Byrum CE Et Al_1999_A Neuroanatomic Model for Depression

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

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

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

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


(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


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,


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


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


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

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.

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).


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


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.

References

ADOLPHS, R., TRANEL, D., DAMASIO, H., and DAMASIO, A. R. (1995) Fear and the human amygdala. J. Neurosci. ti: 5879-91.

AGGLETON, J.P. (1992) The functional effects of amygdala lesions in humans: A comparison with findings from monkeys. In: Aggleton, J.P. (Ed.), The Amygdala, 483-503, Wiley-Liss, New York.

ALEXANDER, G. E. and CRUTCHER, M. D. (1990) Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends Neurosci. 13: 266-271.


ALEXANDER, G. E., DELONG, M. R., and STRICK, P. L. (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann. Review Neurosci. 9: 357-381.

ARMONY, J. L., SERVAN-SCHREIBER, D., COHEN, J. D., and LEDOUX, J. E. (1995) An anatomically constrained neural network model of fear conditioning. Behav. Neurosci. 1(29: 246- 57.

AUSTIN, M. P., DOUGALL, N., ROSS, M., MURRAY, C., OCARROLL, R. E., MOFFOOT, A., EBMEIER, K. P., and GOODWIN, G. M. (1992) Single photon emission tomography with QQmTc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum. J. Affect. Disord. 2: 31-43.

BAGSDALE, C. W. and GRAYBIEL, A. M. (1990) A simple ordering of neocortical areas established by the compartmental organization of their striatal projections. Proc. Natl. Acad. Sci. a: 6196- 6199.

BARONE, R. C., WAYNER, M. J., SCHAROUN, S. L., GUEVARA-AGUILAR, R., and AGUILAR- BATURONI, H. U. (1981) Afferent connections to the lateral hypothalamus: A horseradish peroxidase study in the rat. Brain Res. Bull. Zr 75-88.

BAXTER, L. R., PHELPS, M. E., MAZZIOT-TA, J. C., SCHWARTZ, J. M., GERNER, R. H., SELIN, C. E., and SUMIDA, R. M. (1985) Cerebral metabolic rates for glucose in mood disorders studied with positron emission tomography with fluorodeoxyglucose lBF. Arch. Gen. Psychiatry. 42: 441-447.

BENCH, C. J., FRISTON, K. J., BROWN, R. G., SCOTT, L. C.; FRACKOWIAK, R. S., and DOlAN, R. J. (1992) The anatomy of melancholia--focal abnormalities of cerebral blood flow in major depression. Psychol. Med. 22: 607-15.

BENCH, C. J., FRISTON, K. J., BROWN, R. G., FRACKOWIAK, R. S., and DOLAN, R. J. (1993) Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol. Med. 23: 579-90.

BENCH C. J., FRACKOWIAK, R. S., and DOlAN, R. J. (1995) Changes in regional cerebral blood flow on recovery from depression. Psychol. Med. 25: 247-61.

BJORKLUND, A. and LINDVALL, 0. (1984) Dopamine-containing systems in the CNS. In: Handbook of Chemical Neuroanatomy: Classical Transmitters in the CNS (Vol. 2). A. Bjorklund, T. Hofkelt, and M. Kuhar (Eds.), pp 55-122, Elsevier, Amsterdam.

BOWEN, D. M., NAJLERAHIM, A., PROCTER, A. W., FRANCIS, P. T., and MURPHY, E. (1989) Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life. Proc. Natl. Acad. Sci. 86: 9504-9508.

BREITER, H. C., ETCOFF, N. L., WHALEN, P. J., KENNEDY, W. A., RAUCH, S. L., BUCKNER, R. L., STRAUSS, M. M., HYMAN, S. E., and ROSEN, B. R. (1996) Response and habituation of the human amygdala during visual processing of facial expression. Neuron. II: 875-87.

