue, sleep disturbance,
cognitive dysfunction, stiffness, and tenderness and is diagnosed based on clinical
case definition criteria (Nicholas et al. 2019; Wolfe et al. 1990, 2016). Clinical
presentations of FMS are heterogeneous and multimorbidity is common. Estimates
suggest over half of FMS patients have comorbid depression/major depressive
disorder, over one-third have bipolar disorder, panic disorders, anxiety disorders,
or post-traumatic stress disorder, and nearly half may have comorbid myalgic
encephalomyelitis/chronic fatigue syndrome (Kleykamp et al. 2021; Ramírez-
Morales et al. 2022). Comorbid chronic pain conditions such as headache or
orofacial pain, temporomandibular disorder, and irritable bowel syndrome are also
common (Kleykamp et al. 2021). The global prevalence of CWP has been estimated
as 11.8% and is more common in females with a ratio of 2:1 (Mansfield et al. 2016).
The global prevalence of FMS is lower at 2.7%, but with a higher female-to-male
ratio of 3:1 (Nicholas et al. 2019; Queiroz 2013).
Exercise Training for Chronic Pain: Available Evidence,. . . 345

6.1 Exercise for Chronic Widespread Pain and Fibromyalgia

Syndrome

A series of Cochrane systematic reviews and meta-analyses have investigated

randomized controlled trials (RCTs) of different types of exercise interventions for
FMS including: resistance training (Busch et al. 2013), aquatic training (Bidonde
et al. 2014), aerobic training (Bidonde et al. 2017), flexibility training (Kim et al.
2019), mixed exercise training (Bidonde et al. 2019), and mind-body exercise
training (Theadom et al. 2015). Primary outcomes included health-related QoL,
pain intensity, stiffness, fatigue, physical function, physical fitness, withdrawals,
and adverse events. Preferred measures for each outcome were guided by consensus
statements from the Outcome Measures in Rheumatoid Arthritis Clinical Trials
initiative for clinical trials in FMS (Choy and Mease 2009). The overall certainty
of the evidence was based on the Grading of Recommendations Assessment,
Development, and Evaluation (GRADE) approach. The clinical importance of
each treatment effect was based on the Philadelphia Panel guidelines, which consider
a minimally clinically important difference as a 15% absolute improvement in pain
intensity or a 15% relative improvement for all other outcomes (Albright et al. 2001).
The main findings from each Cochrane review are described below.
Resistance Training Busch et al. (2013) evaluated five RCTs (241 participants)
that compared resistance training versus control, aerobic training, or flexibility
training. Compared to control conditions, there was low certainty evidence that
resistance training for 16 to 21 weeks (2–3 sessions/week) improved QoL, physical
function, pain intensity, tenderness, fatigue, and strength. Effect sizes were moderate
to large (SMD range: 0.50–1.89) and many outcomes reached the threshold to be
considered clinically important differences. One included study provided low cer-
tainty evidence that improvements for QoL, fatigue, and pain intensity were retained
12 weeks after the intervention, but these were small and considered clinically
unimportant, suggesting that persistent training may be required to sustain benefits.
Relative to aerobic exercise interventions, resistance training elicited smaller
improvements in pain intensity and sleep quality. When compared to flexibility
training, resistance exercise appeared to induce greater improvements in QoL, pain
intensity, fatigue, and sleep quality. The certainty of these findings ranged from low
to very low based primarily on the small number of studies and the risks of bias
attributed to issues regarding inadequate blinding, selective reporting, and allocation
concealment.
Aquatic Training Bidonde et al. (2014) evaluated 16 RCTs (881 participants) that
compared aquatic training to control, land-based training, or different aquatic train-
ing programs. Aquatic training consisted of aerobic, resistance, and/or flexibility
exercises performed in a pool. Interventions lasted 3 to 32 weeks (1–4 sessions/
week; 30–70 min/session). There was low to moderate certainty evidence that
aquatic training, compared to control, improved QoL, physical function, pain inten-
sity, stiffness, tenderness, sleep quality, anxiety, cognitive performance, and fitness
346 J. V. Ninneman et al.

outcomes. The improvement in stiffness was large (SMD = -1.00, 95% CI: -1.91,
-0.10) and considered clinically important. Effect sizes for the remaining outcomes
were small to moderate (SMD range: -0.44 to -0.63). Protocols with longer
durations, higher frequencies, or greater accumulated time spent in the pool gener-
ally resulted in larger effect sizes for QoL, pain intensity, and strength outcomes.
Larger improvements in QoL and strength were also shown in studies reporting
lower baseline pain among their participants.
Aerobic Training Bidonde et al. (2017) evaluated 13 RCTs (839 participants) that
compared aerobic training to control, different aerobic training programs, or
non-exercise interventions. The average length of intervention was 15 weeks with
most sessions occurring three times per week for an average of 35 min. There was
moderate certainty evidence that aerobic training improved QoL and low certainty
evidence that it improved pain intensity, physical function, fatigue, and stiffness.
Improvements in pain intensity and physical function were considered clinically
important. Interventions with training volumes lower than those recommended by
the ACSM still improved FMS symptoms. Three studies provided low certainty
evidence that improvements in pain intensity and physical function remained
24 to 208 weeks after intervention, but these estimates were small and imprecise,
suggesting that persistent training may be required to sustain benefits. Results from
comparisons to other aerobic training programs or non-exercise interventions were
unclear given the low to very low certainty evidence, small number of studies, and
large heterogeneity between studies.
Flexibility Training Kim et al. (2019) evaluated 12 RCTs (743 participants) that
compared flexibility training to control, aerobic training, resistance training, or other
interventions. The average length of intervention was 12 weeks with one to three
sessions per week. There was very low certainty evidence that flexibility training
was more beneficial than aerobic training for stiffness (MD = -29.6, 95% CI: -
51.47, -7.73, 0–100 scale, with lower scores for less stiffness), but this was based
on one study with a small sample size (N = 15). No other significant differences
were found when comparing flexibility to resistance training or to untreated controls.
The certainty of the evidence for these outcomes was very low.
Mixed Exercise Training Bidonde et al. (2019) evaluated 29 RCTs (2088 partic-
ipants) that compared mixed exercise training to control, other exercise, or
non-exercise interventions (e.g., biofeedback, medications). Mixed exercise inter-
ventions included at least two types of exercise (i.e., aerobic, resistance, or flexibil-
ity). The average length of intervention was 13 weeks with an average of three
sessions per week ranging from 45 to 60 min in duration. There was moderate
certainty evidence that mixed exercise improved QoL, physical function, and fatigue
compared to control with the confidence intervals including both clinically important
and unimportant improvements for each outcome. Improvements for pain intensity
(moderate certainty) were small and considered clinically unimportant. There was
low certainty evidence for improved stiffness with the confidence interval including
both clinically important and unimportant changes. Very low certainty evidence
Exercise Training for Chronic Pain: Available Evidence,. . . 347

from a small number of heterogeneous studies made it unclear whether these

improvements were retained following intervention or how they compared to other
exercise or non-exercise interventions.
Mind-Body Exercise Training Theadom et al. (2015) evaluated 11 RCTs involv-
ing mind-body exercise including tai chi, yoga, qi-gong, dance, and Pilates. There
was very low-quality evidence of improvements for physical function, pain inten-
sity, and mood in some of the studies. However, differences between the interven-
tions, control groups, and outcomes used in these studies made conclusions difficult.
Collectively, these Cochrane reviews identified small-to-moderate group-average
improvements in multiple outcomes for patients with FMS following exercise.
Aerobic, aquatic, and mixed exercise training interventions provided the strongest
evidence, with mixed exercise having moderate certainty evidence of clinically
significant improvements in QoL, physical function, and fatigue. These findings
are likely attributable to the larger samples in these reviews and their inclusion of
additional studies. Further studies of resistance, flexibility, and mind-body exercise
training will allow for better comparisons between exercise modalities. The original
studies also varied in which outcomes were investigated, with more studies provid-
ing data for QoL and pain intensity than for outcomes such as fatigue, stiffness,
physical function, or physical fitness.
Similar withdrawal rates between interventions and control conditions were
found, suggesting exercise may be generally tolerated by FMS patients. However,
the collection and reporting of adverse events was inconsistent and often inadequate
in the analyzed studies. Among those that did, low rates and no serious adverse
events were reported. The most frequently mentioned adverse events included
increased pain, soreness, or fatigue during and/or after exercise.
Few of the original studies focused on fitness outcomes and many did not
measure activity levels outside the intervention, making it difficult to quantify the
exact relationship between exercise and clinical outcomes. Additionally, the per-
centage of females in the original studies ranged from 89–100% and the Cochrane
reviewers only included studies of patients meeting criteria for FMS. This makes it
difficult to generalize these findings to males and to those with CWP who do not
meet criteria for FMS. A recent study by Stegner et al. (2021) examined the effects of
resistance training (16 weeks; 2 sessions/week) in a predominately male sample of
Gulf War Veterans that included both individuals who met CWP criteria alone and
those who met additional criteria for FMS (Stegner et al. 2021). Training improved
group averages for global perception of change and muscular strength, but had no
effect on pain severity, fatigue, sleep quality, or total mood disturbance compared to
a waitlist control condition. Device-measured physical activity data indicated that
physical activity levels were maintained throughout the trial. No serious adverse
events were reported and adherence to the protocol was high (87% of training
sessions attended) indicating that the resistance exercise training program was
generally well-tolerated.
348 J. V. Ninneman et al.

