REVIEW ARTICLE The Anatomy of Mood Disorders Structural Neuroimaging Studies

Jair C. Soares and J. John Mann

Review of

The structural neuroimaging findings in mood disorders were reviewed, to evaluate evidence for a neuroanatomic model ofpathophysiology, involving the prefrontal cortex, the basal ganglia, the amygdala-hippocampus complex, thalamus, and connections among these structures. Global atrophy is not consistently found. The best replicated finding is an increased rate of white matter and periventricular hyperintensities. A smaller frontal lobe, cerebellum, caudate, and putamen appear present in unipolar depression. A larger third ventricle, and smaller cerebellum and perhaps temporal lobe appear present in bipolar disorder. These localized structural changes involve regions that may be critical in the pathogenesis of mood disorders. Generalized and localized anatomic alterations may be related to age or vascular disease. The clinical and biological correlates o f these changes need to be investigated to allow development of a more complete model ofpathophysiology o f mood disorders. 1997 J.C. Soares and J.J. Mann

Key Words: Mood disorders, neuroanatomy, structural, neuroimaging, pathophysiology, magnetic resonance imaging, computed tomography BIOL PSYCHIATRY1997;41:86--106

Introduction
Some difference I find amongst writers, about the principal part affected in th& disease, whether it be the brain, or heart, or some other member. Most are of opinion that it is the brain: for being a kind of dotage, as a similar part, be it by consent or essence, not in his ventricles, or any obstructions in them, for then it would be an apoplexy, or epilepsy, .... but in a cold, dry distemperature of it in his substance, which is corrupt and become too cold, or too dry, or else too hot, as in madmen and such as are inclined to it... (Sir Robert Burton, 1577-1640, in The Anatomy of Melancholy)
From the Laboratories of Neuropharmacology, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Address reprint requests to J. John Mann, MD, Department of Neuroscience, New York State Psychiatric Institute, 722 W. 168th Street, Box 28, New York, NY 10032. Received September 27, 1995; revised December 18, 1995.

The possibility that brain abnormalities responsible for depression may be detectable has stimulated structural brain imaging studies. Developments in structural neuroimaging by computed tomography (CT) and magnetic resonance imaging (MRI) in the past 15 years have facilitated the direct examination of specific brain structures, making possible the study of the relationship between anatomy and psychopathology. In 1980, Jacoby and Levi published the first CT study of mood disorder patients. The first MRI study of this disorder was published in 1983 (Rangel-Guerra et al 1983). The advent of MRI brought several advantages, allowing more accurate localization and high-resolution measurement of brain structures, not involving radiation, and providing unprecedented gray-white matter resolution (Steiner and Bydder 1984). Developments in MRI processing have improved quantitative volumetric analysis of
0006-3223/97/$17.00 PII S0006- 3223 (96)00006-6

1997 J.C. Soares and J.J. Mann

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I Prefrontal Cortex [

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Figure 1. Neuroanatomic model of mood regulation. regions of cortical and subcortical gray matter at higher levels of resolution (Krishnan et al 1993a). It is recognized that lesions in some specific neuroanatomic areas due to brain disease, e.g., stroke or brain tumor, may lead to development of secondary depression (Robinson et al 1984a; Starkstein and Robinson 1989; Cummings 1993). In primary (not due to known associated brain disease) mood disorders, emerging findings begin to challenge the previous notion of "functional" in opposition to "organic" disorders, with suggestions that anatomic brain changes can be identified. We and others propose that both primary and secondary mood disorders may involve abnormalities in specific brain frontosubcortical neuroanatomic circuits (Robinson et al 1984a; Buchsbaum 1986; Jeste et al 1988; Nasrallah et al 1989; Starkstein and Robinson 1989; Beats 1991; Drevets et al 1992; McDonald and Krishnan 1992; Cummings 1993; George et al 1993; Guze and Gitlin 1994; Mayberg 1994; Mega and Cummings 1994; Austin and Mitchell 1995). The prefrontal cortex has extensive connectivity to cortical and subcortical circuits that may underlie its importance in cognitive functions and modulation of limbic activity (Weinberger 1993). The main subcortical structures participating in these circuits are the basal ganglia, thalamus, hypothalamus, brain stem, and the white matter tracts that connect these structures among themselves and to the cerebral cortex (Salloway and Cummings 1994). A limbic-thalamic-cortical circuit consisting of the amygdala, the mediodorsal nucleus of the thalamus, and the medial and ventrolateral prefrontal cortex, and a limbic-striatalpallidal-thalamic circuit comprising the striatum, the ventral pallidum, and the components of the other circuit are the main neuroanatomic circuits that have been proposed to participate in the pathophysiology of mood disorders (see Figure 1). The basal ganglia connect with cortical and limbic regions through circuits that, despite functioning segregatedly, are organized in parallel (Alexander et al 1986, 1990), in such a way that lesions in different parts of these circuits could result in malfunction. Additionally, the cerebellum, through connections with brain stem and

limbic structures, may also be involved in mood regulation (Berton and Torello 1982). Abnormalities in these brain regions, or in contiguous areas that can affect the connections between these regions, could reflect malfunction of these circuits, associated with development of mood disorders. Alternatively, abnormalities in these circuits could confer vulnerability to mood disorders, and its onset could be determined by interactions with environmental and genetic factors. Deficits during brain development due to these factors could result in hypodevelopment of particular brain areas, which could be related subsequently with mood disorders. The aging process or pathology such as vascular brain disease could result in atrophy of some of these regions. Thus, the influence of genetic, environmental, developmental, and degenerative factors during the development of these brain structures, in ways still not understood, may determine the onset of mood disorders. There is a developing confluence with evidence from functional neuroimaging studies suggesting abnormalities in some of the same key brain regions participating in these neuroanatomic circuits (Buschbaum 1986; Baxter 1991; Cummings 1993; George 1994; George et al 1993, 1994; Ketter et al 1994; Mayberg 1994; Mayberg et al 1994); however, there is a need for systematic study of these regions by both structural and functional neuroimaging. This study reviews the structural CT and MRI findings in mood disorder patients to examine the above proposed neuroanatomic model. We hypothesized that mood disorders are characterized by localized rather than generalized structural alterations in the brain, involving regions in these neuroanatomic circuits. Additionally, the clinical and biological correlates of these brain abnormalities are reviewed.

Generalized

Brain Abnormalities

Diffuse brain abnormalities may damage among other regions the specific structures participating in mood regulation, and thus be related to development of depression. We will start by reviewing the evidence for generalized brain abnormalities, and then consider studies of specific brain regions. Generalized disease includes global cerebral atrophy, and white matter or periventricular hyperintensities.

Cerebral Atrophy
Several indices of generalized cerebral atrophy were used in different studies, including ventricular size or volume, sulcal width, cerebral volume, and most recently gray and white matter volume. The initial studies used gross measures of global atrophy, with examiner's ratings of sulcal

