Prog.

Neuro-PsychopharmacoL

& BioL Psychiat. 1999, Vol. 23, pp. 17.5193

Copyright D 1999 Elsetier Science Inc
Printed

in The USA.

All rights reserved

027%X346/99/$-see

ELSEVIER

PII

front matter

80278-5845(98)00105-7

A NEUROANATOMIC

MODEL FOR DEPRESSION

Christopher E. Byrum, Eileen P. Ahearn, and K. Ranga R. Krishnan

Duke University Medical Center

Department of Psychiatry and Behavioral Sciences
Durham, North Carolina, U.S.A.

(Final form, December, 13%)

Contents
1.

2.
2.1
2.2
2.3
2.3.1
2.3.2
3.
4.
5.
5.1
5.2
5.3
5.4
5.5
5.6
6
7

Abstract
Introduction
Neuroanatomy
Amygdala
Cingulate Gyrus
Frontal Lobe
Orbitofrontal Lobe
Dorsolateral Prefrontal Cortex
Basal Ganglia
Monoamine Systems
Clinical Evidence
Amygdala
Cingulate Gyrus
Frontal Lobe
Basal Ganglia
Monoamine Systems
Hemispheric Differentiation
A Neuroanatomic Model of Depression
Conclusions
References

Abstract
Byrum, Christopher E., Eileen P. Ahearn, and K. Ranga R. Krishnan: A Neuroanatomic Model for
Depression. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1999, ZS, pp. 175-193.
81999 Elsevier Science Inc.

1. Emotion and mood, once thought to be governed solely by the limbic system of the brain, now are
thought to be influenced by numerous nonlimbic central nervous system structures as well.

175

176

C.E. Byrum

er al.

2. The present review discusses several important brain structures and neuroanatomic pathways
thought to be involved in affect and mood disorders, including the amygdala, frontal neocortex,
cingulate gyrus, basal ganglia, and the monoamine systems.
3. The authors propose a specific neuroanatomic model for depression that emphasizes that a
distributed system of extensively interconnected CNS structures mediates emotion and affect.
Keywords: affective, amygdala, basal ganglia, depression, limbic system, monoamines, mood,
neuroanatomy, neuroimaging.
Abbreviations: central nervous system (CNS), corticotropin releasing factor (CRF) dorsolateral
prefrontal cortex (DLPFC), functional magnetic resonance imaging (fMRI), positron emission
tomography (PET), regional cerebral blood flow (rCBF), single photon emission computed
tomography (SPECT).

1. Introduction
Our understanding of the biological basis of affective disorders has been advanced in recent years
by sophisticated brain imaging techniques as well as by information gleaned from new biologic
therapies. Emotion and mood, once thought to be governed solely by the limbic system of the brain,
now are thought to be influenced by numerous nonlimbic central nervous system (CNS) structures
as well, including cerebral cortex, basal ganglia, thalamus, hypothalamus, and parts of the
brainstem. The processes of mood and emotional response are indeed complicated and only partly
understood. Furthermore, the neuroanatomy and pathophysiology of mood disorders, which can
encompass extremes of emotion, remains an area of intensive research effort.
The purpose of this paper is twofold. First, we will discuss several important brain structures and
neuroanatomic pathways thought to be involved in affect and mood disorders, including the
amygdala, cingulate gyrus, dorsolateral prefrontal cortex, orbitofrontal cortex, basal ganglia, and the
monoamine systems.

Second, the authors will propose a specific neuroanatomic model for

depression.

2. Neuroanatomv
2.1 Amygdala
The amygdala is a medial temporal lobe structure that appears to be the central processing station
which evaluates the emotional significance of sensory stimuli (Halgren, 1992). The amygdala, which
is in fact a complex made up of a number of subnuclei, is striking in the breadth of its anatomical
connections (Fig 1). In addition to extensive and often reciprocal connections with broad areas of
neocortex, the amygdala has connections with allocortical areas including entorhinal and subicular
cortex and the cingulate gyrus (de Olmos, 1990). Subcortical connections of the amygdala include

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A neuroanatomic model for depression