6.2 Guidelines for Exercise in Chronic Widespread Pain

and Fibromyalgia Syndrome

Recent clinical practice guidelines have recommended exercise along with other
non-pharmacological therapies as first-line treatments for managing FMS (NICE
2021; Macfarlane et al. 2017; Kundakci et al. 2022a). Note that the following
guidelines do not differentiate CWP from FMS; this is likely attributable to historical
ambiguities surrounding the vocabulary and diagnostic criteria used for these con-
ditions (Butler et al. 2016). In 2021, the United Kingdom’s National Institute for
Health and Care Excellence (NICE) published guidance for the management of
chronic primary pain conditions (NICE 2021). The guidelines include offering
patients supervised group exercise programs for managing their symptoms and
promoting long-term general health. These programs should also take a patient’s
individual needs, preferences, and abilities into account. These recommendations are
based on their review of 91 RCTs showing that exercise reduced pain (23 studies)
and improved quality of life (22 studies) compared to usual care. Most interventions
included supervised group-based exercise and most examined either female patients
with FMS (58 studies) or patients with chronic neck pain (31 studies). They found no
evidence that treatment effectiveness differed between pain conditions, therefore the
NICE guidelines suggest applying these recommendations across all chronic pri-
mary pain conditions.
In 2017, the EULAR updated their recommendations for the management of
FMS, which suggest initial treatment should focus on patient education and
non-pharmacological therapies (Macfarlane et al. 2017). Of all the therapies
reviewed (both pharmacological and non-pharmacological) only aerobic and
strengthening exercise were given a “strong-for” recommendation by the committee.
The guidelines suggest following patient education with individualized and graded
physical exercise, which can be combined with other therapies if needed. However,
some have questioned how the committee determined the strength of their recom-
mendations due to apparent inconsistencies in how the criteria were applied,
suggesting that the evidence for cognitive behavioral therapy should have also
been given a strong-for recommendation (Thieme et al. 2017).
In 2022, a multidisciplinary expert panel performed a Delphi consensus to
provide recommendations for core and adjunctive non-pharmacological interven-
tions for pain, fatigue, sleep, and depression in FMS patients (Kundakci et al.
2022a). Panelists were asked to consider evidence from a recent meta-analysis
(Kundakci et al. 2022b) as well as their clinical experience. Aerobic exercise was
considered a core component of treatment for all four symptoms, along with patient
education, sleep hygiene, and cognitive behavioral therapy. Mind-body exercise was
considered a core treatment for pain, fatigue, and sleep, but an adjunct for depres-
sion. Strengthening exercise was considered a core treatment for pain and fatigue but
was not recommended for sleep or depression. Flexibility was recommended as a
core treatment for pain but was not recommended for the other three symptoms.
Exercise Training for Chronic Pain: Available Evidence,. . . 349

Clinical practice guidelines for FMS report the likely benefits of increasing
physical activity and usually emphasize the importance of tailoring exercise to the
patient’s needs, preferences, and abilities. However, there is often little information
provided for the clinician or the patient regarding how to implement this advice. The
ACSM, as part of their Exercise is Medicine efforts, created an infographic for
“Being Active with Fibromyalgia” promoting individual strategies for engaging in
various physical activities (https://www.exerciseismedicine.org/wp-content/
uploads/2021/04/EIM_Rx-for-Health_Fibromyalgia.pdf). Guidance is focused on
the individualized nature of FMS, emphasizing starting slow, keeping impact low,
and adjusting activity based on daily symptoms. Information regarding frequency,
intensity, and durations for aerobic and strength training activities is included, along
with information on navigating symptom flares, recovery, and personal choices.
Additional guidance is provided for flexibility, mixed exercise, yoga, tai chi, and
dance.

6.3 Potential Mechanism of Action in Chronic Widespread

Pain and Fibromyalgia Syndrome

Although their exact etiology and pathophysiology remain unclear, CWP and FMS
are often attributed to abnormal neural signaling in the central nervous system (CNS)
leading to an amplification of pain perception and contributing to the broader
symptoms that are associated with FMS (Clauw et al. 2011). This is supported by
evidence for structural, functional, and biochemical abnormalities in the CNS,
heightened sensitivity to various stimuli, and less robust pain inhibition, along
with limited evidence of peripheral abnormalities that may contribute to pain
symptoms (Sluka and Clauw 2016). Neuroinflammation is one potential factor that
may underlie CNS dysfunction and symptoms in FMS (Bains et al. 2023). Regular
exercise training can reduce neuroinflammation in neurological diseases and pro-
mote neuroplasticity by increasing multiple neurotrophic factors (Allen et al. 2015;
Scheffer and Latini 2020; Spielman et al. 2016); however, no exercise trials of FMS
have tested this mechanism. Animal models of widespread hyperalgesia have dem-
onstrated that regular physical activity is protective and, in some cases, blocks the
development of hyperalgesia (Lesnak and Sluka 2020; Lima et al. 2017; Sluka et al.
2012, 2013). These studies use repeated (5 days apart) injections of low pH saline
(e.g., pH 4 or pH 5) to produce widespread mechanical hyperalgesia–meant to mimic
CWP and FMS (Sluka et al. 2013). These studies further demonstrate that the
widespread hyperalgesia is 1) prevented when mice are given access to a running
wheel for 8 weeks prior to the low pH saline injections, and 2) treated when they are
given access to a running wheel for 3 weeks after the development of widespread
hyperalgesia (Lesnak and Sluka 2020; Lima et al. 2017).
The protective and pain-relieving effects of exercise are associated with activa-
tion of the NR1 subunit of N-methyl-d-Aspartate receptors in the brainstem (e.g.,
350 J. V. Ninneman et al.

nucleus raphe magus & rostral ventromedial medulla; (Sluka et al. 2012). These
studies suggest that regular physical activity can prevent chronic pain and treat it by
enhancing CNS nociceptive regulatory activity, but to the best of our knowledge
these mechanisms have not been rigorously tested in human chronic pain
populations. One scoping review of human exercise training trials in FMS reported
that 29 different potential mechanisms underlying the pain-relieving effects of
exercise were identified (Neelapala et al. 2023). Both physiological and psycholog-
ical mechanisms were proposed, and the most frequently discussed effects of
exercise were exercise-induced hypoalgesia, autonomic modulation, improved
sleep, increased muscle oxygenation, increased self-efficacy, improved mental
health, and the general benefits of an aquatic environment. In general, most of the
proposed mechanisms were not directly supported and the hypothetical reasoning
was largely based on limited research in healthy populations.

7 Neuropathic Pain

Defined as pain directly attributed to a somatosensory system lesion or disease

(Treede et al. 2008), neuropathic pain is estimated to affect somewhere between
7–10% of the general population (van Hecke et al. 2014). According to the new
ICD-11, chronic neuropathic pain is a primary diagnosis with the secondary classi-
fication being determined by the nervous area (i.e., central or peripheral) affected by
the identified lesion or disease (Scholz et al. 2019). Although frequently character-
ized by “neuropathic-like” symptoms (e.g., allodynia, hyperalgesia, ongoing burn-
ing pain, paroxysmal electric shock-like pain), symptoms of this type are neither
required nor sufficient for a diagnosis of neuropathic pain (Bannister et al. 2020).
These symptoms often become chronic and generally are not well managed with
standard analgesic therapies (Colloca et al. 2017). Patients with neuropathic pain
will also regularly report numbness, tingling, gait and balance disturbance, and
problems with fine motor skills (Dhawan et al. 2020). A diagnosis of neuropathic
pain for treatment is complicated and requires, at a minimum, a clinical examination
to verify that patient history, pain symptoms, and other sensory responses all support
a neuroanatomically plausible explanation (Finnerup et al. 2016). Even so, a diag-
nosis cannot be confirmed without a test locating the lesion or identifying the disease
that corresponds to the previously proposed neurological dysfunction. The neuro-
logical dysfunctions that may give rise to neuropathic pain can be induced through a
variety of other conditions. Consequently, neuropathic pain is associated with a
number of common conditions, including postherpetic neuralgia, diabetic peripheral
neuropathy (DPN), spinal cord injury (SCI), chemotherapy-induced peripheral neu-
ropathy (CIPN), HIV polyneuropathy, multiple sclerosis, amputation, peripheral
nerve damage, and stroke (Treede et al. 2008; Colloca et al. 2017). First-line
pharmacotherapy for neuropathic pain generally falls into the classes of tricyclic
antidepressants, serotonin and norepinephrine reuptake inhibitors, pregabalin, and
gabapentin. Many sufferers of neuropathic pain, however, are also managing
Exercise Training for Chronic Pain: Available Evidence,. . . 351

nociceptive pain and thus may be prescribed two or three analgesic medications in
combination to manage their symptoms (Bannister et al. 2020). Given the expense
and side effects associated with these treatments, not to mention their somewhat
modest success rate, alternative cost-effective non-pharmacologic therapies, like
exercise and physical therapy, should be explored.

7.1 Exercise in Neuropathic Pain

Compared to the other chronic pain conditions covered in this chapter, the body of
research investigating the effectiveness of exercise and physical therapy for neuro-
pathic pain is relatively small (Leitzelar and Koltyn 2021). In addition, the trials
designed to explore the impact of exercise often focus on neuropathic pain as the
result of a singular condition (e.g., DPN, CIPN, SCI) rather than general neuropathic
pain. As that is the case, we will cover the evidence in support of exercise and
physical therapy as treatments for neuropathic pain within a few of the particular
patient groups.
Diabetic Peripheral Neuropathy Diabetes mellitus affects a large portion of the
world population and is a growing problem. It has been estimated that more than
46 million people in the United States alone are living with diabetes (Wang et al.
2021). The most common complication of diabetes is DPN, which is estimated to
affect nearly half of all diabetic patients (Albers and Pop-Busui 2014). While
exercise has become a standard component of treatment for diabetes, its role in the
prevention or treatment of DPN is less established. For example, a meta-analysis of
exercise interventions designed to reduce neuropathic pain in patients with type
2 diabetes by Tatkiola et al. (2022) concluded that there was moderate quality
evidence to support a significant improvement in pain complaints following exercise
interventions in patients with type 2 diabetes. Even so, given the small number of
studies which met their criteria, and the heterogeneity of the interventions reviewed
(i.e., aerobic exercise alone or in combination with resistance exercise, high-
intensity interval training, and flexibility training), the authors felt they could not
make specific recommendations beyond the suggestion that exercise prescriptions
should include a combination of aerobic and resistance exercise and be of a duration
of 8–12 weeks before expecting any improvement. In a separate systematic review of
the literature on exercise for neuropathic pain, the authors identified only two RCTs
designed to investigate exercise as a treatment for painful DPN (Zhang et al. 2021).
Nonetheless, their judgment was that there is moderate-level evidence to support
aerobic or combined exercise regimens as a method of pain reduction in diabetic
patients who have pain. In contrast to Tatkiola et al., the expert consensus convened
in the process of preparing this review recommended general exercise with an
emphasis on the distal extremities or moderate-to-vigorous aerobic exercise as a
possible treatment for diabetic-related pain.
352 J. V. Ninneman et al.

