Regional cerebral blood flow in mood disorders: IV. Comparison of mania and depression

PSYCHIATRY RESEARCH NEUROIMAGING ELSEVIER

Psychiatry Research: Neuroimaging 61 (1995) 1-10

Regional cerebral blood flow in mood disorders: IV. Comparison of mania and depression Eric Rubin *a'b, Harold A. Sackeim a'b, Isak Prohovnik a'b, James R. Moeller a'b, D a v i d B. S c h n u r c, S u k d e b M u k h e r j e e d aNew York State Psychiatric Institute, 722 West 168th Street, New York, NY 10032, USA bDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA eDepartment of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574, USA dDepartment of Psychiatry, Medical College of Georgia, 1515 Pope Avenue, Augusta, GA 30912-3800, USA

Received 2 February 1994; revision received 19 September 1994; accepted 7 November 1994

Abstract

Cortical regional cerebral blood flow (rCBF) was assessed in minimally medicated, relatively young adults in episodes of either acute mania (n = 11) or major depression (n = 11) and in matched normal control subjects (n = 11), using the mxenon inhalation method, under eyes-closed, resting conditions. The three groups were equivalent in global CBF. Both patient groups showed significant reductions of rCBF in anterior cortical areas and reduction of the normal anteroposterior gradient. In addition, there was evidence of abnormal, albeit similar, patterns of flow lateralization on a regional basis in both clinical groups compared with normal subjects. An exploratory analysis revealed preliminary evidence of rCBF differences between the clinical groups, localized to the inferior frontal cortex. Otherwise, the evidence in this study suggests that young adult manic and depressed patients are predominantly similar in cortical rCBF parameters. Keywords: Bipolar disorder; Affective disorder; Xenon inhalation; Cerebral blood flow; Frontal cortex

1. Introduction Functional brain imaging offers an opportunity to examine cerebral correlates of affective disorders. Some studies have suggested that patients in episodes of major depression have abnormal * Corresponding author, Department of Biological Psychiatry, New York State Psychiatric Institute, 722 West 168th Street, New York, NY 10032, USA; Tel: +1 212 9605568; Fax: +1 212 960-5854.

patterns of regional cerebral blood flow (rCBF) and regional metabolic rate for glucose (rCMRglu; see Sackeim and Prohovnik, 1993, for a review). In severely depressed inpatients, some investigators have reported reductions in global rCBF or rCMRe:u, as well as specific topographic deficits (Baxter et al., 1985, 1989; Buchsbaum et al., 1986; Sackeim et al., 1990; Yazici et al., 1992). Other investigators have reported no differences between depressed patients and normal control subjects

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E. Rubin et al./Psychiatry Research: Neuroimaging 61 (1995) 1-10

(Silfverskifld and Risberg, 1989) or elevated CBF in specific cortical regions in depressed patients (Drevets et al., 1992). These inconsistencies may in part be related to factors such as age, diagnosis, severity of illness, and concurrent medication. Even less consistency exists about findings of rCBF or rCMRglu in acute mania, and the practical impediments to enlisting such patients in imaging studies should not be underestimated. In the largest series to date, Silfverskifld and Risberg (1989) observed no differences between manic patients and normal control subjects in regional or global CBF. This comparison was compromised by the heterogeneous medication regimens administered in the manic sample. Indeed, Silfverskirld and Risberg (1989) found significant negative correlations between neuroleptic dosage and global CBF in the manic patients. With small samples of patients in mixed or manic states, Baxter et al. (1985) suggested that mania is associated with increased global CMRglu. Repeated studies were also conducted in a rapid-cycling patient who manifested a 36% increase in global CMRglu during hypomania relative to depression (Baxter et al., 1985). We reported a similar phenomenon in another rapid-cycling bipolar patient with repeated rCBF assessments (Mukherjee et al., 1984). In a subsequent report, Baxter et al. (1989) observed that the ratio of rCMRou in the anterolateral prefrontal cortex relative to the hemisphere was reduced on the left side in 10 bipolar depressed subjects compared with six bipolar manic patients and control subjects. The manic and depressed groups did not differ in this comparison for the right hemisphere. Kishimoto et al. (1987) observed globally increased uptake of l lC glucose into amino acid pools in three manic patients. Migiiorelli et al. (1993) presented preliminary evidence that rCBF is reduced in the right relative to the left temprobasal region, but they did not quantify global flow. Therefore, the initial evidence weakly suggests that mania, relative to major depression or euthymia, may be associated with increased CBF and CMR. On theoretical grounds, the comparison of patterns of asymmetry in major depression and acute mania is of considerable importance. Several investigators have reported that rCBF or rCMR~u