Neocortex: unimodal sensory and heteromodal association cortex

Allocortex, including hippocampus and other limbic structures

Striatum

.+-

Amygdala

Hypothalamus

Thalamus

LI
Brainstem

Fig 1. Selected anatomical connections of the amygdala. Double-headed arrows indicate reciprocal
connections. The thickness of the line is approximately proportional to the density of the
connection. All of these structures are extensively innervated by both the serotonergic and
noradrenergic systems.

the hippocampus and septal nuclei, the thalamus and hypothalamus, and the basal ganglia (de
Olmos, 1990).
The amygdala receives complex sensory information from higher-order sensory cortex and
heteromodal association cortex in frontal and temporal lobes and insular cortex (Turner et al., 1980;
Van Hoesen et al., 1972; Whitlock and Nauta, 1958). Thus the amygdala receives sensory
information that has been highly processed, wherein complex patterns of information are identified
as objects, people, events, etc. The amygdala then evaluates and assigns emotional significance
to these objects and events by mechanisms which are unclear. The information impinging on the
amygdala has been shown to be interpreted in light of past experiences which may be imbued with
considerable affective tone (Rolls, 1992).
Lesion studies have demonstrated the significance of the amygdala in affective processing. In
animal studies, damage to the amygdala leaves the animal unable to process the emotional
significance of sensory information (Kluver and Bucy, 1937; Aggleton, 1992). A number of clinical
studies have demonstrated the involvement of the amygdala in emotional response and the
recognition of emotion, especially involving aversive stimuli and fear. Bilateral amygdala damage

178

C.E. Byrum et al.

in humans compromises recognition of fear in facial expressions (Adolphs et al., 1995). Functional
magnetic resonance imaging (fMRI) experiments have suggested the amygdala is preferentially
activated in response to fearful stimuli (Breiter et al., 1996). Positron emission tomography (PET)
studies have shown that the left amygdala responds to a greater extent than the right to fearful
stimuli, suggesting lateralization of emotional recognition in the amygdala (Schneider et al., 1995).
Moreover, the amygdala is involved in fear conditioning, control of stress-induced metabolic
activation of monoaminergic systems in the prefrontal cortex, and integration of behavioral and
neuroendocrine components of the stress response (Armony et al., 1995; Ferry et al., 1995;
Goldstein et al., 1996).
Once the amygdala has assigned emotional significance to the current events or situations,
efferent projections from the amygdala to the hypothalamus, basal ganglia, brainstem, and cerebral
cortex will mediate various aspects of a persons response to the event or situation. Projections to
the hypothalamus and brainstem mediate the autonomic and humoral responses. Projections to
the basal ganglia modulate the motor behavior.

Efferent projections from the amygdala to the

prefrontal cortex and the dorsomedial nucleus of the thalamus participate in the association loops
of the basal ganglia.

The connections between the amygdala and the neocortex, especially

language areas, provide the pathway for the labeling of affect.

2.2 Cingulate Gyrus
The cingulate gyrus is part of the limbic lobe and is heavily interconnected with the amygdala,
medial orbitofrontal cortex, temporal neocortex, dorsolateral prefrontal cortex, hippocampus,
parahippocampal gyrus, and inferior parietal lobe (Parent, 1996). The anterior part of the cingulate
gyrus is a large region around the genu of the corpus callosum. This area is divided into affective
and cognitive subregions (Vogt et al., 1992). The affective region, which includes Brodmann areas
24 and 25, is important in regulating autonomic and endocrine functions, and like the amygdala it
has been implicated in assigning emotional valence.
2.3 Frontal Lobe
2.3.1 Orbitofrontal Neocortex The orbitofrontal cortex is a component of the paralimbic cortical
circuit and consists of several distinct areas. It is involved in higher order association functions that
include the integration of emotion, behavior, and various sensory processes. The orbitofrontal
cortex is composed of many highly interconnected subunits which are cytoarchitectonically and
functionally distinct (Carmichael and Price 1996).

Orbitofrontal cortex has extensive reciprocal

connections with the dorsomedial thalamic nucleus (which innervates nearly the entire frontal
cortex), and is closely linked to the cingulate gyrus, amygdala, temporal neocortex, and insula

179

A neuroanatomic model for depression

(Carmichael and Price 1995). Orbitofrontal cortex also has dense connections with caudate nucleus
and nucleus accumbens.
Patients with lesions limited to medial orbitofrontal cortex exhibit various sensory and personality
deficits including social withdrawal (Rolls, 1996).
identification of facial expressions.

