Behavioral Neuroscience

Edited by Sara Palermo and Rosalba Morese

 Behavioral Neuroscience
Edited by Sara Palermo and Rosalba Morese

Published in London, United Kingdom

Supporting open minds since 2005
Behavioral Neuroscience
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Edited by Sara Palermo and Rosalba Morese

Contributors
Valentina Ignatova, Maria Uscinska, Silvio Bellino, Estela Castilla-Ortega, Patricia Sampedro-
Piquero, Luis J. Santín, John Stewart, Olga Penagarikano, Marta Fernández, Teresa Sierra-Arregui,
Ita Puusepp, Tuisku Tammi, Minna Huotilainen, Teija Kujala, Elina Kuusisto, Sonja Laine, Kirsi Tirri,
Götz Egloff, Dragana Djordjevic, Sara Palermo, Rosalba Morese

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Behavioral Neuroscience
Edited by Sara Palermo and Rosalba Morese
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 Meet the editors

Sara Palermo has an MSc in Clinical and Community Psychol-

ogy and a PhD in Experimental Neuroscience. Currently, she is
a postdoc research fellow at the University of Turin (Italy). She
is a research member of the Center for the Study of Movement
Disorders and the Placebo Responses Mapping Group at the
Department of Neuroscience. She is also a research member of
the Neuropsychology of Cognitive Impairment and CNS Degen-
erative Diseases Group at the Department of Psychology.
Sara Palermo is an ordinary member of the Italian Society of Neuropsychology, the
Italian Association of Psychogeriatrics, the Italian autonomous association adhering
to SIN for dementias, and the International Society for Interdisciplinary Placebo
Studies. Importantly, she is involved in the European Innovation Partnership on
Active and Healthy Aging.

Rosalba Morese holds a Bachelor’s degree in Psychology at the

University of Parma and a PhD in Neuroscience at the University
of Turin to develop new techniques and approaches in cognitive
and social neuroscience.
She is an expert in cognitive and social neuroscience, neuroeco-
nomics, psychophysiology, and psychology. She performs neuro-
imaging studies in social contexts to investigate neural correlates
involved during social interactions, such as social exclusion, social support, empa-
thy, communicative intention, and social decision making. She is currently working
at Università della Svizzera italiana, Switzerland.
Contents

Preface XIII

Section 1
Definition and Operational Framework of the 21st Century 1

Chapter 1 3
Introductory Chapter: Neuroscience Wants Behavior
by Sara Palermo and Rosalba Morese

Chapter 2 9
Neurophenomenology, Enaction, and Autopoïesis
by John Stewart

Chapter 3 17
Influence of Gut Microbiota on Behavior and Its Disturbances
by Valentina Ignatova

Section 2
Behavioral Neuroscience in Developmental Age - Examples of Hot Topics in
Healthy and Pathological Subjects 45

Chapter 4 47
Challenges for Behavioral Neuroscience: Prenatal, Postnatal, and Social Factors
by Götz Egloff and Dragana Djordjevic

Chapter 5 75
Mindsets and Failures: Neural Differences in Reactions to Mistakes among
Second-Grade Finnish Girls
by Ita Puusepp, Tuisku Tammi, Minna Huotilainen, Teija Kujala, Elina Kuusisto,
Sonja Laine and Kirsi Tirri

Chapter 6 87
The Cerebellum and Autism: More than Motor Control
by Marta Fernández, Teresa Sierra-Arregui and Olga Peñagarikano
Section 3
Behavioral Neuroscience in Adulthood - Examples of Hot Topics in
Psychiatry and Addiction 105

Chapter 7 107
Treatment-Induced Brain Plasticity in Psychiatric Disorders
by Maria Uscinska, Andrea Polla Mattiot and Silvio Bellino

Chapter 8 123
Aberrant Brain Neuroplasticity and Function in Drug Addiction: A Focus on
Learning-Related Brain Regions
by Patricia Sampedro-Piquero, Luis J. Santín and Estela Castilla-Ortega

XII
 Preface

What do we mean by “behavioral neuroscience?”

This book aims at providing an overview of behavioral neuroscience and deepening

neuronal mechanisms and brain circuits that regulate the fundamental aspects of
human behavior, such as cognitive and emotional functions. It is intended to give
the reader the most up-to-date vision of how the interaction between biological
mechanisms and neurocognitive processes leads to complex and highly organized
behaviors.

The authors offer original contributions to develop new perspectives in behavioral

neuroscience thanks to the originality of their ideas, theories, research, scientific
results, and discussions.

The first part of the book deals with the definition of behavioral neuroscience and
the presentation of the framework in which it is located.

The introductory chapter emphasizes how behavioral neuroscience concerns

not only the biological bases of behavior but also the more complex phenomena
of mind and brain. Indeed, the great challenge of neuroscience is to understand
behavior and thought. One of the main topics of discussion in the twentieth century
was whether mental activities are functions different from brain activities or if they
also represent functional expressions of the brain neurons. Only in the twenty-first
century do we begin to have information of fundamental importance on the nature
of highly organized and complex mental processes such as consciousness, will, and
social cognition. Today we still find ourselves having to answer this question: Are we
our brain?

The second chapter opens the book on the interesting “neurophenomenological”

perspective to establishing correlations between descriptions of lived experience
and brain states. The question we want to answer is: How can a neuronal state be a
state of consciousness?

The third chapter describes the contribution of intestinal microorganisms for

modulation of many systems and human behavior. The author thus underlines well
how exploring the interaction of gut microbes and human brain will not only allow
us to better understand the pathogenesis of neuropsychiatric disorders, but will also
provide us with new opportunities for the design of novel immuno- or microbe-
based therapies.

The second part of the book deals with the contributions of behavioral neurosci-
ence in the field of child neuropsychiatry.

The first chapter of this section is dedicated to social factors and early psychosocial
interventions that can modify (in a positive way) the trajectories of the mind–
brain relationship. The second chapter outlines the role of mindsets and failure
in explaining learning differences among students. An experimental study in the
Finnish elementary school context is the starting point for a constructive discussion
in the light of earlier neuroscientific research related to mindsets, including limita-
tions and suggestions for future research in the field. The last chapter of the sec-
tion opens to the topic of neuropsychiatric pathology in children. The association
between cerebellar neuroanatomical alterations and autism is analyzed, opening a
new avenue for further research.

The third part of the book deals with the contributions of behavioral neuroscience
in the field of adult neuropsychiatry.

The first chapter of this section is aimed at an in-depth examination of treatment-

induced brain plasticity in psychiatric disorders. Although neural substrates of
symptoms expression have been studied extensively, neural mechanisms mediating
post-treatment amelioration of symptoms and brain networks functionality remain
poorly characterized. We now have to rethink mental disorders, re-evaluating the
treatment possibilities given by learning and brain plasticity.

The last chapter reviews the altered brain structure and function associated with
drug addiction, with a focus on brain regions involved in learning and motivated
behavior. Particular attention is paid to the consequences of reduced ability to
experience rewards and emotional dysregulation, leading to persistent memories of
pleasure related to drugs responsible for the onset of the harmful “addiction cycle.”

It is a small book with great content. The book offers an excellent synopsis of per-
spectives, methods, empirical evidences, and international references. Therefore,
it represents an extraordinary opportunity to target neuroscientific hot topics and
outline new horizons in the study of the relationship between brain and behavior.

“Neuroscience is by far the most exciting branch of science because the brain is the
most fascinating object in the universe. Every human brain is different—the brain
makes each human unique and defines who he or she is.”
Stanley B. Prusiner

Sara Palermo, PhD

Department of Psychology,
University of Turin,
Italy

Rosalba Morese, PhD

Faculty of Communication Sciences,
Università della Svizzera Italiana,
Switzerland

XIV
 Section 1

Definition and
Operational Framework
of the 21st Century

1
Chapter 1

Introductory Chapter:
Neuroscience Wants Behavior
Sara Palermo and Rosalba Morese

1. Introduction

What do we mean by “behavioral neuroscience”? This is the branch of neurosci-

ence developed from Wilhelm Wundt’s and William James’s physiological psychol-
ogy and addressed to the study of the “the neural and biological bases of behavior,
including effects of lesions and electrical stimulation, recording of electrical
activity, genetic factors, hormonal influences, neurotransmitter and chemical
factors, neuroanatomical substrates, effects of drugs, developmental processes, and
environmental factors” [1].
Historically, neuroscience is born with the identification of the neuron as an
autonomous and functionally independent cellular unit of the nervous system. The
studies carried out to define the properties of the neuron have benefited from the
progress made in various disciplines, in particular using methods to measure ionic
and molecular displacements at the subcellular level and—thanks to the original
psychopharmacology, psychophysiological, and neuroimaging approaches—the
progress made in the knowledge of integrated systems at the base of the behavioral
variations of the individual [2]. In the beginning, neurotransmitters such as acetyl-
choline, 5-hydroxytryptamine, and GABA have been discovered, and the structural
aspects of membrane receptors for different molecules with neurotransmitter
functions have been analyzed. Subsequently and of particular interest was the
identification of endorphins and their receptors on nerve cells [2]. With the identi-
fication and study of endorphins, a new approach to the analysis of substances that
perform a modulating function on the genesis and transmission of nerve impulses
has been developed. As part of the research on cellular differentiation by chemical
substances, molecules have been identified that play a fundamental role on the
growth and tropism of the nerve cell [2]. The prototype of these substances is the
nerve growth factor isolated in the early 1950s by the Italian neuroscientist Levi-
Montalcini [3].
In short, neuroscience initially contributed to defining the functioning of the
neuron and the role of neurotransmitters, of neuromodulating molecules, and of
those with trophic action.
In parallel, the biomedical approach has allowed the use of various investigation
techniques to explore the anatomic-functional structure of the nervous system as
an integrated unit, both in normal and pathological conditions. In this sense, the
progress made in neuroradiology and neuroimaging must be seen. The neuroscience
approach has therefore extended to the description of molecules able to control the
genesis of some brain proteins (the so-called genetic engineering) [2]. In particular,
molecular biology has allowed us to study amino acid sequences of peptides that
seem to play a physiological or pathological role, in relation to the different condi-
tions of isolation and characterization [2].

3
Behavioral Neuroscience

To date, behavioral neuroscience also includes psychoneuropharmacology

studies, which have analyzed the complex interactions between substrates of the
central nervous system, the distribution of various molecules, and the state of brain
functioning [2]. The result is practical acquisitions, which are extremely important
in the synthesis of psychotropic drugs widely used in the therapy of neurotic and
psychotic states.
Behavioral neuroscience concerns not only with the biological bases of behavior.
It concerns with the more complex phenomena of the mind and brain.

2. From brain activities to mental activities

Not only bío but also psyche: the great challenge of neuroscience is to understand
behavior and thought.
Although humans have wondered about the control of behavior for thousands
of years, only fairly recently has a mechanistic view of the brain taken hold [4, 5].
The concept of localization of function was an important milestone for behavioral
neuroscience. Today we know that the contemporaneous functional modulation of
different cerebral areas varies in a predictable way depending on what a subject is
doing. Thanks to modern neuroimaging and a more carefully validated understand-
ing of human cognition, a detailed view of the brain organization is now emerging.
Modular systems are outdated; the network approach is the current one [2].
One of the main topics of discussion in the twentieth century was whether
mental activities—such as thought, emotions, self-awareness, and will—are func-
tions different from brain activities, such as the movement of a limb, the perception
of a color, etc., or if they also represent functional expressions of the brain neurons.
Mental and cerebral activities would seem to be the unique and indivisible expres-
sion of the activities of the neuronal and glial elements that make up the brain
organ. Although the expression is different in quality and in the ways in which it
manifests itself, both activities are due to a single mechanism by which neurons
communicate with each other and with the rest of the body [2]. The neural circuits
and their realization are encoded in the animal genome, while the environmen-
tal stimuli play a fundamental role for the definitive realization of the synaptic
connections.
Neurons, organized in ganglia, complex structures, and networks, process nerve
impulses, memorize them, and emit behavioral responses. It is probable that once
we fully understand these first two levels—that of the functions of the individual
neurons and that of the activities of the neural networks—we will arrive at the elu-
cidation of the type of circuits (or nervous activities) with which subjects are able
to decide a specific motor act or a reminiscent act and the mechanisms by which the
brain, at the same time as processing sensory inputs, makes subjects aware of all
these operations.
Only today, we begin to have information of fundamental importance on the
nature of mental processes such as consciousness, will, social cognition, and
enormously complex problems that constitute the core of the third level of brain
functions.

3. Brain-behavior relationship

Disorders of the brain and nervous system (such as Alzheimer’s disease,

Parkinson’s disease, stroke, and traumatic brain injuries) highlight the importance
of the biological bases of behavior. The brain-behavior relationship seems to be the

4
Introductory Chapter: Neuroscience Wants Behavior
DOI: [Link]

descendant of the Cartesian mind-body dualism, where the brain is the biological
component and behavior the psychological one.
Despite the passing of the centuries, the body-mind dualism continues to be an
unresolved problem in this day and age. At the beginning of the history of neuro-
science, the mind and brain were kept apart as if they were separate and distinct
concepts. Nevertheless, the notion that the brain and behavior function separately
turns out to be an impediment to scientific progress, since they are related in a more
complex way than one might imagine. Indeed, the brain-behavior relationship
is modulated by different factors: the environment, sociocultural and historical
aspects, phylogeny, genetics, and ontogeny.
Today we still find ourselves having to answer this question: Are we our brain?
As recently suggested by Dede and collaborators, “the development of brain-
behavior relationship depended thereafter on interdisciplinary collaboration, and
scientists’ ability to formulate new experimental questions and designs, but mainly
on the methods devised for studying both parts of this dipole” ([6], p. 12). Today,
behavioral neuroscientists balance three general research perspectives in designing
their research [6]:

• Correlation: body and behavioral measures covary.

• Somatic intervention: manipulating the body may affect behavior.

• Behavioral intervention: experience affects the brain.

Indeed, behavioral neuroscience research is now conducted at a level of analysis

ranging from molecular events to the functioning of the entire brain and complex
social situations.

4. The nature and purpose of the book

Revising the story of brain-behavior relationship research since its begin-

ning, a treasure of information about how the brain works seems to have been
discovered. Nevertheless, neuroscientists’ research will continue until no more
questions can arise [7]. Indeed, the benefits of the correlation-somatic-behavioral
research approach [6] are greatly enhanced by the combined use of new technolo-
gies: neuroimaging, ICT-IoT assessment methods, and machine learning. It can be
assumed that computerized functional localization is now a reality and that the
brain-behavior relationship has already moved on to the next stage of its develop-
ment (what we have just named the third level of brain functions). Considering
the above, this volume aims at providing an overview of behavioral neuroscience
and deepening neuronal mechanisms and brain circuits that regulate the funda-
mental aspects of human behavior, such as cognitive and emotional functions. It is
intended to give the reader with the most up-to-date vision on how the interaction
between biological mechanisms and neuropsychological processes leads to complex
and highly organized behaviors. The approach is multidisciplinary, and various
levels of investigation are represented.

5
Behavioral Neuroscience

Author details

Sara Palermo1* and Rosalba Morese2

1 Department of Psychology, University of Turin, Turin, Italy

2 Department of Psychology, Center for Cognitive Science, University of Turin,

Turin, Italy

*Address all correspondence to: [Link]@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

6
Introductory Chapter: Neuroscience Wants Behavior
DOI: [Link]

References

[1] Thompson RF. In: Smelser N, Baltes

P, editors. International Encyclopedia
of the Social and Behavioral Sciences.
Oxford, UK: Pergamon (Elsevier); 2001.
ISBN 9780080430768

[2] Kandel ER, Schwartz JH, Jessell TM,

Siegelbaum SA, Hudspeth AJ. Principles
of Neural Science. 5th ed. New York:
McGraw-Hill; 2012. ISBN 0-07-139011-1

[3] Cohen S, Levi-Montalcini R,

Hamburger V. A nerve growth-
stimulating factor isolated from
sarcom as 37 and 180. Proceedings of
the National Academy of Sciences.
1954;40(10):1014-1018

[4] Lezak MD. Domains of behavior

from a neuropsychological perspective:
The whole story. Integrative views of
motivation, cognition, and emotion. In:
Nebraska Symposium on Motivation.
Vol. 41. Lincoln: University of Nebraska
Press; 1994. pp. 23-55

[5] Lezak MD. Neuropsychological

Assessment. 5th ed. Oxford, UK: Oxford
University Press Inc.; 2012. ISBN:
9780195395525

[6] Dede E, Zalonis I, Gatzonis S,

et al. From discovering to better
understanding the relationship
between brain and behavior. Integrative
Neuroscience Research. 2017;1(1):5-16

[7] Reitan RM. Certain differential

effects of left and right cerebral
lesions in human adults. Journal
of Comparative and Physiological
Psychology. 1955;48:474-477

7
Chapter 2

Neurophenomenology, Enaction,
and Autopoïesis
John Stewart

Abstract

The project of neurophenomenology, initiated by Francisco Varela, aims at

establishing correlations between descriptions of lived experience (as elicited by the
explicitation interview technique) and brain states (as measured with increasing
precision and detail by the new brain imaging techniques). However, on their own,
such correlation aggravates rather than solve Chalmers’ “hard problem”–how can
a neuronal state be a state of consciousness? The question that arises is thus how to
interpret such correlations. I will argue that this requires putting the brain in the
body of an animal living in the world. Epistemologically, this amounts to putting
neuroscience in the context of cognitive science (Varela’s concept of enaction)
and cognitive science in the context of biology (Maturana and Varela’s concept of
autopoïesis).

Keywords: neurophenomenology, enaction, autopoïesis, conscious experience,

cognition, life, Varela

1. Introduction

In 1995, Chalmers [1] identified what he called the “hard problem” of conscious‑
ness. The question is, how can a purely physicochemical event such as a set of action
potentials in a set of brain cells (and why brains, rather than the heart or the gut?!)
actually be a subjective, conscious experience. Chalmers wrote: “Why is it that when
our cognitive systems engage in visual and auditory information processing, we
have visual or auditory experience: the quality of deep blue, the sensation of middle
C? … Why should physical processing give rise to a rich inner life at all? It seems
objectively unreasonable that it should, and yet it does.” Over 20 years later, we are
hardly any nearer a solution; the problem remains entire.
In Section 2, I will present the “neurophenomenology” proposed by Varela [2],
which provides empirical evidence on the neural correlates of consciousness. While
entirely valid and indeed intriguing, this work does not solve the “hard problem”;
I will argue that in a way it makes matters even worse, because the correlations it
reveals are not explanatory, but they require explanation‑although in the conclu‑
sion, I will suggest that there is actually more to it than this.
In Section 3, I will present the concept of “enaction” [3]. In order for conscious
experience to be possible, there must be something to be conscious of: “what is it
like? …”, the question of qualia. Enaction is the process, whereby a living organism
brings about or enacts its own characteristic lived world of experience. The clas‑
sic example is the “world of the tick” as evoked by von Uexküll [4], originally in
1902, who provided a compelling view of “what it is like to be a tick.” An additional

9
Behavioral Neuroscience

feature is that whereas the original, prototypical example of enaction is the lived
world of an animal, and this concept also applies to humans. And more specifically,
this means that each and every one of the humans enacts our own lived world, every
minute of every day of our lives. This introduces a note of first‑person subjectivity,
which contrasts with the third‑person objectivity more usual in scientific discourse.
In the previous paragraph, I said that enaction is the process, whereby a living
organism brings forth its lived world of experience. This raises the question as to
whether being alive may not be a prerequisite for experiencing consciousness. There
are two aspects to this: on the one hand, a “brain in a vat” would arguably not be
properly conscious; on the other, it is only in science fiction that mechanical robots
with computerized “brains” can be conscious. In order to deepen our understand‑
ing of what it takes to be fully alive, in Section 4, we will look at autopoïesis, the
process whereby living organisms continually fabricate themselves. This is something
that every living organism does, even a lowly bacterium; but a brain in a vat, just
by itself without being part of an organism, does not; neither does any man‑made
machine, not even the most powerful computer imaginable with or without a
sophisticated connectionist architecture.
In the box below, I provide definitions of some major concepts in this field.

Definitions of major concepts

Enaction. Enaction is the process, whereby a living organism brings forth its own specific “lived world.”
The prototype example is the “world of the tick,” as described by von Uexküll and detailed in the text. It is
to be noted that “enaction” also applies to human beings, including each of us, ourselves, which introduces a
dimension of first‑person subjectivity unusual in scientific discourse.
Autopoïesis. Autopoïesis is the process, whereby living organisms continually produce themselves. They
are thus processes rather than things; they only become “things” again when they are dead. This feature
differentiates the humblest living organism, even a bacterium, from the most sophisticated robot with
a computer “brain,” since these robots do not produce themselves, they are made and repaired from the
outside, by human engineers; in other words, they are heteropoïetic.
Dissipative structure. In thermodynamically open systems (qv), there can be spontaneous generation
of dynamic dissipative structures, dynamic forms which are par excellence processes rather than things.
Mundane examples are tornadoes or a whirlpool in a river. Living organisms belong to the class of dissipa‑
tive structures. However, whereas common examples such as whirlpools are essentially ephemeral, lasting
only as long as special external conditions over which they have no controls maintained; living organisms
are potentially immortal, having the capacity to perpetuate themselves indefinitely (see autopoïesis).
Thermodynamic systems: open and closed. In classical thermodynamics, there are two sorts of system.
In a closed system, there are no exchanges with anything external to the system; it is in such systems that
“entropy” (i.e. disorder) can be properly calculated and it demonstrably increases monotonically. In open
systems, by contrast, there is a continual flow of energy and matter through the system. In this case,
“entropy” cannot be properly calculated, and so no longer increases. In such systems, dynamic dissipative
structures (qv) can arise spontaneously, and maintain themselves indefinitely.

Finally, in conclusion, I will attempt to draw these various threads together.

2. Neurophenomenology

A notable attempt to solve the “hard problem”—or rather, to dissolve it away—is

the neurophenomenology proposed by Varela [2]. There are two strands to neu‑
rophenomenology. On one hand, there are the modern techniques of brain imag‑
ing, which provide rich empirical data—fine‑grained, precisely localized, in real
time—on cerebral activity. On the other hand, there is a serious attempt to obtain
valid descriptions of first‑person subject consciousness. It is notoriously difficult to
obtain such descriptions; spontaneous introspection is disconcertingly unreliable.
In a well‑known experiment, repeated by various authors, two similar subjects are

10
Neurophenomenology, Enaction, and Autopoïesis
DOI: [Link]

Attention. Three attentional networks contribute to distinguishing conscious from nonconscious cognitive
events: orienting to sensory stimulation, activating patterns from memory, and maintaining an alert state.

Present-time consciousness. Phenomenological studies reveal a basic three‑part structure of the present, with
threads into past and future horizons. These structural invariants link naturally to observations in cognitive
neuroscience, which show that there is a minimal time required for the emergence of neural events that
correlate to a cognitive event. This noncompressible time framework can be analyzed as a manifestation of
the long‑range neuronal integration in the brain linked to a widespread synchrony.

Body image and voluntary motion. The nature of the will as expressed in the initiation of a voluntary action
is inseparable from consciousness and its examination. Recent studies give an important role to neural
correlates, which precede and prepare voluntary action, and the role of imagination in the constitution of a
voluntary act.

Perceptual filling-in. This phenomenon involves the spontaneous completion of a percept, so that the
appearance (i.e., a visual contour) is distinct from the physical correlate (incomplete borders, as in illusory
contours). The neuronal data on filling‑in correlate well with the phenomenological observation: there is an
important difference between “seeing as” (visual appearance) and “seeing what” (a visual judgment).

Fringe and center. In traditional phenomenology, there is a two‑part structure of the visual field between a
“center” and a “fringe.” This correlates well with the structure of the retinal, between “foveal” area with a
high density of retinal cells and a “peripheral” area with much lower density.

Emotion. In recent years, there have been significant advances in identifying the brain correlates of emotions.
Evidence points to the importance of specific neuronal structures such as the amygdala, the lateralization of
the processes involved, and on the role of arousal in emotional memory.

Table 1.
Basic brain mechanisms for consciousness.

shown, but slightly with different portraits, and were asked to designate the one
they prefer. They are then shown a slightly enlarged version of the portrait, other
portrait, and asked to explain why they chose it. Blithely unaware of the subterfuge,
the subjects dutifully spin a yarn explaining why they preferred the portrait they
had not chosen. At a more basic level, when asked to describe their experience of
a visual perception, naïve subjects base themselves on what they know, or think
they know, about the object in question (an apple, a house, a dog…). It was in order
to counter this tendency that Husserl [5], the founding father of phenomenology,
developed the practice of “eidetic reduction,” that is, putting aside or bracketing out
one’s knowledge of the object, in order to focus on the actual experience itself. This
is not easy, but possible if due care is taken. In Varela’s own work, he employed an
“interview method” to obtain reliable descriptions of subjective experience [6].
With these methods and also drawing on the literature, Varela obtained some
convincing results. The major results are detailed in Table 1.
So where does this leave us? These neural correlates of consciousness are, in their
own way, impressive indeed. However, with respect to the “hard problem,” there
is a sense in which we are worse off than ever. The point is that these correlates are
just that; they do not actually explain anything, and indeed they themselves require
explanation. There is actually something more to Varela’s neurophenomenology
than this, and I will return to this point in conclusion. However for the moment, we
will now take a look at what might lie behind these correlations.

3. Enaction

To start with, it will be salutary to go back to basics and look at what it is that
neurons actually do. Physiologically, their primary role is to connect sensory inputs
to motor outputs. They are well suited to this task, since their basic mode of action
is the action potential; and the cells of both sensory organs (eyes, ears, noses, tactile

11
Behavioral Neuroscience

receptors, etc.) and effector organs (principally muscles) also function with action
potentials. It is thus quite convenient to connect receptor organs to neurons, and neu‑
rons to effector organs, by means of synapses. The point here is that by this means,
the actual connections between sensory organs and effector organs is quite flexible:
any sensory organs can be connected to any effector organ, and the connection can
be excitatory or inhibitory depending on what is appropriate in terms of the sensory‑
motor dynamics thus set up. In order to appreciate the ecological significance of this,
the time has come to introduce the notion of enaction, the process whereby a living
organism enacts, or brings about, its own characteristic “lived world.”
The prototype example is the “world of the tick” as described by von Uexküll
[4]. This lived world is enacted by three simple sensation‑action cycles. (i) The
female tick climbs to the end of the branch of a bush, and … waits, maybe for
weeks. If she senses an odor of butyric acid, she lets herself fall. (ii) If she falls on
a hairy surface, she crawls until she finds a smooth area (if not, she climbs back
up onto the bush and starts over). (iii) She then sticks her proboscis through the
surface, and if she finds a liquid at 37°C underneath, she sucks to satiety. This
makes sense when we know that (in context) butyric acid is secreted by the sweat
glands of mammals; the hairy surface will then be the fur of the mammal; and
the liquid at 37°C will be the blood of the mammal (which the tick needs to feed
her eggs; she then fertilizes the eggs from a store of sperm, after which she lays
the eggs and her life cycle is complete). Of course, the tick does not know that,
as such; indeed, she is barely conscious. But the important point for us here is
that these simple sensory motor dynamics are set up by the wiring of the tick’s
simple peripheral nervous system. Note that this would not work if activation of
the butyric acid sensors did anything other than triggering the motor action of
letting herself fall; if the tactile sensors of a hairy versus smooth surface triggered
anything other than crawling to a smooth surface, and sticking the proboscis
through the surface; and if the temperature sensors of liquid at 37°C did not
trigger the action of sucking. The example is magnificent; in this way, the tick, a
tiny animal, which can only crawl slowly, manages the feat of catching a mammal
far bigger and faster than herself, and not only that but getting to suck its blood.
Thus, although the tick is barely conscious, the wiring of her nervous system
is instrumental in setting up the meaningful lived world that she is minimally
conscious of. This is indeed a basic point; Husserl noted that “consciousness” is
always consciousness of, consciousness is always “intentional,” aiming at some‑
thing meaningful. So what we see here is that way before we get to the higher level
consciousness experienced by humans, the nervous system is fundamental to
setting up the whole situation.
Before moving on, there is another aspect to enaction; that is, as conscious living
beings, each and every one of us enacts our own lived world, every minute of every
day. This introduces a note of first‑person subjectivity that is unusual in scientific
discourse; I will return to this point also in the conclusion.

4. Autopoïesis

I now address the point that consciousness would seem to be a feature reserved
to living organisms; it is only in science fiction that computers and computerized
robots are conscious (the film “Space Odyssey 2001” with the computer “Hal,”
and the film “Her” in which the hero falls in love with his “operating system”).
This raises the question as to what it is about living organisms that makes them
candidates for consciousness. After all, computerized robots can perfectly have
artificial nervous systems that set up their sensory motor dynamics. One lead is that

12
Neurophenomenology, Enaction, and Autopoïesis
DOI: [Link]

all living organisms, even the simplest, have the property that they are autopoïetic,
that is, they are pure processes that are continually “making themselves”; and this is
something that even the most powerful computer, or the most sophisticated robot
with a “brain” having a connectionist architecture, even attempts to do. Living
organisms are thermodynamically open systems, with a continuous flow of energy
and matter, which are essential to their existence (a living organism only becomes a
“thing” again when it is a dead corpse). In this respect, living organisms are similar
to other “dissipative structures” such as cyclones, or eddy currents in a river; with
the difference that they actively promote the conditions that will enable them to
perdure, which cyclones and rivers do not. It is in order to do this that they engage
actively with their environment, in the course of which they enact their lived
worlds. So maybe this is why a “brain in a vat” would arguable not be conscious; it
is a brain in a living animal, in the world, which appears as the seat of consciousness.
Exactly why consciousness is reserved to living organisms is not entirely clear, and
worthy of deeper study.
Ironically, it is not the most highly evolved forms of human consciousness that
are the most mysterious; Jaynes [7] has provided a highly suggestive account of how
sophisticated reflexive consciousness might have arisen through the “breakdown
of the bicameral mind”. The “bicameral mind” in question is the sort of trance
in which prophets (Old Testament) and heroes (Odyssey) “heard voices” telling
them what to do. Nowadays, we call this “auditory hallucination” and shut up
those concerned in a psychiatric asylum, whereas at that time, they were valued
members of their communities. However, that may be, “hallucinations” are clearly
the result of cerebral activity, as are dreams to which they are closely related. No;
what is most mysterious is the basic form of “animal consciousness,” which seems
not only to be all‑or‑nothing but also to increase gradually along the evolutionary
scale from fish to reptiles to mammals. This correlates with brain size but once again,
correlation is not cause; a correlation is not an explanation, but rather a feature,
which remains to be explained. Discussions of a scientific approach to consciousness
are sometimes compared to the question of vitalism; living organisms were long
considered as mysterious. Optimistic objectivists now consider that the advances
in biology have rendered vitalism a problem of the past; with the suggestion that
if we just continue with enough good natural science, the same will happen for the
question of consciousness. I would like to suggest that things may not be so entirely
straightforward.

