C H A P T E R
29
The Emotional Brain
L. Pessoa
University of Maryland, College Park, MD, United States
INTRODUCTION
In his seminal contribution, in 1878, Broca
described the great limbic lobe comprising
the interior surface of the cortex and a set of
related structures. These structures were later
part of the first major circuit theory of emo-
tion, namely, the circuit of Papez. By the mid-
dle of the 20th century, ideas by Papez and
others were further refined and extended by
MacLean into the concept of the “limbic sys-
tem,” according to which emotion depends
on a well-defined and delimited set of brain
regions. The “emotional brain” was suggested
to be responsible for both response systems
and feeling states/processes, given that emo-
tion was characterized by a combination of
changes in physiological arousal, behav-
ioral expression, and, importantly, subjective
experience.
This chapter describes several components
of the emotional brain. As outlined in the expo-
sition in the following sections, the concept of
a “limbic system” has given way to a modern
understanding of emotion as highly integrated
with other brain systems. It is thus preferable
to avoid the term “limbic system” altogether, as
advocated for some time by many leading emo-
tion researchers.
Conn’s Translational Neuroscience
http://dx.doi.org/10.1016/B978-0-12-802381-5.00046-4 635
REGIONS OF THE EMOTIONAL
BRAIN
In this section, several important regions of
the emotional brain are discussed. Although
the exposition is centered on particular regions,
they do not work in isolation. Instead, they par-
ticipate in large, distributed neural networks
whose constituent regions, collectively, carry
out functions and behaviors of interest. There-
fore, although the exposition emphasizes a
region’s participation in emotional functions,
to understand the emotional brain it is criti-
cal to characterize large-scale circuits within
which regions are embedded (further discussed
in sections From Regions to Circuits and How
Are Emotions Organized in the Brain?). In this
sense, there is no one, separately identifiable
“emotional brain,” but instead regions that play
important roles in emotion (Fig. 29.1).
Amygdala
Anatomically, the amygdala is a complex
structure containing more than a dozen richly
interconnected nuclei. However, based on sev-
eral types of information, including connectiv-
ity and distribution of neurotransmitters, some
have questioned whether this collection of nuclei
Copyright © 2017 Elsevier Inc. All rights reserved.
636 29.  THE EMOTIONAL BRAIN

FIGURE 29.1  Emotional brain. Several brain structures participate in emotional mechanisms in important ways. Some of
the regions discussed in the chapter are shown schematically here. PAG, periaqueductal gray.

should be considered a functional–anatomical medium spiny neurons. Furthermore, In terms

unit. Indeed, the title of a provocative paper
by leading researchers was “What is the amyg-
dala?” Nevertheless, it is useful to consider at
least two subunits of this structure: the “lateral
amygdala” (at times called “basolateral amyg-
dala”) involving the lateral, basal, and accessory
basal nuclei, and the “central amygdala” involv-
ing the central nucleus (Fig. 29.2). These nuclei
are typically further subdivided into subnuclei,
such as the medial and lateral divisions of the
central amygdala.
Structurally, the lateral amygdala exhibits a
cytoarchitecture that is closer to that seen in cor-
tex, which is organized in a layered manner. The
majority of lateral amygdala neurons are gluta-
matergic (excitatory) spiny projection neurons
and about 20% of its neurons are GABAergic
(inhibitory) interneurons. The central amyg-
dala exhibits a more simplified cytoarchitecture
with incipient lamination, and is a striatum-
like structure that is composed of GABAergic
of embryological origin, the amygdala consists
of distinct groups of nuclei with distinct precur-
sors linked to the lateral and central amygdala
(among others).
The two amygdala subdivisions display con-
nectivity patterns that are quite distinct from
each other (Fig. 29.3). The lateral amygdala
receives substantial sensory information from
cortex and is richly connected with temporal,
cingulate, insular, and prefrontal cortex; connec-
tions with parietal cortex also exist but are more
modest. In contrast, the central amygdala has
extensive interconnections with the hypothala-
mus and brain stem nuclei (including sites in the
midbrain, pons, and medulla) that are involved
in behavioral, autonomic, and neuroendocrine
responses; cortically, the central amygdala is
interconnected with the medial prefrontal cor-
tex, orbitofrontal cortex, and insula.
The amygdala is a key brain structure for
aversive memory acquisition, a notion that is
FIGURE 29.2  Human amygdala. (A) Lateral view of an MRI scan with the approximate location of the amygdala out-
lined on the lateral surface; line represents location of coronal section in panel B. (B) Coronal section showing position of left
and right amygdala. (C) Coronal section with box around left amygdala. (D) Enlarged, Nissl-stained section of left amyg-
dala nuclei from panel C. Acc, accessory; PAC, periamygdaloid cortex; PC, posterior cortical. Reproduced with permission from
Schumann CM, Bauman MD, Amaral DG. Abnormal structure or function of the amygdala is a common component of neurodevelop-
mental disorders. Neuropsychologia 2011;49:745–759.

