Understanding Emotions: Origins and Roles of the Amygdala

Abstract

Emotions arise from activations of specialized neuronal populations in several parts of the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental area. Feelings are conscious, emotional experiences of these activations that contribute to neuronal networks mediating thoughts, language, and behavior, thus enhancing the ability to predict, learn, and reappraise stimuli and situations in the environment based on previous experiences. Contemporary theories of emotion converge around the key role of the amygdala as the central subcortical emotional brain structure that constantly evaluates and integrates a variety of sensory information from the surroundings and assigns them appropriate values of emotional dimensions, such as valence, intensity, and approachability. The amygdala participates in the regulation of autonomic and endocrine functions, decision-making and adaptations of instinctive and motivational behaviors to changes in the environment through implicit associative learning, changes in short- and long-term synaptic plasticity, and activation of the fight-or-flight response via efferent projections from its central nucleus to cortical and subcortical structures.

Full text

biomolecules
Review
Understanding Emotions: Origins and Roles of the Amygdala
Goran Šimi´c 1,* , Mladenka Tkalˇci´c 2, Vana Vuki´c 1, Damir Mulc 3, Ena Špani´c 1, Marina Šagud 4,
Francisco E. Olucha-Bordonau 5, Mario Vukši´c 1and Patrick R. Hof 6


Citation: Šimi´c, G.; Tkalˇci´c, M.;
Vuki´c, V.; Mulc, D.; Špani´c, E.; Šagud,
M.; Olucha-Bordonau, F.E.; Vukši´c,
M.; R. Hof, P. Understanding
Emotions: Origins and Roles of the
Amygdala. Biomolecules 2021,11, 823.
https://doi.org/10.3390/
biom11060823
Academic Editor: Vladimir
N. Uversky
Received: 25 April 2021
Accepted: 26 May 2021
Published: 31 May 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School,
10000 Zagreb, Croatia; vukic.vana@gmail.com (V.V.); espanic@hiim.hr (E.Š.); mariovuksic@net.hr (M.V.)
2Department of Psychology, Faculty of Humanities and Social Sciences, University of Rijeka,
51000 Rijeka, Croatia; mlat@ffri.hr
3University Psychiatric Hospital Vrapˇce, 10090 Zagreb, Croatia; damir.mulc@hotmail.com
4Department of Psychiatry, Clinical Hospital Center Zagreb and University of Zagreb School of Medicine,
10000 Zagreb, Croatia; marinasagud@mail.com
5
Department of Medicine, School of Medical Sciences, Universitat Jaume I, 12071 Castellón de la Plana, Spain;
folucha@uji.es
6
Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount
Sinai, New York, NY 07305, USA; patrick.hof@mssm.edu
*Correspondence: gsimic@hiim.hr
Abstract:
Emotions arise from activations of specialized neuronal populations in several parts of
the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical
structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental
area. Feelings are conscious, emotional experiences of these activations that contribute to neuronal
networks mediating thoughts, language, and behavior, thus enhancing the ability to predict, learn,
and reappraise stimuli and situations in the environment based on previous experiences. Contem-
porary theories of emotion converge around the key role of the amygdala as the central subcortical
emotional brain structure that constantly evaluates and integrates a variety of sensory information
from the surroundings and assigns them appropriate values of emotional dimensions, such as va-
lence, intensity, and approachability. The amygdala participates in the regulation of autonomic and
endocrine functions, decision-making and adaptations of instinctive and motivational behaviors to
changes in the environment through implicit associative learning, changes in short- and long-term
synaptic plasticity, and activation of the fight-or-flight response via efferent projections from its
central nucleus to cortical and subcortical structures.
Keywords: amygdala; emotion; evolution; fear; anxiety
1. Introduction
Emotions played a major role in survival during human evolution and in effective
psychological functioning in human societies [
1
]. Unlike reflexes—automatic and un-
controllable narrowly-tuned responses to specific stimuli—emotions emerged and were
selected in evolution because they better addressed problems of adaptation to a constantly
changing environment [
2
]. Among others, adaptive abilities to find food, water and shelter,
to find sexual partners (mates), to provide adequate protection, nurturing, and care for off-
spring, and most importantly, to avoid danger and escape from life-threatening situations
were probably critical [
3
]. It has been speculated that emotions initially arose when reflexes
were “decoupled” to include another layer of nerve cells on top of them—the evolutionary
emergence of central emotional states [4].
Most contemporary theories of emotion are based on the assumption that emotions
are biologically determined [
3
]. Consistent with this biological approach is the finding
that some basic, primary emotions, such as anger, fear, joy, sadness, disgust, and surprise,
are innate, expressed in the first six months of life, and associated with specific facial
Biomolecules 2021,11, 823. https://doi.org/10.3390/biom11060823 https://www.mdpi.com/journal/biomolecules

Biomolecules 2021,11, 823 2 of 58
expressions. As such, they have been equally recognized in different cultures around the
world [
5
]. According to Ekman and others, different facial expressions of primary emotions
are interpreted and reproduced similarly across different cultures [
6
,
7
]. Although people in
different cultures are relatively equally successful at recognizing facial expressions of basic,
primary emotions [
5
], estimating the intensity of these expressions, however, depends on
the cultural context [
8
]. An illustration of facial expressions of the three primary emotions
is shown in Figure 1.
Figure 1. Emotional facial expressions of three basic, primary emotions.
At the top is a neutral facial expression. In
the bottom row, facial expressions of anger, joy, and fear are shown, respectively. Although individual emotions can be
recognized and analyzed even from the microexpressions of facial muscles, for the sake of clarity the expressions of emotions
in these photographs are accentuated. See text for details. Photographs by Andrea Piacquadio, taken from [9].
Darwin was probably the first to study the evolution of emotional reactions and facial
expressions systematically and to recognize the importance of emotions for the adaptation
of the organism to various stimuli and environmental situations [
10
]. After a detailed
description of individual facial expressions as well as the motor apparatus involved in
the expression of each individual emotion in his 1872 book, The expression of emotions
in man and animals, he concluded that emotions in humans, just as in animals, have a
common evolutionary history [
11
]. By presenting the findings that certain emotional facial
expressions have universal meaning for people in different parts of the world, Darwin
anticipated research of facial expressions that would not begin until more than a century
later. From an evolutionary perspective, emotions allow for the coordination of a whole
range of different processes with the goal of resolving immediate and urgent issues [
12
–
14
].
2. Classical Theories of Emotion
Some of the first theories of emotion attempted to explain the close relation between
physiological changes and the subjective experience of an emotion or a feeling. James,

Biomolecules 2021,11, 823 3 of 58
Lange, and Sergi independently assumed, counterintuitively, that subjective emotional
experience is caused by changes in the body [
15
–
17
]. What they meant was that fear, for
example, is experienced due to bodily changes brought about by a specific environmental
stimulus and that interpretation of that physical response due to changes in the autonomic
nervous system (ANS) results in an emotional experience. In their view, after being faced
with a frightening stimulus, a physiological response to that stimulus would occur before
the subjective experience of an emotion.
James defined in 1884 that “the bodily changes follow directly the perception of the
exciting fact, and that our feeling of the same changes as they occur is the emotion” [
17
].
Specific brain areas (e.g., visual or auditory cortices) process a particular stimulus and
evaluate its meaning and relevance. If the stimulus is emotionally important, the infor-
mation is relayed to the ANS, whose activation leads to a fight-or-flight response. The
“conscious part” of the brain then detects bodily arousal and interprets the emotional
nature of the experienced physiological state [
18
]. According to James, different emotions
are experienced differently because they arise from different constellations of physiological
responses. This James–Lange theory, the first theory of emotion, was later modified and
called the peripheral theory of emotions (see below) because it emphasizes the importance
of bodily responses for the emergence of emotions [
19
,
20
]. One of the examples that speaks
in favor of James’s theory is the effect of benzodiazepines, a class of anxiolytic drugs, which
are also muscle relaxants [
4
]. According to the theory, tense muscles signal anxiety to the
brain. So, when muscles relax, the brain no longer receives this information and the subject
becomes less anxious.
Damasio has recently complemented and reformulated the peripheral theory of emo-
tions [
19
,
20
]. His reasoning can be summed up in the claim that emotions are unconsciously
formed in the central nervous system (CNS) based on interoceptive and proprioceptive
afferent body signals and correlate, to a large extent, with consciously produced feelings
in the later course of processing the initial stimuli (this interpretation overlaps with the
somatic marker theory [
21
], see below). Although this theory does not provide a holistic
view of emotions and their processing, it has significantly contributed to the idea that
emotional experiences involve knowing one’s current and previous bodily states, which
is the basis of the concept of embodied cognition [
22
]. According to Damasio, without
the self-representation of one’s own image (of the whole body) and its constant updating,
adults would be as helpless as newborns because emotions unaccompanied by conscious
feelings would not be sufficient for survival. However, once embodied, emotions can
exist exclusively within the CNS, as exemplified by deafferentation phenomena, such
as phantom pain. The CNS must consistently update all information about the state of
the body to regulate all the processes that keep it alive as the only way an organism can
maintain homeostasis and survive in a constantly changing environment. According to
the concept of embodied cognition, emotions are grounded throughout the individual
as well as its entire personal experience involving the adaptation of all systems to sen-
sory experience [
23
]. Damasio proposed that the main difference between humans, apes,
and other animals is the level and elaboration of body self-image, which in humans, is
extremely large (broader core self-image) and includes autobiographical memory, while
in other species, it includes only a significantly lower level (core self-image), depending
on the degree of cortical development [
19
,
20
,
24
]. Damasio’s proposal also implies that
there is no pure perception (i.e., interpretation without bodily experiences) and that by
controlling motor behavior and its consequences on proprioception and interoception,
one could regulate one’s emotions and thus influence feelings. This concept is used, for
example, in dance psychotherapy, where the therapist helps the patient to evoke, process,
and regulate certain emotions through movement [
25
]. Likewise, exploring and practicing
new and yet unknown motor patterns can help a person experience new, hitherto unusual
feelings [
25
]. The same principle explains the relatively small but significant finding that
the use of botulinum toxin A applied to the muscles used in frowning (mm. corrugatores
supercilii) leads to a better mood [
26
], whereas it leads to a bad mood when applied to the

Biomolecules 2021,11, 823 4 of 58
muscles required for laughing (mm. risorii,mm. zygomatici majores). Consequently, forced
laughing leads to a small but significant, greater subjective feeling of contentment and
happiness over time (the facial muscle feedback loop, also known as the facial feedback
hypothesis) [27–29].
Contrary to the James–Lange theory, Cannon and, later, Bard hypothesized that the
subjective experience of emotion occurs simultaneously and independently of autonomous
bodily changes, which they assumed are always of a similar magnitude no matter what
emotion is involved (a view that was refuted by Ekman and others only in 1983) [
30
].
They also believed that bodily changes are slower than emotions, such that the addition
of hormones cannot change the emotional state (now demonstrated not to be true, as
an intravenous cholecystokinin injection can cause a panic attack, whereas cortisol, D-
cycloserine, and orexin have direct influence on anxiety levels, fear conditioning and
extinction) [
31
,
32
], as well as that complete surgical separation of the abdominal organs
does not change the emotional behavior of animals. Cannon believed that bodily reactions
(increased heart rate, glucose mobilization, centralization of the blood circulation, and
other effects) were the response of the organism to a sudden, threatening situation, leading
to maximal activation of the sympathetic nervous system and preparing the body for
the fight-or-flight response [
33
]. Not accepting James’ hypothesis that “every emotion is
tied to a distinct body state”, his interpretation was that all emotional events affecting
the sympathetic nervous system lead to general, non-discriminatory physical arousal.
Moreover, he believed that the CNS is capable of eliciting any emotion, even without
receiving information from the peripheral nervous system (PNS). On the other hand, Bard
tried to determine which areas of the brain were responsible for the generation of emotions
through experiments of ablation of the cerebral cortex. The proposed explanation is today
known as the Cannon–Bard or thalamic theory of emotions, as it emphasizes the importance
of the thalamus in emotional processing. According to Cannon and Bard’s interpretation,
emotional events have two separate effects on the brain: they stimulate the ANS to elicit
the physiological arousal that prepares the body to respond to a threat, and simultaneously,
they cause the cerebral cortex to perceive emotions; therefore, autonomic arousal and
cognitive interpretation of an emotional event are processed simultaneously but separately.
According to this view, the thalamus is the main structure in which these two pathways
separate, as it relays sensory information to the cerebral cortex, while simultaneously
sending descending signals to the spinal cord to stimulate visceral changes that accompany
an emotion.
In experiments observing the behavior of decorticated cats (“acute thalamic cats”),
Cannon and Bard observed that these cats had a tendency to attack all objects in their
immediate environment furiously and unreasonably, while increasing sympathetic activity
yielded tail wagging, violently alternating leg twitching, back bending, claw scratching,
and biting. Because such activity occurred in the absence of an externally evoked expe-
rience of anger, and could be provoked by the slightest stimulus, such as a light touch,
Cannon and Britton called such behavior “a sort of sham anger/sham rage” [
34
]. Based
on these experiments, it was hypothesized that the thalamus is responsible for expressing
emotions in response to a stimulus and that the cerebral cortex inhibits the expression of emo-
tions [
35
–
37
]. Further studies refuted this theory, including the importance of the thalamus
in experiencing emotions. Even Bard himself in 1928 concluded that the “false rage” in
cats does not occur if the cutting line by which decortication is performed goes from the
posterior part of the cerebral cortex to the the anterior (line B in Figure 2), and not the
posterior, hypothalamus (line A in Figure 2; in both cases a part of the thalamus is removed,
Figure 2), a finding that was also confirmed by his experiments with the direct stimulation
of the hypothalamus (electrode C in Figure 2) [35–38].

Biomolecules 2021,11, 823 5 of 58
Figure 2. Schematic representation of Bard’s experiments on cats.
Behavior described as “false
anger/false rage” occurs if the cutting line when decorticating a cat goes from the posterior part of
the cerebral cortex through the anterior part of the hypothalamus (line marked with (
B
)), but not if it
goes through its posterior part (line marked with (
A
)). In both cases, a small part of the caudoventral
part of the thalamus remains preserved (marked in blue). Electrical stimulation of the hypothalamus
with an electrode (without cutting) leads to anger and fear (
C
). The schematic follows Bard’s textual
description (Bard, 1928) [35]. CCx—cerebral cortex; Hyp—hypothalamus. See text for details.
At the time, it was already well known that the hypothalamus, not the thalamus, is
directly involved in sympathetic activation. For example, it was known that damage to the
hypothalamospinal tract, a pathway whose fibers project from the hypothalamus to the
sympathetic ciliospinal center in the spinal cord, leads to ipsilateral Horner’s syndrome.
Moreover, in subsequent and more elaborate experiments similar to Bard’s, Hess showed
that electrical stimulation of various parts of the hypothalamus in non-anesthetized cats
could slow down the heart rate and make the cat calm, tame, and sleepy, speed up the pulse
and cause fear and anger, cause hunger or thirst, and induce other autonomic reactions
and extrapyramidal motor signs and instinctive behaviors, as well as “affective-defensive
reaction”—an excited cat would attack the first available object in its environment [
39
].
Thus, the basic premise of the thalamic theory of emotions that physical reactions do not
lead to emotions was rejected. As already mentioned, even when individuals are only
asked to make a certain facial expression or speak the word for an emotion, they usually
experience a fraction of the emotion associated with it. Finally, Panksepp showed in the
1980s that animals that exhibit anger-related behaviors do indeed feel anger, and therefore
one cannot speak of “false anger” or “false rage” [40,41].
Schachter and Singer considered that activation of ANS acts as a signal that stimulates
cognitive processes that give final meaning to an emotional state. As physiological arousal
is nonspecific and relatively similar for all emotions, a subject cannot determine his/her
current state and therefore activates the process of “cognitive labeling”, which recalls pre-
vious experiences related to arousing stimuli and, depending on the available information,
gives different meanings to emotional states. It was shown much later that in this type
of learning, the instinct plays a great role because, for example, rhesus monkeys very
quickly learn to fear snakes and snake-like objects just by looking at the reactions of other
monkeys, while fear conditioning is much slower for other objects (such as a flower) [
42
].
As Schachter and Singer were interested in situations where there is no immediate explana-
tion for an increased level of general arousal or excitement, they designed experimental
conditions in which subjects need to evaluate their own arousal in the absence of objective
standards or previous experience, assuming that people would engage in social compar-
ison as a source of information in order to minimize feelings of insecurity in situations
without previous personal experience. The experiment included 185 men who were told
that the experimenters intended to evaluate the effects of a small and harmless injection of

Biomolecules 2021,11, 823 6 of 58
a vitamin on visual abilities [
43
]. After determining pulse frequency, the subjects received
a subcutaneous injection of half a cubic centimeter of an adrenaline solution (1:1000) or a
placebo (same volume of saline) instead of “the vitamin”. Some participants were correctly
informed that they actually received adrenaline to induce sympathetic activation, and
those subjects felt palpitations, tremor, and redness of the face for about 15–20 min. as
a direct consequence of receiving the injection; others were misinformed that their feet
will tingle after the injection, they will feel itching, or they may have a mild headache,
while some were not informed at all about what to expect. After receiving the injection, all
participants filled out a questionnaire in a separate room where the assistant was present,
and his role was not known to the participants. The assistant was instructed to pretend to
be a participant given the same injection of “the vitamin” and to behave either cheerfully
or angrily. As expected, the results showed that participants who were accurately informed
about the effects of the injection did not experience any particular emotional experience
since they knew why ANS arousal had occurred. However, some of the participants who
did not know what to expect from the injection (of adrenaline) experienced feelings of
either euphoria or anger that wereinduced by the assistant’s behavior. These results are
partly in line with the James–Lange theory of emotions, as it states that bodily reactions are
perceived as emotions, but to some extent are also compatible with that part of the Cannon–
Bard theory, which assumes that the basis of different emotions lies in non-discriminatory
general physiological arousal. Compared to well-informed participants, those who did not
have an adequate explanation for their excitement tended to attribute it to environmental
(social) factors. From the answers on the subjective experience of emotions obtained by
the questionnaire and the analysis of emotional behavior of the respondents, Schacter and
Singer concluded that uninformed participants who experienced physical arousal but did
not know that it was a consequence of adrenaline injection attributed their physical changes
depending on the behavior of the assistant. Participants who received the placebo generally
did not have any particular emotional experience, regardless of the assistant’s behavior,
as they did not experience activation of ANS. It was concluded that the emotional state
resulted from the interaction of bodily arousal and cognitive interpretation of that arousal.
This paradigm was called the two-factor theory of emotions [
43
]. These findings revealed
that experiencing emotions is strongly influenced by cognitive processes of interpretation
and evaluation, a fact now embedded in the foundations of all contemporary theories of
emotion.
Arnold and Lazarus further developed existing theories of emotion. According to
Arnold, emotions are the result of an unconscious evaluation of a situation, whereas
feelings are a conscious reflection of that unconscious assessment, a hypothesis supported
by the fact that even a subliminal stimulus can produce an emotion [
44
]. In contrast to
all other theories, only Arnold did not hold ANS necessary for generation of an emotion.
Arnold contributed to theories of emotion also by describing the three main dimensions of
assessing events in the environment: whether events are potentially beneficial or potentially
harmful/threatening; the presence vs. absence of an incentive/arousing stimulus; and
the degree of difficulty to avoid or approach that stimulus. It is difficult to say how many
and which dimensions of assessment are the most important, but later research by Smith
and Ellsworth indicates eight main dimensions of cognitive appraisal in emotion: (1)
attention—the degree to which someone focuses on a stimulus/situation/event and how
much she/he thinks about it, (2) assessment of the probability of an outcome (to what
extent an outcome is expected, or to what degree one is convinced that something will
happen), (3) control/skill of managing the situation—the degree to which one can control
the outcomes, or the extent to which we think we understand the current situation, predict
its future development, and face its consequences, (4) comfort—the degree of positive
or negative valence of a stimulus/situation/event, (5) perceived obstacles—the extent to
which the goal one strives to achieve is hindered or blocked in relation to given efforts, 6)
responsibility—the degree to which a person or some other factor is responsible for an event,
(7) justification—the degree to which an event is fair and deserved, or unfair/undeserved,

Biomolecules 2021,11, 823 7 of 58
which includes compliance with personal, but also with social standards, and 8) presumed
effort—the degree to which someone must spend their energy and time to respond to a
stimulus/situation/ event [45,46].
According to Arnold, feelings arising from an unconscious assessment represent
tendencies for action. Feelings are different, as they trigger tendencies in different situations,
but they are also individually variable because the same stimulus can provoke different
emotional reactions in different people. Based on some of these considerations, Lazarus
developed the idea that emotions arise as a result of series of evaluations [
47
]. According
to Lazarus, the primary assessment (appraisal) is aimed at determining the positive or
negative significance of a particular event for an individual’s well-being (i.e., comfort
vs. discomfort). After the primary, there is a repeated assessment (reappraisal) aimed
at determining a person’s ability to cope with the consequences of an event, taking into
account her/his skills, strength, experience, and other characteristics. The underlying
idea of all emotion theories based on cognitive assessment is the existence of a series
of continuous evaluations of stimuli within a situation, with each of these evaluations
progressively leading to increasingly complex decisions. At the core of these theories is the
assumption that the one’s own interpretation/assessment/opinion/memory of a situation,
object, or event can contribute to the experience of different emotional states. Conforming
to this understanding, assessment occurs before emotion, i.e., emotions are the result of
cognitive processes. This theory is, therefore, called the cognitive–mediational theory of
emotion [
47
], as repeated appraisal often changes or corrects first impressions and thus,
also the resulting emotions.
It appears that emotions are not opposed to reason, but that they are even more
fundamental, as they have the ability to guide and manage behavior, even in novel contexts
and in the absence of logical thinking. A comparative overview of all four classical theories
of emotions is illustrated in Figure 3.
Figure 3. Simplified schematic representation of classical theories of emotion.
Photographs taken from [
9
,
48
]. ANS—
autonomic nervous system. See text for details.

Biomolecules 2021,11, 823 8 of 58
2.1. Contemporary Theories of Emotions
Recently, there have been many attempts to provide a single, all-inclusive, universal
theory of emotions. The most acknowledged ones are the somatic marker hypothesis,
the theory of emotions as (psychological) constructions, and the higher-order theory of
emotion.
2.1.1. Somatic Marker Hypothesis—Interoceptive Theory of Emotions
This theory was introduced by Damasio and coworkers [
20
,
24
,
49
]. The term somatic
implies musculoskeletal and visceral body parts, whereas somatic markers represent
emotional reactions containing a strong physical or bodily component that supports the
decision-making process [
20
]. Emotional reactions are based on a person’s experiences
from previous similar situations. From earliest experiences in infancy, somatic markers
continuously increase the efficiency and accuracy of decision-making, as they allow a quick
overview of possible alternatives, which are then subjected to more detailed cognitive
processing, leading to the final decision. As such, bodily states caused by the experience
of pleasant emotions (rewards) or unpleasant ones (punishments) signal the potential
occurrence of a particular outcome and guide behavior in such a way that a person chooses
alternatives that bring pleasure or benefit [
50
]. The theory is based on observations of
patients with injuries to the frontal lobe, especially with the involvement of its ventromedial
part of the prefrontal cortex (vmPFC), including the well-known case of Phineas Gage.
These patients show severe difficulties in making decisions and goal-oriented behaviors,
either personal or social, despite having other intellectual abilities (such as attention,
working memory, general intelligence, and reasoning) largely preserved. They also find
it difficult to plan everyday actions, future short- and long-term goals, family and social
activities [
20
]. Importantly, they also struggle with expressing emotions and experiencing
feelings in situations where this is expected from them. Thus, besides more or less normal
intellectual functioning and impaired decision-making, they have significant problems in
the domain of emotional behaviors. Because they can no longer include emotions in the
interpretation of complex situations, they cannot follow social norms and make decisions
for their own benefit. This fact can be demonstrated, for example, by their failure on the
Iowa gambling task, which serves to simulate real-life decision-making [
49
]. According
to Damasio, such patients have a disorder of somatic markers that would otherwise help
them to anticipate the consequences of their behavior and guide them to choose the most
favorable decisions. Somatic markers can arise on the basis of primary or secondary
emotions, where emotions have the role of inducing them, and as such, somatic markers
can be understood as guides in decision-making and social behavior. In this sense, changes
in somatic and visceral states would predict what individual external stimuli might cause
to our body and anticipate what effects of such stimuli increase or decrease the likelihood
of survival in different contexts. In uncertain situations, somatic markers will limit the
number of possible choices of behavior, thus facilitating decision-making. When primary
emotions occur in an environment, they automatically elicit an innate response consisting
of two processes (stages): in the first stage, a specific feeling is created that has a pleasant
or unpleasant valence, whereas in the second stage, somatic markers will help choose
the best response among possible options (automatic emotional response). According to
the theory of somatic markers, the amygdala is the key place in the CNS that triggers
somatic states from primary emotions, as it matures before the cerebral cortex of the frontal
lobe. These somatic markers in the amygdala form an initial repertoire of bodily responses
in directing the child’s choice of reactions to a situation, while somewhat later in life
the vmPFC generates secondary emotions from primary ones, as it receives information
about them via the uncinate fasciculus. Magnetic resonance tractographic analysis of the
microstructural maturation of the uncinate fasciculus, as judged from fractional anisotropy
index, revealed that the development of this bundle of axons is longer than any other
fiber system in the entire CNS, lasting at least up to 30 years of life, which correlates
well with its protracted development throughout adolescence [
51
,
52
]. When it comes to