BUCHSBAUM, M. S., WU, J., DELISI, L. E., HOLCOMB, H., KESSLER, R., JOHNSON, J., KING, A. C., HAZLETT, E., IANGSTON, K., and POST, R. M. (1986) Frontal cortex and basal ganglia metabolic rates assessed by PET with [*F]2-deoxyglucose in affective illness. J. Affect. Disorders. 1Q: 137-l 52.


CAHILL, L., HAIER, R. J., FALLON, J., ALKIRE, M. T., TANG, C., KEATOR, D., WU, J., and MCGAUGH, J. L. (1996) Amygdala activity at encoding correlated with long-term, free recall of emotional information. Proc. Natl. Acad. Sci. g3: 8016-21.

CALNE, E. D. and SHOULSON, I. (1983) Psychiatric syndrome in Huntingtons disease. Am. J. Psychiatry. 140: 728-733.

CARMICHAEL, S T. and PRICE, J. L. (1995) Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys. J. Comp. Neurol. X@ 615641.

CARMICHAEL, S. T. and PRICE, J. L. (1996) Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys. J. Comp. Neurol. 371: 179-207.

CARROLL, B. J., CURTIS, G. C., and MENDELS, J. (1976) Neuroendocrine regulation in depression: II. Discrimination of depressed from nondepressed patients. Arch. Gen. Psychiatry. 3: 1051-1058.

COFFEY, C. E., FIGIEL, G. S., DJANG, W. T., CRESS, M., SAUNDERS, W. B., and WEINER, R. D. (1988) Leukoencephalopathy in elderly depressed patients referred for ECT. Biol. Psychiatry. 24: 143-161.

COFFEY, C.E., WILKINSON, W.E., WEINER, R.D., PARASHOS, I. A., DJANG, W. T., WEBB, M. C., FIGIEL, G. S., and SPRITZER, C. E. (1993) Quantitative cerebral anatomy in depression. Arch. Gen. Psychiatry. 5Q: 7-16.

CUMMINGS, J.L. (1985) Clinical Neuropsychiatry, Grune and Stratton, Orlando, pp 185190.

DAVIDSON, R. J. (1992) Anterior cerebral asymmetry and the nature of emotion. Brain Cogn. 2Q: 125-151.

DE OLMOS, J. S. (1990) The Amygdala. In: The Human Nervous System, G. Paxinos (Ed.), pp 583-710, Academic Press, San Diego.

DOlAN, R. J., BENCH, C. J., LIDDLE, P. F., FRISTON, K. J., FRITH, C. D., GRASBY, P. M., and FRACKOWIAK, R. S. (1993) Dorsolateral prefrontal cortex dysfunction in the major psychoses; symptom or disease specificity? J. Neurol. Neurosurg. Psychiatry. 56: 12904.

DOLAN, R. J., BENCH, C. J., BROWN, R. G., SCOTT, L. C. and FRACKOWIAK, R. S. (1994) Neuropsychological dysfunction in depression: the relationship to regional cerebral blood flow. Psychol. Med. a: 849-57.

DREVETS, W. C. and RAICHLE, M. E. (1992) Neuroanatomical circuits in depression: implications for treatment mechanisms. Psychopharmacol. Bull. 28: 261-74.

DREVETS, W. C., VIDEEN, T. O., PRICE, J. L., PRESKORN, S. H., CARMICHAEL, S. T., and RAICHLE, M. E (1992) A functional anatomical study of unipolar depression. J. Neurosci. 12: 3628-41.

DREVETS, W. C., PRICE, J. L., SIMPSON, J. R., TODD, R. D., REICH, T., VANNIER, M., and RAICHLE, M. E. (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 3&$: 824-7.

190 C.E. Bymm et al.

EBERT, D. and EBMEIER, K. P. (1996) The role of the cingulate gyrus in depression: from functional anatomy to neurochemistry. Biol. Psychiatry. 39: 104450.