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atrophy or ventricular dilatation. Some of the studies used manual tracing to measure ventricular-brain ratio (VBR), having the limitations of less accuracy implicit in this method. Subsequently, semiautomated approaches to the calculation of the VBR in MRI studies were developed, bringing more precision. Most recent studies used semiautomated or automated measures of gray and white matter volume, as a more refined way of studying the volume of different brain regions (Cohen et al 1992; Krishnan et al 1993a). VENTRICLESMEASURES. Twelve controlled CT studies (Pearlson and Veroff 1981; Nasrallah et al 1982a; Tanaka et al 1982; Scott et al 1983; Pearlson et al 1984a; Shima et al 1984; Dolan et al 1985; Lippman et al 1985; Kolbeinsson et al 1986; Schlegel and Kretzschmar 1987; Ames et al 1990; Wurthmann et al 1995) of 22 (Jacoby and Levi 1980; Weinberger et al 1982; Rossi et al 1987, 1989; Dewan et al 1988a; Iacono et al 1988; Abas et al 1990; Beats et al 1991; van den Bossche et al 1991; Shiralshi et al 1992) found significantly increased lateral ventricle size in mood disorder patients. Two studies used categorical ratings done by clinician (Jacoby and Levi 1980; Lippman et al 1985), two used linear measures (Tanaka et al 1982; van den Bossche et al 1991), three used VBR and linear measures (Schlegel and Kretzschmar 1987; Dewan et al 1988a; Wurthmann et al 1995), and the other studies used VBR measures. Eight of the 17 VBR studies did not find significant differences compared to controls. Four of these studies were done in elderly patients (Jacoby and Levi 1980; Ames et al 1990; Abas et al 1990; Wurthmann et al 1995), and only two had positive findings (Ames et al 1990; Wurthmann et al 1995). These studies involved samples of unipolar (UP) and bipolar (BP) patients, and results seem independent of diagnostic subtype. Uncontrolled MR/studies in elderly depressed patients referred for electroconvulsive therapy (ECT) found rates of lateral ventricle enlargement of 67-69% (Coffey et al 1988, 1989; Figiel et al 1989a). In contrast, only three (Andreasen et al 1990; Figiel et al 1991b; Rabins et al 1991) of 12 controlled MR/studies found enlarged lateral ventricles in UP or BP patients compared to controls (Dupont et al 1987; Johnstone et al 1989; Swayze et al 1990; Lesser et al 1991; McDonald et al 1991; Risch et al 1992; Shah et al 1992; Coffey et al 1993a; Harvey et al 1994). These studies had varied methodology, with five studies using examiner's ratings (Dupont et al 1987; Johnstone et al 1989; McDonald et al 1991; Figiel et al 1991b; Rabins et al 1991), three VBR measures (Lesser et al 1991; Andreasen et al 1990; Risch et al 1992), and four automated area and volume measures (Swayze et al 1990; Shah et al 1992; Coffey et al 1993a; Harvey et al 1994). Three (Rabins et al 1991; McDonald et al 1991; Lesser et

al 1991) of the 10 studies were done in elderly samples; only one found enlarged ventricles (Rabins et al 1991). Six (Dupont et al 1987; Johnstone et al 1989; Swayze et al 1990; McDonald et al 1991; Risch et al 1992; Harvey et al 1994) of nine (Andreasen et al 1990; Figiel et al 1991b; Strakowski et al 1993a) studies in BPs were negative; one of them found increased VBR measures only in male BPs (Andreasen et al 1990). In UPs, three studies (Lesser et al 1991; Risch et al 1992; Shah et al 1992) of four (Rabins et al 1991) had negative results. Two (Schlegel and Kretzschmar 1987; Beats et al 1991) of four (Tanaka et al 1982; Iacono et al 1988) controlled CT studies found increased measures of third ventricles in mood disorder patients. These studies used linear measures of third ventricle, and involved mixed samples of UPs and BPs. One study (Dewan et al 1988a) found third ventricle width significantly increased in BPs, but when measures of 3VBR (area of third ventricle/brain area) were considered, no statistically significant differences were found. Another study (Strakowski et al 1993a) using MRI volumetric measures found increased third ventricle in first episode manics. In UPs, one MRI study with examiner's ratings found increased third ventricle measures (Rabins et al 1991), but this was not confirmed in a CT study with area measures (Wurthmann et al 1995) or a MRI volumetric study (Coffey et al 1993a). There is suggestion that ventricular enlargement may be related to depression in patients with ischemic lesions, based in one controlled CT study in a small sample (n = 13) of poststroke major depression patients (Starkstein et al 1988). In this study, significantly larger lateral and third VBRs were found in depressed compared to nondepressed patients, suggesting that subcortical atrophy preceding the stroke may produce a vulnerability for depression. One retrospective CT study (Woods et al 1990) investigated VBR measures in a sample of BPs over periods of 1-4.5 years, and no evidence of progression in ventricular size was found in the BP group. Thus, most studies reported negative results, and any disagreement was not explicable on the basis of age or subtype of mood disorder. Suggestions of enlargement of the third ventricle in BPs need to be replicated in controlled volumetric studies. The possibility of preexisting subcortical atrophy in poststroke depression needs to be proven. SULCAL MEASURES. Sulcal measures were not significantly different from controls in CT studies of elderly and nonelderly depressed LIPs or BPs (Jacoby and Levi 1980; Nasrallah et al 1982b; Lippman et al 1985; Iacono et al 1988; Ames et al 1990), but not in all studies (Dolan et al 1986; Kolbeinsson et al 1986; Wurthmann et al 1995). Three uncontrolled MRI studies with elderly depressed

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patients reported considerable rates (91-96%) of sulcal atrophy (Coffey et al 1988, 1989; Figiel et al 1989a), but only one (Rabins et al 1991) of four (Zubenko et al 1990; Lammers et al 1991; Coffey et al 1993a) controlled MRI studies found significantly increased sulcal atrophy in UP patients. These studies used examiner's qualitative ratings of sulcal atrophy. Two controlled MRI studies did not find evidence of abnormalities in cortical volume of BPs (Harvey et al 1994) or elderly UPs (Krishnan et al 1993b). Compared to the CT scans, the MRI with its better image quality allows more accurate determination of sulcal enlargement. Thus, there is no consistent evidence for sulcal enlargement in mood disorders. CEREBRALVOLUME, Seven controlled MRI studies did not find significant differences in measures of cerebral volume between depressed UPs or BPs and controls (Husain et al 1991a; Krishnan et al 1992; Axelson et al 1993; Coffey et al 1993a; Aylward et al 1994; Harvey et al 1994; Dupont et al 1995); However, one study (Strakowski et al 1993a) found decreased total white matter volume, and a relative increase in gray matter in firstepisode manic patients. Dupont et al (1995) did not find significant differences in cortical gray matter volume comparing UPs, BPs, and normal controls. Overall, all but one study did not find evidence of abnormalities in cerebral volume in UPs or BPs. Studies differentiating gray and white matter volume are required to determine whether total gray matter volume is abnormal in mood disorders.

White Matter Lesions

CT densities of right and left anterior white matter were found to be significantly increased in BPs in a controlled study (Dewan et al 1988a). A few uncontrolled MRI studies found increased rates of subcortical white matter hyperintensities in ECT-referred depressed patients (Coffey et al 1987, 1989; Figiel et al 1989a). Six (Coffey et al 1990; Zubenko et al 1990; Lesser et al 1991; Rabins et al 1991; Howard et al 1993; Krishnan et al 1993b) of seven (Guze and Szuba 1992) controlled studies in elderly major depression patients (mostly UPs) showed significantly increased rates of subcortical white matter or periventricular hyperintensities in patients, but in nonelderly patients, only one (Coffey et al 1993a) of two studies (Guze and Szuba 1992) found an increase. Furthermore, the sample in the Coffey et al (1993a) study, with a mean age of 62.4 ___ 16.4 years, included many older subjects. One MRI study found increased rates only for severe white matter hyperintensities in UPs compared to controls (Brown et al 1992). Another MRI study found significantly increased rates of white matter hyperintensities in

elderly compared to nonelderly UPs (Guze and Szuba 1992). One anecdotal report accounted for increased subcortical white matter hyperintensities in a young adolescent in the first manic episode (Botteron et al 1992). Four (Dupont et al 1987, 1990; Swayze et al 1990; Figiel et al 1991b) of six (Brown et al 1992; SWakowski et al 1993b) controlled MRI studies found increased rates of subcortical white matter or periventricular hyperintensities in BPs. One study with elderly BPs found significant differences only for large white matter lesions (McDonald et al 1991), and another only in older patients (Aylward et al 1994). One recent study did not fmd significant differences in the rates of deep white matter hyperintensities, but did find significantly increased periventricular hyperintensities in BP type I compared to BP type II patients or controls (Altshuler et al 1995). Dupont et al (1995) used quantitative MRI techniques to study white matter abnormalities, and found increased volume of abnormal white matter in BPs compared to age-matched controls, but not in UPs. There is also evidence from one case report of increase in size and number of white matter hyperintensities temporally correlated with development of depression in a previously healthy patient (Lesser et al 1993). Prospective studies should further investigate these findings under controlled conditions. Thus, there is strong evidence that increased rates of subcortical white matter and periventricular hyperintensities are present in BPs and elderly UPs. For nonelderly UPs the evidence is still equivocal. These white matter lesions may interrupt fibers in the proposed neuroanatomic model of mood regulation, resulting in disconnection among those regions, which may result in depression. The etiology of these white matter hyperintensities is not established, but a vascular cause has been proposed (Awad et al 1986a; Coffey et al 1989; Lesser et al 1991; Schmidt et al 1991). It is possible that they are associated with depression due to cerebrovascular disease, which is more common in the elderly, and differs from causes in younger patients.

