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Neuropsychologia
Abstract Volume 176, 5 November 2022, 108354 Modeling longitudinal changes in

Introduction hippocampal subfields and…

relations with
Developmental memory
Cognitive from early-
Neuroscience, Vo…
Section snippets
Low-to-moderate level of perceived Kelsey L. Canada, …, Tracy Riggins
to mid-childhood
References (99)
stress strengthens working Adolescent Mental Health and
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abc a, d, a,
Assaf Oshri , Zehua Cui Max M. Owens Cory A. Carvalho
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Linhao Zhang, …, Assaf Oshri

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• Perceived stress is curvilinearly related to neural
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• Low-to-Moderate levels of stress benefit working Mentions

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• Extreme levels of stress are harmful to WM neural
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Abstract

The negative impact of stress on neurocognitive functioning is

extensively documented by empirical research. However, emerging
reports suggest that stress may also confer positive neurocognitive
effects. This hypothesis has been advanced by the hormesis model of
psychosocial stress, in which low-moderate levels of stress are expected
to result in neurocognitive benefits, such as improved working memory
(WM), a central executive function. We tested the hormesis hypothesis,
purporting an inverted U-shaped relation between stress and
neurocognitive performance, in a large sample of young adults from the
Human Connectome Project (n = 1000, Mage = 28.74, SD = 3.67, 54.3%
female). In particular, we investigated whether neural response during a
WM challenge is a potential intermediary through which low-moderate
levels of stress confer beneficial effects on WM performance. Further,
we tested whether the association between low-moderate prolonged
stress and WM-related neural function was stronger in contexts with
more psychosocial resources. Findings showed that low-moderate levels
of perceived stress were associated with elevated WM-related neural
activation, resulting in more optimal WM behavioral performance (α
*β = −0.02, p = .046). The strength of this association tapered off at high-
stress levels. Finally, we found that the benefit of low-moderate stress
was stronger among individuals with access to higher levels of
psychosocial resources (β = −0.06, p = .021). By drawing attention to the
dose-dependent, nonlinear relation between stress and WM, this study
highlights emerging evidence of a process by which mild stress induces
neurocognitive benefits, and the psychosocial context under which
benefits are most likely to manifest.

Introduction

Psychosocial stress exerts deleterious effects on neurocognitive function

across the lifespan (de Kloet et al., 2005; Lupien et al., 2009; McEwen et
al., 2015). Working memory (WM) is a key executive function that is
susceptible to the negative impact of stress (Evans, Farah and Hackman,
2021; Oshri et al., 2019). Extant research suggests that WM deficits
associated with uncontrolled stress underlie a wide range of
psychopathology (Evans and Schamberg, 2009; Klein et al., 2001;
Morgan III, Doran, Steffian, Hazlett, & Southwick, 2006). However, the
effects of stress on cognitive functions, including WM, may not be
linear. An established hypothesis in biomedical research suggests that
the effect of stress on adaptive functioning emerges in a curvilinear,
inverted U-shaped dose-response pattern (Calabrese, 2008a, 2008b).
The psychosocial hormesis hypothesis (Oshri, 2022) suggests that
exposure to low-moderate stress levels induces beneficial adaptation,
up to a threshold, from which point, increasingly higher levels of
prolonged stress induce functional inefficiency and toxicity. The present
study tests the hormesis model of psychosocial stress by examining
relations between recent prolonged perceived stress and
neurobehavioral response to a WM challenge among a large sample of
healthy adults.

Extant research shows linkages between exposure to a range of

psychosocial stress (e.g., adverse parenting, work, and poverty) and WM
behavioral performance problems in youth and adults (Evans and
Schamberg, 2009; Farah et al., 2006; Mika et al., 2012; Noble et al.,
2007; Oshri et al., 2019). Studies on youth show that executive functions
such as WM are particularly vulnerable to toxic stress, whereas high
WM capacity is a potent protective factor from severe psychosocial
stress (Gary W Evans and Kim, 2013; Karalunas et al., 2017). WM and
other executive functions are critical for goal-directed behavior in
general and problem solving and adaptation in particular (Greiff et al.,
2015; Wiley and Jarosz, 2012). However, more recent empirically
supported theories suggest that stress may also enhance cognitive
performance (Frankenhuis and De Weerth, 2013; Sapolsky, 2015). In a
small cross-sectional study of 20 healthy young adults, Oei et al. (2006)
suggested that psychosocial stress impaired WM performance, but this
adverse effect was present only at high-stress levels. Although this
study did not directly test the hormesis hypothesis, it provided
preliminary evidence that stress exerts a nonlinear effect on cognition.