Chemotherapy-Induced Peripheral Neuropathy Neurotoxic cancer therapies,

such as taxanes, are generally considered to be responsible for CIPN. Across all
forms of this type of treatment, the incidence rate of CIPN is estimated at 38%,
although depending on the specific therapy it may be as high as 90% (Kerckhove
et al. 2017). Exercise has gained prominence as a possible therapy for other cancer
treatment-related symptoms (Mustian et al. 2009), but the evidence to support its use
as a treatment for CIPN is less clear. Kanzawa-Lee and colleagues (Kanzawa-Lee
et al. 2020) completed a systematic review of the literature to evaluate the effective-
ness of exercise on CIPN symptoms. They identified seven RCTs and six quasi-
experiments which met their criteria for inclusion. The authors noted consistent
improvements in CIPN symptoms, including pain and instability, with the exercise
interventions employed. All interventions evaluated included a combination of
exercise types (e.g., aerobic, resistance, balance), but each of those that included
an aerobic exercise component demonstrated a significant improvement at the study
conclusion. Even so, given the wide heterogeneity in exercise prescriptions and the
moderate-to-high risk of bias determined for each of the studies, the authors con-
cluded that definitive evidence for the effectiveness of exercise on CIPN pain is still
lacking. A more recent review focused on exercise programs initiated at the start of
chemotherapy, prior to the onset of CIPN symptoms (Lopez-Garzon et al. 2022).
The authors concluded generally that exercise may be helpful in preventing CIPN
symptoms. However, only two of the studies included monitored the response of
pain symptoms to exercise and just one of those exhibited a significant improvement
in pain (Kleckner et al. 2018).
Spinal Cord Injury Although there is strong support for the prescription of
exercise and physical therapy for patients recovering from or managing an SCI
(Martin Ginis et al. 2018; Hoekstra et al. 2020; Tweedy et al. 2017), the evidence for
the influence of exercise on neuropathic pain associated with an SCI is particularly
limited. Case in point, Toloui et al. (2023) conducted a systematic review and meta-
analysis of clinical and preclinical controlled trials designed to investigate the
effectiveness of physical exercise interventions for neuropathic pain following
SCI. Notably, the authors were unable to identify a single human subjects trial
which met their inclusion criteria. Nonetheless, they conducted an exploratory
analysis of five RCTs designed to assess the effectiveness of exercise on pain in
SCI patients. Although they judged the trials included to have a high risk of bias, the
authors concluded that exercise improved the general perception of pain in chronic
SCI patients, but that shoulder pain in these same patients was not significantly
improved. The authors evaluation of the preclinical literature was that exercise
results in significant improvements in mechanical allodynia, thermal hyperalgesia,
and cold allodynia in rodent models of SCI. In general, there appears to be a fair level
of evidence across conditions that exercise may be beneficial for patients suffering
from neuropathic pain, but the consensus seems to be that more research is necessary
to confirm the optimal prescription (Leitzelar and Koltyn 2021; Zhang et al. 2021).
Exercise Training for Chronic Pain: Available Evidence,. . . 353

7.2 Guidelines on Exercise for Neuropathic Pain

We were unable to identify organizational guidelines for exercise specific to the

prevention or management of neuropathic pain. In general, research organizations
focused on exercise recommendations for the treatment of the underlying causes of
neuropathic pain (e.g., diabetes, cancer, etc.). In some cases, suggestions for starting
exercise with peripheral neuropathy are included, but none of the guidelines we
reviewed offered prescriptions tailored to specifically address neuropathic pain. For
instance, the American Diabetes Association recommended that type 1 and 2 diabetic
patients adopt the standard physical activity guidelines for healthy adults with a few
caveats (Colberg et al. 2016). Beyond the standard 150 min/week of aerobic exercise
and 2–3 sessions/week of resistance training, balance training was specifically
recommended (2–3 sessions/week) for those suffering from peripheral neuropathy.
The authors went on to make the point that exercising with neuropathy may be
difficult, given the condition’s potential impacts on gait, balance, and sensation.
Hence, they advised the consideration of non-weight bearing activities. Similarly,
the ACSM guidelines for diabetic patients adds that exercisers with peripheral
neuropathy should limit their participation in activities which may be hard on their
feet (e.g., hiking, jogging) and avoid activities requiring a high degree of balance.
Regardless, as noted by others, exercise guidelines for reducing neuropathic pain in
diabetic patients have not yet been defined (Tatikola et al. 2022).
In regard to CIPN, the ACSM convened a multidisciplinary roundtable in order to
develop a consensus statement on exercise guidelines for cancer patients (Campbell
et al. 2019). The roundtable participants made recommendations for aerobic exercise
(3 sessions/week of at least 30 min) and resistance exercise (2 sessions/week) for
8–12 weeks for patients in treatment to manage cancer-related health outcomes but
did not extend those guidelines to address CIPN or cancer-related pain. They
concluded that there simply was not enough evidence to endorse exercise as a
preventative or treatment for either. The American Society of Clinical Oncology
published treatment guidelines for CIPN and similarly concluded that the lack of
published data on the prevention or treatment of CIPN with exercise prevented them
from making recommendations for or against its use in this population (Derman and
Davis 2021).
Guidelines for exercise in SCI were also centered around promoting
cardiometabolic health, physical fitness, and function rather than managing pain,
neuropathic, or otherwise. The International Spinal Cord Society advocated that SCI
patients work their way up to a regimen of 20 min of moderate-to-vigorous exercise
and three sets of resistance exercises for all major muscle groups, each twice per
week, to improve and maintain fitness (Martin Ginis et al. 2018). No discussion of
neuropathic pain, however, was included in the write-up for these guidelines.
Likewise, Exercise and Sports Science Australia omitted any commentary on the
influence of exercise on neuropathic pain with their rather more rigorous recom-
mendations for SCI patients; 30 min or more of moderate aerobic activity on 5 or
more days per week, 2 or more days per week of strength training, and 2 or more
354 J. V. Ninneman et al.

days per week of flexibility training. These guidelines, once more, were presented
with a goal of improving and maintaining health and fitness, rather than reducing
pain complaints.

7.3 Potential Mechanisms for Action in Neuropathic Pain

The evidence for the mechanisms by which exercise may have an impact on
neuropathic pain comes primarily from animal research. In their comprehensive
review of exercise and neuropathic pain, Leitzelar and Koltyn (2021) covered a
wide range of human and animal studies and proposed that potential mechanisms for
pain reduction as a result of exercise could include: 1) normalization of microglial
activity in the dorsal root ganglion, 2) prevention of the upregulation of
pro-inflammatory cytokines while stimulating anti-inflammatory cytokine release,
and 3) enabling the regeneration of diseased or damaged neurons by regulating
neurotrophin activity. A more recent review by Wang et al. (2023) focused exclu-
sively on the possible role of exercise in normalizing/regulating microglial activity in
spinal pathways as a possible mechanism for neuropathic pain reduction. The
authors concluded that the literature supports a role for microglial activity in the
regulation of neuropathic pain via exercise, but the clinical evidence on how the
mode and/or intensity of exercise may influence this system is lacking.
Exercise has been described by many in the literature as having “anti-inflamma-
tory” effects (Pedersen 2017) and it has been proposed that exercise may reduce
neuropathic pain by influencing patients’ inflammatory state. As an example, a
multicenter RCT designed to evaluate the effect of 6 weeks of walking and resistance
exercise on CIPN symptoms and inflammatory responses was conducted by
Kleckner et al. (2018, 2019). The trial was somewhat unique in that participants
were cancer patients starting a neurotoxic chemotherapy and they were instructed to
begin the exercise program in conjunction with their treatment, rather than waiting
for CIPN symptoms to develop. The exercise regimen was deemed to be beneficial
for the prevention and treatment of CIPN-related pain (Kleckner et al. 2018) and, in a
secondary analysis, the authors further demonstrated collective changes in cytokine
concentrations which were judged to improve the participants’ inflammatory profile
(Kleckner et al. 2019). These studies, however, are just two among a relatively small
number of clinical studies designed to address questions on the relationship between
exercise and inflammation in neuropathic pain. More research is needed before a
firm conclusion can be drawn on the role of exercise and inflammation in
neuropathic pain.
The relationship between exercise and nerve regeneration and repair was
explored in a systematic review of human and animal studies by Chiaramonte
et al. (2023). The authors determined that the body of evidence in animal studies
supported the conclusion that physical exercise conducted in the early stages fol-
lowing neuronal damage or injury can facilitate axonal regeneration in peripheral
sensory and motor nerves. They also reported that exercise could help to reduce the
Exercise Training for Chronic Pain: Available Evidence,. . . 355

likelihood of harmful or maladaptive growth and connections. Regarding the human

subject literature, however, they were unable to make any firm conclusions given the
lack of relevant studies.

8 Conclusions

In many primary and secondary chronic pain conditions, meta-analytic data support
the use of multiple modes, intensities, frequencies, and durations of exercise training
to improve pain, physical function, and QoL. Moderate to large pain reductions
occur following exercise training and this effect is often comparable to other
standard treatment options. Aerobic capacity and muscular strength are often
improved, which are benefits that are unique to exercise training and not often
observed with pharmacologic and behavioral therapies. The long-term benefits of
exercise are likely related to continued participation in regular physical activity or
exercise. Adverse events are rare, although limited by lack of uniform measurement
and reporting standards, and are likely to be mitigated by an individualized exercise
program that accounts for symptom severity and exercise tolerance. Guidelines for
exercise in chronic pain conditions are often non-specific with respect to optimal
dose, intensity, type, and frequency. One notable exception is that resistance exer-
cises that are designed to target the musculoskeletal structures that surround local-
ized pain such as in chronic LBP and CCP have been shown to be more effective
than general exercise training. The mechanisms by which exercise improves pain are
not well understood and have not been rigorously nor systematically tested in
humans. Future research should focus on determining why exercise works and
how interventions can be designed to optimally activate the mechanism.
Although a robust literature base exists for multiple chronic pain conditions, there
are several limitations. Considerable heterogeneity among studies exists, including
differences in the prescribed exercise parameters, reported outcomes, statistical
analyses, and the clinical criteria used for inclusion/exclusion of participants; and
the certainty of the evidence is often reported as low (although strong evidence also
exists). Thus, it is not currently known what exercise prescription will work best for
which condition or for any single individual. Many investigators do not appear to
account for baseline pain or overall illness severity when designing a study or
interpreting its findings. This is important as baseline differences in symptoms can
influence the clinical meaningfulness of a change for a given outcome (Smith et al.
2020). Floor and ceiling effects can also contribute to a lack of improvement when
baseline pain is either too low or too high. The results for most outcomes we
reviewed were based on mean changes between groups. However, only reporting
average results can be misleading since responses to treatment can vary substantially
between individuals. Responder analyses are recommended as an additional method
for analyzing RCT data, but these were rarely reported in the original studies. These
analyses examine the percentage of patients whose improvements met certain
thresholds and can be used with cumulative distribution functions to better
356 J. V. Ninneman et al.

demonstrate variability in treatment effects (Smith et al. 2020). Greater inclusion of

these types of analyses will assist with determining for whom certain exercise
prescriptions are most efficacious and ultimately may help clinicians tailor treatment
plans for individual patients. Physical activity that occurs outside of the intervention
is rarely measured and could have meaningful effects on results–i.e., accounting for
changes in physical activity and sedentary behaviors that may occur across the trial
and at follow-up. Lastly, studies often do not control for participant expectations,
fear of movement, or other relevant behavioral factors that are known to influence
pain outcomes. Despite these limitations, exercise training is consistently associated
with moderate to large improvements in pain and associated beneficial physical and
psychological outcomes, is generally safe for most people with chronic pain, and it is
recommended by most major clinical organizations.