Damage to orbitofrontal cortex can impair

Damage to orbitofrontal cortex in animal studies impairs the

learning and reversal of stimulus-reinforcement associations. Orbitofrontal cortex appears to play

an executive function in controlling and correcting reward-related and punishment-related behavior,
and thus in emotion. In many ways it has a role analogous to the amygdala (Rolls, 1996).
2.3.2 Dorsolateral Prefrontal Cortex (DLPFC) The area of the lateral convexity of prefrontal cortex
that includes Brodmann areas 6, 9, and 46 is often broadly lumped together as the DLPFC. The
DLPFC is involved in working memory function. This region is interconnected with other regions of
frontal cortex, cingulate gyrus, amygdala, and basal ganglia (de Olmos, 1990; Zilles, 1990; Parent,
1996).

3. Basal Gan&
The basal ganglia consists of input nuclei and output nuclei. The input nuclei, comprising the
caudate, putamen, and ventral striatum, are known collectively as the striatum and receive afferent
input from virtually all areas of cortex (Parent, 1996). Cortical input to the striatum exhibits a
distinctly regional pattern. The putamen is innervated by sensorimotor cortex, whereas the caudate
nucleus preferentially receives input from association areas of frontal, temporal, parietal, and
cingulate cortex. Furthermore, afferent input from limbic and paralimbic cortex, hippocampus, and
amygdala primarily terminates in the ventral striatum, which includes the nucleus accumbens, part
of the olfactory tubercle, and the ventral parts of the caudate and putamen.

Based on this

corticostrlatal innervation pattern, the striatum is divided into sensorimotor, associative, and limbic
territories, respectively (Parent, 1996). This regional organization is maintained throughout the
basal ganglia.
The basal ganglia had long been believed to integrate multiple diverse cortical inputs based on
serial convergence of these pathways. In the past decade, the concept of parallel processing in the
basal ganglia has gained wide acceptance. Every cortical area has a separate functional pathway
through the striatum that lies adjacent to and interdigitates with that of functionally related cortical
areas (Alexander et al., 1986; Bagsdale and Graybiel, 1990). In addition to the massive cortical
innervation, the striatum receives prominent afferent input from the thalamus and substantia nigra
(Parent, 1996). The dense thalamic input originates primarily in the centromedian-parafascicular

C.E. Byrum

180

complex and intralaminar nuclei.

et al.

The centromedian nucleus mainly projects to sensorimotor

territory of the striatum whereas the parafascicular nucleus, which receives input from the limbic
areas, projects to the limbic and associative areas of the striatum.
The striatal nuclei project exclusively to the globus pallidus, which is the main output nucleus of
the basal ganglia, and to the substantia nigra (pars reticulata).

The parallel, segregated

organization of the striatal nuclei is maintained within the pallidal complex. The globus pallidus has
internal and external segments, as well as a ventral subcommissural portion known as the ventral
pallidum. The ventral pallidurn, which receives its major striatal input from the ventral striatum, also
receives direct input from the amygdala.
The main pallidal projection is to the thalamus (the centromedian and ventral tier nuclei). The
ventral pallidum projects to limbic structures, including the dorsomedial thalamus, amygdala, lateral
habenula, and hypothalamus.
Alexander et al. (1986) described the functional architecture of the basal ganglia circuits,
identifying five corticostriatothalamic circuits. Several of the circuits involve cortical areas thought
to be involved in the pathophysiology of affective disorders, including prefrontal and temporal
neocortex and limbic allocortex, including a cingulate circuit.

These authors emphasize the

functional parallel arrangement of the basal ganglia circuits which is maintained throughout the
striatum,

globus

pallidus,

and

substantia

nigra.