5. Conclusion

In conclusion, I would like to return to some issues that I raised earlier. As we

have seen, Varela’s “neurophenomenology” highlights some of the neural correlates
of consciousness. But as I said, if this were all, it would aggravate rather than solv‑
ing Chalmers’ “hard problem.” But in fact it is not all. Varela’s main point—which
may be well missed by those reading it as one more academic text—is that if we
really wish to address the phenomenon of consciousness, we must be prepared to
take into account the fact that it is a phenomenon that is only properly instantiated
in the form of first-person subjectivity. And this means that if we wish to seriously
engage with it, we cannot escape the necessity of ourselves bringing into play our
own individual consciousness. Varela writes:

“One must take seriously the double challenge my proposal represents. First, it
demands a re-learning and a mastery of the skill of phenomenological description.
Second: a call for transforming the style and values of the research community itself.

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Behavioral Neuroscience

To the long-standing tradition of objectivist science this sounds anathema, and it

is. But this is not a betrayal of science: it is a necessary extension and complement.
Science and experience constrain and modify each other as in a dance. This is
where the potential for transformation lies. It is also the key for the difficulties this
position has found within the scientific community. It requires us to leave behind a
certain image of how science is done, and to question a style of training in science
which is part of the very fabric of our cultural identity”.

The consequence is that with respect to the “hard problem,” the nature of “hard”
becomes reframed in two senses:

1. It is hard work to train and stabilize new methods to explore experience.

2. It is hard to change the habits of science in order for it to accept that new tools
are needed for the transformation of what it means to conduct research on
mind and for the training of succeeding generations.

Interestingly enough, a similar theme comes up with respect to the concept of

enaction. As I have already indicated, there is potentially an existential dimension to
enaction; scientists are after all human beings, as thus like all living organisms enact their
lived world every minute of every day. Taking this personally, it means that I am actually
responsible for the quality of what my enacted world leads me to experience. We are on
dangerous ground here for “normal science”: science is supposed to aim at objectivity;
and it is very widely supposed that attaining objectivity requires the elimination of
subjectivity. But subjectivity, if it is assumed as such, is neither more nor less than first‑
person experience as lived from the inside; and we have just seen that precisely, which is
at the core of enaction. In other words, enaction, if it is taken seriously in what I person‑
ally see as its core, poses a manifest threat to our normal functioning as scientists.
Of course what happens is that any “normal” scientist will seek to defuse this
threat – both individually and as a community. I do hope I am not being pretentious
or disdainful here; I think I understand too well what is going on, because I know the
cost. But still I do want to stand my ground, to stand up, and be counted. I maintain
that if enaction is defused, it is betrayed. I propose that we take a closer look at this.
One of the main ways—certainly not the only one—that enaction defused is by
converting it into a much safer research program of what has been called “4E cogni‑
tion” [8]. The “4Es” are: embodied, embedded, extended, and enacted cognition.
This is a smart move (if one is indeed trying to defuse enaction so as to get back into
the comfort zone of “normal” science), for the following reason. Varela himself
envisaged enaction as the framework for a possible paradigm in Cognitive Science,
and others have attempted to follow up on this [3]. Now, in any such attempt, the
notions that cognition is embodied, embedded (it is more usual to say “situated”),
and extended undeniably play key roles. So as a proponent of “existential enac‑
tion,” I cannot protest against the association of enaction with the other three “Es.”
However, what I can and do protest about is adding in “enacted” as an ancillary
element at the end of the list. In my view, these three E’s are subservient to the over‑
riding theme of enaction. Mixing them up indiscriminately, in the way that is done
by proponents of the “4Es,” leads to missing the wood for the trees.
To sum up, then, I would like to conclude by an invitation. As I have tried to explain,
the neuroscience of consciousness potentially opens up a breach in our normal function‑
ing as scientists; it offers the opportunity for those so inclined to introduce a subjective,
existential dimension into their work. Of course, one can bring a horse to the water, but
one cannot force him to drink. This is particularly so here, where intimate personal atti‑
tudes are at stake. But I hope that I have done enough to make the invitation appealing.

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Neurophenomenology, Enaction, and Autopoïesis
DOI: [Link]

Author details

John Stewart
Centre de Recherche Enaction Design (CRED), Technological University of Compiègne,
Compiègne, France

*Address all correspondence to: js4a271@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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Behavioral Neuroscience

References

[1] Chalmers D. Facing up to the

problem of consciousness. Journal of
Consciousness Studies. 1995;2:200‑219

[2] Varela F. Neurophenomenology: A

methodological remedy for the hard
problem. Journal of Consciousness
Studies. 1996;3:330‑335

[3] Stewart J, Gapenne O, Di Paolo E,

editors. Enaction: Toward a New
Paradigm for Cognitive Science. Boston:
MIT Press; 2010

[4] von Uexküll J. A stroll through the

worlds of animals and men: A picture
book of invisible worlds. Semiotica.
1992;89(4):319‑391

[5] Husserl E. Ideas Pertaining to

a Pure Phenomenology and to a
Phenomenological Philosophy—First
Book: General Introduction to a Pure
Phenomenology. The Hague: Nijhoff;
1913 Translated by F. Kersten, 1982

[6] Petitmengin C. Describing one’s

subjective experience in the second
person. An interview method
for the science of consciousness.
Phenomenology and Cognitive Sciences.
2006;5:229‑269

[7] Jaynes J. The Origin of Consciousness

in the Breakdown of the Bicameral
Mind. Boston: Houghton Mifflin; 1976

[8] Menary R. Introduction to the

Special Issue on 4E Cognition.
Phenomenology and the Cognitive
Sciences. 2010;9:459‑463

16
Chapter 3

Influence of Gut Microbiota on

Behavior and Its Disturbances
Valentina Ignatova

Abstract

Hippocrates statement that “All disease begins in the gut” continues to be up

to date more than 2000 years later. Growing number of scientific reports focus on
the important role of intestinal microorganisms for modulation of many systems
and human behavior. As a key component of the gut brain, gut microbiota influ-
ences the development and maturation of the hypothalamic-pituitary-adrenal
axis, affects the development and function of the immune system, regulates the
blood-brain barrier, modulates the synthesis and recognition of neurotransmitters,
regulates neurogenesis, formation of myelination and supports the development
and function of the brain. Disruption of gut-brain axis function is associated with
alterations in the stress response and might contribute to neuropsychiatric diseases
as depression, autistic spectrum disorders, rapid eye movement sleep behavior
disorder, Parkinson disease, Alzheimer disease and other mental conditions. Studies
in animal models are crucial for guiding research on brain-gut-microbiome axis in
humans, as the impact of microbiota on specific brain regions and aspects of animal
behavior will help in the selection of tasks for cognitive assessment. Exploring
the interaction of gut microbes and human brain will not only allow us to better
understand the pathogenesis of neuropsychiatric disorders, but will also provide us
new opportunities for the design of novel immuno- or microbe-based therapies.

Keywords: gut microbiota, brain, gut-brain axis, behavior disturbances,

modulation, human behavior, animal models

1. Introduction

Hippocrates statement that “All disease begins in the gut” continues to be up to

date more than 2000 years later. The fields of microbiology, gastroenterology and
neuroscience have evolved gradually over time and remarkable progress in modern
medicine has been achieved not only in their individual trajectories, but also in their
active interaction. It has recently become evident that gut bacterial flora can greatly
influence all aspects of physiology, including gut-brain communication, brain func-
tion and even behavior [1].
The population of microorganisms, localized in the human gut and consisting
of bacteria, viruses, protozoa, fungi etc., definitely exceeds the number of cells that
make up the human body. The collection of these microorganisms, their genomes
and the factors that they produce are all part of the gut microbiome [2, 3]. The role
of microorganisms that make up the intestinal flora can be identified as patho-
genic, neutral, or useful for the host. The beneficial bacteria known as probiotic
bacteria predominate in the intestine of healthy subjects. The word probiotic has

17
Behavioral Neuroscience

Greek origin and its meaning states “for life”. In fact, probiotics are referred to live
microbes which are important for maintaining the intestinal microbial balance and
have the capacity to keep and improve the health of their human host” [4–6].
The intestinal microbiota and its metabolites influence modulation of gastro-
intestinal (GI) functions through their ability to affect gut permeability, mucosal
immune function, intestinal motility and sensitivity, and also activity of the enteric
nervous system (ENS) [6, 7]. Multiple mechanisms, including endocrine and neu-
rocrine pathways, are suggested to be involved in gut microbiota-brain signaling.
On the other hand, the brain can in turn alter microbial composition and behavior
via the autonomic nervous system (ANS) [8].
Evidences from studies in rodents raised in a germ-free (GF) setting pointed
that the gut microbiota influences the development of emotional behavior,
stress- and pain-modulation systems and brain neurotransmitter systems.
Furthermore, perturbations of microbiota occurring as a result of probiotics and
antibiotics application exert lead to effects on some of these modalities in adult
animals [8–11].
The absence of micro-organisms in the gastrointestinal tract (GIT) of mice
shows a reduction in the number of Peyer’s patches and IgA producing B-cells in
the lamina propria versus healthy controls, whereas the introduction of microbes
reverses these effects [12, 13]. It is curious that, GF mice also provide evidence of an
overactive hypothalamic-pituitary-adrenal (HPA) axis and reduced monoaminergic
activity, suggesting that microbial colonization can have lasting effects on central
systems, which are involved in the psychopathology of depression [14].
Some of the most common species/probiotics are bifidobacteria. Shortly after
birth, up to 90% of the bacteria found in children’s GIT are bifidobacteria, and in
adults they still account for approximately 3–5% of the microflora [15]. Moreover,
in inflammatory diseases such as irritable bowel syndrome (IBS), treatment with
bifidobacteria normalizes the existing disequilibrium between pro-inflammatory
and anti-inflammatory cytokines in this disease [16, 17]. Based on the established
important role of the balance between anti- and pro-inflammatory cytokines in the
pathophysiology of depression [18, 19], it can be hypothesized that probiotics may
have potential antidepressant properties. Of course, the potential benefits of probi-
otics as adjuvant therapy in depression are currently being discussed [20]. A recent
study of Benton et al. has demonstrated a beneficial effect of long-term probiotic
treatment on the mood of healthy subjects [5, 21].
It is supposed, that the violation of the two-way functional connection between
brain and gut microbiota take a part in the pathogenesis of certain diseases of “gut-
brain-axis” such as IBS and impairments of GI-functionality [1, 22] but it could be
also involved in the pathogenesis of a lot of significant neuropsychiatric diseases:
autism spectrum disorders (ASDs) [1, 23], Parkinson’s disease [24], mood disorders
[25]; and chronic pain conditions [1, 5, 26].
Unfortunately, the information how these findings could be transferred to
healthy humans or to disease states involving the brain or the gut-brain axis is still
insufficient. Further research with focus on this topic for translation to human
physiology and to diseases such as irritable bowel syndrome, autism, anxiety,
depression, and Parkinson’s disease should be performed [8].
The interaction between gut microbiota and brain at the levels of gut-brain axis
and their influence on manifestation of gastrointestinal, mental and neuropsychiat-
ric diseases is presented at Figure 1.
The aim of the review is to examine the dependence between the functioning of
microbiota-gut-brain axis and human behavior and how it can contribute to a better
understanding of human psychology and choosing an appropriate therapeutic
approach in cases of behavior disturbances.

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Influence of Gut Microbiota on Behavior and Its Disturbances
DOI: [Link]

Figure 1.
Bidirectional interactions between gut microbiota and brain. Relationship with medical conditions [27].

2. Method of searching

An advanced search was performed in electronic database (PubMed,

MEDLINE), based on the combinations of the following key words and phrases
as entry screening criteria: “gut microbiota”, “brain”, “behavior disturbances”,
“modulation”, “microbiota-gut-brain axis”, “influence of gut microbiota on human
behavior”, “abruption of microbiota-gut-brain axis”, “animal models of interrupted
microbiota-gut-brain axis”. The time period of the search was unlimited. The
relevant information was selected from systematic reviews, meta-analysis, books
chapters, original articles, conference abstracts and theses, published in English.
The exclusion criteria targeted case reports which were not entered in the analysis.
The reference of the related scientific sources from the selected articles was addi-
tionally checked and the relevant of them were also included in the recent work.
A relationship between functioning of intestinal microbiota and human behavior
was searched. Based on the above listed criteria, initially were retrieved 3 books,

Figure 2.
Method of searching.

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Behavioral Neuroscience

60 scientific reviews, 98 original articles, 3 abstracts. The final number of selected

and really used scientific works was as follows: 3 book chapter, 57 scientific reviews,
94 research studies, 2 paper abstracts on the current topic “Influence of gut micro-
biota on behavior and its disturbances”—Figure 2. The chronology of knowledge
regarding microbiota-gut-brain axis and its influence on human behavior was also
tracked. The similarities of points of view and results, as well as the contradictions
in published literature were analyzed. The possibilities for psychological and drug
interventions in patients with behavior disturbances based on the summarized
conclusions were also highlighted.

3. Role of gut-brain axis for mental health

The essential interaction between the gut and the brain through the gut-brain
axis is well established. The environment and related factors render influence
on central nervous system (CNS), as well as on HPA axis. Furthermore, the CNS
interacting with the ENS, the intestinal muscular and mucosal layers via vegetative
afferent and efferent tracts, modulates gut functions as permeability, mucus secre-
tion, motility, as well as host immunity [13, 28, 29]. Thus, CNS inputs can affect
the gut functions, while gut inputs could modify specific CNS processes [1, 30].
Interruption of these bidirectional interactions may provoke neuroinflammation
processes and could be involved in the pathogenic ways responsible for develop-
ment of CNS disorders [13].

3.1 Anatomy of the gut-brain axis

The functioning of the colon is modulated by both internal (intrinsic) and

external (extrinsic) neural pathways [31].

3.1.1 Intrinsic innervation

The ENS is integrative system of neurons with structural complexity and

functional heterogeneity, similar to these of brain and spinal cord. Its main role is to
control motility, secretion, mucosal transport and blood flow of the GIT [32]. The
ENS realizes these functions via motor neurons, localized in ganglia, composing a
final common pathway to the effector cells of the GIT. Although these specialized
motor neurons receive some impulses from CNS through parasympathetic and
sympathetic pathways, their function is predominantly coordinated by sensory
neurons and interneurons localized within the ENS [30].

3.1.2 Extrinsic innervation

[Link] Splanchnic “sympathetic” nerves

Their noradrenergic fibers within the wall of the GI tract arise from cell bod-
ies embedded in the prevertebral sympathetic ganglia. The major “sympathetic”
projections to the large intestine originate from the inferior mesenterial ganglia and
the remaining noradrenergic fibers to the rectum are provided by the pelvic ganglia.

[Link] Vagal (parasympathetic) innervation

The vagal nerve transfers information between the internal organs and the brain-
stem. It contains both afferent and efferent nerve fibers and innervates the entire

20
Influence of Gut Microbiota on Behavior and Its Disturbances
DOI: [Link]

gut with exception of the distal third of the colon. Vagal afferents terminate in the
nucleus of the solitary tract (NTS) whose impulses go up through the parabrachial
nucleus (PBN) to the thalamus, limbic system and insula [33, 34]. Spinal fibers pass
up via the spinothalamic tract and the dorsal spine columns. Respectively, the spi-
nothalamic pathway goes ascendingly to the thalamus, and the dorsal columns give
projections to the gracile nucleus and cuneate nucleus in the upper medulla. Efferent
impulses from the last rostral medullar structures reach the thalamus through the
medial lemniscus. In turn, thalamic projections ascend to the primary somatosensory
cortex and insula [30]. Vagus motor nuclei are represented by nucleus ambiguus
(NA) and dorsal motor nucleus (DMN). The DMN is a source of efferents to the
smooth muscles of the gut that form synapses with the neurons of the MP [7, 33].

3.2 Gut microbiota influences and human brain function

3.2.1 ANS modulation of the gut microbial environment

Impaired intestinal transit caused by compromised migratory motor complexes

(under parasympathetic modulation) is associated with an increased microbial
colonization in the small intestine [5, 35–37]. The frequency of regular migrating
motor complex is influenced by the number of feeds, quality of sleep and stress.
Acute stress is associated with increased parasympathetic output to the small and
large intestine and decreased vagal output to the stomach [38]. ANS affects the
mechanisms of immune activation at the level of intestinal epithelium. This pro-
cess could be influenced trough modulation of the intestinal immune cells such as
macrophages and mast cells against gut luminal microbes through antimicrobial
peptides or indirectly via changing the access of gut microbiota to the intestinal
immune cells [1, 39]. This process could be influenced trough modulation of the
intestinal immune cells such as macrophages and mast cells against gut luminal
microbes through antimicrobial peptides or indirectly via changing the access of gut
microbiota to the intestinal immune cells.
Preclinical studies proved that increased permeability of intestinal epithelium
after exposure to different stressors is result of easier translocation of gut micro-
biota followed by driving of immune response [1, 40, 41].

3.2.2 Effects of host’s signal molecules on the function of the intestinal microbiota

Neuronal and neuroendocrine signaling molecules as catecholamines, serotonin,

cytokines, GABA, dinorphine, etc. dispersed into the gut lumen through neurons,
immune and enterochromaffin cells can also play a role in the modification of
intestinal environment [1, 8, 42], probably regulated by the CNS [43]. Many stress
factors result to increasing of both plasma and luminal gut levels of catecholamines
as norepinephrine [8, 44]. In vitro experiments indicated that some pathogen
microbes could change their proliferative ability after exposition to exogenous
catecholamines. Norepinephrine may accelerate the proliferation of several strains
of intestinal pathogenic microorganisms and could increase the virulence of
Campylobacter jejuni [1, 45, 46].

3.2.3 Microbe-to-host signaling by microbial signaling molecules

Metabolites produced by intestinal microbiota, including short chain fatty acids

(SCFAs), bile acid metabolites and neuroactive agents such as GABA, tryptophan
precursors and metabolites, serotonin and catecholamines, including free metabo-
lites and cytokines released during the immune response to microbes may deliver

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Behavioral Neuroscience

the signal to the host via local cell receptors in the intestine [37, 47]. These factors
can also give signals via neurokines through afferent vagal and spinal pathways and
endocrine mechanisms to target non-GI tracts, including vagal afferents in the por-
tal vein and receptors in the brain. A significant part of the metabolites identified
in the circulation are with intestinal microbial origin [48, 49]. The enteroendocrine
cells, as well as the neurons forming the submucosal and myenteric ganglia, express
different types of SCFA receptors [50] A diet that includes Bifidobacterium breve
leads to elevated levels of fatty acids in the brain, but unfortunately there is not a
clear explanation for that mechanism [1].
Actual studies confirm that multiple nuclear receptors (NRs) are expressed
in the GI tract and several microbe-produced metabolites act as ligands of NRs.
Intestinal bacteria secrete metabolites including indole derivatives, hormones and
secondary BAs, which play role of natural ligands for the host’s NRs [51]. In this
way the microbial metabolites can realize biological effects in the human body via
regulation of the host’s gene expression. These dynamic interactions permit overall
control on the health or disease development in the host through direct effect of the
microbiota on the human physiology [11]. Via signaling to the brain, the microbiota
regulates metabolism, CNS development, inflammation as well as mood and behav-
ior. It is essential that the human host has the ability to voluntarily influence and
meliorate its own microbiota through nutritional or probiotic interventions [52].
Latest research found that, in the presence of the microbiota, the intestinal
epithelial lining generates physiological levels of oxidative stress. On the other
hand, these interfere both with the composition and functionality of the microbiota
(e.g., anaerobes thrive in the presence of electron acceptors) and directly with the
gut permeability. This lead to increased probability of xenobiotic molecules to reach
the systemic circulation as well as the CNS [53].
Another well-known interaction between the microbiota and CNS involves
astrocytes. Astrocytes represent a functionally diverse group of glial cells, which are
responsible for ion homeostasis, neurotransmitter balance, storage of glycogen, the
integrity of the blood brain barrier (BBB), realizing of the neuronal signaling, which
play a main role in the neuroinflammation process [54]. The inflammation could be
suppressed by modulation of type I interferon signaling in astrocytes, initiated by
microbial metabolite products, which activate the aryl hydrocarbon receptors (AhRs),
The indoles, released from gut microbiota, act as AhR agonists [55]. The dietary
tryptophan in intestinal cavity, which is undigested, is transformed into indole in the
presence of the microbial enzyme tryptophanase. Then the indoles could be modified
through microbial or viler enzymes to indole derivate with various affinity [10, 56].

4. Dysregulation of the gut-brain axis. Evidences from experiments on

animals

Alterations in the microbial contain of the GIT are considered to contribute to

inflammatory and functional bowel disorders and psychiatric comorbidities. The
results of recent studies using various strains of mice and rats, various strains of
probiotics and various experimental paradigms reported a number of microbial
bowel modulation effects in emotional behavior [57–59], learning and memory
[60], social interactions [61] and nutritional behavior [62].

4.1 Experiments on mood changes in disturbed gut-microbiota in rats

The first experiments in young GF mice which confirmed the influences of

gut microbiota on postnatal development of the hypothalamic-pituitary response

22
Influence of Gut Microbiota on Behavior and Its Disturbances
DOI: [Link]

to stress were performed by Sudo et al. in 2004. It is interesting, that the GF mice
expressed reduced anxiety-like behavior in the elevated plus maze (EPM), a reliable
behavioral test that examines approach and avoidance behavior in mice, compared
to specific pathogen free (SPF) mice [63].
Desbonnet et al. evaluated the potential antidepressant properties of probiotics
through testing of rats chronically treated with Bifidobacteria infantis in the forced
swim test [5]. Probiotic administration in naive rats had no effect on swimming
behaviors. However mitogen stimulation in probiotic treated rats lead to substantial
reduction of IFN-γ, TNF-α and IL-6 cytokines compared to controls (p < 0.05). In
addition, the plasma concentrations of tryptophan (p < 0.005) and kynurenic acid
(p < 0.05) were significantly elevated in the rats, treated with bifidobacteria [20].
Treatments with Bifidobacteria also lead to reduced 5-HIAA concentration in the
frontal cortex and a decrease in DOPAC in the amygdaloid cortex [5].
Schroeder et al. provided evidences for production of benzodiazepine ligands in
a rat model of encephalopathy or butyrate acting as a histone D-acetylesterase that
was shown to have an antidepressant effect [64, 65].
The study of Arseneault-Breard et al. gave the first evidences for beneficial effect of
probiotics L. helveticus R0052 and B. longum R0175 on post-myocardial infarct depression
in rats. This positive probiotic influence was engaged in maintaining of the gut barrier
integrity, which is possibly associated with the host’ inflammatory state after MI [84].
The association of increased HPA axis responses and reduced anxiety-like
behaviors observed in several of the studies performed in GF mice suggests that
HPA axis and nonhypothalamic (anxiety-like behavior) components of central
stress circuits may be affected on different ways according to the GF conditions,
depending on species and mouse strain. These findings suggest that the increased
HPA axis activity in GF animals may represent a response of the organism to the
loss of microbiota-related energy sources [8].
Savignac et al. demonstrated that the two Bifidobacterium strains used in their
study were able to improve the anxious phenotype of innately anxious BALB/c mice
in a strain-specific manner and the effect was better than that from the admin-
istered antidepressant escitalopram. These findings support the statement that
probiotics could be a reliable alternative for treatment of mood disorders [142].

Figure 3.
Impact of gut microbiota and external stress factors on behavior [66].

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Behavioral Neuroscience

On Figure 3 is presented influence of both gut microbiota and external stressors

on behavior.

4.2 Experiments on behavior changes in disturbed gut-microbiota in rats

The increased hippocampal brain-derived neurotropic factor (BDNF) registered

in the ATM-treated mice is corresponding with their gregarious behavior. A recent
study found increased BDNF expression in the amygdala during fear learning
[67, 68]. Over activation of the amygdala also has been implicated in depression and
anxiety [67, 69]. Lower levels of BDNF in the amygdala of ATM treated mice were
associated with increased exploratory behavior.
Bercik et al. found that SPF mice who received antimicrobial agents per os
demonstrated enhanced exploratory behavior and hippocampal expression of
BDNF. This finding was associated with temporary alteration of the representa-
tives of their microbiota and was not accompanied by inflammatory status, altera-
tion of gastrointestinal neurotransmitters levels, nor with vagal or sympathetic
function. Intraperitoneal application of antimicrobial agents to SPF mice, similar
to their oral administration in GF mice had no influence on behavior. Increased
exploratory behavior and high hippocampal levels of BDNF were reported in GF
BALB/c mice, colonized with microbiota from NIH Swiss mice. Suppression of
exploratory behavior was demonstrated in GF NIH Swiss mice, colonized with
BALB/c microbiota [2, 70].
The study of Bercik et al. did not provide proof for intestinal inflammation, as
oppose to Verdú et al.’ investigation [71], where administration of ATMs in a higher
dose and for a longer period was made in NIH Swiss mice. In the Bercik’s experi-
ment embarrassment of the intestinal microbes did not change myeloperoxidase
activity, histology or cytokine profile of the colon [8]. No differences in serotonin,
dopamine, or noradrenaline content in the gut of ATM-al. treated mice were
observed, suggesting that these neurotransmitters are not involved in mediating the
behavioral changes observed in the model.
Li et al. and Bercik et al. reached similar results on memory and learning skills
in adult mice [11], applying different nutritional supplements to animals at a very
early age with the following disruption of the intestinal flora in very young age.
Working and referred memory was better in the animals on rich in beef diet as
opposed to the mice on standard meal [8].
Neufeld et al. supposed that the low anxiety-like phenotype was accompa-
nied by long-term changes in plasticity-related genes in the hippocampus and
amygdala. They found altered GF behavior, accompanied by a decrease in the
N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central
amygdala, increased BDNF expression and decreased serotonin receptor 1A
(5HT1A) expression in the dentate granule layer of the hippocampus. It is the first
work which demonstrated an altered behavioral phenotype related with lack of
gut microbiota [59].
In their work Bravo et al. registered increased levels of GABAB1b mRNA in cin-
gular and prelimbic areas in mice treated for a long time with L. rhamnosus (JB-1),
while the concentration of these neurotransmitters was reduced in the hippocampus,
amygdala and locus coeruleus in the same experimental animals. Furthermore, the
GABAAα2 level was reduced in the prefrontal cortex and amygdala, and increased in
the hippocampus. The observed mice expressed reduced response to stress, associ-
ated with releasing of corticosterone. Similar neurochemical and behavioral effects
were not expressed in mice, who has underwent vagotomy [12, 73].
In their study Park et al. demonstrated that depressed-like behavior in mice
that underwent bilateral olfactory bulbectomy (OBx) was associated with altered

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Influence of Gut Microbiota on Behavior and Its Disturbances
DOI: [Link]

colonic motility and a shift in the microbiota profile. Their experiment also sup-
posed that increased prokinetic neuropeptide, gut hormone and serotonin in the
colonic wall are mediators of the altered motility [25]. Their finding was consistent
with those of Rodes et al. who showed changed colonic transit and altered stability
of the colonial microbial community [74].
Hsiao et al. demonstrated GI barrier defects and microbiota alterations in the
maternal immune activation (MIA) mouse model who displayed ASD signs. MIA
generation, who has received Bacteroides fragilis (human commensal microbe) per
os, has evolved altered bacterial gut content which predisposes to impaired commu-
nication and manifestation of stereotypic, anxiety and sensorimotor behavior. The
described experimental model showed change in profile of the serum metabolites
and their levels. It is other evidence for the gut microbiota impact on human behav-
ior through the gut microbiome-brain functional axis and it could help in searching
of relevant probiotic treatment of behavior disturbances in neurodevelopment
diseases in human [3, 75].
It was found that gut microbiota status reduce social interactions in GF mice
and probiotics improve social interactions in a post-MI rat model. Desbonnet et al.
examined whether the degree of information transfer during social interaction is
disrupted in GF mice. In their experiment GF mice spent a decreased proportion
of time engaged in social investigation and substantially greater proportion of
time engaged in repetitive self-grooming behavior during social interaction. After
GF bacterial colonization these behaviors were normalized, which is evidence for
involvement of microbiota in modulation of such behaviors. However, the quality
of information transfer during the interaction was not affected in GF mice, indicat-
ing that the ability to process information per se during social interaction was not
affected in GF mice [76].
It is important to note that many of the psychologic deficits, registered in GF
mice, are specific to males in which higher incidence of neurodevelopmental
disorders was registered compared to females [59, 63, 77–79]. de Theije et al.
demonstrated that gender-specific inflammatory conditions are present in the
small intestines of VPA in utero-exposed mice and are accompanied by a disturbed
serotonergic system both in the brain and in the intestinal tract [80]. Gut microbi-
ota-associated behavioral changes were reported in different ASD mouse models
using valproic acid administration or maternal infection; in the latter instance
some behavioral disorders were favorably influenced by probiotic therapy with
Bacteroides fragilis [8, 9].
Several studies proposed the influence of intestinal microorganisms on eating
behavior [80], probably as a consequence of modified fatty acid receptors, gut
receptors, responsible for taste, alteration of the intestinal transportation mecha-
nisms or disturbed releasing of satiety hormones [9, 81, 82].
Crumeyrolle-Arias et al. found that lack of intestinal microbiota in sensitive to
stress strain rats lead to neuroendocrine and behavior reactions of acute stress and
significant changed degree of the dopaminergic turnover in the higher brain struc-
tures which modulate stress and anxiety—another support for the crucial impact of
the gut microbiota on the higher brain activities [9, 15, 83, 84].
Recently it was reported that impaired permeability of the blood brain barrier in
GF mice probably will restrict reaching of the liver bacterial metabolites to the brain
[85]. Numerous remodeling experiments in GF animals confirmed that deviations
of brain metabolism and behavior could be preserved through reconstitution of the
gut microbial composition [1, 86].
Wong et al. found that genetically determined caspase-1 deficit in mice suppresses
the anxiety-depressive like behavior and improves the motor activity and locomo-
tor abilities, as well prevents manifestation of depressive symptoms after chronic

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Behavioral Neuroscience

exposition at stressors. On the other hand, minocycline as pharmacological antagonist

of caspase-1 alleviates the depressive like symptoms in wild type mice provoked by
stress. Actually, both chronic stress and pharmacological inhibition of caspase-1
modify the composition of fecal microorganisms almost in the same way [3, 87].
The GF model has some limitations, which suppose that the investigators
should be cautious in extrapolating the conclusions obtained in animals on people.
Important is the fact that GF mice are born under aseptic conditions, such as sepa-
ration from the mother via cesarean section and directly placement of the newborn
in an special insulator in which the air, in which everything is sterilized, including
the air, food and water. The biochemistry of brain and gut intestine is quite differ-
ent [1, 81], HPA axis responses [63], in emotional, [58], social [75, 79], metabolic
function, and ingestive behaviors [82] between GF animals and control animals
which contain normal or pathogen-free flora obtained by colonization from the
mother [8, 78]. However, up to date studies with animal model proved that the gut
microbiota can influence the central nervous system in the absence of substantial
changes in local or circulating cytokines or specific intestinal neurotransmitter.
It is unambiguous that bacterial products can get access to the brain via the
bloodstream, they can act through the immune system via cytokine releasing by
the mucosal immune cells, or through the endocrine system by triggering gut
hormone release from enteroendocrine cells [9, 87]. Since GF animal models are not
analogous to the development of the human brain, premature conclusions about the
significance of these findings to humans should be avoided [88].