Psychosocial stress is considered a subjective construct because it is

defined as a state in which an organism perceives that its homeostasis is
threatened (Chrousos, 2009). Neurobiological and behavioral responses
are adaptive when stress is acute and situational (Ursin and Eriksen,
2004). When psychosocial stress is not transitory and perceived to be
beyond one's control, the sustained neurobiological impacts may be
toxic and behaviorally maladaptive, as described by the allostatic load
theory (McEwen et al., 2015). Despite being well-documented, the
adverse effects of stress vary as a function of severity and across
individuals, with some emerging research reporting benefits of stress on
cognitive function and adjustment (Crane et al., 2019; Höltge et al.,
2019).

The hormetic effect refers to a curvilinear dose-response relation in

which a low dose of environmental stress (adversity or toxicity) induces
constructive neurobiological and neurobehavioral processes to promote
adaptation up to a threshold of stress level (Oshri, 2022). Once this
threshold is reached, adjusting to higher stress levels becomes
increasingly demanding and may be cognitively deleterious (Calabrese
and Baldwin, 2002; Mattson, 2008b). Of note, in the psychosocial
hormesis model, we refer to cumulative or prolonged stress levels as
opposed to normative acute stress. Emerging research shows the
benefits of experiencing prolonged and moderate stress levels on
cognition and human adjustment (Crane et al., 2019; Höltge et al., 2019).
However, the hormetic process goes beyond the current documentation
of benefits related to stress. The hormesis model of psychosocial stress
purports (Oshri et al., 2022) that an organism's exposure and attendant
preparation for stress is facilitated through a process called
preconditioning, which underlies the strengthening effect and
contributes stress tolerance and possibly the emergence of neural and
psychological adaptation to future stress (Calabrese et al., 1999).
Specifically, when exposed to low-moderate stress levels, the organism
can strengthen and reorganize in anticipation of exposure to future
threats. Based on this hypothesis, preconditioning underlies an
inoculation phase in which the organism is cued to reorganize, prepare,
and behaviorally cope with subsequent stress more effectively.

Fig. 1 presents a generic conceptual model of the hormetic relation

between stress severity (i.e., perceived stress level in the past month)
and neurocognitive functioning. Neurobiological, cognitive, and
behavioral changes are triggered as a function of stress severity, ranging
between low and moderate under normal circumstances. In this range,
stress kindles adaptive long-term neurocognitive changes that may
serve as an increased capacity to maintain neurocognitive functioning,
despite future stress that may exceed moderate levels. This
strengthening area occurs up to a threshold of stress severity at the apex
of the inverted U curve (Calabrese and Mattson, 2017). At the threshold
stress level, cognitive performance starts to decrease as a function of
increased stress. Beyond this critical threshold, in the
buffering/protective phase, the positive effect related to increasing stress
ends while a decline in cognitive performance is predicted. Yet, this
adaptive neuropsychobiological process still serves to buffer the full
impact of stress on cognitive performance, compared to minimal stress.
At very high stress levels, adverse neuropsychobiological effects eclipse
beneficial cognitive processes. Beyond this point, the effect of higher
stress severity become increasingly harmful and is hence referred to as
the damaging/toxic phase. Thus, the hormetic process is comprised of
strengthening and protective phases that may function to promote long-
term adaptation and protection from moderate-to-high levels of stress
(Calabrese, 2016, Calabrese and Mattson, 2017).

Testing the hormetic model at the neural level adds conceptual and
applied utility. Conceptually, there is inherent value to cognitive
neuroscience to better understand the interactions of neural and
behavioral systems. Neuroimaging studies of the cognitive effects of
stress may provide cognitive and behavioral science knowledge beyond
“where” questions to address “how” questions – how neural activity in
specialized regions may subserve specific behavioral functions
necessary to sustain environmental stress. The potential applied
benefits of the hormetic model are also promising. The effects of stress
on WM neural systems have been increasingly demonstrated as
important links in models of risk prevention and intervention.
Measuring these effects on neural systems and how they link to
functional outcomes, such as WM performance, may advance discovery
of opportunities for model-driven targets of prevention and
intervention (Melby-Lervåg and Hulme, 2013; Snider et al., 2018). For
example, understanding how adversity is linked to WM performance
can later be examined as a cognitive resource for resilience. Moreover,
understanding neural mechanisms may also yield specific novel
neuromarkers that can be used to quantify risk and assess the efficacy of
stress-related interventions (Snider et al., 2018). Such neuromarkers
have been complimentary in other research areas, such as decision-
making and addiction, providing added predictive utility over
behavioral measures (Gowin et al., 2014; Krakauer et al., 2017; Paulus et
al., 2005) and revealing sustained neuroprotective effects against the
negative consequences of adversity (Rosen et al., 2018).