Biomolecules 2021,11, 823 9 of 58
secondary emotions, somatic markers are generated by OFC, especially vmPFC, which
links individual situations to somatic states, meaning that these reactions are based on both
the feelings and previous experiences of individual emotions.
The somatic marker theory provides a neuroanatomical framework for understand-
ing the impact of emotions on decision-making and behavior in general [
24
]. Altogether,
vmPFC is the key place where all somatic markers are generated from secondary emotions.
The vmPFC receives projections from all sensory modalities, both directly and indirectly.
This is also the only part of the frontal lobe associated with ANS that also has extensive
reciprocal connections with the hippocampus and amygdala. The vmPFC mediates at least
three broad domains of behavior: a reward-based decision-making process, which arises
through interactions with the ventral striatum and amygdala; regulation of emotions with
negative valence, which occurs through interactions with the amygdala, bed nucleus of
stria terminalis (BNST), periaqueductal gray (PAG), hippocampus, and the dorsal part
of the anterior cingulate cortex (ACC); and multiple aspects of social cognition, such as
recognition of emotional facial expressions, ability to attribute mental states (beliefs, inten-
tions, desires, emotions, knowledge) to oneself and others (also called the theory of mind),
processing relevant self-related information through interactions with posterior cingulate
cortex (PCC), precuneus, dorsomedial PFC (dmPFC) and amygdala [
53
]. Therefore, injury
or pathological changes to the vmPFC lead to more or less serious difficulties in social
behavior and decision-making, which also impairs everyday functioning. The influence
of somatic markers can occur on multiple levels, both conscious and unconscious, and
involves different parts of the brain: vmPFC, amygdala, somatosensory cortex, insula,
basal ganglia, ACC, brainstem, as well as humoral signals and afferent pathways signaling
bodily states. Primary emotions are innate and crucial at a time when the ventromedial
OFC is immature. When primary emotions occur in a certain context, they automatically
provoke an innate response consisting of two stages: first, a specific feeling that has either
a positive (pleasant) or negative (unpleasant) valence; and second, as a separate process,
somatic markers will help select the best possible response, that is, the behavior among all
the possible options available at that time. These automatic responses are first controlled
by the amygdala, which matures before the cerebral cortex of the frontal lobe. When
it comes to secondary emotions, somatic markers are generated by the vmPFC, which
categorizes and associates individual situations with somatic states, meaning that these
reactions are based on both feelings and previous experiences of individual emotions.
Thus, somatic markers can arise on the basis of both primary and secondary emotions,
and they can be understood as inducers of certain responses that help us and guide us in
decision-making and social behavior. In this sense, changes in somatic and visceral states
represent anticipation of what certain external stimuli could cause to our body (harm it or
be useful), so proper anticipation of the effect of such stimuli will increase the likelihood
of survival in different contexts. In uncertain situations, somatic markers will limit the
number of possible choices and thus facilitate and speed up making the right decisions.
In conclusion, the somatic marker theory proposes that the amygdala mediates somatic
markers as a response to generated primary emotions, whereas vmPFC is a key hub where
features of a given external stimulus are converted into the visceral states associated with
the biological importance of that stimulus [54].
The somatic marker hypothesis shares certain features with the James–Lange theory
of emotions, such that feelings and conscious experience generally arise from the rep-
resentation of bodily states embedded and distributed across multiple areas and levels
of the nervous system, including cortical and subcortical structures [
55
]. The somatic
marker hypothesis further assumes that the representation of the body is necessary not
only for emotions [
56
], but also for a broader core self-image, crucial for feelings to arise [
4
],
which is in agreement with the notion that conscious experience cannot occur without
feelings and interoception [
57
,
58
]. While presenting an elegant theory of how emotion
influences decision-making, the somatic marker hypothesis requires additional empirical

Biomolecules 2021,11, 823 10 of 58
support to remain tenable in regard to psychopathic traits, moral decision-making, and
other issues [59].
2.1.2. Theory of Constructed Emotion
The psychologically constructed emotion theory was proposed by Feldman
Barrett [
60
–
62
]. The initial assumption is that the brain creates internal models based
on experience, and uses them to predict future events, chooses the best actions to deal with
upcoming situations and anticipate their consequences. Information that the brain has
not predicted (prediction error) is coded and consolidated whenever it results in physio-
logical changes. Once the prediction error is minimized, prediction becomes perception
or experience. Thus, prediction explains the causes of sensory events and directs further
action.
Accordingly, the brain constantly constructs concepts and creates categories with
the goal of identifying input sensory information, drawing conclusions about causes,
and implementing action plans, whether or not a person is consciously focused on them.
When an internal model creates an emotional concept, its eventual categorization results
in an emotional episode (“instance of emotion”). Feldman Barrett assumes that certain
categories of emotions do not have a specific substrate that can be unambiguously localized
in precisely defined areas of the brain, as judged from strongly diverged activations among
studies that investigated the localization of anger, happiness, sadness, and disgust [
62
,
63
].
Even someone with isolated damage to the amygdala (such as patient S.M., see below)
can correctly recognize fearful faces when his/her attention is directed toward the eyes of
the stimulus face, which is due to the fact that the eyes are the most important feature for
identifying this emotion [
64
]. In favor of this view, it should be added that inhalation of
35% CO
2
evoked fear and panic attacks in three patients with bilateral amygdala damage,
indicating that the amygdala is not required for fear and panic, making an important
distinction between fear triggered by external threats from the environment versus fear
triggered internally by CO2[65].
Emotion categories are as real as any other construct that requires awareness to exist.
According to the theory of constructed emotion, emotions such as fear, anger, or sadness
are socially and experientially constructed categories and therefore, vary with culture and
time [
4
]. In neuroscientific jargon, construct refers to a group of distributed activity patterns
of specific neuronal populations. An individual emotion is constructed in the same way as
all the other perceptions, through information flow within neural circuits. Consequently,
the brain neither specializes in processing emotions nor are emotions innate. Instead, it is
the innate ability of the brain to create assumptions or predictions to construct an emotional
episode depending on a given situation, as is so for many other general processes related
to a particular domain (e.g., memory, perception, or attention) [
4
]. In other words, the
relationship between the brain and emotions should be observed through a prism of the
understanding that a given brain structure or area can have multiple functions, depending
on the currently active functional network and co-activation patterns in all active areas at a
given time [66].
The internal model that the brain creates to maintain allostasis is at the heart of the
constructed emotion theory. Allostasis, unlike homeostasis, refers to the effective allocation
of resources for changing the physiological and behavioral systems within an organism to
achieve homeostasis, so that the organism can grow, survive, and reproduce [
67
]. Allostasis
is not a body state, but a process through which the brain regulates bodily functions
according to cost/benefit criterion, requiring the ability to anticipate future bodily needs
and meet them before they arise [
67
]. The brain monitors many variables and integrates
their values with previous knowledge and experience to anticipate needs and set priorities.
As such, the brain is not a passive organ responding only to input signals and acting
on the basis of the negative feedback principle (as is the case with most homeostatic
mechanisms), yet it actively constructs perceptions based on internal models, predicting

Biomolecules 2021,11, 823 11 of 58
future input signals and calculating prediction error (i.e., differences between predictions
and input signals).
According to Sterling’s allostasis model, the design of efficient predictive regulation
depends on the brain’s ability for sensing the current state, integrating this information
with prior knowledge to optimize regulatory decisions, and on relaying current sensory
information to higher-order brain levels so that today’s learning becomes tomorrow’s
“prior knowledge” [
67
]. In his “carrot and stick” model of allostatic anticipatory regulation,
the “carrot” component is the midbrain reward system, whereas the “stick” component
is the amygdala, as it integrates a large number of lower level physiological signals from
the entire body, such as steroid hormones and peptides that regulate blood pressure,
hypothalamic and brain stem signals containing visceral information (e.g., from the nucleus
of the solitary tract), and signals from serotonergic neurons of the raphe nuclei of the PAG
that modulate arousal levels and mood [
67
]. The amygdala is heavily and reciprocally
connected with the hippocampus and vmPFC and these pathways provide a constant flow
of information on needs and past dangers to design a plan of action. Figuratively speaking,
the amygdala reports its “concerns” to the PFC, which decides what to do and performs
planning for the future [
67
]. As posited, especially by Friston, the brain is, therefore, an
organ intended for predictive regulation, the active prediction and interpretation of input
sensory information [
68
]. The theory of constructed emotion is based on the concept of
predictive coding, which assumes that the brain is an interface that creates internal models
at different functional levels and that any function of the brain (perception, cognition,
emotion) arises from, comparing the current model and input sensory signals [
69
]. In
regard to interoceptive feelings, expectations and predictions of one’s own bodily states
make a significant part of conscious emotional experience [
4
,
69
]. However, according to
the constructed emotion theory, the key difference from Damasio’s assumptions is that the
brain creates emotions from predictions that subsequently trigger physical events in the
body (and not the opposite, as is assumed by the somatic marker theory).
Feldman Barrett explains that the primary, innate emotions in the first six months
of life arise from physiological processes and interoception. According to the theory of
constructed emotion, these states, however, should not be marked as emotions, as they are
simply information about the state of bodily functions that contain insufficient detail for a
child to act upon in the first six months of life. The child will be able to act purposefully (of
its own volition) only with the maturation and activation of the corticospinal tract, a process
which begins at about 6 months of age. More precisely, according to this theory, emotions
are just brain predictions that connect bodily states to events in the environment so that
the person knows how to (re)act. Only sometimes, as a by-product of these predictions,
emotions arise.
2.1.3. Higher-Order Theory of Consciousness and Fear Conditioning
The basic idea underlying higher-order theory of consciousness developed by LeDoux
is the existence of a general cortical system (higher order) responsible for generating
conscious experience from information received from first-order networks [
4
,
70
–
72
]. For
example, in the case of visual information, a person becomes aware that she/he is seeing
something; if it is information sent by subcortical, lower-order structures, such as the
amygdala, the person becomes aware of an emotion, generally called a feeling. LeDoux
hypothesizes that objectively measurable behaviors and physiological responses are driven
by emotional stimuli controlled by subcortical first-order circuits, including the amygdala
(unconscious or implicit level), while subjective emotional experience results from cortical
higher-order circuit activities, especially involving the vmPFC, rostromedial (rmPFC) and
dmPFC and OFC, but also the dorsolateral PFC (dlPFC) involved in working memory and
related higher cognitive functions [73,74].
LeDoux defines fear as a feeling that enters a person’s consciousness and also bases
his higher-order theory of consciousness on this subjective cortical experience [
75
] in the
presence of danger, whether it is real or potential [
72
]. The human brain is capable of

Biomolecules 2021,11, 823 12 of 58
anticipating threatening events, even those that are unlikely to ever happen. The individual
recognizes fear in oneself as an internal experience, and in others as external associated
manifestations, such as freezing, escaping, trembling, frightened facial expressions, etc. In
evolutionary terms, fear is associated with the activation of neural circuits responsible for
survival [10].
Fear conditioning is an example of associative learning, a process by which the brain
creates memories about the relationship between two events (Figure 4). In a situation of
fear-conditioning, an experimental animal receives a neutral conditioned stimulus, usually
a sound, followed by an aversive unconditioned stimulus, such as an electric shock to the
paw. After one or more pairings, the conditioned stimulus elicits a conditioned emotional
response that occurs naturally in the presence of a dangerous, threatening stimulus, such
as a predator. The conditioned emotional response includes changes in behavior and ANS
as well as in hormonal activity induced by the conditioned stimulus. Fear conditioning is
also used to examine the brain mechanisms of implicit learning and memory in animals
and humans.
Studies in humans have confirmed the key role of the amygdala in fear condition-
ing as well as in various forms of psychopathological behavior [
13
]. Thus, damage of
the amygdala in humans disables fear conditioning, while reduced volume of the right
amygdala, along with reduced volume of BNST and other associated structures, have been
documented in some sexual offenders [
76
]. However, the amygdala does not function
independently of other structures, but is part of larger neural circuits involving sensory
systems, the motor system, the hippocampus (that provides contextual information) and
the PFC (responsible for regulation of amygdala reactivity, so that hypofunction of the PFC
will lead to amygdala hyperreactivity). The amygdala contributes to these fear circuits
in two ways: directly, by detecting the threat on an unconscious level and regulating
behavioral and physiological responses, and indirectly, through cognitive systems, in the
emergence of a conscious feeling of fear. Moreover, there are two main afferent pathways
that lead to the amygdala: a faster “low-road pathway” that reaches the amygdala di-
rectly from the sensory nuclei of the thalamus without prior cortical processing (without
reaching the level of consciousness) and activates the amygdala in a 12 ms time-frame,
and a slower “high-road pathway” that activates the amygdala through the thalamus and
cerebral cortex [
73
,
74
,
77
]. The low-road/high-road dichotomy is supported by studies of
nonconscious processes in healthy subjects using magnetoencephalography (where early
recorded, low-road amygdala activations upon emotional stimuli occurred after 40–140 ms,
whereas later, high-road amygdala responses were recorded after 280–410 ms, subsequent
to frontoparietal cortex activity, this time also being modulated by the attentional load) [
78
],
blindsight patients [
79
], and in patients with electrodes implanted in the amygdala during
preparation for treatment of epileptic seizures [80].
LeDoux (2002) illustrated the independence of emotional processing from the con-
scious control of emotional behavior by stating that the feeling of fear appears only after an
individual has unconsciously reacted to the perceived threat and changes in ANS have oc-
curred. He used the term “fear system” to describe the whole process, including the role of
the amygdala in controlling the fear response, but also in providing elements that indirectly
contribute to the creation of a conscious feeling of fear [
73
]. More recently, LeDoux stated
that he was wrong when using the term “fear system” to describe the role of the amygdala
in both detecting and responding to danger because it is now commonly accepted that
the term “fear” is used only to describe the conscious feeling that occurs when a person
is frightened. Therefore, LeDoux proposed a new reconceptualization of the phenomena
involved in the emergence and study of emotions [
71
,
72
]. Despite the proposed changes
in the conceptualization and understanding of the concept of emotion, the results of the
studies that LeDoux and his coworkers conducted are important links for understanding
defensive behavior in animals and humans and provide a basis for understanding the oc-
currence of pathological fears associated with increased reactivity of the amygdala and the
development of anxiety disorders [
81
]. The proposed reconceptualization revolves around

Biomolecules 2021,11, 823 13 of 58
the idea that the amygdala is of paramount importance when it triggers physiological
responses to threats nonconsciously [
82
,
83
] but of only relative (minor) importance when it
comes to subjective feelings. Typically, direct electrical stimulation of the amygdala reliably
elicits physiological responses, but subjects do not report feelings, even when asked for
a verbal report [
84
,
85
]. Moreover, patients with lesions of the amygdala can consciously
report emotional experiences, including fear [65,86].
Figure 4. Simplified schematic representation of neural circuits underlying fear conditioning.
Pathways that process
a conditioned stimulus (CS, auditory pathway, green) and an unconditioned stimulus (US, spinothalamic anterolateral
pain pathway, red) via the ventroposterolateral (VPL) and ventroposteromedial (VPM) nuclei and the medial geniculate
body (MGN) of the thalamus monosynaptically, and via the cerebral cortex of Brodmann’s areas 3, 1, and 2 (primary
somatosensory cortex); 41 and 42 (primary auditory cortex) polysynaptically converge on the lateral nucleus of the
amygdala (LA, the LA receives the majority of afferent fibers). CS-US convergence in LA initiates long-term potentiation
(LTP), leading to the creation of a learned association between the two stimuli. LA activity is then transferred to the central
nucleus (CE, the central nucleus of the amygdala), which sends most of the efferent projections to a number of different
cortical and subcortical areas through which the amygdala directly regulates autonomic responses and context-dependent
behavior: ANS, reflexes, and hormone secretion. Sympathetic activation includes mydriasis, tachycardia, hypertension,
peripheral vasoconstriction, cessation of peristalsis, sphincter contraction, and other effects. All these effects help organisms
to cope with threat. Synaptic plasticity also changes in neurons in other nuclei of the amygdala (intentionally omitted
here). ACTH—adrenocorticotropic hormone; BA—Brodmann’s area; BNST—bed nucleus of stria terminalis; CPRN—
caudal pontine reticular nucleus; DTN—dorsal tegmental nucleus; EEG—electroencephalogram; LC—locus coeruleus;
LH—lateral hypothalamus; MGN—medial geniculate nucleus; NBM—nucleus basalis Meynerti; N. V—trigeminal nerve;
N. VII—facial nerve; PAG—periaqueductal gray; PBN—parabrachial nuclei; PVN—paraventricular nucleus; VPL and
VPM—ventroposterolateral and ventroposteromedial thalamic nuclei; VTA—ventral tegmental area. The schematic is made
according to LeDoux [73,74].

Biomolecules 2021,11, 823 14 of 58
According to the higher-order theory of emotion, a subjective experience of emotions
should be generally different in subjects with damage to the first-order circuits associated
with emotions (patients with amygdala damage) and patients with damage to higher-order
circuits associated with emotions, such as patients with alexithymia, for example, but this
remains to be determined.
3. The Structure of the Amygdala
The amygdala is formed by several nuclei and cortical fields located bilaterally in the
anteromedial part of temporal lobes of the cerebrum (Figure 5). There are several concepts
about what the term amygdala should encompass as well as whether it is a single structure
or a set of extensions from different parts of the brain [87].
In primates, the amygdala is usually divided into 13 nuclei and cortical fields [
88
–
91
].
Most agree that the amygdala can be divided into several groups of nuclei, as some
nuclei show certain anatomical and functional similarities. The deep or basolateral group
contains the lateral, basal, accessory basal and the paralaminar nucleus. The superficial
or corticomedial group includes the cortical nucleus in contact with the relatively thin
periamygdaloid paleocortex, the central and medial nuclei as two functionally similar
nuclei, and the nucleus of the lateral olfactory tract, which some authors do not include
as a part of the amygdala. The BNST might be added to this group although most do not
consider it a part of the amygdala. It should be noted that the central nucleus (CE) has a
more specific functional role and connections, so it can be observed separately. Additional
nuclei include the anterior amygdaloid area, the amygdalohippocampal area, and groups
of inserted neuronal clusters (Figure 6).
3.1. The Lateral Nucleus (LA)
The lateral nucleus (LA) extends across the entire length of the amygdala. It is
the largest nucleus of the human amygdala [
92
] with a high density of nerve cells [
93
].
The LA is extremely well connected intrinsically (its individual parts are interconnected)
as well as with other nuclei of the amygdala, mostly with the basal nucleus [
94
]. It
receives poor reciprocal projections from other nuclei, mostly from the basal, accessory
basal or central nuclei [
95
]. The lateral nucleus is also the main afferent structure of the
amygdala, and as such, receives topographic projections from various neocortical fields.
These signals are then transmitted both to other amygdala nuclei and other parts of the
lateral nucleus [
77
,
96
]. Glutamatergic projections are sent to central and medial as well
as basomedial and basolateral nuclei [
97
]. Consequently, information flow through the
amygdala proceeds from lateral to medial parts [
98
]. Weak projections from the LA and CE
also end in the amygdalohippocampal area on small to medium-sized neurons [95].

Biomolecules 2021,11, 823 15 of 58
Figure 5. Simplified representation of the structure and location of the amygdala.
The upper part of the schematic shows
the human brain when viewed from the lateral side, where the brainstem, cerebellum, and four lobes of the cerebrum can be
seen. The middle part of the schematic shows the structures present on the coronal plane through the temporal lobe of
the cerebrum on which the position of the amygdala can be observed. The lower part of the schematic shows an enlarged
amygdala with its individual nuclei. a.c.—anterior commissure. See text for details.

Biomolecules 2021,11, 823 16 of 58
Figure 6. Simplified schematic representation of the connections of individual amygdala nuclei with numerous cortical
and subcortical structures, and their role in processing functionally different types of information.
Amygdala nuclei are
marked in colors as shown in Figure 5. BLA—basolateral (basal) nucleus; BM—basomedial (accessory basal) nucleus; CE—
central nucleus; Co—cortical nucleus; EC—entorhinal cortex; IN—intercalated neurons; ME—medial nucleus; LA—lateral
nucleus; PL—paralaminar nucleus. See text for details.
3.2. The Basolateral Nucleus (BLA)
The basolateral nucleus (BLA, more commonly called just the basal nucleus), contains
the largest neurons of the amygdala and is also called the “cortex within the amygdala” [
99
],
as those pyramidal neurons share many morphological characteristics and immunohis-
tochemical profiles with cortical pyramidal neurons [
100
]. The majority of afferent fibers

Biomolecules 2021,11, 823 17 of 58
in BLA come from the LA [
101
,
102
]. The BLA sends the majority of efferent projections
toward the OFC, mPFC, and ventral striatum, with the nucleus accumbens (NAc) as the
largest targeted group of neurons [
103
]. The BLA receives the strongest projections from
the LA, and further sends processed information to the CE. It is important to note that the
BLA sends projections to a number of cortical areas that project to the LA [
104
], forming
sensory information flow loops between the amygdala and cerebral cortex [
105
]. The
intrinsic activity of different populations of GABAergic interneurons determines the output
activity of efferent pathways from the amygdala [
106
]. In the BLA, fear and reward are
encoded by phasic activation of distinct populations of neurons, while anxiety results in
persistent activity changes [
107
]. Likewise, different groups of neurons are involved in
consolidating the memory of objects, situations, and events that elicited the fear response
(the feeling of fear), thus mediating fear conditioning [
108
]. The direct manipulation of
the amygdala neural circuits in rodents by usage of optogenetic and pharmacogenetic
activation or inhibition, in conjunction with behavioral and electrophysiological analysis,
revealed causal relations between different cell types, especially in the BLA, and their
projections, which are sufficient to alter behavior in various domains (freezing, anxiety,
feeding, social behavior) [
103
]. The activity and synaptic connections within populations
of GABAergic neurons change depending on life experience, which helps in understanding
and explaining how different, earlier events shape current behavior.
3.3. The Basomedial Nucleus (BM)
The basomedial nucleus (BM) is also known as the accessory basal nucleus. Topo-
graphically, it represents a bridge between the BLA and CE [
109
]. It mostly projects into the
CE, especially its medial part [110]. Neurons in the BM secrete a variety of peptides, such
as corticotropin-releasing hormone/factor (CRH/CRF), enkephalins, and neurotensin, and
express dopaminergic and serotonin receptors [
111
]. Interestingly, these neurons express
estrogen receptors as well. Therefore, this area is thought to play an essential role in
shaping motivational behavior under the influence of sex hormones.
3.4. The Amygdalohippocampal Area
The amygdalohippocampal area represents the most caudal part of the amygdala. Most
internal connections come from the LA, BLA, BM, medial, and CE nuclei [
95
,
110
,
112
]. Pro-
jections from this area seem to terminate in the BLA, medial nuclei, and the periamygdaloid
cerebral cortex [
113
]. The anterior amygdaloid area is poorly developed in primates and also
poorly connected to the other nuclei.
3.5. The Paralaminar Nucleus (PL)
The paralaminar nucleus (PL) is a narrow band of densely packed neurons along
the ventral and rostral boundaries of the amygdala, mostly along the BLA (basal nu-
cleus). It is characterized by a high density of neurons resembling glia and non-pyramidal
neurons [
100
,
114
]. A relatively high concentration of CRH receptors and benzodiazepine
receptors has been demonstrated in this nucleus, as well as abundant innervation with
serotonin fibers [
115
,
116
]. Paralaminar nucleus receives afferent fibers mainly from the
LA [112], whereas it projects into the BLA (basal) nucleus [94,113].
3.6. The Intercalated Neurons (IN)
The intercalated neurons (IN) correspond to a small group of nerve cells located in
internuclear fibrillar areas, mostly in the rostral parts between the BLA (basal) and the
BM nuclei. These are mainly interneurons, with GABA as their principal neurotransmitter,
and they also abundantly express dopaminergic D
1
and opioid
µ
receptors [
117
,
118
].
Despite the relatively small number of cells and their dispersion, their role is extremely
important [
119
,
120
]. The neural circuits in which they participate receive direct projections
from the OFC, LA, and BLA (basal) nuclei, and project into the CE [
121
], where they exert

Biomolecules 2021,11, 823 18 of 58
an inhibitory effect. Their critical role is reflected in their activity, which alleviates the
physiological response to fear, acting through inhibition of the CE [122].
3.7. The Central Nucleus (CE)
The central nucleus (CE) is the main source of efferent fibers of the amygdala; it
shows many similarities with the striatum in the basal ganglia [
123
]. Over 90% of neurons
in the CE are GABAergic [
124
–
127
]. The medial part of the CE receives glutamatergic
projections from the BM, whereas the lateral part receives GABAergic input from the
medial nucleus [
128
]. GABAergic neurons in the lateral part of the CE express a variety
of neuropeptides that act as neuromodulators [
129
]. These peptides are thought to be
produced only in conditions of pain [
129
,
130
] or stress [
124
,
131
], but not in normal circum-
stances. They can be divided into those that amplify (i.e., CRH/CRF, dynorphin, orexin,
vasopressin) and those that reduce (i.e., oxytocin (OXT), neuropeptide Y, nociceptin, and
other endogenous opioids) anxiety and pain [
124
]. In addition to modulating the affective
features of pain, pain can be further reduced by enhancing the descending activity of
the endogenous analgesic system (mostly raphespinal projections from the caudal group
of serotonin raphe nuclei B1 (nucleus raphe pallidus), B2 (nucleus raphe obscurus) and
B3 (nucleus raphe magnus)) to inhibitory interneurons of the posterior horn neurons of
the spinal cord that control the entrance of nociceptive signals (Melzack and Wall, gate
control theory) [
132
]. Additionally, oxytocin is a great pro-social hormone, as it increases
cooperation and connection with other people and domesticated animals, especially dogs
and horses [
133
,
134
]. The CE, after the hypothalamus, contains the highest density of
CRH/CRF in its GABAergic neurons [
135
]. In short, considering the overall abundance
of receptors for modulating neurotransmitters, hormones and various peptides, it can be
concluded that many neurotransmitters and hormonal systems affect the activity of the
amygdala and its role in emotional processing [
136
]. Activation of the lateral part of the
CE, which projects to PAG in mice, produces characteristic freezing behavior in situations
of real or perceived danger and also mediates a significant part of other bodily reactions
in the fear response [
137
]. GABAergic projections from the lateral part of the CE also
exert strong influence over the hypothalamus and brain stem [
110
,
129
]. Even though the
corticomedial area is phylogenetically older [
138
], in sharp contrast to rodents, the BLA
in primates is significantly larger than the corticomedial area. This is presumably due
to dense reciprocal connections between the BLA and the cerebral cortex [
103
]. The LA
influences the CE directly, through excitation by glutamatergic projections, and indirectly,
through GABAergic neurons [
129
]. Interestingly, the LA is not directly connected to the
corticomedial area, but only to the central part of the CE [
95
,
103
]. Thus, input signals are
always pre-processed before exiting the amygdala. Therefore, the CE can be thought of as
having a unique role in converting sensory information into a physiological response and
behavior change [124].
3.8. The Medial Nucleus (ME)
The medial nucleus (ME) of the amygdala can be considered to be in conjunction
with the cortical nucleus with which it shares a laminar structure and also with the CE,
with which it partially shares the functional role. It also mostly contains GABAergic
neurons [
127
]. As is the case with other nuclei of the amygdala, activation of the ME
is also associated with psychological stress, which, in turn, leads to activation of the
hypothalamic–pituitary axis and secretion of ACTH (Figure 4).
3.9. The Cortical Nucleus (Co)
The cortical nucleus (Co), as the entire superficial group of amygdala nuclei, is di-
rectly connected to the olfactory system and participates in the processing of olfactory
stimuli [
139
,
140
]. The nucleus of the lateral olfactory stria is relatively smaller in primates
than in rodents and other mammals, and has three layers, just like all nuclei of the superfi-

Biomolecules 2021,11, 823 19 of 58
cial group [
139
,
141
]. It seems to be poorly connected to other nuclei, and plays the role of
olfactory processing [142,143].
3.10. The Periamygdaloid (Prepiriform) Cortex
The periamygdaloid (prepiriform) cortex is sometimes called the corticoamygdaloid
or amygdalopiriform transition area. Due to the heterogeneity of this paleocortical region,
there have been many attempts for its classification [
90
,
144
,
145
]. It receives olfactory
projections directly from the olfactory bulb as well as indirect projections from the piriform
cortex [
139
,
146
]. It projects into the LA and receives weak intrinsic projections from the
BM, medial, and CE nuclei [90,110,147].
A simplified flow of information through the amygdala from the neuroanatomical
perspective is schematically shown in Figure 7.
Figure 7. Simplified neuroanatomical representation of information flow within the amygdala.
BLA—basolateral nu-
cleus of the amygdala; CE—central nucleus of the amygdala; Co—cortical nucleus of amygdala; IN—intercalate neurons;
LA—lateral nucleus of amygdala; ME—medial nucleus of amygdala; BM—basomedial (accessory basal) nucleus of the
amygdala. The schematics is made according to Wieronska et al., (2010) [
148
], Orsini and Maren (2012) [
111
], Benarroch
(2015) [149], Gilpin et al., (2015) [116], Janak and Tye (2015) [147], and Sangha et al., (2020) [80].
The balance between excitation and inhibition determines the overall degree of amyg-
dala excitability. The BLA complex consists of 80% pyramidal, glutamate neurons, while
20% are GABAergic [
111
]. Although GABAergic neurons are fewer in number, they
normally exert effective control over excitatory neurons and modulate the response to
anxiogenic stimuli (see below) [
129
,
150
]. The balance between excitation and inhibition