5. Findings from clinical, imaging and neurophysiological tests on the

human brain-gut axis

Gut to brain pathways have been explored through cortical evoked potentials
(CEPs), magnetoencephalography (MEG), positron emission tomography (PET),
and functional magnetic resonance imaging (fMRI) [30].
Loening-Baucke et al. applied anorectal CEP in children with constipation and
encopresis and found significantly prolonged latencies of the early-onset potentials,
suggesting a defect in afferent pathway conduction [89].
The perception of painful stimuli is accompanied by activation of anterior
cingulate area in people in a healthy condition, as opposite to subjects suffering
from IBS in which activation of left prefrontal cortex occurs probably due aberrant
CNS processing [5] Subsequent research in patients with IBS also suggest that rectal
hypersensitivity induced by repetitive distention of the sigmoid colon correlates
significantly with increased blood flow in the thalamus and that an aberrant
thalamic response to pain could be the reason for the abnormal sensitization.
In studies of Ertekin et al. and Herdman et al. conducted at different times
reproducible EMG responses on the part of external anal sphincter were evoked
by cortical magnetoelectric stimulation. Turnbull et al. managed to differentiate
the topographic areas of the external anal sphincter and the pelvic floor muscles
represented at the medial side of the primary motor brain cortex using TCMS. This
representation is bilateral and shows asymmetry in some individuals [7, 30, 90–92].

6. Effect of interventions targeting the gut microbiota

Known approach for registration the effects of intestinal microbes on brain

function is the use self-reporting measures to determine how the brain function
alters under the influence of induced from probiotics microbial proliferation.

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Influence of Gut Microbiota on Behavior and Its Disturbances
DOI: [Link]

The level of anxiety and psycho-emotional stress was reduced in human (both
male and female), treated with Lactobacillus and Bifidobacterium versus persons who
toke control substance in a randomized placebo-control trial. However other study
using different strain Lactobacillus does not succeed to confirm this conclusion.
But another study using a different Lactobacillus probiotic, failed to confirm
these findings [21, 93]. The limitations in the study design including the size of the
cohort, the mood of the surveyed contingent, the used assessment tools, the inter-
individual differences in microbial composition and the differences between the
probiotics may be the cause of the discrepancy in the results.
Another approach is to use functional MRI (fMRI) to assess changes in the
human brain in response to gut microbial modulation. One study showed that
chronic ingestion of a probiotic consortium altered functional brain responses in
healthy women [94]. In this study, the answer to the emotional face recognition
task was measured with fMRI in healthy women before and after intake of active
probiotic for 4 weeks, unfermented dairy product or no treatment. Women who
were treated with probiotics demonstrated diminished response to the task of
emotionally recognizing in extensive brain networks, including territories, respon-
sible for sensation and emotions. Self-assessment of anxiety and depression was
not significantly different between in between the studied groups. But altered fMRI
responses proposed a substantial change in response to emotional negative stimuli.
Separate functional brain imaging study explored the modulatory impact of gut
microbiota in subjects with mild cognitive impairment and hepatic encephalopathy
through administration of non-absorbable antibacterial agent [95]. More successful
coping with the cognitive task corresponded with increased subcortical activity
and better frontoparietal connectivity on fMRI. Other investigation with antibiotic
administration in people with the same diseases during 8 weeks also confirmed
improved cognitive level and established altered serum metabolites with supposed
bacterial origin [1, 26, 96].

7. Role of microbiota-gut-brain axis in neurological and psychiatric

diseases

Changes in the microbial environment, as a result of different stressors, are

linked with alterations of barrier, motility and activation of the immune system.
Perturbation of this axis lead to changes in the stress-response and behavior, which
are thought to be involved in several CNS diseases, such as anxiety, depression
autism, Parkinson’s disease and Alzheimer’s disease [97].
Neuropsychiatric comorbidity, including depression and anxiety, is common
finding in patients with a functional GI disorder such as the IBS and it reaches 60%
of this somatic pathology. On the other hand, IBS has also been related with changes
in the gut microbiota including reduced diversity and temporal instability at the
genus level. It is interesting to note that behavioral and psychological changes are
often present in patients with active celiac disease, which are associated with find-
ings of regional cerebral hypoperfusion in their brains [25, 98].
Some recent works reported for changed expression of GABA A receptor and its
B subunits, responsible for the primary inhibitory brain mediation [73, 99, 100],
subunits of NMDA receptors, realizing excitatory neurotransmission [101], concen-
tration of serotonin 1A and tryptophan. Some of the above mentioned alterations
corresponded with disturbed emotional behavior, which supports the interaction
between microbial composition and behavior [1, 8].
In recent years evidence has emerged that neurodegenerative diseases (NDs) are
strongly associated with the microbiome composition in the gut [101, 102].

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Behavioral Neuroscience

7.1 Role of microbiota-gut-brain axis in mood disorder

A “leaky gut” is suggested to play a pathogenic role in depression. There are

evidences for altered intestinal permeability in patients with mood disorder and
their first degree relatives [18]. For most of the depressed patients the brain-gut axis
function is impaired, including imbalance in brain neurotransmitters, decline of
brain neuroplasticity, dysfunction of hypothalamic-pituitary-adrenal axis, chronic
periphery inflammation and neuroinflammation, as well as gastrointestinal dis-
eases and gut microbiota dysbiosis [103]. However, the impact of depression on the
microbiota has not yet been studied [25].
Wong et al. proposed that suppression of caspase-1 plays a protective role in modu-
lation of the interaction between representatives of the intestinal microbiota and the
state of stress. They reported the importance of signals from inflammasome along the
gut microbiota-inflammasome-brain axis which attribute to modification of cerebral
processes, especially for manifestation of anxiety-depressive symptoms [3, 87].
Acute tryptophan depletion (ATD) in subjects suffering from depression, was pre-
ceded by bimodal emotional processing, corresponding with bimodal manifestation
of the clinical symptom. It was proved in a small patient’s cohort where the alleviation
of depressive symptoms occurred 24 h after ATD and the mood processing was at
the better level about 5 h after depletion. The opposite processes were registered in
patients who experienced worsening of the depressive symptoms [2, 104].
Serotonin is a key element of this axis, acting as a neurotransmitter in the CNS
and in the ENS, located in the gut wall. This transmitter is formed in neuroendo-
crine cells and plays a role of paracrine hormone in the intestine. Serotonin is also
an endocrine hormone which passes into the blood and bind to the platelets. Besides
its system effects like maintaining the bone density and participation in metabolite
processes, it performs a key connection between both ends of the gut-brain axis
[105]. It is interesting that most of the serotonin is produced at the periphery pre-
dominantly in the tGI epithelium, but also in bones, breast and pancreas. Only 5%
of its synthesis is realized at central level. The only difference in ways of serotonin
synthesis is the use of tryptophan hydroxylase type 1 in peripheral mechanism and
instead of it-type 2-in the central one [105]. The reversal process of serotonin degra-
dation is performed with the help of monoamine oxidase and aldehyde dehydroge-
nase to 5HIAA both in the periphery and in the CNS [2, 96, 106].

7.1.1 Microbiota-gut-brain axis in major depression

Major depression disorder (MDD) is an incapacitating multifactorial psychiatric

disease, which is characterized by a range of symptoms affecting both emotional
and cognitive domains [107]. The hypothesis of activated peripheral blood mono-
cytes and T lymphocytes is well known [18]. Another supposed mechanism is
impaired excitation/inhibition balance that is potentially mediated by the reduced
amount of GABA. The low concentration of brain-derived neurotrophic factor has
been proposed as a unifying hypothesis for reduced cell numbers in frontal cortex
and amygdala and also for reduced hippocampal volume. Despite the great advances
in the knowledge of this disease, its etiology and pathophysiology are still not fully
understood [108].
It is important that metabolites as hippurate, dimethylamine and dimeth-
ylglycine derived from the blood of patients with MDD are actually products
of their intestinal microbiota [109]. Similar to findings in animal experiments
in depression, limited number of studies in humans with small cohorts found
changes of the gut microbiota strains [25, 110]. All this trials proposed the poten-
tial relationship between the alteration of gut microbiota composition and MDD
manifestation [18].
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Influence of Gut Microbiota on Behavior and Its Disturbances
DOI: [Link]

Significant difference in the isolated bacteria from stool samples of 58 Chinese

subjects, diagnosed with major depression compared to 63 healthy individuals was
found. Y.
The following three main bacterial phyla are specific for the gut microbiota
of depressed subjects: Firmicutes, Actinobacteria and Bacteroidetes. Depression
behavior models were created through transplantation of stool samples taken from
five subjects with depression into germfree mice. And vice versa, transplantation of
feces from five healthy individuals did not lead to behavioral effect. Mice receiving
microbiota from patients with depression showed disturbances in hippocampal
gene activation and also in carbohydrate and amino-acid metabolism [16, 109].
This study provided convincing evidence that the depressive phenotype could be
transferred by transplantation of the microbiota.
Kelly et al. recruited 34 patients with major depression and 33 healthy individu-
als with similar demographics. Plasma levels of cytokines, C-reactive protein,
salivary cortisol and plasma lipopolysaccharide-binding protein were determined
by ELISA, and showed alterations supporting a proinflammatory phenotype linked
with depression. Depression was associated with decreased gut-microbiota rich-
ness and diversity. A fecal microbiota transplant was prepared from a subgroup of
patients with depression or from healthy individuals and transferred by oral gavage
to a microbiota-deficient rat model [114].
But further research in larger samples and unified MDD populations is required
to confirm whether disturbances in gut microbiota have a causative role for the
onset of MDD.

7.2 Microbiota-gut-brain axis in autistic spectrum disorders (ASD)

During the early onset of this developmental disorder an autistic enterocolitis

and changes in intestinal permeability occur [111]. Moreover, urinary metabolic
phenotyping has determined biochemical changes that were consistent with abnor-
malities in the composition of the gut microbiota, found in autistic children.
Recent studies suggest that changes in antigenic load due to the impairment of
gut barrier function is triggering factor for clinical manifestation of autism [112].
Desbonnet et al. are the first scientists who found that microbiota are crucial for the
programming and presentation of distinct normal social behaviors, including social
motivation and preference for social novelty, while also being important regula-
tors of repetitive behaviors. Taking into account that these aspects of behavior are
impaired in neurodevelopmental disorders such as schizophrenia and autism [5]
and with a male preponderance, these data extend our knowledge regarding the
genesis of neurodevelopmental disorders of altered sociability. A better under-
standing of the underlying mechanisms of these social deficits, which may include
modulation of immune cell cytokines release, changes in vagal nerve activity and
neuroendocrine function, can help for developing of innovative and more effective
strategies in managing of these social disturbances [76].
A study of Kang et al. revealed less abundance of Bifidobacteria species and the
mucolytic bacterium Akkermansia muciniphila in children with autism [114–116].
Other experiment showed less diverse gut microbial composition with lower levels
of Prevotella, Coprococcus, and unclassified Veillonellaceae in ASD [117]. Another
study showed a significant increase in several mucosa-associated Clostridiales,
whereas a decrease in Dorea, Blautia and Sutterella was seen in AUTISM-FGID [118].

7.3 Microbiota-gut-brain axis in Alzheimer disease

Alzheimer disease is a progressive neurodegenerative illness associated with

accumulation of proteinaceous misfolded amyloid-b (Ab) fibrils and oligomers,
29
Behavioral Neuroscience

together with neurofibrillary tangles consisting of hyperphosphorylated tau protein

in the cerebral cortex and other brain regions [118]. Recent research indicates that
alterations of the gut microbiome could activate proinflammatory cytokines and
increase intestinal permeability, leading to insulin resistance, which has also been
found in AD [119].
Bacterial representatives of the gut microbiome excrete lipopolysaccharides
(LPSs) and amyloids. These products lead to forceful pro-inflammatory and innate-
immune effects, activate the system Following enhanced amyloid aggregation, as
well secondary degeneration occur, which are typical signs of AD, together with
impaired cleansing mechanisms of Aβ peptide [17, 120, 121]. It has been suggested
that diet and specific nutrients could alert the composition of the intestinal micro-
biota and might influence the production or aggregation of amyloid proteins [29,
114, 122].

7.4 Microbiota-gut-brain axis in Parkinson disease and its prodromes

Currently it is well established that Parkinson’s disease (PD) is not a pure move-
ment disorder of the CNS but also a gastrointestinal disease [115–117], which affects
the ENS [123–125]. The main premotor PD symptoms include rapid eye movement
sleep behavior disorder, hyposmia, constipation and depression [126].
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia
which results from the loss of physiological motor inhibition and is manifested with
abnormal behavior during REM sleep. That disorder leads to varying degrees of
complex motor activity which ranges from sleep talking to violent dream enacting
behaviors potentially harmful for the subject or bed partner [127, 133].
In their study Heintz-Buschart et al. revealed differential abundances of gut
microbial taxa (such as Akkermansia) in Parkinson disease (PD) and its prodromal
state idiopathic REM sleep behavior disorder compared to healthy controls. The
majority (about 80%) of the differential gut strains in patients with PD are very
similar to those in subjects with idiopathic REM sleep behavior disorder. Most com-
mon are Anaerotruncus and Bacteroides, which correspond to non-motor symptoms
of the disorders. Metagenomic sequencing of specific microbial samples allows the
genomic reconstruction [23, 128]. Other studies registered reduction of microor-
ganisms as Faecalibacterium, Coprococcus, Blautia, Prevotella and Prevotellaceae in
gut of subjects, suffering from PD. These alterations are non-disease specific at a
lower taxonomic level, for example at phylum stage, but at higher taxonomic level
as genus or species, was registered some overlap between alpha synucleinopathies
such as PD and multisystem atrophy (MSA) [3, 102].
It has been shown that PD patients with RBD exhibit much higher frequencies
of phosphorylated asyn pathology in the colon and in the skin compared to PD
patients without RBD [129]. Also, idiopathic RBD subjects exhibit marked pathol-
ogy in the sympathetic and parasympathetic nervous system, but a relatively intact
dopamine system [130].
For Prevotella such reduction has also been observed in RBD patients. Based on
the attributed functional properties of these bacteria, such alterations could affect
gut barrier integrity, short-chain fatty acid (SCFA) production, and inflammation.
This would be in line with reports of a leaky gut and reduced levels of SCFAs and
lipopolysaccharide binding protein in PD patients.
An interesting link between gut microbiota and asyn pathology could be
cross-seeding of amyloid pathology induced by bacterial amyloid proteins such as
curli.
So far, human microbiome studies in PD have been carried out exclusively in
medicated patients, except for one study that included also idiopathic RBD patients

30
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DOI: [Link]

[131]. While the PD associated microbiome alterations have been confirmed in

drug adjusted analyses, confounding effects which could be result of COMT inhibi-
tors intake cannot be excluded. Another potential confounder is colonic dysmotil-
ity, which may independently alter microbiota composition [132, 133].
Thus, observed brain and behavioral changes may be mediated by the absence
of intestinal microbes directly or indirectly through one or more of the non-brain-
related alterations. The latest data show that the intrauterine environment is not
sterile, and it can even be supposed that microbial metabolites of the intestine from
the maternal microbes of the intestine may have an effect on the development of
the fetal brain [75]. The altered signaling of the cecum to the brain secondary to the
massive cecal dilation associated with this model may alter the development of the
brain regions that process this input [88].

8. Discussion

The gut microbiota has co-evolved with its host for millennia and influences
positively many functions of the host organism, as digestion, production of nutri-
ents, detoxification, defense against pathogens and immune regulations [2, 3, 123].
As a key component of the gut brain, gut microbiota influences the development and
maturation of the HPA axis [134], affects the development and function of the immune
system [135], regulates the blood-brain barrier [136], modulates the synthesis and
recognition of neurotransmitters [73], regulates neurogenesis, formation of myelination
[137], and supports the development and function of the brain [78]. Microbiota-gut-
brain axis plays a crucial role for manifestation of mental disorders [103].
Following the development of gut microbiota, the scientists not only focus on
the top-down effects of the brain-gut axis (from brain to gut), but they also devote
special attention to the bottom-up influences (from gut to brain) [138]. Alterations
of the “gut brain” as pathological changes of intestinal microbiota affect the brain
activity and have an impact on behavior. In turn, the emerging brain changes
provide feedback on the gut. Uniting the brain and the colon, the brain as targeting
gut microbiota organ is becoming a key trend in neuroscience and reliable field for
successful management of neuropsychological disorders [11, 103].
Treatment with antidepressants has achieved a significant improvement from
the introduction of selective serotonin re-uptake inhibitors and rather the intro-
duced serotonin and noradrenaline re-uptake inhibitors, however, there are still
outstanding clinical requirements for the treatment of depression, and better thera-
peutic strategies are needed, especially with regard to the treatment of depressive
cure and additional comorbid painful physical conditions such as GI discomfort [5].
There are confirmations for intestinal microbe changes in patients suffering from
major depression [114, 139], as well as in IBS. Considering the serious evidence
from laboratory animal models in which the stress affects brain-gut-microbial axis,
this area requires more research in humans. In addition to the effects on the immune
system, probiotics have also been shown to improve carbohydrate malabsorption
[140], which in turn is associated with both early signs of depression and reduced
levels of tryptophan [141].
There is a reasonable assumption that probiotic treatment can produce a
beneficial effect on mood by raising serotonin precursor levels, tryptophan, and
hence increasing serotonin availability [5]. Despite these promising initial find-
ings on microbiota and stress-related disorders, there is a relative lack of research
among healthy individuals linking the composition and function of the microbes
inhabiting the human intestine and levels of chronic stress or susceptibility to
acute stress [26].

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Behavioral Neuroscience

Studies in animal models are crucial for guiding research on brain-gut

microbiome-axis in humans, as the impact of microbiota on specific brain regions
and aspects of animal behavior will help in the selection of tasks for cognitive
assessment. Such studies will also be useful in identifying which bacteria may
be of particular importance. For example, in rodent models, a specific strain of
Bifidobacterium longum was found to alter cognition, [142], as well as stress-related
behavior and physiology, and a similar effect profile was subsequently observed in
people given this strain [26, 143].
Recent research indicates that the gut microbiota is associated with health in the
elderly, with those in long-term care having a less diverse microbiota than those liv-
ing in the community [144]. Even in healthy aging, some aspects of cognition could
be deteriorated. Despite the growing interest in this problem, there is still lack of
sufficient studies, especially of long-term longitudinal research examining changes
in the human gut microbiota with aging. The high inter-individual variation in
the gut microbiota also impedes interpretation. Such research efforts should occur
in the context of rapid acceleration of genetic sequencing technologies for better
characterizing of the gut microbiota [26, 145].
We are witnesses of extraordinary merging of research approaches in different
areas of psychiatry, gastroenterology and neurology which significantly improve
our understanding of neuropsychiatric diseases and more clearly explain the close
relationship between GI and mood disorders. As a result the therapeutic strategies
in some mental illnesses significantly advanced. For example, IBS, recognized
as linked with psychosocial and GI disorders [6, 146] and often accompanied by
depressive symptoms [147, 148] has improved since introduction of an interdisci-
plinary approach [5]. Although the brain and gut are organs with quite different
functions at first glance, the emerging part of the scientific sources provides proofs
for their synergy along the “brain and gut axis” and suppose that not only the brain
may affect the intestinal function but also the gut, both by direct and by indirect
mechanisms can cause alterations in CNS [6, 149], and in stress-related disorders
such as depression [5].
It is not known whether the observed changes in the microbiome play a causal
role in the development of the intestinal pathology in PD or whether they are a
consequence of the altered intestinal function. However, observations that motor
symptoms, neuroinflammation, asyne pathology and intestinal motility may be
modulated by manipulation of the gut microbes in transgenic asyne-overexpressing
mice suggest that such causative effects are possible [150, 151].
In order to establish which mechanisms connect microbe alterations and PD,
such studies should use a multiomics approach, including meta-genomic, metatran-
scriptional and metabolomic assays, in combination with assessment of host factors
such as intestinal biopsy, permeability studies, cytokine levels and host genotype.
For this purpose multi-center consortia need to cooperate to ensure a sufficient
cohort size and standardized methodology [132].
A fuller understanding of the human “hologenome,” of human microbial
ecosystems and their secretory products should provide a deeper insight into their
contribution to age-related neurological diseases associated with amyloidogenesis,
CNS inflammation and progressive neurodegeneration [120].
It is suggested that modulating the gut microbiome through specific nutritional
interventions and the use of prebiotics and probiotics might represent an effective
strategy to reduce the level of chronic inflammation and Ab associated with AD,
possibly preventing or ameliorating AD symptoms [29].
A deeper understanding of how psychological development and social and cul-
tural factors affect the brain-gut-microbiome axis will contextualize the role of this
axis in humans and give a light on the necessary psychological interventions that

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DOI: [Link]

will improve the health of the brain-gut-microbiome axis. Interventions apparently

aimed at alleviating disorders in a part of the brain-intestinal-microbial axis (e.g.,
depression psychotherapy) may still affect other parts of the axis (e.g., microbial
composition and function) and functional GI disorders such as IBS are disorder of
the axis, not an isolated problem of both psychology and gastrointestinal function.
Discipline psychology should be aware of these interactions in order to help create a
future research program in this emerging research area [26, 152].

9. Conclusion

The gut microbiota influences the brain biochemistry and hence—the behavior
irrespective of the autonomic nervous system, specific GI neurotransmitters, or
inflammation. The intestinal commensals communicate with the human body via
immune, endocrine and neural mechanism. These functional pathways are part
of the microbiota- gut-brain-axis and according to preclinical evidence the gut
microbes can recruit the above mentioned bidirectional communication relation-
ship to modulate not only the brain development and functioning, but also our
behavior. Disruption of gut-brain axis function is associated with alterations in the
stress response and might contribute to neuropsychiatric diseases as mood disorder,
ASD, REM sleep behavior disorder, Parkinson disease, Alzheimer disease and other
mental conditions. Exploring the interaction of gut microbes and human brain will
not only allow us to better understand the pathogenesis of neuropsychiatric disor-
ders, but will also provide us new opportunities for the design of novel immuno- or
microbe-based therapies.

Conflict of interest

No.

Author details

Valentina Ignatova
Clinic of Neurology, Multiprofile Hospital of Active Treatment, National Heart
Hospital, Sofia, Bulgaria

*Address all correspondence to: valyaig@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

33
Behavioral Neuroscience

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 Section 2

Behavioral Neuroscience
in Developmental Age -
Examples of Hot Topics in
Healthy and Pathological
Subjects

45
Chapter 4

Challenges for Behavioral

Neuroscience: Prenatal, Postnatal,
and Social Factors
Götz Egloff and Dragana Djordjevic

Abstract

Behavioral medicine has neglected social aspects for a long time. In the pre- and
postnatal context, these are especially important, as parental competencies in
the relational objects of the infant may be compromised by both inner and outer
factors, thus potentially compromising the infant’s psychic development. The
findings on pre- and postnatal stages of human development have shown that early
psychosocial interventions can help out to some extent. Approaches for parents,
which have mainly evolved from the findings of psychoanalysis and mother-infant
research, must be augmented by a social perspective, just like postnatal concepts
have been augmented by prenatal intervention approaches. The latter reach from
how parents-to-be can be prepared for parenthood to how to support attachment
and relation in infants, toddlers, and older children. Scientific behavioral reasoning,
augmented by subjectivity- and objectivity-related concepts, provides a framework
to work with, so that potential deprivation can be faced seriously. Intervention
approaches focusing on bonding, on relational issues, and on educational practices
are introduced, covering the most important time spans of psychic development
from the mother-unborn period to the mother-infant period.

Keywords: prenatal, postnatal, social, interventions, mother-infant research

1. Introduction

Psychoanalysis and infant mental health research offer a large amount of knowl-
edge about human development, pathology and interventions, which can partially
be grounded in the findings of neuropsychoanalysis [1, 2]. These findings connect
to what Stierlin conceptualized as relational individuation, or co-individuation
(“Bezogene Individuation”: the principle that “the higher the level of individuation
in a family member, family, or group is, the higher the level of personal relating
becomes, and is required at the same time”) [3], a concept that originally aimed at
psychic identities of members of a family system. The concept generally supports
the principle of socialization modes in Lloyd deMause’s approach of psychogenetic
personality development [4, 5]. The psychogenetic personality concept illuminates
the modes of manifestation of transgenerational psychodynamics, and even takes
into account physiologically based premature birth in humans [6]. The concept
hints at the mutual interaction of individual and societal development [7], which
will show in subjectivity and in socialization modes. Illuminating their organic

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Behavioral Neuroscience

substructure might be one of the challenges of future behavioral neuroscience, an

interdisciplinary exchange of concepts and of mutual impregnation, the aim of
future scientific cooperation. The question of how to bring together brain, mind,
and the social will be one of the difficult tasks.
In the course of recent infant mental health research, fetal brain development
has been examined from a bio-psychosocial perspective [8], as has been by Roth
[9] from a neuroscientific one. In his depiction of prenatal and early postnatal
processes of brain development, three levels in the limbic system correlate with
temperament, with early experiencing, and with subsequent socialization, of which
the latter may be responsive to compensatory intervention. Psyche, in the neurosci-
entific perspective, is strictly related to brain physiology, a controversial [10] still
worthwhile approach, since it has been shown that early experiences will influence
brain function and structure in humans [11]. What has mostly been accepted is that
the concept of subject autonomy is generally challenged owing to Freud’s observa-
tion, “Der Reflexvorgang bleibt das Vorbild auch aller psychischen Leistung (The
reflex act remains the type of every psychic activity as well),” [12] which he stated
to put psychic mechanisms in connection with automatic reflex processing, in order
to emphasize the predominance of unconscious psychic processes. Around 100
years later, the findings about intuitive responses being in middle position between
innate reflex behavior and seemingly more “rational” behavior, have been brought
up thanks to video microanalyses of dyadic interaction of infants and parents.
In this context, parental competencies are referred to as intuitive competencies
[13–15]. These are elicited within a time frame of 200–600 ms. Not only mothers,
also fathers, children, and other relational objects have been observed to show
these; they are universal and to be found in persons of any age, any gender, and in
any culture [16].
Spitz, in the 1960s, observed that the physical presence of the mother, i.e., of one
relational object, is the basic precondition for successful infant mental development
[17, 18]. Severe social deprivation in hospitalized and institutionalized children,
which grew up without responses to their needs showed compromised development
in many aspects [19, 20]. By now, diagnostic approaches and options of treatment
of infants and toddlers even encompass a psychodynamic concept [21], focusing
on conflict, structure, and relation perspectives, thus paving the way for develop-
ing a rather focus-oriented treatment approach. This will probably be used more
frequently in the future, just like operationalized psychodynamics in OPD-2 has
increasingly been used in studies of the last years [22]. Although operationalized
psychodynamics has widely improved the clinical view of human development,
misconceptions have not been avoided: specific cultural and social influences on the
infant’s development are still grossly neglected. Socioeconomic factors on mothers’
sensitivity and on family functioning have only begun to be examined [23].