EBERT, D., FEISTEL, H., and BAROCKA, A. (1991) Effects of sleep deprivation on the limbic system and the frontal lobes in affective disorders: a study with Tc-99m-HMPAO SPECT. Psychiatry Res. 4Q: 247-51.

EBERT, D., FEISTEL, H., BAROCKA, A., KASCHKA, W., and MOKRUSCH, T. (1993) Atest-retest study of cerebral blood flow during somatosensory stimulation in depressed patients with schizophrenia and major depression. Eur. Arch. Psychiatry Clin. Neurosci. 242: 250-4.

EVERITT, B. J. and ROBBINS, T. W. (1992) Amygdala-ventral striatal interactions and reward- related processes. In: The Amygdala, J. P. Aggleton, (Ed.), pp 401-429, Wiley-Liss, New York.

FERRY, B., SANDNER, G., and DI SCALA, G. (1995) Neuroanatomical and functional specificity of the basolateral amygdaloid nucleus in taste-potentiated odor aversion. Neurobiol. Learn. Mem. 64: 169-80.

FOLSTEIN, S., FOLSTEIN, M. F., and MCHUGH, P. R. (1979) Psychiatric syndromes in Huntingtons disease. Adv. Neurol. 2: 281-289.

GEORGE, M. S., KElTER, T. A., and POST, R. M. (1994) Prefrontal cortex dysfunction in clinical depression. Depression. 2: 59-72.

GLOOR, P., OLIVER, A., QUESNEY, L. F., ANDERMANN, F., and HOROWITZ, S. (1982) The role of the limbic system in experimental phenomena of temporal lobes epilepsy. Ann. Neural. l2: 129-144.

GOLDSTEIN, L. E., RASMUSSON, A. M., BUNNEY, B. S., and ROTH, R. H. (1996) Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat. J. Neurosci. Is: 4787-98.

GOODWIN, G. M., AUSTIN, M. P., DOUGALL, N., ROSS, M., MURRAY, C., OCARROLL, R. E., MOFFOOT, A., PRENTICE, N., and EBMEIER, K. P. (1993) State changes in brain activity shown by the uptake of 99mToexametazime with single photon emission tomography in major depression before and after treatment. J. Affect. Disord. 29: 243-53.

GRAYBIEL, A. M. (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci. I.$ 244-253.

HALGREN, E. (1992) Emotional neurophysiology of the amygdala within the context of human cognition. In: The Amygdala, J. P. Aggleton, (Ed.), pp 191-228, Wiley-Liss, New York.

HILTON, S. M., (1979) The defense reaction as a paradigm for cardiovascular control. In: Integrative Functions of the Autonomic Nervous System, C. M. Brooks, K. Koizumi, and A. Sato, (Eds.), pp 443449, Elsevier, Amsterdam.

HOLSBOER, F. (1995) Neuroendocrinology of mood disorders. In: Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer (Eds.), pp 957-969, Raven Press, New York.


ITO, H., KAWASHIMA, R., AWATA, S., ONO, S., SATO, K., GOTO, R., KOYAMA, M., SATO, M., and FUKUDA, H. (1996) Hypoperfusion in the limbic system and prefrontal cortex in depression: SPECT with anatomic standardization technique. J. Nucl. Med. x: 410-4.

KAADA, B.R., (1960) Cingulate, posterior, orbital anterior, insular and temporal pole cortex. In: Handbook of Physiology: Sec. 1. Neurophysiology, J. Field and H. W. Magoun (Eds.), pp 1345 1372, American Physiology Society, Washington DC.

KANAYA, T. and YONEKAWA, M. (1990) Regional cerebral blood flow in depression. Jpn. J. Psychiatry Neurol. 44: 571-6.

KELIAND, M. D., FREEMAN, A. S., and CHIODO, L. A. (1990) Serotonergic afferent regulation of the basic physiology and pharmacological responsiveness of nigrostriatal dopamine neurons. J. Pharmacol. Exp. Ther. 251: 803-809.