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Exercise and Schizophrenia

Fabiola González, Olga Montoya, and Simon Rosenbaum

Contents
1 Prevalence, Etiology, and Background on Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
2 Schizophrenia and Human Movement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
3 Physical Inactivity, Cardiorespiratory Fitness, and Exercise Interventions in People
with Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
4 Antipsychotic Use and Exercise in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
5 Physical Activity Recommendations for Adults with Schizophrenia . . . . . . . . . . . . . . . . . . . . . . 374
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

Abstract Schizophrenia is a complex mental disorder that affects millions of people

worldwide and has a profound impact on various aspects of life, including physical
activity. The relationship between schizophrenia and physical activity is an area of
growing interest in medical and health research from a physical, mental, and
psychosocial health perspective. Physical activity and structured exercise have
been identified as promising interventions to improve physical and psychological
health outcomes of people living with schizophrenia. This chapter provides a brief
overview that explores various aspects of the relationship between physical activity,
exercise, and schizophrenia. The impact of schizophrenia on human movement is
discussed, along with an overview of physical activity and cardiorespiratory fitness
levels in adults with schizophrenia. Additionally, the influence of exercise interven-
tions on physical and psychological outcomes will be discussed, along with current
physical activity recommendations for those living with schizophrenia.

Keywords Exercise · Physical activity · Schizophrenia

F. González and O. Montoya

Escuela Colombiana de Rehabilitación, Bogotá, Colombia
S. Rosenbaum (✉)
Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, NSW,
Australia
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 367
Curr Topics Behav Neurosci (2024) 67: 367–380
https://doi.org/10.1007/7854_2024_505
Published Online: 10 August 2024
368 F. González et al.

1 Prevalence, Etiology, and Background on Schizophrenia

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) published by the American Psychiatric Association (APA) classifies
schizophrenia as a serious mental disorder that affects a person’s thoughts and
behaviors (American Psychiatric Association 2013). There has been a debate as to
the definition and classification, specifically whether schizophrenia is part of a
disorder (a group of symptomatic dimensions that cluster in different combinations
in different people and for which there may or may not be one or more underlying
illnesses) or whether it is a disease (a nosological entity with specific causes,
symptoms, treatment, and course) (van Os 2009). A diagnosis of schizophrenia is
made when a person presents with at least two of the following symptoms for a
significant period (usually longer than one month): delusions, hallucinations, disor-
ganized speech, highly disorganized or catatonic behavior, and negative symptoms
such as reduced emotional expression (American Psychiatric Association 2013).
Although its etiology is not fully understood, evidence exists for an underlying
neurophysiological basis, and schizophrenia involves a complex interaction between
genetic, biochemical, and environmental factors that affect brain functioning (Patel
et al. 2014; McGrath et al. 2008). Schizophrenia is usually diagnosed between the
ages of 16 and 30 years following a first episode of psychosis (Patel et al. 2014;
McGrath et al. 2008). Schizophrenia is a complex mental disorder that affects
approximately 1% of the world’s population (McGrath et al. 2008). Psychosis and
the diagnosis of schizophrenia are related to disturbances in perception, thinking,
mood, and behavior (American Psychiatric Association 2013; McGrath et al. 2008).
Symptoms are divided into “positive” symptoms, such as hallucinations and delu-
sions, and “negative” symptoms, which include apathy, lack of drive, poverty of
expression, social withdrawal, and poor self-care (American Psychiatric Association
2013). Adults living with schizophrenia experience clinical symptoms (e.g., delu-
sions, hallucinations) that vary widely between and within individuals over time
(Kuipers et al. 2014). These symptoms, such as delusions and hallucinations, are
often integrated into broader disorders along with symptoms of mania and depres-
sion. Although characterized by these symptoms, they are likely to be the result of
multiple etiopathogenic causes and pathways, converging on similar outcomes
(Patel et al. 2014; McGrath et al. 2008; Kuipers et al. 2014).
Schizophrenia is also thought to lead to alterations in cognitive, emotional, and
sensory processing, which has led researchers to speculate that it is possible that
individuals with schizophrenia may exhibit alterations in brain regions/networks
responsible for such processes (e.g., attention has been devoted to amygdala,
hippocampus, and cerebellum) (Xavier and Vorderstrasse 2016). Alterations in
functional connectivity may affect communication between different brain regions
and contribute to the characteristic symptoms of schizophrenia (Luvsannyam et al.
2022). At the neurochemical level, schizophrenia is associated with alterations in the
transmission of neurotransmitters, such as dopamine, serotonin, and glutamate
(Luvsannyam et al. 2022; Ruiz et al. 2010). Increased dopaminergic activity has
Exercise and Schizophrenia 369

been observed in certain brain regions, which is believed to be related to the

appearance of positive symptoms of schizophrenia, such as hallucinations and
delusions. It has also been suggested that a decrease in glutamate function may be
related to the negative and cognitive symptoms of the disease (Luvsannyam et al.
2022; Kasai et al. 2002; St Clair and Lang 2021). It is important to note that
neurological involvement in schizophrenia can vary from individual to individual
and can be influenced by numerous factors, such as age of onset, severity of
symptoms, and response to treatment (Kasai et al. 2002). Clearly, schizophrenia is
a complex and multifactorial disorder, and understanding its neurobiological basis is
still under investigation (Kasai et al. 2002). Early recognition and intervention are
critical in effectively treating and managing schizophrenia from both a mental and
physical health perspective (Patel et al. 2014; Fusar-Poli et al. 2017). A 2014 meta-
analysis of observational studies found that a prolonged duration of untreated
psychosis (DUP) is associated with more severe symptoms, more intense positive
and negative symptoms, difficulty achieving remission, lower social functioning,
and an unfavorable global outcome (Penttilä et al. 2014).

2 Schizophrenia and Human Movement

Impacts on various aspects of human movement have been observed in adults with
schizophrenia, including, but not limited to, specific postural patterns, gait cycles,
and subjective bodily experiences (Bernard and Mittal 2014). People with schizo-
phrenia often experience difficulties in planning and executing coordinated move-
ments (Tonna et al. 2023). These difficulties may manifest as generalized
clumsiness, uncoordinated or stiff movements, and decreased fluidity of movements
(Tonna et al. 2023; Varlet et al. 2012). Individuals often exhibit alterations in gait,
such as slower, less coordinated, or uneven gait patterns, which affect mobility.
These gait abnormalities are often manifested in conjunction with alterations in
posture (Tonna et al. 2023). Maintaining a balanced, upright posture often becomes
a challenge for people with schizophrenia, possibly due to a combination of motor
and cognitive dysfunctions. In addition, studies have reported on alterations in
nonverbal behavior and movement coordination during social interactions (Varlet
et al. 2012). Relatedly, an investigation examining pendulum swings revealed that
patients with schizophrenia face challenges in social coordination, as they typically
exhibit fewer stable patterns and a tendency not to lead in intentional coordination
situations (Teng et al. 2016). This indicates that schizophrenia affects social coor-
dination and the dynamics of interactions and that explicit processes may be more
affected than implicit ones (Teng et al. 2016). Beyond observable movements,
schizophrenia significantly influences the subjective experience of one’s own
body. Distorted perceptions of the body may result in unusual sensations or discom-
fort. Additionally, motor parameters such as increased roll area and reduced gait
cadence differentiate early-onset patients from adults with schizophrenia, providing
insight into the different phases of the disorder (Teng et al. 2016; Picard et al. 2008).
370 F. González et al.

At the neurophysiological level, people with schizophrenia may have alterations

in the connections of sensory-perceptual networks related to movement, such as the
cerebellum, basal ganglia, and motor cortex (Picard et al. 2008). As such, these
alterations may affect the integration of sensory information and the generation of
appropriate motor patterns (Picard et al. 2008). Motor symptoms in schizophrenia
can vary significantly among affected individuals; some people may experience
excessive and uncontrolled movements, known as dyskinesias, while others may
have a general decrease in motor activity, known as akinesia (Teng et al. 2016).
These symptoms may be influenced by antipsychotic medication used in the treat-
ment of schizophrenia, which may also have unwanted effects on the motor system
(Mathews et al. 2005). Lastly, positive and negative symptoms of schizophrenia,
such as hallucinations, delusions, apathy, and social withdrawal, may interfere with
motivation and participation in motor learning activities (Marvel et al. 2004).

3 Physical Inactivity, Cardiorespiratory Fitness,

and Exercise Interventions in People with Schizophrenia

People with schizophrenia spend increased time in sedentary behaviors and are at an
elevated risk of physical inactivity (Taliercio et al. 2020; Kiwan et al. 2020; Stubbs
et al. 2018a, 2016; Firth et al. 2015). For example, Stubbs et al. (2018a, b), in a meta-
review and position statement by the European Psychiatric Association (EPA),
found that less than 50% of patients with schizophrenia meet the internationally
recommended physical activity levels of 150 min of moderate-intensity aerobic
exercise per week (Stubbs et al. 2018a). Additionally, a systematic review with a
pooled analysis by Stubbs et al. showed that adults with schizophrenia (N = 3,453;
mean age = 40 years old, mean BMI = 30.00) engage in approximately 80.44 min of
light physical activity per day (95% CI: 68.32–92.52 min/day) and were found to
engage in less vigorous physical activity (g = -0.39, 95% CI: -0.60 to -0.18)
compared to those without a diagnosis of schizophrenia (Stubbs et al. 2016). This
study also highlighted that in the prodromal and early stages of schizophrenia,
physical inactivity has been shown to be associated with an increased risk of
developing the disease (Stubbs et al. 2016). Another review also revealed that
greater depressive symptom severity and older age among adults with schizophrenia
was associated with lower levels of physical activity (Firth et al. 2015).
Additionally, a study focused on analyzing physical activity levels in Nigerian
patients with schizophrenia suggests that clinical and sociodemographic factors are
linked to physical activity participation (Esan and Ephraim-Oluwanuga 2022). In
this study, a total of 215 patients were recruited from psychiatric hospitals in Ibadan,
Nigeria, and their level of physical activity was assessed using the International
Physical Activity Questionnaire (IPAQ) short form. The results revealed that the
majority of the participants (67.1%) had a low level of physical activity (i.e., did not
meet physical activity guidelines). Physical activity was related to patients’
Exercise and Schizophrenia 371