2. Anthropological basics and mother-infant research

The intrauterine development of the cerebral cortex occurs in exact stages. Each
developmental step is a vulnerable period, which is sensitive to insults rendering
the brain susceptible to structural malformations and functional impairments [8].
Neurogenesis shows billions of neurons being produced during the development
of the central nervous system. It mainly occurs at the inner edge of the neural tube
wall, later ventricles, and spinal cord. Cell division begins once the neural tube has
closed at 4–5 weeks after conception, which is 6–7 weeks of gestation. Most neurons
are formed at 12–18 weeks of gestation. Around 200 billion neurons are produced
in the human brain, and 40 billion in the neocortex alone, of which the half are

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Challenges for Behavioral Neuroscience: Prenatal, Postnatal, and Social Factors
DOI: [Link]

eliminated during the maturation process, resulting in a final number of 100 billion
neurons at 40 weeks in full-term infants. Maternal stress during the first trimester
has been linked to an increased risk of pathology, suggesting that the expression
of genes in early fetal life is influenced by external factors, leading to behavioral
and cognitive malfunction or to psychiatric disorder like schizophrenia [8]. Stress-
induced reduction of neurons in late fetal life is probably associated with increased
damage of neurons. Adding to it, the conspicuous findings on correlations of mater-
nal mental disorders in pregnancy to the child’s subsequent psychic development
can be examined from different perspectives, as can psychic development within a
broader context.
From a psychoanalytic perspective, there is a perinatal constant of originary
separation as inscription of lack within the ego. It is a separation of the ego from
the developing subject through “objet petit a.” The object, the so-called other, is the
object-cause of desire. It is the driving force, which makes the subject seek some-
thing, organically mirrored in the mesocortical and mesolimbic seeking systems
of the frontal lobe. The subject in encountering the object experiences entering the
Real beyond symbolization. If it was not for physiological prematurity in humans
[24], one might argue that human seeking is merely for reasons of expansion, or
exploring. Still, it is originary separation adding to physiological prematurity, which
seems to induce primary “homelessness” in Homo sapiens [7]. The subject comes to
exist through seeking only.
While German pioneer of psychosomatics Thure von Uexkuell gave point to the
tuning of inner and outer world in animal life, in humans the relation to nature is
flawed, or altered (“altéré”). It is altered, Lacan noticed, “through a certain dehis-
cence (déhiscence) of the organism internal, through a primordial discord (discorde)
(…), as is shown in the signs of discontent and in physical incoordination in the first
months of the newborn. The objective rationale of the anatomical imperfectness
of the pyramidal system (…) confirms this view, which we formulate as obtaining
true specific prematurity of birth in humans” [25]. Along such an anthropological
constant, it should be common ground to assume biological and sociopsychological
aspects to be relevant to human development.
The biological aspect refers to instinctual life in connection with separation.
Anxiety is the most basic of experiences and can be reactualized at any time.
Such a reactualization of anxiety figures in anxiety of the cut (“coupure”): it is
in cutting, dissociation, separation [26], which is first and foremost in birth, and
then in castration and punishment. Although the latter belong to the sphere of the
Symbolic, they actualize the first, stemming from the sphere of the Imaginary. As
Catherine Malabou points out, death is prefigured in castration. Castration anxiety
does not primarily represent the loss of a specific object but rather the indetermi-
nate threat of separation, of a cut. In connection with repetition compulsion and
the “fort/da” game in “Beyond the Pleasure Principle” [27], the anticipation of
separation from the self is a primal motive (“Ur-Angst”). Any trauma experienced
is in terms of such psychodynamics, namely since probably “all events—even ‘real’
or traumatic events—ultimately occur at the heart of the psyche’s separation from
itself (…)” [26].
The psychological aspect refers to symbolization through employing language in
human development after the early mother-infant stage has been passed through. At
that stage, it is about basic trust (“Ur-vertauen”) in order to overcome mechanistic
thinking (“pensée opératoire”) and alexithymia in the infant, and the Imaginary has
provided space for the infant to develop. Symbolization will increasingly enter the
Imaginary, over-writing the experiences the infant has made before. Ludwig Janus
has called attention to the concept of transcription, or transliteration (“Umschrift”),
occurring from one developmental stage to another, which Freud in a letter to Wilhelm

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Behavioral Neuroscience

Fliess remarked in 1896 [28]. However, the failing of symbolical over-writing, i.e., of
restructuring or rewriting of the Imaginary, can be a marker of psychosis [29], or, on
the imaginary-organic pole, of asymbolic conversion [30]. In “The Interpretation of
Dreams” [12], Freud describes dreams as expressions of the primary process, in which
wish fulfillment is executed. Thus, dream, delusion, and confabulation and other
psychosis-like disorders of thinking can be viewed as working temporarily in lieu of
the demands of the frontal lobe control system.
From a psychoanalytic perspective, disorder is the result of quite a normal
struggle for conflict solution in differing gradations of primary, i.e., preverbal,
processual thinking, and secondary, i.e., verbal, processual thinking. Pathology
can be read in gradations of normalcy. Outer stressors can trigger a reactualization
of preverbal, i.e., pre- and postnatal affects [7]. These encompass many factors
contributing to compromise conflict solution. Disorder will take the very gradation
the subject is susceptible of, only to produce as little conflictive tension as possible.
At preverbal stages, disorder will mainly be body disorder; conversion can take
place before any symbolization is possible.
At this point, the seemingly societal decline of symbolic references might make
any structural framing, i.e., inner positioning, difficult to achieve [29]. Inner posi-
tioning can be taken as being connected to outer positioning in its literal sense: as an
example, the ancient Greek “polis” would be a place of enabling positioning for—a
few select—people to grow into thinkers like Plato and Aristotle. For them, it would
provide space and structure to developing thought and concept. A frame would be
provided in which personal relations could grow into becoming the background
of successful development [31]. In contrast, today’s ever-existing interpellation to
people manifests in a very concrete societal trend of commodified relations calling
for even less inner positioning, adding to, and retroacting on, the withdrawal of
sustained societal structure, rendering more and more impossible people partici-
pate in major social achievements [32]. Such a trend might also compromise psychic
functioning of parents and mothers-to-be severely. It might be the phenomenon
of “new morbidity” in infants, which is in the trend toward early functional and
psychic disorders and toward chronification, closely associated with this societal
trend. At any rate, biological and psychological aspects of human development
show humans to be prone to dysfunctional internal conflict processing, probably
even more when obscure personality traits seem to be promoted [33], while virtual
media foster the loss of sense of reality [34]. Such depravation can be seen in the
phenomenon that present-day western societies increasingly call for behavioral and
experiential conformity: changing its character, the issue of diversity becomes an
interpellation of conformity. Depravation retroacting on poor psychic structure in
people might prevail for generations [15], especially when a societal mode of too
much freedom in some areas and too much restraint in others takes effect. It would
be worthwhile examining how the organic substructure of psychological function-
ing and societal superstructure are intertwined, and how the “culture of commodi-
fication” [35] affects the mother-infant relationship. Looking at research on mirror
neurons [36], it is not out of the question that such processes affect subject develop-
ment on a macrolevel beyond the microlevel of mother-infant relations.
On a microlevel, especially postpartum depression in mothers has been the
subject of extensive research investigations [37–39]. As is widely known by now, in
interaction with their newborns depressive mothers show decreased responsive-
ness, increased passivity and/or intrusiveness, increased withdrawal, and decreased
expression of positive emotions, and they tend to regulate the effects of their
newborns in an insufficient way. Moreover, Papoušek and von Hofacker [40] have
generally pointed out the connection between psychopathology traits in mothers
and maladaptive patterns in their intuitive competencies. Correlations of maternal

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Challenges for Behavioral Neuroscience: Prenatal, Postnatal, and Social Factors
DOI: [Link]

mental disorders in pregnancy to the child’s subsequent psychic development [41]

are often conspicuous, yet by no means automatic. Such are certainly individual and
can be influenced. Infant mental health observations could show slight but distinct
negative influences of infant crying and sleeping problems on the child’s subsequent
social development [42]; infants’ regulatory problems contribute substantially to
external and internal psychic problems in early childhood [43]. Adding to recent
behavioral oxytocin research [44] of the human “attachment system,” from a
perspective of behavioral neuroscience, it would be worthwhile exploring the
testosterone-perspective of the human “lust system,” and the dopamine-perspective
of the human “love system.”
Familial strain of different kinds can lead to dysfunctional relational patterns;
missing or inadequate internal educational models in parents can have a similar
effect [45]. As to intuitive parental competencies, it has become evident that
intrapsychic and interpersonal factors can compromise the expression of these.
Likewise, it must be assumed that the level of expressing such competencies
might be dependent on social factors. This issue has widely gone unrecognized
[15, 46]. Social factors viewed from a microperspective give way to a question-
ably individualized concept in which societal motion, e.g., toward fragmentation
and irrationality through anomic tendencies, is neglected. It should not be sur-
prising to see irrationality increase with too many choices [47]; any compromis-
ing of the formation of psychic function will lead to people’s attempts at escaping
mentalization. Given mentalization is the key to at least some of parental
competencies issues, more are still pending; e.g., the capability of executing ego-
functions may have developed in an individual, but may not be expressed. At any
rate, in a perspective of mentalization as basic ego-function, such capability is a
precondition of role-taking and changing of perspectives. Empathy corresponds
with this function and is often missing, especially in somatoform disorder. In
practice, somatoform disorders are often diagnosed as functional syndromes
[48]; i.e., somatization shows in body disorder. Alexithymia often accompanies
somatoform disorder; it should also be viewed in a context of societally induced
personality issues.
Parents´ cause attributions often reveal such a connection. In general somato-
form disorder, from both older children and parents, psychosocial cause attribu-
tions are more often the case than in, e.g., asthma bronchiale to which rather
genetic, external, and somatic causes are attributed [49]. Also, there are only
moderate matches of subjective disorder beliefs in older children and parents:
preframed attribution questionnaires generate higher scores of matches than half-
open qualitative explorations do [50]. Generally, high diversity in parents’ knowl-
edge and cause attributions of their children’s symptoms [51] invites to improve
communication on many levels. Although it is obvious that pathological personal-
ity traits are associated with the ability to understand emotional states of others
[52], social cognition aspects, of which mentalization is mostly in focus, are on a
microperspective of family interaction. Although subscribing to a psychodynamic
perspective, hereby only a small aspect is examined. In case that identity issues play
a significant role, identification presupposes an original to identify by [53]. It has
to meet requirements of highly differing concern [54] and has to do with subjective
experience of identity [55].

3. Development and pathology

Fedor-Freybergh, from a prenatal viewpoint, has rehearsed the problematic

nature of increasing discontinuities emerging from social destabilization reaching

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Behavioral Neuroscience

back to early prenatal traces of memory [56, 57]. The general message seems to be
that through the processes of neuronal migration, organization, wiring, myelina-
tion, shaping and eliminating of excess neurons [8], even earliest information is
sustained. Still, an approach of the earlier the better in several aspects of interven-
tion has not yet been fully realized, as can be derived from the findings of epi-
genetics and fetal programming [58].
In prenatal stages of increased neuronal plasticity, milieu factors influence
protein synthesis and program reference input in biological systems such as the
HPA axis. While early postnatal epigenetic alterations are still partially influence-
able [59, 60], the Barker hypothesis [61–63] postulates highly probable influ-
ences from the fetal period on cardio-metabolic functioning [62] and on brain
functioning [64]. Some pregnancy-associated disorders have shown to connect to
fetal experiencing [65], which also hints at the fetal period to be highly important
for psychosomatic development. At least, it can be said to be responsible for the
development of an archetypal mode of bonding and ambivalence (“Urbindung”
and “Urambivalenz”). Taking into account that regulatory disorders in infants
are obviously correlated with insufficient dealings within the family system,
especially the family but also institutional surroundings of early childhood like
kindergarten and preschool play a significant role in influencing personality.
Research findings on regulatory disorders [66–70] provide dyadic insights but
do not tend to regard triads [71], let alone setting, context, or background [72];
that is why many findings of attachment research [73] need to be augmented by
a more panoramic view of relations. Also, an intergenerational perspective of
trauma impact [74] carries weight since it provides vertical insight into modes of
re-traumatization.
The pivotal role in human developmental pathology is certainly played by
violence, as it shows in externalized action with huge destructive potential.
Individuals with violent behavior inflict injuries on others, either physically,
psychically, or both. Individual; i.e., subjective violent behavior, as social
scientists like Hurrelmann [75] have shown, is mainly to be understood as gener-
ated by intrapsychic, interpersonal and social conflicts. Still, even an obvious
inclination to aggression must not be assessed pathological in general; aggression
encompasses a zestful constituent part [76]; it goes heavy on libido, i.e., on the
dopaminergic system. That is why violence must not be confused with aggres-
sion in the shape of expansion and initiative, which belong to the individual
developmental process. In contrast, violence as a mode of destructive aggression
will have to undergo a transformation into pro-social modes before it is real-
ized. As is often the case, etiopathology of psychic disorders can only partially
be traced back [77]. Yet, concepts of phenomenology like, e.g., pathogenetic
situation [10, 39], can reasonably be applied, and diverse traits of complex
trauma can be observed out of which violence emerges [78]. Traumatized
children have problems with changing perspectives since persisting stress from
complex trauma has severely compromised their modes of experiencing, adding
to lifelong trauma-associated conditions like dissociation [78, 79]. Presently, a
phenotypical similarity in dissociation and severe psychopathology like schizo-
phrenia is being discussed [80].
It is obvious that high levels of interdisciplinary exchange will be necessary to
meet the challenges of brain, mind, and social factors (cp. Figure 1). In order to
conceptualize further research on their intertwining, subjectivity formation and
social objectivity have to be differentiated. The following concepts are thus not
along the differentiation of subjective and objective aspect in dual-aspect monism
as in the conception of Kessler et al. [81] but describe the subject in a grid of collec-
tive predisposition into which it has to develop.

52
Challenges for Behavioral Neuroscience: Prenatal, Postnatal, and Social Factors
DOI: [Link]

Figure 1.
Bio-psychosocial factors model of violent behavior, modified after Schick 2017.

3.1 Subjectivity formation

The mirror stage in the infant’s development provides no coherent experience of

the image in the mirror. Anamorphic as it is, it tends to convey rather fragmented
than coherent aspects of the personality-to-be. That is why Lacan considered coher-
ence an illusion, also owing to the fact that infantile dependence and helplessness
are not conveyed in the mirror image. In referring to physiological prematurity,
Lacan is close to Otto Rank’s concept in which the whole self (“Total-Ich”) precedes
the partial self (“Partial-Ich”). Anything which is postnatal will only remain partial.
Along birth, any wholeness will inevitably be lost: this is what humans will have to
accept in life [82]. Here, we have a deceptive case of anthropology: there is not any
totality possible. Infantile identification with the mirror image brings about alien-
ation, or alteration, to the emerging subject, as well as dehiscence and discord—
seemingly biological yet a specifically human feature [83]. Basic vulnerability stems
from this stage; it can shake the infant when it is confronted with outer objects. Any
identification, e.g., with parents, siblings, or teachers bears refractions.
When the mother reflects the infant, the infant creates an imaginary space
through projecting his own reflected bodily self [30]. It is eventually connected
to the fantasy, or anticipation, of separation by a cut. This phenomenon is linked
to the illusion of coherence, which provides stability; on the other hand, there is a
subversion-proneness due to an inherent amount of fictitiousness and externality
within the developmental process. In the course, the outer world is perceived more
coherent, more indisputable than it really is. More often than not, those objects
out there are experienced as identifiable egos having unity, permanence and, first
of all, substance. But those objects generally comprise a fair share of ourselves,
which we tend to have abdicated ambivalence and fragmentation: after all, we
wonder why those objects are that fragile. So, imaginary coherence provides
people with anxiety too. The earliest developmental stages, pre- and postnatal,
are gateways to imaginary formations of ideals via identification and reproduction
of social roles. Taking on societal relations that begin at this point, the subject
remaining is prone to ideological indoctrination. Social environment might fill
the subjects’ fantasies at worst distracting the subject from recognizing reality,

53
Behavioral Neuroscience

eventually leading to escapism [84]. The infant’s bewilderedness at that stage

makes for irritation, and for readiness to fetch interpellation.
Violent behavior is to be called subjective violence, as it is clearly visible and
shows in acts of crime. Yet, the location of subjective conflict is not necessarily
identical with the location of expressed violence. Children often enact at-home-
conflicts in school or kindergarten. Experiences of victimization and conflict may
be brought back home, leading to aggressive behavior, e.g., in sibling or in parent
interaction. At any rate, violent behavior may be used as a personal solution within
a given structure, thus subjective acting manifests as violent acting. What is known
is that in families with high psychic dysfunctionality parents are not capable of
taking enough care of their children, either physically or psychically. Subjectively
violent individuals often seem to have such a background [85], and they have
often been victims of violence themselves [86]. Sometimes there has been a lack
of attachment in mother-infant-relations existing from birth onwards, or there
are disorders of early attachment that have developed in the infant’s first year of
age, or different sorts of subjective psychopathology in parents affect the infant’s
emotional development. Still, social status and the status of societal development
may compromise psychic competencies, as can be concluded from very different
research perspectives [33, 34, 87]. Dysfunctional and noncoherent educational
practices in some families, which can puzzle and disturb children and direct their
development toward dysfunctional modes of behavior may even be amplified by the
loss of societal structure; at least it may disturb families in developing consistent
educational modes [15, 46]. Some findings on subjective violence indicate an early
lack of empathy in children, a lack of impulse control, and a lack of anger manage-
ment in connection with early deprivation phenomena. Deviant behavior in the
shape of criminal behavior can be viewed as developmental pathology, especially if
lack of empathy or lack of emotional reactivity [88] can be diagnosed. Even when
in offenders lack of reflective functioning [89] seems to be the key to their violent
acting, and their experiences of abuse and violent behavior can be linked to their
lack of individual mentalization [90], an important role in socialization must also
be seen in educational institutions’ repressive force, which mostly will not support
empathy but competition. Competition may not be bad, still empathy needs to
be supported as levels of empathy indicate the levels of pro-social behavior [91].
Moreover, any subjective behavior can be viewed as a solution-type compromise
that is workable on a personal level and is due to the dialectics of acquiescence and
resistance in the process of subjectivity formation. Even when such behavior may
only be one among several psychic solutions of the individual, it cannot be surpris-
ing when some children react violently according to their personal biographic
experiencing (cp. Figure 2)—which would be a long-term and somewhat functional
mode of behavior [92].

3.2 Social objectivity

While zestful aggression makes for what can be called anthropology of the
political [76] that does not deny subjective libidinous aggression aspects, violence
must be viewed from a perspective of multifactorial subjective and objective con-
nection. Objective violence is to be differentiated from the subjective kind [93, 94].
Contrary to subjective violence, which is committed by individuals and groups,
objective violence emerges through objective reality itself; it is systemic, anony-
mous violence that is seemingly without reason but conceptual, more uncanny than
direct precapitalist socioideological violence, which could be imputed to individu-
als’ intentions [94]. Objective violence stems from the generated frame in which
people exist and act. It is the societal background in which ideology evolves in the

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Figure 2.
Subjective and objective factors model of violent behavior.

subject. Individuals expressing subjective violence in this context have to be viewed

being subjectively and objectively motivated. From an objective perspective, violent
acts might be an attempt at realizing representation [32]; from a subjective perspec-
tive that would be the wish for reality—which turns out to be second reality [32, 34].
That would be a matter of substructure hitting upon superstructure, as is brain
hitting upon societal commodification demands [95]. The contours of society are
not only shaped by continuous interpellation through societal systems of economics
and politics but the seemingly smooth functioning of society is at the same time
obliged to generate outbursts of individual, i.e., subjective violence. What may be
conceptualized as personal shortcomings in individuals can also be traced back to
objective violent structure characterized by societal depravation. What may appear
as solely internal conflicts the subject has to solve seems co-determined by the
ideological structure that dominates their surroundings.
As there are cultural differences in societies, which are said to be quite similar—
a mundane example is that Americans show higher scores of body image dissatisfac-
tion than Italians [96]—it is that what may look like internal processes only should
also be viewed as the result of internalized societal relations of which an individu-
ally processed relation of the subject to their surroundings is formed. This relation
may either, more or less, remain on a fantasmatic level tending to repress reality, or
develop toward a rather realistic level. More than enough, human readiness for pro-
jective processing [97], i.e., for fantasmatic modes of creating personal reality, is an
anthropological constant, which seems due to physiological prematurity in humans
in the course of evolution. Adding severely to it, subject-object-differentiation
nowadays is increasingly blurred owing to the loss of representation in virtualized
surroundings [32]. That is why it is not possible to retrieve authenticity, if ever
there was one. As people tend to hang on to the concept of authenticity especially in
highly virtualized surroundings, “one always wishes to see the other act naturally,
but this eludes him and thus becomes an object of fetish and intrigue” [55].
Fundamental issues of identification and representation still go unresolved [53].
Societal motion may seem detached from individual action at first but is not. It has
strong effects on everyday dealings. Objective societal structure, at least in Western
Europe, is currently dominated by high degrees of personal freedom and its concur-
rent, restraint, at the same time. The shibboleth of absolving societal structure

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from its responsibility of taking effect on human living conditions [98] promotes
such a motion. Instead, bio-psychosocial environment viewed as a result of early
interaction combined with societal interpellation hitting upon organic substructure
provides a reasonable framework to work with. Certainly, given the inevitable
entanglement of the individual in the socialization process confronting multiple
determinants [71], the question must be raised whether or not a subject can be a
subject undamaged at all [99]. Peter Zima ascertains the subject to be inherently
pending between rejection and indispensability, between subjugation and freedom
[100]. Still, as Resch and Parzer point out, it is not subjective realities and interpre-
tations that will prevail but phenomena like death, pain, and poverty. Such phe-
nomena cannot be misread, cannot be reframed [101]. They belong to objectivity.
Only some of deprivation phenomena are man-made, while others are not.

4. Pre- and postnatal interventions

4.1 Findings

Early communication influences development and learning processes in chil-

dren [102]. On a microlevel, Papoušek has described the significance of communi-
cative acting for early emotional relatedness [103]. On a macrolevel, phylogenetic
human development concepts have augmented ontogenetic aspects of prenatal
and perinatal development, broadening the concepts of postnatal development.
Examples of how prenatal psychosomatic factors in mothers-to-be can affect their
experiencing and retroact on gestation and delivery have often shown congruence,
all the more those with a focus on imminent preterm delivery [65, 104], which is an
issue with high significance as preterm infants require special treatment [105]. The
issue of neurodevelopmental outcome in preterm newborns is still highly problem-
atic and connected with new morbidity [70, 106–110], therefore new approaches
in neonatal intensive care units have been developed and implemented [14, 70].
Recent findings that, e.g., preterm delivery correlates with infant eating disorders
[111] should not be surprising; other findings indicate prenatal and perinatal fac-
tors in new morbidity [58]. Today’s zeitgeist has only begun to be examined: it tends
to favor noncommitment [101], pointing to the connection of new morbidity with
societal motion [97].
Although for decades there have been efforts reaching out to prenatal aspects
of mental health [112], structured programs are relatively new in Germany. As to
overall parenting and early childhood, interdisciplinary and cross-cultural col-
laborations have emerged [113, 114]. On an individual level of childhood educa-
tion, structured programs have successfully been established in many educational
institutions in Germany [115–117]. The majority of early intervention programs
available have mostly been adaptations from the USA. Comparisons between USA
and German programs have proven to be difficult due to structural differences
in health services [118]. In Germany, they mostly focus on the mother-infant-
relationship [114], when a focus on postpartum depression and anxiety would be
equally relevant. Recent meta-analyses show that programs starting during preg-
nancy were evaluated as the best when they had a high frequency of home visits
[119, 120]. There are findings of advantages of close and personal relating to one
another, which comes close to a therapeutic setting. Moreover, maternal symptom
burden was relieved the most in a setting with psychotherapeutic elements estab-
lished for mothers having to cope with preterm delivery [121]. Generally, maternal
symptom burden relief has been the most observed effect in programs while there
were only small effects in interventions on maternal competencies re-enforcement.

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Also, only small effects on child development have been observed, and these have
been lower and more heterogeneous than the effects on mothers-to-be. Then
again, having more than 20 sessions has proven helpful for the infant’s physical
development [119].
The early intervention approaches depicted below are not supposed to be ther-
apy for mothers and infants. Instead, these are psychodynamics-oriented programs
and concepts, which focus on potentially significant topics in pre- and postnatal
stages of development. They have evolved from many of the findings above and
have purposely been designed to support mental health of parents and children:
from the unborn during pregnancy to the newborn and after, and to parenting in
general. The programs take care of the microlevel of inner family issues. Here they
are presented in order of diachronic developmental aspects reaching from prenatal
to postnatal development.

4.1.1 “Mutter-Kind-Bindungsanalyse” (mother-infant bonding analysis)

Mother-infant bonding analysis [122, 123] is a procedure of accompany-

ing women in pregnancy enabling them to get in contact with their unborn; an
approach for which Phyllis Klaus’s work paved the way [124]. It is not a structured
program in the narrow sense of the word but a fairly structured interventional
sequence of individual sessions. By these, early before delivery first steps of build-
ing a relation between mothers-to-be and their unborn are encouraged. Through
relaxation on a couch, women focus on their perception of signals from the unborn.
These will show in the shape of emotions, images, thoughts, and fantasies on a so-
called “inner screen,” which both unborn and mother are related to. This communi-
cative channel can be seen as “umbilical cord” of psyche, enabling a dialog, which
is supposed to promote the intrauterine development of the unborn. The bonding
analyst will support mothers-to-be get in contact with the unborn by encouraging
them, by interpreting, and by helping to overcome blockades if necessary. Twenty
to thirty sessions during the second half of pregnancy are usually taken, that is
from twentieth to fortieth gestational week. Exactly this time frame is known as
the unborn’s highest brain sensitivity and vulnerability period [125]. The history of
mother-infant bonding analysis goes back to the early 1990s when Budapest-based
Jenö Raffai recognized in his work with patients the importance of the prenatal
mother-unborn-relationship for the infant’s and the adult’s further development.
Together with the Hungarian psychoanalyst György Hidas, he conceptualized a
research and treatment method that developed into bonding analysis. Especially the
focus on children’s personality development through the well-being of mothers in
pregnancy and birth-giving might serve as the prenatal reference to autobiographi-
cal memory [126].

4.1.2 “SAFE”

The structured program “SAFE”—Sichere Ausbildung für Eltern (Secure

Education for Parents) [127] aims at what is best for mothers in pregnancy, during
delivery, and in parenting issues. The main issue of the program is to avoid transfer-
ring of traumatic childhood experiences toward the infant. “SAFE” helps parents-
to-be develop confidence in dealings with the infant. As early as in pregnancy they
learn to recognize and react appropriately to the signals the infant shows. This is
helpful in developing a secure mode of attachment in infants since securely attached
infants show more capability of empathy, are more creative, and are more capable
of cognitive processing, as well as they search easier for help when needed. The
well-examined program also addresses real-life issues like; e.g. “do parents have to

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be always present?” or, “what to do when parents are having different needs from
those the baby does,” and “when does pampering start, and which limits does an
infant need, and when?” The program is for parents-to-be up to the seventh month
of pregnancy, and it is continued after delivery until baby’s first birthday; parents
may continue up to the second or third birthday. There is a training of sensitivity
toward the infant within a group in 10 days of class. Groups are run by two mentors
in whole day seminars, 4 days during pregnancy, six after delivery. Stabilization and
imagination exercises in stressful situations are conducted, especially in adaptation
phase after delivery. A parental sensitivity training video supports the reading of
signals and needs of the baby. A scientific foundation via attachment interviews
with parents, diagnostic questionnaires, and other evaluation tools has recently led
to first results [128].

4.1.3 “Skin-to-skin-care”/“kangaroo care”

An early experience of the infant’s feedback is very important not only for
intuitive parenting regulation but also for parental attachment behavior. The
mother’s feeling of self-efficacy evoked by the infant’s feedback paves the way for
relying on her intuitive competencies. One successful method to moderate early and
unexpected separation of the infant from the mother’s body, which can make both
child and parents tend to insecure modes of bonding [129], is “skin-to-skin care,”
or “kangaroo care.” Kangaroo care originally stems from the 1970s when Colombian
mothers were advised to take their babies home and carry them on their chests for
days and weeks. Through this intervention, infants were supplied with warmth
and fed with milk [130]. Adapted to newborn intensive care unit (NICU) applica-
tion, and incorporated in the NICU setting, “kangaroo care” became one of the
most important care standards in developed countries nowadays [14, 131]. In the
meantime, there have been many findings on the advantages of continuous bodily
contact and on interaction between infant and parents. Recent findings on oxytocin
and bonding add to a perspective of incorporating bodily and psychic factors; a
recent study found lower depression scores in parents after giving neonatal massage
[132]. It seems that people’s ancient intuitive knowledge about bodily contact can
be said to have been verified again and again; skin contact turned out to be highly
important [58].

4.1.4 “NIDCAP®”

“NIDCAP®,” i.e., Newborn Individualized Developmental Care and Assessment

Program has been developed by Heidelise Als and her team members at Boston
Children’s Hospital. By distinguishing normal from abnormal neonatal behavior
and in trying to obtain some prognostic conclusions about long-term development
from newborn period behavior, Als became aware of the enormous influence that
intensive care does have on the behavior of full-term and preterm newborn infants.
Starting with these observations, the entire concept that should enable optimal
development of each premature infant through individual care, and in spite of
interfering intensive care treatment influences, was developed and patented [133, 134].
Neonatal care according to “NIDCAP®” principles has become more and more
popular all over the world; it has been imported and implemented in Europe and
is applied in the NICU at the Neonatology Unit at the University of Heidelberg,
Germany. It has been designed for professionals that deal with preterm infants and
their parents; its main issue is “reading the preterm infant” [135]. The individual
intervention consists of daily (7 days a week) observation and evaluation of the
infant’s behavior, of support for care-givers in understanding the infant’s stress and

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comfort signals, and of suggestions for parents and staff in terms of ways to sup-
port the infant’s development, i.e., adjust their care according to these signals. The
concept treats infants as active participants in the care provided, which is certainly
most reasonable [14].

4.1.5 “Das Baby verstehen” (understanding your baby)

“Das Baby verstehen” [136] is a structured program for expectant mothers

and their partners. Couples are supported through a midwife who will focus on
the overall life situation of the family-to-be. Everyday communication between
parents and their babies is illustrated in the instructions. The “reading” of the
infant is at the center of most of the course lessons. Live video tapes support the
instructions. Playful exercises will focus on the personal well-being of parents-to-
be as well as on how to remain a couple when there will be three of them. In 2003
and 2004 the program was developed at the University of Heidelberg, followed
by a revision in 2005, with accompanying evaluation in a German county district.
The strengths and shortcomings of the expert trainings as well as of the courses for
parents were explored, aiming at an integrative package of counseling for parents
with infants up to the age of three. In this way, potential development of dysfunc-
tional interaction in families is avoided early in order to prevent bodily and mental
disorders in infants. The underlying concept has been depicted in a textbook of
basic findings [137].

4.2 Approaching kindergarten age: “Faustlos”

Empathy as well as the competence to change one’s perspective are key issues in
the prevention of violent acting. In Germany, Mollenhauer et al. [54] elaborated
on such in what can still be called a basic reference textbook on how socialization
in family and society works, i.e., from a psychosocially integrated perspective.
The second International Conference on Social-Emotional Learning, which took
place at the University of Heidelberg [138] reactivated that perspective exploring
both differences and similarities in countries and cultures, so that a multinational
background makes sure concepts are compatible with each other [139].
A program for kindergartens like “Faustlos” [140–142], which has been
designed for four-to-six-year-olds, seems to be most effective in preschoolers, yet
even younger children participating in it will benefit as well. It is an adaptation of
Seattle-based program, “Second Step” [143], translated to German-speaking coun-
tries as “no fists.” The program has been developed and evaluated at the University
of Heidelberg [144, 145]; a pre/post randomized control trial behavioral study
proved the program to be effective especially as to a decrease of verbal aggression in
children [15, 115, 116, 146, 147]. Competencies of self-regulation turned out to be
of paramount importance, something, which is especially difficult in traumatized
and insecurely attached children. Though not replacing therapy, “Faustlos” offers
a wide variety of techniques and strategies for children to learn how to cope with
inner impulses. Also, the program is conducted by constant relational persons in
a closed group cycle of 1 year. This gives children a secure realm of learning and
transfer in which no-one is excluded from the group. Instead, children learn from
one another how to apply “Faustlos” competencies and dicta in everyday life. In
order to increase favorable effects intergenerationally, the program makes use of
involving parents reaching out to improve dealings with their children, regardless of
age. Social-emotional learning aims at skills and competencies to be learned within
an interactional framework. At the heart of “Faustlos” there are three issues to be
transferred to children: getting to know empathy and the training to be empathic,

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learning to be capable of controlling one’s impulses, and dealing with emotions

of anger and rage. These issues are playfully dealt with by way of 28 continuous
lessons. Each lesson contains a story that is told by the educator and is illustrated
by an accompanying picture. Each lesson is structured the same way: at first, the
topic of the lesson is outlined by playfully fantasying what the lesson will bring.
Moreover, hand puppets (a toy dog and a toy snail) open up getting in contact with
each other, further illustrating the issue of the lesson to come. This is followed by
the actual lesson in which the story is told, is shown in the picture, and is discussed
with the group. Role-playing, or alternative exercises at the end of the lesson will
make sure the transfer to everyday life of children is initiated. Additionally, the
educator is advised to return to the contents of the lesson during the following
week. Ideally, one lesson per week is conducted. Since children learn how to cope
with inner impulses, the range of possible reactions in stressful and conflict situ-
ations is broadened. Moreover, the aspect of mastering transitional stages seems
quite important to both boys and girls participating in the program, which in the
face of missing rites has a point in its own right [148, 149]. While male and female
processes of individuation as reflected in ancient robinsonades show the male one
to be rather abrupt and sometimes revolutionary, the female rather processual and
preserving—still it is transformation proper [7]—in programs like this, transition
as a developmental process should be examined.