Biomolecules 2021,11, 823 20 of 58
thought to be present in a healthy person under non-threatening circumstances is shown
in Figure 8.
Figure 8. Balanced ratio of excitation and inhibition in amygdala in a healthy individual in a non-threatening situation.
AMPA—
α
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; BLA—basolateral nucleus of the amygdala; CE—central
nucleus of the amygdala; GABA—
γ
-aminobutyric acid; IN—intercalated neurons; LA—lateral nucleus of amygdala;
NMDA—N-methyl-D-aspartate.
The neural network of the amygdala is very dense with high synaptic density per
neuron. Hypoactivity of GABAergic neurons and/or increased activation of glutamate
neurons lead to amygdala hyperexcitability that manifests as anxiety [
98
]. One of the key
features of anxiety disorders is the inability to suppress fear appropriately in situations that
do not pose a real danger [
102
]. All other neurotransmitter and neuromodulator systems
in amygdala modulate the activity of GABAergic and glutamate neurons. Activation of
GABAergic neurons in the output part of the CE results in inhibition of the physiological
response and vice versa [
151
]. However, excitation of GABAergic IN neurons by glutamate
projections from the LA results in inhibition of GABAergic neurons in the CE, ultimately
leading to an enhancement of the physiological fight-or-flight response. Such an effect
of one group of GABAergic neurons upon the other is called disinhibition. It is believed
that the stressors that lead to excitation of the amygdala, whether it is “normal” excitation
in healthy individuals or excessive excitation in various disorders, cause a decrease in
the activity of projection GABAergic neurons coming out of the CE of the amygdala and
consequently lead to the disinhibition of the hypothalamic–pituitary axis, as well as the

Biomolecules 2021,11, 823 21 of 58
disinhibition of a series of nuclei in the brainstem that are under strong influence of these
pathways [151] (Figure 9).
Figure 9. Schematic representation of the predominance of excitation over inhibition in circumstances of imminent
danger, but also in anxiety and other functional disorders of the amygdala.
The central nucleus of the amygdala contains
different populations of GABAergic neurons. This area mediates inhibitory control over the lateral region of the amyg-
dala [
111
]. AMPA—
α
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; BLA—basolateral nucleus of the amygdala;
CE—central nucleus of the amygdala; GABA—
γ
-aminobutyric acid; IN—intercalated neurons; LA—lateral nucleus of
amygdala; NMDA—N-methyl-D-aspartate.
4. Connections of the Amygdala
The amygdala is reciprocally connected to many cortical and subcortical areas via
different fiber bundles, four of which seem to be most important: the lateral olfactory
bundle, the stria terminalis, the posterior part of the anterior commissure, and the ventral
amygdalofugal pathway, which also includes the ansa peduncularis [
152
]. The importance
of the projections of the lateral olfactory bundle into the amygdala lies in the fact that they
mediate the unconscious, but, unlike other sensory systems, there is a direct influence
of olfactory information on the generation of emotions. Projections from various brain
regions enter the amygdala through the lateral nucleus, which serves as the main entering
point to the amygdala [
129
,
153
]. The LA receives excitatory input from glutamate neurons
that stimulate postsynaptic glutamate N-methyl-D-aspartate (NMDA) and
α
-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on both glutamate and
GABAergic neurons. In a simplified view, the activity of amygdala at base levels is the
result of balanced inhibitory and stimulatory inputs [
129
]. Furthermore, the LA is thought
to have a key role in the consolidation and reconsolidation of fear memories, which can

Biomolecules 2021,11, 823 22 of 58
be prevented with NMDA receptor antagonists [
109
,
154
] or the protein synthesis inhibitor
anisomycin, respectively [155].
In all primates, the largest afferent fibers in the amygdala come from the associative
cortical fields of the ventral visual pathway that provides processed information about
objects and faces. This information arrives in the lateral nucleus where it is evaluated
together with information from other sensory modalities to determine whether it is a
known stimulus or a potential threat based on previous experiences. Visual and auditory
information come topographically separated into the lateral nucleus, which enables a faster
response to danger, but also indicates that stimuli from all the senses are not required
to cause a fear response [
156
]. Likewise, these sensory inputs may be further summed
up in the LA neurons (temporal and spatial synaptic integration), which may lead to a
delayed response in cases when the stimulus is too weak to cause immediate activation of
the amygdala and a change in behavior [157].
After passing the LA, sensory signals are processed in virtually all parts of the amyg-
dala (BLA, CE, IN, etc.) and the generated information is further integrated with various
other afferent signals. Conditioned impulses then leave the CE and BM. The CE is consid-
ered to provide the main efferent projections of the amygdala, including those to the BNST
and PBN [
158
,
159
]. However, efferent projections, especially to the neocortex, hippocam-
pus, and ventral striatum, emerge from the BLA and BM as well. In a simplified view,
the CE “converts” emotionally important sensory stimuli into a physiological response
(changes in heart rate, changes in blood pressure, sweating, tremor, and somatic sensations)
and modulates behavior. The final response is the result of processing of much complex
and context-dependent information, which is provided by the hippocampo–entorhinal
input (see below) [
99
]. Using the method of retrograde transport of horseradish peroxidase
in cats, Russchen and Lohman were among the first to show that the entorhinal cortex
projects into the nuclei of the amygdala. They found that neurons of the deep layers of the
entorhinal cortex send axons to the CE and BLA [
160
]. This projection is topographically
organized: the medial parts of the entorhinal cortex are projected onto the medial parts of
the CE and BLA, while the lateral parts are projected into the lateral parts of these nuclei.
Russchen and Lohman showed that the layer II neurons of the entorhinal cortex project to
the corticomedial nuclei of the amygdala [
160
]. In rats, a population of pyramidal neurons
of layer III and layer IV of the entorhinal cortex send their axons to the periamygdaloid
cortex [
161
]. Altogether, it is not surprising that the amygdala is compared to an interface
between the frontal cortex and the hippocampus/entorhinal cortex. A simplified flow of
information through the amygdala is schematically shown in Figure 10.

Biomolecules 2021,11, 823 23 of 58
Figure 10. Simplified representation of the information flow within the amygdala.
BLA—basolateral nucleus of the
amygdala; CE—central nucleus of the amygdala; Co—cortical nucleus of amygdala; LA—lateral nucleus of amygdala;
ME—medial nucleus of amygdala; vmPFC—the ventromedial prefrontal cortex; BM—basomedial (accessory basal) nucleus
of the amygdala. The schematics are made according to Sah et al., (2017) [
108
], Asami et al., (2018) [
162
], and Neugebauer
(2020) [135].
In addition, other brain areas and circuits that regulate the activity of the amygdala
should also be appreciated. Unprocessed, direct information from the thalamus requiring
immediate response represents a direct pathway crucial for prompt reaction to danger
before the information has reached consciousness (the low-road pathway). Corticostriotha-
lamic circuits regulate the flow of signals that reach the amygdala after being consciously
and contextually processed and perceived (the high-road pathway) [
105
]. Hippocampo–
entorhinal circuits also provide information about the context in which the fear occurred,
which includes previously memorized information about previous encounters with the
stimulus and similar contexts experienced, structurally (mainly) connected to the BLA and
vmPFC. Activation of those pathways can also contribute to anxious behavior [
109
,
163
].
Finally, the main connections between the amygdala and hippocampo–entorhinal circuits
run through the fornix and stria terminalis [138,164,165].
Conscious processing requires time, slowing down the flow of information through
the high-road pathway. The vmPFC, ACC, and the dlPFC are thought to monitor the
cessation of fear-inducing stimuli, thus regulating amygdala activity. More specifically,
the vmPFC integrates emotional and cognitive information, and has an important role
in decision-making and behavioral intertemporal choices, whereas dlPFC, as the end

Biomolecules 2021,11, 823 24 of 58
point for the dorsal visual pathway, is critical to carry out working memory, especially
in remembering previous sensory events as well as attention maintenance and planning
responses to emotional stimuli [
166
]. The vmPFC has an inhibitory effect on the amygdala,
and reduces the reaction to the stressor/stressful event, as well as having an excessive
emotional reactivity. Therefore, greater vmPFC activity means greater conscious effort
and suppressed activity of the amygdala, along with a tendency to evaluate external
experiences positively [
167
]. Optimal emotion regulation is thought to arise from the
balance between the PFC and amygdala activity [
168
]. Stress negatively affects this activity
of the PFC, which explains why a strategy of cognitive reappraisal in real-life situations is
often ineffective [10].
The ACC is a part of a functional system of self-awareness and is implicated across
a broad range of emotional processes and behaviors, including contribution to social
cognition by estimating emotional facial expressions [
169
] and how motivated other in-
dividuals are and error prediction processing related to costs and benefits during social
interactions [
170
]. ACC dysfunction, perhaps mediated by the inhibitory influence of the
amygdala [
171
], also results in learned helplessness, where an inability to determine the
emotional aspect of the difference between the expected reward and outcome results with
demotivation and an inability to handle goal-directed tasks, although regions that are en-
gaged in the processing of the task stimuli are even more active [
172
]. Individually variable
degrees of sensitivity to emotional signals, both exteroceptive and interoceptive, also largely
depend on the activity of the ACC [
173
,
174
]. Although considered to mediate primarily
affective functions [
175
], it is generally accepted that ACC neurons are the main site of
integration of attention with visceral, autonomic, and emotional information [
174
,
176
,
177
].
The concept that the “extended amygdala” [
178
–
180
], where the extended amygdala
includes the corticomedial (superficial) complex of amygdala nuclei, sublenticular substan-
tia innominata, the NAc, and the BNST, postulates that the extended amygdala mediates
the integration of rewarding (positive) and punishing (aversive) sensory stimuli by trans-
lating the motivation generated through the NAc neurons into motor activity [
178
,
181
].
There is significant asymmetry in this system in normal individuals because the sensitivity
of the cerebral cortex of the frontal lobe to reward stimuli is significantly higher in the left
hemisphere than in the right, probably due to the stronger expression of dopaminergic D
2
receptors [182].
In addition to the amygdala and the OFC, the insula serves a critical role in emotional
awareness [
58
] and is involved in the regulation of emotions, feelings, cognition–emotion
integration and social networking [
183
–
188
]. The insula, due to its strong connection
with subcortical and cortical areas that regulate autonomic, physical and emotional in-
formation, plays a key role in maintaining homeostasis, and generating emotions and
awareness [
189
–
191
]. Due to its incredible complexity [
192
] and involvement in evaluative,
experiential and expressive aspects of internally generated emotions as a part of the paral-
imbic cortex, the insula specializes in behaviors that integrate environmental stimuli with
the inner milieu [185,193,194].
Patients with damage to insula have a changed decision-making pattern involving
risky gains and risky losses, compared to a group of healthy individuals [
183
,
184
,
195
].
Such patients make significantly riskier choices than healthy individuals in a potential gain
situation. Therefore, it is suggested that risky decision-making depends on the integrity
of the neural circuitry that includes several areas of the brain involved in experiencing
and expressing emotions: the insula, amygdala, and vmPFC. Within this neural circuit,
the insula is responsible for implicit thinking that makes it easier to face risk and gain in
uncertain conditions. The insula is, therefore, probably important in providing an intuitive
feeling of correctness when making a decision to avoid or accept risk.
Regarding the abundant connections between the amygdala and numerous subcortical
structures and cortical areas, it can be concluded that the amygdala is associated with
biological instincts, such as thirst, hunger, and libido, but also with motivation states—the
level of arousal, orientation, and response to environmental threats—as well as social,

Biomolecules 2021,11, 823 25 of 58
reproductive, and parental behavior [
164
,
165
]. All these behaviors are directly related to
emotional (affective) states mediated by the amygdala, so there is almost no part of the
CNS that is not directly, or at least indirectly, unaffected by the activity of the amygdala.
5. Fetal Development of the Amygdala in Human
The primordial amygdala appears about 5.5 weeks after conception. The corticomedial
and basolateral groups and the anterior amygdaloid region are the first cell clusters to be
identified simultaneously [
196
–
198
]. The hippocampus is in close contact with the primor-
dial cell clusters of the amygdala, and their neuroanatomical relationship persists until the
end of development. Medial forebrain bundle fibers that extend from the tegmentum to
reach the olfactory bulb pass near the amygdala. The developmental origin of the amygdala
is not entirely understood as to whether it is a diencephalic or telencephalic structure, or a
developmentally homogeneous structure. This dates back to Johnston’s first description
of the development of the amygdala in 1923, when he hypothesized that the amygdaloid
complex consisted of “six or more clusters of cells, some of which represent primitive
olfactory areas found in fish and others that are newly formed in terrestrial animals by
the process of growth, cell migration and folding of the adjacent piriform cortex” [
144
].
The amygdala is obviously not a homogeneous structure, for there are similarities in the
cytoarchitectural structure with the cerebral cortex and with the basal ganglia. Over time,
Johnston’s division has been gradually accepted. Johnston divided the amygdala nuclei
into two groups based on embryological and phylogenetic observations. He included
the central, medial, and cortical nuclei together with the nucleus of the lateral olfactory
stria among the “primitive” cell groups, while he classified the basal and lateral nuclei
as phylogenetically younger structures that are formed by cortical ingrowth and cell mi-
gration [
144
]. In his ontogenetic study, Macchi recognized the centromedial complex (the
central and medial nuclei), and the basolateral complex (the basal and lateral nuclei) [
197
].
Macchi also distinguished the anterior amygdaloid area, cortical nucleus, and intralaminar
nuclei, but did include the nucleus of the lateral olfactory stria in the amygdala at any
stage of development [
197
]. Crosby and Humphrey divided the amygdala nuclei into a
corticomedial and basolateral complex and the anterior amygdaloid region [
196
,
199
]. As
such, agreement on the amygdala subdivision cannot be reached on the basis of histological
and phylogenetic observations alone.
At 6.5 postnatal weeks, cell clusters within the amygdala are larger but still without
evident subdivisions, and the first fiber bundles appear [
200
]. The anterior region is
almost equal in length to the rest of the amygdaloid complex; however, its relative size
decreases with further development. The axons connecting the amygdala with the preoptic
and hypothalamic area pass through this area almost transversely. The ME becomes
relatively larger. The basolateral complex, being still a single unit, is continued into the
primordial neostriatum, and the primordial primary olfactory (piriform) cerebral cortex is
formed. The neuroblasts that constitute the cortical nucleus are not numerous, but rather
scattered over the surface of the basolateral complex. The amygdala establishes reciprocal
connections with the olfactory tubercle, and the first connections to the epithalamus also
form via the striothalamic bundle. At the beginning of the 7th week of gestation, the
stria terminalis is already formed, and connections with the cholinergic nuclei in the
diencephalon, hippocampus, and diencephalic structures begin to develop [
200
]. The
nuclei of the basolateral group of the amygdala begin to differentiate, with the basal
nucleus being especially distinguishable, while the lateral one develops a little later. The
NAc, globus pallidus, and medial forebrain bundle can be clearly identified. The putamen
suddenly emerges in the 8th gestational week and pushes the amygdala toward the lateral.
The central nucleus of the amygdala also differentiates during this period [200].
At the beginning of the fetal period, the development of the cerebral cortex continues,
while the differentiation of the main nuclei of the amygdala is completed. The further
development of the amygdala in humans, but not in other mammals, causes a change in po-
sition, or more specifically, a rotation of structures around the ME. From phylogenetic and

Biomolecules 2021,11, 823 26 of 58
ontogenetic perspectives, the ME changes the least, in contrast to the lateral nucleus, which
achieves the largest increase in volume and position, being the main afferent structure of
the amygdala. Because phylogenetic development shows a tendency to increase the surface
area of the cerebral cortex (telencephalization), the evolutionarily increased surface area of
the human cerebral cortex is reflected by an increase in the volume of the amygdala nuclei,
receiving most inputs from the periphery. At about 12 weeks post-conception, specific,
transient ovoid structures develop, especially in the lateral nucleus of the amygdala [
200
].
Then, the proliferation, migration, and differentiation of nerve cells lead to a rapid increase
in the amygdala volume. Around the 20th week of gestation, the transient ovoid structures
gradually disappear, and the increase in volume slows down. Repeated increase in volume
occurs in the middle fetal stage, probably as a result of the establishment of major connec-
tions, primarily frontolimbic [
201
], but also of efferent projections to subcortical regions of
the brain. The amygdala undergoes further changes in the late fetal stage resulting from
myelination and other maturation processes, including apoptosis.
Further perinatal and postnatal developmental changes of the amygdala are associated
with the establishment of structural and functional frameworks and continue to the age of
2 years [
202
]. The majority of connections are formed or have already been completed at
birth, and the pattern of functional development of resting-state default-mode networks
follows myelination and maturation [
203
]. It should be noted that the strong growth of
cortical and subcortical gray matter occurs during the first year of life although the cortex
matures later [
204
,
205
], and the further development of the amygdala, as well as the entire
central nervous system, is mainly marked by reorganization, fine-tuning, and reshaping
of already-established neural circuits [
206
]. The ontogenesis of individual primary and
secondary emotions in the first two years of life is shown in Figure 11. As stated, the
uncinate fasciculus does not finish myelination until about 30 years of age [51].
Figure 11. Ontogenesis of individual primary and secondary emotions in the first two years of life
. According to
Banham Bridges (1932) [207].

Biomolecules 2021,11, 823 27 of 58
A model of early cognitive development helps to understand when and why certain
emotions arise by specifying the cognitive tools that infants or children possess. A schematic
representation of the development of selected emotional and cognitive abilities in children
is shown in Figure 12. Emotions help children to interpret the world around them and there
are different ways (“rationalizations”) by which they cope with emotions with negative
valence (strategies of early emotional regulation) that are also dependent on the developed
cognitive skills. Although the emotion of fear arises around 6–7 months of age and
correlates with the development of amygdalofugal pathways, fear reaches a climax around
the age of 18 months and involves the fear of strangers (stranger anxiety) and fear of
possible separation from the mother or primary caregiver (separation anxiety). Social
referencing refers to children’s ability to understand how they should feel or behave in
certain situations [208].
Figure 12. Schematic representation of the development of select emotional and cognitive abilities in children.
ACC—
anterior cingulate cortex; vmPFC—ventromedial prefrontal cortex. The part of the schematic related to the stages of
development is made according to Lewis and Granic (2010) [209].
6. Damage to the Amygdala and Klüver–Bucy Syndrome
In 1938, Klüver and Bucy described an unusual emotional behavior in monkeys
resulting from damage to structures of the medial part of the temporal lobe [
210
]. The most
significant feature of the syndrome was a lack of fear [
211
], which manifested as a tendency
to approach objects that normally cause fear. This deficit is also called “psychic blindness”
due to the inability of an individual to attach an emotional value to living beings, events,
or objects.
Although monkeys naturally display repulsion, distrust, and a degree of aggression
toward strangers, as well as the development of subtle hierarchical relationships with other
pack members, those whose amygdala has been partially or completely bilaterally removed

Biomolecules 2021,11, 823 28 of 58
are reckless, overfriendly, hypersexual and fearless, not only toward other monkeys but
also toward potential predators and unknown/unwanted beings. The behavior is repeated
even after having an unpleasant experience, for example, after being bitten by a snake; the
monkeys are not afraid to approach them again, and hypersexuality continues toward both
sexes even after being beaten by a dominant male.
Because patients with Klüver–Bucy syndrome suffer bilateral damage or removal of
the medial part of the temporal lobe, the clinical picture includes deficits related to both
hippocampal formation and the amygdala. The main symptom of bilateral structural or
functional hippocampectomy is severe global amnesia, or the inability to convert short-term
memory into long-term memory. Structural or functional bilateral amygdalectomy causes
the following symptoms of Klüver–Bucy syndrome: loss of fear and increased obedience,
tameness, non-aggression, oral exploration of objects, hypersexuality, compulsive interest
for any visual stimulus (hypermetamorphosis, or utilization behavior), loss of emotionality,
visual agnosia (inability to recognize previously known faces and objects) and affective
flattening in about half of the cases, and bulimia (hyperphagia with a tendency to eat inap-
propriate “food”). Klüver–Bucy syndrome can be caused by over 25 different pathological
states, ranging from infections, such as shigellosis, to methamphetamine withdrawal [
212
].
7. Emergence of Individual Emotions in the Amygdala
Emotional regulation is extremely important in everyday life, above all in social inter-
actions. The primary role of the amygdala is to facilitate the adaptation of the individual
to its environment [
104
], where emotions with negative valence are associated with an
increased activity of the amygdala, whereas emotions with positive valence, such as ro-
mantic love, are associated with the deactivation of the amygdala [
213
]. Dysfunction of
the amygdala is primarily associated with disordered emotional regulation of fear and
aggression.
7.1. Aggression
From a biological perspective, aggression is understood as a survival tool and includes
defensive aggression (as in defending the territory and offspring) and predatory aggression
(as in competition for food). Other aggressive behaviors that do not meet these criteria are
considered pathological [
214
]. Aggressive behavior is one of the most difficult problems in
human society, covering the entire spectrum of behaviors from verbal threats to homicide.
As a term, aggression is defined as any behavior that causes harm to others and oneself.
Violence is a narrower term within aggression, and means the direct infliction of harm. Such
behavior can be impulsive or premeditated. This dichotomous model divides aggression
into impulsive aggression, which is a result of an affective reaction to a provocation, where
a person cannot resist sudden aggressive instincts “triggered” by an intense emotion of
anger, and planned aggression, which does not involve a physiological response [
138
]. The
characteristics of these two main types of aggression and their biological substrates are
summarized in Table 1.
The division of aggression types in Table 1is not absolute because some disorders have
characteristics of both impulsive and planned aggression, as may be the case in dissocial
(antisocial) personality disorder. Another problem is that most studies of aggression did
not use any classification of aggression subtypes. Sometimes, a collection of different
characteristics can be found in one individual: antisocial personality disorder (antisocial
behavior, impulsiveness, selfishness, emotional insensitivity, lack of empathy and remorse),
machiavelism (manipulation, blackmailing, and exploitation of others, lack of morality,
violation of social rules for one’s own benefit) and narcissism (a sense of grandiosity
and fantasizing about unlimited power, influence, strength and ideal love, complacency
and constant obsession with one’s own importance, beauty and uniqueness, demanding
excessive admiration, jealousy toward all other people that a narcissistic person perceives
as rivals, arrogance)—the so called “dark triad”. Narcissistic personality disorder is about
three times more frequent in males than in females (~18% vs. ~6%). At the same time,

Biomolecules 2021,11, 823 29 of 58
in those individuals, an internal struggle with lack of self-confidence and failure is often
present, and for most of them, the fundamental problem is the incapability to face either the
approval or disapproval of other people. Such people do not forgive anyone, often jump
from one relationship to another, and usually show aggression only in close relationships
(at first glance, they may seem to be successful members of society). A third type of
aggression can be added to this dichotomous division: this type occurs under the influence
of psychoactive substances, a common example being the sudden onset of aggressiveness
in an alcoholic state.
Table 1.
Division and characteristics of the two main types of aggression, and the role of the amygdala. ANS—autonomic
nervous system; OFC—orbitofrontal cortex; PAG—periaqueductal gray matter; PTSD—post-traumatic stress disorder;
TBI—traumatic brain injury; vmPFC—ventromedial prefrontal cortex. Information according to Blair (2010) [
215
], Begi´c
(2014) [216], Bogerts et al., (2018) [217], Farah et al., (2018) [218], and Gouveia et al., (2019) [138].
Aggression Type Characteristics Conditions in which It
Occurs The Role of the Amygdala
Impulsive (reactive)
Unplanned, caused by
increased arousal to a
provocation or a threat,
accompanied by a feeling of
anger; primary intention is to
destroy the victim (usually the
provocateur)
Intermittent explosive
disorder, autism, impulsive
type of emotionally unstable
personality, post-TBI
disorders, PTSD
Increased activity, especially of the
amygdala in the right hemisphere,
with decreased control of the
amygdala via PFC (decreased PFC
activity); increased activity of the
ANS, which includes increased
reactivity of the “threat system”
(medial part of the amygdala,
hypothalamus, PAG)
Planned (proactive,
instrumental)
Planned in advance,
associated with a reduced
degree of compassion
(empathy); intention is to
achieve a certain goal (usually
some personal benefit)
Antisocial (DSM5)/dissocial
(ICD-10) personality disorder
Decreased volume of amygdala and
its activity, especially in tasks
involving compassion; decreased
amygdala functional connectivity
with vmPFC, OFC, and posterior
cingulate cerebral cortex, decreased
OFC activation to provocation
Traditional understanding suggests that the amygdala releases aggression after PFC
decreases its control on the amygdala so that aggressive behavior is further potentiated
through “executive centers” in the hypothalamus and sympathetic centers in the spinal
cord [
214
]. Indeed, the amygdala, hypothalamus, and brain stem are thought of as “triggers
of aggression” [
217
]. However, stimulation of medial and basolateral amygdala nuclei in
experimental animals is observed to produce aggressive behavior with a range of aggres-
sive behaviors proportional to the degree of activation, whereas decreased activity of the
same regions leads to prosocial and submissive behavior [
214
]. In regard to aggression, it
thus seems that there is a functional diversity within the amygdala itself. For instance, stim-
ulation of the ME increases territorial, but decreases predatory, aggression [
214
]. The ME is
also associated with mating and protective behavior toward territory and offspring [
219
].
On the other hand, stimulation of the CE increases predatory aggression, so the term
“independent center of aggression” was coined [
214
]. Increased activity of the CE is even
thought to have a role in pathological aggression associated with reduced emotionality.
However, simultaneous activation of the ME and CE is linked to violent behavior [
214
].
Generally, violent behavior is often the result of several combined factors, particularly
increased amygdala activity due to genetic predisposition and an unfavorable environment
during early development, that both lead to decreased activity of brain areas responsible
for empathic behavior, primarily the vmPFC and OFC [
217
]. Watching scenes of unjustified
violence in normal individuals activates primarily lateral parts of the OFC (processing
the punitive stimuli) and insula (empathizing with the victim), whereas the vmPFC is
activated only when watching scenes of self-defense [
220
]. A correlation was observed
between reduced amygdala volume and aggressive, violent, and criminal behavior, along