FIGURE 29.3  Amygdala connectivity. (A) Output connections from the lateral amygdala. Connections to parts of the
parietal cortex, including the intraparietal sulcus, are not shown. Numbers refer to approximate locations of Brodmann areas.
(B) Output connections of the central amygdala. Connections to cortex are not shown. (A) Reproduced with permission from
Nieuwenhuys R, Voogd J, van Huijzen C. The human central nervous system. 4th ed. New York: Springer-Verlag; 2008. (B) Adapted with
permission from Nieuwenhuys R, Voogd J, van Huijzen C. The human central nervous system. 4th ed. New York: Springer-Verlag; 2008.
638 29.  THE EMOTIONAL BRAIN
supported by studies using multiple experi-
mental paradigms and measures of conditioned
responses (Box 29.1). Note that the term “aver-
sive conditioning” is used here instead of “fear
conditioning” because fear is a subjective men-
tal state not accessible in nonhuman animals
(unfortunately, many researchers continue to
use the term “fear” when studying rodents or
other animals).
Aversive conditioning employs techniques
of classical conditioning (also called Pavlov-
ian conditioning). In aversive conditioning,
the subject is exposed to a neutral conditioned
stimulus (CS), such as a tone or a light, which
typically co-terminates with an aversive uncon-
ditioned stimulus (US), such as a foot-shock.
With training, the CS (tone/light) acquires aver-
sive properties and, when subsequently pre-
sented alone, elicits a conditioned response. In
BOX 29.1
STUDYING “FEAR” AND “ANXIETY”
It is productive to operationalize “fear” as
acute threat and “anxiety” as potential threat,
such as in the Research Domain Criteria (abbre-
viated RDoC) initiative of the National Insti-
tute of Mental Health. Acute threat is linked to
imminent and discrete threat, such as when a
CS signals the possibility of a shock. Potential
threat is linked to contexts in which harm may
be experienced, such as when entering a room in
which a shock may be delivered. More generally,
acute and potential threat can be distinguished
according to the degree of certainty regarding
the timing and form of the threat. Behaviorally,
cues that indicate an immediate threat give rise
to “fearful” defensive behaviors, whereas more
diffuse, distal, or unpredictable threat cues pro-
duce “anxious” risk assessment behavior. In the
literature, there is widespread inconsistency in
how terms such as “fear,” “anxiety,” “stress,”
“distress,” “worry,” and so on are employed,
rodents, responses include freezing behavior
(technically, a nonresponse), alterations in auto-
nomic nervous system activity, release of stress
hormones, analgesia, and facilitation of reflexes.
Subsequently, conditioned responses can be sup-
pressed if the CS is repeatedly presented alone,
a phenomenon called “extinction” (see section:
Interactions Between the Amygdala and Medial
Prefrontal Cortex).
The lateral amygdala receives multiple sen-
sory signals, including auditory, visual, and
somatosensory stimuli that convey informa-
tion about both conditioned and unconditioned
stimuli. Such convergence positions the lat-
eral amygdala to be able to form associations
between the two. Evidence supporting the idea
that the lateral amygdala is critical for aversive
learning comes from multiple sources. First,
lesion or inactivation of the amygdala during
suggesting that, if these terms are used at all,
clear operationalizations are needed. In nonhu-
man animals, terms such as “fear” and “anxiety”
are preferably avoided given that they reflect
subjective mental states.
Aversive conditioning constitutes the central
experimental paradigm to study acute threat. In
this paradigm (see main text), an initially neutral
stimulus evokes a negative state through asso-
ciation with an aversive event. Potential threat
is studied, among others, via exposure to threat-
ening contexts (such as a brightly lit space for
rodents, or a dark room for humans) and via con-
text conditioning (where unpredictable aversive
events are paired with a certain context or place).
Past research tended to emphasize the role of
particular brain areas in generating states linked
to acute or potential threat. However, mounting
evidence indicates that these states rely on neu-
ronal circuits that involve multiple brain regions.
 Regions of the Emotional Brain
learning prevents associations from taking place
(but typically these lesions, though they might
include the lateral amygdala, are not limited to
this sector). Second, responses elicited by the CS
in the lateral amygdala are modified after pair-
ing with the US. Specifically, during aversive
conditioning, cells in the lateral amygdala of rats
show plasticity during exposure to a CS. Cells
that are responsive to the CS prior to condition-
ing increase their firing after it. Third, recent
studies employing modern techniques based on
optogenetics indicate that activity-dependent
plasticity in the lateral amygdala is necessary for
aversive learning. For example, aversive condi-
tioning can be inactivated through optogenetic
depression of sensory inputs to the lateral amyg-
dala, and later reactivated by optogenetic activa-
tion of these inputs.
The central amygdala is a major participant
in the generation of conditioned responses—
at times referred to as “emotional responses.”
This role is supported by projections to multiple
autonomic and skeletomotor regions involved
in aversive conditioned responses, including
the following: the periaqueductal gray (PAG),
which participates in freezing behavior that is
characterized by the absence of overt behavior;
the lateral hypothalamus, which participates in
sympathetic activation; and caudal parts of the
reticular formation in the pons, which partici-
pate in the potentiation of the startle reflex. The
central amygdala also projects to multiple brain
stem nuclei that originate neurotransmitter sys-
tems with widespread outputs to the forebrain,
including the following: the dopaminergic
ventral tegmental area and adjacent substantia
nigra pars compacta; the noradrenergic locus
coeruleus; the serotonergic raphe nuclei; and the
cholinergic basal forebrain nuclei. In all, several
conditioned responses depend on the central
amygdala and its projections to these regions.
One way to summarize some of the func-
tions of the lateral and central amygdala during
aversive conditioning is as follows. The lateral
amygdala establishes associations, thus allow-
ing the CS to access the motivational value of its
639
particular US. This information can then be used
by the central amygdala and its hypothalamic,
midbrain, and other brain stem targets, thus giv-
ing rise to “emotional” responses such as freez-
ing, fear-potentiated startle, and modulation of
arousal and attention.
This serial scheme of amygdala function in
which the lateral amygdala passes on informa-
tion to the central amygdala is a valuable heuris-
tic and research tool. However, it captures only
a specific mode of amygdala functioning. This
is because the central amygdala receives direct
inputs from cortical and subcortical structures
too (cortical input includes the medial prefrontal
cortex and orbitofrontal cortex), which contrib-
ute to the acquisition of Pavlovian associations.
The Bed Nucleus of the Stria Terminalis
and the Extended Amygdala
The strial terminalis is a major fiber pathway
of the amygdala that courses upward and loops
around medially in the direction of the hypo-
thalamus. Among others, it carries fibers from
the amygdala to the thalamus, hypothalamus,
and septum; it also carries fibers projecting from
these areas back to the amygdala. Whereas the
stria terminalis fiber bundle is relatively easy to
visualize in three dimensions, it is much harder
when viewed via standard cross-sectional ana-
tomical planes. Along the stria terminalis, it is
possible to identify several small masses of cells,
which together comprise the bed nucleus of the
stria terminalis (BNST; Fig. 29.4).
Broadly speaking, the BNST can be subdi-
vided into lateral and medial parts. The lateral
BNST (BNSTlat) is closely associated with the
central amygdala, and together they have been
suggested to be part of a central “extended
amygdala.” The BNSTlat projects to the hypo-
thalamus and brain stem, as does the central
nucleus of the amygdala (as reviewed previ-
ously). Indeed, the central amygdala and the
BNSTlat have similar anatomical connectiv-
ity patterns. Furthermore, neurons in the cen-
tral amygdala and the BNSTlat share similar
640 29.  THE EMOTIONAL BRAIN

FIGURE 29.4  Bed nucleus of the stria terminalis (BNST). (A) Approximate location of the BNST in the human brain. (B)
Coronal myelin sections showing cell masses of the BNST. Abbreviations for the structures of main interest: BSTLD, laterodor-
sal part of the BNST; BSTLDcn, central subdivision of the BSTLD; BSTM, medial part of the BNST; CdL, lateral aspect of the
caudate; CdM, medial aspect of the caudate; CdV, ventral aspect of the caudate; ic, internal capsule; LH, lateral hypothalamus;
Pu, Putamen; st, stria terminalis. (B) Reproduced with permission from Yilmazer-Hanke DM. Amygdala. In: Mai JK, Paxinos G,
editors. The human nervous system. 3rd ed. Amsterdam: Elsevier; 2012. p. 759–834.