The

existence

of

multiple

parallel

corticostriatothalamic circuits suggest a capacity to support parallel concurrent processing of an

enormous number of variables. The functioning of the basic circuit is depicted in Fig 2.
The output nuclei of the basal ganglia exert a tonic inhibitory influence on thalamic target neurons.
This inhibitory oufflow is modulated by two parallel but opposing pathways within the basal ganglia.
In the direct pathway, excitatory input from the cortex to the matrix and striosomes of the striatum
increases the GABA-mediated inhibition of the internal segment of the globus pallidus neurons by
striatal projection neurons. The reduced activity of these GABAergic pallidal neurons disinhibits the
thalamic target neurons, which in turn increases excitatory input to the cortex. The indirect pathway
involves an inhibitory projection from the striatum to the external globus pallidus (GABA), an
inhibitory projection from the globus pallidus to the subthalamic nucleus (GABA), and an excitatory
projection from the subthalamus to the internal globus pallidus (glutamate).

The net effect of

activation of this pathway is disinhibition of the subthalamic nucleus resulting in excitation of the
internal globus pallidus and inhibition of thalamic target neurons (Alexander and Crutcher, 1990).
Besides the two loop circuits, an additional circuit involves the activation or inhibition of substantia
nigra neurons by dopamine. Dopamine, which has opposite effects on the two loop circuits,

181

A neuroanatomic model for depression

+ GLU

GLU

GLU
GABA

,I-

Nigra

GABA

GLU

I+
GLU

-----+

Globus
_
- 1
Thalamus
Pallidus
i
Internal IGABA
I
I

Indirect Pathway

Direct Pathway

Fig 2. Cortex-Basal Ganglia-Thalamus circuits. Indicated are the neurotransmitters involved

(GABA, gamma-aminobutyric acid; Glu, glutamate; DA, dopamine), and whether the connection is
excitatory (+) or inhibitory (-). The net effect of activation of the direct pathway is disinhibition of
thalamic neurons and increased excitatory input to the cortex. The net effect of activation of the
indirect pathway is inhibition of thalamic neurons and decreased excitatory input to the cortex.

normally maintains a balance between the circuits (Parent, 1996). Thus, the net effect of dopamine
may be to reinforce any cortically initiated activation of a particular basal ganglia-thalamic-cortical
circuit by both facilitating conduction through the circuits direct pathway, which has a net excitatory
effect on the thalamus, and reducing conduction through the indirect pathway, which has a net
inhibitory effect on the thalamus.

4. Monoamine @stems
The amygdala, cortex, and basal ganglia are modulated by three monoamine projection systems
that originate in the brainstem (Parent, 1996). Both serotonin and norepinephrine diffusely innervate
the entire neocortex, amygdala, basal ganglia, and diencephalon.

Dopaminergic cells in the

substantia nigra (pars compacta) innervate the caudate and putamen, and other dopaminergic cells
in the ventral tegmental area (Al 0) innervate the nucleus accumbens.
The serotonergic, noradrenergic, and dopaminergic systems exhibit complex interactions (Sethy
and Harris, 1982; Potter et al., 1985; Kelland et al., 1990). An essential point is that perturbation

182

C.E. Byrum et al.

of one system will result in changes in activity of one or both of the other monoamine systems. The
diffuse innervation of virtually the entire cerebrum by these systems means that dysfunction of one
or more systems will have profound consequences

However, the precise roles each system plays

and the ways that they interact remain unclear.

5. Clinical Evidence
The neuroanatomic substrates of depression clearly have yet to be defined in a meaningful way.
There are, however, clues provided both by CNS disease states associated with affective disorders,
as well as brain imaging studies and metabolic and neurochemical studies of the brain in patients
with affective disorders. Table 1 summarizes functional imaging studies in patients with major
depression. Regional cerebral blood flow (rCBF) is used as an index of activity in particular brain
regions.