Regional Brain Abnormalities

Cortical Regions
FRONTAL LOBE. These studies are summarized in Table 1. Increased T1 values were found in the frontal white matter of depressed UPs, but not in BPs (Dolan et al 1990). These findings were not confirmed for elderly UPs (Krishnan et al 1991a). Increased T1 values may reflect increased free water in the brain white matter (Conlon and Trimble, 1987). It is not clear what specific neuropathology correlates with these T1 changes, but they may be indicative of prefrontal location of relevant brain abnormality.

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Table 1. Frontal Lobe Findings in Mood Disorders

Author Dolan et al (1990) Coffman et al (1990) Krishnan et al (1991a) Krishnan et al (1992) Coffey et al (1993a) Schlaepfer et al (1994) 24 13 30 52 20 29 50 50 48 76 27 60 Sample RDC MDD normal controls BP DSM-III-R normal controls MDD DSM-III-R normal controls MD DSM-III normal controls MD DSM-III normal controls BPs DSM-III-R normal controls Age 42.0 46.0 33.0 28.8 69 71.5 48.3 49.3 62.4 61.6 34.9 31.6 _+ 10 -+ 7.0 _+ 6.2 _+ 7.2 _+ 12.3 - 5.0 + 17 _+ 18 + 16.4 -+ 15.9 _+ 8.6 _+ 8.0 Subtype 10 UP 14 BP Psychotic UPs UPs 44 UPs, 4 BPs, ECT referred BPs Methods MRI 0.08T MRI 1.5T MRI 1.5T MRI 1.5T MRI 1.5T MRI 1.5T Results Significantly higher T1 values in frontal WM of LIPs but not BPs Trend to smaller mean frontal area in patients T1 relaxation times not significantly different Frontal brain width significantly smaller in patients Mean total frontal volume significantly smaller in patients No significant difference in gray matter volume of dorsolateral PFC

UP, unipolars;BP, bipolar; MD, major depression;MDD, majordepressivedisorder; WM, white matter; PFC, prefrontalcortex; MRI, magneticresonanceimaging; RDC, research diagnostic criteria.

In UPs, Krishnan et al (1992) found a smaller frontal brain width. Coffey et al (1993a) found a 7% smaller total frontal volume in severely depressed ECT-referred LIPs and BPs. In BPs, Coffman et al (1990) found a trend for smaller frontal areas in patients; Schlaepfer et al (1994) did not find significant differences in gray matter volume of dorsolateral prefrontal cortex compared to controls. These studies mostly measured a crudely defined frontal lobe, only one study analyzing more defined regions of the prefrontal cortex (Schlaepfer et al 1994). In conclusion, there is some evidence of structural abnormalities in the frontal lobe of UPs, but not in BPs. There is a need for well-designed studies of prefrontal cortical gray matter volume, with better localization of medial, dorsolateral, and ventrolateral prefrontal cortex, to investigate more precisely the involvement of these subregions of the frontal lobe in mood disorders. The prefrontal cortex appears to be a key region in the neuroanatomic model of mood regulation, being probably an important anatomic area implicated in LIP depression. TEMPORALLOBE. Anecdotal evidence suggests a relationship between temporal lobe abnormalities and development of mania, particularly for fight temporal lesions (Johnson and Campbell 1990; Starkstein et al 1990). MRI studies report that T1 relaxation times (Dolan et al 1990; Krishnan et al 1991a) and temporal lobe volume (Coffey et al 1993a) in UPs are normal. One CT study found increased density of the right temporal lobe of BPs (Dewan et al 1988a). One (Hauser et al 1989a) of two (Johnstone et al 1989) MRI studies reported smaller temporal lobe areas in patients. One (Altshuler et al 1991) of three (Swayze et al 1992; Harvey et al 1994) MRI studies found smaller temporal lobe volumes in patients. Paradoxically, one of these studies (Harvey et al 1994) found increased left temporal volumes in BPs compared to controls, resulting from increased gray matter. Cortical

gray matter volume of superior temporal gyrus was not significantly different from controls (Schlaepfer et al 1994). These studies are summarized in Table 2. Regarding temporal lobe asymmetries in BP patients, four studies (Altshuler et al 1991; Rossi et al 1991; Swayze et al 1992; Harvey et al 1994) found significantly smaller left than right temporal lobe volumes in patients and controls, but Johnstone et al (1989) found right temporal lobe areas significantly smaller than left. BP females did not have this normal temporal asymmetry in one study (Swayze et al 1992). Overall, there is disagreement as to the presence of structural temporal lobe abnormalities in BPs. Temporal lobe changes have been found in four of seven MRI studies in BPs, but not in UPs. In BPs, both decreased and increased temporal lobe volumes have been reported, and the meaning of these conflicting findings needs to be clarified. Most of the studies that found abnormalities reported decreased temporal lobe measures. Further studies with better delineation of temporal lobe structures are needed to address this question. The temporal lobe contains key structures in the neuroanatomic model of mood regulation, and anatomic changes in this area appear more specific to BP depression. PARIETAL LOBE. The few studies that have investigated the parietal lobe in mood disorders did not find abnormalities. In one study (Dolan et al 1990), T1 relaxation times in right or left parietal lobes were not significantly different among BPs, UPs, and controls. In another study (Schlaepfer et al 1994), gray matter volume in inferior parietal cortex of BPs was normal.

Subcortical Regions
THALAMUS. Anecdotal evidence suggested that fight thalamic infarctions might be related to development of

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Table 2. Temporal Lobe Findings in Mood Disorders

Author Dewan et al (1988a) Hauser et al (1989a) Johnstone et al (1989) 26 22 17 21 20 21 24 13 20 29 10 10 48 47 48 76 26 34 Sample DSM-III BPs controls RDC AD normal controls DSM-III BPs normal controls RDC MDD normal controls MDD DSM-III-R normal controls RDC BPs normal controls DSMIII BPs normal controls MD DSM-III normal controls RDC BPs normal controls Age 32.7 31.1 40.5 12.8 33.8 6.2 35.2 M/42.5 F 32.9 M/39 F 42 10 46 7 69 12.3 71.5 5 39.8 9.0 37 12.0 33.4 M/34.6 F Age not stated 62.4 16.4 61.6 15.9 35.6 (21-49) 31.6 (19-49) 34.9 8.6 31.6 8.0 BPs 15 BPs, 2 UPs BPs Subtype Methods CT GE 8800 MRI 0.5T MRI 0.15T Results Significantly increased density in R temporal lobe, and trend on L Temporal lobe/cerebral area significantly smaller in patients Temporal horn area and temporal lobe area not significantly different No significant differences in T1 values in R or L temporal lobes T1 relaxation time not significantly different in temporal lobe R and L temporal lobe volume significantly smaller in patients No significant differences in temporal lobe volume No significant differences in temporal lobe volume L temporal lobe volume significantly larger in patients, due to increase in gray matter No significant differences in gray matter volume of superior temporal gyms

Dolan et al (1990) Krishnan et al (1991a) Altshuler et al (1991) Swayze et al (1992) Coffey et al (1993a) Harvey et al (1994)

10 UPs, 14 BPs UPs BPs BPs 44 UPs, 4 BPs, ECT referred BPs

MRI 0.08T MRI 1.5T MRI 0.5T MRI 0.5T MRI 1.5T MRI 0.5T

Schlaepfer et al (1994)