remission status, with higher activity levels among those in remission. In addition,
inverse correlations were found between physical activity and education, waist
circumference, and severity of depression. Additionally, positive relationships
were observed between physical activity and social and occupational functioning
(Esan and Ephraim-Oluwanuga 2022). It is noteworthy that the level of physical
inactivity in this study compares with that of high-income countries, despite these
countries having extensive facilities for physical activities like gyms, soccer fields,
basketball courts, and walking trails.
The low proportion of participants with an adequate level of physical activity
(i.e., meeting guidelines) is consistently reported in studies of patients with schizo-
phrenia (Daumit et al. 2005; Lee et al. 2018). Individuals without schizophrenia tend
to be more active, lead less sedentary lifestyles, and face fewer social or cognitive
barriers that limit their participation in physical activities (Stubbs et al. 2018b).
Additionally, they often experience fewer mental health issues that might otherwise
influence their ability to maintain a regular exercise routine (Stubbs et al. 2018b).
This is unfortunate as physical activity appears to be beneficial for adults with
schizophrenia (Stubbs et al. 2018a). Evidence from a recent systematic review
revealed that greater participation in moderate- to vigorous-intensity exercise was
associated with reduced cardiometabolic risk, reduced psychotic symptoms and
comorbid psychiatric symptoms, and improved cognitive function (Firth et al. 2015).
It has also been demonstrated that individuals with schizophrenia typically
exhibit lower levels of cardiorespiratory fitness compared to age-matched controls
(Abdel-Baki et al. 2013; Vancampfort et al. 2015). Vancampfort et al. systematically
examined seven different aerobic exercise interventions and found significant
improvement in cardiorespiratory fitness (g = 0.40, 95% CI = 0.16–0.64) among
adults with schizophrenia following the varying exercise interventions (intervention
duration ranged from 6 to 32 weeks, with 2–3 weekly sessions of 30–60 min of either
cycling, walking, or treadmill running) (Vancampfort et al. 2015). As a result of
these findings, researchers and practitioners in this area have stressed the importance
of cardiorespiratory fitness as a primary target of physical activity and exercise
interventions among adults with schizophrenia (Abdel-Baki et al. 2013;
Vancampfort et al. 2015). This makes intuitive sense based on some of the findings –
specifically that low cardiorespiratory fitness is a significant predictor of cardiovas-
cular disease and overall mortality (Lee et al. 2010).
In addition to cardiorespiratory fitness, several trials have examined the influence
of exercise interventions on multiple disorder-specific and more general mental
health outcomes (e.g., positive and negative symptoms, cognition, sleep, physical
functioning). A systematic review by Firth et al. revealed that in people experiencing
their first episode of psychosis, exercise combined with cognitive training signifi-
cantly improved total psychiatric symptoms, negative symptoms, psychosocial
functioning, and verbal short-term memory (Firth et al. 2015). An important finding
from this review was that the benefits of exercise occurred independent of changes in
body weight. However, it should be noted that weight loss and at a very minimum
weight maintenance should still be considered an important component for adults
with schizophrenia as poor physical health in adults with schizophrenia has been
372 F. González et al.

shown to be positively associated with the duration of the illness, greater likelihood
to smoke cigarettes, increased incidence of metabolic syndrome, and greater
schizophrenia-specific symptom severity (Firth et al. 2015). Additionally, a recent
meta-analysis of 22 studies evaluated the effects of different types of exercise
interventions on negative symptoms of schizophrenia (Vogel et al. 2019). Specifi-
cally, the analysis focused on studies with mind-body interventions (yoga, Wu-style
Cheng, Tai chi Chuan, relaxation, and breath control), aerobic exercise (cycling,
jogging, jumping, dancing, aerobic video games, elliptical and bench exercises) and
resistance training (machine and functional training). Results revealed that mind-
body exercise interventions and aerobic exercise interventions led to medium
(Hedges g = 0.46) and small (Hedges g = 0.34) reductions in negative symptoms
of schizophrenia, respectively, compared to a control condition (Vogel et al. 2019).
Unfortunately, the effect of resistance training could not be examined, and the
overall methodological quality of the included studies was deemed to be poor
(Vogel et al. 2019).
The effects of exercise interventions on quality of life and sleep in patients with
schizophrenia have also been recognized. Korkmaz Aslan and Ekinci (2022) inves-
tigated the effect of a structured exercise program on quality of life and sleep in
subjects with schizophrenia using the Pittsburgh Sleep Quality Index and World
Health Organization Quality of Life scales. The 12-week intervention involved
40-min sessions: 5 min were allocated to a warm-up, 30 min were allocated for
stretching exercises, resistance training, and aerobic exercise, with a 5-min cool-
down. Results from this trial revealed significant improvements in quality of life and
sleep quality for the exercise intervention group compared to the control group
(Korkmaz Aslan and Ekinci 2022).
Previous research has also found improvements in cognitive performance
(in addition to schizophrenia-specific symptoms) following participation in exercise
interventions. For example, Shimada and colleagues conducted a recent systematic
review and meta-analysis (k = 15 studies, N = 593) and found that participation in
aerobic exercise interventions (average duration of 50.3 min, 2.54 times per week for
12 weeks) significantly improved global cognition compared to a control condition
(SMD = 0.21, 95% CI = 0.12–0.30) (Shimada et al. 2022). Additionally, a recent
meta-analysis by Sabe and colleagues examined the influence of various different
aerobic (including walking or high-intensity interval training) and/or resistance
exercise interventions of varying intensities (moderate to vigorous) session durations
(between 45 and 270 min per week) and intervention durations (8–24 weeks) on
positive and negative schizophrenia symptoms in adults with schizophrenia (Sabe
et al. 2020). All studies included in this meta-analysis administered exercise as an
adjunctive intervention to standard antipsychotic pharmacotherapy. Results showed
a significant improvement in positive symptoms and a large reduction in negative
symptoms (as assessed via the Positive and Negative Syndrome Scale) after aerobic
exercise but not after nonaerobic exercise interventions (e.g., resistance exercise)
(Sabe et al. 2020).
Additionally, a study examined the relationship between functional exercise
capacity and global functioning in patients with schizophrenia (Vancampfort et al.
Exercise and Schizophrenia 373

2012). Sixty-eight male and twenty-five female inpatients were evaluated using the
six-minute walk test and the Global Assessment of Functioning (GAF) scale, along
with other symptom assessment tools. The results showed a moderate association
(Pearson correlation coefficient of 0.59) between distance walked on the 6-min walk
test and GAF score, suggesting that exercise capacity is related to global functioning
in these patients (Vancampfort et al. 2012). In addition, distance walked was also
found to correlate with negative, depressive, and cognitive symptoms, body mass
index, smoking status, and antipsychotic medication dosage (Vancampfort et al.
2012). The findings suggest that, in addition to global assessment of functioning,
inclusion of the 6-min walk test could be beneficial in inpatient settings to measure
the functional consequences of schizophrenia and its treatment. This could provide a
more complete understanding of the physical and functional status of patients with
schizophrenia.
In addition to the aforementioned psychological outcomes, a recent study exam-
ined the effects of a 12-week aerobic exercise intervention on several functional and
physiological outcomes (Szortyka et al. 2022). Results revealed that individuals that
participated in the exercise intervention exhibited reductions in systemic inflamma-
tion, reductions in body mass index, and reductions in elevated blood pressure
(Szortyka et al. 2022). There have also been recent attempts to understand the impact
of exercise on hippocampal volumes in adults with schizophrenia. To date, there
have been equivocal findings. For example, Joe Firth and colleagues conducted a
meta-analysis (k = 14) that revealed that aerobic exercise had no significant effect on
total hippocampal volumes (Firth et al. 2018). In contrast, Li and colleagues
conducted a meta-analysis and reported increased right hippocampal volume for
participants following participation in an aerobic exercise intervention, compared to
nonexercising control conditions (Li et al. 2017). Additional research is needed
among adults with schizophrenia to determine the precise role of aerobic exercise
interventions in preventing age-related decline in the hippocampus.
Lastly, a systematic review analyzed the impact of exercise on the global func-
tioning of adults (M age = 37.9) with schizophrenia, most of which were overweight
or obese (Korman et al. 2023). Most participants maintained stable psychiatric
medication for 4–12 weeks prior to the study. The exercise interventions examined
as part of this review had a mean duration of 12 weeks and were performed primarily
in a group setting at a frequency of 3 times per week. Types of exercise included
aerobic exercise, resistance training, combined aerobic and resistance training, and
combined standing and stretching postures with aerobic activities. Exercise sessions
were supervised by trained physical therapists, exercise therapists, mental health
ward staff, or researchers. Aerobic exercise of moderate to vigorous intensity had a
positive effect on the overall functioning of patients with schizophrenia. Aerobic
exercise had a greater impact on global functioning compared to other types of
exercise. The study also explored the effects of exercise on daily living skills and
social functioning. Preliminary evidence suggests that exercise may improve daily
living skills (Korman et al. 2023).
374 F. González et al.

4 Antipsychotic Use and Exercise in Schizophrenia

Antipsychotics are commonly prescribed for patients with schizophrenia. As a result,

it is plausible that the lower observed activity rates in schizophrenia could be a
byproduct of the treatment (and not simply having a diagnosis of schizophrenia).
Additionally, antipsychotics are also typically associated with significant weight
gain (Allison et al. 1999). For example, meta-analytic evidence examining weight
gain in first- and second-generation antipsychotics revealed that several antipsy-
chotics (e.g., olanzapine, clozapine) caused a significant increase in weight (Allison
et al. 1999). Subsequent studies expanded upon these findings and indicated that
olanzapine and clozapine are the drugs that contribute most to weight gain, whereas
aripiprazole, cariprazine, lurasidone, and ziprasidone have lesser metabolic effects
(Rummel-Kluge et al. 2010; Pillinger et al. 2020). However, clinical decisions about
antipsychotics should consider both long-term clinical improvement and metabolic
side effects (Rummel-Kluge et al. 2010; Pillinger et al. 2020). Given that antipsy-
chotics generally result in weight gain, it is plausible to suggest that exercise may be
an effective and readily accessible treatment to adverse health outcomes associated
with weight gain. However, a recent pilot study investigated attendance and adher-
ence to exercise in schizophrenia patients taking olanzapine and experiencing
significant weight gain. Despite providing access to exercise facilities, only 5% of
the participants adhered to the exercise program for six months. Most patients did
not regularly attend exercise sessions, primarily citing lack of motivation (Archie
et al. 2003). These results (along with the prior research demonstrating low physical
activity levels) highlight that although exercise may be beneficial for this population,
getting individuals to adhere long enough for exercise to exert a positive impact
remains a difficult challenge. The low activity levels and adherence rates to exercise
programs are unfortunate as physical exercise appears to influence some of the same
neuroprotective factors that are considered targets of antipsychotic drugs and
nutraceuticals. For example, as discussed throughout this volume, exercise reduces
neuroinflammation, regulates neurotrophic growth factors promotes remyelination,
and stimulates neurogenesis (Cotman et al. 2007; Chieffi et al. 2017).