KLUVER, H. and BUCY, P. C. (1937) Psychic blindness and other symptoms following bilateral temporal lobectomy in rhesus monkeys. Am. J. Physiol. 119: 352-353.

KRETTEK, J. E. and PRICE, J. L. (1978) Amygdaloid projections to subcortical structures within the basal forebrain and brainstem in the rat and cat. J. Comp. Neurol. 178: 225-253.

KRISHNAN, K. R. R. (1992) Depression-neuroanatomical substrates. Behav. Ther. 23: 571-583.

KRISHNAN, K. R. R. (1993) Neuroanatomical substrates of depression in the elderly. J. Geriatric Psych. Neurol. 6: 39-58.

KRISHNAN, K. R., MCDONALD, W. M., ESCALONA, P. R., DORAISWAMY, P. M., NA, C., HUSAIN, M. M., FIGIEL, G. S., BOYKO, 0. B., ELLINWOOD, E. H., and NEMEROFF, C. B. (1992) Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Arch. Gen. Psychiatry. 49: 553-7.

LEDOUX, J. E. (1984) Cognition and emotion: Processing functions and neural systems. In: Handbook of Cognitive Neuroscience, K. R. Scherer and P. Ekman (Eds.), pp 247-258, Erlbaum, Hillsdale, NJ.

LEDOUX, J.E. (1986) Neurobiology of emotion. In: Mind and Brain, J. E. LeDoux and W. Hirst (Eds.), pp 301-354, University Press, New York.

LEDOUX, J.E. (1992) Emotion and the Amygdala. In: The Amygdala, J. P. Aggleton, (Ed.), pp 339- 352, Wiley-Liss, New York.

LESSER, I. M., MENA, I., BOONE, K. B., MILLER, B. L., MEHRINGER, C. M., and WOHL, M. (1994) Reduction of cerebral blood flow in older depressed patients. Arch. Gen. Psychiatry. ail: 677-86.

LOWEY, A. D., MCKELLAR, S., and SAPER, C. 8. (1979) Direct projections from the A5 catecholamine cell group to the intermediolateral cell column. Brain Research, 124: 309-314.

MAES, M., DIERCKX, R., MELTZER, H. Y., INGELS, M., SCHOl-TE, C., VANDEWOUDE, M., CAlABRESE, J., and COSYNS, P. (1993) Regional cerebral blood flow in unipolar depression measured with To99m-HMPAO single photon emission computed tomography: negative findings. Psychiatry Res. a: 77-88.

192 C.E. Byrum et al

MAES, M. and MELTZER, H. Y. (1995) The serotonin hypothesis of major depression. In: Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer (Eds.), pp 933-944, Raven Press, New York.

MAYBERG, H. S., LEWIS, P. J., REGENOLD, W., and WAGNER, H. N. (1994) Paralimbic hypoperfusion in unipolar depression. J. Nucl. Med. 35: 929-34.

NAUTA, W. J. H. (1971) The problem of the frontal lobe: A reinterpretation. J. Psychiatry Res. 8: 167-187.

PARENT, A. (1996) Carpenters Human Neuroanatomy, Williams & Williams, Baltimore.

POTTER, W., SCHEININ, M., GOLDEN, R. N., RUDORFER, M. V., COWDRY, R. W., CALIL, H. M., ROSS, R. J., and LINNOILA, M. (1985) Selective antidepressants and cerebrospinal fluid. Lack of specificity on norepinephrine and serotonin metabolites. Arch. Gen. Psych. 42: 1171- 1177.

ROBINSON, R. G. and TRAVEL& J. I. (1996) Neuropsychiatry of mood disorders. In: Neuropsychiatry, B. S. Fogel, R. B. Schiffer, and S. M. Rao (Eds.), pp 287-305, Williams and Wrlkins, Baltimore.