27 DSM-III BPs 60 normal controls

BPs

MRI 1.5T

UP, unipolar; BP, bipolar; MD, major depression; AD, affective disorder; R, right; L, left; M, male; F, female; CT, computed tomography; MRI, magnetic resonance imaging; RDC, research diagnostic criteria; ECT, electroconvulsive therapy.

mania (Cummings and Mendez 1984). Increased CT density was found in thalamus of BPs in one controlled study (Dewan et al 1988a), but two later MRI studies did not find significant differences in T1 values in BPs (Dolan et al 1990) or elderly UPs (Krishnan et al 1991a) compared to controls. One controlled MRI study did not find evidence of abnormalities in thalamus volume in elderly UPs (Krishnan et al 1993b). No significant differences in measures of thalamus volume were found in first-episode manics compared to normals (Strakowski et al 1993a); however, one recent MRI study (Dupont et al 1995) found significantly increased thalamus volume measures in BP patients compared to normal controls, and significantly decreased measures in UPs compared to controls. Thus, there is conflicting evidence of abnormalities in the thalamus of mood disorder patients. There is a paucity of high-resolution MRI volumetric studies. This region is part of a neuroanatomic model of mood regulation, and further studies should investigate its role in mood disorders. The size and lack of demarcation of thalamic nuclei make it difficult to obtain reliable measures. There is also the possibility of isolated cases due to a specific acquired damage to this area. HIPPOCAMPUS. Decreased T1 relaxation times were found in the hippocampus of UPs in one
AMYGDALA,

controlled MRI study, particularly in elderly patients (Krishnan et al 1991a). Two other MRI studies (Coffey et al 1993a; Axelson et al 1993) did not find significant differences in amygdala-hippocampus complex volumes between UP patients and controls. In BPs, MRI measures of hippocampal area were not significantly different from controls (Hauser et al 1989a), but volumetric MRI measures of fight hippocampus were reported to be smaller in one controlled study (Swayze et al 1992). Amygdala area or amygdala-hippocampal complex volume were not significantly different (Swayze et al 1992). One recent controlled MRI study paradoxically found increased volume measures of hippocampus in BPs, with left hippocampus significantly larger than fight in patients and controls (Kemmerer et al 1994). Thus, there is no consistent evidence of structural abnormalities in amygdala-hippocampus. The conflicting findings regarding hippocampal volume in BPs need to be further explored, particularly in light of findings of a possible smaller temporal cortex (Hauser et al 1989a; Altshuler et al 1991). Disagreements in studies may be partly explained by difficulties in the delimitation and measurement of this structure. Anatomic changes in these structures, if present, lend further support for the neuroanatomic model of mood regulation proposed to be implicated in mood disorders.

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Table 3. Basal Ganglia Findings in Mood Disorders

Author Dewan et al (1988a) Dolan et al (1990) Rabins et al (1991) Husain et al (1991a) Krishnan et al (1992) Swayze et al (1992) Krishnan et al (1993b) 26 22 24 13 21 14 41 44 50 50 48 47 25 20 17 16 30 30 26 34 36 30 26 Sample DSM-III BPs controls RDC MDD normal controls DSM-III-R MDD normal controls DSM-III MD normal controls DSM-III MD normal controls DSM-III BPs normal controls DSM-III MD normal controls DSM-III-R BPs normal controls DSM-III-R BPs normal controls RDC BPs normal controls DSM-III-R BPs DSM-III-R UPs normal controls Age 32.7 31.1 42 _+ 10 46 _+ 7 Age not reported 55.3 -+ 18.8 56.4 --- 19.2 48.3 +- 17 49.3 _+ 18 33.4 M/34.6 F Age not stated 74.1 _+ 6.6 72.5 _+ 3.6 28.4 _+ 6.8 30.9 - 7.3 39.3 --_ 11.1 37.6 ___9.0 35.6 (21-49) 31.6 (19-49) 36.6 --_ 10.8 38.6 -_+ 10.6 39.1 4- 9.4 BPs 10 LIPs, 14 BPs Elderly UPs UPs UPs BPs Elderly Subtype Methods CT GE 8800 MRI 0.08T MRI 1.5T MRI 1.5T MRI 1.5T MRI 0.5T MR! 1.5T Results Significantly increased density in R and L caudate in patients No significant differences in T1 values in R or L caudate Significantly increased rates of BG lesions in patients Significantly smaller putamen volume in patients Significantly smaller caudate volume in patients Caudate and putamen volumes not significantly different Significantly smaller caudate and putaminal complex volumes in patients No significant differences in caudate measures Significantly larger R and L caudate volume in male BPs No significant differences in volume of subcortical tissue Caudate and lenticular nucleus volumes not significantly different

Strakowski et al (1993a) Aylward et al (1994) Harvey et al (1994) Dupont et al (1995)

First episode manics BPs BPs 30 UPs, 36 BPs

MRI 1.5T MRI 1.5T MR1 0.5T MRI 1.5T

UP, unipolar; BP, bipolar; MDD, major depression disorder; MD, major depression; BG, basal ganglia; R, right; L, left; M, male; F, female; CT, computed tomography; MRI, magnetic resonance imaging; RDC, research diagnostic criteria.

BASAL GANGLIA, Two (Krishnan et al 1992; Husain et al 1991a) of three (Dupont et al 1995) controlled MRI studies found significantly smaller putamen and caudate volumes in UPs bilaterally. The one negative study (Dupont et al 1995) found a trend for smaller caudate and lenticular volumes in UPs, but this was not statistically significant. Since the sample in this study was younger, this could reflect differences in patient population. In elderly UPs, one MRI study found significantly decreased volumes of caudate and putamen complex compared to age-matched controls (Krishnan et al 1993b). In BPs, one controlled CT study (Dewan et al 1988a) found increased density on right and left caudate nucleus in patients; and one (Aylward et al 1994) of four (Swayze et al 1992; Strakowski et al 1993a; Dupont et al 1995) controlled MRI studies found larger caudate volumes bilaterally in male patients. One study (Harvey et al 1994) used volume measures of broadly defined "subcortical tissue," and did not find significant differences from controls. These resuits are summarized in Table 3. These findings taken together with evidence of increased white matter hyperintensities in subcortical regions of UPs and BPs compared to age-matched controls (Dupont et al 1987, 1990; Coffey et al 1990, 1993a; Swayze et al 1990; Zubenko et al 1990; Figiel et al 1991b; Lesser et al 1991; McDonald et al 1991; Rabins et al 1991; Brown et al 1992; Howard et al 1993; Krishnan et al

1993b; Dupont et al 1995) suggest that these anatomic regions may indeed have structural abnormalities in mood disorders. Significantly increased CT densities in the left and right heads of the caudate were found in elderly depressed patients (mostly UPs) compared to controls (Beats et al 1991). There is also evidence that silent cerebral infarction involving subcorfical structures may be involved in a great part (65.9-93.7%) of senile and presenile major depression (Fujikawa et al 1993), highlighting the potential importance of the basal ganglia in mood disorders. Thus, there is evidence that depressed UPs have smaller basal ganglia volumes. This does not appear to be the case for BPs. Caudate nucleus may actually be enlarged in BPs, in contrast to UPs, but this finding has not been replicated. These appear to be crucial areas in the neuroanatomic model of mood disorders.