morphological and neurochemical character-
istics (they are mostly GABAergic as found in
striatal brain regions).
Functionally, the BNSTlat is important for
maintaining prolonged threat preparedness that
is associated with the processing of potential
threat (see Box 29.1). Consider the paradigm of
light-enhanced startle. Rats produce a startle
reflex when presented with brief noise bursts.
The amplitude of this acoustic startle can be mea-
sured during different contexts. In one study,
during the first phase, rats were tested in the
dark. During the second phase, rats were tested
again in the dark or, alternatively, in the pres-
ence of bright light (which is highly aversive to
rats). Exposure to bright light for 5–20 min led to
a significant increase in acoustic startle amplitude
going from the dark to the light (light-enhanced
startle) compared with startle amplitude when
the rats remained in the dark. Critically, inactiva-
tion of the BNST (but not the central amygdala)
eliminates the light-enhanced startle.
An influential framework suggests that the
amygdala is more closely associated with acute
threat (“fear”) and the BNST is more closely asso-
ciated with potential threat (“anxiety”). Recent
research, including with novel techniques such
as optogenetics, is consistent with this general
idea but also reveals important ways in which
amygdala and BNST circuits participate in mul-
tiple aspects of threat processing. For example,
activation/deactivation of projection neurons
from the lateral to the central amygdala can be
used to influence the time mice will spend on
open fields (a behavior that is typically actively
avoided by mice), a form of potential threat.
Thus, the lateral and central amygdala are not
only involved in the processing of acute threat
(the latter is revealed by standard conditioning
paradigms).
Hypothalamus
The hypothalamus contains a number of
nuclei and, as its name implies, is located just
below the thalamus (and thus just above the
brain stem) (Fig. 29.1; see also Fig. 29.4). The
importance of the hypothalamus in emotion
 Regions of the Emotional Brain
was established in the first decades of the 20th
century, as highlighted by the work of Bard and
Cannon, who showed that coordinated emo-
tional expressions were compromised when the
hypothalamus was excised. The involvement of
the hypothalamus in emotion and other basic
functions was fittingly summarized in 1929 by
Cushing (considered by many to be the father
of modern neurosurgery) in the following way:
“Here in this well-concealed spot, almost to be
covered with a thumb nail, lies the very main-
spring of primitive existence–vegetative, emo-
tional, reproductive.”
Since the 1920s and 1930s, our knowledge
of hypothalamic function has been greatly
extended and refined, and current understand-
ing concurs with the earlier notion that the hypo-
thalamus is involved in several important basic
operations. For example, it participates in many
complex homeostatic mechanisms and contrib-
utes to neuroendocrine outputs. Indeed, hypo-
thalamic mechanisms contribute to a wealth of
processes: circadian rhythms, wakefulness and
sleep, stress responses, temperature regulation,
food intake, thirst, sexual behaviors, and defen-
sive behaviors. In all these cases, the hypothala-
mus works in concert with a multitude of other
sites, several of which are located in the brain
stem and spinal cord.
In broad terms, the hypothalamus has been
subdivided into several parts: rostrocaudally
into the preoptic, anterior, medial (also called
tuberal), and posterior regions, and mediolat-
erally into periventricular, medial, and lateral
zones. Within those sectors, multiple “nuclei”
or “areas” have been described. However, the
hypothalamus poses considerable challenges
for systematic study because compact group-
ings of neuronal elements are not always seen
in some “areas.” In fact, even the overall borders
of the hypothalamus are ill defined (eg, caudally
the hypothalamus transitions gradually into the
midbrain tegmentum).
Historically, the hypothalamus has been con-
ceptualized in terms of “descending” systems,
641
a view that is conveyed by its designation as
the “head ganglion” of the autonomic nervous
system. Indeed, the hypothalamus has robust
connections that synapse at multiple brain stem
sites, including the PAG, midbrain reticular
formation, dorsal raphe, parabrachial nucleus,
locus coeruleus, nucleus of the solitary tract,
as well as sites in the medulla and spinal cord.
Notably, several of these sites have “ascending”
projections that reach the hypothalamus too.
The stress response is among the many func-
tions in which the hypothalamus participates; in
this case as part of the hypothalamic–pituitary–
adrenal (often abbreviated HPA) axis. Neurons
in the paraventricular nucleus of the hypothala-
mus, which synthesize corticotropin-releasing
hormone (CRH), integrate stress-relevant sig-
nals from multiple brain regions and launch the
neuroendocrine response to stress. CRH stimu-
lates the release of the adrenocorticotropic hor-
mone from the pituitary, which in turn drives
the release of glucocorticoids from the adrenal
glands (sitting atop the kidneys). These “stress
hormones,” such as corticosterone and cortisol,
have a wide range of effects, including increas-
ing blood pressure and glucose levels, and sup-
pressing inflammatory and immune responses.
The hypothalamus is also implicated in
defensive behavior. In the cat, for example, the
behavioral components of this reaction include
ear retraction, hissing, growling, and strik-
ing with the forepaw; autonomic responses
include pupil dilation, piloerection, accelerated
heart rate, and elevated blood pressure. Classic
work by Hess and many others in the 1920s–50s
showed that a defense response can be elicited
by electrical stimulation of brain areas in and
around the hypothalamus. In the literature,
specific defensive behaviors are at times linked
to specific “centers.” For example, in the rat, a
hypothalamic “attack area” has been described,
and includes parts of the lateral hypotha-
lamic area and the ventromedial hypothalamic
nucleus. Whereas characterizations such as this
have conferred a certain degree of specificity to
642 29.  THE EMOTIONAL BRAIN

FIGURE 29.5  Hypothalamus and structure–function relationship. Hypothalamic regions (R1, …, R6) are involved in
many functions (or behaviors), and functions rely on many hypothalamic regions. The three-dimensional landscape repre-
sents levels of activity across space. The patterns of activity indicate that multiple regions of the hypothalamus are engaged
during a certain function/behavior. In this manner, the function is associated with a pattern of activity across the hypothala-
mus (and elsewhere in the brain), and not activation of a specific hypothalamic nucleus. Adapted with permission from Newman
SW. The medial extended amygdala in male reproductive behavior. A node in the mammalian social behavior network. Ann N Y Acad Sci
1999;877:242–257.