Biomolecules 2021,11, 823 30 of 58
with weaker connectivity between the amygdala and vmPFC and OFC, whose activity
was decreased [
220
]. Such persons are incapable of empathy, being unscrupulous and
egocentric instead, most often narcissistic and manipulative, incapable of loving and truly
caring about someone, and also incapable of experiential learning and feeling ashamed,
guilty, embarrassed and regretful. Such behavior together with highly expressed aggres-
siveness usually begins early in childhood, likely under the influence of genetic and various
other factors.
7.2. Fear
Fear, the oldest and strongest emotion, played a crucial role in the evolution of
vertebrates [
10
]. While aggression is important for defending territory, protecting off-
spring and catching prey, fear is essential for facing danger. The amygdala is considered
the key structure in preparing an organism to react to danger or engage in a fight-or-
flight response [
155
,
156
]. Even though it certainly participates in the evaluation of other
emotions [
146
], its role in the detection of fear is primary and evolutionarily the most
important [
10
]. Fear and consequent behaviors are thus, either suppressed or general-
ized in dangerous situations [
80
]. Besides its key role in the experience of fear and the
fight-or-flight response, the amygdala is crucial in emotional memory [
221
], processing
emotionally charged stimuli from the environment and attributing emotional significance
to this information, whether relevant or not [167].
The BLA is considered the key area for the process of fear conditioning [
80
,
129
], as
demonstrated by LeDoux and others through experiments conducted in rodents [
103
]. By
performing precise neuroanatomical lesions in rats, they revealed that information from sen-
sory systems comes through both the thalamus and the cerebral cortex into the BLA [
122
].
It has been shown that the BLA decides whether generalization or discrimination will
occur during conditioning. The more similar the conditioned stimulus and the context in
which each subsequent test was performed at 24-hour intervals, the greater the likelihood
of the generalization of fear and the consequent response via the CE [
103
,
109
]. BLA activity
is increased in anxiety disorders. Its glutamatergic neurons’ excitation generates anxiety,
whereas stimulation of GABAergic neurons in the CE reduces it [
207
]. Moreover, BLA is
considered the regulator of social behaviors given that its activity enhances desirable social
behaviors and the reward experience, while inhibition of the BLA diminishes it [
103
]. Fur-
thermore, stimulation of the BLA relieves anxiety and freezing behavior, whereas inhibition
produces the opposite effect [109].
8. The Amygdala and Anxiety Disorders
Anxiety disorders are the most common psychiatric disorders: about 14% of the
population meets the criteria for some of these disorders at least once in their lifetime [
222
].
Although an appropriate response to danger is crucial for survival, it is equally important
to distinguish real from false danger [
80
,
103
]. If humans were not be able to do so, stimuli
signaling danger would cause impulsive fight-or-flight reactions too often. However, if
the situation development is correctly predicted and assessed, this control mechanism will
prevent unnecessary psychological and physiological reactions [
223
]. Neuronal circuits
involving the amygdala, hippocampus, and PFC are responsible for fear response control,
while modulation of amygdala activity mainly depends on the vmPFC.
From an evolutionary perspective, due to the adaptive role in adverse events, the
complete absence of anxiety would likely be detrimental. Nevertheless, fear, anxiety,
and concern lose their adaptive value in anxiety disorders. In comparison to healthy
individuals, anxious persons exhibit two types of changes: the exaggerated experience of
fear, sometimes in the complete absence of danger, and subsequent avoidant behavior; and
after cessation of danger, persistence of the fear alarm, and the individual behaving as if
under constant threat. The current understanding suggests that the basis of anxiety lies
in inappropriate regulation of neuronal circuits that supervise emotional and physiologic
responses to potential threats [129]. As such, the response to unpleasant stimuli or paired

Biomolecules 2021,11, 823 31 of 58
neutral stimuli is either amplified (conditioning) or it subsides. In healthy individuals,
there is a balance between these two processes. Pathological anxiety results from excessive
arousal of afferent pathways that signalize fear or insufficient activity of descending
pathways that inhibit fear-induced behavior [
102
]. In anxiety disorders, amygdala reactivity
is generally increased, not just to threatening situations and stimuli, but also to neutral
ones. This finding could explain the experience of severe anxiety in patients with anxiety
disorders even in the apparent absence of any real threat. The most differentiating factor
between the types of anxiety disorders are the circumstances in which anxiety occurs as
well as its intensity (level).
Briefly, a hypersensitive and hyperreactive amygdala, especially its basolateral part, is
the common feature of panic disorder, social phobias, and, to a lesser extent, PTSD and
generalized anxiety disorder (GAD) [
224
]. Preclinical studies in experimental animals
have shown that such BLA hypersensitivity can be induced by fear conditioning. Due
to synaptic changes that mediate associative learning in the BLA, a neutral stimulus is
sufficient to elicit a fear response [
84
]. Increased amygdala activity leads to activation
of the hypothalamo–pituitary axis and a subsequent increase in hormone levels (ACTH,
adrenaline, cortisol) that produce characteristic somatic symptoms of anxiety. It is thought
that increased amygdala activity in anxious people requires greaterPFC activity to suppress
unpleasant emotions caused by anxiety [
129
]. However, both the stimuli and the areas of
PFC involved greatly differ. For example, it has been shown that the vmPFC suppresses fear
by acting upon the BM, while dmPFC exerts a direct effect on intercalated neurons [
122
].
Both anxiety disorders and depressive disorder share a common feature of increased
amygdala activation since in both conditions, the amygdala and entorhinal cortex in
the right hemisphere are more active compared to healthy individuals, especially when
performing tasks related to the induction of fear or unpleasant emotions in general [
225
].
Similarly, as in anxiety disorders, greater amygdala activity and reduced PFC activity have
been observed in experimental models of depression [226].
8.1. Generalized Anxiety Disorder
The key feature characterizing generalized anxiety disorder (GAD) is the inability to
differentiate threatening stimuli from neutral ones [
224
]. Both the volume and activity of
the amygdala are increased in people with this disorder, along with amygdala connectivity
with other brain areas, especially dlPFC and ACC [
227
]. The most consistently identified
abnormalities in GAD are a hyperactive amygdala and hypoactive PFC [
216
,
220
]. Co-
morbidities with other anxiety disorders and depression are frequently found in patients
suffering from GAD, complicating the research and causing inconsistencies in results of
different studies [222,228].
8.2. Social Phobias
A fundamental feature of social phobia is the excessive fear of a negative assessment
by other people. Social phobia, as well as other types of (specific) phobias are among the
most common anxiety disorders [
222
]. If protection against an immediate danger is crucial
for survival of all vertebrates, a freezing behavior can also be understood as an adaptive
mechanism. The CE plays a key role in freezing behavior. A similar process can occur in
humans, although instead of defending against predators, activation of such behavior may
be triggered by social contexts, such as public performance. In this scenario, additional
mechanisms are required to overcome freezing to perform publicly [
223
]. Individuals
suffering from social phobia exhibit increased amygdala reactivity while watching pho-
tographs of faces expressing anger or contempt [
223
]. In these individuals, the amygdala
appears to be overly sensitive to frightening stimuli in social situations without altering
sensitivity to other contents. Excessive amygdala activity is also associated with decreased
activity of the OXT system [
134
], and the degree of functional connectivity between the
amygdala and vmPFC in the left hemisphere is also reduced. Thus, not only the structure

Biomolecules 2021,11, 823 32 of 58
of the amygdala, but also the structural integrity of its connections with the vmPFC seem
to be disrupted.
8.3. Post-Traumatic Stress Disorder
The amygdala is one of the areas in the brain involved in the development of PTSD as
the starting point for the process of activation of the hypothalamo–pituitary axis and the
cascade of physiological responses to acute stress. An appropriate response to acute stress
is a vital adaptive mechanism, but its prolongation causes various biopsychosocial (previ-
ously, psychosomatic) disorders. Chronic stress leads to higher expression of CRH/CRF
in the CE and BLA, which has an anxiogenic effect [
124
]. The CRF is considered to be
responsible for the anxiogenic effect of different stressors, while OXT has an anti-stress
effect [
124
]. This anxiolytic effect of OXT is mediated by a morphologically distinct sub-
population of astrocytes that express OXT receptors [
227
]. Furthermore, stress decreases
GABAergic activity and also the sensitivity of GABAergic receptors [
228
]. Reduced activity
of GABAergic interneurons automatically leads to overactivity of glutamatergic neurons,
and increased excitatory activity in the LA, as already stated, has an anxiogenic effect.
The amygdala mediates both conditioned and unconditioned memory of stressful
events, so its activity increases during recollection. Studies using functional magnetic
resonance imaging (fMRI) have shown an increase in spontaneous amygdala activity, as
well as amygdala activity, when recalling traumatic events [
229
]. This explains why people
suffering from PTSD have hippocampal atrophy without change in amygdala volume.
Exposure to chronic stress is thought to lead to impairment of memory dependent on
the functional integrity of the hippocampus, whereas memory stored in the amygdala is
preserved [
230
]. Furthermore, BLA levels of brain-derived neurotrophic factor (BDNF)
increase under the influence of stress, additionally leading to establishing memory for
stressful events, while PFC control over the amygdala is reduced [
228
]. This helps to
explain other characteristics of PTSD, such as impaired memory for facts that are not
emotionally significant, while remembering stressful events in detail.
8.4. Panic Disorder
The most defining features of panic disorder are sudden attacks of intense fear with
dramatic somatic (sweating, tremor, palpitations, feeling of suffocation, nausea) and cog-
nitive symptoms (fear of death and loss of control). A panic attack can be induced in
experimental conditions by infusion of sodium lactate or by inhalation of carbon diox-
ide [231].
Most people recover from a sporadic panic attack without professional help or treat-
ment, but some develop panic disorders over time if they can no longer clearly distinguish
threatening stimuli from neutral ones, and experience inappropriate fear of certain objects,
people, or situations. Although very unpleasant, panic attacks are not directly dangerous
to health, and can manifest themselves through any form of anxiety disorder (GAD, PTSD,
obsessive–compulsive disorder, social phobias) or occur in isolation. In a panic attack,
which usually occurs over a short period, in addition to the feeling of great fear (loss of
control, alienation from the environment and other people, death), the amygdala strongly
activates the ANS, especially its sympathetic part.
Spontaneous panic attacks occur following excessive activation of the amygdala to
neutral external stimuli. Individuals suffering from a panic disorder have reduced volumes
of the right LA and BLA and therefore, the volume of the right amygdala is significantly
reduced, too [
162
]. The LA recognizes sensory stimuli and the BLA detects potential threats
and forwards this information to the CE, resulting in the aforementioned somatic symptoms
of sympathetic activation. The misperception of danger likely precedes a panic attack,
which is especially true for the misinterpretation of bodily sensations [
232
]. Furthermore,
people with panic disorders over-process images of frightened faces compared to healthy
controls, which is associated with greater amygdala activation [
233
]. Preclinical models
indicate a disturbed balance between excitation and inhibition in the BLA and CE [
231
,
232
].

Biomolecules 2021,11, 823 33 of 58
A reduced density of GABAergic neurons in the BLA is, in fact, correlated to an increase in
the intensity of fear [
231
]. The amygdala represents the main hub of the fear network in
a panic disorder, which also includes the thalamus, hippocampus, hypothalamus, PAG,
and brainstem [
232
] for which individuals suffering from a panic disorder have a lowered
threshold for activating.
9. The Role of the Amygdala in Consumption and Negative Effects of Alcohol
The consumption of alcohol induces a change in emotional state in terms of relax-
ation and euphoria, in addition to relieving stress and anxiety [
234
,
235
]. Nonetheless,
alcohol shows a broad spectrum of effects, ranging from altruistic to extremely aggressive
behavior [236–238].
Alcohol disrupts the balance between inhibitory and excitatory neurotransmission in
the amygdala. GABAergic transmission in the BLA and CE is enhanced under the influence
of alcohol, while glutamatergic transmission is reduced in the same regions [
124
]. The acute
action of alcohol is anxiolytic, sedative and positively reinforcing [
124
]. The anxiolytic
effect of alcohol appears to be achieved primarily through the action of ethanol on the
amygdala, while the euphoric effect is achieved by stimulation of the NAc [
239
]. Like other
sedatives, alcohol mostly acts through GABA receptors. In small amounts, it enhances the
action of GABA-A and GABA-B receptors, and in larger quantities, the release of dopamine
activates serotonergic 5-HT
3
receptors and blocks NMDA receptors. In addition to sedation,
the short-term effects of alcohol include loss of inhibition, decreased anxiety, and impaired
motor coordination [240–242].
However, chronic alcohol consumption leads to hyperexcitability of glutamatergic
systems, most pronounced in the development of tolerance in which decreased effects of
alcohol in the NAc and amygdala occur [
239
], and in withdrawal syndrome. Individuals
with increased excitability of BLA pyramidal neurons are more anxious and have a greater
tendency to consume alcohol [
239
]. Alcohol reduces amygdala activation when observing
faces expressing fear [
239
]. Early life stress and chronic stress later in life [
243
] lead to
increased excitability of the BLA, and alcohol can reverse that effect. However, the link
between alcohol and stress seems to be bidirectional. Due to the development of tolerance,
the anxiolytic effect of alcohol gradually weakens, while amygdala excitability [
239
] and
addiction increase [
244
]. Lack of alcohol leads to dysphoria and craving, further supporting
the addiction. In a state of developed dependence, the reward system is active but a normal
reward no longer activates it, as predicted by the incentive–sensitization theory [245] and
confirmed by functional imaging studies [246].
In addition, alcohol impairs the processing of emotions within the amygdala, so that a
person under influence can misinterpret another person’s behavior as threatening. Alcohol
disrupts the connections between the PFC and amygdala, leading to reduced control over
executive functions, which includes consideration of consequences, control of behavior
and cognitive assessment of the self and one’s social relationships [247,248].
10. The Influence of the Amygdala on the Brain Reward System
Unpleasant emotions, such as fear, have great and overriding adaptive value. How-
ever, the ability to feel satisfaction for any subjective success is also necessary for a long
and healthy life [
249
]. Pleasant emotions are a catalyst for success because they enable and
encourage problem solving, cognitive flexibility, social cooperation and the achievement
of goals [
249
]. A high level of positive emotion is associated with a greater degree of
optimism, self-confidence, and efficiency, as well as better regulation of emotions and
self-well-being [
250
]. Although moral and social norms impose altruism and reciprocal
relations, the goal of most is always the greatest possible subjective well-being with the
lowest possible price/effort. From that perspective, the feeling of reward (pleasure) can
be seen as “the greatest trick of evolution” [
251
]. Although this trick serves to motivate
the individual to achieve the greatest possible ability to survive and reproduce, it can also

Biomolecules 2021,11, 823 34 of 58
be a source of affective disorders, addiction and psychopathology, especially in modern,
wealthy societies [251].
A reward is any object, event, stimulus, situation or activity that induces pleasant
emotions, leads to behavior aimed at approaching the source of the reward and results
in positive reinforcement that operates under the principle of maximization in decision-
making, such as to maximize pleasure/benefit and minimize pain/discomfort with least
cost [
252
]. In psychological terms, the brain’s reward system consists of a number of
components of which three are the most important: (1) liking—a fundamental reaction
to a stimulating hedonic stimulus; there is a general consensus that the opioid system is
the most important for the process of liking (e.g., the injection of opioids will induce both
liking and desire); (2) wanting (desire)—a reflection of motivation toward some incentive
sensory stimulus; the process of motivation is mediated primarily by the mesocortical
dopaminergic system (see below); and (3) learning—most often in the form of classical or
instrumental conditioning, or cognitive representations [253].
Each of these components can be further divided into an explicit and implicit sub-
component. We experience explicit processes consciously, while we cannot always be
aware of the implicit ones (e.g., we may like or dislike someone or something, but we
are not aware of it). Consequently, the explicit liking consists of conscious hedonic feel-
ings, while the implicit “liking” includes all affective reactions whether we can measure
them objectively or not. Unlike liking, wanting (desire) does not contain any hedonic
(sensory) pleasure, so it can neither increase nor decrease it. Although part of the larger
whole of the brain’s reward system, wanting (desire) is thought to be largely dependent
on decision-making when faced with multiple potential goals at the same time [
254
]. The
explicit wanting subcomponent consists of subjective, goal-oriented plans and all known
or imagined stimulating cognitive representations that we know or assume, or have some
kind of cause-and-effect understanding of how to achieve them. In addition, for their
realization we expect that they will be directly pleasant. Implicit “wanting” means all
possible rewards and their indications when this motivational value is assigned to them by
the dopaminergic mesolimbic system during unconscious processing (see below). Thus,
implicit rewards may suddenly become “motivational magnets”. For example, due to some
stimulating feature, the animal may be motivated to eat an inedible object or a cocaine
addict may collect crack crystals from the floor even though she/he knows that it is actually
just crystalline sugar [
255
]. Due to the fact that they do not represent common, conscious
desires whose presumed outcome is always known, such implicit “desires” derived from
mesolimbic activation are put in quotation marks [
255
]. Explicit learning refers to all types
of learning based on conscious expectation of a reward, as well as those in which we
understand the cause-and-effect nature of outcomes, while implicit learning includes all
forms of associative learning, especially conditioning and reinforcement, which do not
require awareness or attention. Although the above division is made for didactic reasons
and simplification, no component of learning can be separated from the influence of emo-
tions operationalized through projections of the amygdala onto the different parts of the
reward system.
Neuroanatomical, electrophysiological and neuropharmacological experiments con-
ducted until the mid-1980s revealed that four groups of interventions applied in experi-
mental animals could lead to reward, including injection of amphetamines into the NAc,
injection of morphine into the VTA, electrical stimulation of the VTA, and electrical stim-
ulation of the medial forebrain bundle (MFB). Based on these and other findings, main
elements of the neural circuits that make up the brain’s reward system have been defined
(Figure 13).

Biomolecules 2021,11, 823 35 of 58
Figure 13. Schematic representation of dopaminergic projections that make up the brain reward system.
The projections
originate from the neurons of the ventral tegmental area (VTA, black star) and go to the ventral striatum (ventral pallidum),
especially the nucleus accumbens septi (NAc, small blue ellipse, mesolimbic pathway), orbitofrontal cortex (OFC, large blue
ellipse) and prefrontal cortex (PFC, yellow ellipse, mesocortical pathway), anterior cingulate cortex (ACC, purple ellipse)
and mediobasal telencephalon (basal forebrain, BF, green ellipse), entorhinal cortex (EC), hippocampus (H) and amygdala
(A). The release of dopamine from projecting VTA neurons in other parts of the CNS, especially the hippocampus (H) and
the amygdaloid nucleus (A) is associated with the memory of (otherwise neutral) individual stimuli/objects/events present
during rewarding, which gives them motivational importance [
256
–
258
]. It is thought that dopaminergic projections from
the substantia nigra, pars compacta (SNc, red rectangle) to the dorsal striatum, i.e., caudate nucleus (CN) and putamen (P)
also transmit information that associate salient sensory stimuli with reward and reward prediction error, but in this context
they are associated with the dopaminergic “tone” necessary to perform conscious motor movements and to reprogram
motor patterns that will facilitate obtaining the same reward in the future [
259
]. Green dashed arrows represent projections
of the PFC and ACC in the OFC. These projections are thought to exert cognitive (top-down) control over glutamatergic and
GABAergic interactions in the OFC, a key region responsible for making behavioral choices, such as emotional go/no-go
decisions. Schematic modified from Šešo-Šimi´c et al., 2010 [169].
The most important reward pathway in the brain is the mesocorticolimbic dopamin-
ergic system, the backbone of which is composed of the VTA, NAc and OFC. Midbrain
dopaminergic neurons in the VTA play a key role in reward-dependent motivation and
behavior and are controlled by projections from the rostromedial tegmental nucleus (RMTg)
and the dorsal raphe nucleus (DRN). Through projections from the VTA into different
parts of the CNS, dopamine attaches motivational valence to the processed contents in
order to create a sense of current (projections to NAc) or future reward (projections to the
PFC), adjusts the value of the stimuli in light of the new experience/context, creating a
sense of satisfaction associated with the stimulus or its cues (projections in the NAc and
ventral striatum), and supports the consolidation of associative conditioning (projections
to the amygdala) and episodic memories (projections to the hippocampus). Due to the
secretion of higher amounts of dopamine in the striatum, all naturally rewarding activities
lead to increased motor activity: when happy, we jump; and when sad, we stay, helplessly,

Biomolecules 2021,11, 823 36 of 58
for a long time in the same place. Dopaminergic projections from the SNc into the dorsal
striatum (caudate nucleus, CN, and putamen, P) also serve to reprogram motor patterns
that will facilitate the realization of the same award in the future. In addition to motivation
(“wanting”, desire), through the amount of dopamine secreted in the NAc, dopaminergic
projections from the VTA also encode an error between the predicted and realized level of
reward, due to which the subjective value of the reward is constantly changing [260–262].
Addictive drugs are initially rewarding, mediated by the NAc, septum and other
areas of the ventral striatum, but also reinforcing, mediated by the neurons in the VTA.
Repeated reinforcement results in the sensitization of NAc neurons and the creation of a
strong desire (“wanting”) to re-take the drug despite increasing dislike and negative conse-
quences: mental and physical dependence, tolerance, and craving (incentive–sensitization
theory) [
245
,
263
,
264
]. The theory has a broader impact not only on the explanation of
addiction and drug addiction, but is also applicable to the explanation of all other ad-
dictive and compulsive behaviors, such as gambling, shopping (binge shopping), binge
drinking, overeating (binge eating), excessive need for sports, sexual activity and the use
of pornographic content, where only desire (“wanting”) is expressed and liking is often
lacking.
The mesocorticolimbic pathway conveys information relevant to associating perceptu-
ally incentive sensory stimuli with the reward as well as reward prediction error, that is,
the relationship between the rewarding stimulus and expectation [
259
]. For example, if
in a restaurant we get better food than we expected, it will increase our predictions that
the food in that restaurant will be good, so we will probably come again [
260
]. Moreover,
the error of predicting a reward that codes for the subjective value of any reward through
dopamine secretion in the NAc has much deeper and more far-reaching effects, namely,
when we analyze the positive errors of the expected reward, such as rewards that are
higher than expected, our expectations for future rewards also increase. In the case that
the first subsequent prize deviates less than the predicted error, it will also produce a less
positive error of the expected prize. Therefore, we will need ever greater rewards in order
to achieve the same error of predicting the reward and the same degree of satisfaction [
260
].
Consequently, we will constantly seek an ever greater reward (pleasure). Such maximiza-
tion of the reward is certainly useful in evolutionary terms because animals and humans do
what they enjoy since pleasure is a “side effect” of achieving some evolutionary goal, such
as feeding or reproduction. The feeling of comfort through evolution is set up in such a
way that the pleasure cannot last forever because we would no longer think of survival and
reproduction. Therefore, the anticipation of pleasure is extremely strong, and the pleasure
itself is only short-lived. Thus, the search for an ever-increasing degree of comfort also
has undesirable “side effects” for everyday life, such as the creation of a constant desire
for increased economic consumption beyond the required existential minimum. Such a
distorted perception, namely the disproportion between desires and possibilities, due to
the inability of economically rational control of making intertemporal choices, can lead to
emotional crises, various affective and eating disorders and psychopathology [260–265].
Mental and physical dependence do not have to be the same for each addictive
substance. For example, due to anxiety, anhedonia, depression and suicidal thoughts,
psychological dependence on cocaine in abstinence is usually much higher than physi-
cal dependence, while in heroin addiction, the opposite is true: physical symptoms of
withdrawal syndrome, such as vomiting, diarrhea, muscle cramps, sweating, tremor and
insomnia, are more severe than those that are psychological. The term tolerance refers
to the reduced effect after repeated intake of the same dose; to achieve the same effect,
it is necessary to constantly increase the dose of the addictive agent. Upon restraint, the
reward system does not return to its initial state, because sensitization occurs—a process
opposite to tolerance [
265
]. Sensitization is thought to occur due to the accumulation of the
transcription factor
∆
FosB in the NAc, which activates numerous, still insufficiently known,
genes and signaling pathways, including those important for synaptic plasticity, long-term
potentiation and consolidation leading to morphological restructuring of dendritic spines

Biomolecules 2021,11, 823 37 of 58
as one of the most important cellular substrates of long-term memories associated with
addictive substances [
266
]. The consequence of sensitization of neurons in the NAc is craving,
a drug seeking behavior. A simplified scheme of the main sites and mechanisms of action of
some common drugs of dependence on the brain’s reward system and the modulating role of
the amygdala according to recent research findings are given in Figure 14.
Figure 14.
Schematic drawing of the main sites and mechanisms of action of some common addictive drugs on the brain
reward system: reward learning and motivation are strongly influenced by the amygdala. Thick blue arrows from OFC,
AMY, and HF to NAc convey contextual information associated with the addictive substance and contribute to relapse.
Although many addictive substances directly stimulate the release of dopamine from neurons in the VTA that are projected
into the NAc, it must not be forgotten that the same effect (activation of VTA) with drug-related stimuli can be achieved
indirectly through projections from the amygdala to the PFC and then from PFC to VTA [
265
]. In a state of developed
dependence, the reward system is active, but the usual (normal) reward can no longer activate it. This state of motivational
toxicity is expressed in hardened addicts. It is manifested by a lack of interest in career, social and sexual relations, financial
status and increased engagement in the procurement and consumption of drugs. The diagram does not show the efferent
projections of NAc that go to the basal ganglia and ventral pallidum. Neurons of the ventral pallidum are projecting through
the mediodorsal nucleus of the thalamus into the PFC and striatum, and additional projections go into the RMTg, the
compact part of the substantia nigra (SNc), and the reticular formation of the pons. Not shown are glutamatergic projections
from the thalamus and ACC into Nac, as well as projections of NAc and ventral pallidum into the lateral hypothalamus.
AMPA—α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMY—amygdala; AP-1—transcription factor activating
protein 1; ATP/Ado—adenosine triphosphate/adenosine; BLA—basolateral nucleus of amigdala; DA—dopamine; DRN—
dorsal raphe nucleus;
∆
FosB & JUN—truncated member of the Fos family of transcription factors and JUN protein (
∆
FosB
↑
*
in RMTg applies only to psychostimulants); GABA—
γ
-aminobutyric acid; GLU—glutamate; HF—hippocampal formation;
LTD—long-term depression; MDMA—3,4-methylenedioxymethamphetamine (ecstasy); NAc MSN—medium spiny neurons
in nucleus accumbens septi; OFC—orbitofrontal cortex; RMTg—rostromedial tegmental nucleus; VSu—ventral subiculum;
VTA—ventral tegmental area. See text for details.
In the case of failure in achieving the planned goals and the expected reward, especially
in situations of chronic stress when free cortisol levels become significantly elevated, a
person will unconsciously activate the brain reward system in some other, usually well-
known and direct way. Such poor intertemporal choices (which favor short-term gain