Posterior Fossa Structures

CEREBELLUM. Increased rates of cerebellum atrophy were reported in a controlled CT study of young manic patients (Nasrallah et al 1982b). Another controlled CT study (Weinberger et al 1982) found increased rates of vermian atrophy in a sample of affective disorder patients; however, in one controlled study (Dewan et al 1988a) CT densities of vermis and fight or left cerebellum were

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normal in BPs. A controlled CT study in a sample of UPs and BPs did not find significant differences in rates of cerebellar atrophy (Yates et al 1987). Two controlled MRI studies found decreased cerebellar vermis area (Shah et al 1992) and mean cerebellar volume (Escalona et al 1993) in UPs, in samples of mostly nonelderly patients. Thus, there is evidence of smaller cerebellum in UPs and BPs. The evidence for abnormalities in UPs is stronger, because it comes from controlled area and volume studies, while the evidence in BPs comes mainly from studies using examiner's ratings. Further volumetric studies are needed to replicate these findings. The cerebellum, through its projections to limbic areas, may be an important region in a neuroanatomic model of mood disorders. BRAIN STEM. Smaller areas of medulla and total brain stem, but not midbrain or pons, were found in one MRI study in UPs compared to controls (Shah et al 1992). Based on the evidence reported in this one study, further studies should evaluate these brain regions in UPs and BPs.

tion was found in depressed patients, suggesting that activation of hypothalamic-pituitary-adrenal (HPA) axis may be related to pituitary volume in these patients (Axelson et al 1992). Krishnan (1993) concluded that this enlargement is anterior, because the posterior pituitary is of neural origin, and constitutes less than 20% of the gland. These results are consistent with hyperactivity of the HPA system, as are reports of adrenal gland enlargement in patients with major depression (Amsterdam et al 1987; Rubin et al 1995).
LATERALITY OF ANATOMIC LESIONS. Left frontal lobe lesions secondary to stroke or trauma were associated with higher rates and increased severity of depression (Lipsey et al 1983; Robinson et al 1984a, 1984b, 1988; Eastwood et al 1989; Astrom et al 1993; Hen-mann et al 1993; Jorge et al 1993), but not in all studies (Sinyor et al 1986; House et al 1990; Sharpe et al 1990; Agrell and Dehlin 1994; Andersen et al 1995; Ng et al 1995). These lesions were either cortical or subcortical (Starkstein et al 1987); however, an association between depression and rightsided lesions has also been described (Folstein et al 1977), but these lesions appeared to be more posterior (Robinson et al 1984a). In one study (Starkstein et al 1987), poststroke lesions on the right hemisphere were associated with euphoria or indifference. Lesions caused by tumor resection from frontal or parietal association cortexes, combined with paralimbic lesions, were associated with more depressive symptoms, and in this study laterality of lesion was not important (lrle et al 1994). Overall, left anterior lesions have been more associated with depression. Conflicting findings in different studies may be explained by different patient populations (e.g., inpatient versus community-based samples), different diagnostic criteria and follow-up instruments, and time intervals for assessments. Mania is less frequent than depression following a stroke or brain injury. Cummings and Mendez (1984) suggested, based on anecdotal reports, that right-sided lesions, mainly in the diencephalic region, could be related to development of mania. Right hemispherectomy was also suggested in one case report to result in BP symptomatology (Forrest 1982). A controlled study of patients with secondary mania showed that the right hemisphere is more frequently the site of the lesion (Starkstein et al 1987). Based in a small case series, Starkstein et al (1990) suggested that development of mania after brain injury could be related to right-sided lesions, in the basal region of the right temporal lobe. In another study, mania was related to subcortical and cortical right hemisphere lesions (Starkstein et al 1991). Since mania is less common than depression after stroke or brain injury, it may be more

Others
CORPUS CALLOSUM. Corpus callosum area in BPs was normal in one controlled MRI study (Hauser et al 1989b), but it was significantly decreased in another controlled study in psychotic BPs (Coffman et al 1990). In UPs, one MRI study (Wu et al 1993) found larger anterior and posterior quarters of corpus callosum compared to controis, but another controlled MRI study did not find evidence of abnormalities in corpus callosum area (Lammers et al 1991). Thus, it is unclear whether anatomic changes are present in this region. A reduction in corpus callosum area may be confined to psychotic patients, but these initial findings need to be further investigated. SEPTUM PELLUCIDUM. Measures of septum pellucidum area in UPs were normal in one controlled MRI study (Lammers et al 1991). A higher rate of cavum septum pellucidum was found in schizophrenics compared to mood disorder patients, but not in mood disorder patients compared to controls (Jurjus et al 1993). In conclusion, there is no evidence of septum pellucidum abnormalities in mood disorders in the few studies conducted so far.
PITUITARY. Increased pituitary volume was found in depressed patients compared to controls (Krishnan et al 199 lb). A significant correlation between pituitary volume and 10-PM postdexamethasone plasma cortisol concentra-

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difficult to cause, or there may be fewer vulnerable individuals in whom it can be triggered. Although the studies of poststroke or head traumarelated mood disorders have some disagreement regarding the importance of lesion laterality, right hemisphere lesions seem to be more frequently associated with mania, and left-sided lesions, particularly frontal, are associated with depression.

results is that there is an age-related degenerative brain change related to late-onset depression.

Bipolar versus Unipolar Dichotomy

In UPs, the main structural findings are: 1) increased rates of subcortical white matter and periventricular hyperintensities in elderly patients (Coffey et al 1990, 1993a; Zubenko et al 1990; Rabins et al 1991; Lesser et al 1991; Howard et al 1993; Krishnan et al 1993b); 2) decreased cerebellar vermis area (Shah et al 1992) and mean cerebellar volume (Escalona et al 1993); and 3) decreased volume of caudate and putamen (Husain et al 1991a; Krishnan et al 1992, 1993b). In BPs, the most consistent abnormalities are: 1) increased rates of subcortical white matter and periventricular hyperintensities in nonelderly and elderly patients (Dupont et al 1987, 1990, 1995; Swayze et al 1990; Figiel et al 1991b; McDonald et al 1991; Aylward et al 1994; Altshuler et al 1995); 2) increased third ventricle measures (Schlegel and Kretzschmar 1987; Dewan et al 1988a; Strakowski et al 1993a); and 3) smaller cerebellar measures (Nasrallah et al 1982b; Weinberger et al 1982). The findings of decreased right hippocampus volume in BPs (Swayze et al 1992) may be related to equivocal evidence of temporal lobe abnormalities (Dewan et al 1988a; Hauser et al 1989a; Johnstone et al 1989; Altshuler et al 1991; Swayze et al 1992; Schlaepfer et al 1994); however, this finding has recently been disputed with reports of increased hippocampus volume in BPs (Kemmerer et al 1994). One study found increased caudate volumes in male BP patients (Aylward et al 1994), if correct, suggesting that in BPs the basal ganglia may be affected in a different manner than UPs. Regarding the evidence of increased third ventricle in BPs, it is unclear why BPs and not UPs would selectively have enlargement in this region. One possible explanation is that because third ventricle is limited laterally by diencephalic structures, including thalamus and hypothalamus, this might eventually reflect decrease in the size of these nearby structures in BPs. Nonetheless, there is no consistent direct evidence so far that these areas are structurally abnormal in BPs (Strakowski et al 1993b). Frontal lobe may be affected in UP depression (Dolan et al 1990; Krishnan et al 1992; Coffey et al 1993a), but not clearly in BP (Dolan et al 1990; Schlaepfer et al 1994), suggesting that anatomic changes in the prefrontal cortex may be more specific for UP disorder. This differential pattern of brain involvement in UPs and BPs suggests that these two types of mood disorders are biologically different. That could underlie differences in the presentation of depression in these two subtypes. For instance, BP depression tends to have more severe and

Clinical and Biological Correlates of Neuroradiological Findings

Several studies have investigated the clinical and biological correlates of these different structural findings. These studies focused on investigation of relationship with age of onset, subtype, including the UP versus BP dichotomy, cognitive impairment, course of illness, treatment responsiveness, and specific aspects of psychopathology.