5. Evaluation

Along the diachronic developmental perspective of the approaches depicted

above, aside from “NIDCAP®,” the “Faustlos” program for children has probably
been evaluated the most, leading to augmentations in elementary and secondary
education [141, 150, 151]. As to the kindergarten curriculum, identifying emotions
turned out to be easier for children who took part in the program than for those who
did not; the same for pro-social dealings with conflicts. The change of perspective
through stories seen from different personal viewpoints is strongly supported in the
program; something which has regularly been reported as revelatory [152, 153] as
it calls attention to divergent experiencing. Generally, a specific anxiety-reducing
effect supporting the transfer of competencies to everyday life has been shown in
the program [154], which is highly important since effects on the level of intrapsy-
chic emotion entail even more appropriate interpersonal pro-social behavior
[91, 153]. Moreover, it has widely been well-accepted and therefore has been imple-
mented at many kindergartens in Germany.
Practically, maternal symptom burden relief remains a highly important goal
of intervention in the other approaches above. As has been shown, symptom relief
has direct impact on the infant’s development [120]. Personal reactivation and
repetition of one’s own experiences, such as preverbal, maybe even intrauterine
[123] strain and other conflict formations leave their imprint on mothers-to-be:
what can be said is that programs starting prenatally will approach mothers-to-be
relatively early. This holds true for “SAFE” and “Das Baby verstehen,” which are
well-structured and designed for parents, and tend to address important everyday
dealings with the infant such as the reading of signals in a closed or half-open group
setting, with different emphases, respectively [128, 137]. Somewhat different from
these, “Mutter-Kind-Bindungsanalyse” has been conceptualized as an individu-
ally shaped setting in which the emotionality of mothers-to-be and their empathic
dealing with the unborn are approached in mid-pregnancy. Regarding this concept,
the main case study results are promising [123, 155]. Especially combining of any
of the structured programs with mother-infant bonding analysis would be worth

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DOI: [Link]

studied. As there is much diversity in parents’ perceptions of cause of children’s

symptoms [51], especially an early introspective psychosomatic intervention like
mother-infant bonding analysis is promising. It has been recommended in particu-
lar by neonatology experts that have intensely applied “skin-to-skin/kangaroo care”
or “NIDCAP®” [8]. The most important benefit from “skin-to-skin/kangaroo care,”
as studies have shown, is a change in the mother’s perception of her child, attribut-
able to the skin-to-skin contact (“bonding effect”), which supports and promotes
attachment between infant and mother. Mothers in “skin-to-skin/kangaroo care”
feel more competent (“resilience effect”) in stressful situations in the NICU
[14, 156–158], and mother-infant relations develop better; a tendency to less inter-
action disorders and less crying at the age of 6 months has been observed.
“NIDCAP®” has shown to have numerous positive effects on both the somatic
and the neurological short-term development as well as on long-term devel-
opmental outcome of preterm infants such as motor and mental development,
development of intelligence, behavioral development, and mother-infant interac-
tion [159–162]. It also showed the first in vivo evidence of positive effects of early
postnatal experience on brain development, i.e., of enhanced brain function and
structure [11, 14]. This study demonstrated that the quality of the unborn’s experi-
encing influences brain development significantly. Recently, further studies in the
field have been conducted, such as on the effects of music and the mother’s voice
[14, 131, 163].

6. Conclusion

From perspectives of pre- and postnatal development, further research should

be in what Panksepp termed affective neuroscience [164], an approach that does
not deny drive and instinct and is most compatible with a psychoanalytic perspec-
tive. The findings of psychoanalysis and mental health research view affect as
pivotal driving force in human development. That is why an ethological perspec-
tive will be helpful too, like in attachment research [165], or in the behavioral
biology of Csikszentmihalyi showing that psychic satisfaction is in the process of
pursuing, i.e., in anticipation itself [166]. Savoring the anticipation of something
ahead is constitutive of the psychoanalytic process [167]; it is in itself psycho-
therapeutic, and it might be an effective factor in the programs depicted above.
Still cognitive perspectives must be taken into account, on grounds of relational
and phenomenological approaches [168] in connection with setting, context, and
background [72].
There have been illuminating descriptions of the processes taking place in
psychoanalysis [29, 81, 167]; many of these might analogously be examined in
order to conceptualize objective processes of how subjectivity formation is affected
by social objectivity [95]. It is not out of the question that the findings on mirror
neurons can contribute to depicting such connection [36]. It should also be obvi-
ous that both biological factors and cultural upbringing have effect on the subject’s
development. The well-known problems of recent subjectivity formation have been
documented culturally and clinically. We are dealing with the paradox of an inher-
ent incompatibility in the “subiectum,” in that it is underlying and at the same time
subjugated; this means any absolutization will lead to aporia [100]. The question of
scientific approaches, which at the time are dominated by relatively strict empiricist
accesses and default interpretive accesses reveals limitations. A good balancing of
quantitative and qualitative findings will be necessary to meet what can truly be
called comprehensive psychology of human behavior, which lies in a combination
of neuroscience and interpretation on grounds of reasonable concepts.

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Author details

Götz Egloff1* and Dragana Djordjevic2

1 Practice for Psychoanalysis and Psychotherapy, Mannheim, Germany

2 University Children’s Clinic, Niš, Serbia

*Address all correspondence to: [Link]@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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DOI: [Link]

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Chapter 5

Mindsets and Failures: Neural

Differences in Reactions to
Mistakes among Second-Grade
Finnish Girls
Ita Puusepp, Tuisku Tammi, Minna Huotilainen, Teija Kujala,
Elina Kuusisto, Sonja Laine and Kirsi Tirri

Abstract

Mindsets have been identified as an important factor in explaining learning

differences among students. Growth mindset students have been shown to recover
from mistakes easier than fixed mindset students, and recent neuroscientific
research has shown differences in the brain’s event-related potentials to errors in
fixed and growth mindset participants. The purpose of this study was to examine
and evaluate these differences in the Finnish elementary school context. To achieve
this, event-related potentials of ten 8-9-year-old female students, five of them with
a fixed mindset and five with a growth mindset, were recorded during a go/no-go
task. Differences between the two groups emerged; however, they were different
from the results of some previous studies in the field. These findings are discussed
in the light of earlier neuroscientific research related to mindsets, including limita-
tions and suggestions for future research in the field.

Keywords: mindset, implicit belief, education, error monitoring,

event-related potential, error-related negativity, error-related positivity, Finland,
elementary school

1. Introduction

In this chapter, mindsets and differences in the neural mechanisms of atten-

tion allocation and other automatic reactions to errors between fixed and growth
mindset students are discussed. The chapter presents results from a pilot study
examining and evaluating these differences among girls in the Finnish elementary
school context. These findings are discussed in the light of previous neuroscience
research related to mindsets, including limitations of the studies conducted so far
and suggestions for future research in this field.
Mindsets are implicit beliefs individuals hold about the malleability of basic
qualities and abilities. People with a fixed mindset (the entity theory) believe
human qualities are static; those with a growth mindset (the incremental theory)
believe basic qualities can be developed [1]. The theory about mindsets helps us
understand how people make sense of the world and their experiences [2].

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Behavioral Neuroscience

The theory can, for example, help us understand individual differences in goal
pursuit, self-regulation, and response to feedback and setbacks by shedding light
on how people construct meaning, interpret their experiences, and respond to their
world. Indeed, there is a growing literature describing the connections between
different mindsets to different behaviors and outcomes (e.g., see [3, 4]).
Mindsets are also highly relevant when it comes to the educational context.
Indeed, in the last decades, they have been identified as an important factor in
explaining learning differences among students [5]. Moreover, they seem to be
especially relevant in certain academic domains, such as mathematics [6, 7].
Mathematics seems to be a subject about which people tend to hold more of a fixed
mindset when compared to other educational subjects [6, 8]. Indeed, compared
to achievement in social science and other subjects, achievement in mathematics
is often believed to depend more on an innate ability that is uncontrollable [8].
Interestingly, holding a growth mindset about mathematical ability seems to be
especially beneficial for girls when compared to boys, leading to higher grades in
math [9]. Thus, as growth and fixed mindsets seem to be differentially related to the
students’ academic outcomes, the effort they put into learning, and the way stu-
dents cope with setbacks and failures, it is highly important to consider and address
mindsets in the educational context [7, 10–12].
In order to shed more light on mindsets and how they affect behavior, there has, in
the recent years, been a growing interest in understanding the mechanisms behind the
relations between mindsets and behavioral outcomes, including interest in the pos-
sible neural mechanisms that are involved in these processes [13–17]. Indeed, individ-
uals with a growth mindset tend to recover from setbacks easier than individuals with
a fixed mindset, and neural activity concerning automatic reactions to errors seems to
be involved in this ability to rebound from mistakes (for review, see [18]). Although,
thus far the neuroscientific research related to mindsets is still rather scarce, especially
concerning studies conducted on children. We found only two studies connecting
neuroscience and the theory of mindsets, which have focused on children [15, 17].
Most of the neuroscientific studies on mindsets have examined the connec-
tions between mindsets and electroencephalogram (EEG) recordings, more
specifically the connections between mindsets and event-related potentials
(ERPs) [13, 14, 16, 17]. Mangels and colleagues [13] had the participants of the
study answer general knowledge questions and used EEG recordings to measure
their neural responses to the feedback for the questions. In other studies [14,
16, 17], the researchers used a go/no-go or Flanker’s task and measured the
participants’ neural responses to errors. All of these studies showed differences
in the neural mechanisms, more specifically in the ERPs, of fixed and growth
mindset participants, which might reflect differences in the processing of errors
and feedback between fixed- and growth-minded participants. More specifically,
researchers [14, 17] have found growth mindset to be related to an enhanced
amplitude of the error-related positivity (Pe) component of ERPs, with no differ-
ences in the amplitude of error-related negativity (ERN). In study [13], growth
and fixed mindset participants differentiated in the anterior frontal P3 to negative
performance-relevant feedback, which might refer to negative feedback having a
stronger affective effect in the case of a fixed mindset. In study [16] P3 amplitude
was larger, and late Pe amplitude was smaller in participants with an induced
growth mindset when compared to the participants with an induced fixed mind-
set. In addition to the studies using EEG recordings, there are two studies that
have used functional magnetic resonance imaging (fMRI) to explore the neural
mechanisms connected to mindsets [15, 19].
At the same time, even though these neural differences between growth and
fixed mindset have been shown to be present among undergraduates and children

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DOI: [Link]

Figure 1.
Visual representation of the research design.

in North America, we found only one neuroscientific study on mindsets that has
addressed different cultural contexts [19]. This study focused on mindsets about
emotion regulation and not about intelligence. Still, results from that study and other
previous raise questions about the cultural dependency and context of mindsets and
their relations and, thus, point to the need for research on mindsets also in different
cultural contexts [7, 20, 21]. This discussion illustrates the importance of investigat-
ing mindsets and their neural mechanisms also in different cultural contexts.
Taking into account the previous discussion and the stated importance of
connecting psychological, educational, and neuroscientific research when study-
ing mindsets [18], the purpose of our pilot study was to examine and evaluate the
neural differences of attention allocation to mistakes between growth and fixed
mindset girls in the Finnish elementary school context. Relying on the previous
research in this field, we expected to detect differences in the error-monitoring
ERPs of growth and fixed mindset participants. For this ERN and Pe were recorded.
ERN has been associated with immediate, perhaps unconscious, error-correction or
simply conflict-detection processes [22, 23]. Pe has been associated with conscious
error awareness, attention allocation to errors [22], and conscious processing of
motivationally significant events [24]. It has been suggested that Pe possibly reflects
a subjective emotional error assessment process, which could be modulated by
the individual significance of the error [23, 25]. As can be seen in Figure 1, at the
psychological level, we assume that several processes take place, related to perceiv-
ing the task, making decision about the response, performing the action, detecting
whether the action was right or wrong, and, finally, in the case of an error, evaluat-
ing the error and its consequences. At the level of the neural signals or ERPs, we can
measure responses related to visual perception and action preparation (not reported
in this study due to the averaging according to button press), the Pe response and
the ERN response. These responses depend on the task (go trial or no-go trial), the
action (button pressed or not pressed), and the correctness of the button press and
are expected to also depend on the mindset of the participant.

2. Methods

Participants of the study were 10 right-handed second-grade female students

aged 8–9 years (mean = 8.50, SD = 0.53). All of the participants were native Finnish

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Behavioral Neuroscience

speakers and students from a Finnish public elementary school, namely, the Viikki
Teacher Training School of the University of Helsinki, where the student teach-
ers practice under the guidance of mentors who are highly skilled in teaching.
Additionally, research, practice, and development activities have a crucial role in
Viikki Teacher Training School. The school has learning resources available for
different learners with advanced pedagogies in use. Elementary school students in
Viikki School are in general local children from the neighborhood, which can be
described as a medium socioeconomic status district when compared to other areas
in Helsinki [26].
The students’ participation in this pilot study was voluntary, and parental,
school principal, and municipal officials’ written consents were obtained. The
study was part of a bigger research project, which had already been reviewed and
approved by University of Helsinki Ethical Review Board before. The partici-
pants had the right to cancel their participation at any moment of the study and
measurements.
Participants had previously been classified as growth or fixed mindset students
in the following manner: during individual interviews a researcher had asked
the students 10 questions of a 5-point Likert-type scale questionnaire based on
Gunderson and colleagues’ mindset questionnaire used among children in previous
research [27, 28]. They were also asked to describe how they understand the words
“intelligence” and “giftedness.” During that interview the participants were encour-
aged to bring up examples or questions related to the questionnaire.
The experiment was conducted by two experimenters during the school day in
a separate space at the school premises. Before the experiment, the students were
briefed about the process; they were encouraged to ask questions about the experi-
ment and were reminded that they can cancel their participation at any moment.
Participants then completed the task on a laptop. After the task, participants were
debriefed about the experiment and compensated. The whole procedure lasted for
approximately 1 h per participant.
The task was an age-appropriate go/no-go task adapted from Grammer and
colleagues’ study [29]. Participants were told that the task was a game in which
they had to help a zookeeper catch animals and were instructed to press a button
every time they saw a picture of an animal (go trial) except when the animal was
an orangutan (no-go trial), because orangutans were also helping the zookeeper.
The task consisted of a practice block (9 go trials, 3 no-go trials) followed by 16
blocks (30 go trials, 10 no-go trials) making up a total of 640 trials. Each stimulus
was presented for 750 ms followed by a blank screen for 500 ms (response window
1250 ms). The participants were allowed small breaks between blocks and a longer
one between blocks 8 and 9.
The task was conducted with presentation software (Neurobehavioral Systems,
Inc., Albany, CA). EEG data were recorded with portable equipment (BrainVision
QuickAmp amplifier) using 32 Ag-AgCl active electrodes (ActiCap, Brain Products,
Germany) including two mastoid electrodes, one nose and one vertical eye move-
ment electrode. Electrolyte gel (Signa Gel, Bio-Medical Instruments, Inc., Warren,
MI) was used at each electrode. The data were recorded with BrainVision Recorder
at 500 Hz sampling rate.
After recording, the EEG data were processed with Matlab R2017b software
(Mathworks, Natick, MA) with EEGLAB 14.1.2b toolbox. The signal was high-pass
filtered at 0.1 Hz and epoched 1250 ms before and 500 ms after response. In addi-
tion to visual inspection, artifactual epochs were rejected by detecting abnormal
trends and abnormal spectra, and eye movement artifacts were removed using
independent component analysis (ICA) [30]. The data were re-referenced to the
average of the two mastoid electrodes. Response-locked grand average ERPs for

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Mindsets and Failures: Neural Differences in Reactions to Mistakes among Second-Grade Finnish…
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channels Fz and Pz were calculated and baseline corrected by subtracting the mean
amplitude from −150 to −50 ms pre-response. For figures, the waveforms were low-
pass filtered using a Butterworth filter of order 3 with a cutoff frequency of 30 Hz.
Behavioral data from the go/no-go task included response accuracy and reaction
time measures for each trial. These were further processed in R statistical software
(version 3.4.3) and used to compute measures for post-error adjustments, following
Moser and colleagues [14].

3. Results

The responses to correct trials and error trials differed in both groups.
Moreover, as expected, differences of error-monitoring ERPs between growth
and fixed mindset students emerged, suggesting different attention allocation
to mistakes, which is believed to play an important role in bouncing back after
failure (Figure 2). It can be seen from the data that the difference curve calculated
between the correct and error trials was larger in children with fixed mindset when
compared to children with growth mindset. In the frontal areas (observed at Fz
channel) in the early latencies 100–200 ms after response (the button press), the
ERN amplitude (calculated as the difference between positivity on error trials and
relative to that on correct trials, see Figure 3) is larger in the children with fixed
mindset. There is no difference in the shape or timing of the ERN response in the
two groups.
The data also show clear differences between the groups in the Pe component,
the difference signal calculated between the correct and the error trials in the
parietal electrodes (observed at Pz channel) in later latencies (200–500 ms after
response). Fixed mindset was associated with larger Pe difference than growth
mindset.

Figure 2.
Response-locked waveforms for correct and error trials in fixed (upper panel) and growth mindset groups
(lower panel) at frontal Fz (left) and parietal Pz (right) electrodes.

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Behavioral Neuroscience

Figure 3.
Response-locked subtraction signals in fixed and growth mindset groups at frontal Fz (left) and parietal Pz
(right) electrodes. Here, response to correct trials is subtracted from the response to the error trials.

At the behavioral level, growth mindset participants showed decreased post-

error accuracy, meaning that they got less correct responses on trials following
error hits than on trials following correct hits; this was opposite for the fixed
mindset group. There was no considerable difference in post-error reaction times,
but overall reaction times were shorter for the fixed mindset group, especially in
error trials. Fixed mindset participants also made less error hits and more correct
hits, i.e., their overall performance was slightly better. This is in line with results
by Torpey et al. [31], who found that a more positive Pe is associated with greater
accuracy and shorter reaction time in error trials. Overall, these results suggest
that participants with a fixed mindset responded faster and, while allocating atten-
tion to errors, did not show improvement/adjustment in behavioral terms, such as
post-error slowing.

4. Discussion

This pilot study contributes to the international mindset research by testing the
mindset theory and experimental design, previously used in North America, in the
Finnish context. It also provides evidence for differences in the neural mechanisms
of attention allocation and in automatic reactions to errors between individuals with
growth and fixed mindsets. Namely, in this study, the ERN amplitude was larger
in the children with fixed mindset. Large ERN can be interpreted as more neural
resources allocated to the detection of the error and also the further processing
after detecting the error [32]. In addition to this, fixed mindset was also associated
with larger Pe difference than growth mindset. These responses may reflect further
processing of the errors, recovery after the errors, and reallocation of attentional
resources to avoid future errors [33]. This suggests that fixed mindset children in
this pilot study seem to invest a lot of effort in processing their errors and reorient-
ing after the error has occurred. Growth mindset students also showed decreased
post-error accuracy, while this was opposite for the fixed mindset group.
Interestingly, even though clear differences between the two groups emerged,
these findings are somewhat inconsistent with the results from previously con-
ducted research in North America [14, 17]. Namely, researchers [14, 17] have found
growth mindset to be related to an enhanced amplitude of the Pe and better accu-
racy after mistakes, but not to ERN. Thus, the findings on the amplitude of Pe and

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Mindsets and Failures: Neural Differences in Reactions to Mistakes among Second-Grade Finnish…
DOI: [Link]

also post-error accuracy were strikingly different from the findings from the North
American studies. In addition to this, in this pilot study, differences in ERN were
found, while this did not differentiate between growth and fixed mindset partici-
pants in the North American studies.
One possible explanation for this difference in the results of this pilot study,
when compared to previous studies, is the young age of the participants. Namely,
ERN seems to fluctuate during development [34]. Consistent with this, researchers
[35] showed in their study that in younger children (8-to-10-year-old), a smaller
ERN related to parent-reported anxiety, whereas in older children (11–13-year-
olds), a larger ERN was significantly related to anxiety [35]. Consequently, the
authors of the mentioned study discussed that it is possible that the relationship
between increased error-related brain activity and anxiety may not emerge before
early adolescence. Thus, one could speculate that it might be the same regarding the
relationship between ERN and mindsets.
When discussing the differences between the results concerning Pe in this pilot
study and previous studies, it is worth to mention that also Schroder and col-
leagues [17] showed that more attention allocation to errors (Pe) is not necessary
for growth mindset children to recover from mistakes. Indeed, they did not find
Pe to have the mediating role in recovering from mistakes as it had for grown-ups
in the study conducted by Moser and colleagues [14]. Also the correlation found
between growth mindset and Pe in study [17] on children was rather modest,
and there were actually many growth mindset children who had average or below
average Pe amplitudes. In addition to this, even though there is a difference in the
time windows when compared to the current pilot study, in study [16] Schroder
and colleagues found no differences in the early Pe (150–350 ms post-response time
window) but found a smaller late Pe (350–750 ms post-response time window)
amplitude in adult participants with an induced growth mindset when compared
to the participants with an induced fixed mindset. Even though Pe has been shown
not to have a similar age-related fluctuation as ERN [34], the inconsistencies of
these findings might refer to other mechanisms involved in the processes of deal-
ing with mistakes related to mindsets. Indeed, Meyer and colleagues also showed
that smaller Pe amplitude related to greater parent-reported anxiety only among
older children, with younger children’s anxiety level having no significant effect
on Pe [35]. Thus, taking into account the mentioned research concerning ERPs, it
is possible to speculate that as the ERN fluctuates during development, a clearer
relationship between increased error-related activity and mindset also may pos-
sibly not emerge before early adolescence, at least concerning ERN. The findings
on Pe in this study, though, are somewhat controversial when compared to other
studies and require further research on the developmental processes involved in
error-related brain activity and mindsets, as the results suggest that there might be
other mechanisms involved in the processes of dealing with mistakes when it comes
to mindsets. Thus, in the future it would be important to conduct more research on
the neural mechanisms related to mindsets among different age groups, including
more participants and including both boys and girls as the current pilot study had a
small sample size and only included girls as participants. Moreover, it would also be
important to include participants from different schools and possibly more diverse
socioeconomic backgrounds.
In addition to this, the results of this pilot study might differ from the previ-
ous ones due to a different cultural context. As mentioned in the first part of this
chapter, there are studies that refer to possible culture- and context-dependency
of mindsets [7, 19–21]. Thus, it would be important to study mindsets in different
cultural contexts and also conduct comparative studies investigating mindsets, their
functioning, and relations to neural mechanisms.

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Behavioral Neuroscience

None of the neuroscientific research concerning mindsets has taken academic-

domain-specificity into account. Previous studies using EEG recordings have
measured mindsets about and used a task/test addressing general intelligence [13];
measured or induced mindsets about general intelligence [14, 16, 17] and the EEG
measurements have been done during a completion of a go/no-go task or a Flanker’s
test. Even though the mindset measurement reflects the general underlying dimen-
sion of the mindset tendency in addition to the directly reflecting the mindset about
intelligence [36], it is possible to speculate that the go/no-go task or Flanker’s test
used might not be reflecting the domain of intelligence for the participants. As these
ERPs are measured and should theoretically reflect automatic reactions to errors of
a person with a growth vs. fixed mindset, the ERPs may reflect the person’s implicit
beliefs in another domain than intelligence, which was measured or induced in
these studies. Rather one could speculate that these tests might resemble more of
a computer game than a test concerning intelligence, and thus, it might be more
relevant comparing these ERPs regarding a growth vs. fixed mindset about the abil-
ity to play computer games, which might be remarkably different from the mindset
that the individual holds about their intelligence or other domains like mathematics.
Indeed, among these studies, as mentioned above, only Mangels and colleagues [13]
have used a design, where the mindset measured and task used for EEG measure-
ments match in their domains. Namely, they used measures of theories of intelli-
gence (TOI) and a task, which included general knowledge questions. As mindsets,
though, have been shown to have such considerable relations to academic outcomes
[7], one important future direction would be measuring academic-domain-specific
mindsets and using tasks/tests from the matching academic domain during the EEG
measurements. This would enable to study the automatic reactions to errors in the
specific academic domain of the held mindset and would thus yield to theoretically
more sound results. One possibility to do this would be to modify the go/no-go task
or Flanker’s test to be more domain-specific, for example, resembling a math test
and then comparing the ERPs from this test to the participants’ academic-domain-
specific (math-specific in the case of this example) mindsets.
All in all, understanding the neural mechanisms related to mindsets will enable,
when combined with findings from other fields of research, the planning and
construction of more successful interventions to encourage growth mindset. Taking
into account the underlying neural mechanisms and structures of mindsets will
enable to tap into how these implicit beliefs interact with cognitive and also other
higher psychological processes, in order to improve students’ learning experience
and results. Moreover, it will help to understand how these interactions affect
behavioral outcomes not only in the academic but also a variety of other contexts.

Notes

The earlier version of this chapter was presented in April 2019 as a talk at the
International State-of-the-Art Symposium: Recent connections between Brain,
Neuroscience and Education, which was part of the American Educational Research
Association (AERA) Annual Meeting 2019 in Toronto, Canada.

Abbreviations

ERN error-related negativity

ERP event-related potential
Pe error-related positivity

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Author details

Ita Puusepp1*, Tuisku Tammi2, Minna Huotilainen3, Teija Kujala4, Elina Kuusisto5,
Sonja Laine6 and Kirsi Tirri7

1 Faculty of Educational Sciences, University of Helsinki, Helsinki, Finland

2 Cognitive Science, Department of Digital Humanities, University of Helsinki,

Helsinki, Finland

3 Faculty of Educational Sciences and Cognitive Brain Research Unit, CICERO

Learning Network, University of Helsinki, Helsinki, Finland

4 Cognitive Brain Research Unit, University of Helsinki, Helsinki, Finland

5 Department of Education, University of Humanistic Studies, Utrecht,

The Netherlands

6 Faculty of Educational Sciences, Training Schools, University of Helsinki,

Helsinki, Finland

7 Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki,

Finland

*Address all correspondence to: [Link]@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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Behavioral Neuroscience

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Chapter 6

The Cerebellum and Autism:

More than Motor Control
Marta Fernández, Teresa Sierra-Arregui
and Olga Peñagarikano

Abstract

Autism spectrum disorder is a neurodevelopmental disorder characterized by

deficits in social cognition at its core. Human and animal studies converge in the
existence of a network of key brain structures involved in the perception, integra-
tion, and coding of social cues. These structures mainly involve areas traditionally
associated with cognitive function, such as the prefrontal cortex; processing of
emotions, such as the amygdala; and motivation and reward, such as the nucleus
accumbens. The cerebellum, conventionally associated with motor functions, is
lately being considered as a key structure within the social circuitry. Cerebellar
neuroanatomical alterations are among the most replicated findings in postmortem
brain samples of patients with autism. In addition, cerebellar defects have been pro-
posed to affect the functioning of distal brain areas to which the cerebellum proj-
ects. In fact, animal studies support the inclusion of the cerebellum as part of the
brain network regulating social cognition and provide a mechanistic tool to study
its function within the social network. In this chapter, we review current evidence
from human and animal studies, opening a new avenue for further research.

Keywords: autism, social behavior, neural circuit, cerebellum, dopamine,

VTA, NAcc, animal model

1. Introduction

Autism spectrum disorder (ASD) represents a group of heterogeneous neuro-

developmental conditions characterized by deficits in social cognition, together
with the presence of restricted and/or repetitive patterns of behaviors, activities,
or interests [1]. Social cognition refers to those cognitive processes that allow
individuals to successfully navigate the challenges of living in a social group. Thus,
a functional social cognitive system involves the integration of several domains
of behavior including attention, memory, emotion, and motivation to be able
to understand identity, potential actions, social hierarchy, and emotional status
of a conspecific and therefore guide the appropriate behavioral response [2]. In
autism, deficits in social cognition processes are found at multiple levels, such as
failure to initiate or respond to social interactions, lack of interest in social situa-
tions, abnormal social approach, difficulties expressing and understanding verbal
and nonverbal communication (i.e., body language and facial expressions), and
problems adjusting behavior to different social situations, among others [1]. Autism
affects roughly 1 in 59 children, becoming one of the primary mental health issues

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worldwide [3]. In addition to the main symptoms, ASD is usually associated with
other behavioral and/or neurological problems, such as hyperactivity, epilepsy,
aggression, irritability, sleep problems, gastrointestinal symptoms, and sensory
processing abnormalities [4].
Although currently accepted to be highly genetic (over 90% of the risk of
developing ASD is due to genetic variation) [5], the etiology of ASD is complex,
and its genetic architecture is diverse. Common allelic variation with small effect
sizes is responsible for most cases, while rare but highly penetrant mutations that
usually lead to other syndromes associated with autism are observed in about 20%
of the cases [6]. In addition to genetic factors, exposition to some environmental
factors during prenatal periods has also been associated with autism. Some of the
most replicated are the intake of valproic acid, a drug used to treat epilepsy, during
pregnancy and maternal infections. In all, the combination of interactions between
genetic predisposition and environmental factors will determine the development
of the disorder [7]. Given the clinical and etiological heterogeneity of ASD, the
investigation of its pathophysiology has been challenging. From a research point
of view, the study of “single gene” causes of autism, although rare in the popula-
tion, has been proven to be useful to understand its pathophysiology and develop
targeted treatments. In addition, animal models of monogenic causes of autism are
easily generated and constitute a critical component of research. Research from
both human and animal studies converge in a series of key brain structures and
circuits involved in social cognition and their dysfunction in autism. Within these
circuits, the cerebellum, traditionally associated with movement control, is becom-
ing an important player in the social brain network. In this chapter, we will first
start by describing the social brain circuitry traditionally thought to be affected in
autism; we will then present evidence for the role of the cerebellum as a new player
in the social circuitry and its role in the pathophysiology of ASD; finally, we will
present data from animal models of monogenic causes of ASD in which a cerebel-
lar pathology has been described such as Fragile X syndrome (FMR1), tuberous
sclerosis syndrome (TSC1/TSC2), and Phelan-McDermid syndrome (SHANK3),
supporting the role of the cerebellum in social defects. In all, we believe the cur-
rent evidence grants the need of further research of the cerebellar role in ASD
pathophysiology.

