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ELSEVIER
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
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 front matter
PII 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
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
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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 177
I Neocortex: unimodal sensory and heteromodal association cortex
Allocortex, including hippocampus and other limbic structures I
Striatum .+- Amygdala - 0 J z
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
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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
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A neuroanatomic model for depression 179
(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). Damage to
orbitofrontal cortex can impair
identification of facial expressions. 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
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180 C.E. Byrum et al.
complex and intralaminar nuclei. 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,
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A neuroanatomic model for depression 181
GLU
I I + GLU
GABA 1 Nigra ] GABA
+ ,I- ,
GLU
I-
+ GLU l
+ Globus _ -----+ Pallidus
I- Internal GABA
GLU
i
1 +
- Thalamus
Indirect Pathway
I I
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
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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
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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.
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184
5.3 Frontal Lobes
C.E. Byrum et al.
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.
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A neuroanatomic model for depression
5.6 Hemispheric Different&M
185
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. In addition, hypothalamic sources
of CRF are densely innervated by
both norepinephrine and serotonin (Parent, 1996). Antidepressant
medications affect the
hypothalamus-pituitary-adrenal axis at several levels and alter
circulating cortisol (Holsboer, 1995).
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186 C.E. Byrum et al.
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
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A neuroanatomic model for depression 187
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 pathnways
involved in mood regulation is very limited and
thus the model we have described is speculative. It should be
noted that this model does not
address the etiology of depression. 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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