Early versus Late Onset of Illness

Enlarged ventricles were suggested to be associated with late onset of depression (Jacoby and Levi 1980; Shima et al 1984). Several authors tried subsequently to correlate global or localized structural neuroimaging changes with age at onset of illness. Three (Rossi et al 1987; Rabins et al 1991; Alexopoulos et al 1992) of five (Roy-Byrne et al 1988; Churchill et al 1991) studies found a positive correlation between age at onset and global measures of brain atrophy. These studies involved mostly UPs. In another study, increased lateral and third ventricle measures were found in late-onset compared to early-onset UPs (Alexopoulos et al 1992). Four (Churchill et al 1991; Figiel et al 1991a; Howard et al 1993; Hickie et al 1995) of six (Zubenko et al 1990; Figiel et al 1991c) studies found a positive correlation between age at onset and white matter hyperintensities in UPs, and one study (Dupont et al 1990) did not find significant correlation for BPs. No significant correlation between age at onset and T1 relaxation times was found in UPs or BPs (Dolan et al 1990). Three studies looked at the correlation between age at onset and regional atrophy. Caudate (Krishnan et al 1992) and right amygdala-hippocampus (Axelson et al 1993) volumes correlated negatively with age of onset in UPs; and temporal lobe areas in BPs did not (Hauser et al 1989a). No significant correlation between age at onset and measures of CT density was found in a sample of elderly depressed patients (mostly UPs) (Beats et al 1991). Thus, a later age of onset seems to correlate with increased measures of global atrophy and white matter hyperintensities, and perhaps with regional atrophy in some specific brain regions. The implication of these

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melancholic features, while UP depression appears to have a broader pattern of symptom presentation. To which extent this results from different patterns of brain involvement has still to be investigated.

Relationship with Psychopathology

Psychosis beginning at late age has been correlated with increased rates of nonspecific brain abnormalities, such as increased white matter hyperintensities or increased global atrophy (Lesser et al 1992). In mood disorders, measures of global atrophy have been correlated with psychotic symptoms. Five (Targum et al 1983; Luchins et al 1984; Schlegel and Kretzschmar 1987; Rothschild et al 1989; Shiraishi et al 1992) of nine CT studies (Pearlson et al 1984b; Standish-Barry et al 1985; Roy-Byrne et al 1988; DeLisi et al 1992) found a positive correlation between lateral ventricle measures and psychotic symptoms; however, when delusional and nondelusional elderly UPs were directly compared in several MRI cortical measures no significant differences were found (Rabins et al 1991). In one CT study (Rothschild et al 1989), psychotic depressed UPs had increased atrophy in inferior parietal brain bilaterally compared to nonpsychotic depressed patients, and no differences in prefrontal or superior temporal regions. History of psychosis was not correlated with MRI measures of temporal lobe in UPs or BPs (Hauser et al, 1989a). Three studies did not find significant correlation between white matter hyperintensities and history of psychosis in BPs (Dupont et al 1987, 1990; Figiel et al 1991b). Five studies did not find significant correlation between presence of psychotic symptoms and white matter hyperintensities in mood disorder patients (Dupont et al 1987, 1990; Coffey et al 1989; Figiel et al 1991b; Rabins et al 1991). In conclusion, there is evidence suggesting that lateral ventricle measures are correlated with psychotic symptoms in depressed patients, but not white matter hyperintensities. No significant differences in VBR were found between endogenous and nonendogenous patients in one CT study (Schlegel et al 1989a). In this study, VBR and width of third ventricle were positively correlated with melancholia scores, most significantly with retardation-related items. Interestingly, another study suggested that nonmelancholic patients had greater VBR measures, but no direct comparison between melancholic and nonmelancholic groups was provided (Shima et al 1984).

Shima et al 1984; Johnstone et al 1989; DeLisi et al 1992), but some studies in mood disorders did not confirm these findings (Dolan et al 1985; Standish-Barry et al 1985; Kolbeinsson et al 1986; Schlegel and Kretzschmar 1987; Roy-Byrne et al 1988). One study suggested that increased ventricular measures were related to increased mortality in elderly mood disorder patients (Jacoby et al 1981). White matter hyperintensities appear positively correlated with number of hospitalizations (Dupont et al 1987, 1990), but not with duration of illness (Dupont et al 1990, 1995). There are also suggestions of negative correlations between chronicity of illness and VBR (Roy-Byrne et al 1988), fight temporal lobe volume (Altshuler et al 1991) and amygdala-hippocampus volume (Axelson et al 1993). No significant correlation between gray and white matter densities and indicators of chronicity of illness were found in a CT study (Beats et al 1991). One CT study suggested a positive correlation between VBR and unemployment (Pearlson et al, 1984a, 1984b), but another (Dewan et al 1988b) did not find a significant relationship between employment history and CT abnormalities. Several studies tried to correlate CT or MRI anatomic measures with severity of depression. One (Schlegel et al 1989a) of four (Kellner et al 1983; Roy-Byrne et al 1988; Pearlson et al 1989) CT studies found a positive correlation of VBR measures and severity of depression in samples of BPs and UPs. Two MRI studies did not find significant correlation between white matter hyperintensities and severity of depression in UPs or BPs (Coffey et al 1989; Dupont et al 1990). One study did not find significant differences in CT ventricular measures between severely depressed and minor depressive patients (van den Bossche et al 1991). Four MRI studies looked at other measures, such as caudate volume (Krishnan et al 1992), cerebellar volume (Escalona et al 1993), amygdala-hippocampus volume (Axelson et al 1993), and T1 values in caudate, thalamus, frontal, parietal, and temporal regions (Dolan et al 1990), without finding any significant correlations with severity of depression. Thus, chronicity may positively correlate with white matter hyperintensities or different measures of regional atrophy, but not clearly with global atrophy. Severity does not appear to correlate with ventricular size or with other anatomic measures.

Treatment Responsiveness
Few studies have looked at the relationship between anatomic lesions and responsiveness to treatment. BPs with and without CT abnormalities did not differ in responsiveness to lithium therapy (Dewan et al 1988b). Three studies (Figiel et al, 1989b, 1990a, 1990b) found a

Chronicity and Severity of Illness

A positive correlation between indices of global atrophy and chronicity has been suggested in mood disorder and schizoaffective patients (Pearlson et al 1984a, 1984b;

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relationship between basal ganglia lesions, periventricular and deep white hyperintensities, and the development of delirium induced by antidepressants and ECT in elderly depressed patients. Global evidence of atrophy was not associated with delirium. A negative correlation between severity of white matter hyperintensities and treatment response was reported in depressed patients (Hickie et al 1995). Another study (Figiel et al 1991c) suggested that caudate white matter hyperintensities were related to susceptibility to neuroleptic-induced parkinsonism in elderly depressed patients. Andreasen et al (1990) did not find significant correlation between ventricular enlargement and treatment response in UPs and BPs. Ventricular size has not been found to correlate with previous response to ECT (Standish-Barry et al 1985). One study suggested increased measures of third ventricle area in psychotic patients with delayed response to neuroleptics (Kaplan et al 1990). Thus, the few studies that looked at this question did not find conclusive evidence of correlation between structural brain changes and treatment response. Subcortical white matter changes seem related to development of treatment complications, such as ECT-induced delirium or parkinsonism secondary to neuroleptic treatment, and perhaps to worse treatment response.

Cognitive Impairment
Five (Pearlson et al 1989; Rothschild et al 1989; Abas et al 1990; Coffman et al 1990; Dewan et al 1988b) of six (Andreasen et al 1990) controlled studies found significantly higher cognitive impairment in depressed patients with evidence of global brain atrophy. In one of these studies, it was also correlated with smaller frontal areas (Coffman et al 1990), and in another with inferior parietal atrophy (Rothschild et al 1989). Extensive white matter lesions were also related to cognitive impairment (Dupont et al 1990, 1995; Steingart et al 1986, 1987; Junque et al 1990; Hickie et al 1995). In poststroke depression, anterior and left-sided lesions were correlated with increased cognitive impairment (Robinson et al 1988; Bolla-Wilson et al 1989). Thus, cognitive impairment in mood disorders appears to be related to global atrophy, extensive white matter lesions, and perhaps localized lesions to the frontal lobe.