Biomolecules 2021,11, 823 38 of 58
rather than long-term success), as well as the inability to refrain from immediate comfort
to achieve a later, more rewarding goal, are associated with poorer emotion regulation.
Additionally, although many people experiment with various addictions and drugs, from
legal ones, such as coffee and cigarettes, to illegal ones, a relatively small number of
them develop a real and complete addiction. Both of these individual differences may
be associated with a pattern of attachment at an early age [
169
]. Numerous experimental
results support this conclusion. For example, one experimental model showed that rats that
were maternally separated and those that were non-handled for the first 14 days after birth
were later hyperactive when moved to new environment, and also showed significantly
higher sensitivity to cocaine and amphetamine-induced locomotor activity [
267
]. These
animals, compared to controls, had a significantly higher increase in dopamine in NAc
after a mild stress (such as tail-pinch test) [
267
]. This result confirms that lack of care
and attachment relationships during the early postnatal period leads to profound and
long-term changes in emotional development with consequent increased reactivity of the
mesocorticolimbic dopaminergic system to stress and addictive substances. Due to the
slower maturation of the OFC, such children will exhibit disinhibition syndrome more
often in later childhood, will not be able to calm down easily even in mildly stressful events
and communicate their negative emotions with the primary caregiver in the way that their
peers do.
Finally, it is worth emphasizing that both very stressful situations (e.g., crises after
natural disasters) and highly rewarding atmospheres (e.g., shopping malls) activate the
mesocorticolimbic dopamine system. In such situations, it is more likely that we will
judge an incentive stimulus as “desirable” and, for example, buy something that we do
not particularly like. Experimental data of optogenetically controlled dopamine release
from VTA neurons in the NAc confirmed that a (controlled) increase in the concentration
of secreted dopamine in NAc prior to reward increases the sensitivity of a conditioned rat
to the price (the required number of lever pressures per food pellet) to be paid for that
reward, whereas an increase in dopamine release in NAc after the prize is given makes the
animals less sensitive to the price [268,269].
11. Short Description of Clinical Cases Presenting with Disturbed Emotional
Experience and Behavior
Probably the most known cases of disturbed emotional experience and behavior in
the history of neuroscience is the case of Phineas Gage, a man whose injuries unequivo-
cally showed that damage to the frontal lobe affects personality, behavior, and emotional
experience [
270
]. A detailed analysis of Gage’s skull using structural MRI showed that the
iron bar severely damaged the frontal lobe of both hemispheres, with the most pronounced
damage to the left ventromedial prefrontal cortex, an area crucial for decision- making
and emotional regulation [
271
]. A re-analysis of the Phineas Gage case confirmed the
assumption that the PFC, especially its ventromedial part, is associated with emotional reg-
ulation. This conclusion is strongly supported by the reciprocal association of the vmPFC
with subcortical structures, primarily the hypothalamus and amygdaloid nucleus, which
control and regulate fundamental instinctive behaviors aimed at survival and reproduction
(hunger, thirst, fear, escape, aggression, libido), the autonomic and endocrine systems,
emotion processing and social cognition [
272
]. Recent research indicates Gage’s extensive
damage to the white matter of the frontal lobe as well as the white matter of the anterior
parts of temporal lobes and amygdala, as evidenced using a virtual tractogram (diffusion
tensor imaging, DTI) of his traumatic brain injury [
273
]. Unfortunately, insufficient de-
tails on Gage before and after the accident have been preserved to allow more precise
pathological–clinical correlations and unambiguous conclusions to be drawn about the
effects of his injury on subsequent behavior.
Patient S.M. had very pronounced bilateral amygdala damage caused by the rare
autosomal recessive Urbach–Wiethe disease, resulting from a mutation in the extracellular
matrix protein 1 gene. Due to the mutation of this gene, numerous pathological changes
occur, the most pronounced being the deposition of hyaline material in the patient’s skin

Biomolecules 2021,11, 823 39 of 58
and bilateral calcification of the amygdala and periamygdaloid gyrus in 50–75% of patients,
usually starting at the age of 10 [
274
]. The general intellectual and other basic perceptual
and cognitive abilities of patient S. M. were within normal values at the time of admission
to the hospital. It is therefore not surprising that between the ages of 10 and 20, she did
not notice that she cannot feel fear, and she was brought to the hospital at the age of 20
due to symptoms of epilepsy. Severe amygdala atrophy was revealed first by computed
tomography (CT) and thereafter by MRI, whereas the adjacent white matter showed only
minimal damage. During neuropsychological testing, S. M. showed highly specialized
impairment associated with the emotion of fear [
275
]. For example, she did not show a
conditioned electrodermal response to fear, had difficulty recognizing facial expressions
showing fear (but could recognize facial expressions of other emotions), and did not feel fear
(while experiencing other emotions normally). However, S. M. experienced a panic attack
after inhaling carbon dioxide (which usually causes a feeling of suffocation), indicating that
the panic state resulting from suffocation does not require amygdala activation. She was
also prone to fear conditioning in certain situations—for example, she refused to seek help
of a dentist because of the pain she had experienced at the dentist’s previously [
61
]. Finally,
S. M. did not have an inability to understand the concept of fear, e.g., she could clearly
describe situations that could evoke fear, as well as sounds in voice recordings that reflected
fear, indicating that the conceptual knowledge of emotions is largely separated from the
emotional states themselves. Therefore, thinking about emotions (e.g., the use of terms and
words associated with emotions), conscious experience of emotion and emotional state are
three different phenomena.
The case of 14-year-old boy B. W. with a congenital focal malformation of the left
vmPFC was published by Boes et al., in 2011 [
276
]. At the age of 6, his parents noticed
that the boy had become disobedient and defiant both at school and at home: there were
minor incidents of theft (e.g., stealing cookies, which he then sold), lying, aggression, anger,
swearing, disobedience, and carrying a pocket knife to school. At the age of 7–9, this behavior
worsened, and since punishing the boy had no effect, he continued to study from home.
Despite behavioral problems and a lack of motivation, B. W. showed an enviable level
of intelligence. At the age of 11, he was admitted to the emergency department due to
feelings of hopelessness, worthlessness, and suicidal ideation that lasted for two months
with worsening of the aforementioned symptoms—the boy was even more aggressive,
destructive, non-empathetic, impulsive, hyperactive and hypersexual, even though he had
not yet reached puberty (he constantly watched pornographic websites and demanded
peers to undress in front of him). Although he could not plan well, he still tried to
manipulate other people with the sole purpose of satisfying his personal needs, just like
an inveterate psychopath. He would get angry and have uncontrolled outbursts of anger
if others prevented him from accomplishing anything he intended. He showed deep
disrespect for any authority and disturbed moral judgment. He used a lighter to set fire to
the house where he lived and several times to the church he went to with his parents. He
was arrested for attempted burglary. He lied and stole without remorse. He threatened
his mother with a knife. Because his father restrained him from hurting his brothers and
sisters, he hit him hard in the head with a wrench; according to his father, he did so coldly,
“without any emotion”. Unlike previous MRI images taken at the ages of 4 and 9 years
on a 1.5 T MRI device, only now, at the age of 13, has a 3 T MRI scan been taken, and this
finally explained his clinical picture of a complex partial epilepsy and behavioral disorder.
The main findings were a focally thickened cerebral cortex, loss of a clear boundary
between gray and white matter, and enhanced white matter signal of the gyrus rectus,
i.e., the vmPFC and adjacent areas (in T2 and fluid attenuated inversion recovery (FLAIR)
sequences; these two methods are best for detecting changes in white matter). The signal
could not be improved by the contrast, and the hyperintensity of the white matter of the
gyrus rectus spread toward the frontal horn of the left lateral cerebral ventricle, suggesting
a possible Taylor-type focal cortical dysplasia radial migration disorder, but this was not
confirmed by postoperative histological analysis. The MRI showed that the malformation

Biomolecules 2021,11, 823 40 of 58
affected parts of Brodmann’s areas 11, 12, 25 and 32. Extensive preoperative mapping
of the entire vmPFC revealed small clusters of dysplastic neurons in the left amygdaloid
nucleus and the adjacent cerebral cortex of the anterior medial and lateral temporal cortex,
which was confirmed by neuropathological analysis after resection. Similarly to other
people with left vmPFC damage, B.W. could not pass the Iowa gambling task, i.e., learning
from which decks it is good to take cards [
49
]. The behavioral and neuropsychological
profile of B.W. is consistent with previously described cases of focal vmPFC damage and
the amygdala disconnected from the frontal input. Therefore, it comes as no surprise that,
just like most other patients with pathological changes or injury to the vmPFC, B. W. had
relatively normal performance on standard neuropsychological tests.
Other comparable cases of disturbed behavior in relation to emotional experience
include the following: the case of patient B., who suffered from bilateral damage mainly of
the insula due to Herpes simplex infection [
183
]; patient Roger, who suffered from bilateral
damage to insula, ACC, and amygdala also due to Herpes simplex encephalitis [
184
]; and
patient A.P., who, similar to S.M., had bilateral calcification of the amygdala due to Urbach–
Wiethe disease [
277
]. The neuropathological findings and altered behaviors of these six
cases are summarized in Table 2.
Table 2. Selected clinical cases of disturbed emotional experience and behavior. See text for details.
Case Basic Neuropathological Findings Altered Behavior Reference(s) No.
Phineas Gage
Bilateral damage of the frontal lobe,
especially vmPFC, including the
extensive damage to the white matter
of the frontal lobe as well as the
anterior parts of temporal lobe and
amygdala (amygdala disconnected
from the frontal lobes)
Careful and reliable person before the
injury after the injury became emotionally
unstable, impulsive, unpredictable,
dishonest, capricious, reckless, having
disturbed social skills and difficulties in
making decisions (“no longer Gage”)
[270–273]
Patient S.M.
Bilateral calcification of the amygdala
and periamygdaloid gyrus due to the
Urbach–Wiethe disease
Patient S.M. had highly specialized
impairment associated with the emotion
of fear: she could not experience fear nor
she could recognize facial expressions
showing fear
[61,274,275]
Boy B.W.
Congenital ventromedial prefrontal
cortex malformation involving
Brodmann areas 11, 12, 25 and 32,
clusters of dysplastic neurons in the left
amygdaloid nucleus
Throughout his childhood, this boy with a
relatively normal cognitive performance
on standard neurophychological tests
displayed incremental emotional
instability, impulsivity, lack of empathy,
hypersexuality, and had been
manipulative and aggressive towards
others, including his own parents
[276]
Patient B.
Bilateral destruction mainly of the
insula due to Herpes simplex infection,
but to a lesser extent also of the
orbitofrontal and temporal cortex,
anterior part of the ACC, hippocampus,
EC, amygdala and a part of basal
telencephalon
Severe global amnesia, dense impairment
of retrograde memory and shallow mental
content, but, except for taste and olfaction,
all aspects of feeling were intact
[183]
Patient Roger
Bilateral damage to insula, ACC, and
amygdala due to Herpes simplex
infection
Major deficits included global amnesia,
anosmia (the inability to percieve
smell/odor), and ageusia (the inability to
taste), while his experience of pain was
intact, at times even excessive
[184]

Biomolecules 2021,11, 823 41 of 58
Table 2. Cont.
Case Basic Neuropathological Findings Altered Behavior Reference(s) No.
Patient A.P.
Selective bilateral damage to the
amygdala due to the Urbach–Wiethe
disease
A pleasant, cheerful young woman
notable for her tendency to be somewhat
coquetting and disinhibited, e.g., she had
been quick to become friendly with
examiners, and had often made mildly
innapropriate sexual remarks. She had
also suffered from a significant defect in
visual, nonverbal memory, executive
control manifesting with innapropriate
social behaviors, and had deficits on tests
of category formation, cognitive flexibility,
and abstract reasoning
[277,278]
Patient B. is important, as this case showed that despite bilateral destruction of the
insula, which caused the olfactory and taste changes, he had normal emotional reactions
and feelings. Thus, the authors concluded that it is the subcortical level that ensures basic
feeling states, while the cortical level of emotion processing probably largely relates feeling
states to cognitive processes, such as decision-making and imagination [
183
]. Similar to
patient B, patient Roger also had bilateral herpes simplex damage to the insula, ACC, and
amygdala [
184
]. The patient’s cognitive abilities were within normal ranges, including
speech, language, attention, working memory, and metacognition. His major deficits in-
cluded global amnesia, anosmia, and ageusia, while his pain experience was not impaired
(but sometimes even intensified), confirming that the insula, ACC, and amygdala (struc-
tures of a putative “pain matrix” that has been suggested to reflect the affective dimension
of pain) are not necessary for feeling the suffering inherent to pain. Roger’s heightened
degree of pain affect actually suggests that these regions may be more important for the
regulation of pain rather than providing substrate for pain’s conscious experience [184].
Regardless of the fact that in patients such as S.M. [
279
–
281
] and A.P. [
277
], due to
calcification of the amygdala, the dominant finding was a loss of fear, it should be em-
phasized once again that the amygdala (especially the left amygdala) is not only involved
in generating and processing the emotion of fear, but also with other types of emotional
signals, including the generation of loss aversion, including monetary loss aversion, by
inhibiting actions with potentially deleterious outcomes [
278
]. When tested, patients A.P.,
A.M., and B.G. showed a greater tendency than the controls to rate occluded-face stimuli
(occluded-face stimuli contain less information than whole-face stimuli) as more approach-
able than whole faces, which suggests that the amygdala’s role in approach behavior
extends beyond responses to specific stimuli [
282
]. The electrophysiological and fMRI
studies demonstrated that individuals with unilateral or bilateral amygdala injuries have
also significantly impaired recognition of a number of different social emotions, such as
guilt and adoration, compared to control groups [
4
,
283
,
284
]. The fact that these individuals
are more likely to have significantly impaired recognition of social rather than fundamental
emotions further confirms that the amygdala also specializes in processing stimuli with
complex social meaning and significance.
12. The Role of the Amygdala in Sensation Seeking, Psychosis, Major Depression and
Other Psychiatric Disorders
Distinct morphological and functional features of the amygdala have been reported
across psychiatric disorders. The amygdala plays a key role in both emotional processing
and stress response; alterations in amygdala neural activation on emotional tasks were re-
ported in patients with disorders associated with stress and disturbed emotional perception,
such as affective disorders. However, amygdala reactivity on specific cues was not uniform
across the affective disorders spectrum, given the different amygdala activation patterns
during emotion processing in unipolar depression and bipolar disorder. Of note, the major-

Biomolecules 2021,11, 823 42 of 58
ity of fMRI studies showed greater amygdala activation on negative emotional stimuli in
unipolar depression than in bipolar disorder, while the opposite was reported for positive
stimuli [285]. While increased amygdala activation was observed in patients with bipolar
disorder across all illness phases, similar findings were also observed during attention
tasks that had no emotional components, suggesting the additional role of the amygdala in
cognition [
286
]. A recent meta-analysis reported smaller amygdala volumes in participants
with major depressive disorder (MDD) compared to healthy controls, although greater
differences between groups were observed for hippocampal volume [
287
]. Interestingly,
amygdala volumes in bipolar patients did not differ from healthy controls [288].
Negative emotions that are induced by telling a subject that a painful stimulation will
be delivered shortly may result in either amplification of pain if a mild pain stimulus is
delivered (hyperalgesia) or in the perception of pain when a tactile stimulus is applied
(allodynia) [
279
]. In other words, anxiety about pain activates brain circuits that may
increase or decrease the feeling of pain. Using this paradigm, neuroimaging studies
in patients with MDD compared with healthy controls showed significantly lateralized
perception of pain in depressed patients, as thermal pain tolerance and electrical pain
tolerance were significantly increased on the right hand side [
280
], and impaired ability to
modulate pain experience in MDD patients, due to increased emotional reactivity during
the anticipation of pain. Subjects with MDD compared with healthy controls showed
increased activation in the right anterior insula, dorsal part of the ACC, and right amygdala
during anticipation of painful, relative to nonpainful, stimuli, increased activation in
the right amygdala and decreased activation in the PAG, rostral ACC and PFC during
painful stimulation relative to nonpainful stimulation, and greater activation in the right
amygdala during anticipation of pain, which was associated with greater levels of perceived
helplessness [281].
A recent metaanalysis comprising 1141 patients and 1242 healthy controls in 54 studies
showed that both young and adult patients with MDD showed abnormal neural activities
in the ACC, insula, superior and middle temporal gyrus, and occipital cortex during
emotional processing. However, hyperactivities in the superior and mid frontal gyrus,
amygdala, and hippocampus were observed only in adult patients, while hyperactivity
in the striatum was only found in young patients compared to the controls [
289
]. Apart
from the fact that both young and adult patients with MDD have the negative processing
bias during emotional processing, these findings suggest that adult patients with MDD are
more subject to impaired appraisal and emotional reactivity, while young patients with
MDD are more prone to an impaired perception process [
289
]. After comparing 313 MDD
patients with 283 healthy controls, another metaanalysis of the resting-state functional
activity in medication-naïve patients with their first episode of MDD revealed that MDD
patients had significant and robust resting-state hyperactivity, mainly in the left amygdala
and the left hippocampus [
290
]. These results confirmed the earlier notion that the left
hyperactive amygdala in depression affects both the onset and maintenance of emotional
dysfunction by eliciting dysfunctional negative biases at automatic stages of affective
information processing [291].
Real-time fMRI coupled with neurofeedback allows a person to see and regulate the
localized hemodynamic signal from his or her own brain. Using this method, an applied
neurofeedback training was given to healthy and depressed individuals with the amygdala
as the neurofeedback target to increase the hemodynamic response during positive autobi-
ographical memory recall. The initial results of this approach are encouraging and suggest
its clinical potential in alleviating symptoms of depression [
292
], especially stress-induced
depression [293].
In sharp contrast to MDD, patients with schizophrenia, even in the early phase, had
smaller amygdala volumes relative to both healthy groups and bipolar patients [
288
].
Patients with schizophrenia had also decreased structural connectivity between the amyg-
dala and orbitofrontal cortex and abnormal resting-state functional connectivity with the
medial prefrontal cortices [
288
]. Such findings may be related to specific symptoms of

Biomolecules 2021,11, 823 43 of 58
schizophrenia. For example, increased amygdala activity may have a role in distress and
the perception of threat, related to auditory hallucinations [
294
]. There are also important
differences in the nature of motivational deficits associated with psychosis vs. depression.
Namely, depressive individuals, particularly those who experience anhedonia, have the
presence of impairments in in-the-moment hedonics (“liking”), and such deficits may prop-
agate forward to impairments in other constructs that are dependent on reward responses,
such as anticipation, learning, effort, and action selection, which could reflect alterations in
dopaminergic and opioid signaling in the striatum related to depression or specifically to
anhedonia in depressed people [
295
]. In contrast, there is relatively intact in-the-moment
hedonic processing in psychosis, but there are impairments in other components involved
in translating reward to action selection. In particular, psychotic individuals exhibit al-
tered reward prediction and associated striatal and prefrontal activation, impaired reward
learning, and impaired reward-modulated action selection [295].
Individuals with sensation-seeking traits have generally higher thresholds for threat
detection, which may arise from amygdala—inferior frontal gyrus interaction. Inferior
frontal gyrus suppresses amygdala activity, resulting in feeling less fear, which may result in
reckless behavior of drug abuse [
296
]. Sensation seeking is associated with an initial blunted
amygdala response [
297
], which may result in pursuing more stimulating rewards, using
risky and reckless behavior. Sensation (novelty) seeking is defined as the motivation to seek
out novel, complex, and arousing experiences and is one of the three main independent
dimensions of temperament (the other two being reward dependence and harm avoidance)
and one of the four main independent dimentions of impulsivity (the other three being
lack of premeditation, lack of persistence, and urgency) [
298
]. Impulsivity is considered a
major endophenotype associated with disorders of behavioral control, such as substance
use and pathological gambling, as well as co-morbid neuropsychiatric disorders, such as
bipolar disorder and borderline personality disorder [299].
Adolescents endorse greater sensation- and novelty-seeking motivation and reduced
behavioral markers of anxiety than adults (with the peak of sensation seeking coming
and going earlier in females than in males). From an evolutionary perspective, orienta-
tion toward novelty seeking and risky actions could represent an advantageous mode
of interacting with the environment during adolescence, given the heightened demands
on adolescents to find novel territories, mates, and resources [
300
]. Sensation seeking is
closely related to the extent to which adolescents utilize emotionally relevant information
in decision-making, e.g., concerning the gain and loss of territories, mates, and resources.
Using the Iowa Gambling Task to quantify approach vs. avoidance-based decision-
making in children, adolescents, and young adults, Cauffman and colleagues (2010) [301]
found that levels of approach toward potential reward took on a curvilinear function, with
the maximal sensitivity to positive feedback and risky choices (including risky [unpro-
tected] sexual behavior) occurring during the adolescent years (peaks in late adolescence
around ages 18–20; in contrast, use of negative feedback to avoid negative outcomes
strengthen with age in a linear manner, not showing full maturity until the adult years).
This age trend of sensation seeking has been replicated across many cultures [
302
,
303
] and
confirms the conventional wisdom saying that people become more cautious and conserva-
tive with age. However, adolescents do not reveal these tendencies in all situations, but only
in the arousing, thrilling contexts [
304
,
305
], when they tend to disregard information about
the odds of gain and loss and report greater reliance on “gut-level” and “excitement” cues
to shape their choices, ultimately impairing their performance. The social context has been
shown also to propel adolescents’ decision-making in the direction of risk. Adolescents
are more likely to make dangerous moves while driving in the presence of peers [
306
] and
are more prone to deviant behavior when with others than when alone [
307
]. It still needs
to be clarified which of the proposed potential mechanisms predominantly underlie peer
influence: enhanced desire to impress, peers introducing a “cognitive load”, the capacity
for peers to shift orientation toward reward, or heightened physiological and emotional
arousal in the context of peer evaluation [308].

Biomolecules 2021,11, 823 44 of 58
There is substantial evidence that some alleles in the dopaminergic system (such
as those for COMT,DAT1,MAOA, and genes for dopamine receptors, especially DRD4
and DRD2) and the serotonin-transporter-linked polymorphic region (5-HTTLPR) gene
variants are related to executive attention, temperament, attachment, psychosis risk, and
sensation seeking [
309
,
310
]. One of these genes, the gene for the dopamine receptor 4
(DRD4) in chromosome 11, was found to influence sensation-seeking behavior as early
as 18–20 months in interaction with the quality of parenting [
311
]: when the 7-repeat
allele was present, relatively low-quality parenting produced higher sensation-seeking
ratings, but when the 7-repeat allele was absent, sensation seeking was moderate and low,
regardless of parenting quality. This finding of the susceptibility of children and adults
with the 7-repeat allele to parental and other environmental influences has been replicated
many times [
312
–
314
], supporting the view that reward processing in appetitive motivation
has an important role in sensation seeking. Besides sensation seeking in toddlers when
combined with poor parenting, DRD4 gene polymorphisms have been associated with
several other phenotypes, including an increased risk of attention deficit hyperactivity
disorder (ADHD), impulsivity, and lower levels of response inhibition [311,315].
On a number of occasions, patient S. M. reported a high level of excitement and
enthusiasm while riding a rollercoaster and also wanted to try skydiving [
316
]. While
these observations suggest a high level of “sensation seeking”, in everyday life S.M. rarely
engaged in purposeful risk-taking behavior, perhaps due to her inability to afford such
activities [316].
Altogether, these results suggest that damage of the amygdala causes behavioral
disinhibition that may interact with unemotional traits in a number of ways. Low levels
of fear may result in unresponsiveness to parental discipline, ambivalence about parental
or peer disproval, and low levels of anxiety in response to one’s own misbehavior [
317
].
These factors conceivably combine to produce a child who is unafraid of being disciplined,
unmotivated to behave appropriately, and unable to feel remorse for his or her misbehav-
ior. Therefore, disinhibition may represent a risk factor for reactive aggression as well
as for sensation seeking and a lack of empathy and remorse. Reactive aggression and
psychopathology both implicate hypoactivity of both the amygdala and OFC [318,319].
13. Decision-Making and Interdependence of Emotion and Cognition
The ability to anticipate the outcome, as well as the time available for reaching a
decision, play important roles in decision-making, too. Only humans and some non-
human primates, and perhaps some other species (elephants, dolphins), can be surprised
when events do not unfold as expected [
320
]. Surprise, one of the primary emotions, is
the reflection of the uncertainty of the outcome and the connection between cognition and
affect since it simultaneously involves probability estimation, intuition and the expected
reward, and, depending on the outcome, secondary emotions of sadness or rejoicing arise.
The pattern of brain activity during surprise mostly includes the inferior frontal gyrus of
the right hemisphere, followed by the ventrolateral OFC and the attention-related areas of
the cingulate cortex and precuneus. As the response time is faster, the more emotionally
charged the stimulus is, emotions accelerate the resolution of such conflicts and reduce the
time for which the individual is unable to (re)act [
321
]. As stated earlier, such monitoring
for possible conflicts and an intuitive system of emotional go/no-go decisions are mediated
by neurons of the ACC, whose main feature is the high speed of decision-making since
they do not search for the best possible answer, but only the emotional dimension of a
better immediate answer that gives a higher probability of survival.
The belief that reason and feelings are separate systems has a long history in Western
philosophy, literature, and science. However, cognition and emotion are today understood
as interrelated phenomena, and their integrated action is necessary for normal adaptive
functioning [
322
,
323
]. Neural circuits underlying emotions and cognition are in constant
interaction with one another and, as such, they affect attention and perception, decision-
making and reasoning in a complementary fashion [
324
]. It is a reciprocal relationship,

Biomolecules 2021,11, 823 45 of 58
hence emotional states can strongly influence selective attention, working memory, and
cognitive control; similarly, attention and working memory contribute to the voluntary
regulation of emotions [325,326].
The findings from human studies are consistent with those obtained from animals.
For example, studies using fMRI have shown increased levels of activity in the amygdala
in response to a neutral stimulus paired with an aversive event compared to a neutral
stimulus that did not anticipate an aversive event [
327
]. Moreover, finding that patients
with damage to the amygdala do not show a conditioned, autonomic response to visual or
auditory stimuli is also consistent with the results of animal studies [
328
]. The amygdala is
involved in the development of phobias as well as in the maintenance of specific fears and
generalized anxiety, together with the vmPFC [329–331].
Studies of the effects of emotions on attention have shown that emotionally charged
stimuli are more likely to reach consciousness in situations where attention capacities are
limited and that the amygdala plays a key role in mediating that effect [
332
,
333
]. Generally,
the effect of emotions on memory is two-fold: in certain conditions, emotions improve
memory, and in others they interfere with it, depending on the networks used. Using exper-
imental tasks of working and episodic memory with simultaneous imaging of brain activity,
the effect of amygdala activation results in emotional distractors having a short-term neg-
ative effect on working memory, and a long-term positive effect on improving episodic
memory through increased activity of the amygdala and hippocampus in combination
with decreased activity of the dlPFC, combined with increased activity of the ventrolateral
PFC (vlPFC) [
324
,
334
]. Moreover, people that are more sensitive to the disruptive effects
of emotions on working memory showed a higher degree of amygdala activity and a
lower activity of PFC. A better understanding of the mechanisms that mediate the different
effects of emotions on cognition is definitely a way to understand affective disorders, such
as anxiety and depression, since in these disorders this interaction is dysfunctional. As
the amygdala participates in the consolidation of fear-related memories, its dysfunction
is thought to either lower or raise the threshold for activation in anxious situations. If
it becomes too low, hyperactive anxiety states and phobias can occur during negative
conditioning or learning aversive reactions. Individual differences in the volume and
concentration of the gray matter of the amygdala may also underlie the association be-
tween personality traits, especially extraversion and neuroticism. For example, one study
showed that extraversion is positively correlated with the concentration of gray matter in
left amygdala, while neuroticism is negatively correlated with gray matter concentration in
the right amygdala [330,335].
The lateral prefrontal cortex (lPFC) is considered a major area of integration of emotion
and cognition [
336
–
340
]. However, it is not a single area of the brain that has this supervi-
sory role, but instead a series of dynamically interconnected neural networks of which the
central places are occupied by hubs of connections that are critical for the regulation of in-
formation flow and the integration of information between the dlPFC, vlPFC, OFC, vmPFC,
ACC, cerebral cortex of the intraparietal sulcus, anterior insula, and amygdala [
335
,
339
]. In
addition, the anterior insula critically limits the capacity of the cognitive control network
to mediate the coordination of thoughts, feelings and actions [
340
]. Emotions can be un-
derstood only in the context of adaptive, synchronized interactions of widely distributed
cortical and subcortical neural networks that mediate complex adaptive behaviors, such
as perception, cognition, motivation, and actions in which the amygdala plays a central
modulatory role [
339
,
341
–
343
]. Human intelligence arises from the complex interaction
of cognitive processes that are modified by different levels of emotional self-awareness
and motivation. Awareness of one’s emotions and feelings and the ability to empathize
and use judgment are required abilities and skills to enable cognitive embodiment, social
awareness and self-regulation of cognitive processes.
Author Contributions:
Conceptualization, G.Š.; writing—original draft preparation, G.Š.; writing—
review and editing, all authors. All authors have read and agreed to the published version of the
manuscript.