hypothalamic areas, it is important to empha-
size that there is no one-to-one mapping
between area and function. Instead, hypotha-
lamic areas are involved in many functions (eg,
stress responses, temperature regulation, food
intake, and defensive behavior), and at the same
time functions rely on many hypothalamic areas
(Fig. 29.5). Most importantly, the functions in
which the hypothalamus participates are deter-
mined by neuronal networks that extend well
beyond this structure.
Periaqueductal Gray
The brain is bathed in a colorless fluid also
found in the spine called the cerebrospinal fluid
which, among other things, provides buoyancy
and protection to the brain. The PAG (also called
central gray) surrounds the cerebral aqueduct
containing cerebrospinal fluid (hence the name)
in the rostral brain stem (Figs. 29.1 and 29.6).
Cortically, the PAG receives input from several
areas along medial prefrontal cortex, including
cingulate areas and dorsomedial sectors, as well
as orbitofrontal cortex, insula, and temporal
cortex. Subcortically, the PAG receives input
from a variety of structures, including amyg-
dala, hypothalamus, dorsal raphe, parabrachial
nuclei, pontine and medullary reticular forma-
tion, and spinal cord. Many of these regions
receive reciprocal projections from the PAG.
Cytoarchitectonic features and physiologi-
cal responses indicate that PAG subregions are
organized more or less like columns that are
aligned in parallel to the long axis of the brain
stem (vertically in humans; horizontally in
rodents) (Fig. 29.6). At least two columns help
organize defensive behaviors (although recent
data also reveal local integration of inputs, that
is, within columns). Excitation of neurons in the
“active” column generates behaviors such as
facing and backing away, or a full-blown flight
reaction, reactions that are very similar to natu-
ral ones produced by a rat or cat when threat-
ened or attacked. Excitation of neurons in the
“passive” column generates an entirely different
reaction, namely, the cessation of ongoing activ-
ity and profound hyporeactivity, with the animal
neither orienting nor responding to its environ-
ment. This type of freezing behavior is similar to
 Regions of the Emotional Brain
FIGURE 29.6  Periaqueductal gray (PAG). The PAG is
organized as elongated columns of neurons. Figure idea based
on Figure 1 of Bandler R, Shipley MT. Columnar organization in
the midbrain periaqueductal gray: modules for emotional expres-
sion? Trends Neurosci 1994;17:379–389.
that of an animal that has incurred an injury, or
after defeat in a social encounter. An important
feature of the behaviors elicited by PAG excita-
tion is that they are coordinated actions; that is,
they are not simply isolated reactions (such as a
knee-jerk reflex), but full-blown behaviors.
The PAG plays an important role in nocicep-
tion (pain signaling). The PAG receives direct
(and indirect) nociceptive input from the dorsal
horn of the spinal cord, which is sensitive to noci-
ceptive information from the viscera, skin, and
other organs. In addition, the PAG is reciprocally
interconnected with the parabrachial nucleus
and the nucleus of the solitary tract. The latter
fulfills a key role in the processing of visceral
643
information and, like the parabrachial nucleus,
provides an interface between autonomic and
sensory systems. Activation and behavioral
data indicate that PAG columns are important
during responses to different classes of pain.
Interestingly, the PAG is involved in analgesia
too. Early studies in rats that used simple with-
drawal reflexes as a measure of pain showed
that stimulation of the PAG inhibited responses
to noxious stimulation. Subsequent experiments
demonstrated antinociceptive effects in humans
too. For example, electrical stimulation of the
PAG produced clinically significant pain relief.
Cingulate Cortex
The cingulate cortex surrounds the entire
extent of the corpus callosum. The anterior sec-
tor of the cingulate gyrus (Fig. 29.7A) is involved
in a broad range of processes, including willed
action, executive function, and emotion. A
remarkable property of this cortical tissue is that
its “descending” projections are probably more
extensive than that of any other cortical region
and includes major connections to autonomic
regulatory structures; notably to lateral hypo-
thalamus, PAG, parabrachial nucleus, and the
nucleus of the solitary tract. This connectivity is
consistent with studies that have documented
effects of cingulate electrical stimulation on vir-
tually all autonomic processes, as well as many
endocrine mechanisms.
Conversely, the cingulate cortex is the recipi-
ent of ascending signals from the brain stem.
The most notable of these is perhaps the one
from the nucleus of the solitary tract, the major
visceral sensory cell group in the brain. Sev-
eral nociceptive circuits also reach anterior and
mid-cingulate areas indirectly via the thalamus.
Thus, the cingulate cortex participates in more
than “motor” (ie, output) autonomic functions.
The anterior part of the cingulate cortex is one
of the most intensely studied areas in human
neuroimaging, and is activated by a wide range
of experimental paradigms. Based on early
644 29.  THE EMOTIONAL BRAIN

FIGURE 29.7  Anterior sector of the cingulate cortex. (A) Medial surface of cortex with the anterior sector of the medial
prefrontal cortex outlined in black. General locations of dorsal (D) and ventral (V) parts of the medial prefrontal cortex are
indicated. Anatomically, the cingulate cortex is delimited dorsally by the cingulate sulcus, although cortex dorsal to the sul-
cus is often referred to as “cingulate cortex.” S, subgenual anterior cingulate cortex. (B) Cognition and emotion in the medial
frontal cortex. Foci of activation across studies of negative affect and cognitive control, demonstrating extensive overlap
between the two. (B) Kindly provided by Alex Shackman and adapted with permission from Shackman AJ, Salomons TV, Slagter HA,
Fox AS, Winter JJ, Davidson RJ. The integration of negative affect, pain, and cognitive control in the cingulate cortex. Nat Rev Neurosci
2011;12:154–167.