Table 1
Regional Cerebral Blood Flow (rCBF) in Major Depression

Kanaya and Yonekawa, 1990: SPECT: Generalized decrease in cerebral rCBF, left greater than
right.
Ebert et al., 1991: SPECT: hypoperfusion in the left anterolateral prefrontal cortex.
Austin, et al., 1992: SPECT: Generalized reduced uptake (cortical and subcortical), especially in
temporal, inferior frontal, and parietal areas.
Bench et al., 1992: PET: Decreased rCBF in the left anterior cingulate and the left DLPFC.
Drevets et al., 1992: PET: In familial pure depressive disease (FPDD), increased rCBF in an area
that extended from the left ventrolateral prefrontal cortex onto the medial prefrontal cortical
surface. Both the depressed and the remitted groups demonstrated increased activity in the
left amygdala, though this difference achieved significance only in the depressed group.
Bench et al., 1993: PET: Reduced rCBF in left DLPFC, left anterior cingulate, and left angular
gyrus.
Dolan et al., 1993: SPECT: Patients with poverty of speech had significantly lower rCBF in the left
DLPFC.
Ebert et al., 1993: SPECT: hypofrontal (DLPFC)
Goodwin et al., 1993: SPECT: Patients with a major depressive episode after full recovery.
Significant bilateral increases in tracer uptake were confined to basal ganglia and inferior
anterior cingulate cortex.
Table 1 Continued

A neuroanatomic model for depression

183

Maes et al., 1993: SPECT: negative study.

Lesser et al., 1994: SPECT: older (~50) drug-free depressed patients. Generalized decrease in
rCBF, with the orbital frontal and inferior temporal areas affected bilaterally. rCBF was also
reduced in higher brain slices in the right but not the left hemisphere.
Mayberg et al., 1994: SPECT: patients with severe unipolar depression that was unresponsive to
drug therapy, on medications. The rCBF was significantly decreased bilaterally in the frontal
cortex, anterior temporal cortex, anterior cingulate gyrus, and caudate in the depressed
patients, especially in the paralimbic regions, specifically, the inferior frontal and cingulate
cortex.
Bench et al., 1995: PET: Reduced rCBF in the DLPFC, anterior cingulate cortex and angular gyrus.
Remission was associated with a significant increase in rCBF in the left DLPFC and medial
prefrontal cortex including anterior cingulate.
Rubin et al., 1995: PET: significant reductions of rCBF in anterior cortical areas and reduction of
the normal anteroposterior gradient.
Ito et al., 1996: SPECT: Significant decreases in rCBF in the prefrontal cortices, limbic systems and
paralimbic areas were observed in depression groups compared with the normal control
group.

5.1 &nygdala
The involvement of the amygdala in stress-induced metabolic activation of monoaminergic systems
in the prefrontal cortex and integration of behavioral and neuroendocrine components of the stress
response (Goldstein et al., 1996) suggests a role in many of the behavioral aspects of depression.
PET studies have shown that there is increased letI amygdala activity in depressed patients both
in the depressed and in the remitted state (Drevets et al., 1992). This raises the possibility that the
amygdala may be critical in the development of depression. However, it must be noted that this
data has not yet been replicated by other groups. The limited functional imaging data involving the
amygdala can be attributed to its small size.

However, fMRl may provide the higher resolution

needed for detailed functional studies of this structure.

5.2 Cinaulate Gyrus

A number of studies have demonstrated involvement of the cingulate gyrus in depression (Ebert
and Ebmeier, 1996). Remission has been associated with increased cerebral blood flow (Goodwin
et al., 1993; Bench et al., 1995). Drevets et al. (1997) also implicated the subgenual region of this
gyrus which is closely interlinked with the medial orbitofrontal cortex.

184

C.E. Byrum

et al.

5.3 Frontal Lobes

Clinical evidence has implicated the frontal lobes in depression (George et al., 1994). Numerous
studies have demonstrated a high incidence of affective disorders in patients with strokes or tumors
in the frontal lobe (Robinson and Travella, 1996; Strauss and Keschner, 1935). Similarly, after
traumatic brain injury depressive symptoms are more common when the frontal lobes are involved
(Robinson and Travella, 1996). Furthermore, Coffey et al. (1993) reported decreased size of the
prefrontal lobes in patients with depression.
PET and single photon emission computed tomography (SPECT) studies have implicated the
DLPFC, orbitofrontal cortex, thalamus, and caudate nucleus in the pathogenesis of depression
(Bench et al., 1993). Several studies have demonstrated alterations in blood flow in the medial
orbital prefrontal cortex and DLPFC in depression and in remission of symptoms (Drevets et
al.,1992; Dolan et al., 1993; Ebert et al.,1993; Lesser et al., 1994; Bench et al., 1995). These
studies clearly indicate a role for these frontal lobe areas in depression.