Biomolecules 2021,11, 823 46 of 58
Funding:
The work of G.Š. is funded by the Croatian Science Foundation grant IP-2019-04-3584
and in part by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience
CoRE-NEURO (“Experimental and clinical research of hypoxic-ischemic damage in perinatal and
adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional
Development Fund).
Acknowledgments:
G.Š., M.T., D.M., M.Š. and M.V. published a comparable version of this work in
the Croatian language throughout several book chapters in 2020 [343].
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
A (AMY)—amygdala
5-HT—5-hydroxytryptamine (serotonin)
ACC—anterior cingulate cortex
AMPAR—α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
ANS—autonomic nervous system
AP-1—transcription factor activating protein 1
ATP/Ado—adenosine triphosphate/adenosine
BA—Brodmann’s area
BF—basal forebrain
BLA—basolateral nucleus of amygdala
BNST—bed nucleus of stria terminalis
BPD—borderline personality disorder
CE—central nucleus of amygdala
CN—caudate nucleus
CNS—central nervous system
Co—cortical nucleus of amygdala
CPRN—caudal pontine reticular nucleus
CRH/CRF—corticotropin releasing hormone/factor
CS—conditioned stimulus
DA—dopamine
dlPFC—dorsolateral prefrontal cortex
dmPFC—dorsomedial prefrontal cortex
DRN—dorsal raphe nucleus
DSM-5—Diagnostic and Statistica Manual of mental disorders, 5th revision
DTN—dorsal tegmental nucleus
EC—entorhinal cortex
EEG—electroencephalogram
FLAIR—fluid attenuated inversion recovery MRI sequence
fMRI—functional magnetic resonance imaging
GABA—gamma (γ) aminobutyric acid
GAD—generalized anxiety disorder
H—hippocampus
HF—hippocampal formation
IN—intercalated neurons of the amygdala
ICD-10—International Classification of Diseases, 10th revision
LA—lateral nucleus of amygdala
LC—locus coeruleus
LH—lateral hypothalamus
lPFC—lateral prefrontal cortex
LTD—long-term depression
LTP—long-term potentiation
MDD—major depressive disorder
MDMA—3,4-methylenedioxymethamphetamine (ecstasy)
ME—medial nucleus of amygdala

Biomolecules 2021,11, 823 47 of 58
MGN—medial geniculate nucleus of thalamus
mPFC—medial prefrontal cortex
NAc—nucleus accumbens septi
NAc MNS—medium spiny neurons of NAc
N. V—trigeminal nerve
N. VII—facial nerve
NMDAR—N-methyl-D-aspartate receptors
OFC—orbitofrontal cortex
OXT—oxytocin
P—putamen
PAG—periaqueductal gray
PBN—parabrachial nuclei
PCC—posterior cingulate cortex
PL—paralaminar nucleus
PNS—peripheral nervous system
PTSD—post-traumatic stress disorder
PVN—periventricular nucleus
rmPFC—rostromedial prefrontal cortex
RMTg—rostromedial tegmental nucleus
BDNF—brain-derived neurotrophic factor
DTI—diffusion tensor imaging
SNc—substantia nigra, pars compacta
TBI—traumatic brain injury
UC—unconditioned stimulus
vlPFC—ventrolateral prefrontal cortex
vmPFC—ventromedial prefrontal cortex
VPL—ventroposterolateral nucleus of thalamus
VPM—ventroposteromedial nucleus of thalamus
VTA—ventral tegmental area
References
1. Vingerhoets, A.; Nykliˇcek, I.; Denollett, J. Emotion Regulation: Conceptual and Clinical Issues; Springer: New York, NY, USA, 2008.
2.
Graˇcanin, A.; Kardum, I. Primary emotions as modular mechanisms of the human mind. In Brain and Mind: A Lasting Challenge;
Žebec, M.S., Sabol, G., Šaki´c, M., Topi´c, M.K., Eds.; Institute of Social Sciences “Ivo Pilar”: Zagreb, Croatia, 2006; pp. 89–103.
3. Fox, E. Emotion Science; J.B. Metzler: Stuttgart, Germany, 2008.
4. Adolphs, R.; Anderson, D.J. The Neuroscience of Emotion: A New Synthesis; Princeton University Press: Princeton, NJ, USA, 2018.
5. Ekman, P. An argument for basic emotions. Cogn. Emot. 1992,6, 169–200. [CrossRef]
6.
Keltner, D.; Ekman, P. Facial expression of emotion. In Handbook of Emotions, 2nd ed.; Lewis, M., Haviland-Jones, J., Eds.; Guilford
Publications: New York, NY, USA, 2000; pp. 236–249.
7.
Keltner, D.; Ekman, P.; Gonzaga, G.C.; Beer, J. Facial expression of emotion. In Handbook of Affective Sciences; Davidson, R.J.,
Scherer, K.R., Goldsmith, H.H., Eds.; Oxford University Press: New York, NY, USA, 2003; pp. 415–432.
8.
Matsumoto, D.; Ekman, P. American-Japanese cultural differences in intensity ratings of facial expressions of emotion. Motiv.
Emot. 1989,13, 143–157. [CrossRef]
9.
Wikimedia Commons: Images. Available online: https://commons.wikimedia.org/wiki/Category:Images (accessed on
25 April 2021).
10.
Šimi´c, G.; Vuki´c, V.; Kopi´c, J.; Krsnik, Ž.; Hof, P.R. Molecules, mechanisms, and disorders of self-domestication: Keys for
un-derstanding emotional and social communication from an evolutionary perspective. Biomolecules
2020
,11, 2. [CrossRef]
[PubMed]
11. Darwin, C. The Expression of the Emotions in Man and Animals; Murray: London, UK, 1872.
12.
Cosmides, L.; Tooby, J. Evolutionary psychology and the emotions. In Handbook of Emotions; Lewis, M., Haviland-Jones, J.M., Eds.;
The Guilford Press: New York, NY, USA, 2000.
13. Dolan, R.J. Emotion, Cognition, and Behavior. Science 2002,298, 1191–1194. [CrossRef] [PubMed]
14.
Al-Shawaf, L.; Conroy-Beam, D.; Asao, K.; Buss, D.M. Human Emotions: An Evolutionary Psychological Perspective. Emot. Rev.
2015,8, 173–186. [CrossRef]
15.
Sergi, G. Principi di Psicologie: Dolore e Piacere. Storia Naturale dei Sentimenti; Dumolard, F., Ed.; Librai Della Real Casa: Milan, Italy,
1894.
16. Lange, C. The Emotions; Dunlap, E., Ed.; Williams & Wilkins: Baltimore, MA, USA, 1885.

Biomolecules 2021,11, 823 48 of 58
17. James, W. What is an emotion? Mind 1884,34, 188–205. [CrossRef]
18. Wickens, A. Introduction to Biopsychology; Pearson: Harlow, UK, 2009.
19. Damasio, A.R. The Feeling of What Happens. Body and Emotion in Making of Consciousness; Heinemann: London, UK, 1999.
20.
Damasio, A.R. The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philos. Trans. R. Soc. B Biol. Sci.
1996,351, 1413–1420. [CrossRef]
21.
Dunn, B.D.; Dalgleish, T.; Lawrence, A.D. The somatic marker hypothesis: A critical evaluation. Neurosci. Biobehav. Rev.
2006
,30,
239–271. [CrossRef] [PubMed]
22.
Horoufchin, H.; Bzdok, D.; Buccino, G.; Borghi, A.M.; Binkofski, F. Action and object words are differentially anchored in the
sensory motor system—A perspective on cognitive embodiment. Sci. Rep. 2018,8, 6583. [CrossRef] [PubMed]
23. Barbalet, J.M. William James’ Theory of Emotions: Filling in the Picture. J. Theory Soc. Behav. 1999,29, 251–266. [CrossRef]
24.
Bechara, A.; Damasio, A.R. The somatic marker hypothesis: A neural theory of economic decision. Games Econ. Behav.
2005
,52,
336–372. [CrossRef]
25.
Eshafir, T.; Tsachor, R.P.; Welch, K.B. Emotion Regulation through Movement: Unique Sets of Movement Characteristics are
Associated with and Enhance Basic Emotions. Front. Psychol. 2016,6, 2030. [CrossRef]
26.
Lewis, M.B.; Bowler, P.J. Botulinum toxin cosmetic therapy correlates with a more positive mood. J. Cosmet. Dermatol.
2009
,8,
24–26. [CrossRef]
27.
Coles, N.A.; Larsen, J.T.; Lench, H.C. A meta-analysis of the facial feedback literature: Effects of facial feedback on emotional
experience are small and variable. Psychol. Bull. 2019,145, 610–651. [CrossRef]
28.
Ansfield, M.E. Smiling When Distressed: When a Smile Is a Frown Turned Upside Down. Pers. Soc. Psychol. Bull.
2007
,33,
763–775. [CrossRef]
29.
Kraft, T.L.; Pressman, S.D. Grin and bear it: The influence of manipulated facial expression on the stress response. Psychol. Sci.
2012,23, 1372–1378. [CrossRef]
30.
Ekman, P.; Levenson, R.W.; Friesen, W.V. Autonomic nervous system activity distniguishes among emotions. Science
1983
,221,
1208–1210. [CrossRef]
31.
Harro, J.; Vasar, E. Cholecystokinin-induced anxiety: How is it reflected in studies on exploratory behavior? Neurosci. Biobehav.
Rev. 1991,15, 473–477. [CrossRef]
32.
Sears, R.M.; Fink, A.E.; Wigestrand, M.B.; Farb, C.R.; de Lecea, L.; Ledoux, J.E. Orexin/hypocretin system modulates amyg-dala-
dependent threat learning through the locus coeruleus. Proc. Natl. Acad. Sci. USA 2013,110, 20260–20265. [CrossRef]
33. Cannon, W.B. Organization for physiological homeostasis. Physiol. Rev. 1929,9, 399–431. [CrossRef]
34.
Cannon, W.B.; Britton, S.W. Studies on the conditions of activity in endocrine glands: XV. Pseudaffective medulliadrenal se-cretion.
Am. J. Physiol. 1925,72, 283–294. [CrossRef]
35.
Bard, P. A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system. Am. J.
Physiol. Content 1928,84, 490–515. [CrossRef]
36.
Bard, P. On emotional expression after decortication with some remarks on certain theoretical views: Part, I. Psychol. Rev.
1934
,41,
309–329. [CrossRef]
37.
Bard, P.; Rioch, D.M. A study of four cats deprived of neocortex and additional portions of the forebrain. Bull. Johns Hopkins Hosp.
1937,60, 73–147.
38.
Breedlowe, S.; Watson, N.; Rosenzweig, M. Biological Psychology: An. Introduction to Behavioral, Cognitive, and Clinical Neuroscience,
7th ed.; Sinauer Associates: Sunderland, MA, USA, 2010.
39. Akert, K. Walter Rudolf Hess (1881–1973) and His Contribution to Neuroscience. J. Hist. Neurosci. 1999,8, 248–263. [CrossRef]
40. Panksepp, J. Toward a general psychobiological theory of emotions. Behav. Brain Sci. 1982,5, 407–422. [CrossRef]
41.
Panksepp, J.; Zellner, M.R. Towards a neurobiologically based unified theory of aggression. Rev. Int. Psychol. Soc.
2004
,17, 37–62.
42.
Mineka, S.; Keir, R.; Price, V. Fear of snakes in wild- and laboratory-reared rhesus monkeys (Macaca mulatta). Learn. Behav.
1980
,
8, 653–663. [CrossRef]
43.
Schachter, S.; Singer, J. Cognitive, social, and physiological determinants of emotional state. Psychol. Rev.
1962
,69, 379–399.
[CrossRef]
44. Young, P.T.; Arnold, M.B. Emotion and Personality. Am. J. Psychol. 1963,76, 516. [CrossRef]
45. Smith, C.A.; Ellsworth, P.C. Patterns of cognitive appraisal in emotion. J. Pers. Soc. Psychol. 1985,48, 813–838. [CrossRef]
46. Ellsworth, P.C. Appraisal Theory: Old and New Questions. Emot. Rev. 2013,5, 125–131. [CrossRef]
47. Lazarus, R.S. Thoughts on the relations between emotion and cognition. Am. Psychol. 1982,37, 1019–1024. [CrossRef]
48. Unsplashed.com: Free Picture. Available online: http://ww1.unsplashed.com/ (accessed on 25 April 2021).
49.
Bechara, A.; Damasio, A.R.; Damasio, H.; Anderson, S.W. Insensitivity to future consequences following damage to human
prefrontal cortex. Cognition 1994,50, 7–15. [CrossRef]
50.
Bechara, A.; Tranel, D.; Damasio, H. Characterization of the decision-making deficit of patients with ventromedial prefrontal
cortex lesions. Brain 2000,123, 2189–2202. [CrossRef]
51.
Lebel, C.; Walker, L.; Leemans, A.; Phillips, L.; Beaulieu, C. Microstructural maturation of the human brain from childhood to
adulthood. NeuroImage 2008,40, 1044–1055. [CrossRef]
52.
Burnett, S.; Blakemore, S.-J. The Development of Adolescent Social Cognition. Ann. N. Y. Acad. Sci.
2009
,1167, 51–56. [CrossRef]

Biomolecules 2021,11, 823 49 of 58
53.
Hiser, J.; Koenigs, M. The Multifaceted Role of the Ventromedial Prefrontal Cortex in Emotion, Decision Making, Social Cognition,
and Psychopathology. Biol. Psychiatry 2018,83, 638–647. [CrossRef]
54.
Reimann, M.; Bechara, A. The somatic marker framework as a neurological thory of decision-making: Review, conceptual
comparisons, and future. J. Econ. Psychol. 2010,31, 767–776. [CrossRef]
55. Damasio, A.R. Descartes’ Error: Emotion, Reason, and the Human Brain; Grosset/Putnam: New York, NY, USA, 1994.
56.
Damasio, A.R. William James and the modern neurobiology of emotion. In Emotion, Evolution, and Rationality; Evans, D., Cruse, P.,
Eds.; Oxford University Press: Oxford, UK, 2012.
57.
Damasio, A.R.; Carvalho, G.B. The nature of feelings: Evolutionary and neurobiological origins. Nat. Rev. Neurosci.
2013
,14,
143–152. [CrossRef]
58.
Gu, X.; Hof, P.R.; Friston, K.J.; Fan, J. Anterior insular cortex and emotional awareness. J. Comp. Neurol.
2013
,521, 3371–3388.
[CrossRef] [PubMed]
59.
Fagan, S.E.; Kofler, L.; Riccio, S.; Gao, Y. Somatic marker production deficits do not explain the relationship between psy-chopathic
traits and utilitarian moral decision making. Brain Sci. 2020,10, 303. [CrossRef] [PubMed]
60.
Feldman Barrett, L. The theory of constructed emotion: An active interference account of interoception and categorization. Soc.
Cogn. Affect. Neurosci. 2017,12, 1–23.
61.
Barrett, L.F.; Satpute, A.B. Historical pitfalls and new directions in the neuroscience of emotion. Neurosci. Lett.
2019
,693, 9–18.
[CrossRef] [PubMed]
62. Feldman Barrett, L. How Emotions are Made. The Secret Life of the Brain; Houghton Mifflin Harcourt: Boston, MA, USA, 2017.
63. Barrett, L.F. Emotions as natural kinds? Perspect. Psychol. Sci. 2006,1, 28–58. [CrossRef]
64.
Adolphs, R.; Gosselin, F.; Buchanan, T.W.; Tranel, D.; Schyns, P.; Damasio, A.R. A mechanism for impaired fear recognition after
amygdala damage. Nat. Cell Biol. 2005,433, 68–72. [CrossRef]
65.
Feinstein, J.S.; Buzza, C.; Hurlemann, R.; Follmer, R.L.; Dahdaleh, N.S.; Coryell, W.; Welsh, M.; Tranel, D.; Wemmie, J.A. Fear and
panic in humans with bilateral amygdala damage. Nat. Neurosci. 2013,16, 270–272. [CrossRef]
66.
Celeghin, A.; Diano, M.; Bagnis, A.; Viola, M.; Tamietto, M. Basic Emotions in Human Neuroscience: Neuroimaging and Beyond.
Front. Psychol. 2017,8, 1432. [CrossRef]
67. Sterling, P. Allostasis: A model of predictive regulation. Physiol. Behav. 2012,106, 5–15. [CrossRef]
68. Friston, K. The free-energy principle: A unified brain theory? Nat. Rev. Neurosci. 2010,11, 127–138. [CrossRef]
69.
Ohira, H. Predictive processing of interoception, decision-making, and allostasis: A computational framework and implications
for emotional intelligence. Psychol. Top. 2020,29, 1–16. [CrossRef]
70. LeDoux, J. Rethinking the Emotional Brain. Neuron 2012,73, 653–676. [CrossRef] [PubMed]
71. LeDoux, J.E. Anxious: Using the Brain to Understand and Treat. Fear and Anxiety; Penguin Boks: New York, NY, USA, 2015.
72. LeDoux, J.E. Semantics, Surplus Meaning, and the Science of Fear. Trends Cogn. Sci. 2017,21, 303–306. [CrossRef] [PubMed]
73. LeDoux, J.E. Synaptic Self ; Penguin Books: New York, NY, USA, 2002.
74. LeDoux, J.E. The Emotional Brain; Simon and Schuster: New York, NY, USA, 1996.
75.
Brown, R.; Lau, H.; LeDoux, J.E. Understanding the Higher-Order Approach to Consciousness. Trends Cogn. Sci.
2019
,23, 754–768.
[CrossRef]
76.
Schlitz, K.; Witzel, J.; Northoff, G.; Zierhut, K.; Gubka, U.; Fellmann, H.; Kaufmann, J.; Tempelmann, C.; Wiebking, C.; Bogerts, B.
Brain pathology in pedophilic offenders: Evidence of volume reduction in the right amygdala and related diencephalic structures.
Arch. Gen. Psychiatry. 2007,64, 737–746. [CrossRef]
77.
Pitkänen, A.; Savander, V.; LeDoux, J.E. Organization of intra-amygdaloid circuitries in the rat: An emerging framework for
understanding functions of the amygdala. Trends Neurosci. 1997,20, 517–523. [CrossRef]
78.
Luo, Q.; Holroyd, T.; Majestic, C.; Cheng, X.; Schechter, J.; Blair, R.J. Emotional automaticity is a matter of timing. J. Neurosci.
2010
,
30, 5825–5829. [CrossRef]
79.
Stock, J.V.D.; Tamietto, M.; Sorger, B.; Pichon, S.; Grezes, J.; de Gelder, B. Cortico-subcortical visual, somatosensory, and motor
activations for perceiving dynamic whole-body emotional expressions with and without striate cortex (V1). Proc. Natl. Acad. Sci.
USA 2011,108, 16188–16193. [CrossRef]
80.
Pourtois, G.; Schettino, A.; Vuilleumier, P. Brain mechanisms for emotional influences on perception and attention: What is magic
and what is not. Biol. Psychol. 2013,92, 492–512. [CrossRef]
81.
Shackman, A.J.; Fox, A.S. Contributions of the Central Extended Amygdala to Fear and Anxiety. J. Neurosci.
2016
,36, 8050–8063.
[CrossRef]
82.
Tamietto, M.; de Gelder, B. Neural bases of the non-conscious perception of emotional signals. Nat. Rev. Neurosci.
2010
,11,
697–709. [CrossRef]
83.
Öhman, A. Automaticity and the Amygdala: Nonconscious Responses to Emotional Faces. Curr. Dir. Psychol. Sci.
2002
,11, 62–66.
[CrossRef]
84.
Bornemann, B.; Winkielman, P.; Van Der Meer, E. Can you feel what you do not see? Using internal feedback to detect briefly
presented emotional stimuli. Int. J. Psychophysiol. 2012,85, 116–124. [CrossRef]
85.
Inman, C.S.; Bijanki, K.R.; Bass, D.I.; Gross, R.E.; Hamann, S.; Willie, J.T. Human amygdala stimulation effects on emotion
physiology and emotional experience. Neuropsychol. 2020,145, 106722. [CrossRef]

Biomolecules 2021,11, 823 50 of 58
86.
Anderson, A.K.; Phelps, E.A. Is the Human Amygdala Critical for the Subjective Experience of Emotion? Evidence of Intact
Dispositional Affect in Patients with Amygdala Lesions. J. Cogn. Neurosci. 2002,14, 709–720. [CrossRef]
87. Swanson, L.W.; Petrovich, G.D. What is the amygdala? Trends Neurosci. 1998,21, 323–331. [CrossRef]
88.
Heimer, L.; De Olmos, J.; Alheid, G.; Pearson, J.; Sakamoto, N.; Shinoda, K.; Marksteiner, J.; Switzer, R. The human basal forebrain.
Part II. In Handbook of Chemical Neuroanatomy; Elsevier: Amsterdam, The Netherlands, 1999; pp. 57–226.
89.
Amaral, D.G.; Price, J.L.; Pitkänen, A.; Carmichael, S.T. Anatomical organization of the primate amygdaloid complex. In The
Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction; Aggleton, J.P., Ed.; Wiley-Liss: New York, NY, USA,
1992; pp. 1–66.
90.
Price, J.L.; Russchen, F.T.; Amaral, D.G. The limbic region: II. The amygdaloid complex. In Handbook of Chemical Neuroanatomy; Vol.
Integrated Systems of the CNS (Part, I); Bjorklund, A., Hokfelt, T., Swanson, L.W., Eds.; Elsevier: Amsterdam, The Netherlands,
1987; pp. 279–388.
91.
Gloor, P. The amygdaloid system. In The Temporal Lobe and Limbic System; Gloor, P., Ed.; Oxford University Press: New York, NY,
USA, 1997; pp. 591–721.
92.
Barger, N.; Stefanacci, L.; Semendeferi, K. A comparative volumetric analysis of the amygdaloid complex and basolateral division
in the human and ape brain. Am. J. Phys. Anthr. 2007,134, 392–403. [CrossRef]
93.
Schumann, C.M.; Amaral, D.G. Stereological estimation of the number of neurons in the human amygdaloid complex. J. Comp.
Neurol. 2005,491, 320–329. [CrossRef]
94.
Pitkänen, A.; Amaral, D.G. Demonstration of projections from the lateral nucleus to the basal nucleus of the amygdala: A PHA-L
study in the monkey. Exp. Brain Res. 1991,83, 465–470. [CrossRef]
95.
Aggleton, J.P. A description of intra-amygdaloid connections in old world monkeys. Exp. Brain Res.
1985
,57, 390–399. [CrossRef]
96.
Pitkänen, A.; Kemppainen, S. Comparison of the distribution of calcium-binding proteins and intrinsic connectivity in the lateral
nucleus of the rat, monkey, and human amygdala. Pharmacol. Biochem. Behav. 2002,71, 369–377. [CrossRef]
97.
Smith, Y.; Paré, D. Intra-amygdaloid projections of the lateral nucleus in the cat: PHA-L anterograde labeling combined with
postembedding GABA and glutamate immunocytochemistry. J. Comp. Neurol. 1994,342, 232–248. [CrossRef]
98.
Agoglia, A.E.; Herman, M.A. The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry. Alcohol
2018
,72,
61–73. [CrossRef]
99. AbuHasan, Q.; Reddy, V.; Siddiqui, W. Neuroanatomy, Amygdala; StatPearls Publishing: Treasure Island, FL, USA, 2020.
100. Braak, H.; Braak, E. Neuronal types in the basolateral amygdaloid nuclei of man. Brain Res. Bull. 1983,11, 349–365. [CrossRef]
101. Spampanato, J.; Polepalli, J.; Sah, P. Interneurons in the basolateral amygdala. Neuropharmacology 2011,60, 765–773. [CrossRef]
102. Janak, P.H.; Tye, K.M. From circuits to behaviour in the amygdala. Nat. Cell Biol. 2015,517, 284–292. [CrossRef]
103.
Sangha, S.; Diehl, M.M.; Bergstrom, H.C.; Drew, M.R. Know safety, no fear. Neurosci. Biobehav. Rev.
2020
,108, 218–230. [CrossRef]
104.
Stefanacci, L.; Amaral, D.G. Some observations on cortical inputs to the macaque monkey amygdala: An anterograde tracing
study. J. Comp. Neurol. 2002,451, 301–323. [CrossRef]
105.
Cho, Y.T.; Ernst, M.; Fudge, J.L. Cortico-Amygdala-Striatal Circuits Are Organized as Hierarchical Subsystems through the
Primate Amygdala. J. Neurosci. 2013,33, 14017–14030. [CrossRef]
106. Ressler, R.L.; Maren, S. Synaptic encoding of fear memories in the amygdala. Curr. Opin. Neurobiol. 2019,54, 54–59. [CrossRef]
107.
Lee, S.-C.; Amir, A.; Haufler, D.; Pare, D. Differential Recruitment of Competing Valence-Related Amygdala Networks during
Anxiety. Neuron 2017,96, 81–88. [CrossRef]
108. Sah, P. Fear, anxiety and amygdala. Neuron 2017,96, 1–2. [CrossRef] [PubMed]
109.
Yang, Y.; Wang, J.-Z. From Structure to Behavior in Basolateral Amygdala-Hippocampus Circuits. Front. Neural Circuits
2017
,11,
86. [CrossRef] [PubMed]
110.
Price, J.; Amaral, D. An autoradiographic study of the projections of the central nucleus of the monkey amygdala. J. Neurosci.
1981,1, 1242–1259. [CrossRef] [PubMed]
111.
Orsini, C.A.; Maren, S. Neural and cellular mechanisms of fear and extinction memory formation. Neurosci. Biobehav. Rev.
2012
,
36, 1773–1802. [CrossRef] [PubMed]
112.
Pitkänen, A.; Amaral, D.G. Organization of the intrinsic connections of the monkey amygdaloid complex: Projections origi-nating
in the lateral nucleus. J. Comp. Neurol. 1998,398, 431–458. [CrossRef]
113.
Amaral, D.G.; Insausti, R. Retrograde transport of D-[3H]-aspartate injected into the monkey amygdaloid complex. Exp. Brain
Res. 1992,88, 375–388. [CrossRef] [PubMed]
114.
Kawaguchi, Y.; Aosaki, T.; Kubota, Y. Cholinergic and GABAergic interneurons in the striatum. Nihon Shinkei Seishin Yakurigaku-
Zasshi (Jpn. J. Psychopharmacol.) 1997,17, 87–90. [CrossRef]
115.
Bauman, M.D.; Amaral, D.G. The distribution of serotonergic fibers in the macaque monkey amygdala: An immunohisto-chemical
study using antisera to 5-hydroxytryptamine. Neuroscience 2005,136, 193–203. [CrossRef]
116.
Decampo, D.M.; Fudge, J.L. Where and what is the paralaminar nucleus? A review on a unique and frequently overlooked area
of the primate amygdala. Neurosci. Biobehav. Rev. 2012,36, 520–535. [CrossRef]
117. Millhouse, O.E. The intercalated cells of the amygdala. J. Comp. Neurol. 1986,247, 246–271. [CrossRef]
118. Jacobsen, K.X.; Höistad, M.; Staines, W.A.; Fuxe, K. The distribution of dopamine D1 receptor and m-opioid receptor 1 receptor
immunoreactivities in the amygdala and interstitial nucleus of the posterior limb of the anterior commissure: Relationships to
tyrosine hydroxylase and opioid peptide terminal systems. Neuroscience 2006,141, 2007–2018.