imaging studies, it was proposed that this ante-
rior region could be subdivided into a rostral
“affective division” and a caudal “cognitive divi-
sion,” sectors putatively sensitive to emotional
and cognitive manipulations, respectively. Recent
meta-analyses of neuroimaging studies that take
into account hundreds of studies have revealed,
instead, considerable overlap of sites in medial
prefrontal cortex engaged during negative affect
and cognitive control (Fig. 29.7B). Activation sites
of negative affect studies encompass a broad
expanse of medial prefrontal cortex, as do those
of cognitive control studies, although the lat-
ter exhibit a discernible concentration of sites in
more dorsal regions. Indeed, studies of cognitive
control observed activation sites in dorsomedial
prefrontal cortex more often than they did in ven-
tromedial prefrontal cortex. Notably, however,
in studies of negative affect, activation of dorsal
and ventral prefrontal cortex was equally likely.
These findings thus undermine the notion of a
strict segregation between emotion and cognition
in medial prefrontal cortex.
The participation of the anterior cingulate
cortex in emotion has important clinical impli-
cations. Chronic deep brain stimulation of the
white matter in the vicinity of the subgenual
cingulate cortex (Fig. 29.7A) produces consid-
erable remission of symptoms in at least some
treatment-resistant depression patients. A cur-
rent hypothesis is that treatment efficacy is
mediated via cascading effects of the initial sub-
genual stimulation on a distributed network of
brain regions, such as the amygdala, hypothala-
mus, striatum, and orbitofrontal cortex.
In rodents, parts of the medial PFC, the so-
called “prelimbic” and “infralimbic” cortices,
that have important roles in emotion are dis-
cussed in section “Interactions Between the
Amygdala and Medial Prefrontal Cortex.”
Orbitofrontal Cortex
Orbitofrontal cortex is the portion of prefron-
tal cortex that sits just above the orbits of the
eyes and extends posteriorly several centimeters
to form the frontal base of the brain (Fig. 29.8).
Based on anatomical connectivity information, it
has been suggested that the orbitofrontal cortex
can be subdivided into orbital and medial compo-
nents, or networks. The orbital network receives
wide-ranging sensory information and appears
to integrate it, particularly in relation to the
assessment of food and reward. The medial net-
work is distinctively and heavily connected with
regions of the medial wall of the brain, including
those of cingulate cortex and surrounding areas.
In contrast to the orbital network, the medial
 Regions of the Emotional Brain
FIGURE 29.8  Orbitofrontal cortex. Ventral surface of the
brain showing the approximate location of the orbitofrontal
cortex.
network receives few sensory inputs. Impor-
tantly, the medial orbitofrontal cortex projects
to the hypothalamus and other areas involved
in visceral processing. In fact, via the hypo-
thalamus, the descending medial orbitofrontal
influence has the potential to extend as far as
autonomic centers in the spinal cord. In contrast,
there are relatively few projections to the hypo-
thalamus from the orbital network.
Anterior Insula
Insular cortex is the part of cortex folded
within the lateral sulcus (also called the “Syl-
vian fissure”) between the frontal and temporal
lobes—it is thus not visible from the lateral sur-
face of the brain (cortex covering it is referred to
as the “operculum,” meaning “lid”) (Fig. 29.9).
The anterior insula is strongly involved in the
processing of bodily signals as it contains repre-
sentations of the internal state of the body. This
representation involves signals from many body
645
FIGURE 29.9  Anterior insula. The insula is a territory of
cortex folded within the lateral sulcus between the frontal
and temporal lobes, and is not visible from the lateral surface
of the brain. The approximate location of the anterior insula
(AI) is shown.
parts, including the viscera, signals reporting
temperature, pain, itches, muscular sensations,
touch, and other bodily sensations. Both sympa-
thetic and parasympathetic bodily signals are at
first conveyed to the posterior insula, and then
to the anterior insula via the mid-insula. These
properties have led researchers to suggest that
the anterior insula participates in the representa-
tion of “feelings” from the body.
In all, whereas an output or motor role is
often emphasized for the cingulate cortex, an
input or sensory role is frequently emphasized
for the insula. But as discussed earlier, the cin-
gulate cortex also receives visceral, ascending
signals from important autonomic nuclei. In the
case of the insula, descending connections to the
hypothalamus and brain stem (for instance, the
parabrachial nucleus) also exist. Thus, in both
cingulate cortex and the insula, bidirectional
circuits are present, although they are likely
asymmetrical in their efficacies (stronger role
for output for the cingulate and stronger role for
input for the insula).
Interestingly, in human neuroimaging stud-
ies, researchers have found that the anterior
646 29.  THE EMOTIONAL BRAIN
insula is engaged by a remarkable array of tasks
spanning perception, cognition, and emotion.
Indeed, the anterior insula has been suggested to
be among the most functionally diverse regions
of the brain.
FROM REGIONS TO CIRCUITS
Earlier we reviewed some of the regions that
participate in emotional processing. But more
broadly, how should we understand the brain
basis of complex mental functions such as emo-
tion? Many accounts of mental function empha-
size the importance of particular brain regions.
In the case of emotion, the hypothalamus, for
example, was considered an emotion “center”
for several decades. Likewise, the amygdala has
played a major role in models of the emotional
brain in the past few decades. However, it is
increasingly recognized that functions arise via
the coordinated action of multiple brain regions
that participate in distributed circuits. In this
section, particular examples of this type of “dis-
tributed processing” are illustrated in the con-
text of emotional processing.
Large-Scale Amygdala Networks
A remarkable property of the amygdala is
its massive interconnectivity; as many as 1000
separate cortical and subcortical pathways may
exist. The connectivity is all the more notable
given that it involves all cortical lobes (though
connections to parietal cortex are sparser) as
well as subcortex (see Fig. 29.3). Combined,
these properties indicate that the amygdala is
an extensively interconnected hub, namely, a
region that exhibits a high degree of anatomical
connectivity (Fig. 29.10). Indeed, computational
analysis of databases that collate anatomical con-
nectivity suggests that several amygdala nuclei
(including the lateral nucleus and the accessory
basal nucleus) should be considered as part of
a “core” brain circuit, all of whose regions have
extremely high connectivity (see section: Prin-
ciple 1: Massive Anatomical Connectivity).
The pattern of connectivity between the
amygdala and prefrontal cortex is of particu-
lar interest given the latter’s role in cognitive
functions. In addition to substantial connec-
tions between the amygdala and both medial
and orbital aspects of prefrontal cortex, bidirec-
tional connectivity is present along the lateral
surface too, although these connections are rela-
tively weak. More generally, to understand how
amygdala signals are potentially “broadcast” to
all sectors of prefrontal cortex, it is important
to consider prefrontal connectivity itself. In one
study, although the amygdala was estimated to
be directly connected to about 40% of prefron-
tal regions, about 90% of prefrontal cortex was
shown to be capable of receiving amygdala sig-
nals after a single additional connection within
prefrontal cortex. This “one-step” property
shows that amygdala signals are not necessar-
ily confined to orbital and medial prefrontal
territories, both of which are directly connected
with the amygdala. Furthermore, this architec-
ture indicates how amygdala signals are able to
influence responses in lateral prefrontal cortex,
even though direct connections to this part of
cortex are relatively weak.
Let us consider the potential implications of
the amygdala’s connectivity on its influence on
signal processing in the brain. Even a simpli-
fied view of its anatomical connectivity shows
that, minimally, it belongs to three networks—in
addition to prefrontal networks—as discussed
in the previous paragraph. The first is a “visual
network,” as the amygdala receives fibers from
anterior parts of temporal cortex. Indeed, cells in
the amygdala respond to visual stimuli, includ-
ing faces, with response latencies a little longer
than cells in anterior visual cortex (a region that
responds to abstract visual stimuli such as spe-
cific shapes, as well as faces). The amygdala, by
its turn, influences visual processing via a set of
projections that reach most of ventral occipito-
temporal cortex (including primary visual
 From Regions to Circuits 647

FIGURE 29.10  Brain connectivity graph. The amygdala (Amyg) is highly connected brain region. Note that the central
position of the amygdala in the figure does not mean that it is the most connected (or “central”) region in the brain; other
highly connected regions, including the hippocampus (Hipp) and entorhinal cortex (ER), could have been displayed at the
center. Reproduced with permission from Pessoa L. On the relationship between emotion and cognition. Nat Rev Neurosci 2008;9:148–158
and adapted with permission from Young MP, Scannell JW, Burns GA, Blakemore C. Analysis of connectivity: Neural systems in the
cerebral cortex. Rev Neurosci 1994;5:227–249.