2. Neural circuits involved in social cognition

In humans, brain regions implicated in social cognition have been identified

mainly by lesion studies or by functional magnetic resonance imaging (fMRI)
detecting differential activation in response to social versus nonsocial cues.
Accordingly, a network of key brain structures involved in the perception, integra-
tion, and coding of social cues have been identified, receiving the denomination
of “the social brain.” These structures comprise brain areas traditionally involved
in cognitive processes, such as frontal and temporal cortices; motivation and reward,
such as the basal ganglia; and processing of emotions, such as the amygdala [8–10].
Proper function of the social brain should be considered in terms of the coordi-
nated activity of the neural network involving these structures [11]. Accordingly,
individuals with autism have been reported to present structural and/or functional
alterations in these areas. Aberrant cortical organization is a pathological observa-
tion commonly seen in postmortem brain tissue of individuals with ASD [12].
Connectivity studies using fMRI indicate alterations in the PFC, with increased
local and decreased long-range connectivity [13], which might be accounted for
by the observed disorganized cortical structure. Structural MRI studies report

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increased amygdala size in children with autism, and the extent of amygdala
enlargement is correlated with social deficits [14]. However, fMRI studies con-
versely report both hyperactivation [15] and hypoactivation [8] of the amygdala in
response to social stimuli. These contrasting results have been suggested to indicate
either a failure of the amygdala to engage upon social stimuli or, alternatively, an
overreaction to such stimuli, coding them as threatening. Both cases would in turn
result in social withdrawal. Similar contrasting results have been found when study-
ing the reward system in ASD, as some studies observe a generalized decreased
activation of the NAcc independent of stimuli [16], and others indicate that the
hypoactivation is stimulus-dependent as individuals with ASD react to cues that are
salient to them but not necessarily to neurotypical individuals [17], indicating that
in autism a different set of cues might be coded as salient.
The cerebellum, conventionally associated with motor functions, is lately
being considered a key structure within the social circuitry [18]. In fact, cerebellar
neuroanatomical alterations, including the reduced size and number of Purkinje
cells, are among the most replicated findings in postmortem brain samples of
individuals with autism [19]. In addition, cerebellar defects have been proposed to
affect the functioning of distal brain areas to which the cerebellum projects [20].
For example, the PFC long-range connection deficits observed in ASD mentioned
above include the cerebellum [13]. The developmental disconnection hypothesis of
autism suggests that certain areas of the brain that normally connect to the frontal
lobe become disconnected during development. Thus, a change in connectivity in
a certain area could affect the functioning of other brain regions either through
compensation or adaptation of nearby circuitries [21]. Along these lines, deficits in
connectivity of the cerebellum could account for dysfunction in connected areas,
being possible to affect some of the social brain structures previously mentioned.
Although human neuroanatomical and functional studies have been very useful
in the identification of the brain regions involved in social cognition, animal studies
are critical to understand how information is processed at the circuit and molecular
level, from the perception of the stimulus to the expression of a behavioral response.
The mouse (Mus musculus) is currently the most widely studied, mainly for practical
reasons and technical amenability. In addition, as mammals, mice present the same
key brain structures and express a wide range of social behaviors that can be easily
measured in the lab [22]. A schematic representation of the brain structures and
circuits implicated in social cognition processes in rodents is presented in Figure 1.
Animal studies have corroborated the role of previously described structures in
social behavior and have given insight into circuit function. For example, disruption
of the ratio between cortical excitation and inhibition (E/I) has been extensively
hypothesized to be a causal mechanism in autism [23]. Again, one must consider
that the cortical E/I balance is a complex process controlled both locally and distally
by neuromodulation from connecting circuits, arguing against the specificity of
a certain structure as preferentially involved in ASD since alterations in distally
connected regions could also lead to an altered cortical E/I ratio. Nevertheless, in
2011, the application of the recently developed optogenetic techniques allowed to
test for the first time this hypothesis in vivo [24]. The authors found that increas-
ing, but not reducing, the E/I balance in the PFC would lead to social dysfunction
in mice. Similarly, recent studies have indicated the role of the reward system and,
specifically, dopaminergic projections from the ventral tegmental area to the NAcc,
in the modulation of social interaction. Dopamine (DA) is a neurotransmitter
traditionally linked to movement control and reward processing, including social
reward and domains of behavior that are modulated by two separated DA pathways.
DA-producing neurons are located in two main brain areas, the ventral tegmental
area (VTA) and the substantia nigra (SN). The nigrostriatal pathway originates in the

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Behavioral Neuroscience

Figure 1.
Brain circuits linked to social cognition in mice. Olfactory signals from a social stimulus are perceived through
the olfactory bulb and transferred to the amygdala (AMYG) and probably other structures to be processed.
This social cue will modulate the activity of several structures. One of such, the ventral tegmental area (VTA),
mainly composed of dopaminergic neurons, projects to the PFC (executive function) and NAcc (reward
system). Of note, the cerebellum modulates VTA activity implying a role in social behavior and reward.
Adapted from [28].

SN and projects to the striatum, modulating movement; and the mesocorticolimbic

pathway, involved in cognitive processes including social cognition, originates in the
VTA and is further subdivided into two pathways: the mesocortical pathway, which
projects to the cortex, and the mesolimbic pathway which projects to limbic areas such
as the NAcc [25]. Recently, it has been found that in mice, optogenetic stimulation of
dopaminergic VTA-NAcc projections increased, while inhibition decreased during
the time the animals were engaged in social exploration [26]. Interestingly, very
recently Carta et al. [27] have demonstrated the role of the cerebellum in modulation
of the reward pathway through direct control of the activity of the VTA, which could
have profound implications for social behavior. The authors found that the cerebel-
lum sends excitatory projections to the VTA and that optogenetic modulation of the
cerebellum-VTA pathway bidirectionally modulated social behavior and reward.
Considering previous studies where stimulation of VTA-NAcc DA projections
modulates social behavior, it is highly likely that the cerebellum indirectly controls
the activity of these projections. A cartoon deciphering the main brain structures
and connections involved in social cognition in mice is presented in Figure 1.

3. The cerebellum

The cerebellum (Latin, little brain) is located in the posterior cranial fossa.
Classically, the cerebellum has been linked to motor behaviors; however, more
recent studies provide evidence for a role of the cerebellum in higher functions such
as cognition, language, and social and affective behaviors [18].

3.1 Cerebellar anatomy

Structurally, the cerebellum is constituted of ten lobules: lobules I through V

(which form the anterior lobe), lobules VI through IX (posterior lobe), and lobule X
(flocculonodular lobe). Lobules VII and VIII are further subdivided (VIIA and VIIB

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The Cerebellum and Autism: More than Motor Control
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and VIIIA and VIIIB); besides, the hemispheric extension of lobe VIIA is expanded
and forms two major lobules, Crus I and Crus II. Dividing the cerebellum ventrally
into two hemispheres, there is a central midline called the vermis (Figure 2) [20].
Within this anatomical division, a functional division according to the connection of
each lobe can be found, establishing a topographic organization (see Subsection 3.2).
At the cellular level, the cerebellum is composed of an outer cortex constituted
of gray matter, the cerebellar cortex, and an inner core formed mainly by white
matter which encloses the deep cerebellar nuclei, the sole output channel of the
cerebellum (see below). The cerebellar cortex is structured in three different cell
layers: (1) Molecular layer: it is the outer layer, and it is composed of two types of
cells, basket, and stellate neurons. Both are inhibitory and are part of the regulatory
system of Purkinje cells. (2) Purkinje cell layer: it is located below the molecular
layer. The Purkinje cells (PCs) represent the only output from the cerebellar cortex
and are inhibitory. These neurons have a wide dendritic arbor, which extends to
the top of the surface of the molecular layer, and project their axons to the deep
cerebellar neurons in the inner cerebellar core, which are the only output of the
cerebellum. (3) Granular layer: it is the deepest layer of the cerebellar cortex, and it
is composed of excitatory granule cells which send their axons toward the molecular
layer, forming the parallel fibers and making contacts with dendrites of PC. Granule
neurons together with basket and stellate cells in the molecular layer constitute the
main regulatory system of PC. Inhibitory interneurons—Golgi cells—are also found
within the granular layer and act by altering the mossy fiber-granule cell synapse
(see below). The Golgi cells receive input from the parallel fibers and provide an
inhibitory feedback to the cells of origin of the parallel fibers (the granule cells).
Neurons in the deep cerebellar nuclei represent virtually all the output from the
cerebellum. They receive inhibitory information from the PC and excitatory inputs
from outside the cerebellum through the mossy and climbing fibers. The climbing
fibers are originated in the brain stem (posterior part of the brain, continuous to
the spinal cord, composed by the midbrain, the pons, and the medulla oblongata),
particularly in the inferior olivary nucleus of the medulla oblongata. These axons

Figure 2.
Structural anatomy of the human cerebellum. Representation of the cerebellar lobules: anterior, posterior, and
flocculonodular and their subdivisions. Lobules VII and VIII are further subdivided into lobules A and B. Crus
I/Crus II constitutes further subdivisions of lobule VIIA. The vermis represents a midline separating the
cerebellum in two hemispheres. Modified from [20].

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Behavioral Neuroscience

make excitatory synapses with PC dendrites and with neurons in the deep cerebellar
nuclei. The mossy fibers originate from several parts of the brain and spinal cord.
These fibers form excitatory synapses with granule cells and with neurons of deep
cerebellar nuclei. In turn, PCs receive two types of excitatory input from outside
the cerebellum, one directly from the climbing fibers and the other indirectly via
the parallel fibers of the granule cells (Figure 3) [29]. Anatomical investigations in
animals and postmortem humans have established that cerebro-cerebellar con-
nections are contralateral to each other and include an efferent cerebello-cortical
pathway from the cerebellar nuclei to the cerebral cortex through the thalamus and
an afferent cortico-cerebellar pathway through the pons.

3.2 Cerebellum connections and topography

The cerebellum has a unique topographic organization such as each region is

attributed with a separate function based on their specific connectivity. Thus, the
anterior lobe and lobule VIII contain the representation of the sensorimotor cerebel-
lum; lobules VI and VII (including Crus I/Crus II and lobule VIIB) of the posterior
lobe comprise the cognitive cerebellum; and the posterior vermis encompasses the
limbic cerebellum. Dysfunction in the connection of these cerebellar areas with the
spinal cord or cerebral regions will result in alterations in movement or cognitive
functions, respectively [30, 31]. More specifically, the cerebellum has been proposed
to have an important role in language by means of its connections with cortical areas
implicated in this process. Studies using viral tracing in nonhuman primates report

Figure 3.
Main cerebellar circuits. The mossy and climbing fibers carry the input information toward the cerebellum. The
PC transmit the information to the deep cerebellar nuclei, which are the cerebellar output. The interactions
between the cells are represented with (+) in case of excitatory connections and (−) when connections are
inhibitory. Modified from [29].

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the existence of strong connections between right Crus I/Crus II and different corti-
cal regions implicated in language, such as Brodmann’s area BA46 in the PFC [32]. In
fact, dysfunction in cerebellar-prefrontal loops might underlie poorer performance
on measures of language-related executive function in human patients with cerebel-
lar abnormalities [33]. The cerebellum also seems to play a role in several social and
affective processes. For example, imitation is a critical skill for implicit learning of
social rules, and fMRI studies in humans show that during a task that involves obser-
vation and imitation of an action performed by a human model, activation of the
Crus I/Crus II regions in the posterior cerebellum is increased [34]. Also, during a
passive viewing paradigm, a stronger activation in the posterior cerebellum (lobules
VI, VII, and X) has been found when comparing social versus nonsocial stimuli [35].
In fact, a recent meta-analysis of over 350 fMRI studies exploring the role of the
cerebellum in social cognition supports that it plays a crucial role in several social
paradigms such as mirroring (i.e., observation of human motion) and mentalizing
(i.e., interpreting other people’s thoughts and intentions) [36, 37].

4. Evidence that the cerebellum is involved in ASD

In the recent years, there has been increasing evidence showing a crucial role for the
cerebellum in the etiology of ASD [38–40]. Although the field of cerebellar research
in disorders of social cognition such as autism is still in its early stages, below we will
describe the main structural and functional cerebellar abnormalities that have been
described to date in autism, which provide strong evidence to grant further research.

4.1 Structural cerebellar abnormalities found in autism

The cerebellum is actually one of the most consistent sites of neural abnormali-
ties found in autism [41]. Specifically, the reduced size and number of PCs are
among the most replicated findings in postmortem brain tissue of individuals with
autism [19]. This reduction in PC in autism patients has been found to be more
pronounced in the Crus I/Crus II region of lobule VIIA [42]. Accordingly, a reduc-
tion in gray matter volume, smaller ratio of gray to white matter, and smaller vermis
lobules VI–VII have been found in children with autism compared to controls
[43, 44]. Further, in ASD patients, the degree of reduction in gray matter of Crus I/
Crus II has been repeatedly found to correlate with the severity of symptoms in the
social interaction and communication behavioral domains of ASD [39, 45]. Of note,
some reports using adult brains indicate the presence of gliosis as an accompanying
factor to the reduction of PC [46]. Other observed cerebellar cellular abnormalities
are the presence of neuro-inflammatory processes [47].
Besides structural and cellular alterations, molecular abnormalities have also
been reported in the cerebellum of ASD individuals. Alterations in the distribu-
tion of the mRNA levels of glutamic acid decarboxylase 67 (GAD67), an enzyme
involved in the synthesis of the inhibitory neurotransmitter GABA, have been
found. Thus, decreased GAD67 mRNA has been reported in PC [48], while
increased GAD67 mRNA has been reported in cerebellar interneurons [49]. These
cerebellar imbalances could account for the proposed E/I disequilibrium in ASD, as
they could affect cerebro-cerebellar circuits [50].

4.2 Abnormalities of cerebellar function

Studies in humans using resting-state functional connectivity (rsFC) techniques

have reported connectivity alterations between cerebellar and cortical areas in

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autism compared to typically developing individuals. Overall, a general cerebro-

cerebellar over-connectivity has been found in the ASD group. However, both
hyper-connectivity and hypo-connectivity have been reported depending on the
regions analyzed. For example, cerebellar-sensorimotor FC (premotor and primary
motor cortices, somatosensory temporal cortex, and occipital lobe) has been found
to be atypically increased in ASD, while cerebellar-supramodal FC (prefrontal
cortex, posterior parietal cortex, and inferior and middle temporal gyri) has been
found to be decreased [51]. Analysis of cerebellar FC with language-related areas
revealed a significantly reduced FC in ASD between the cerebellum and Broca’s area
and Wernicke’s area [52], suggesting that the cerebellum plays a role in language
functioning. Studies aiming at assessing the developmental pattern of cerebello-
cerebral FC also report developmental alterations in ASD. FC between the cerebel-
lum and subcortical regions was found to decrease in neurotypical individuals,
while it increased in ASD [53]. It must be noted that no specific correlation between
FC patterns and autism behavior has been detected, although reduced connectiv-
ity seems to be accompanied by an increase in the severity of the disorder [52], as
assessed by the Social Communication Questionnaire, an ASD screening measure
consisting of a brief (40-item) parent report that focuses on ASD symptomatology
likely to be observed by a primary caregiver.
Few studies have investigated to date the FC between the cerebellum and
cortical areas during task performance in ASD. During a sequential finger-tapping
task, activations in motor circuits were found in both cases and controls. However,
children with typical development showed activation of cerebellar structures that
were silent in autistic children (lobules IV/V and anterior cerebellum). In addition,
a reduced FC between premotor areas and the cerebellum was observed in autistic
children, suggesting alterations in long-range cerebro-cerebellar connections [54].
In a task that requires perception and imitation of human actions, fMRI detected
an engagement between the posterior superior temporal sulcus (pSTS) and the
cerebellar region Crus I [55]. Interestingly, the degree of functional coactivation
of pSTS and Crus I could predict social deficits in ASD in the “mentalizing skills”
questionnaire, a parent report for specific social cognition skills based on imagina-
tive mental activity that allows an understanding of the behavior of other people
(intentions, needs, desires, or goals). Thus, stronger Crus I-pSTS interactions were
associated with better mentalizing ability [55]. On a similar note, during a task that
involves decoding the interactions between animated figures, aimed at examin-
ing the “theory of mind” network, that is, the ability to attribute mental states to
others, a reduced cerebellar activation, particularly in Crus I, in participants with
ASD was found [56]. Although many more studies are needed, overall the above-
presented data indicate a role for cerebellar connections with key cortical social
brain sites and, specifically for region Crus I/Crus II, in the pathogenesis of ASD.

5. Evidence from monogenic forms of ASD

The clinical and genetic heterogeneity present in ASD has made the study of
the pathophysiology of the disease challenging. The study of genetically defined
autism, as in the case of monogenic forms of ASD, which show a relatively homo-
geneous and well-characterized clinical manifestation, allows us to understand
cellular and molecular mechanisms relevant to the disease. Although monogenic
causes of ASD are often syndromic and not all patients with the syndrome show
autistic features, by studying patients with and without ASD, we can start decipher-
ing the pathomechanisms that lead to the disorder. As shown below, human post-
mortem and brain imaging studies of syndromic forms of ASD support the role of

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the cerebellum in the pathophysiology of the disease. Animal models of monogenic

autism are easily generated and provide opportunities for direct manipulation of
these brain regions and circuits to test their precise functions in social behavior
paradigms. We will describe below the main syndromes with reported cerebellar
dysfunction and supporting data from animal models (Table 1). In all, human and
animal data point out a role for the cerebellum in social deficits in ASD.

5.1 Fragile X syndrome (FMR1 gene)

Fragile X syndrome (FXS) is the most common form of inherited intellectual

disability, and ~30% of FXS patients are also diagnosed with ASD. FXS is consid-
ered also as the most common genetic cause of ASD, representing around 3% of
ASD individuals. FXS arises from loss of function mutations in the X-linked FMR1
gene, which result in either total absence or functional inactivation of the encoded
protein (FMRP), an mRNA-binding protein involved in translational regulation
[65]. Although FXS affects many brain regions, cerebellar PC loss and cell displace-
ment, as seen in idiopathic autism, have been reported in human postmortem stud-
ies of FXS [66]. Interestingly, imaging studies have identified specific abnormalities
in the posterior cerebellar vermis (lobules VI–VII) in FXS patients with ASD that
are not seen in FXS patients without comorbid ASD diagnosis. Further, these

Mouse Structural abnormalities Functional abnormalities Refs.

model

Fmr1 KO • Decreased deep nuclei volume • Deficits in eyeblink conditioning [57–

60]
• Reduced number of neurons in deep • Altered parallel fibers-PC
nuclei synapses
• Increased astrocytes in deep nuclei
• Reduced volume of cerebellar cortex
• Reduced cerebellar volume during
development
• Elongated spines in PC

Fmr1-PC • Reduced cerebellar volume • Deficits in eyeblink conditioning [60]

cKO
• Cellular loss deep nuclei • Altered parallel fibers-PC
synapses
• Elongated spines in PC

TSC1-PC • Abnormal spine density • Decreased PC excitability [61,

cKO +/− 62]
• Neurodegeneration of PC • Deficits in eyeblink conditioning
TSC1-PC • Neurodegeneration of PC starting at • Decreased PC excitability [61,
cKO −/− 2 months 62]
• Deficits in eyeblink conditioning
TSC2-PC • Increased size of PC and apoptosis N/A [63]
cKO+/−

SHANK2 N/A • Decreased PC plasticity [64]

KO
• Altered parallel fibers-PC
synapses

SHANK3 • Decreased density of PC • Deficits in eyeblink conditioning [62]

ΔC
• Lower spine density in PC
• Reduced complexity of dendritic tree
in PC

Table 1.
Cerebellar abnormalities in mouse models of ASD.

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Behavioral Neuroscience

lobules are also abnormal in non-syndromic ASD [57]. Moreover, positive correla-
tions between the size of the posterior vermis and several subscales of the autism
behavior checklist, a list of nonadaptive behaviors that represent an individual’s
challenges to respond appropriately to daily life situations, in persons with FXS,
have been reported [58]. On a different note, recent postmortem work has shown
reductions in FMRP in cerebella and frontal cortices of subjects with autism who do
not carry a mutation for FXS [59].
The Fmr1 knockout (KO) mouse is a validated and widely studied animal model
of ASD. By means of high-resolution MRI imaging to study brain structure, the cer-
ebellum in Fmr1 KO mice was found to show significant volume alterations compar-
ing with wild-type controls. Specifically, the deep cerebellar nuclei, which transfer
the output of the cerebellar cortex to the thalamus and cerebral cortex, were smaller
in Fmr1 mice. Moreover, this reduced volume was accompanied by loss of neurons
and increase in astrocytes, as measured by immunohistochemical techniques [60].
Later, the same authors also identified a volume reduction in the cerebellar cortex in
these mice [67]. Further, a detailed study by diffusion tensor imaging of postnatal
development in the Fmr1 KO mouse showed reduced cerebellar volume in the first
few weeks after birth [68]. In addition to the full KO, a conditional Fmr1 KO mouse
(Fmr1 cKO) has also been generated. Deletion of Fmr1 specifically in PC leads to
several structural and functional abnormalities in the cerebellum also seen in the
full Fmr1 KO, such as a reduction of cerebellar volume, cellular loss in the cerebellar
nuclei, and longer spines in PC. Functionally, an enhanced LTD induction at the
parallel fiber synapses that innervate these spines is seen [63]. In addition, both
Fmr1 KO and PC-Fmr1 cKO mice present alterations in classical delay eyeblink
conditioning, a Pavlovian associative learning where subjects learn to execute an
appropriately timed eyeblink in response to a previously neutral conditioning
stimulus in which the cerebellum plays a key role. Specifically, the percentage of
conditioned responses and their peak amplitude and peak velocity were reduced.
[63]. Interestingly, FXS patients were found to display the same cerebellar deficits in
eyeblink conditioning as mutant mice [63]. Together these results suggest that the
deficits in eyeblink conditioning are likely due to the loss of FMRP in PC.

5.2 Tuberous sclerosis (TSC1/TSC2 genes)

Tuberous sclerosis (TS) is another rare syndromic disorder associated with

ASD. TS is characterized by the development of non-cancerous tumors in the brain
and other organs leading to neurological symptoms such as developmental delay,
epilepsy, and ASD. It is an autosomal dominant condition caused by mutations in
either the TSC1 or TSC2 genes, which form a tumor suppressor complex involved in
the regulation of the mTOR signaling pathway. Approximately 40% of TS patients
are co-diagnosed with ASD, and, interestingly, those with cerebellar lesions have
been found to have a more severe ASD diagnosis [61]. Further, PC loss has been
found in postmortem cerebellum samples from TSC patients [62].
Several lines of mutant TSC mice have been generated and studied in detail. A
mutant mouse in which the Tsc2 gene was selectively deleted from PCs starting at
postnatal day 6 was generated to mimic patients with one nonfunctioning TSC2
allele [62]. The haploinsufficiency of TSC2 caused a progressive increase in PC
cell size and subsequent death from apoptosis. TSC2-null PCs showed increased
endoplasmic reticulum and oxidative stress, which were rescued by treatment with
the mTOR inhibitor rapamycin. In a subsequent study, the authors reported that
PC-TSC2-haploinsufficient mice showed social deficits and repetitive behaviors
[64]. These observations indicate that selective loss of TSC2 in PCs in a TSC2-
haploinsufficient background is enough to lead to autistic-like behavioral deficits.

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A conditional PC-TSC1 KO mouse has also been generated. Both heterozygous and
homozygous losses of TSC1 in mouse cerebellar PCs result in autistic-like behaviors,
including abnormal social interaction and repetitive behavior and vocalizations, in
addition to decreased PC excitability. Similar to TSC2 mutants, treatment of TSC1
mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological
and behavioral deficits. Strikingly, PC-TSC1 homozygous mice, but not PC-TSC1
heterozygous mice, showed PC loss at 2 months of age. The fact that PC-TSC1
heterozygous mice showed autistic symptoms and PC excitability alterations in
the absence of PC loss suggests that the decrease in PC excitability is likely driving
the phenotype [69]. Further, this model has also been reported to show deficits
in eyeblink conditioning; they specifically show lower percentage of conditioned
response in this test [70]. These findings demonstrate new roles for TSC1/TSC2 in
PC function and define a molecular basis for a cerebellar contribution to cognitive
disorders such as autism.

5.3 Phelan-McDermid syndrome (SHANK3 gene)

Phelan-McDermid syndrome (PMS) is due to heterozygous chromosome 22q13

deletions and is often co-diagnosed with ASD. The clinical manifestations of PMS
include global developmental delay/intellectual disability and absent or delayed
speech [71]. Although the deletion encompasses numerous genes, a good candidate
that could account for ASD symptoms is SHANK3, a gene within which mutations
have independently been associated with non-syndromic ASD. ASD patients with
SHANK3 deletions are also known to have severe core symptoms and mental dis-
abilities [72]. Although to our knowledge there is no data addressing the effect of
SHANK3 mutations on cerebellar anatomy and function, recent research suggests
that mutations in SHANK3 may be related to cerebellar abnormalities. SHANK3 is
highly expressed in cerebellar granule cells [73] and has been suggested to play a
role in the recruitment of axon terminals to cerebellar granule cell dendrites [74].
In addition, cerebellar vermis hypoplasia has been found in patients with PMS,
suggesting that SHANK3 may be involved in cerebellar development [75].
Multiple mouse lines with SHANK3 mutations exist, and several display
behaviors analogous to the core symptoms of autism, including isoform-specific
SHANK3B KO [76], SHANK3 (∆exons4–9) deleting major isoforms of the gene
[77], and SHANK3 (∆C), deleting the C-terminal region of the gene [78]. SHANK3
(∆C) mice present a decreased density of PC compared to controls [70], and they
show deficits in the eyeblink conditioning task, showing lower percentage of
conditioning response and a delay in the response latency [70].
Interestingly, mutations in other proteins from the SHANK family, such as
SHANK2, have been also linked to ASD. A KO mouse for SHANK2 shows alterations
in social and repetitive behaviors and presents changes in PC electrophysiologi-
cal characteristics, such as decreased intrinsic PC plasticity, synaptic strength at
the PC-parallel fiber synapse, and enhanced inhibitory input into PC. Further
PC-specific SHANK2 KO replicated these findings, arguing for a cerebellar role in
autistic-like behaviors [79].

6. Conclusion

The cerebellum has been recently indicated as a key structure not only for
sensorimotor control but also for language, social cognition, and emotion, via
its extensive connections with cortical areas. In the present work, we aimed to
provide an up-to-date overview of current findings on cerebellar involvement

97
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in the pathophysiology of ASD. Anatomical studies report cerebellar abnormali-

ties in postmortem brain tissue from autistic individuals, neuroimaging studies
indicate abnormal cerebellar activation when performing social paradigms, and
animal models of monogenic forms of autism converge on the cerebellum as one of
the common sites of abnormalities. The cerebellum represents an emerging field
of interest for ASD research, based on the hypothesis that ASD is a connectivity
disorder and cerebellar dysfunction could impact other brain areas within the social
network, leading to the core ASD symptoms. Although the literature in this new
field is at a very early stage, based on the presented data, future studies should not
exclude the cerebellum in analyses of structural and functional differences in ASD.

Acknowledgements

This work was supported by the following grants: Spanish Ministry of Economy
and Competitiveness/European Regional Development Fund (MINECO/FEDER
grant SAF2015-64163-R). OP is a Ramon y Cajal Fellow (RYC-2013-12558), MF is
supported by a predoctoral fellowship from the Spanish Ministry of Economy and
Competitiveness MINECO (BES-2016-078420), and TS-A is supported by a predoc-
toral fellowship from the Basque Government.

Author details

Marta Fernández, Teresa Sierra-Arregui and Olga Peñagarikano*

Department of Pharmacology, University of the Basque Country (UPV/EHU),
Spain

*Address all correspondence to: [Link]@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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DOI: [Link]

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 Section 3

Behavioral Neuroscience
in Adulthood - Examples
of Hot Topics in Psychiatry
and Addiction

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Chapter 7

Treatment-Induced Brain
Plasticity in Psychiatric Disorders
Maria Uscinska, Andrea Polla Mattiot and Silvio Bellino

Abstract

In tandem with a better-informed neurobiological model of mental illness,

psychiatry has progressively been shaped into its current state of clinical neurosci-
ence. The traditional dichotomy of organic versus endogenous mental disorders has
been replaced by the growing recognition that all changes in mental processes are
accompanied by changes in structures or functions of the brain. Thus, all psychi-
atric interventions are deemed to have a biopsychosocial nature, whereby drugs in
addition to their effect on the brain have a psychological effect, and psychothera-
pies beyond their psychological effects may alter the brain. In this view, the ultimate
goal of any psychiatric treatment is to induce neural plasticity in a manner that
restores the full original function and potential of the injured brain. Herein present
chapter gives an insight into how evidence-based treatments achieve their thera-
peutic effects on the level of cerebral reorganization across a host of psychiatric
disorders. The main theme of this work is the posited mechanism of neuroplasticity
on neural-systems level for each treatment modality.

Keywords: therapy, drugs, treatment, psychosis, schizophrenia, depression,

disorder, antidepressant, antipsychotic, neuroimaging, fMRI, cognitive, plasticity,
mood stabilizers, neural correlates

1. Neural parameters of therapeutic change

Mechanisms of neuroplasticity constitute fundamental processes behind

learning and memory, that determine the ability of neuronal systems to incor-
porate novel environmental stimuli and to make appropriate adaptive response.
Delineating cerebral processes of recovery from an insult to the brain holds promise
for developing more refined and novel treatment modalities to target specific areas
of pathology. Functional neuroimaging studies provide a mean to characterize
changes in brain function related to psychiatric interventions. Well-established in
indexing biomarkers of psychiatric disorders, novel neuroimaging techniques are
now used to depict patterns of neural plasticity mediating post-treatment ameliora-
tion of symptoms. Various modalities provide indices of brain activity by measuring
cerebral blood flow or glucose metabolism including functional magnetic resonance
imaging (fMRI), 18fluorodeoxyglucose positron emission tomography (FDG-PET),
and 99mtechnetium hexamethylpropyleneamineoxime single photon emission
computed tomography (99mTc-HMPAO SPECT) [see ref. 1 for a detailed review]
One powerful imaging modality that has significantly advanced our knowledge
in this field is the task-based functional magnetic resonance imaging (t-fMRI).

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It consists of a paradigm defined by a functional measurement including a stimula-

tion adjusted to the brain area under investigation. The subject is required to perform
a defined motor or sensorimotor, language or another cognitive or visual tasks in
the MRI scanner while typically GRE T2*-weighed echo planner images (EDI) are
rapidly acquired [for a more in-depth description of fMRI see ref. 1]. Local changes
in cerebral blood flow (CBF) during task execution relative to resting state are used
to infer brain regions/networks functionally involved in specific tasks. To ultimately
determine the specificity and amount of therapy-induced neuroplasticity, multiple
pre-, and post- therapy scans are compared against activity pattern changes in other
active treatment groups and a no-treatment waiting-list group [2]. With this in
mind, the next section follows with an overview of main findings associated with
intervention-induced neuroplasticity and their interpretations.