Biomolecules 2021,11, 823 51 of 58
119.
Amano, T.; Unal, C.T.; Paré, D. Synaptic correlates of fear extinction in the amygdala. Nat. Neurosci.
2010
,13, 489–494. [CrossRef]
120.
Likhtik, E.; Popa, D.; Apergis-Schoute, J.; Fidacaro, G.A.; Paré, D. Amygdala intercalated neurons are required for expression of
fear extinction. Nat. Cell Biol. 2008,454, 642–645. [CrossRef]
121.
Paré, D.; Royer, S.; Smith, Y.; Lang, E.J. Contextual Inhibitory Gating of Impulse Traffic in the Intra-amygdaloid Network. Ann. N.
Y. Acad. Sci. 2006,985, 78–91. [CrossRef]
122.
Adhikari, A.; Lerner, T.N.; Finkelstein, J.; Pak, S.; Jennings, J.H.; Davidson, T.J.; Ferenczi, E.A.; Gunaydin, L.A.; Mirzabekov, J.J.;
Ye, L.; et al. Basomedial amygdala mediates top-down control of anxiety and fear. Nat. Cell Biol. 2015,527, 179–185. [CrossRef]
123. Adolphs, R.; Tranel, D.; Damasio, H.; Damasio, A.R. Fear and the human amygdala. J. Neurosci. 1995,15, 5879–5891. [CrossRef]
124.
Roberto, M.; Kirson, D.; Khom, S. The Role of the Central Amygdala in Alcohol Dependence. Cold Spring Harb. Perspect. Med.
2021,11, a039339. [CrossRef]
125. McDonald, A.J. Cytoarchitecture of the central amygdaloid nucleus of the rat. J. Comp. Neurol. 1982,208, 401–418. [CrossRef]
126.
Pitkanen, A.; Amaral, D. The distribution of GABAergic cells, fibers, and terminals in the monkey amygdaloid complex: An
immunohistochemical and in situ hybridization study. J. Neurosci. 1994,14, 2200–2224. [CrossRef] [PubMed]
127.
McDonald, A.; Augustine, J. Localization of GABA-like immunoreactivity in the monkey amygdala. Neuroscience
1993
,52,
281–294. [CrossRef]
128.
Fudge, J.; Tucker, T. Amygdala projections to central amygdaloid nucleus subdivisions and transition zones in the primate.
Neuroscience 2009,159, 819–841. [CrossRef] [PubMed]
129.
Gauthier, I.; Nuss, P. Anxiety disorders and GABA neurotransmission: A disturbance of modulation. Neuropsychiatr. Dis. Treat.
2015,11, 165–175. [CrossRef]
130.
Aouad, M.; Charlet, A.; Rodeau, J.-L.; Poisbeau, P. Reduction and prevention of vincristine-induced neuropathic pain symptoms
by the non-benzodiazepine anxiolytic etifoxine are mediated by 3α-reduced neurosteroids. Pain 2009,147, 54–59. [CrossRef]
131.
Purdy, R.H.; Morrow, A.L.; Moore, P.H., Jr.; Paul, S.M. Stress-induced elevations of
γ
-aminobutyric acid type A receptor-active
steroids in the rat brain. Proc. Natl. Acad. Sci. USA 1991,88, 4553–4557. [CrossRef]
132.
Navratilova, E.; Nation, K.; Remeniuk, B.; Neugebauer, V.; Bannister, K.; Dickenson, A.H.; Porreca, F. Selective modulation of
tonic aversive qualities of neuropathic pain by morphine in the central nucleus of the amygdala requires endogenous opioid
signaling in the anterior cingulate cortex. Pain 2020,161, 609–618. [CrossRef]
133.
Nasagawa, M.; Mitsui, S.; En, S.; Ohtani, N.; Ohta, M.; Sukuma, Y.; Onaka, T.; Mogi, K.; Kikusui, T. Social evolution. Oxyto-cin-
gaze positive loop and the coevolution of human-dog bonds. Science 2015,348, 333–336. [CrossRef]
134. Gottschalk, M.G.; Domschke, K. Oxytocin and Anxiety Disorders. Curr. Top. Behav. Neurosci. 2017,35, 467–498.
135. Neugebauer, V.; Mazzitelli, M.; Cragg, B.; Ji, G.; Navratilova, E.; Porreca, F. Amygdala, neuropeptides, and chronic pain-related
affective behaviors. Neuropharmacology 2020,170, 108052. [CrossRef]
136. Gross, C.T.; Canteras, N.S. The many paths to fear. Nat. Rev. Neurosci. 2012,13, 651–658. [CrossRef]
137.
LeDoux, J.E.; Iwata, J.; Cicchetti, P.; Reis, D.J. Different projections of the central amygdaloid nucleus mediate autonomic and
behavioral correlates of conditioned fear. J. Neurosci. 1988,8, 2517–2529. [CrossRef]
138.
Gouveia, F.V.; Hamani, C.; Fonoff, E.T.; Brentani, H.; Alho, E.J.L.; De Morais, R.M.C.B.; De Souza, A.L.; Rigonatti, S.P.; Martinez,
R.C.R. Amygdala and Hypothalamus: Historical Overview With Focus on Aggression. Neurosurgery
2019
,85, 11–30. [CrossRef]
139.
Carmichael, S.T.; Clugnet, M.-C.; Price, J.L. Central olfactory connections in the macaque monkey. J. Comp. Neurol.
1994
,346,
403–434. [CrossRef]
140.
Keshavarzi, S.; Sullivan, R.K.; Ianno, D.J.; Sah, P. Functional Properties and Projections of Neurons in the Medial Amygdala. J.
Neurosci. 2014,34, 8699–8715. [CrossRef]
141.
Millhouse, O.E.; Uemura-Sumi, M. The structure of the nucleus of the lateral olfactory tract. J. Comp. Neurol.
1985
,233, 517–552.
[CrossRef]
142.
Vaz, R.P.; Cardoso, A.; Sá, S.I.; Pereira, P.; Madeira, M.D. The integrity of the nucleus of the lateral olfactory tract is essential for
the normal functioning of the olfactory system. Brain Struct. Funct. 2017,222, 3615–3637. [CrossRef]
143.
Zald, D.H.; Pardo, J.V. Emotion, olfaction, and the human amygdala: Amygdala activation during aversive olfactory stimulation.
Proc. Natl. Acad. Sci. USA 1997,94, 4119–4124. [CrossRef]
144. Johnston, J.B. Further contributions to the study of the evolution of the forebrain. J. Comp. Neurol. 1923,35, 337–481. [CrossRef]
145.
Jimenez-Castellanos, J. The amygdaloid complex in monkey studied by reconstructional methods. J. Comp. Neurol.
1949
,91,
507–526. [CrossRef] [PubMed]
146.
Van Hoesen, G. The differential distribution, diversity and sprouting of cortical projections to the amygdala in the rhesus monkey.
In The Amygdaloid Complex; Ben-Ari, Y., Ed.; Elsevier: Amsterdam, The Netherlands, 1981; pp. 77–90.
147.
Turner, B.H.; Gupta, K.C.; Mishkin, M. The locus and cytoarchitecture of the projection areas of the olfactory bulb inMacaca
mulatta. J. Comp. Neurol. 1978,177, 381–396. [CrossRef] [PubMed]
148.
Wiero´nska, J.M.; Nowak, G.; Pilc, A. Metabotropic Approaches to Anxiety. In Glutamate-Based Therapies for Psychiatric Disorders;
Springer: Berlin, Germany, 2010; pp. 157–173.
149.
Benarroch, E.E. The amygdala: Functional organization and involvement in neurologic disorders. Neurology
2014
,84, 313–324.
[CrossRef] [PubMed]

Biomolecules 2021,11, 823 52 of 58
150.
Partridge, J.G.; Forcelli, P.A.; Luo, R.; Cashdan, J.M.; Schulkin, J.; Valentino, R.J.; Vicini, S. Stress increases GABAergic neu-
rotransmission in CRF neurons of the central amygdala and bed nucleus stria terminalis. Neuropharmacology
2016
,107, 239–250.
[CrossRef] [PubMed]
151. Duvarci, S.; Pare, D. Amygdala Microcircuits Controlling Learned Fear. Neuron 2014,82, 966–980. [CrossRef] [PubMed]
152.
Li, M.; Ribas, E.C.; Wei, P.; Li, M.; Zhang, H.; Guo, Q. The ansa peduncularis in the human brain: A tractography and fiber
dissection study. Brain Res. 2020,1746, 146978. [CrossRef]
153.
Stefanacci, L.; Amaral, D.G. Topographic organization of cortical inputs to the lateral nucleus of the macaque monkey amygdala:
A retrograde tracing study. J. Comp. Neurol. 2000,421, 52–79. [CrossRef]
154.
Herry, C.; Ferraguti, F.; Singewald, N.; Letzkus, J.; Ehrlich, I.; Lüthi, A. Neuronal circuits of fear extinction. Eur. J. Neurosci.
2010
,
31, 599–612. [CrossRef]
155.
Nader, K.; Schafe, G.E.; Le Doux, J.E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.
Nat. Cell Biol. 2000,406, 722–726. [CrossRef]
156. Adolphs, R. The Biology of Fear. Curr. Biol. 2013,23, R79–R93. [CrossRef]
157.
Romanski, L.M.; Clugnet, M.C.; Bordi, F.; LeDoux, J.E. Somatosensory and auditory convergence in the lateral nucleus of the
amygdala. Behav. Neurosci. 1993,107, 444–450. [CrossRef]
158.
Halsell, C.B. Differential distribution of amygdaloid input across rostral solitary nucleus subdivisions in rat. Ann. N. Y. Acad. Sci.
1998,855, 482–485. [CrossRef]
159.
Gilpin, N.W.; Herman, M.A.; Roberto, M. The Central Amygdala as an Integrative Hub for Anxiety and Alcohol Use Disorders.
Biol. Psychiatry 2015,77, 859–869. [CrossRef] [PubMed]
160. Russchen, F.T.; Lohman, A.H.M. Afferent connections of the amygdala in the cat. Folia Anat. Iugosl. 1979,9(Suppl. S1), 57–63.
161. Veening, J. Cortical afferents of the amygdaloid complex in the rat: An HRP study. Neurosci. Lett. 1978,8, 191–195. [CrossRef]
162.
Asami, T.; Nakamura, R.; Takaishi, M.; Yoshida, H.; Yoshimi, A.; Whitford, T.J.; Hirayasu, Y. Smaller volumes in the lateral and
basal nuclei of the amygdala in patients with panic disorder. PLoS ONE 2018,13, e0207163. [CrossRef]
163.
Saunders, R.C.; Rosene, D.L.; Van Hoesen, G.W. Comparison of the efferents of the amygdala and the hippocampal formation in
the rhesus monkey: II. Reciprocal and non-reciprocal connections. J. Comp. Neurol. 1988,271, 185–207. [CrossRef]
164.
Insausti, R.; Amaral, D.G.; Cowan, W.M. The entorhinal cortex of the monkey: III. Subcortical afferents. J. Comp. Neurol.
1987
,264,
396–408. [CrossRef]
165.
Pitkänen, A.; Kelly, J.L.; Amaral, D.G. Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the
entorhinal cortex in the macaque monkey. Hippocampus 2002,12, 186–205. [CrossRef]
166.
Miller, L.A.; Taber, K.H.; Gabbard, G.O.; Hurley, R.A. Neural Underpinnings of Fear and Its Modulation: Implications for Anxiety
Disorders. J. Neuropsychiatry Clin. Neurosci. 2005,17, 1–6. [CrossRef]
167.
Kim, M.J.; Loucks, R.A.; Palmer, A.L.; Brown, A.C.; Solomon, K.M.; Marchante, A.N.; Whalen, P.J. The structural and func-tional
connectivity of the amygdala: From normal emotion to pathological anxiety. Behav. Brain Res. 2011,223, 403–410. [CrossRef]
168.
Besteher, B.; Gaser, C.; Nenadi´c, I. Brain Structure and Subclinical Symptoms: A Dimensional Perspective of Psychopathology in
the Depression and Anxiety Spectrum. Neuropsychobiology 2019,79, 270–283. [CrossRef]
169.
Šešo-Šimi´c, Ð.; Sedmak, G.; Hof, P.R.; Šimi´c, G. Recent advances in the neurobiology of attachment behavior. Transl. Neurosci.
2010,1, 148–159. [CrossRef]
170.
Apps, M.; Rushworth, M.F.; Chang, S.W. The Anterior Cingulate Gyrus and Social Cognition: Tracking the Motivation of Others.
Neuron 2016,90, 692–707. [CrossRef] [PubMed]
171.
Bauer, H.; Pripfl, J.; Lamm, C.; Prainsack, C.; Taylor, N. Functional neuroanatomy of learned helplessness. NeuroImage
2003
,20,
927–939. [CrossRef]
172.
Seligman, M.E.P. Erlernte Hilflosigkeit. Erweitert um Franz Petermann: Neue Konzepte und Anwendungen; Psycholo-gie-Verlags-Union:
Winheim, Germany, 1995.
173. LeDoux, J.E. Emotion circuits in the brain. Annu. Rev. Neurosci. 2000,24, 155–184. [CrossRef]
174.
Lane, R.D.; Reiman, E.M.; Axelrod, B.; Yun, L.S.; Holmes, A.; Schwartz, G.E. Neural correlates of emotional awareness. Evi-dence
of an interaction between emotion and attention in the anterior cingulate cortex. J. Cogn. Neurosci.
1998
,10, 525–535. [CrossRef]
175. Papez, J.W. A proposed mechanism of emotion. Arch. Neurol. Psychiatry 1937,38, 725. [CrossRef]
176.
Nimchinsky, E.A.; Vogt, B.A.; Morrison, J.H.; Hof, P.R. Spindle neurons of the human anterior cingul. Ate cortex. J. Comp. Neurol.
1995,355, 27–37. [CrossRef]
177.
Hyman, S.E.; Malenka, R.C.; Nestler, E.J. Neural mechanisms of addiction: The Role of Reward-Related Learning and Memory.
Annu. Rev. Neurosci. 2006,29, 565–598. [CrossRef]
178. Koob, G.F.; Le Moal, M. Neurobiology of Addiction; Elsevier: Berlin, Germany, 2006.
179.
Nauta, W.J. The problem of the frontal lobe: A reinterpretation. Princ. Pract. Posit. Neuropsychiatry Res.
1972
,3-4, 167–187.
[CrossRef]
180.
Walker, D.L.; Davis, M. Role of extended amygdala in short-duration versus sustained fear: A tribute to Dr. Lennart Heimer.
Brain Struct. Funct. 2008,213, 29–42. [CrossRef]
181.
Olucha-Bordonau, F.E.; Fortes-Marco, L.; Otero-García, M.; Lanuza, E.; Martínez-García, F. Amygdala: Structure and function. In
The Rat Nervous System, 4th ed.; Paxinos, G., Ed.; Academic Press: San Diego, CA, USA, 2015; pp. 441–490.

Biomolecules 2021,11, 823 53 of 58
182.
Tomer, R.; Slagter, H.A.; Christian, B.T.; Fox, A.S.; King, C.R.; Murali, D.; Gluck, M.A.; Davidson, R.J. Low to win or hate to lose?
Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward versus punishment. J. Cogn. Neurosci.
2014
,26,
1039–1048. [CrossRef] [PubMed]
183.
Damasio, A.; Damasio, H.; Tranel, D. Persistence of Feelings and Sentience after Bilateral Damage of the Insula. Cereb. Cortex
2012,23, 833–846. [CrossRef] [PubMed]
184.
Feinstein, J.S.; Khalsa, S.S.; Salomons, T.V.; Prkachin, K.M.; Frey-Law, L.A.; Lee, J.E.; Tranel, D.; Rudrauf, D. Preserved emo-tional
awareness of pain in a patient with extensive bilateral damage to the insula, anterior cingulate, and amygdala. Brain Struct. Funct.
2016,221, 1499–1511. [CrossRef]
185.
Salas, C.E. “No man is an island”: Recent findings on the emotional consequences of insula damage. Neuropsychoanalysis
2015
,17,
1–6. [CrossRef]
186.
Terasawa, Y.; Kurosaki, Y.; Ibata, Y.; Moriguchi, Y.; Umeda, S. Attenuated sensitivity to the emotions of others by insular lesion.
Front. Psychol. 2015,6, 1314. [CrossRef]
187.
Gu, X.; Liu, X.; Van Dam, N.T.; Hof, P.R.; Fan, J. Cognition–Emotion Integration in the Anterior Insular Cortex. Cereb. Cortex
2013
,
23, 20–27. [CrossRef]
188.
Spagna, A.; Dufford, A.J.; Wu, Q.; Wu, T.; Zheng, W.; Coons, E.E.; Hof, P.R.; Hu, B.; Wu, Y.; Fan, J. Gray matter volume of the
anterior insular cortex and social networking. J. Comp. Neurol. 2018,526, 1183–1194. [CrossRef]
189.
Craig, A.D. (Bud) Significance of the insula for the evolution of human awareness of feelings from the body. Ann. N. Y. Acad. Sci.
2011,1225, 72–82. [CrossRef]
190.
Craig, A.D. How do you feel. In An Interoceptive Moment with Your Neurobiological Self ; Princeton University Press: Princeton, NJ,
USA, 2015.
191. Gasquoine, P.G. Contributions of the Insula to Cognition and Emotion. Neuropsychol. Rev. 2014,24, 77–87. [CrossRef]
192.
Šimi´c, G.; Hof, P.R. In search of the definitive Brodmann’s map of cortical areas in human. J. Comp. Neurol.
2015
,523, 5–14.
[CrossRef]
193.
Mesulam, M.M. (Ed.) Principles of Behavioral and Cognitive Neurology, 2nd ed.; Oxford University Press: New York, NY, USA, 2000.
194.
Wicker, B.; Keysers, C.; Plailly, J.; Royet, J.P.; Gallese, V.; Rizzolatti, G. Both of us disgusted in my insula: The common neural
basis of seeing and feeling disgust. Neuron 2003,40, 655–664. [CrossRef]
195.
Weller, J.A.; Levin, I.P.; Shiv, B.; Bechara, A. The effects of insula damage on decision-making for risky gains and losses. Soc.
Neurosci. 2009,4, 347–358. [CrossRef]
196.
Humphrey, T. The development of the human amygdala during early embryonic life. J. Comp. Neurol.
1968
,132, 135–165.
[CrossRef]
197. Macchi, G. The ontogenic development of the olfactory telencephalon in man. J. Comp. Neurol. 1951,95, 245–305. [CrossRef]
198.
Muller, F.; O’Rahilly, R. The amygdaloid complex and the medial and lateral ventricular eminences in staged human embryos. J.
Anat. 2006,208, 547–564. [CrossRef]
199.
Crosby, E.C.; Humphrey, T. Studies of the vertebrate telencephalon. II. The nuclear pattern of the anterior olfactory nucleus,
tuberculum olfactorium and the amygdaloid complex in adult man. J. Comp. Neurol. 1941,74, 309–352. [CrossRef]
200.
Nikoli´c, I.; Kostovi´c, I. Development of the lateral amygdaloid nucleus in the human fetus: Transient presence of discrete
cy-toarchitectonic units. Anat. Embryol. 1986,174, 355–360. [CrossRef] [PubMed]
201.
Vasung, L.; Huang, H.; Jovanov-Miloševi´c, N.; Pletikos, M.; Mori, S.; Kostovi´c, I. Development of axonal pathways in the human
fetal fronto-limbic brain: Histochemical characterization and diffusion tensor imaging. J. Anat.
2010
,217, 400–417. [CrossRef]
[PubMed]
202.
Gilmore, J.H.; Knickmeyer, R.C.; Gao, W. Imaging structural and functional brain development in early childhood. Nat. Rev.
Neurosci. 2018,19, 123–137. [CrossRef] [PubMed]
203.
Saygin, Z.M.; Osher, D.E.; Koldewyn, K.; Martin, R.E.; Finn, A.; Saxe, R.; Gabrieli, J.D.; Sheridan, M. Structural Connectivity of
the Developing Human Amygdala. PLoS ONE 2015,10, e0125170. [CrossRef]
204.
Uematsu, A.; Matsui, M.; Tanaka, C.; Takahashi, T.; Noguchi, K.; Suzuki, M.; Nishijo, H. Developmental Trajectories of Amygdala
and Hippocampus from Infancy to Early Adulthood in Healthy Individuals. PLoS ONE 2012,7, e46970. [CrossRef]
205.
Ostby, Y.; Tamnes, C.K.; Fjell, A.M.; Westlye, L.T.; Due-Tønnessen, P.; Walhovd, K.B. Heterogeneity in subcortical brain de-
velopment: A structural magnetic resonance imaging study of brain maturation from 8 to 30 years. J. Neurosci.
2009
,29,
11772–11782. [CrossRef]
206.
Gabard-Durnam, L.J.; Flannery, J.; Goff, B.; Gee, D.G.; Humphreys, K.L.; Telzer, E.; Hare, T.; Tottenham, N. The development
of human amygdala functional connectivity at rest from 4 to 23years: A cross-sectional study. NeuroImage
2014
,95, 193–207.
[CrossRef]
207. Banham Bridges, K.M. Emotional Development in Early Infancy. Child. Dev. 1932,3, 324. [CrossRef]
208.
Liew, J. Effortful Control, Executive Functions, and Education: Bringing Self-Regulatory and Social-Emotional Competencies to
the Table. Child. Dev. Perspect. 2012,6, 105–111. [CrossRef]
209.
Lewis, M.D.; Granic, I. Phases of social-emotional development from birth to school age. In The Developmental Relations Among
Mind, Brain and Education: Essays in Honor of Robbie Case; Ferrari, M., Vuletic, Lj., Eds.; Springer: New York, NY, USA, 2010;
pp. 179–212.

Biomolecules 2021,11, 823 54 of 58
210.
Klüver, H.; Bucy, P.C. An Analysis of Certain Effects of Bilateral Temporal Lobectomy in the Rhesus Monkey, with Special
Reference to “Psychic Blindness”. J. Psychol. 1938,5, 33–54. [CrossRef]
211.
Weiskrantz, L. Behavioral changes associated with ablation of the amygdaloid complex in monkeys. J. Comp. Physiol. Psychol.
1956,49, 381–391. [CrossRef]
212. Das, J.M.; Siddiqui, W. Klüver Bucy Syndrome; StatPearls Publishing: Treasure Island, FL, USA, 2021.
213. Bartels, A.; Zeki, S. The neural basis of romantic love. NeuroReport 2000,11, 3829–3834. [CrossRef]
214.
Haller, J. The role of central and medial amygdala in normal and abnormal aggression: A review of classical approaches. Neurosci.
Biobehav. Rev. 2018,85, 34–43. [CrossRef]
215.
Blair, R.J. Neuroimaging of psychopathology and antisocial behavior: A targeted review. Curr. Psychiatry Rep.
2010
,12, 76–82.
[CrossRef]
216. Begi´c, D. Psychopathology; Medicinska Naklada: Zagreb, Croatia, 2014. (in Croatian)
217.
Bogerts, B.; Schöne, M.; Breitschuh, S. Brain alterations potentially associated with aggression and terrorism. CNS Spectrums
2017
,
23, 129–140. [CrossRef]
218.
Farah, T.; Ling, S.; Raine, A.; Yang, Y.; Schug, R. Alexithymia and reactive aggression: The role of the amygdala. Psychiatry Res.
Neuroimaging 2018,281, 85–91. [CrossRef]
219.
Wang, Y.; He, Z.; Zhao, C.; Li, L. Medial amygdala lesions modify aggressive behavior and immediate early gene expression in
oxytocin and vasopressin neurons during intermale exposure. Behav. Brain Res. 2013,245, 42–49. [CrossRef]
220.
Adebimpe, A.; Bassett, D.S.; Jamieson, P.E.; Romer, D. Intersubject Synchronization of Late Adolescent Brain Responses to Violent
Movies: A Virtue-Ethics Approach. Front. Behav. Neurosci. 2019,13, 260. [CrossRef]
221. Sun, Y.; Gooch, H.; Sah, P. Fear conditioning and the basolateral amygdala. F1000Research 2020,9, F1000. [CrossRef]
222. Bandelow, B.; Michaelis, S. Epidemiology of anxiety disorders in the 21st century. Dialogues Clin. Neurosci. 2015,17, 327–335.
223.
Molosh, A.I.; Dustrude, E.T.; Lukkes, J.L.; Fitz, S.D.; Caliman, I.F.; Abreu, A.R.R.; Dietrich, A.D.; Truitt, W.A.; Donck, L.V.;
Ceusters, M.; et al. Panic results in unique molecular and network changes in the amygdala that facilitate fear responses. Mol.
Psychiatry 2018,25, 442–460. [CrossRef]
224.
Madonna, D.; DelVecchio, G.; Soares, J.C.; Brambilla, P. Structural and functional neuroimaging studies in generalized anxiety
disorder: A systematic review. Rev. Bras. Psiquiatr. 2019,41, 336–362. [CrossRef]
225.
Janiri, D.; Moser, D.A.; Doucet, G.E.; Luber, M.J.; Rasgon, A.; Lee, W.H.; Murrough, J.W.; Sani, G.; Eickhoff, S.B.; Frangou, S.
Shared neural phenotypes for mood and anxiety disorders: A meta-analysis of 226 task-related functional imaging studies. JAMA
Psychiatry 2020,77, 172–179. [CrossRef]
226.
Récamier-Carballo, S.; Estrada-Camarena, E.; López-Rubalcava, C. Maternal separation induces long-term effect on mono-amines
and brain-derived neurotropic factor levels on the frontal cortex, amygdala, and hippocampus: Differential effects after a stress
challenge. Behav. Pharmacol. 2017,28, 545–557. [CrossRef]
227.
Kolesar, T.A.; Bilevicius, E.; Wilson, A.D.; Kornelsen, J. Systematic review and meta-analysis of neural structural and functional
differences in generalized anxiety disorder and healthy controls using magnetic resonance imaging. Neuroimage Clin.
2019
,24,
102016. [CrossRef] [PubMed]
228.
Fonzo, G.A.; Etkin, A. Affective neuroimaging in generalized anxiety disorder: An integrated review. Dialog Clin. Neurosci.
2017
,
19, 169–179.
229.
Wahis, J.; Baudon, A.; Althammer, F.; Kerspern, D.; Goyon, S.; Hagiwara, D.; Lefevre, A.; Barteczko, L.; Boury-Jamot, B.; Bellanger,
B.; et al. Astrocytes mediate the effect of oxytocin in the central amygdala on neuronal activity and affective states in rodents. Nat.
Neurosci. 2021,24, 1–13. [CrossRef] [PubMed]
230.
Malikowska-Racia, N.; Salat, K. Recent advances in the neurobiology of posttraumatic stress disorder: A review of possible
mechanisms underlying an effective pharmacotherapy. Pharmacol. Res. 2019,142, 30–49. [CrossRef]
231.
Kunimatsu, A.; Yasaka, K.; Akai, H.; Kunimatsu, N.; Abe, O. MRI findings in posttraumatic stress disorder. J. Magn. Reson.
Imaging 2020,52, 380–396. [CrossRef]
232.
Duvarci, S.; Pare, D. Glucocorticoids Enhance the Excitability of Principal Basolateral Amygdala Neurons. J. Neurosci.
2007
,27,
4482–4491. [CrossRef]
233.
Preter, M.; Klein, D.F. Panic, suffocation false alarms, separation anxiety and endogenous opioids. Prog. Neuro Psychopharmacol.
Biol. Psychiatry 2008,32, 603–612. [CrossRef]
234.
Sobanski, T.; Wagner, G. Functional neuroanatomy in panic disorder: Status quo of the research. World J. Psychiatry
2017
,7, 12–33.
[CrossRef]
235.
Kaldewaij, R.; Reinecke, A.; Harmer, C.J. A lack of differentiation in amygdala responses to fearful expression intensity in panic
disorder patients. Psychiatry Res. Neuroimaging 2019,291, 18–25. [CrossRef]
236.
Carrigan, M.; Uryasev, O.; Frye, C.B.; Eckman, B.L.; Myers, C.R.; Hurley, T.; Benner, S.A. Hominids adapted to metabolize ethanol
long before human-directed fermentation. Proc. Natl. Acad. Sci. USA 2015,112, 458–463. [CrossRef]
237.
El-Guebaly, N.; El-Guebaly, A. Alcohol Abuse in Ancient Egypt: The Recorded Evidence. Int. J. Addict.
1981
,16, 1207–1221.
[CrossRef]
238. Steele, C.M.; Josephs, R.A. Alcohol myopia: Its prized and dangerous effects. Am. Psychol. 1990,45, 921–933. [CrossRef]
239. Darke, S. The toxicology of homicide offenders and victims: A review. Drug Alcohol Rev. 2009,29, 202–215. [CrossRef]