cortex). Thus, for instance, responses to emo-
tional faces are stronger than those to neutral
ones in occipito-temporal cortex.
The second is the well-known “autonomic
network,” as evidenced by connectivity with
subcortical structures such as the hypothalamus
and PAG. Via this network, the amygdala par-
ticipates in many complex autonomic mecha-
nisms, such as enhancing bodily arousal.
The third is a “value network,” as evidenced
by its connectivity with orbitofrontal cortex,
medial prefrontal cortex, and striatum. The
orbitofrontal cortex, for example, is important
for determining the relative value of the current
“state,” and orbitofrontal responses differentiate
events, even those removed from actual reward
delivery, if they provide information about the
likelihood of a future reward.
In total, the amygdala affiliates with dif-
ferent sets of regions, and thus participates in
several networks, in a highly flexible and con-
text-dependent manner. Other notable aspects
of amygdala connectivity include interactions
between the amygdala and the basal forebrain
that are important for attentional functions (see
section: Basal Forebrain), as well as how sub-
stantial projections from the amygdala to visual
cortex influence competition mechanisms in
visual cortex, thus contributing to attention as
well.
648 29.  THE EMOTIONAL BRAIN
Interactions Between the Amygdala and
Medial Prefrontal Cortex
As described, the pairing of an otherwise
neutral CS with an aversive US leads to aver-
sive learning; subsequent presentation of the CS
alone generates several of the properties of the
US, including freezing behavior and other phys-
iological responses that prepare the organism to
handle the impending danger. However, upon
repeated presentations of the CS without accom-
panying USs, the acquired responses dissipate.
For example, freezing behavior to a tone that
was previously paired with shock decreases.
This phenomenon, which is called extinction,
does not simply amount to forgetting, but instead
appears to involve new learning that inhibits or
overrides past learning. In other words, extinc-
tion is not a passive forgetting process, but an
active learning one. In the rat, a ventral por-
tion of the medial prefrontal cortex is critically
involved in extinction. Animals with lesions to
this so-called infralimbic region of medial pre-
frontal cortex show resistance to extinction, that
is, they show resistance to unlearning the origi-
nal CS-to-US association.
The role of prefrontal cortex in extinction
resonates with the long-held idea that this
region helps regulate behavior, for instance, as
espoused by the 19th century British neurologist
Hughlings Jackson who proposed that “higher”
centers exert inhibitory control over “lower”
brain regions. However, the picture of higher
regions inhibiting lower ones is too impover-
ished. Indeed, recent studies implicate a region
of the medial prefrontal cortex called the pre-
limbic cortex in “fear” excitation (this region is
immediately dorsal to the infralimbic cortex).
Importantly, the prelimbic cortex appears to be
critical for fear expression. Prelimbic neurons
exhibit sustained increases in activity lasting tens
of seconds that parallel the time course of aver-
sive behaviors. In all, the prelimbic and infralim-
bic cortex appear to integrate multiple types of
inputs with emotional significance to regulate
the extinction and expression of behaviors asso-
ciated with aversive stimuli. Finally, evidence
for contributions of different parts of the medial
prefrontal cortex in extinction and response
expression has also been garnered in humans.
Like in rodents, more dorsal (and posterior in
humans) parts are involved in response expres-
sion (and appraisal/evaluation of emotional
stimuli) and ventral (and anterior in humans)
parts are involved in response extinction.
Hypothalamic Circuits
However important the hypothalamus may
be for descending influences, a significant recent
insight is that the mammalian cerebral cortex and
the hypothalamus share massive bidirectional
connections. In the rat, the best-studied mam-
mal species, there are four major routes from the
hypothalamus to the cerebral cortex (Fig. 29.11).
These include a robust direct projection to all
parts of the cortical mantle, and three indirect
routes by way of the thalamus, basal brain nuclei
(specifically, basal forebrain and amygdala), and
brain stem. In all, the hypothalamus appears to
be the largest source of nonthalamic direct input
to the cortex. In the rat, some notable targets of
hypothalamic input include regions in medial
prefrontal cortex (infralimbic, prelimbic, and
anterior cingulate cortex) and insular cortex.
Interestingly, less prominent projections of the
hypothalamus to lateral prefrontal cortex and
even to primary sensory areas have been found.
The connections between prefrontal cortex and
the hypothalamus have also been investigated
in nonhuman primates, where they were found
to closely resemble those observed in rats. Nota-
bly, the hypothalamus has widespread projec-
tions to all sectors of the prefrontal cortex.
In sum, whereas the hypothalamus is involved
in a host of “basic” control functions, it is part
of an extensive bidirectional connective system
with cortex and many other subcortical struc-
tures in a manner that allows for integration of
 From Regions to Circuits
FIGURE 29.11  Hypothalamic ascending connectivity.
Summary of the four major pathways from the hypothala-
mus to cerebral cortex schematized on a flattened represen-
tation of the rat brain. The basal ganglia here refer to the
basal forebrain and the amygdala complex. Note that one of
the indirect connections first descends to the brain stem. BG,
basal ganglia; BS, brain stem; CTX, cortex; HY, hypothala-
mus; TH, thalamus. Reproduced with permission from Risold
PY, Thompson RH, Swanson LW. The structural organization of
connections between hypothalamus and cerebral cortex. Brain Res
Brain Res Rev 1997;24:197–254.
wide-ranging signals. Critically, the hypothala-
mus is linked to other structures that have them-
selves broad connectivity, including the basal
forebrain and the amygdala, further expanding
its potential for influencing information pro-
cessing. These insights thus resonate with the
observation by Morgane that the hypothalamus
is “only a single link in a larger multicircuit com-
plex rather than … an entity unto itself control-
ling any behavior as some form of command
center” (p. 7). This view stands in stark contrast
to the traditional viewpoint that the hypothala-
mus functions as a “head ganglion” that func-
tions as an overall controller region.
Basal Forebrain
The basal forebrain comprises a heterogeneous
set of structures close to the medial and ventral
surfaces of the cerebral hemispheres (Fig. 29.12).
These include the magnocellular basal nucleus,
which contains the basal nucleus of Meynert and
other cell groups. The basal forebrain originates
ascending cholinergic (and GABAergic) projec-
tions that innervate extensively throughout the
entire cortex. Major projections reach visual,
649
FIGURE 29.12  Basal forebrain. The basal forebrain
comprises heterogeneous structures close to the medial
and ventral surfaces of the brain. The basal forebrain origi-
nates ascending cholinergic (and GABAergic) projections
that innervate extensively throughout the entire cortex. The
approximate location of the basal forebrain is shown.
parietal, cingulate, frontal (including lateral and
orbital regions), and insular cortex (Mesulam,
2000); substantial connections have also been
found to both the hippocampus and amygdala
(Mesulam et al., 1992).
Acetylcholine released onto cortical neurons
facilitates their response. Studies suggest that
directly applying acetylcholine or stimulating
the basal forebrain can increase the signal-to-
noise ratio of neuronal responses and sharpen
response tuning curves. More broadly, given
its widespread connections, the basal forebrain
is in a favorable position to influence multiple
sites across the brain, including sensory regions
which play a central role in responding to envi-
ronmental stimuli. Overall, these topographi-
cally distributed effects result in increased
vigilance, alertness, or attention.
Emotional content can influence signal pro-
cessing across the brain via the basal forebrain
650 29.  THE EMOTIONAL BRAIN
because of the inputs that this structure receives.
Connections from cortex originate from sites in
orbitofrontal, temporal, insular, and cingulate
cortex, all of which are important for emotion.
Major subcortical projections to the basal fore-
brain originate from the amygdala (in particular,
the central amygdala), hypothalamus, and vari-
ous brain stem cell groups, including midbrain
dopaminergic cells and the locus coeruleus. In
all, given its overall connectivity pattern, the
basal forebrain is in a position to influence pro-
cessing across the brain based on multiple types
of signals, including those central to emotion.
Lateral Prefrontal Cortex
The role of lateral prefrontal cortex in a range
of cognitive operations is well documented.
Indeed, this region is perhaps the paradigmatic
“cognitive” brain region. Yet, the connectiv-
ity pattern of lateral prefrontal cortex is quite
extensive, indicating that its functions should
be conceptualized more broadly. For example,
the dorsolateral prefrontal cortex is not only an
important hub, but is also strongly connected
with other regions that are topologically cen-
tral themselves, which considerably expands
the reach of the dorsolateral prefrontal cortex
in influencing, and being influenced by, other
regions. Being robustly bidirectionally con-
nected to medial and orbital prefrontal areas, as
well as to the insula, the lateral prefrontal cortex
has access to afferent signals from the body and,
at the same time, the region can influence signals
that reach the body. Furthermore, as previously
discussed, the amygdala is not only directly con-
nected to a substantial set of prefrontal regions,
but nearly all of prefrontal cortex is capable of
receiving amygdala signals after a single addi-
tional connection within prefrontal cortex itself
(what was referred to as the “one-step” prop-
erty). Overall, the connectivity pattern of the
lateral prefrontal cortex allows it to play a sig-
nificant role in the integration of “cognitive”
and “emotional” signals.
Distributed Circuits and the Evolution of
the Emotional Brain
From an evolutionary perspective, it is some-
times stated that cognition can be considered
“the tip of the iceberg,” often associated with
“newer” parts of the cortex, while the “rest of the
iceberg” involves emotional processes that fre-
quently rely on “old” subcortical brain regions.
Furthermore, so the story goes, the “old” emo-
tional system functions in a largely autonomous
manner.
The brain has what can be considered old sys-
tems. For example, anatomical and behavioral
data suggest that ray-finned fishes and land ver-
tebrates probably share an ancestor that already
possessed an amygdala. And the amygdala of
the ancestral amniote (which includes reptiles,
birds, and mammals) is believed to have pos-
sessed an amygdala with so-called pallial and
subpallial components, namely the ancestral
form of the basolateral and central amygdala
highlighted in this chapter. However, “old”
regions do not exist within a “layered” architec-
ture, with newer structures simply added on top
of old ones, such that the ones on top control the
ones at the bottom (Fig. 29.13). The examples dis-
cussed in the preceding sections, including the
amygdala and the hypothalamus, illustrate that
the old/new conceptualization that is central to
many versions of the emotional brain, does not
take into account the extensive anatomical con-
nectivity of brain circuits.
Recent studies focusing on the amygdala
further inform the understanding of the evolu-
tion of a region that is important for emotion.
For example, the lateral, basal, and accessory
basal subregions of the amygdala are consider-
ably more “developed” in monkeys than in rats
(based on morphological characteristics, such as
cell counts and the volume of subregions). One
suggestion is that the differences between rats
and monkeys are linked to the degree of con-
nectivity of these nuclei with other brain struc-
tures, in line with the framework of correlated
 How Are Emotions Organized in the Brain? 651