ROBINSON, R. G. and SZETELA, B. (1981) Mood change following left hemisphere brain injury. Ann. Neurol. 9: 7453.

ROLLS, E. T. (1992) Neurophysiology and functions of the primate amygdala. In: The Amygdala, J. P. Aggleton, (Ed.), pp 143-165, Wiley-Liss, New York.

ROLLS, E. T. (1996) The orbitofrontal cortex. Philos. Trans. R. Sot. Lond. B. Biol. Sci. X& 1433- 43.

RUBIN, E., SACKEIM, H. A., PROHOVNIK, I., MOELLER, J. R., SCHNUR, D. B., and MUKHERJEE, S. (1995) Regional cerebral blood flow in mood disorders: IV. Comparison of mania and depression. Psychiatry Res. 61: I-IO.

SCHATZBERG, A. F. and SCHILDKRAUT, J. J. (1995) Recent studies on norepinephrine systems in mood disorders. In: Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer (Eds.), pp 91 I-920, Raven Press, New York.

SCHNEIDER, F., GUR, R. E., MOZLEY, L. H., SMITH, R. J., MOZLEY, P. D., CENSITS, D. M., AlAVI, A., and GUR, R. C. (1995) Mood effects on limbic blood flow correlate with emotional self-rating: a PET study with oxygen-15 labeled water. Psychiatry Res. 61: 265-83.

SETHY, H. and HARRIS, D. M. (1982) Role of beta adrenergic receptors in the mechanism of action of second generation antidepressants. Drug Dev. Res. 2: 403406.

STARKSTEIN, S. E. and ROBINSON, R. G. (1987) Affective disorders and cerebrovascular disease. Brit. J. Psychiatry. II.!%: 170-182.

STARKSTEIN, S. E., ROBINSON, R. G., and PRICE, T. R. (1987) Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain. IX!: 1045-59.


STARKSTEIN, S. E., SABE, L., VAZQUEZ, S., TESON, A., PETRACCA, G., CHEMERINSKI, E., DI LORENZO, G., and LEIGUARDA, R. (1996) Neuropsychological, psychiatric, and cerebral blood flow findings in vascular dementia and Alzheimers disease. Stroke. 21: 406-14.

STRAUSS, H. and KESCHNER, M. (1935) Mental symptoms in cases of tumour of the frontal lobe. Arch. Neurol. Psychiatry. 33: 986-l 105.

TUCKER, D. M., STENSLIE, C. E., ROTH, R. S., and SHEARER, S. L. (1981) Right frontal lobe activation and right hemisphere performance. Arch. Gen. Psychiatry. 38: 169-174.

TURNER, B. H., MISHKIN, M., and KNAPP, M. (1980) Organization of the amygdalopetal projections from modality-specific cortical association areas in the monkey. J. Comp. Neurol. m: 515-543.

VAN HOESEN, G. W., PANDYA, D. N., and BUTTERS, N. (1972) Cortical afferents to the entorhinal cortex of the rhesus money. Science. 175: 1471-1473.

VOGT, B.A., FINCH, D. M., and OLSON, C. R. (1992) Functional heterogeneity in cingulate cortex: The anterior executive and posterior evaluative regions. Cerebral Cortex. 2: 435441.

WHITLOCK, D. G. and NAUTA, W. J. H. (1956) Subcortical projections from the temporal neocortex in Macaca mulatta. J. Comp. Neurol. IQ& 183-212.

WILLNER, P. (1995) Dopaminergic mechanisms in depression and mania. In: Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer (Eds.), pp 921-931, Raven Press, New York.

ZILLES, K. (1990) Cortex. In: The Human Nervous System, G. Paxinos (Ed.), pp 583-710, Academic Press, San Diego.

Inquiries and reprint requests should be addressed to:

K. Ranga R. Krishnan, M.D. Box 3018 Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham, NC 27710

Documents

Byrum CE Et Al_1999_A Neuroanatomic Model for Depression