Despite the potential for protective long-term hormetic effects of low-

moderate stress, research shows significant interindividual variability in
response to stress, which has been linked to access to protective
psychosocial resources. The beneficial effects of psychosocial assets
have been explained by the cognitive-behavioral theory (Bandura,
1993). As personal and interpersonal assets (e.g., self-efficacy, social
capital and friendship, meaning and purpose) attenuate adverse effects
of stressors (Jain et al., 2012), they might be critical to establishing and
maintaining an individual's location along the hormetic curve. For
example, higher levels of self-efficacy, larger social capital, and higher
levels of perceived purpose in life are associated with more effective
coping and more positive outcomes following psychosocial stress
(Cassidy, 2015; Murray Nettles, Mucherah and Jones, 2000; Rutten et al.,
2013; Rutter, 1987; Schwarzer and Warner, 2013). According to Bandura
(1982), higher levels of personal resources, such as self-efficacy,
empower individuals to more effectively achieve goals, despite
challenging stress, through cognitive strategies such as attention
shifting, re-focusing, and reorganizing. This body of literature converges
to suggest that psychosocial assets might help attenuate the levels of
stress perceived by individuals, and thus constitute putatively critical
contexts to examine when testing the hormetic effects of stress on
cognition and behavior.

The present study tested the hormesis hypothesis for psychosocial

stress. Specifically, we tested whether individuals who report low-
moderate levels of prolonged perceived stress show an elevation in WM
capacity via WM neural response that may provide them with resources
to cope with stress. We hypothesized that WM-related neural activation
is a potential mechanism through which low-moderate stress levels
confer cognitive benefits leading to increases in WM behavioral
performance. Accordingly, individuals who reported low-moderate
levels of perceived stress would show increased neural activation in a
WM network during a WM task and attendant increases in behavioral
performance, confirming the positive effect of limited doses of
perceived stress. On the other hand, higher levels of perceived stress
would be associated with a decline in WM-related neural activation and
attendant behavioral performance, eventually leading to toxic effects
related to higher levels of perceived stress. Further, we expect the
hormetic effect to be moderated by the level of resources available to
the individual. Therefore, we predicted the hormetic association
between perceived stress and WM-related neural activation would be
more pronounced among individuals with higher access to psychosocial
resources.

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Section snippets

Sample

Data used in the present study were collected as part of the Human
Connectome Project (HCP; Van Essen et al., 2013). The HCP sample
included 1,206 healthy young adults (Mage = 28.84, SD = 3.69, 54.4%
female) between the ages of 22–37 with no documented history of
neurological disorders or mental illness. Participants came from 300
families and were recruited to broadly reflect the racial and ethnic
composition represented by the U.S. 2000 decennial census (73.5%
European American, 16.0% African …

Preliminary analyses

Bivariate correlations, means, and standard deviations of participants’

demographic characteristics, N-back WM behavioral performance, self-
report levels of perceived stress and psychological and social resources
are presented in Table 2a. …

Measurement model of WM factors

An initial correlation analysis showed that the WM-related neural

activations in all nine targeted ROIs exhibited significant associations
with the 2-back WM behavioral accuracy (see Table 2b). All ROIs on the
right hemisphere had, on average, stronger …

Discussion

A large corpus of research has documented the negative impact of

perceived stress on cognition (Orem et al., 2008; Potter et al., 2009). The
present study sought to examine the following hormesis hypothesis
(Oshri, 2022) — Do limited levels of stress induce positive effects on
WM-related neural activation and attendant behavioral performance
among healthy human subjects? Using a sample of 1,000 adults, we
tested a curvilinear (convex) association between perceived stress and
WM, a key component …

Conclusion

Existing literature has consistently documented the detrimental effects

of perceived psychosocial stress on cognitive functioning. However, the
potential neurocognitive benefits induced by stress are less investigated.
Emerging from the toxicology, hormesis describes a process where
moderate quantities of a toxin can promote an organism's adaptation.
Informed by the hormetic framework, the present study investigated
the curvilinear association between perceived stress and WM, an
essential …

Credit author statement

This study was a secondary data analysis using data from the Human
Connectome Project. All authors have read and approved the manuscript
for submission to Neurobiology of Stress, have made a substantial
contribution to the conception, design, gathering, analysis and/or
interpretation of data and a contribution to the writing and intellectual
content of the article, and acknowledge that they have exercised due
care in ensuring the integrity of the work. The authors do not have
conflicts of …

Acknowledgments
“Data were provided [in part] by the Human Connectome Project, WU-
Minn Consortium (Principal Investigators: David Van Essen and Kamil
Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers
that support the NIH Blueprint for Neuroscience Research; and by the
McDonnell Center for Systems Neuroscience at Washington University."
Drs Oshri and Owens Dr. role in this work was also funded by National
Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)
P50DA051361.

Work on this …

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