FIGURE 29.13  Brain evolution. (A) Brain evolution conceptualized as an additive process, with newer structures being
added on top of older ones, and exerting control over them. Although this view was espoused by some comparative neu-
roanatomists in the early 20th century, and popularized well into later parts of the century (most notably in the idea of the
“triune brain”), it does not reflect current knowledge of comparative neuroanatomy. Importantly, it does not take into account
the extensive anatomical connectivity of brain circuits in general, and between cortical and subcortical regions in particular,
as schematically shown in part (B).

evolution between components of functional
systems. In this view, the lateral, basal, and
accessory basal nuclei are more developed in
primates than in rodents, paralleling the greater
development of the cortical areas with which
these nuclei are interconnected in primates. In
other words, the relative development of these
amygdala nuclei is influenced by their inter-
connections with other brain structures. Fur-
thermore, such correlated evolution would be
responsible for a higher convergence and inte-
gration of information in the primate amygdala.
HOW ARE EMOTIONS ORGANIZED
IN THE BRAIN?
In the late 1940s, MacLean proposed the idea
of a “limbic system” to explain how emotion
is organized in the brain. Although the term is
probably one of the most widely used in neu-
roscience, the concept has proven too unwieldy
and unstable to be scientifically useful. Impor-
tantly, agreement regarding the brain regions
that belong to this system has never been
attained. Because of this, the term is often used
in a circular fashion to indicate the “emotional
brain” and, as some have pointed out, the term
“limbic system” substitutes naming for under-
standing. Thus, the designation “emotional
brain” is preferable, and the term “limbic sys-
tem” should be abandoned.
Nevertheless, two concepts related to early
notions of the “limbic system” are worth con-
sidering. One concept is the broad organizing
principle that along a medial–lateral axis of the
brain, a gradient of affective/motivational sen-
sitivity is observed. By and large, medial brain
structures (along the inner edge or limbus of
the brain) are more sensitive to affective and
motivational variables, while more lateral brain
regions are less so. But the sensitivity is a matter
of degree because all brain regions are suscep-
tible to emotional and motivational influences,
to some degree. There are important exceptions
to this broad principle. For example, the anterior
insula, which participates in important emotion-
related functions, lies more laterally (although it
is covered by the operculum of the frontal and
parietal cortices).
Another concept is the broad principle that
parts of the brain that are more sensitive to emo-
tional variables are less structured. Many brain
regions important for emotional processing are
652 29.  THE EMOTIONAL BRAIN
subcortical, and subcortex is cytoarchitectur-
ally poorly structured. Cortex varies in degree
of lamination, from three main layers to six or
more well-demarcated layers. Agranular cortex
contains three layers (it lacks a conspicuous
layer IV), dysgranular cortex has four layers,
and granular cortex contains six layers. Because
cortex along Broca’s “great limbic lobe” (ie,
the medial edge of the hemispheres) is mostly
not granular, it follows from its location and
the medial–lateral gradient noted previously
that less individuated cortex is relatively more
involved in emotional processing.
Next, three other principles of the emotional
brain are described.
Principle 1: Massive Anatomical
Connectivity
Computational analysis of anatomical con-
nectivity demonstrates that both cortical and
subcortical brain regions are massively inter-
connected (Fig. 29.14). Massive connectivity is
not limited to specific sectors of the brain but
instead includes all of them: occipital, tempo-
ral, parietal, and frontal lobes, as well as cingu-
late, insula, thalamus, and basal brain regions
(subcortical nuclei at the base of the forebrain,
including the amygdala and basal ganglia).
Related analyses have described a tightly
integrated “core circuit” spanning all of the
brain sectors mentioned earlier. This core circuit
is topologically central, that is, strongly con-
nected to all other regions of the core and the
rest of the brain. The core circuit was proposed
to have several important properties: (1) it is a
subnetwork that is far more tightly integrated
than the overall brain network; (2) information
likely spreads more swiftly within the core than
through the overall brain network; and (3) the
overall brain network communicates with itself
mainly through the core.
Although the property of massive anatomi-
cal connectivity is a principle that applies to the
entire brain, the organization of emotion in the
brain must be understood from the standpoint of
this general architectural property. Furthermore,
it is noteworthy that many regions implicated in
emotion were proposed to be part of the brain’s
core circuit. Finally, the property of extensive
anatomical connectivity is further illustrated,
for example, by the discussion of the amygdala
and hypothalamus in section “From Regions to
Circuits.”
Principle 2: Anatomical Connectivity to
and From the Body
Because emotion is closely linked to bodily
states, brain circuits that involve signals to and
from the body are important for emotion.
To illustrate the to-the-body part, consider the
hypothalamus. Classical studies showed that
“decortication” (ie, removal of cortex) alone did
not abolish emotional expression, but that decor-
tication plus ablation of the hypothalamus has
a much more substantial effect on this expres-
sion. Current understanding of hypothalamic
function indeed reveals that this structure is
involved in important body-related operations.
As described in section “Hypothalamus,” hypo-
thalamic mechanisms contribute to a wealth of
processes, including circadian rhythms, wake-
fulness and sleep, stress responses, temperature
regulation, food intake, thirst, sexual behaviors,
and defensive behaviors. To carry out these
functions, the hypothalamus works in concert
with a multitude of other sites, several of which
are located in the brain stem and spinal cord.
Cortical regions with substantial body-related
signals include the medial orbitofrontal cortex,
the cingulate gyrus, and the insula—illustrating
the from-the-body part. Consider, for example,
the insula: the physiological condition of the
entire body is conveyed to the posterior insu-
lar cortex, including individually mapped and
distinct feeling-related signals from the body.
These signals are also present in the mid-insula
and the anterior insula, which integrate body-
related signals with activity that is associated
 Principle 3: High Functional Connectivity With Most of the Brain 653