2. Putative neuroplastic mechanisms of pharmacotherapy

Pharmacotherapy constitutes first-line treatment modality for majority of

psychiatric disorders, and various theories exist as to how drug-induced neu-
rochemical changes reverse different psychiatric symptoms. The posited purely
neurotransmitter-based mechanism of action postulates either increased or reduced
synaptic concentration of a target neurotransmitter that is implicated in a given
disorder. This model is challenged by disjunction in the timescale of the onset of
neurochemical versus therapeutic effects, wherein the potentiation or attenuation
of neurotransmitter function often occurs within hours of administration and the
clinical improvement is typically seen days or weeks after [3]. In quest of new rapid-
acting agents, contemporary approaches to understanding of drug action focus on
the role of adaptive neuroplastic processes that correlate in time with the onset of
clinical improvement, hence are hypothesized to represent a more direct treatment
target.

2.1 Antidepressant drugs and mechanisms of neuroplasticity

Current national and international guidelines recommend serotonin reuptake

inhibitors (SSRIs) as first-line treatment for most patients with major depression,
and the use of serotonin—norepinephrine reuptake inhibitors (SNRI) in patients
resistant to the former [4, 5]. Although novel, better tolerated and more selec-
tive inhibitors of serotonin and norepinephrine reuptake are continuously being
developed, the efficacy of tricyclic antidepressants such as amitriptyline for severe
depression, has never been surpassed [6].
Most of currently licensed antidepressants act to enhance monoamine neuro-
transmission, where they are believed to achieve therapeutic effects by increasing
availability of serotonin or/and norepinephrine, at least initially [7]. On the neural
level, antidepressants normalize aberrant neural activity patterns underlying
negative bias in affective information processing, posited to play central role in the
etiology and maintenance of depressed state [8]. Thus, antidepressants were shown
to attenuate hyperactivity in limbic areas of the brain (amygdala, insula, anterior
cingulate), and enhance regulatory activity in the dorsolateral and medial prefron-
tal cortex as measured by functional magnetic resonance imaging [9, 10]. It was
demonstrated that 7 days treatment with SSRI, citalopram, SNRI, and reboxetine
reversed abnormal patterns of neural response to affective information, and induced
a similar direction of change in healthy individuals [11, 12]. Noteworthy, short-term
SSRI administration normalized amygdala hyperactivity in response to negative
emotional stimuli prior to clinical changes in mood ratings in placebo-controlled

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studies [13]. These findings allow to speculate that treatment-induced early reversal
of negative emotional bias sets the scene for therapeutic recovery over time by
reducing the influence of this key maintaining factor [14].

2.2 Antipsychotic drugs and mechanisms of neuroplasticity

Antipsychotic medication is the mainstay of effective management of psychosis

where schizophrenia is the most prevalent among psychotic disorders. Most of
what we know about antipsychotic drugs action is at the receptor level, where
abnormalities in neurotransmission constitute either an excess or a deficiency of
neurotransmitters, including dopamine, serotonin, and glutamate. Therein first-
generation drugs act as antagonists of dopamine D2 receptors and target most
positive symptoms such as hallucinations and delusions. The receptor-binding
profile of second-generation drugs extends beyond D2 affinity antagonism to other
neuroreceptors including serotonin 5-HT2A in the frontal lobe, thus accounting
for superior efficacy of these drugs in the pathophysiology of negative symptoms
and cognitive disorganization [15, 16]. Overall, treatment response has been shown
to be associated to the level of D2 occupancy, which is the target of all currently
licensed antipsychotics [17]. To delineate therapeutic mechanism of clinically
effective drugs beyond receptor level, research has focused on neural systems
effects before and after pharmacotherapy in medication-naïve patients with first-
episode psychosis. Functional MRI studies revealed pre-treatment functional
alterations within frontostriatal circuitry, marked by patterns of hypoactivity
within the dorsolateral/medial prefrontal cortex coupled with hyperactivity in the
hippocampus and striatum [18–20]. Thus, aberrant frontostriatal circuitry might
represent a potential system- level mechanism of psychosis and a candidate for
treatment target with antipsychotics. Post-treatment findings lend some evidence
to validate this model, showing increases in task-related frontal cortical activation
in patients who underwent 12 weeks of quetiapine fumarate treatment compared
to a drug-naive group [21, 22], and in a small group of patients with schizophrenia
medicated with risperidone [23]. A similar study on cortical structure and function
alterations within 1 year of psychosis onset in unmedicated schizophrenia patients
versus patients under short-term therapy with atypical antipsychotics revealed
a more complex relationship [20]. Although the treatment was associated with
enhanced cognitive control and increased prefrontal, middle temporal, parietal,
and occipital activity, it also revealed post-treatment prefrontal cortical thinning in
the treatment group. The mechanism by which antipsychotics are associated with
the loss of gray matter remains unclear, however neuroinflammatory models posit
elevations in proinflammatory cytokine levels [24], microglia activation [25], and
increased extracellular volume in white and gray matter [26]. Thus, the study adds
to the growing literature on therapeutic mechanisms of antipsychotics, mediated by
normalization of aberrant frontal cortical function, and suggests that caution must
be exercised in interpreting neuroanatomical changes as being potentially deleteri-
ous to brain function.

2.3 Mood stabilizers and mechanisms of neuroplasticity

Lithium and anticonvulsants with mood-stabilizing properties (lamotrigine,

valproate) constitute first-line drug treatment for episodes of depression and
mania with variable inter-episode remission [27–29]. Whilst different compounds
may differentially target specific facets of bipolar disorders, lithium is effective for
all phases including acute depression [30]. On the neural level, functional imag-
ing studies consistently point to pre-treatment frontolimbic dysfunction during

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cognitive control and emotion-paradigms in bipolar disorder patients [31–33].

Thus, abnormal emotion regulation and impaired cognition might be attributed to
interference in cognitive control within medial prefrontal cortex though overactiv-
ity in subcortical structures (amygdala, ACC, insula), involved in emotion genera-
tion and appraisal. Findings of mood stabilizers-induced neural plasticity yield
less consistent results due to methodological limitations that make it difficult to
draw firm conclusions. Whilst some studies find no significant effects of pharma-
cotherapy upon functional measures of cerebral reorganization in bipolar patients
[34–41] others reported increased task-related prefrontal cortical activity coupled
with normalized subcortical limbic activity during emotional processing [38, 39,
42, 43]. Typically, individuals recruited in these studies are able to tolerate medica-
tion withdrawal and washout, and therefore are likely to have a milder form of the
disorder. Given that it is not clinically feasible to withdraw all patients with bipolar
disorder from medication, individuals with a more severe form of the disorder are
likely to be underrepresented in many studies and therefore findings might not be
generalizable to the most at-need of new treatments group.

3. Putative neuroplastic mechanisms of psychotherapy

Although studies of neural parameters of therapeutic change under psychother-

apy are under-represented relative to analogous studies of medications, emerging
literature support the thesis that changes in affect, cognition and behavior mediated
by psychotherapy have demonstrable neuroplastic underpinnings. Since the call for
more neuroscientifically informed approaches to psychotherapy [44], studies have
elucidated neural mechanism of psychotherapy-induced changes in brain activity
profiles across a range of psychiatric disorders.

3.1 Cognitive behavioral therapy and mood disorders

Psychotherapy processes appear to target maladaptive cognitive and emotional

patterns by engaging their biological analogues that are responsive to a discrete
mode of treatment [45]. One salient example involves re-appraisal technique under
cognitive behavioral therapy (CBT) for depression, where patients are invited to
re-interpret their negative perceptions of unpleasant occurrences in a more positive
light. Mood ratings before and after re-thinking negative events revealed improved
positive affect, mediated by elevated activity in dorsolateral and dorsomedial PFC
coupled with decreased activity in the amygdala and orbitofrontal cortex [46]. To
delineate CBT- induced mechanism of neuroplasticity in depression, FDG-PET
scans before and after psychotherapy relative to paroxetine treatment were acquired
from patients instructed to ‘avoid ruminating on any one topic’ during scanning
[47]. Although efficacy of both treatments was comparable, differential activity
patterns emerged in frontal and limbic regions, implying that medication and
psychotherapy might achieve their therapeutic effects in different ways. Whilst CBT
was associated with decreased metabolism in multiple frontal regions including
the dorsolateral PFC together with increased activity in the hippocampus, parahip-
pocampal gyrus, and dorsal cingulate gyrus, paroxetine- induced increased PFC
metabolism, and decrease in hippocampal, parahippocampal, posterior cingulate
and ventral subgenual cingulate activity. This modality-specific mechanism of
neuroplasticity posits that CBT exerts ‘top- down’ changes in cognitive processing
in favor of engaging ventral and limbic regions, which mediate attention to person-
ally salient stimuli, whereas antidepressant drugs prompt ‘bottom-up’ disengage-
ment of ventral, frontal and limbic regions. Although this model runs counter the

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aforementioned emotion regulation model, divergent findings might result from

using healthy subjects in the former study and patients with depression in the latter,
invoking the notion that brain activation results from the interaction between
underlying brain state and treatment modality [48].
In efforts to elucidate CBT- induced neural mechanism of anxiety disorders
functional neuroimaging study examined pre-and-post CBT brain activity patterns
in non-medicated patients with spider phobia and healthy subjects [49]. The former
exhibited elevated activation in the parahippocampal gyrus and right dorsolateral
PFC prior to the treatment, which was normalized with successful group CBT
sessions focused on exposure therapy. Given that parahippocampal gyrus medi-
ates contextual memory, authors suggested that after CBT less demand was placed
on the dorsolateral PFC to construct a cognitive defense to the perceived threat.
Moreover, a therapy- induced shift of activity to the ventral PFC was indexed,
which might play a role in down-regulation of limbic activity and thereby dampen-
ing fear reaction. Collectively, these studies depict a neuroplastic model of cognitive
behavioral therapy which posits altered engagement of dorsal prefrontal circuitry to
down-regulate limbic and ventral prefrontal structures thereby improving affect in
response to emotionally significant contexts.

3.2 Dialectic behavioral therapy and borderline personality disorder

Given that psychotherapy is the gold standard treatment modality for border-
line personality disorder [50], extensive research efforts focused on measuring
brain changes induced by specific modes of therapy. To date, dialectic behavioral
therapy is the most researched, refined and evidenced-based therapy informed by a
deficit model in self-regulation, distress tolerance and interpersonal skills, deemed
to arise from transaction between highly sensitive individuals and invalidating
environments [51, 52]. DBT purports to render individuals more mindful and able
to manage relationships effectively by incorporating the concept of dialectics and
strategy of validation into approach focused on skills acquisition and behavioral
shaping.
Consistent with the skills deficit model of BPD, neuroimaging evidence supports
that acquisition of affective control strategies under DBT balances neural substrates
of emotion regulation. One salient example indexed neural activity alterations
under re-appraisal and reported dampened insula and ACC activity, together
with an enhanced connectivity of the latter to medial and superior frontal gyrus,
superior temporal gyrus, and inferior parietal cortices [53]. Notably, treatment-
induced increase in dorsal ACC activity during exposure to negative stimuli was
associated with improvement self-reported BPD symptoms, suggesting a possible
biomarker of improved affect regulation. In a similar study Winter et al. [54] set out
to establish whether neural correlates of distraction might be amenable to a suc-
cessful DBT. In this view, 31 BPD patients under constant medication were scanned
before and after a 12- week residential DBT-based treatment while performing a
distraction task. When compared to 15 BPD control patients under non-DBT-based
treatment or no treatment at all, and 22 healthy participants, 16 DBT responders
exhibited attenuated activity in the right inferior parietal lobe/supramarginal
gyrus. Notably, this pattern of brain activity was correlated with improvement in
self-reported borderline symptom severity (ZAN-BPD). Furthermore, treatment
was associated with a reduction in the right perigenual ACC activity and increased
activity in these regions during distraction in the context of aversive stimuli. These
findings might reflect a shift from emotional to more cognitive processing in the
context of aversive stimuli, thereby suggesting an improvement in emotional
susceptibility under DBT.

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Taken together aforementioned studies support that DBT processes target

maladaptive emotional patterns by altering their biological analogues that are
responsive to discrete cognitive strategies. DBT normalizes frontolimbic imbalances
as part of the disturbed circuitry, which appear to mediate amelioration of BPD
symptomatology. Caution must be exercised however, while interpreting results as
medications may attenuate emotional responses in BPD patients [55], and giving
combinations of drug subtypes makes it impossible to isolate the effect of a single
agent.

3.3 IPT and depression

IPT is a short-term treatment that typically consists of 12–16 one-hour weekly

sessions focused on improving interpersonal relationships. Drawing directly on
identifiable issues between patients and therapists, it purports to instil the ability to
make the necessary adjustments in interpersonal situations that will help to reduce
symptoms of depression. Several imaging studies have examined biomarkers of
cerebral reorganization induced by IPT relative to pharmacotherapy. One of them
compared the effects of the former and venlafaxine (37.5 mg daily) on regional CBF
using 99mTc-HMPAO SPECT in 28 drug-naive or drug-free patients with MDD
[56]. Whilst comparative clinical improvements were mediated by elevated activity
in the right basal ganglia in both treatment groups, patients in the IPT group also
exhibited an increase in the right posterior cingulate activity. However, drawing
firm conclusion from these findings is hampered by methodological issues as four
patients with a strong preference for venlafaxine could choose the treatment, while
one preferred IPT. Moreover, subjects in the latter evidenced greater striatal perfu-
sion, potentially reflecting design limitation. Brief duration of IPT and relatively
low dose of venlafaxine give rise to the possibility that both treatments were sub-
optimal, thereby underscoring the engagement of limbic and paralimbic recruit-
ment in psychotherapy-induced changes reported in parallel research [56].
A similar study on the effects of IPT and paroxetine relative to healthy controls
[57] reported results analogous to CBT effects described by Goldapple et al. [47].
Whilst treatment response in both groups was associated with an increase in metab-
olism in limbic and paralimbic regions (the right insula and left inferior temporal
lobe) relative to controls, unlike CBT the effects of IPT were mediated by a decrease
in dorsal and ventral prefrontal cortical metabolism. A follow-up study was set out
to correlate treatment-mediated changes in brain activity patterns with ameliora-
tion in mood symptoms measured by the Hamilton Depression Rating Scale and
the tension/anxiety and fatigue clusters of the Profile of Mood States [58]. A cohort
of 39 patients under either paroxetine or IPT for MDD exhibited post-treatment
reductions in ventral and dorsal frontal lobe metabolism, which was associated with
improvements in the anxiety/somatization and psychomotor retardation symptom
clusters. Unlike previous findings of negative correlation between activity in the
dorsolateral PFC and improvement on global depression scores under CBT, in the
present study alterations in dorsolateral PFC activity positively correlated with
improvement in cognitive disturbance. These suggest that each treatment modal-
ity engages dorsolateral PFC function differently to achieve a specific therapeutic
effect. While CBT appears to engage this region to attenuate ‘over-thinking’ in
depression, IPT might induce it to improve general cognitive abilities.

3.4 Psychoeducation and euthymic bipolar disorder

Given that pharmacotherapy is often ineffective for treatment of residual

depressive, dysthymic and dysphoric symptoms [59], researchers have shown

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interest in psychoeducation in targeting emotional and cognitive processes [60–63].

Psychoeducation is a treatment option for bipolar disorder focused on improving
coping strategies to manage symptoms in everyday life, compliance with medication
to prevent thymic relapses, quality of life and social functioning [64, 65]. Whilst
wealth of research exists to support its efficacy in clinical symptoms improvement,
less is known how therapeutic change is achieved on the level of neural functioning.
Favre and collaborates [66] set out to index neural processes before and after
psychoeducation therapy in 16 euthymic bipolar patients (EBP) matched against 16
healthy subjects. Pre-treatment fMRI scans revealed reduced activity of cognitive
control regions (bilateral inferior and left superior frontal gyri, right insula, right
fusiform gyrus and bilateral occipital gyri) and elevated activity of emotion-related
processing regions (bilateral hippocampus, parahippocampal gyri and the left
middle temporal gyrus) in the treatment group. Thus, aberrant cognitive and emo-
tion processing that characterize acute episodes in bipolar disorder appear to persist
during euthymic phase. Post-treatment clinical improvement was mediated by
increased activity of inferior frontal gyri and a pattern of decreased activity of right
hippocampus and parahippocampal gyrus. These findings suggest that psychoedu-
cation improves cognitive control by engaging prefrontal networks and normalizes
generation of emotional responses by quieting activity within limbic networks.

3.5 Cognitive remediation therapy and schizophrenia

Cognitive remediation therapy (CRT) is an evidence-based treatment for neu-

ropsychological deficits in memory, attention, executive function, social cognition
or metacognition across a host of neuropsychiatric disorders [67–69]. There is a
growing literature focused on neurobiological changes that mediate cognitive recov-
ery under this type of intervention in patients with schizophrenia [70–73], mood
disorders [74], mild cognitive impairment [75] and in healthy adults [76]. Majority
of studies examined the effects of cognitive remediation on brain functioning in
patients with schizophrenia and have amounted to several systematic reviews and
meta-analyses [76–78]. Findings lend support to the frontal hypoactivation mecha-
nism of cognitive impairment and suggest that cognitive remediation improves
these networks efficiency. Most commonly reported areas of post-treatment
amelioration in efficiency involved prefrontal and thalamic regions. Meusel and
collaborates [73] set out to describe functional correlates of cognitive remedia-
tion in patients with bipolar disorder or depression versus healthy controls. Thirty
eight subjects completed 10 weeks of treatment and were scanned (fMRI) during
an n-back working memory task and a recollection memory task to investigate the
potential for change within these networks. PRE-POST improvements correlated
with functional activation in lateral and medial prefrontal, superior temporal, and
lateral parietal regions, suggesting neural correlates improved working memory
under cognitive remediation.

4. Discussion

The predominant paradigm of modern psychiatry posits that advances in

neurosciences can unravel the mysteries of mental illness. Since the 1990s were
declared the decade of the brain, imaging evidence has taught us a great deal about
neural correlates of symptoms expression and recovery from an insult to the brain
[79]. Despite remarkable neuroscientific advances, specific mechanisms behind
major mental illnesses, thus far, have not been identified [80]. Moreover, whilst
neurotransmitters are known to mediate synaptic pathways, research has not yet

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been able to explain any psychiatric disorder in terms of chemical imbalances

[81]. Various reasons exist as to why neuroscience is unlikely to provide a definite
understanding of the disordered mind. First and foremost, what is preventing
the scientific strategy to reduce psychiatry to neuroscience is the fact that diag-
noses listed in the Diagnostic and Statistical Manual of Mental Disorders’ are not
diseases but merely syndromes without a precise endophenotype [82]. Moreover,
the pathways from temperamental vulnerabilities to illness cannot be understood
without taking into account psychosocial adversities [83]. In this view, associations
between biomarkers of pathological and treatment processes are unlikely to be
strong or linear. Pharmacotherapy, whilst useful in severe mental disorders, it is not
in any way curative, and psychosocial interventions continue to play an important
role in psychiatric treatment, evoking multiple risk factors and complex interactive
pathways to the disordered mind [84].
Research efforts in tandem with more powerful imaging techniques will further
unravel the intricacy of cerebral organization behind pathological and treatment
processes. Nonetheless, the scientific strategy to reduce psychiatry to neurosciences
is hindered by a discrepancy between a clinical phenomenon and its neural sub-
strate, which is rooted in a conceptual mind and brain gap.

5. Conclusion

Long before the era of functional neuroimaging it was suggested that interven-
tion-driven changes in affect, cognition and behavior appear to have measurable
biological analogues [85]. To date, the potential to characterize neural mechanisms
of recovery processes have amassed vast neuroimaging data on treatment-induced
brain plasticity. Pharmacotherapy and psychotherapy appear to engage neural
circuits that are responsive to a discrete treatment modality. Although both have
similar effects on brain activity patterns in patients who share the same diagnosis,
their neural systems profile is not identical. While the former appears to act in a
bottom- up manner on a subcortical level to regulate higher cortical structures, the
latter acts top-down on cortical activity to subsequently impact subcortical regions.
Although neuroimaging techniques have revolutionized our biological insight
into recovery processes, little can be concluded about the precise neurobiological
mechanism of these changes. The remaining question is whether these changes
elucidate a neural mechanism of treatment action or simply reflect correlates of
symptom amelioration. Despite methodological and theoretical limitations neuro-
imaging literature holds promise to strengthen the credibility and utility of main-
stay in psychiatric treatment, and to improve clinical decision-making.

Conflict of interest

The author has no relevant affiliations or financial involvement with any

organization or entity with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert testimony, grants or
patents received or pending, or royalties. No writing assistance was utilized in the
production of this manuscript.

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Treatment-Induced Brain Plasticity in Psychiatric Disorders
DOI: [Link]

Author details

Maria Uscinska1*, Andrea Polla Mattiot2* and Silvio Bellino2*

1 Centre for Personality Disorders, Department of Neurosciences, University of

Turin, Italy

2 Centre for Personality Disorders, Molinette Hospital, Turin, Italy

*Address all correspondence to: [Link]@[Link],

[Link]@[Link] and [Link]@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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Behavioral Neuroscience

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Chapter 8

Aberrant Brain Neuroplasticity

and Function in Drug Addiction:
A Focus on Learning-Related Brain
Regions
Patricia Sampedro-Piquero, Luis J. Santín
and Estela Castilla-Ortega

Abstract

This chapter will review the altered brain structure and function associated to
drug addiction, with a focus on brain regions involved in learning and motivated
behavior. As evidenced by both clinical and preclinical studies, repeated drug expo-
sure affects whole brain neuroplasticity including the mesolimbic system which
is a main locus for reward, an action-control center such as the dorsal striatum,
and limbic brain regions such as the prefrontal cortex, the hippocampus, and the
amygdala that are involved in behavioral control, memory, and mood. In this way,
the drug-seeking actions that were initially intentional responses become involun-
tary habits governed by the dorsal striatum. Drug addiction may also curse with
a reduced ability to experience rewards that are unrelated to drugs and emotional
dysregulation, while the impairment on limbic regions contributes to generate
cognitive symptoms. These entail persistent memories for previous experiences
with the drug contrasting with a global cognitive decline that may hamper the
acquisition of new, adaptive learnings. Overall, these features promote a desire for
the drug, leading to relapse in drug use. Further drug exposure, in turn, aggravates
its consequences on the brain and behavior, creating the harmful “addiction cycle.”

Keywords: substance use disorders, habits, motivation, memory, mood,

accumbens, striatum, limbic regions

1. Introduction

The use of psychoactive drugs that induce dependence (including psychostimu-

lants (such as cocaine, methamphetamine, etc.), opioids (heroin, methadone, etc.),
cannabinoids, tobacco, and alcohol, among others) is widely extended in the first
world countries [1, 2]. The widespread drug use entails a main socioeconomic bur-
den, because drug use is associated to antisocial behavior and delinquency, violence
and accidents, social exclusion, physical and psychiatric illnesses, and even disabil-
ity and death [1, 2]. In this regard, it is worth mentioning that a recent global study
identified alcohol as the leading risk factor for premature death in the population
aged 15–49 years [1]. Considering the severity of the drug use problem, the World

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Health Organization currently destines efforts for substance abuse management in

order to improve both treatment and prevention programs ([Link]
substance_abuse/publications/drugs/en/).
Nevertheless, while drug use entails significant risks, regular usage of drugs is not
a synonym of suffering a drug addiction disorder. Drug addiction (or substance use
disorder—SUD) is a chronic disorder with a high relapse rate, in which the person
“loses control” over drug intake despite the negative consequences on their daily
life and even against the desire to remain abstinent [3]. Drug addiction may only be
experienced by a subgroup of more “vulnerable” individuals that get in contact with
drugs. Specifically, approximately 11% of people that use drugs would develop a SUD,
meaning an uncontrollable and harmful drug use pattern that may need treatment
[2]. Therefore, the scientific community has invested in investigating those factors or
mechanisms that cause and explain the onset and maintenance of a SUD. As the del-
eterious impact of addictive drugs on the brain—the organ that controls behavior—
became evident, addiction has been considered as a “brain disease” [4]. The current
“brain disease” model of addiction has important implications for SUD prevention
and treatment, since medical interventions that regulate brain functioning (e.g.,
pharmacotherapy) may be valid for addiction, and persons with SUDs may benefit for
public treatment policies reserved to other medical illnesses, while the social stigma is
attenuated since drug addiction is a medical condition instead of a voluntary choice or
an hedonistic act [4]. However, this model is not exempt of criticism [5, 6], partially
because the relevance of social and psychological factors is diminished in favor of the
biological elements, and freeing the person from responsibility underestimates the
importance of the personal willpower and motivation toward therapeutic change.
Setting this controversy aside, there is a consensus in that drug addiction,
being a “brain disease” or not, certainly involves a neurobiological brain dysfunc-
tion that affects behavior. Brain morphological alterations in persons using differ-
ent drug types (such as alcohol, cannabis, cocaine, methamphetamine, heroin, or
tobacco) have been consistently reported even at the macrostructural level, usu-
ally involving significant gray and/or white matter shrinkage [7–13]. Moreover,
functional neuroimage techniques reveal that connectivity among brain regions is
also dysregulated [14]. It is important to note that the aberrant brain structure and
function associated to drug addiction most likely results from a combination of
(biological) brain features that exist previous to drug use as vulnerability factors,
with the neuroadaptations that are induced by the drug itself (Figure 1A). Solid
evidence has been provided in both ways (reviewed in [15]). On the one hand,
individual differences in the form of stable personality traits such as impulsivity,
elevated anxiety, risk-taking, and sensation seeking that are assumed to entail
a particular biological and brain basis [16, 17] may predispose to engage in both
drug use and addiction. On the other hand, brain and behavioral abnormalities
often correlate with drug use patterns (i.e., the amount of drug consumed and/or
the number of years using the drug) and may be completely or partially recovered
by protracted drug abstinence [7, 8, 11, 13, 15, 18], suggesting that they were
directly induced by the continuous action of the drug. Notably, preclinical studies
in laboratory animals (that allow the exposure to the drug to be controlled by the
experimenter) have confirmed both evidences. Individual traits in rodents (e.g.,
increased impulsivity) predict their subsequently exacerbated response to drugs
compared to rodents that do not show this feature (e.g., [19, 20]); and both brain
and behavioral alterations are experimentally induced by administering drugs to
naïve animals (e.g., [21–23]).
Therefore, while it is difficult—especially for clinical research—to elucidate
whether the observed behavioral and brain features are cause or consequence of
drug use, both drug vulnerability factors and drug-induced brain effects are likely

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Aberrant Brain Neuroplasticity and Function in Drug Addiction: A Focus on Learning-Related…
DOI: [Link]

Figure 1.
(A) The “drug addiction cycle.” Numerous factors intervene in the vulnerability for drugs, including a
“vulnerable brain.” Drug consumption induces widespread brain neuroadaptations that, in vulnerable
individuals, would be addiction-like behavioral alterations that are likely to promote further drug use,
aggravating its effects. (B) A non-exhaustive schematic representation of the brain structures and connections
involved the brain circuit of learning, reward, and motivated behavior. A maladaptive functioning of this
circuit supports the etiology and maintenance of drug addiction. Brain structures are colored on the basis
of their main neurochemical content. The dashed line represents the “spiraling” nigrostriatal connections.
Abbreviations: Acb, accumbens; ACTH, acetylcholine; BLA, basolateral amygdala; Dstr, dorsal striatum;
GABA, γ-aminobutyric acid; Hipp, hippocampus; PFC, prefrontal cortex; Sep, septum; SMC, sensorimotor
cortex; VP, ventral pallidum; VTA, ventral tegmental area.

to coexist and be interrelated. In the worst case scenario, a “vulnerable” brain

is exposed to the drug, triggering an exacerbated response to the substance that
increases the amount of drug subsequently consumed, thus also increasing the
potential drug-induced harm (Figure 1A). Without the intent of underestimating
the notable importance of psychological, social, economic, and environmental
factors in the etiology and maintenance of drug addiction, this chapter will focus
on the neurobiological component. In particular, we will review that the integrity
of key brain regions that are normally involved in control of reward, planning,

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learning, and motivated behavior is compromised in drug addiction to favor

uncontrollable drug intake as well as other behavioral symptoms. Specifically, we
will focus on the mesolimbic system, the dorsal striatum, and the limbic regions as
key components of the “brain addiction circuit.”