Biomolecules 2021,11, 823 55 of 58
240.
Darvishi, N.; Farhadi, M.; Haghtalab, T.; Poorolajal, J. Alcohol-Related Risk of Suicidal Ideation, Suicide Attempt, and Completed
Suicide: A Meta-Analysis. PLoS ONE 2015,10, e0126870. [CrossRef]
241.
Gilman, J.M.; Ramchandani, V.A.; Crouss, T.; Hommer, D.W. Subjective and Neural Responses to Intravenous Alcohol in Young
Adults with Light and Heavy Drinking Patterns. Neuropsychopharmacology 2011,37, 467–477. [CrossRef]
242.
McDaid, J.; McElvain, M.A.; Brodie, M.S. Ethanol effects on dopaminergic ventral tegmental area neurons during block of Ib:
Involvement of barium-sensitive potassium currents. J. Neurophysiol. 2008,100, 1202–1210. [CrossRef]
243. Morikawa, H.; Morrisett, R.A. Ethanol action on dopaminergic neurons in the ventral tegmental area: Interaction with intrinsic
ion channels and neurotransmitter inputs. Int. Rev. Neurobiol. 2010,91, 235–288.
244.
Di Volo, M.; Morozova, E.O.; Lapish, C.C.; Kuznetsov, A.; Gutkin, B. Dynamical ventral tegmental area circuit mechanisms of
alcohol-dependent dopamine release. Eur. J. Neurosci. 2019,50, 2282–2296. [CrossRef]
245.
Rau, A.R.; Chappell, A.M.; Butler, T.R.; Ariwodola, O.J.; Weiner, J.L. Increased Basolateral Amygdala Pyramidal Cell Excitability
May Contribute to the Anxiogenic Phenotype Induced by Chronic Early-Life Stress. J. Neurosci. 2015,35, 9730–9740. [CrossRef]
246.
Ramchandani, V.A.; Stangl, B.L.; Blaine, S.K.; Plawecki, M.H.; Schwandt, M.L.; Kwako, L.E.; Sinha, R.; Cyders, M.A.; O’Connor, S.;
Zakhari, S. Stress vulnerability and alcohol use and consequences: From human laboratory studies to clinical outcomes. Alcohol
2018,72, 75–88. [CrossRef]
247.
Robinson, T.E.; Berridge, K.C. The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Res. Rev.
1993,18, 247–291. [CrossRef]
248.
Sell, L.A.; Morris, J.; Bearn, J.; Frackowiak, R.; Friston, K.J.; Dolan, R.J. Activation of reward circuitry in human opiate addicts.
Eur. J. Neurosci. 1999,11, 1042–1048. [CrossRef] [PubMed]
249.
Attwood, A.S.; Munafo, M.R. Effects of acute alcohol consumption and processing of emotion in faces: Implications for un-
derstanding alcohol-related aggression. J. Psychopharmacol. 2014,28, 719–732. [CrossRef]
250.
Crane, C.A.; Godleski, S.A.; Przybyla, S.M.; Schlauch, R.C.; Testa, M. The proximal effects of acute alcohol consumption on
male-to-female aggression: A meta-analytic review of the experimental literature. Trauma Violence Abuse
2016
,17, 520–531.
[CrossRef] [PubMed]
251.
Diener, E.; Chan, M.Y. Happy People Live Longer: Subjective Well-Being Contributes to Health and Longevity. Appl. Psychol.
Heal. Well Being 2011,3, 1–43. [CrossRef]
252.
Lyubomirsky, S.; King, L.; Diener, E. The benefits of frequent positive affect: Does happiness lead to success? Psychol. Bull.
2005
,
131, 803–855. [CrossRef] [PubMed]
253. Berridge, K.C.; Kringelbach, M.L. Pleasure Systems in the Brain. Neuron 2015,86, 646–664. [CrossRef]
254. Schultz, W. Reward prediction error. Curr. Biol. 2017,27, R369–R371. [CrossRef]
255. Berridge, K.C.; Robinson, T.E. Parsing reward. Trends Neurosci. 2003,26, 507–513. [CrossRef]
256. Shizgal, P. Neural basis of utility elimination. Curr. Opin. Neurobiol. 1997,7, 198–208.
257.
Berridge, K.C.; Aldridge, J.W. Decision utility, incentive salience, and cue-triggered „wanting“. Oxf. Ser. Soc. Cogn. Soc. Neurosci.
2009,2009, 509–533.
258. Schultz, W.; Dayan, P.; Montague, P.R. A Neural Substrate of Prediction and Reward. Science 1997,275, 1593–1599. [CrossRef]
259.
Lisman, J.E.; Grace, A.A. The Hippocampal-VTA Loop: Controlling the Entry of Information into Long-Term Memory. Neuron
2005,46, 703–713. [CrossRef] [PubMed]
260.
Nakahara, H.; Itoh, H.; Kawagoe, R.; Takikawa, Y.; Hikosaka, O. Dopamine neurons can represent context-dependent pre-diction
error. Neuron 2004,41, 269–280. [CrossRef]
261.
Bissonette, G.B.; Roesch, M.R. Development and function of the midbrain dopamine system: What we know and what we need
to. Genes Brain Behav. 2016,15, 62–73. [CrossRef]
262.
Schultz, W. Dopamine reward prediction-error signalling: A two-component response. Nat. Rev. Neurosci.
2016
,17, 183–195.
[CrossRef]
263.
Schelp, S.A.; Pultorak, K.J.; Rakowski, D.R.; Gomez, D.M.; Krzystyniak, G.; Das, R.; Oleson, E.B. A transient dopamine signal
encodes subjective value and causally influences demand in an economic context. Proc. Natl. Acad. Sci. USA
2017
,114,
E11303–E11312. [CrossRef]
264. Schultz, W. Recent advances in understanding the role of phasic dopamine activity. F1000Research 2019,8, 1680. [CrossRef]
265.
Nestler, E.J.; Hyman, S.E.; Holtzman, D.M.; Malenka, R.C. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd
ed.; McGraw-Hill Medical: New York, NY, USA, 2015.
266. Everitt, B.J.; Heberlein, U. Addiction. Curr. Opin. Neurobiol. 2013,23, 463.
267. Camerer, C.F.; Fehr, E. When does “economic man” dominate social behavior? Science 2006,311, 47–52.
268.
Calipari, E.S.; Godino, A.; Salery, M.; Damez-Werno, D.M.; Cahill, M.E.; Werner, C.T.; Gancarz, A.M.; Peck, E.G.; Jlayer, Z.; Rabkin,
J.; et al. Synaptic microtubule-associated protein EB3 and SRC phosphorylation mediate structural and behavioral adaptations
during withdrawal from cocaine self-administration. J. Neurosci. 2019,39, 5634–5646. [CrossRef] [PubMed]
269.
Brake, W.G.; Zhang, T.Y.; Diorio, J.; Meaney, M.J.; Gratton, A. Influence of early postnatal rearing condition on mesocortico-limbic
dopamine and behavioral responses to psychostimulants and stressors in adult rats. Eur. J. Neurosci.
2004
,19, 1863–1874.
[CrossRef] [PubMed]
270. Harlow, J.M. Recovery from the passage of an iron bar through the head. Publ. Mass. Med. Soc. 1868,2, 327–347.

Biomolecules 2021,11, 823 56 of 58
271.
Damasio, H.; Grabowski, T.; Frank, R.; Galaburda, A.; Damasio, A. The return of Phineas Gage: Clues about the brain from the
skull of a famous patient. Science 1994,264, 1102–1105. [CrossRef]
272.
Hänsel, A.; von Känel, R. The ventro-medial prefrontal cortex: A major link between the autonomic nervous system, regulation
of emotion, and stress reactivity? Biopsychosoc. Med. 2008,2, 21. [CrossRef]
273.
Van Horn, J.D.; Irimia, A.; Torgerson, C.M.; Chambers, M.C.; Kikinis, R.; Toga, A.W. Mapping Connectivity Damage in the Case
of Phineas Gage. PLoS ONE 2012,7, e37454. [CrossRef]
274. Staut, C.C.; Naidich, T.P. Urbach-Wiethe disease (Lipoid proteinosis). Pediatr. Neurosurg. 1998,28, 212–214. [CrossRef]
275.
Adolphs, R.; Tranel, D.; Damasio, H. Impaired recognition of emotion in facial expressions following bilateral damage to the
human amygdala. Nat. Cell Biol. 1994,372, 669–672. [CrossRef]
276.
Boes, A.D.; Grafft, A.H.; Joshi, C.; Chuang, N.A.; Nopoulos, P.; Anderson, S.W. Behavioral effects of congenital ventromedial
prefrontal cortex malformation. BMC Neurol. 2011,11, 151. [CrossRef]
277.
Tranel, D.; Hyman, B.T. Neuropsychological Correlates of Bilateral Amygdala Damage. Arch. Neurol.
1990
,47, 349–355. [CrossRef]
278.
De Martino, B.; Camerer, C.F.; Adolphs, R. Amygdala damage eliminates monetary loss aversion. Proc. Natl. Acad. Sci. USA
2010
,
107, 3788–3792. [CrossRef]
279. Colloca, L.; Sigaudo, M.; Benedetti, F. The role of learning in nocebo and placebo effects. Pain 2008,136, 211–218. [CrossRef]
280.
Bär, K.-J.; Brehm, S.; Boettger, M.; Boettger, S.; Wagner, G.; Sauer, H. Pain perception in major depression depends on pain
modality. Pain 2005,117, 97–103. [CrossRef]
281.
Strigo, I.A.; Simmons, A.N.; Matthews, S.C.; Craig, A.D. (Bud); Paulus, M.P. Association of Major Depressive Disorder With
Altered Functional Brain Response During Anticipation and Processing of Heat Pain. Arch. Gen. Psychiatry
2008
,65, 1275–1284.
[CrossRef]
282.
Harrison, L.A.; Hurlemann, R.; Adolphs, R. An Enhanced Default Approach Bias Following Amygdala Lesions in Humans.
Psychol. Sci. 2015,26, 1543–1555. [CrossRef]
283. Weymar, M.; Schwabe, L. Amygdala and emotion: The bright side of it. Front. Neurosci. 2016,10, 224. [CrossRef]
284.
Adolphs, R.; Baron-Cohen, S.; Tranel, D. Impaired Recognition of Social Emotions following Amygdala Damage. J. Cogn. Neurosci.
2002,14, 1264–1274. [CrossRef]
285.
Han, K.-M.; De Berardis, D.; Fornaro, M.; Kim, Y.-K. Differentiating between bipolar and unipolar depression in functional and
structural MRI studies. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2019,91, 20–27. [CrossRef]
286.
Sepede, G.; Spano, M.C.; Lorusso, M.; De Berardis, D.; Salerno, R.M.; Di Giannantonio, M.; Gambi, F. Sustained attention in
psychosis: Neuroimaging findings. World J. Radiol. 2014,6, 261–273. [CrossRef]
287.
Nolan, M.; Roman, E.; Nasa, A.; Levins, K.J.; O’Hanlon, E.; O’Keane, V.; Roddy, D.W. Hippocampal and Amygdalar Volume
Changes in Major Depressive Disorder: A Targeted Review and Focus on Stress. Chronic Stress 2020,4, 1–19. [CrossRef]
288.
Ho, N.F.; Chong, P.L.H.; Lee, D.R.; Chew, Q.H.; Chen, G.; Sim, K. The Amygdala in Schizophrenia and Bipolar Disorder: A
Synthesis of Structural MRI, Diffusion Tensor Imaging, and Resting-State Functional Connectivity Findings. Harv. Rev. Psychiatry
2019,27, 150–164. [CrossRef]
289.
Li, X.; Wang, J. Abnormal neural activities in adults and youths with major depressive disorder during emotional processing: A
meta-analysis. Brain Imaging Behav. 2021,15, 1134–1154. [CrossRef]
290.
Ma, X.; Liu, J.; Liu, T.; Ma, L.; Wang, W.; Shi, S.; Wang, Y.; Gong, Q.; Wang, M. Altered Resting-State Functional Activity in
Medication-Naive Patients With First-Episode Major Depression Disorder vs. Healthy Control: A Quantitative Meta-Analysis.
Front. Behav. Neurosci. 2019,13, 89. [CrossRef]
291.
Dannlowski, U.; Ohrmann, P.; Bauer, J.; Kugel, H.; Arolt, V.; Heindel, W.; Suslow, T. Amygdala reactivity predicts automatic
negative evaluations for facial emotions. Psychiatry Res. Neuroimaging 2007,154, 13–20. [CrossRef]
292.
Young, K.D.; Zotev, V.; Phillips, R.; Misaki, M.; Drevets, W.C.; Bodurka, J. Amygdala real-time functional magnetic resonance
imaging neurofeedback for major depressive disorder: A review. Psychiatry Clin. Neurosci. 2018,72, 466–481. [CrossRef]
293.
Lee, E.-H.; Han, P.-L. Reciprocal interactions across and within multiple levels of monoamine and cortico-limbic systems in
stress-induced depression: A systematic review. Neurosci. Biobehav. Rev. 2019,101, 13–31. [CrossRef]
294.
Larøi, F.; Thomas, N.; Aleman, A.; Fernyhough, C.; Wilkinson, S.; Deamer, F.; McCarthy-Jones, S. The ice invoices: Under-standing
negative content in auditory-verbal hallucinations. Clin. Psychol. Rev. 2019,67, 1–10. [CrossRef]
295.
Barch, D.M.; Pagliaco, D.; Luking, K. Mechanisms underlying motivational deficits in psychopathology: Similarities and
differences in depression and schizophrenia. Curr. Top. Behav. Neurosci. 2016,27, 411–449.
296.
Mujica-Parodi, L.R.; Cha, J.; Gao, J. From Anxious to Reckless: A Control Systems Approach Unifies Prefrontal-Limbic Regulation
Across the Spectrum of Threat Detection. Front. Syst. Neurosci. 2017,11, 18. [CrossRef] [PubMed]
297.
Tapia León, I.; Kruse, O.; Stark, R.; Klucken, T. Relationship of sensation seeking with the neural correlates of appetitive
con-ditioning. Soc. Cogn. Affect. Neurosci. 2019,14, 769–775. [CrossRef] [PubMed]
298.
Congdon, E.; Canli, T. The Endophenotype of Impulsivity: Reaching Consilience Through Behavioral, Genetic, and Neuroimaging
Approaches. Behav. Cogn. Neurosci. Rev. 2005,4, 262–281. [CrossRef]
299.
Weiland, B.J.; Heitzeg, M.M.; Zald, D.; Cummiford, C.; Love, T.; Zucker, R.A.; Zubieta, J.-K. Relationship between impulsivity,
prefrontal anticipatory activation, and striatal dopamine release during rewarded task performance. Psychiatry Res. Neuroimaging
2014,223, 244–252. [CrossRef] [PubMed]

Biomolecules 2021,11, 823 57 of 58
300.
Ellis, B.J.; Del Giudice, M.; Dishion, T.J.; Figueredo, A.J.; Gray, P.B.; Griskevicius, V.; Hawley, P.H.; Jacobs, W.J.; James, J.; Volk,
A.A.; et al. The evolutionary basis of risky adolescent behavior: Implications for science, policy, and practice. Dev. Psychol.
2012
,
48, 598–623. [CrossRef] [PubMed]
301.
Cauffman, E.; Shulman, E.P.; Steinberg, L.; Claus, E.; Banich, M.T.; Graham, S.; Woolard, J. Age differences in affective decision
making as indexed by performance on the Iowa Gambling Task. Dev. Psychol. 2010,46, 193–207. [CrossRef]
302.
Chan, W.; McCrae, R.R.; De Fruyt, F.; Jussim, L.; Löckenhoff, C.E.; De Bolle, M.; Costa, P.T.; Sutin, A.R.; Realo, A.; Allik, J.;
et al. Stereotypes of age differences in personality traits: Universal and accurate? J. Person. Soc. Psychol.
2012
,103, 1050–1066.
[CrossRef]
303.
Steinberg, L.; Albert, D.; Cauffman, E.; Banich, M.; Graham, S.; Woolard, J. Age differences in sensation seeking and impulsivity
as indexed by behavior and self-report: Evidence for a dual systems model. Dev. Psychol. 2008,44, 1764–1778. [CrossRef]
304.
Figner, B.; Mackinlay, R.J.; Wilkening, F.; Weber, E.U. Affective and deliberative processes in risky choice: Age differences in risk
taking in the Columbia Card Task. J. Exp. Psychol. Learn. Mem. Cogn. 2009,35, 709–730. [CrossRef]
305. Casey, B.J.; Caudle, K. The teenage brain: Self control. Curr. Dir. Psychol. Sci. 2013,22, 82–87. [CrossRef]
306.
Simons-Morton, B.; Lerner, N.; Singer, J. The observed effects of teenage passengers on the risky driving behavior of teenage
drivers. Accid. Anal. Prev. 2005,37, 973–982. [CrossRef]
307. Zimring, F.E. American Youth Violence; NYU Press: New York, NY, USA, 2014; pp. 7–36.
308.
Sommerville, L.H. Emotional Development in Adolescence. In Handbook of Emotions, 4th ed.; Feldman Barrett, L., Lewis, M.,
Haviland-Jones, J.M., Eds.; The Guilford Press: New York, NY, USA, 2016; pp. 350–365.
309.
Posner, M.I.; Rothbart, M.K.; Sheese, B.E.; Voelker, P. Control networks and neuromodulators of early development. Dev. Psychol.
2012,48, 827–835. [CrossRef]
310.
Gothelf, R.; Law, A.J.; Frisch, A.; Chen, J.; Zarchi, O.; Michaelovsky, E.; Ren-Patterson, R.; Lipska, B.K.; Carmel, M.; Kolachana, B.;
et al. Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome. Biol. Psychiatry
2014
,75, 406–413.
[CrossRef]
311.
Sheese, B.E.; Voelker, P.M.; Rothbart, M.K.; Posner, M.I. Parenting quality interacts with genetic variation in dopamine receptor
DRD4 to influence temperament in early childhood. Dev. Psychopathol. 2007,19, 1039–1046. [CrossRef]
312.
Belsky, J.; Pluess, M. Beyond diathesis stress: Differential susceptibility to environment stress. Psychol. Bull.
2009
,135, 895–908.
[CrossRef] [PubMed]
313.
Sheese, B.E.; Rothbart, M.K.; Voelker, P.M.; Posner, M.I. The Dopamine Receptor D4 Gene 7-Repeat Allele Interacts with Parenting
Quality to Predict Effortful Control in Four-Year-Old Children. Child. Dev. Res. 2012,2012, 1–6. [CrossRef] [PubMed]
314.
Larsen, H.; van der Zwaluw, C.S.; Overbeek, G.; Granic, I.; Franke, B.; Engels, R.C. A variable-number-of-tandem-repeats
polmorphism in the dopamine D4 receptor gene affects social adaptation of alcohol use: Investigation of a gene—environment
interaction. Psychol. Sci. 2010,21, 1064–1068. [CrossRef] [PubMed]
315.
Holmboe, K.; Nemoda, Z.; Fearon, R.M.P.; Csibra, G.; Sasvari-Szekely, M.; Johnson, M.H. Polymorphisms in dopamine system
genes are associated with individual differences in attention in infancy. Dev. Psychol. 2010,46, 404–416. [CrossRef] [PubMed]
316. Amaral, D.G.; Adolphs, R. (Eds.) Living without an Amygdala; The Guilford Press: New York, NY, USA, 2016; p. 12.
317.
Frick, P.J.; Barry, C.T.; Bodin, S.D. Applying the concept of psychopathy to children: Implication for the assessment of antisocial
youth. In The Clinical and Forensic Assessment of Psychopathy; Gacono, C.B., Ed.; Erlbaum: Mahway, NJ, USA, 2000; pp. 3–25.
318.
Davidson, R.J.; Putnam, K.M.; Larson, C.L. Dysfunction in the neural circuitry of emotion regulation—A possible prelude to
violence. Science 2000,289, 591–594. [CrossRef]
319. Blair, R.J.R. Neurological basis of psychopathy. Br. J. Psychiatry 2003,182, 5–7. [CrossRef]
320.
Chandrasekhar, P.V.; Capra, C.M.; Moore, S.; Noussair, C.; Berns, G.S. Neurobiological regret and rejoice functions for aversive
outcomes. NeuroImage 2008,39, 1472–1484. [CrossRef]
321.
Kanske, P.; Kotz, S.A. Emotion speeds up conflict resolution: A new role for the ventral anterior cingulate cortex? Cereb. Cortex
2011,21, 911–919. [CrossRef]
322.
Ochsner, K.N.; Phelps, E. Emerging perspectives on emotion–cognition interactions. Trends Cogn. Sci.
2007
,11, 317–318. [CrossRef]
323.
Storbeck, J.; Clore, G.L. On the interdependence of cognition and emotion. Cogn. Emot.
2007
,21, 1212–1237. [CrossRef] [PubMed]
324.
Phelps, E.A. Emotion and Cognition: Insights from Studies of the Human Amygdala. Annu. Rev. Psychol.
2006
,57, 27–53.
[CrossRef]
325.
Okon-Singer, H.; Hendler, T.; Pessoa, L.; Shackman, J. The neurobiology of emotion—Cognition interactions: Fundamental
questions and strategies for future research. Front. Hum. Neurosci. 2015,9, 58. [CrossRef] [PubMed]
326.
Shackman, A.J.; Fox, A.S.; Seminowicz, D.A. The cognitive-emotional brain: Opportunities [corrected] and challenges for
understanding neuropsychiatric disorders. Behav. Brain Sci. 2015,38, e86. [CrossRef] [PubMed]
327.
LaBar, K.S.; Gatenby, J.C.; Gore, J.C.; LeDoux, J.E.; Phelps, E.A. Human amygdala activation during conditioned fear acqui-sition
and extinction: A mixed-trial fMRI study. Neuron 1998,20, 937–945. [CrossRef]
328.
Bechara, A.; Tranel, D.; Damasio, H.; Adolphs, R.; Rockland, C.; Damasio, A.R. Double dissociation of conditioning and
de-clarative knowledge relative to the amygdala and hippocampus in humans. Science 1995,269, 1115–1118. [CrossRef]
329.
Indovina, I.; Robbins, T.W.; Núñez-Elizalde, A.O.; Dunn, B.D.; Bishop, S.J. Fear-Conditioning Mechanisms Associated with Trait
Vulnerability to Anxiety in Humans. Neuron 2011,69, 563–571. [CrossRef]

Biomolecules 2021,11, 823 58 of 58
330.
Phelps, E.A.; LeDoux, J.E. Contributions of the Amygdala to Emotion Processing: From Animal Models to Human Behavior.
Neuron 2005,48, 175–187. [CrossRef]
331.
Pessoa, L. Emotion and cognition and the amygdala: From “what is it?” to “what’s to be done”? Neuropsychologia
2010
,48,
3416–3429. [CrossRef]
332.
Dolcos, F.; Iordan, A.D.; Kragel, J.; Stokes, J.; Campbell, R.; McCarthy, G.; Cabeza, R. Neural Correlates of Opposing Effects of
Emotional Distraction on Working Memory and Episodic Memory: An Event-Related fMRI Investigation. Front. Psychol.
2013
,4,
293. [CrossRef]
333.
Omura, K.; Constable, R.T.; Canli, T. Amygdala gray matter concentration is associated with extraversion and neuroticism.
NeuroReport 2005,16, 1905–1908. [CrossRef]
334.
Gray, J.R.; Braver, T.S.; Raichle, M.E. Integration of emotion and cognition in the lateral prefrontal cortex. Proc. Natl. Acad. Sci.
USA 2002,99, 4115–4120. [CrossRef]
335. Pessoa, L. On the relationship between emotion and cognition. Nat. Rev. Neurosci. 2008,9, 148–158. [CrossRef]
336. Pessoa, L. The Cognitive-Emotional Brain: From Interactions to Integration; MIT Press: Cambridge, MA, USA, 2013.
337. Pessoa, L. Précis on the cognitive-emotional brain. Behav. Brain Sci. 2015,38, e71. [CrossRef]
338.
Frank, D.; Dewitt, M.; Hudgens-Haney, M.; Schaeffer, D.; Ball, B.; Schwarz, N.; Hussein, A.; Smart, L.; Sabatinelli, D. Emotion
regulation: Quantitative meta-analysis of functional activation and deactivation. Neurosci. Biobehav. Rev.
2014
,45, 202–211.
[CrossRef]
339. Pessoa, L. A Network Model of the Emotional Brain. Trends Cogn. Sci. 2017,21, 357–371. [CrossRef]
340.
Wu, T.; Wang, X.; Wu, Q.; Spagna, A.; Yang, J.; Yuan, C.; Wu, Y.; Gao, Z.; Hof, P.R.; Fan, J. Anterior insular cortex is a bot-tleneck
of cognitive control. Neuroimage 2019,195, 490–504. [CrossRef]
341. Pessoa, L. Understanding emotion with brain networks. Curr. Opin. Behav. Sci. 2018,19, 19–25. [CrossRef]
342.
Pessoa, L.; Medina, L.; Hof, P.R.; Desfilis, E. Neural architecture of the vertebrate brain: Implications for the interaction between
emotion and cognition. Neurosci. Biobehav. Rev. 2019,107, 296–312. [CrossRef]
343.
Šimi´c, G. (Ed.) Introduction to Neuroscience of Emotions and Feelings; Naklada Ljevak: Zagreb, Croatia, 2020; pp. 11–137. (
In Croatian
)