FIGURE 29.14  Computational analysis of whole-brain anatomical connectivity. The analysis considered existing data of
an extensive set of cortical and subcortical regions (indicated via colored rectangles) spanning major brain sectors. The basal
ganglia refer to nuclei at the base of the forebrain, including the amygdala. Reproduced with permission from Modha DS, Singh R.
Network architecture of the long-distance pathways in the macaque brain. Proc Natl Acad Sci USA 2010;107:13485–13490.

with emotionally salient stimuli (eg, via sensory
regions, the temporal pole, and the amygdala).
Thus, the insula, especially its posterior part,
can be considered interoceptive cortex, much
like parts of parietal cortex are somatosensory
cortex, for example.
The combination of principles 1 and 2 reveals
that brain regions that influence the body, and
conversely brain regions that are influenced by
the body, extend well beyond those with more
direct anatomical pathways to and from the body.
PRINCIPLE 3: HIGH FUNCTIONAL
CONNECTIVITY WITH MOST OF
THE BRAIN
Understanding how regions contribute to
brain function requires characterizing how they
are “functionally connected,” in addition, of
course, to how they are anatomically connected.
Functional connectivity is a concept that was
devised to characterize how neurons interact
and was defined as the “coherence” among the
654 29.  THE EMOTIONAL BRAIN

FIGURE 29.15  Functional connectivity. Maps show correlations between a seed region in the posterior cingulate cortex
(PCC) and all other voxels in the brain for a single subject during resting fixation (both positively and negatively correlated
regions are shown). Thus, all colored voxels are functionally connected with the PCC. The bottom plot shows the time course
for a single run for the seed region (PCC, yellow), a region positively correlated with this seed region in the medial prefrontal
cortex (MPF, orange), and a region negatively correlated with the seed region in the intraparietal sulcus (IPS, blue). Reproduced
with permission from Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically orga-
nized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 2005;102:9673–9678.

activity of different neurons. Functional connec-
tivity thus answers the following question: how
coordinated is the activity of two brain regions
that may or may not be directly anatomically
connected (Fig. 29.15)?
Whereas it is natural to anticipate a func-
tional association between brain regions that
are directly connected, the relationship between
structural and functional connectivity is not
always a simple one. A striking example of
structure–function dissociation is illustrated by
an unusual population of adults without the
corpus callosum, a structure that provides the
major communication pathway between the two
hemispheres. Although starkly different struc-
turally relative to controls, individuals without
the callosum exhibited very similar patterns
of functional connectivity (as measured during
rest with functional MRI). Thus, largely normal
coordinated activity can emerge in brains with
dramatically altered structural connectivity. In
all, the functional organization of the brain is
driven by factors that go beyond direct struc-
tural connectivity.
Therefore, to understand the organization of
emotion in the brain, in addition to character-
izing the brain’s structural anatomy, it is neces-
sary to characterize the functional relationships
between brain regions. Importantly, anatomical
architectural features support the efficient com-
munication of information even when strong
direct structural connections are not present,
and support functional interactions that will
vary based on context. This is illustrated, for
 Further Reading
example, by the “one-step” property of amyg-
dala–prefrontal cortex connectivity discussed
previously (amygdala signals reach nearly all
prefrontal regions via a single connectivity step
within prefrontal cortex; section “From Regions
to Circuits”). This anatomical property allows
the amygdala to engage in functional interac-
tions with, for instance, lateral prefrontal regions
that are not supported by strong direct anatomi-
cal connections.
CONCLUSIONS
The search to understand the emotional brain
is as active today as it ever was. With time, the list
of areas that have been proposed to play impor-
tant roles in emotion has grown from having
just a few members (hypothalamus, amygdala)
to a large list. Notably, this list is not “fixed,” but
some members are included and highlighted by
some authors but not others. This is not capri-
cious; instead, it is because brain regions do not
implement a single function (say, the amygdala
is responsible for just aversive learning), but
participate in many functions (the amygdala
is involved in attention and decision making,
among other functions). Therefore, the choice is
one of emphasis. For example, the hippocampus
is centrally important for memory processes.
However, although it was not discussed in this
chapter, it also participates in emotional pro-
cessing, and has been particularly investigated
in its contributions to anxiety.
Another reason the list of emotional brain
regions is not fixed is because the boundaries of
the emotional brain are ill defined. As reviewed
in the present chapter, the brain is characterized
by an architecture that exhibits massive intercon-
nectivity. This connectivity implies that signals
in a given structure can readily influence other
parts of the brain in a few synapses—in many
cases in as few as one or two synapses. Impor-
tantly, brain regions do not implement functions
in isolation. Instead, they are part of distributed
655
circuits that involve nonlocal connections that
bring regions, which are anatomically far from
one another, together into functional circuits.
In all, to understand how emotions are orga-
nized requires understanding general princi-
ples of information processing in the brain (as
a whole). Thus, to understand the emotional
brain, it is critical to understand the sensory,
motor, and cognitive brain. In this way, it is also
possible to characterize and understand the
full ramifications of emotional psychopatholo-
gies, such as the anxiety disorders and depres-
sion, whose impact on mental function is not
restricted to emotion, but necessarily encom-
passes additional dimensions, most notably
cognition.
Further Reading
[1] Bains JS, Cusulin JIW, Inoue W. Stress-related synap-
tic plasticity in the hypothalamus. Nat Rev Neurosci
2015;16:377–88.
[2] Bandler R, Shipley MT. Columnar organization in the
midbrain periaqueductal gray: modules for emotional
expression? Trends Neurosci 1994;17:379–89.
[3] Craig AD. How do you feel—now? The anterior insula
and human awareness. Nat Rev Neurosci 2009;10:59–70.
[4] Davis M, Walker DL, Miles L, Grillon C. Phasic vs sus-
tained fear in rats and humans: role of the extended
amygdala in fear vs anxiety. Neuropsychopharmacol
2010;35:105–35.
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