in one (Kellner et al 1983) of two (Risch et al 1992) studies. Plasma cortisol was positively correlated with VBR in one (Schlegel et al 1989b) of four (Dewan et al 1988c; van den Bossche et al 1991; Coffey et al 1993b) studies. Postdexamethasone cortisol levels correlated with frontal lobe (Coffey et al 1993b) and pituitary (Axelson et al 1992) volumes. Dexamethasone suppression test (DST) nonsuppressors were found to have increased VBRs in two studies (Rao et al 1989; Rothschild et al 1989), but three other studies did not confirm these findings (StandishBarry et al 1985; Schlegel and Kretzschmar 1987; Schlegel et al 1989b). In Cushing's syndrome, where there is an excess of glucocorticoids, there were findings of decreased volume of hippocampal formation, with a significant negative correlation between plasma cortisol levels and hippocampal volume (Starkman et al 1992); however, hippocampal volume was not significantly different between DST suppressors and nonsuppressors, in a sample of depressed patients (Axelson et al 1993). One study involving UP and BP patients did not find significant correlations between VBR measures and cerebrospinal fluid corticotropin-releasing factor (CRF) or adrenocorticotropic hormone (ACTH) levels (Risch et al 1992). Plasma tryptophan was negatively correlated with ventricular measures in depressed patients in one (StandishBarry et al 1986) of two studies (van den Bossche et al 1991). Lower levels of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) have been associated with increased ventricular size in psychotic patients (Lewine et al 1991). A significant negative correlation between serum dopamine-beta-hydroxylase and VBR measures in depressed patients was also reported (Meltzer et al 1984). Deep white matter hyperintensities were associated with lower platelet imipramine binding in elderly depressed patients (Husain et al 1991b). The studies of the HPA axis suggest that HPA overactivity is associated with an enlargement of the pituitary and adrenal glands. Whether this correlates with generalized or focal brain atrophy is unclear. One study (Johnstone et al 1986) in a sample of BP and neurotic patients found an unexpected correlation of increased VBRs and hypothyroidism, which has not been reported in other studies. It is difficult to explain how decreased thyroid hormone levels could be related to increased levels of brain atrophy.

Relationship of Neuroradiological and Biological Markers in Mood Disorders

Several studies examined the relationship between CT and MRI measures and possible biological markers for depression. Almost all studies have addressed the HPA axis. VBR was positively correlated with free urinary cortisol

Discussion
The structural neuroimaging studies reviewed here suggest abnormalities in specific brain regions in patients with primary and secondary mood disorders, in structures participating in a proposed neuroanatomic model of mood regulation. No clear indication of global atrophy was

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found. Thus, the studies reviewed support our hypothesis that mood disorders are associated with regional structural brain abnormalities in particular regions involved in mood regulation, rather than global atrophy. The main abnormalities found in UPs were evidence of smaller basal ganglia, cerebellum, and possibly frontal lobe, which may reflect local atrophy. BP disorder appeared to be associated with larger third ventricle, smaller cerebellum, possibly smaller temporal lobe, and perhaps changes in the hippocampus. Both BPs and elderly UPs have increased rates of subcortical white matter and periventricular hyperintensities. The interaction of factors involved in the pathogenesis of mood disorders, such as genetic and environmental factors, with these specific brain structures, is yet to be clarified. Acquired injuries such as stroke or tumors appear involved in the pathogenesis of mood disorders through lesions in these selected brain regions. The aging process, when it is associated with focal or global brain changes, may contribute to the emergence of depression by causing lesions in these anatomic areas. The prefrontal cortex has been insufficiently investigated in structural imaging studies. The studies reviewed used mostly measures of total frontal lobe, without distinguishing specifically the prefrontal cortex, or its different anatomic subregions. Further MRI studies are needed with direct volumetric measures of prefrontal cortical gray matter, and with further delimitation of its subregions. This brain structure may be very important in mood regulation and in the pathophysiology of mood disorders, perhaps because of its connections to basal ganglia, thalamus, and limbic areas. It seems to have an important role in modulating limbic activity, through its connections with those areas. There is also corroborating evidence from functional and activation studies pointing to dysfunction of the prefrontal cortex in mood disorders (George et al 1994), which may correlate with structural changes. Diseases affecting the basal ganglia are associated with mood disorders (Caine and Shoulson 1983; Rogus et al 1987). Patients with cerebrovascular lesions affecting the caudate nucleus can have neuropsychiatric symptoms resembling depression (Mendez and Lewandowski 1989). The findings of smaller caudate and putamen in UP depression (Husain et al 1991a; Krishnan et al 1992, 1993b) support the hypothesis of regional abnormalities in these structures. For BP depression, the findings of enlarged caudate volume in males (Aylward et al 1994) are difficult to explain, and further studies are needed to try to replicate and clarify the meaning of these abnormalities. The caudate and putamen are part of basal ganglia circuits that receive inputs from the medial temporal structures involved in regulation of emotions, like the amygdala and hippocampus, and have connections to the prefrontal cortex. Thus, these structures may be relevant for mood

regulation, and lesions affecting these circuits may contribute to the pathogenesis of mood disorders. Recurrent stress and aging appear associated with gradual destruction of hippocampal neurons through loss of HPA feedback inhibition (Sapolsky and McEwen 1988). A similar process may occur in depression, and this would explain the DST nonsuppression found in depressed patients. Nonetheless, most of the studies conducted so far did not show evidence of amygdala-hippocampus structural changes in mood disorders (Hauser et al 1989a; Axelson et al 1993; Coffey et al 1993a), and the two positive studies in BP patients (Swayze et al 1992; Kemmerer et al 1994) pointed in opposite directions, one finding increased and the other decreased volume measures. The cerebellum has extensive projections to brain stem and limbic structures. The midline cerebellar nuclei project to norepinephrine and dopamine cell groups in the brain stem, and influence concentration and turnover of catecholamines in animal models (Snider and Snider 1977). The paleocerebellum has projections to brain stem and spinal cord, and to limbic and telencephalic areas (Berton and Torello 1982). These connections may explain its possible role in regulation of mood. The studies in UPs and BPs reviewed here suggest structural abnormalities in this region, which may reflect regional atrophy (Nasrallah et al 1982b; Weinberger et al 1982; Shah et al 1992; Escalona et al 1993); however, volumetric MRI studies have been conducted only in UPs to date. The findings of enlarged third ventricle in BPs (Schlegel and Kretzschmar 1987; Dewan et al 1988a; Strakowski et al 1993a), if replicated in further volumetric studies, may be related to its proximity to diencephalic structures, such as hypothalamus and thalamus, which may be affected in mood disorders; however, there is no direct evidence of structural abnormalities in these regions in mood disorders patients (Dolan et al 1990; Krishnan et al 1991a, 1993b; Strakowski et al 1993a), except for one study (Dupont et al 1995). Nonetheless, because of significant technical limitations in the measurement of these regions, these negative results should be interpreted with caution. No conclusive evidence was found to support a role for global brain atrophy in the pathophysiology of mood disorders. Global cerebral atrophy appears to be nonspecific, being described in different psychiatric and medical conditions (Morris and Rapoport 1990). Regional brain abnormalities, rather than global diffuse atrophy, are associated with mood disorders. A recently published meta-analysis of this literature does not support our conclusions regarding global atrophy (Elkis et al 1995). The authors found evidence for ventricular enlargement and increased sulcal measures when they pooled 33