5.4 Basal Ganglia

Studies of patients with CNS disease have demonstrated involvement of the basal ganglia in
depression.

Patients with Huntington disease, Parkinson disease, or strokes involving the basal

ganglia have a high incidence of affective disorders (Folstein et al., 1979; Calne and Shoulson,
1983; Cummings, 1985; Starkstein et al., 1987). In addition, Coffey et al. (1988) demonstrated a
high incidence of basal ganglia and thalamic lesions in patients with late onset depression.
Furthermore, Krishnan et al. (1992) demonstrated decreases in the size of the caudate and
putamen in depression. Moreover, several PET studies have revealed hypometabolism in the basal
ganglia of depressed patients (Buchsbaum et al., 1986; Baxter et al., 1989; Drevets and Raichle,
1992).

5.5 Monoamine Svstems

Considerable evidence has accumulated implicating serotonin, norepinephrine, and dopamine in
the pathogenesis of affective disorders (Maes and Meltzer, 1995; Schatzberg and Schildkraut, 1995;
Willner, 1995). This evidence comes from studies in postmortem brains, from cerebrospinal fluid
studies in living patients, and from clinical studies involving very effective antidepressant
medications highly specific for one or more of these monoamine neurotransmitter systems. The
importance of the monoamine systems is underscored by the fact that almost all available
antidepressant treatments (including electroshock treatment) alter the function of these systems.

A neuroanatomic

185

model for depression

5.6 Hemispheric Different&M

There is evidence for a right/left hemispheric differentiation in the regulation of affect (Tucker et
al., 1981; Davidson et al., 1992). Starkstein and his group have shown that strokes involving the
left frontal and left basal ganglia regions are more related to the occurrence of depression than
corresponding lesions in the right hemisphere (Starkstein and Robinson, 1987; Starkstein et al.,
1996). Robinson and Szetela (1981) showed that left sided cerebral lesions resulting from ligation
of the middle cerebral artery produce apathy. Most functional imaging studies have also reported
hemispheric differentiation.

PET studies that have examined behavioral parameters have shown

distinct regional patterns with certain aspects of depression and are clearly worth extending (Bench
et al., 1993; Dolan et al., 1994).

6. A Neuroanatomic Model Of Deoression

The model formulated by Krishnan (1992) provides a framework with which to interpret clinical
depression. Emotion can be divided into three components: emotional expression, behavioral and
emotional experience, and emotional evaluation (Ledoux, 1984, 1986). These components of
emotion allow for a phenomenologic understanding of the clinical components of depression and
provide clues as to the neuroanatomic substrate of this illness.
The components of emotional expression can be divided into autonomic and vegetative, humoral,
and skeletomotor. Autonomic expression consists of sympathetic and parasympathetic components
which are mediated by projections originating in the hypothalamus (Loewy et al., 1979). The
amygdala and the medial orbital frontal cortex are also involved in the regulation of autonomic
changes (Kaada, 1960; Hilton, 1979; Barone et al., 1981). The descending projections from the
amygdala to the brainstem likely modulate monoamine systems, which in turn have effects on other
areas of the brain involved in emotional expression, evaluation, and experience.
Autonomic activation leads to release of a number of hormones. Sympathetic activation leads to
the release of epinephrine from the adrenal medulla. Other hormones are released through the
pituitary gland. Cortisol is elevated in depressed patients (Carroll et al., 1976). The secretion of
cortisol probably arises initially from the amygdala through its connection to the hypothalamic nuclei
via the stria terminalis. This pathway stimulates the release of corticotropin releasing factor (CRF),
which in turn stimulates the release of adrenocorticotropin from the anterior pituitary and leads to
excessive cortisol production.

both norepinephrine

In addition, hypothalamic

and serotonin (Parent, 1996).

sources of CRF are densely innervated by

Antidepressant

medications affect the

hypothalamus-pituitary-adrenal axis at several levels and alter circulating cortisol (Holsboer, 1995).

C.E. Byrum et al.