5 Physical Activity Recommendations for Adults

with Schizophrenia

Based on the aforementioned benefits, practitioners may want to consider prescrib-

ing physical activity for adults with schizophrenia. In doing so, practitioners should
consider the most relevant outcomes of interest for their patients and consider the
patient’s baseline physical activity and fitness levels, as well as contextual factors
that may influence motivation to initiate and maintain physical activity participation.
In 2018, an expert group of the EPA issued a guideline on exercise interventions in
the treatment of severe mental illness, including schizophrenia (Stubbs et al. 2018a).
Exercise and Schizophrenia 375

Table 1 Example of how an exercise prescription may evolve for adults with schizophrenia based
on findings derived from prior research
Dosage
Modality Aerobic exercise/cardiorespiratory training
Examples Stationary cycling, jogging, walking, jumping, dance, elliptical, sport
participation, aerobic exercise-based video games
Intensity Moderate to vigorous intensity:
-60–77% Vo2 Max or
-40–75% of reserve heart rate
-55–70% of maximum heart rate
*The intensity should be adjusted according to individual characteris-
tics (e.g., age, physical performance, preferences, contraindications to
physical activity)
*It is recommended that the method for prescription is from % Vo2
Maximum or from % of reserve heart rate.
Frequency Three to five times per week
Duration of sessions Aerobic exercise session can have a minimum duration of 10 and a
maximum of 60 min. Studies reporting weekly duration of ≥ 90 min/
week demonstrate larger effects on aspects related to physical health
(cardiometabolic alterations) and mental health (cognitive functions
and positive/negative symptoms typical of schizophrenia).
Length of program 8 weeks up to 24 weeks, 12 weeks is most commonly used.
Implementation of the Individual or group
program *Group exercise may be associated with greater adherence to exercise
programs with one-on-one support offered where needed.

The panel concluded that combining physical exercise with psychological and
dietary interventions can improve parameters of metabolic syndrome, cardiovascular
fitness, and cognitive performance (Stubbs et al. 2018a). To date, there are no
specific physical activity recommendations for individuals with schizophrenia. It is
recommended that, if feasible, individuals follow the federal guidelines outlined in
Chapter “Introduction” (i.e., 150 min per week of moderate-intensity aerobic exer-
cise or 75 min per week of vigorous-intensity aerobic exercise or an equal combi-
nation of both, in addition to muscle-strengthening exercises on two or more days
per week) (Piercy et al. 2018). Additionally, it is recommended that exercise should
be adapted and supervised according to the individual needs of each person, with
consideration of physical condition and potential comorbidities or contraindications
to exercise, personal preferences, and functional limitations (e.g., age, exercise
capacity, and patient preferences). Given the risk profile of people with schizophre-
nia, collaboration with multidisciplinary teams including physicians and physical
therapists is recommended (Faulkner and Biddle 1999). Table 1 provides an example
of how specific recommendations for schizophrenia populations could evolve based
on the available evidence from prior studies conducted in the area (Vogel et al. 2019;
Sabe et al. 2020; Korman et al. 2023; Oliva et al. 2023; Nyboe et al. 2019; Sunhary
De Verville et al. 2022; Gyllensten et al. 2020).
376 F. González et al.

6 Conclusion

Physical activity and exercise are promising targets for intervention to improve
physical and psychological health outcomes in people with schizophrenia. Evidence
suggests that supportive and supervised moderate to vigorous-intensity exercise
programs can have a positive impact if participants adhere to the program and as a
result may be provided as part of evidence-based care. Implementation of exercise
programs, preferably in a group setting, has been shown to be effective in improving
physical and mental well-being of people with schizophrenia. Potential benefits
include improvements in global functioning, cognition, mood, sleep, and both
negative and positive symptoms of schizophrenia. For practitioners, it is crucial to
consider the appropriate variables and doses of exercise, based on available evi-
dence, for effective prescribing as part of the comprehensive management of schizo-
phrenia symptoms. Although additional research is needed, the collective body of
evidence to date underscores a promising role of exercise in promoting well-being
and improving health in people living with schizophrenia.

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The Placebo Effect in Exercise and Mental
Health Research

John S. Raglin and Jacob B. Lindheimer

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
2 The Placebo: A Brief History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
3 Definitions for Placebos, Placebo Effects, and Related Terminology . . . . . . . . . . . . . . . . . . . . . . 384
4 Navigating Methodological Challenges in Exercise and Mental Health . . . . . . . . . . . . . . . . . . . 386
5 Expectations: Key Terms and Practical Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
6 The Influence of Expectation in Chronic Exercise Paradigms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
7 Minimal Exercise (“Impure Placebo”) Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
8 The Influence of Expectation in Acute Exercise Paradigms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
9 General Summary and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392

Abstract This chapter describes the placebo effect in the context of physical
activity and mental health. Following a brief historical overview, definitions for
placebos, placebo effects, and related terminology are discussed. Next, three major
methodological challenges posed from studying the placebo effect in the context of
exercise are described. Additionally, the role of a primary psychological mechanism
of placebo and nocebo effects – expectations – will be summarized through the lens
of key terminology. Findings from relevant chronic and acute exercise studies that
have measured or manipulated exercise-associated expectations will be presented.
The chapter concludes with recommendations for controlling or quantifying the
placebo effect in exercise and mental health research and its implications in clinical
practice.

J. S. Raglin (✉)
Department of Kinesiology, School of Public Health, Indiana University, Bloomington, IN,
USA
e-mail: [email protected]
J. B. Lindheimer
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 381
Curr Topics Behav Neurosci (2024) 67: 381–394
https://doi.org/10.1007/7854_2024_506
Published Online: 24 July 2024
382 J. S. Raglin and J. B. Lindheimer

Keywords Anxiety · Depression · Expectation · Mood · Nocebo · Psychosocial

It is exercise alone that supports the spirits, and keeps the mind in vigor.
Marcus Tullius Cicero, Roman statesman (106-43 BC).

1 Introduction

Long before the advent of scientific investigation into the benefits of physical
exercise, its impact on mental health was recognized. Research consistently indicates
that physical activity can both improve a variety of psychological variables (e.g.,
mood, energy) in healthy individuals and provide benefits for persons suffering from
clinical disorders such as depression or anxiety that rival those associated with
medication or therapy. Yet, despite over a half century of study, the mechanisms
that underly these psychological benefits remain undetermined (Mikkelsen et al.
2017). This information is not simply a matter of scientific curiosity; it has important
clinical implications determining what psychological conditions are most or least
likely to benefit from exercise and for designing and implementing exercise pro-
grams that optimize improvement. For example, hypothesized biological explana-
tions such as the endorphin hypothesis would logically predict that more vigorous
exercise prescriptions (i.e., increased intensity and/or duration) should evoke a
greater production of endogenous opioids which should then result in larger psy-
chological benefit. Yet, research has generally failed to find dose-response relation-
ships between exercise intensity and changes in mood and affect (Raglin and Wilson
1996; Perkins et al. 2023), which suggests that biological mechanisms (e.g., endor-
phin hypothesis) are not solely responsible for exercise-induced improvements in
various different psychological outcomes. Accordingly, even the earliest reviews of
the exercise and mental health literature emphasized the importance of accounting
for the potential influence of the placebo or the related Hawthorne effect (Morgan
1970), including the beliefs and expectations exercisers possess about “their ability
to profit psychologically from fitness training” (Folkins and Sime 1981). Due to the
potential “contamination” from personal beliefs or incidentally induced expectations
from demand characteristics, some researchers have contended that it is essentially
impossible to distinguish treatment effects from placebo effects in exercise and
mental health studies (Sime 2022), largely because of the inability to blind partic-
ipants to the intervention and develop a convincing placebo substitute for exercise
(Ojanen 1994).
The absence of placebo controls in exercise and mental health research continues
to be raised as a concern. In a paper on the acute psychological benefits of exercise
literature, Szabo concluded that “researchers have neglected the investigation of the
role of the placebo effect in the psychological changes resulting from exercise for
almost two decades” (Szabo 2013). The potential influence of the placebo effect is
particularly relevant in the case of exercise because both the psychological outcomes
The Placebo Effect in Exercise and Mental Health Research 383

(e.g., anxiety, depression, self-esteem) and sensory (e.g., pain) or feeling states (e.g.,
fatigue, energy) assessed in the majority of studies are highly susceptible to placebo
interventions (Lindheimer et al. 2019; Lindheimer et al. 2015).
This chapter will provide an overview of the placebo effect in the context of
psychological responses to physical activity. Following a brief historical discussion,
standardized definitions of the placebo effect and related terminology will be
provided. An overview of the challenges of studying the placebo effect in the context
of exercise and mental health will be presented, as well as findings from studies
which have attempted to navigate these challenges by implementing exercise pla-
cebo conditions or by measuring and in some cases manipulating expectations, an
established psychological mechanism of placebo effects. Lastly, recommendations
for future research directions and clinical practice are provided.