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different studies. They claimed that in a meta-analysis mild or moderate effects that might have been missed in individual studies could be revealed, because of increased power of statistical analysis; however, one has to wonder about the possible confounding effects of combining several studies with very diverse methodologies in the same statistical analysis, such as done in that study. The individual analysis of these studies clearly does not permit this conclusion; actually, the great majority of the best controlled studies in this field, using higher-resolution MRI measures, produced negative findings (Dupont et al 1987; Johnstone et al 1989; Swayze et al 1990; Zubenko et al 1990; Lammers et al 1991; Lesser et al 1991; McDonald et al 1991; Shah et al 1992; Coffey et al 1993a; Krishnan et al 1993b; Harvey et al 1994). Rates of subcortical white matter and periventricular hyperintensities are increased in mood disorder patients (Dupont et al 1987, 1990; Swayze et al 1990; Zubenko et al 1990; Figiel et al 1991b; Lesser et al 1991; McDonald et al 1991; Rabins et al 1991; Brown et al 1992; Coffey et al 1990, 1993a; Guze and Szuba 1992; Howard et al 1993; Krishnan et al 1993b; Aylward et al 1994; Dupont et al 1995). They are also found in other disorders, not being in any way specific to this condition (Gupta et al 1988). These lesions may be relevant by interrupting connections between the different brain regions participating in mood regulation. They appear to be associated with vascular risk factors (Awad et al 1986a; Coffey et al 1989; Lesser et al 1991; Schmidt et al 1991), but not in all studies (Harrel et al 1991; Rabins et al 1991). They may reflect changes in water content of extracellular space, causing an increase in the MRI proton signal. These lesions have been correlated in postmortem samples with loss of myelin, oligodendroglial cells, reactive gliosis, and presence of macrophages (Brun and Englund 1986; Englund et al 1987; Leifer et al 1990; Grafton et al 1991; Chimowitz et al 1992; Scheltens et al 1995). They have also been associated with areas of arteriosclerosis, infarction, dilated perivascular spaces, or vascular ectasia (Erkinjuntti et al 1984; Awad et al 1986b; George et al 1986; Chimowitz et al 1992); however, the relationship between mood disorders and white matter hyperintensities is not yet understood. They may precede the depression, being an anatomic risk factor for its development due to disruption of fiber pathways, or be a consequence of depression, for example, the weight loss or the hypotensive effects of antidepressants. Weight loss in anorectic patients has been found to be related to increased brain atrophy (Krieg et al 1988); however, the hypothesis of them resulting from previous treatment does not appear to have support in the literature (Strakowski et al 1993b). Alternatively, the lesions may not be directly linked with the mood disorder, but part of aging. Since studies involved age-matched controls, this does not appear to

account for the above findings. These lesions may be relevant by disconnecting different fiber pathways in the proposed circuit of mood regulation, causing a functional disconnection between these brain regions. There is evidence from one electroencephalographic study in dementia patients suggesting that white matter hyperintensities may indeed result in functional brain disconnection (Leuchter et al 1994). Since there is evidence of gender differences in brain anatomy (Hauser et al 1989b; Johnstone et al 1989; Allen and Gorski 1990; Andreasen et al 1990; Raz and Raz 1990; Allen et al 1991; Swayze et al 1992; Escalona et al 1991, 1993; Strakowski et al 1993a; Schlaepfer et al 1995), this factor must be taken into consideration, and men and women included in the samples studied. Some of the studies reviewed here involved unbalanced samples regarding gender, which might have been a potential bias for the findings obtained. It is known that alcohol and substance abuse may be responsible for brain anatomic changes (Lader et al 1984; Lippman et al 1985; Lishman 1990; Jernigan et al 1991; Pfefferbaum et al 1992; Aasly et al 1993; Chamess 1993; Shear et al 1994). Additionally, the comorbidity of mood disorders and substance abuse is well-documented (Reich et al 1974; EI-Guebaly 1975; Hasin et al 1985; Sonne et al 1994; Brady and Sonne 1995). The best controlled studies reviewed herein took this important factor in consideration, excluding from their samples patients with such comorbidity, but some did not, mainly the earlier CT studies. Thus, for further studies in this field it is most important to exclude from the studied samples patients with current or past substance abuse, which may be an important confounding variable. MRI brought better possibilities of delimitation of specific brain regions, but one significant methodology problem is that smaller, more complex anatomic regions cannot be easily demarcated and measured (Krishnan et al 1993b). Because of significant difficulties in determining anatomic landmarks in these studies, for structures such as amygdala, hippocampus, and prefrontal Cortex, it is necessary to be conservative in interpreting findings. These difficulties could underlie the conflicting findings obtained for some of these anatomic regions. Further developments in the MRI resolution and image processing, with more sensitive and reliable determination of volume of discrete anatomic regions, is making it possible to examine these findings more precisely. Because of these difficulties, the evidence reviewed here, which gives support to the above-proposed neuroanatomic model, must be seen as tentative. On the other hand, since there is also considerable evidence from functional neuroimaging studies in support of this model (Buschbaum 1986; Baxter 1991; Cummings 1993; George et al 1993; George 1994; Ketter

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et al 1994; Mayberg et al 1994b), these findings may be further replicated in controlled studies addressing the methodological limitations pointed out here. The specificity of the above-discussed anatomic changes has to be determined. Most of the regions found to be anatomically abnormal in mood disorders, such as frontal and temporal lobes, basal ganglia, and cerebellum, have also been found to be abnormal in schizophrenia (Bachneff 1991; Cleghorn et al 1991; Gur and Pearlson 1993). Some CT studies failed to distinguish schizophrenics and mood disorder patients in measures of brain atrophy (Raz and Raz 1990; Rieder et al 1983). But apparently, the severity of the structural brain changes in mood disorders is less, and for schizophrenia more clear evidence of generalized brain changes has been identified (Raz 1993; Elkis et al 1995). What do decreased area and volume brain measures as ascertained by CT or MRI reflect at the neuropathology level? Do they result from atrophy, or alternatively, do they represent hypoplasia of these structures? Anatomic abnormalities in mood disorders have not been systematically investigated in quantitative neuropathology studies. The neuroimaging changes that have been identified in mood disorders are subtle, and may not be detected in macroscopic postmortem anatomic studies. Additionally, postmortem studies have significant limitations, it being difficult to differentiate pre- and postmortem changes. CT and MRI have made possible the study of the in vivo anatomy of the human brain. The MR/ studies allowed higher resolution and more precise volumetric determinations; semiautomated and automated computerized methods for volume calculation of whole brain or individual structures have been found very accurate, when compared to findings in normal fresh postmortem brain specimens (Filipek et al 1989). MRI has also been validated to study human brain development, with findings of patterns of gray and white matter changes very consistent with animal and human postmortem neuropathological studies (Pfefferbaum et al 1994). For patients with different brain lesions, there is a good confluence of structural neuroimaging findings, clinical presentation, and postmortem studies (Becker et al 1995). As reviewed by Jeste et al (1988), the literature in neuropathology postmortem studies in mood disorders is inconclusive, with few studies, mostly with significant limitations in methods and design. Thus, for the regional neuroimaging anatomic changes here reviewed, there is no properly conducted postmortem

studies to date that corroborate and further investigate these findings. Can the localized brain changes identified in mood disorders be the result of a neurodevelopmental abnormality? In schizophrenia, there are several lines of evidence, from different disciplines, suggesting that the identified brain changes could result from abnormalities in brain development (Jones and Murray 1991; Pilowsky et al 1993; Wright et al 1993; Keshavan et al 1994). This has also been speculated to be the case for bipolar disorder (Nasrallah 1991). The decreased size of specific brain regions could result from deficits in brain development, originating, e.g., from viral infection or genetic factors, reflecting hypodevelopment rather than atrophy; however, there is no substantial evidence to validate such claims in mood disorders to date. Thus, it is most probable that the regional changes identified reflect local atrophy in areas of the neuroanatomic model, which may be important in the pathophysiology of mood disorders; however, postmortem and longitudinal neuroimaging studies will have to address and help clarify this question. In summary, focal atrophy of the prefrontal cortex, basal ganglia, and the cerebellum may disrupt circuitry, resulting in UP depression. BP disorder appears associated with cerebellar and possibly temporal lobe changes. Other areas involved in the same circuit, such as the thalamus and amygdala, may be spared. Both disorders seem to be related to increased white matter periventricular hyperintensities. Whether these brain neuroanatomic changes are genetic or acquired, precede or follow major depression, requires studies in high-risk population. White matter lesions may disrupt fiber pathways, a pathophysiological process that seems related to cerebrovascular disease. The integrated study of the anatomy and function of the living human brain by the combination of MRI with functional neuroimaging techniques, like single photon emission computed tomography, positron emission tomography, or functional MRI, has the potential for anatomic localization of abnormalities at the neurotransmitter level. The confirmation of the structural changes reviewed here and the elucidation of their biochemical correlates will help in developing an integrated structural-functional model of mood disorders.

This work was partly supported by grant MH 46745. We thank Mrs. Geny H.U. Soares for technical assistance in the manuscript preparation.

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