2. The mesolimbic system: a locus for drug and non-drug-related

rewards

2.1 Experiencing rewards and learning to predict them

The mesolimbic system has been a traditional focus of drug addiction

research, since it is a key substrate for reward and motivated behavior. The
mesolimbic system comprises the accumbens (also called “ventral striatum”) and
the midbrain ventral tegmental area (VTA) as its main brain nodes and dopamine
(often considered as the molecule of “pleasure and happiness” [24]) as its major
neurotransmitter [25, 26]. The dopaminergic projection neurons in the VTA
release dopamine to the accumbens—either at its core or shell subdivisions—as
well as to memory-related limbic brain regions such as the prefrontal cortex, the
hippocampus, and the amygdala (Figure 1B) [25, 27]. Conversely, these brain
regions regulate VTA activity. Specifically, GABAergic inhibitory pathways from
the accumbens may either stimulate [28] or exert inhibitory feedback control [29]
over dopamine release by targeting either the dopaminergic VTA projection neu-
rons or the inhibitory VTA interneurons [30, 31]. For their part, the glutamatergic
limbic regions are all reciprocally interconnected, and they also project to the
accumbens and to the VTA either directly or by indirect polysynaptic pathways,
to stimulate dopamine release [27, 28, 32, 33] (Figure 1B). This illustrates that
reward and memory systems in the brain are closely interrelated, which makes
sense considering that learning is often driven by rewards, punishments, and
their anticipation (Figure 1B) [34].
The dopaminergic mesolimbic system is involved in experiencing pleasure,
and it is directly activated by primary rewards such as palatable food or sexual
behavior [24], novel stimuli [35], or pleasant music [36]. By engaging its reciprocal
connections to the limbic regions, the accumbens is important for determining
the motivational valence of stimuli and for assessing learning incentives. In other
words, the accumbens discriminates appetitive from aversive stimuli and decides
in which degree they are “liked” or “wanted” [24, 37]. In agreement to this, pre-
clinical research reveals a role of the accumbens in many forms of learning such
as in spatial navigation [38], novel object and place recognition [39], fear condi-
tioning [40], or instrumental behavior [41] (see “preclinical models of learning”
in Box 1), and dopamine in the mesolimbic system promotes an activated state
of alertness, arousal, or “seeking” that would facilitate exploration and reward
gathering [42]. Moreover, the accumbens has an important role in anticipating
the occurrence of rewards by learning which stimuli predicts them (i.e., acquir-
ing conditioned reward-stimuli associations; Table 1) [43]. By association with a
rewarding stimulus, a neutral stimulus becomes a conditioned reward and gains
incentive motivational salience, being able to activate the mesolimbic reward
system by itself [34].
When in the presence of dependence-inducing drugs, the dopaminergic
mesolimbic system is highly activated, engaging different neurobiological
mechanisms depending on the substance (e.g., inhibition of dopamine reuptake
cocaine and methamphetamine [44, 45], stimulation of dopaminergic VTA
neurons alcohol, methamphetamine, nicotine, cannabinoids [46–49], inhibition
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Aberrant Brain Neuroplasticity and Function in Drug Addiction: A Focus on Learning-Related…
DOI: [Link]

Anhedonia: A reduced ability to feel pleasure or joy; a loss of interest for activities or stimuli that were
previously engaging for the individual and elicited positive emotions. It is often a symptom of low mood
(depression-like behavior). Persons with SUDs may suffer anhedonia or “loss of reward” for experiences
that are not related to drugs.
Appetitive, aversive: Qualities of stimuli: rewarding (appetitive) or disliking (aversive).
Craving: An intense, uncontrollable, and anxious desire to use the drug. It is usually elicited by drug-
associated stimuli and it may lead to relapse in drug use.
Declarative memory: This memory overlaps with the most common concept of “memory” as it refers
to the ability to learn (and also recall, forget, etc.) facts, concepts, or words, life events, and spatial or
contextual stimuli (e.g., when America was discovered, what you had for dinner yesterday, where the car
was stationed, etc.).
Dorsal striatum: A motor control brain center that works in consonance with cortical brain regions
(cortico-striatal circuit) to select and initiate appropriate goal-directed responses. The dorsal striatum also
transforms the goal-directed actions that are repeatedly rewarded into automatic habits.
Drug sensitization (vs drug tolerance): Exacerbation of the rewarding or psychomotor effects of the
drug, as a result of the neuroadaptations induced by repeated drug exposure. There is also evidence of the
opposite effect, drug tolerance, meaning that the drug progressively blunts its actions.
Drug-associated stimuli: Those stimuli (objects, places, people, feelings, etc.) that, by associative
learning processes, have been “linked” to the effects of the drug or to drug availability. The presence of
these stimuli is a main cause of relapse, as they trigger both craving feelings and uncontrollable drug-
seeking and drug-taking habits.
Escalation (in drug intake): The phenomenon by which the person progressively increases drug use,
leading to excessive drug intake. It is also evidenced in the preclinical drug self-administration model,
where the animal progressively self-administers more quantities of the drug as the task progresses.
Executive functions: A set of high-level cognitive skills that is important for “ruling” behavior. They
involve decision-making, planning, reasoning, attentional control, cognitive flexibility, inhibition of
undesired behaviors, etc.
Goal-directed behavior: Response directed to obtain a reward. It is planned, conscious, and often useful.
Habits: “Automatic” and involuntary responses that require minimal cognitive resources to be
executed. They are generated after a goal-directed response has been repeated and rewarded numerous
times. While habits are adaptive for everyday functioning, a main problem in drug addiction is that behav-
iors associated to drugs (drug-seeking, drug-taking, etc.) also become uncontrollable habits, contributing to
relapse in drug use.
Incentive (motivational) salience: Refers to the intensity of attention, attraction, or desire (“wanting”)
that is elicited by a stimulus. It is usually related to its rewarding value. Drugs and drug-related stimuli gain
incentive motivational salience in addiction.
Limbic regions: Brain regions mainly involved in the regulation of cognition and emotion. This review
considers the prefrontal cortex, the hippocampus, and the amygdala as main brain limbic areas. They are
impaired by addictive drugs.
Long-term potentiation (LTP), long-term depression (LTD): A form of neuroplasticity that changes
the strength of a synapse, for example, as a result of learning processes or after exposure to a drug of abuse.
In the LTP, the postsynaptic neuron increases its response (e.g., more neurotransmitter is released, or more
neurotransmitter receptors are generated), while in the LTD the postsynaptic response is debilitated.
Mesolimbic system: Brain system mainly comprised by the VTA and the accumbens. It is important for
experiencing, predicting, and assessing rewards and thus for motivated (i.e., goal-directed) behavior. It is
also involved in the motor-activating effects of drugs.
Neuron: The main nerve cell in the brain that processes and transmits information through the
synapsis. The main parts of a neuron are depicted in Figure 2. Projection neurons possess long axons that
allow communication between distant brain regions, while interneurons have shorter axons, limited to a
single brain area.
Neuroplasticity: Neuroplasticity or neuroadaptation refers to changes in the anatomical structure
(dendrites, axon, nuclei, etc.) and function (synaptic strength, neurotransmitter release, etc.) of neurons,
in response to environmental or internal stimuli. Another form of neuroplasticity is the generation of
new neurons in the adult brain (adult hippocampal neurogenesis). Brain neuroplasticity is modulated by
drugs of abuse, yielding an aberrant pattern of brain functioning that contributes to generate and maintain
addiction.
Neurotoxicity: The effect of a hazardous substance that may involve an irreversible loss of the neuron’s
anatomy and function and even its death. Addictive drugs such as alcohol, methamphetamine, or heroin
have demonstrated neurotoxicity.
Neurotransmitters: Chemical messengers synthetized by the neurons that transmit information
between them, acting on specific receptors in the synapse. Glutamate is the main excitatory brain neu-
rotransmitter, as it “activates” the target neuron, while GABA has an inhibitory role; dopamine is critical in
the mesolimbic reward system regulating reward and arousal.

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Preclinical models of addiction: Paradigms or “tasks” that are designed to assess addiction-related
behaviors in animals, usually rodents (i.e., “preclinical” refers to laboratory research—animal or in vitro—
previous to clinical studies in humans). For example, the drug-induced conditioned place preference
assesses drug reward and the learning of drug-stimuli associations, by examining how much the rodent pre-
fers to stay in a maze compartment where the drug was previously administered (which is distinguishable
from a neutral maze compartment as they have different contextual cues). The drug self-administration
paradigm assesses motivation for the drug, by examining how much the rodent presses a level that results in
drug delivery (or how much the rodent keeps insisting in pressing the lever even when the drug is no longer
provided). Pressing the lever is considered as a drug-seeking (or taking) behavior. There are other models
such as the “voluntary drinking” paradigms used for ethanol.
Preclinical models of learning: There are a wide variety of tasks to assess different forms of learning
and memory in rodents. For example, in the spatial navigation tasks, the animal learns to orientate in
the surrounding space to find a particular place in a maze (e.g., the maze exit, or hidden food rewards).
In novelty-based tasks, the animal prefers to explore a novel object or place as long as it remembers the
familiar one(s). Tasks based on associative learning require the animal to associate stimuli; for example,
in fear conditioning, a compartment of the maze where an electric shock is provided is discriminated by
its contextual cues (shock-cue association). In instrumental learning tasks (operant conditioning), the
animal learns to perform a specific response, such as pressing a lever, to obtain a reward, such as food.
Psychiatric comorbidity: Different psychiatric disorders that occur simultaneously in the same indi-
vidual, usually worsening the therapeutic outcome. Drug addiction is often associated to high psychiatric
comorbidity, including mood and anxiety disorders (depression, generalized anxiety, phobias, etc.) and
personality disorders.
Relapse: Resuming drug use after a period of abstinence.
Reward: A stimuli or outcome that is pleasurable and/or beneficial for the individual. Primary
rewards are those stimuli intrinsically pleasurable (e.g., a delicious food), while conditioned rewards are
those that have gained their reinforcing value by being associated with a rewarding stimuli (e.g., the sound
of a bell that rings when the food is ready to serve becomes rewarding).
Substance use disorder (SUD), drug addiction: A chronic and highly relapsing disorder which
its main characteristic is an uncontrollable (and usually excessive) drug intake. Furthermore, addiction
frequently carries a socioeconomic and health burden for the individual, including motivational, emotional,
and cognitive impairment. Unfortunately, these symptoms induced by drugs contribute to further drug use,
generating a “vicious cycle.”
Stress: A physiological response generated by a stimulus perceived as threatening or aversive. The stress
response is dysregulated by addictive drugs, and experiencing stress contributes to relapse in drug use.
Synapse: It is the region where chemical or electrical information is transmitted from one neuron to
another. A typical chemical synapse uses neurotransmitters that are synthetized by the presynaptic neuron
and released through the axon terminals (Figure 2); and then they bind with specific neurotransmitter
receptors in the postsynaptic neuron that may be located in the dendritic spines but also in the axon or soma.
Vulnerability: Referred to addiction, “vulnerability” entails both biological features and behavioral
(personality) traits that predispose the individual to initiate and maintain drug use or to generate a
SUD. For example, exacerbated impulsivity and reduced inhibition of behavior, inclination to take risks,
preference for experiencing novel stimuli or seeking sensations, or an anxious personality are associated
to increased risk for drug abuse. Importantly, the behavioral attributes are assumed to be a reflection of a
particular pattern of brain functioning (i.e., they entail a biological-brain-correlate).
Working memory: It is a short-term memory capacity for concepts or stimuli that do not need to be
remembered in the long-term, but they should be processed (i.e., mentally manipulated or “worked with”)
for a short period of time. For example, working memory is needed for reasoning, planning, and solving
problems or mathematical operations.

Box 1.
Definitions.

of VTA GABAergic interneurons opioids and cocaine [50, 51]. According to the
accumbens’ role for experiencing rewards, the accumbens is involved in enjoying
the recreational feelings induced by drugs [52], in their “activating” psychomo-
tor effects [53, 54], and in learning the stimuli that are predictive of the drug’s
effects or its availability (i.e., drug-stimuli associations [43, 55]). In this way,
rodents with lesions in the accumbens will reduce the expression of drug-seeking
or drug-taking behaviors when they are tested in common preclinical models for
addiction-like responses, such as conditioned place preference or self-administra-
tion paradigms [54, 56–58].

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“Normal” functioning Drug addiction

Mesolimbic • Reward • Drug reward

system (sensitization, tolerance)
• Incentive assessment (“liking”)
• Anhedonia
• Associative learning, reward
prediction • Incentive assessment (“wanting”
drugs)
• Alertness, activation
• Drug-stimuli associations
• Drug psychomotor activation
• Drug craving
• Relapse

Dorsal striatum • Motor learning • Drug-related habits

• Behavior-optimizing habits • Drug craving
• Goal-directed responses • Relapse

Limbic regions • Behavioral control • Behavioral disinhibition

• Executive functions • Cognitive decline
• Working memory • Drug-stimuli associations
• Declarative memory (associative • Emotional dysregulation
learning)
• Drug craving
• Emotional regulation
• Relapse

Behavioral functions and addiction symptoms are linked to the main brain region(s) that supports them, but it should
be noted that these reward and learning-related brain systems act in close synchrony (Figure 1B) to support behavior.

Table 1.
Impaired function of learning-related brain regions in drug addiction.

2.2 Desire for drug overcomes natural rewards in addiction

As a result of its repeated activation by chronic drug exposure, the mesolimbic

system may undergo long-lasting neuroadaptations which are involved in addiction
(Figure 2). In clinical population with SUDs, a reduced volume of the accumbens
has been reported [59, 60], and one postmortem study in cocaine users reveals a loss
of dopaminergic neurons in the midbrain [61]. In drug-withdrawn animals, experi-
ments have described persistent changes in accumbens dendrite branching and
spine density (that are normally increased for alcohol, cocaine, methamphetamine,
and nicotine [62, 63] but decreased for morphine or cannabinoids [63, 64]) as well
as in the VTA (where psychostimulants tend to increase dendritic arborization and
spines [65] but cannabinoids and opioids induce visible morphometrical reductions
in the soma of the dopaminergic neurons [64, 66]).
Importantly, these structural modifications concomitantly occur with pro-
found neurochemical and functional changes (Figure 2, Table 1), including
modifications of the synaptic strength (long-term potentiation, LTP, or long-term
depression, LTD) [67, 68]. The drug-induced neuroplastic and neurochemical
adaptations, involving dopamine and glutamate signaling [69, 70], may aug-
ment the mesolimbic response to the drug. This supports the phenomenon of
“behavioral sensitization,” referring to an exacerbated drug’s rewarding or motor-
activating effects. Drug sensitization has been widely reported in rodents that will
progressively increase locomotor activity and VTA dopamine release after they are
repeatedly exposed to moderate doses of commonly abused drugs (most frequently
to psychostimulants, but also to other drug types [70, 71]). But the evidence of
drug sensitization in humans is more scarce [72]. In fact, there is evidence against

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Figure 2.
A non-exhaustive list of brain structural and functional neuroadaptations induced by addictive drugs. Only
the brain areas that are the focus of this review are depicted; but it should be noted that drugs affect widespread
neuroplasticity in the whole brain. Neurotoxic effects (i.e., neuronal death) have been evidenced for certain
drug types such as alcohol, methamphetamine, or heroin.

the drug-sensitization theory, reporting that the drug-induced dopamine response

could become progressively blunted or habituated, which would then induce drug
tolerance effects instead [72, 73]. Drug tolerance may ultimately lead to increased
drug use, since more quantity of the substance is progressively needed to experi-
ence its effects.
In any case, escalation in drug intake is associated to a notable reduction of
basal dopaminergic transmission in the accumbens and in the whole striatum, as
evidenced by lower levels of endogenous striatal dopamine and reduced expres-
sion of dopamine receptors—mostly the postsynaptic D2 receptor [74–77]. This
may contribute to the fact that, contrasting with the ability of drugs to stimulate
the mesolimbic system, primary rewards may diminish their reinforcing value
in addiction [73, 78]. Accordingly, an increased brain threshold for experiencing
reward (measured by intracranial self-stimulation) and “loss of pleasure” anhe-
donic behaviors (e.g., reduced intake of a highly palatable food) are described in
drug-withdrawn animals (reviewed in [79]). A diminished interest for non-drug
rewards will impede persons with SUD to enjoy daily-life experiences or to attain

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interpersonal and professional goals as they now hold a weak appeal [72]. As
predicted by this “loss of reward” model, drug use may then gain motivational
incentive as a compensation for the decreased sensitivity to natural rewards and the
hypodopaminergic mesolimbic state [73, 78, 79].
Thereby, while in a state of overall reduced reward and motivation for
non-drug experiences, the drug and its associated stimuli would increase their
incentive value in addiction: drugs would be “wanted,” even when they are no
longer “liked” [80]. In relation to this, drug use is highly driven by “craving”, an
intense and uncontrollable desire for the drug that progressively increases during
abstinence periods (i.e., craving incubation) and is greatly triggered or aggra-
vated when drug-associated stimuli are presented, eliciting relapse in compulsive
drug-seeking or drug-taking [55]. Current evidence suggests that the neural bases
of drug craving involve the mesolimbic system but are widespread distributed
through the “brain addiction circuit” (Table 1). As elucidated by preclinical
studies, the accumbens is one of the brain regions that supports drug craving
incubation and relapse, together with dorsal striatal and limbic areas (reviewed in
[81]). Accordingly, functional neuroimage studies in drug users exposed to drug-
associated cues have reported increased activation in either the accumbens, the
dorsal striatum, or the limbic regions in correlation with the intensity of craving
experienced [82–86].

3. The dorsal striatum: where goal-directed behavior becomes habit

Together with the mesolimbic system, the dorsal striatum is a key brain region to
explain addiction. The dorsal striatum, composed by the caudate nucleus and puta-
men, is a center for sensorimotor integration. It receives excitatory inputs from the
thalamus, which is a major relay for sensory signals, and extensive excitatory inputs
from cortical areas that are distributed across the striatal subdivisions through
the cortico-striatal circuit [87] (Figure 1B). In this regard, the dorsomedial striatum
is mainly innervated by cognitive-related prefrontal cortical regions supporting
executive functions (and thus it is mostly involved in goal-directed behavioral
control), while the dorsolateral striatum mostly receives input from primary sensory
and motor cortices (and thus seems more involved in habit learning and motor
execution) [55, 88]. Furthermore, the so-called spiraling nigrostriatal circuit allows
functional and bidirectional serial connections among the dorsal striatum and
the reward centers including the accumbens and the dopaminergic neurons in the
midbrain [55, 88] (Figure 1B).
The dorsal striatum is critical to control motor learning, motor planning, and
motor execution [87] and to engage in motivated goal-directed behaviors, including
those needed for survival [89]. Strikingly, hungry mice with dorsal striatal mal-
function will not initiate feeding behavior even when food is placed right in front of
them, nor they would explore a novel environment [89]. Considering this, the dor-
sal striatum is essential for instrumental learning [87, 90], but its function differs
from the mesolimbic system’s role. While the accumbens predicts the occurrence
of a reward in the presence of reward-associated stimuli, the dorsal striatum is in
charge of selecting and initiating the actions or movement patterns that are ade-
quate to obtain such expected reward in a certain environment. However, once the
reward-associated cue is repeatedly paired with an appropriate action, that results
successfully rewarded, the action progressively becomes a routinary response
that is automatically elicited by the associated stimulus. In other words, the action
becomes a habit [55, 91, 92]. Compared to planned goal-directed responses, habits

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are less flexible and more prone to errors since they are executed unconsciously,
based on past performance, without thoughtful evaluation of the current situation.
Despite this, habits are highly adaptive for normal everyday functioning, since they
allow the dorsal striatum to rapidly select and perform common responses without
demanding cognitive and attentional resources that may be directed elsewhere [93].
Nevertheless, when habits involve undesired drug-seeking and drug-taking
responses, they entail a core problem in drug addiction. In fact, some authors
conceptualize addiction as a “shift” of behavioral control from the accumbens to
the dorsal striatal regions as drug-induced neuroplasticity hijack the striatal circuits
responsible for habit forming [55, 91, 92] (Figure 2). Similarly to what is reported
for the accumbens, there is a depletion in the dorsal striatal dopaminergic signal-
ing as evidenced by lower levels of endogenous dopamine [74, 75] and a reduced
availability of the dopaminergic D2 receptors [76, 77, 94, 95]. However, in addition
to structural plasticity [96], the dorsal striatal neurons may trigger concomitant
synaptic changes in the presence of drugs, resulting either in LTP or LTD in
response to the midbrain dopaminergic input [91, 92], together with a potentiated
glutamatergic transmission attending to an increased density and synaptic facilita-
tion of glutamate receptors [96–98]. Interestingly, while many brain regions in
persons with SUDs usually show a reduced gray matter volume, the dorsal striatum
has been found either reduced or hypertrophied in psychostimulant-dependent
individuals [99–101]. The progressive transition of drug-seeking from a goal-
directed behavior to a compulsive habit under striatal control has been elegantly
modeled by animal research. At the initial phases of drug self-administration, the
expression of this behavior requires the integrity of both the accumbens and the
dorsal striatum [102]. But once the animal is extensively trained for drug-seeking,
cue-induced drug-seeking is disrupted by interventions affecting the dorsal striatal
region selectively (revised in [55]). Furthermore, animals with extended history
of drug exposure will not cease drug-seeking even when this behavior is no longer
“rationally” worth it (e.g., when they must endure highly aversive stimuli such as
electric shocks to obtain the drug [103]), mimicking habitual drug use despite of
negative consequences as found in SUD patients.
In conclusion, striatal neuroplasticity supports the progressive transformation
of conscious and voluntary (i.e., goal-directed) drug-taking actions into habits
(Table 1). Habits are an important cause of relapse as they are compulsive and
uncontrollable by the individual and automatically elicited by drug-associated cues.
This explains that drug-related stimuli (e.g., an alcohol bottle, a razor blade, a place
where the drug was usually consumed, a drug-using companion, or even drug-
associated emotions and thoughts) would trigger drug use—usually accompanied
by intense craving feelings—despite of efforts to remain abstinent [55, 91, 92]
(Figure 1A).

4. Limbic regions: the prefrontal cortex, the amygdala, and the

hippocampus

4.1 Controlling behavior, memory, and mood

While the addiction theories have traditionally focused on the interaction among
the mesolimbic system and the dorsal striatal regions, the limbic brain regions—
such as the prefrontal cortex, the hippocampus, and the amygdala—have gained
increased attention in addiction [27, 104, 105]. As exposed before, the prefrontal
cortex, the hippocampus, and the amygdala are mainly glutamatergic structures all

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reciprocally interconnected [33] that are closely integrated into the reward brain
circuit by receiving direct dopaminergic inputs from the VTA and, conversely, by
regulating accumbens and VTA activity (Section 2.1; Figure 1B).
The limbic system is classically defined as the brain substrate of “emotion”
[106]. The limbic regions modulate the stress response, which is generally stimu-
lated by the amygdala but suppressed by the hippocampus and the prefrontal
cortex by inhibitory feedback mechanisms [107]. The amygdala also plays a pivotal
role in triggering “unpleasant” emotions and responses such as anxiety and fear
[108, 109], though it is also involved in positive emotions and it is activated after
either appetitive or aversive stimuli, to evaluate their motivational value [110].
The limbic regions also hold cognitive functions. The prefrontal cortex has a key
role in behavioral control, by guiding the dorsal striatum to select appropriate
actions through the abovementioned cortico-striatal circuit [88] (Section 3) and
by inhibiting or updating inappropriate behaviors (reviewed in [15]). Accordingly,
the prefrontal cortex is responsible of higher cognitive process such as planning,
reasoning, behavioral flexibility, or decision-making (executive functions), and
it holds the “working-memory” capacity that allows to manipulate information
that is stored in the short-term (reviewed in [15]). The hippocampus is involved in
the acquisition, long-term storage, and further processing (extinction, retrieval,
updating, etc.) of declarative memory [111]. Declarative memory includes the
semantic memory (verbal information, facts, and concepts), the episodic memory
(life events), as well as the spatial memory (contexts and places), so a loss of
hippocampal function drives severe anterograde amnesia [111]. Moreover, the
hippocampus is important for integrating events that are separated in time or space
(thus being crucial for associative learning [112]), and it participates in novelty
detection that contributes to recognize previously presented stimuli, allowing to
lead exploration and/or cognitive resources to the novel ones [113]. Regarding the
amygdala, this region also holds a role in cognition, such as in fear memories [114]
or in facilitating the emotional modulation of declarative memory, since emotion-
ally arousing experiences are more strongly consolidated and remembered than
neutral ones [115] (Table 1).
The initial experiences with drugs would use the regular learning mechanisms
in the limbic regions to be acquired and stored in memory [116]. In this way, the
prefrontal cortex guides the dorsal striatum and acts as an “ON/OFF switch” for
drug-seeking, deciding when this behavior should be allowed or inhibited [105].
Regarding the hippocampus and the amygdala, they interact with the prefrontal
cortex and the accumbens for the learning of drug-stimuli associations; and these
limbic regions collaborate for the subsequent retrieval, extinction, or reinstatement
of the drug-related memories (being the reinstatement, a form of “relapse,” that in
preclinical models is elicited by drug-associated cues, by stress, or by a low dose of
the drug—priming) (reviewed in [15, 27, 116]). Since the drug-related experiences
are rewarding and emotionally arousing, they activate neurobiological pathways
involved in the emotional enhancement of associative memory, which may potenti-
ate their acquisition and subsequent long-term maintenance [116, 117].

4.2 Affective and cognitive alterations are concomitant to drug addiction

After repeated drug exposure, the limbic regions are highly vulnerable to
undergo neuroplastic and/or neurodegenerative changes (Figure 2). A reduced gray
matter volume is often found in the prefrontal cortex, hippocampus, and amygdala
of chronic drug users [7, 10, 12, 59, 118], together with a dysregulated expression of
genes including those involved in GABA and glutamate neurotransmission

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Figure 3.
Reduced adult hippocampal neurogenesis as an example of drug-induced neuroplasticity. Photographs show
the hippocampus (dentate gyrus) of mice treated either with saline or ethanol for 8 days (protocol published in
our previous work [22]). Young neurons expressing the immature neuron marker doublecortin were stained by
immunohistochemistry. Arrow points young neurons showing horizontally disposed nuclei and underdeveloped
dendritic tree in the ethanol-treated animal. Scale bar: 100 μm.

[119, 120] and alteration in LTP or LTD processes [121–124]. Particularly, alcohol
is associated with severe brain damage and neurotoxicity in the limbic system [12],
and sufficient exposure may precipitate severe neurocognitive syndromes such as
lasting dementia [125]. Other limbic neuroadaptations induced by addictive drugs
involve a reduction of adult hippocampal neurogenesis, as evidenced by a recent
postmortem study in persons that abused alcohol [126]. The generation, matura-
tion, and functional integration of new neurons in the adult brain—where the
dentate gyrus of the hippocampus is a main neurogenic niche—has been extensively
described in rodents, for which the new hippocampal neurons participate in many
forms of hippocampal-dependent learning and emotional regulation [127]. While
the existence and functional implications of adult hippocampal neurogenesis
in humans still generate controversy [128], there is currently a wide preclinical
evidence supporting that drugs of abuse modulate—mainly reduce—the adult-born
hippocampal neurons (Figure 3), which has raised interest on the potential involve-
ment of this neuroplastic phenomenon in addiction [27, 116, 129, 130].
Damage of the limbic regions generates the “cognitive” symptoms in drug addic-
tion. The drug-induced neuroplasticity in prefrontal areas involved in the cortico-
striatal circuit contributes to the “loss of control” over drug-seeking behavior that
becomes further governed by the dorsal striatal habits [105, 131, 132] (Section 3;
Table 1). The prefrontal “disinhibition” may affect other behavioral domains,
promoting impulsivity, impaired decision-making, and more involvement in risky
behaviors [133] which, in turn, may contribute to further engagement in drug use
(Figure 1A). Since the limbic regions are required for associative memory, memories
for drug-stimuli associations may become engrained in addiction, being resistant
to extinction and forgetting but prone to reinstatement [117, 134, 135]. Therefore, a
potentiated function of the limbic regions at the initial experiences with drugs may
facilitate their storage in memory; but their impoverished function after repeated
drug exposure may impede these memories to be subsequently extinguished. As
explained before (Sections 2 and 3), the memories for drug-stimuli associations
are relevant in addiction, since they trigger drug craving and habitual drug use
responses.
Furthermore, limbic system malfunction in addiction yields a variable degree
of cognitive decline that may affect both prefrontal- and hippocampal-dependent
domains, including attention, working memory, declarative memory, and execu-
tive functions, as evidenced in both drug-exposed animals and in persons with

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SUDs (Table 1; reviewed in [15]). Cognitive impairment may last for months or
years after ceasing drug use, and, in the most severe cases, it may be irreversible
(e.g., [18, 125, 136–138]). The cognitive decline has relevant clinical implica-
tions, since it is a consistent predictor of addiction treatment dropout and relapse
(reviewed in [15]). In this way, it is possible for cognitive impairment to act as
an indirect indicator of the extent of malfunction of the limbic regions that are
implicated in key behavioral processes that lead to drug use such as behavioral
disinhibition or drug craving (Table 1). Another possibility is that cognitive
impairment may directly compromise the follow-up of addiction treatments by
burdening the acquisition of new adaptive information, such as the contents of
behavioral therapies that usually require a considerable cognitive effort to be
apprehended [139].
Finally, at the emotional level, malfunction of limbic regions during drug
withdrawal may curse with a “negative affect” involving stress and anxiety in addi-
tion to “loss of reward” (Section 2; Table 1) that may trigger drug use by negative
reinforcement (i.e., using drugs to escape the aversive emotional state) [78, 140]
(Figure 1A). In fact, the stress response is frequently dysregulated in persons with
SUDs [141] that are vulnerable to stressful experiences, which are a powerful cause
of relapse in drug use [81, 142]. Furthermore, SUDs have a high psychiatric comor-
bidity (~40%) with mood and anxiety disorders [143–145]. Dual pathology com-
plicates the treatment of drug addiction, since an integrative therapeutic approach
that involves both the SUD and the comorbid psychiatric disorder may be necessary
for these patients [146].

5. Conclusion

This chapter shows that addiction compromises widespread brain neuroplasti-

city and function, which includes—but is not limited to—key brain regions involved
in learning, reward, and motivated behavior. As consequence of repeated drug
exposure, probably acting in combination with pre-existing neurobiological vulner-
ability traits, these regions corrupt their “normal” activity and promote dysfunc-
tional behavior that underlies the etiology and maintenance of the drug addiction
disorder. Considering this, therapies directed to promote adaptive neuroplasticity
that allows these brain regions to regain their original function are valuable in drug
addiction. Importantly, these strategies are not limited to biomedical interventions,
but they may include a wide range of behavioral approaches, such as cognitive
stimulation, considering that engagement in new and appealing experiences may
sculpt brain neuroplasticity, even in the presence of drugs [15]. Therefore, while
addiction may be, in a way, a “brain disease,” many factors should be taken into
account, considering that thoughts, emotions, social, and environmental stimuli
ultimately impact the brain.

Acknowledgements

This study was funded by grants from the Spanish Ministry of Economy
and Competitiveness (MINECO, Agencia Estatal de Investigación) co-founded
by the European Research Development Fund—AEI/FEDER, UE—(“Jóvenes
Investigadores” grant PSI2015-73156-JIN to E.C.O.; grant PSI2017-82604R to L.J.S
and “Juan de la Cierva-Formación” grant FJCI-2015-23925 to P.S.P.) and by the
University of Malaga (Plan Propio 2017—[Link].B1.2017/38 to P.S.P).

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Conflict of interest

Authors declare no conflicts of interest.

List of abbreviations and acronyms

Acb accumbens
ACTH acetylcholine
BLA basolateral amygdala
D2 receptor dopamine receptor “D2”
Dstr dorsal striatum
GABA γ-aminobutyric acid
Hipp hippocampus
LTP long-term potentiation
LTD long-term depression
PFC prefrontal cortex
Sep septum
SMC sensorimotor cortex
SUD substance use disorder
VP ventral pallidum
VTA ventral tegmental area

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Author details

Patricia Sampedro-Piquero1,2*, Luis J. Santín1,2* and Estela Castilla-Ortega1,3*

1 Instituto de Investigación Biomédica de Málaga-IBIMA, Spain

2 Departamento de Psicobiología y Metodología de las Ciencias del

Comportamiento, Facultad de Psicología, Universidad de Málaga, Spain

3 Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de

Málaga, Spain

*Address all correspondence to: [Link]@[Link]; luis@[Link] and

[Link]@[Link]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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 Edited by Sara Palermo and Rosalba Morese

What do we mean by “behavioral neuroscience?”This volume aims at providing an

overview of behavioral neuroscience and deepening neuronal mechanisms and brain
circuits that regulate the fundamental aspects of human behavior, such as cognitive
and emotional functions. It is intended to give the reader the most up-to-date vision
of how the interaction between biological mechanisms and neurocognitive processes
leads to complex and highly organized [Link] recent years the strong impulse
given to research on behavioral neuroscience has produced a large literature that
documents the high level of complexity of the issue, for which it is necessary to
provide a reasoned multidimensional analysis able to integrate the expertise of
different [Link] book offers an excellent synopsis of perspectives, methods,
empirical evidences, and international references. Therefore, it represents an
extraordinary opportunity to target neuroscientific hot topics and to outline new
horizons in the study of the relationship between brain and behavior.

978-1-78985-185-4
ISBN 978-1-78984-051-3

Published in London, UK
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