186

The skeletomotor component of emotional expression is modulated by connections between the

amygdala and the basal ganglia. The amygdala has direct projections to both the basal ganglia and
the cortical motor areas and also provides an indirect pathway to the dopamine neurons of the
brainstem (Graybiel, 1990; Bjorklund and Lindvall, 1984; Krettek and Price, 1978). This latter
pathway appears to be involved in motivation (Everitt and Robbins, 1992). This could involve the
cingulate-basal ganglia circuit.
The second main component of emotion is described as behavioral and emotional experience and
consists of subjective awareness of feelings (Ledoux, 1984, 1986). The brain structures that allow
such awareness are obscure.

However, stimulation of the amygdala can lead to emotional

experience (Gloor et al., 1982). The highly interconnected system that comprises frontal and
cingulate cortex, basal ganglia, amygdala, and hippocampus may prove to be of fundamental
importance.
Emotional evaluation is the third component of emotion and is the process by which the brain
compares sensory input with knowledge and processes the emotional meaning of these stimuli.
The reciprocal connections between the amygdala and cortex are thought to be involved in cognitive
modulation of affective substrates for emotional experience. As reviewed above, the amygdala
receives sensory information that has been extensively processed. The amygdala is thus dealing
with information in an abstract form, such that emotional significance can be assigned to meaningful
concepts.

Studies have demonstrated that the medial orbital surface of the frontal cortex is

important for the processing and storage of emotionally laden information (Nauta, 1971). The
cingulate gyrus is also critically involved in this circuit. The amygdala also receives input from the
hippocampus and from other cortical regions including other prefrontal areas. These areas probably
provide the knowledge basis (memories) for the evaluation of information.
The amygdala therefore serves a central function in the three components of emotion: emotional
expression, behavioral and emotional experience, and emotional evaluation.

The model originally

articulated by Krishnan (1992) suggests that these different pathways are in a state of dynamic flux.
Pathways subserving emotional experience influence the evaluation of sensory stimuli by the
amygdala and similarly, the changes in the autonomic, humoral, and brainstem monoamine systems
lead to modulation of these systems by the cortex, basal ganglia, and amygdala. These pathways
then mediate emotional experience, emotional evaluation, and the expression of emotion.
Depression can be understood in the context of this neuroanatomic model. Negative appraisal can
be attributed to changes in the emotional processing of sensory information by the amygdala, and
depressed mood is likely to be mediated by the pathways reflecting emotional experience. Common

A neuroanatomic

187

model for depression

symptoms of depression such as decreased sexual drive and altered appetite can be mediated by
pathways of emotional expression through the hypothalamic center. Other clinical symptoms which
may arise through the mechanisms of emotional expression include altered sleep (mediated through
the thalamus and the brain stem), fatigue (mediated through the basal ganglia circuits), and apathy
(modulated by both the amygdala and basal ganglia circuits).

Co clusious
Our understanding of the neuroanatomic pathnwaysinvolved in mood regulation is very limited and
thus the model we have described is speculative.
address the etiology of depression.

It should be noted that this model does not

Rather, our attempt is to describe the neuroanatomical

substrates that mediate the various components or symptoms of depression.

What is clear,

however, is that a distributed system mediates emotion and affect. The areas of brain shown to be
involved in components of emotion and depression are so extensively interconnected that a single
component cannot be assigned any exclusive role. Moreover, a single dysfunctional component
of the distributed system, e.g. the monoamine systems, may shift the functioning of the system to
a depressed state, with the other, intact components of the system expressing the various
components of depression.

Thus the amygdala, which clearly plays a central role in emotional

experience, evaluation, and expression, may or may not play an etiologic role in depression.
It is conceivable that damage to any of the components of the distributed system could produce
a depressive syndrome that is more or less constant regardless of the area of the lesion. Clinical
data suggests, however, that although depressive syndromes can have multiple etiologies (e.g.
frontal lobe lesions or basal ganglia lesions or primary monoamine system dysfunction), different
lesion locations do not produce depression with equal frequency.
The development and refinement of functional imaging techniques, in particular high resolution
fMRI studies, promise to provide the clues to the regulation of emotion and the pathophysiology of
depression that currently remain obscure.

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