2 The Placebo: A Brief History

The term placebo was not initially linked to science or medicine. It first appeared in
the fourteenth century Latin bible and was mistranslated as “I will please.” At this
time, the Black plague raged across Europe and people hired to fill in as mourners at
funerals became known as placebos. Soon the term became more broadly used as an
insult describing false sincerity, but it was not until the eighteenth century that the
term placebo became associated with medicine. Its most celebrated initial applica-
tion to science and medicine was conducted in 1784 by Benjamin Franklin. He and
several other leading scientists had been commissioned by King Louis XVI to
investigate the controversial medical treatments of the physician Franz Mesmer.
Foremost among their tests, they utilized a prototype of a placebo control by
blindfolding patients who were then exposed to objects either treated (“mesmer-
ized”) with animal magnetism or left untreated. This manipulation revealed that
patients exhibited similar symptoms of mesmerism whether exposed either to treated
or inert objects. Based on these and other results, the commission concluded that the
effects of animal magnetism were solely the result of “imagination” (Annoni 2020).
The first medical definitions of the placebo began to appear in print in the late
sixteenth century. A surprisingly contemporary definition published in 1811 in a
medical dictionary described a placebo as “an epithet given to any medicine adapted
more to please than to benefit the patient” (Quincy 1811). A century and a half later,
Beecher modestly updated this description by substituting “pharmacologically inert
substances” for the word “epithet” (Beecher 1955). More importantly, in this paper,
Beecher reviewed the findings of medical studies that employed placebo controls
and concluded that they provide actual benefits for an average of 35.2% patients
(Beecher 1955), a claim that spurred both the serious consideration of the placebo
effect and an equally spirited backlash against it which played out in the scientific
literature over the next half century.
Foremost among the critiques of Beecher’s review and other unfavorable per-
spectives on the placebo is the problem of nonspecific effects (Kienle and Kiene
384 J. S. Raglin and J. B. Lindheimer

1997; Roberts 1995), a range of factors that contribute to a partial or complete

remission of medical signs or symptoms but which are not aspects of either the
placebo or medical treatment. Examples of nonspecific effects include regression
toward the mean, spontaneous improvement, and the natural fluctuation of symp-
toms, as well as results invalidated by experimental biases such as the Rosenthal
effect (Kienle and Kiene 1997). The inclusion of a nontreatment control is then
necessary to determine if nonspecific effects are present, an addition that is often
omitted because of the additional expense or because of ethical concerns about
withholding treatment (Kienle and Kiene 1997).
This dim view about the influence or even the existence of the placebo effect has
faded with advent of innovative research that utilized brain imaging technology
during the administration of placebos. The results of this work have revealed that
placebos activate the same neurobiological pathways of the medication they are
associated with, yielding real benefits and increasing the efficacy of many evidence-
based treatments (e.g., pain medication).
Another important innovation in placebo research is the use of novel experimen-
tal designs. For example, the traditional randomized controlled trial (RCT) con-
strains the placebo effect through the use of a conditional (Loehr et al. 2014)
expectation of treatment to minimize its efficacy. In contrast, the balanced placebo
design involves conditions that manipulate the strength of expectation to ascertain its
impact. For example, in one arm of this design, participants who received the
treatment are told they received a placebo (i.e., a 0% expectation of treatment),
allowing researchers to determine the influence of the efficacy of the treatment
without the potential added benefits from expectation. In another arm, participants
are truthfully informed they received the treatment (i.e., a 100% expectation of
treatment), a condition which mimics the clinical setting wherein accurate informa-
tion is provided the treatment along with information about the expected outcome
(e.g., reduced pain). Other innovative approaches include the use of open-hidden
designs, deceptive conditioning, or intentionally induced expectations; each has
provided unique insights into how conditioning and expectation can modulate
placebo outcomes. This work also has important implications in how the placebo
effect may add to the efficacy of medical treatments in the clinical setting.

3 Definitions for Placebos, Placebo Effects, and Related

Terminology

The term placebo classically describes an inert agent or sham intervention that lacks
any inherent capacity to produce a biological or psychological benefit (Kirsch 1985),
whereas a placebo effect refers to the changes specifically attributable to placebo
mechanisms (Evers et al. 2018). Importantly, because classical conditioning and
expectation are also associated with the presentation of an established treatment
(Benedetti et al. 2003), placebo effects can arise without administering a placebo,
The Placebo Effect in Exercise and Mental Health Research 385

meaning that the placebo effect can contribute to the efficacy of active treatments
such as pain medication (Benedetti et al. 2003) and behavioral interventions such as
exercise (Lindheimer et al. 2015). The term placebo response has been applied
synonymously with placebo effect, but it is now defined as all health changes that
result after administration of an inactive treatment (i.e., differences in symptoms
before and after treatment), thus including nonspecific effects (e.g., natural history
and regression to the mean) and experimental artifacts such as demand characteris-
tics (i.e., the Rosenthal effect) (Evers et al. 2018). To distinguish the placebo
response from a true placebo effect, the addition of a nontreatment control would
be required.
Subtypes of placebos have also been identified in the literature, some of which
have relevance to physical exercise research. The inert placebo when used in
medical research must lack any pharmacological and physiological effects. Exam-
ples would include a saline injection or pill filled with corn powder. Establishing a
physical activity intervention that qualifies as an inert placebo would first require
identifying precisely what biological process (e.g., endorphin production) or adap-
tation (e.g., increased cardiovascular capacity) modulates changes in mental health
and then either designing an exercise mode that does not stimulate this mechanism or
if possible, by adding an intervention that would disable this mechanism. For
example, if it were unequivocally determined that endogenous opioid activity was
responsible for acute improvements in mental health, then an inert placebo condition
would involve either an exercise prescription both insufficient in either intensity and
duration to stimulate an increase in opioid production or the administration of an
opioid antagonist during more vigorous exercise. Because there continues to be a
debate over the mechanism(s) responsible for exercise-related changes in mental
health as well as the possibility that different mechanisms explain different outcomes
(e.g., increased energy versus reduced anxiety), identifying an inert exercise placebo
may not be feasible.
An active placebo is designed to be convincing by mimicking the physical
appearance of the medication as well as its sensory characteristics (smell or taste)
and when possible its side effects. Taking the extra steps to create an active placebo
can be valuable because research indicates that active placebos often yield greater
effects compared with generic placebos (Miller and Colloca 2009). However, for
behavioral interventions such as psychotherapy or physical exercise, the question
arises of whether convincing placebo treatments can be identified. In psychiatry
placebo research options such as support therapy, relaxation training and discussion
groups have been employed (Weimer et al. 2015) as placebo conditions. But it has
been noted (Ojanen 1994; Lindheimer et al. 2015) that realistic placebo substitutes
for exercise may be unconvincing or are even impossible. Moreover, experienced
participants can distinguish convincingly designed placebos from treatments that
lack obvious sensory cues, a phenomenon referred to as functional unblinding. In a
study involving frequent tanning bed users (Feldman et al. 2004), the investigators
allowed participants to choose between a UV bed or an identical placebo bed that did
not emit UV rays. It was found that 95% of the participants selected the UV bed
despite the absence of any overt clues or sensory differences between the conditions.
386 J. S. Raglin and J. B. Lindheimer

These results, along with research that has found greater benefits in participants who
strongly believe they have received the active treatment (Beedie et al. 2006), reinforce
the need to assess level of confidence participants have of receiving either the active
treatment or placebo (O’Connor et al. 2018). This would allow for researchers to
conduct post hoc analyses to determine if expectations in participants influenced their
responses to the experimental treatment or placebo during the intervention.
The impure placebo is a medication or treatment with pharmacological or phys-
iological outcomes that either have no documented benefit on the patient’s medical
condition or symptoms or are administered at a low dosage deemed to be ineffective
for improving a patient’s condition (Fent et al. 2011). Several studies have employed
low-intensity exercise conditions (e.g., stretching exercise) as an impure or minimal
treatment placebo under the presumption that improved mental health is a function
of enhanced cardiorespiratory capacity (Martinsen et al. 1989). However, these
studies did not find greater benefits resulting from the more vigorous exercise
prescriptions, which suggests that improvements in cardiovascular capacity are not
the primary driver of psychological improvements from physical exercise and
support the supposition the placebo effect contributes substantially.
The nocebo effect (“I will harm”) stems from the administration of an inert
medication or intervention given along with the expectation of negative outcomes
(e.g., anxiety, pain, fatigue) (Benedetti et al. 2003; Carlino et al. 2014). Additionally,
inert agents or even beneficial medications presented without messages of harm can
sometimes result in a nocebo effect. This is most likely in individuals who already
possess negative expectations because of past experiences (i.e., habitual expectation)
or who observe nocebo responses in others (i.e., social learning). Another means by
which nocebo effects may occur is when individuals receiving a treatment or placebo
paradoxically develop negative expectations during study participation following
unintentional exposure to certain psychosocial cues (i.e., incidentally induced
expectation).
These definitions not only reveal that the efficacy of placebos is influenced by
their sensory characteristics but also by the specific features of the psychosocial
context in which they are administered (Benedetti 2013). These include the role of
the provider of the placebo (e.g., physician, therapist, scientist, exercise instructor)
and the setting in which the placebo is provided (e.g., hospital, laboratory, fitness
club). This has led researchers to broaden the definition of the placebo to acknowl-
edge the influence of these factors, describing it as “simulation of an active therapy
within a psychosocial context” (Price et al. 2008).

4 Navigating Methodological Challenges in Exercise

and Mental Health

Exercise researchers have recognized the need to account for placebo effects in
clinical trials for quite some time (McCann and Holmes 1984). However, this
objective is difficult to achieve for three primary reasons. First, as is the case with
other behavioral interventions, it is debatable whether participants in an exercise
The Placebo Effect in Exercise and Mental Health Research 387

study can be blinded from their treatment assignment. Second, there is no consensus
on what might constitute a valid exercise placebo (e.g., one reflecting every aspect of
exercise except the “active ingredients”). This problem is further compounded by the
lack of reproducible evidence identifying the mechanisms responsible for the psy-
chological improvements associated with exercise. Third, studying placebo effects
in clinical trials is resource intensive and cost prohibitive. That is, to precisely
distinguish treatment effects from placebo effects, the study must include a
no-treatment control arm in addition to the treatment and placebo arms (Kienle
and Kiene 1997).
While the above challenges make it difficult to distinguish placebo effects from
treatment effects in exercise interventions, a small number of randomized controlled
studies used designs which allow some placebo-related inferences to be made.
Seeking to quantify the placebo effect in psychological outcomes of exercise training
(e.g., anxiety, depression, fatigue, cognition), Lindheimer and colleagues conducted
a meta-analysis of nine randomized controlled trials that included an exercise
treatment, control, and “placebo” arm (Lindheimer et al. 2015). In this case, a
placebo condition was defined as “an intervention that was not generally recognized
as efficacious, that lacked adequate evidence for efficacy, and that has no direct
pharmacological, bio-chemical, or physical mechanism of action according to the
current standard of knowledge” (Lindheimer et al. 2015). Notably, the authors found
that approximately 50% of the treatment effect could be explained by placebo
effects, a finding that bears a striking resemblance to a more recent meta-analytic
finding that exercise training was more effective than standard of care or nothing for
chronic pain but was not more effective than placebo (Miller et al. 2022).

5 Expectations: Key Terms and Practical Examples

While the approach taken by Lindheimer and colleagues provided one pathway for
studying placebo effects (Lindheimer et al. 2015), they later recognized that traditional
placebo conditions are not necessarily germane to studying placebo effects in exercise
studies (Lindheimer et al. 2019). Researchers have recognized that established psy-
chological mechanisms of placebo effects can be measured and manipulated to
provide insight into the likelihood and extent to which treatment responses to exercise
are augmented by placebo effects or suppressed by nocebo effects (Lindheimer et al.
2019). While expectations can be generally defined as the belief that a given behavior
will lead to an outcome (Bandura 1977), we define four specific types of expectations
below and provide relevant practical examples from the scientific literature to help
distinguish among these various subtypes of expectation:
1. Habitual expectations: An expectation that reflects an individual’s previous
experiences or cultural beliefs. These expectations are developed prior to engag-
ing in a given study.
Example. A randomized controlled trial by Gordon and colleagues found that
eight weeks of resistance exercise training reduced anxiety symptom severity
388 J. S. Raglin and J. B. Lindheimer

in young adults with subclinical generalized anxiety disorder (d = 0.71)

(Gordon et al. 2021). However, during the trial’s screening phase, 82.3% of
respondents reported that they typically experience decreases in anxiety fol-
lowing exercise (Herring 2022). Thus, it is possible that the reported anxiolytic
effects of the intervention were influenced by placebo effects from habitual
expectations about the positive effects of exercise on anxiety.

2. Study-specific expectations: An expectation that is formed from experiences

occurring during one or more phases of a study (e.g., recruitment, enrollment,
test administration). Two different types of study-specific expectations are intro-
duced below.
(a) Experimentally induced expectation: A study-specific expectation arising
from the investigator’s intentional use of psychosocial cues to illicit a placebo
or nocebo effect (e.g., expectancy manipulation).
Example. Wang and colleagues measured affective responses to cycling
exercise in 95 healthy adults after giving participants positive, negative,
or neutral information about how exercise would make them feel
(Wang et al. 2022). Relative to the neutral information control group,
participants who received positive information had more positive
expectations and reported feeling better both during and following
exercise. Thus, the investigators used the positive information to exper-
imentally induce the expectation that exercising would lead to feeling
better.

(b) Incidentally induced expectation: A study-specific expectation arising from

exposure to psychosocial cues that were unintended by the investigator but
may nevertheless illicit a placebo or nocebo effect (e.g., demand characteris-
tics). These may threaten the internal validity of the study.
Example. Lindheimer and colleagues tested the acute effects of active and
passive cycling on state anxiety in 60 young adults with elevated trait
anxiety (Lindheimer et al. 2017). To minimize psychosocial cues which
might lead participants to develop positive, study-specific expectations,
the investigators avoided statements about testing the therapeutic
effects of exercise in the study advertisement and consent form and
trained test administrators to refrain from discussing the study purpose
with participants. As shown in Fig. 1, effect sizes for reductions in state
anxiety after active and passive cycling were smaller than those
reported by a meta-analysis of 36 randomized controlled trials (Ensari
et al. 2015), perhaps due to the careful consideration of incidentally
induced expectations.
The Placebo Effect in Exercise and Mental Health Research 389

Fig. 1 Effect size

comparison of state anxiety
reductions between a study
of active and passive cycling
(Lindheimer et al. 2017) and
a meta-analysis of
36 randomized controlled
trials (Ensari et al. 2015)

6 The Influence of Expectation in Chronic Exercise

Paradigms

Desharnais and colleagues randomly assigned 48 healthy adults to a ten-week

aerobic exercise program (Desharnais et al. 1993). However, one group was
informed that the exercise program was designed to enhance mental health, while
the other group was only informed about the expected physical benefits. At the end
of the intervention, both groups exhibited significant improvements in physical
fitness but a significant increase for self-esteem occurred only in the group that
received the mental health message, and the authors attributed this improvement to
the placebo effect. In contrast, a recent study involving healthy adults participating in
a seven-week aerobic exercise program failed to replicate these findings (Arbinaga
et al. 2018). One group received a message that the exercise program was explicitly
designed to enhance psychological well-being. Unlike the control group in the
Desharnais et al.’s study in which the control group was not given any message
about the psychological effects of exercise (Desharnais et al. 1993), Arbinaga et al.
included not only an exercise with no expectation group but a third group in which
participants were told the exercise program was not vigorous enough to improve
psychological well-being (Arbinaga et al. 2018). Although the largest average
improvement was found in the positive expectation group, comparable improve-
ments were observed in the other conditions. In an effort to explain the equivocal
findings between studies, the authors noted that repeated information sessions were
employed in the Desharnais’ study, which was in contrast to their study that involved
a single information session, which may have been insufficient to affect participants’
expectations. A third example stems a study of healthy, sedentary middle-aged
adults who were randomized to a six-month walking/jogging intervention (King
et al. 1989). In this case, expectations were not experimentally manipulated. How-
ever, the authors reported significant improvements in self-reported satisfaction with
body image and fitness before and after accounting for habitual expectations in their
statistical model. Thus, the effect of the intervention did not appear to be influenced
by placebo effects.
390 J. S. Raglin and J. B. Lindheimer

7 Minimal Exercise (“Impure Placebo”) Studies

Several studies have attempted to create an exercise placebo condition by using

low-intensity activities such as stretching or passive movement. In an investigation
of the influence of chronic exercise on the self-rated quality of life and other
psychological measures (Daley et al. 2007), women undergoing breast cancer
treatment were randomized to eight weeks of low-intensity aerobic exercise
(<40% of HRR), a placebo-exercise program (light stretching and conditioning),
or standard care. While quality of life improved more in the aerobic exercise
condition, reductions in depression and other psychological variables were also
found in the placebo condition, leading the authors to conclude: “We cannot rule
out the possibility that light body conditioning and stretching exercises of minimal
aerobic exertion also provide psychological benefit to cancer patients” (Daley et al.
2007). Indeed, Martinsen and colleagues found that a light stretching exercise
program resulted in psychological benefits that were equivalent to a more vigorous
aerobic exercise program in clinically anxious patients (Martinsen et al. 1989). On
the other hand, Blumenthal et al. found only a modest correlation (r = -0.25)
between improvements in aerobic capacity and reduced depression in clinically
diagnosed adults following a 16-week exercise program and proposed that other
biological mechanisms may also contribute to the psychological benefits of exercise
(Blumenthal et al. 1999).
To summarize, studies of long-term exercise programs that have attempted to
either alter expectations or utilize minimal intensity “placebo exercise” conditions
have yielded mixed results. The failure of experimentally induced expectations to
alter psychological responses in some studies (Arbinaga et al. 2018) has been
attributed to the use of a single or infrequent communication exercise message. In
the case of low-intensity exercise, prescriptions may evoke biological adaptations
that are less dependent or unrelated to enhanced aerobic capacity, but additional
research is needed to confirm this and other possible factors.

8 The Influence of Expectation in Acute Exercise

Paradigms

A small number of studies have been conducted in which the psychological

responses to a single bout of exercise were influenced by either habitual or exper-
imentally induced expectations. In general, studies in which individuals possess
positive habitual expectations about exercise are associated with greater psycholog-
ical benefits, whether reductions in negative moods (e.g., state anxiety) or increases
in positive mood states such as vigor or energy (Szabo 2013; Anderson and Brice
2011). This highlights the importance of measuring and accounting for habitual
expectations in exercise studies. For instance, an early study by Tieman and col-
leagues found that the effect of light-intensity cycling on state anxiety was smaller
The Placebo Effect in Exercise and Mental Health Research 391

after including habitual expectations as a covariate in their statistical model (Tieman

et al. 2002). However, the results of studies involving experimentally induced
expectations are less consistent. Mothes et al. found that habitual positive expecta-
tions were associated with both greater self-reports of psychological and neurophys-
iological benefits following 30 min of moderate intensity cycling, whereas
experimentally induced positive expectations were associated with neurophysiolog-
ical enhancements only (Mothes et al. 2016). Wang and colleagues found that
experimentally induced, but not habitual, expectations were associated with greater
affect during or after moderate-intensity cycling (Wang et al. 2022). Vaegter et al.
found that negative study-specific expectations led to hyperalgesia (i.e., increased
pain sensitivity) whereas neutral or positive study-specific expectations led to
hypoalgesia (i.e., decreased pain sensitivity) following isometric squat exercise
(Vaegter et al. 2020). Other researchers have observed greater psychological benefits
(i.e., affect) following experimentally induced expectations of positive messages
(Helfer et al. 2014; Kwan et al. 2017). The differences in the findings in these studies
may be due to various factors including the strength of expectations or the psycho-
logical outcomes they are associated with, and further research is clearly needed.

9 General Summary and Recommendations

The mindset and emphasis of scientific inquiry has gradually shifted from lamenting
the inability to distinguish treatment effects from placebo effects in psychological
responses to exercise (Ojanen 1994), to recognizing the importance of studying
mechanisms of placebo and nocebo effects, the psychosocial context in which they
are activated, and how they can be leveraged to enhance the efficacy of exercise
therapy on mental health (Lindheimer et al. 2019). A meta-analysis of the available
research involving both a placebo and control arm has estimated this contribution to
be approximately 50% of the overall benefit (Lindheimer et al. 2015), which is
comparable to the contribution of the placebo effect in the benefits of psychotherapy
for depression (Krogsbøll et al. 2009). Moreover, individuals who possess positive
habitual expectations about exercise experience larger psychological benefits com-
pared to those who have neutral or negative expectations, an important finding given
that many people possess negative outcome expectations about exercise (e.g.,
fatigue, soreness) that can influence their decision to either begin or to continue an
exercise program (Lindheimer et al. 2020; Loehr et al. 2014). The findings of
research attempting to manipulate expectations are not entirely consistent, but it
appears that presenting positive statements about the psychological benefits of
exercise may sometimes result in greater psychological benefits, although it may
require frequent reinforcement of such messages or elaboration of information to
effect these changes (Wang et al. 2022).
These findings have implications for both research and practice. Given that
habitual and experimentally induced expectations often, if not always, influence
the experience of exercise-associated psychological effects, researchers should
392 J. S. Raglin and J. B. Lindheimer

routinely assess expectations both at the outset of exercise intervention studies and
throughout the experimental trial. This information would also help determine if
unintentional expectations developed during study participation, even if efforts were
made to avoid unintentional expectation through the use of single blind controls or
deception.
Conversely, the finding that expectations can either enhance or diminish psycho-
logical responses to exercise has different implications for the clinician. As is the
case in clinical medicine (Evers et al. 2018), it is important to educate exercise
instructors about the potential influence that both the placebo and nocebo effects can
have on the psychological outcomes of exercise. Communicating positive expecta-
tions about both the physical and psychological benefits of exercise to participants
has both the potential to stimulate more positive psychological outcomes and
improve long-term adherence. Moreover, determining whether a patient’s negative
expectations are associated with certain exercise stimulus characteristics (e.g., inten-
sity, mode, duration) may help clinicians develop more effective exercise prescrip-
tions. Indeed, these suggestions may help researchers and clinicians enhance the
mental health benefits of exercise, but additional research is needed to further refine
our understanding of the specific psychosocial conditions that optimize these
benefits.

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