deficits in major depression are most pronounced in left anterior cortical regions (e.g., Baxter et al., 1985, 1989; Martinot et al., 1990; Yazici et al., 1992), and Migliorelli et al. (1993) observed a reduced right-sided temporobasal CBF in manic patients. These findings are compatible with studies on the prevalence and severity of depressive and manic symptoms following acute stroke and other types of brain damage. Such studies have suggested that depressive symptoms are particularly associated with left anterior lesions, while secondary mania and perhaps related affective disturbances, such as pathological laughing, are most commonly observed following right-sided brain damage (Sackeim et al., 1982; Robinson et al., 1984; Starkstein et al., 1987). Given these trends, one might expect opposite patterns of lateralized deficits in functional imaging studies contrasting major depression and acute mania. 2. Methods

2.1. Subjects CBF measurements were carried out on inpatients currently in episodes of either major depression (n = 11) or acute mania (n = 11) and on normal control subjects (n = 11). An attempt was made to match the three groups in the distributions of gender, age, end-tidal Pco2, and hemoglobin, the latter measured within a week of the CBF measurement. Psychiatric diagnosis was established with the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer, 1978) and the Research Diagnostic Criteria (RDC; Spitzer et al., 1977). Exclusion criteria included history of schizophrenia, schizoaffective disorder, other functional psychosis, rapid-cycling bipolar disorder, neurological illness or insult, substance abuse within the past year or any history of substance dependence, or electroconvulsive therapy (ECT) within the previous 6 months. All had physical examinations within normal limits, and no subject had a current significant medical disorder or other condition that might influence rCBF. The depressed group met the RDC for major depressive disorder, endogenous subtype, and had scores >__18 on the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967), with an

E. Rub#; et al. / Psychiatry Research: Neuroimaging 61 (1995) 1-10

average HRSD score of 30.45 (SD = 7.17). The manic group met the RDC for definite bipolar disorder, manic episode, and had scores > 30 for the current episode on the Modified Mania Scale (MMS; Blackburn et al., 1977), with an average MMS score of 59.91 (SD = 20.57). Ratings for mania or depression were made within 48 h of the rCBF measurement. Both the depressed and manic patients were recruited in the context of inpatient ECT treatment protocols. All manic patients had failed at least one pharmacological trial involving >2 weeks of lithium carbonate with blood levels between 1.0 and 1.5 mEq/1 or 2 weeks of neuroleptic treatment at doses equivalent to > 1,500 mg/day chlorpromazine. Depressed patients had been free of psychotropic medications a minimum of 5 days before rCBF measurement (mean = 15.91 days, SD = 8.88), with the exception of lorazepam in 5 of the 11 patients (1 or 2 mg/day) and alprazolam in one patient (0.5 mg/day). With the exception of one manic patient who received 1000 mg chloral hydrate within 24 h of rCBF measurement, the manic patients were free of psychotropic medication >3 days before the rCBF procedure. No patient had received fluoxetine or other longacting antidepressants within 6 weeks of CBF measurement. No patient had recent exposure to a long-acting benzodiazepine, and none had received depot neuroleptics within 1 year of the study.

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Normal control subjects were paid volunteers, recruited through advertisements in local newspapers. They had negative lifetime psychiatric and neurologic histories on medical interview, had not received prescription medication within 3 weeks of study, and were not using commercial preparations that might influence rCBF at the time of the scan. Caffeine and nicotine intake was not controlled for patients or control subjects, and no restrictions for menstrual phase were applied. None of these subjects had been included in previous reports on baseline rCBF abnormalities in mood disorders (Sackeim et al., 1990, 1993). Table 1 presents demographic and clinical features of the three groups. Analyses of variance were conducted on each of the continuous variables in Table 1, with diagnostic group (three levels) and gender as between-subject terms. Diagnostic groups did not enter into any significant effects other than in the analysis of PCO2, where there was a main effect (F= 3.74; df= 2, 27; P = 0.04). Post hoc comparisons, by Fisher's least significant difference statistic, indicated that the depressed group had significantly lower Pco2 compared with both the manic and normal control groups.

2.2. rCBF procedures Procedures for assessment of rCBF have been detailed elsewhere (Sackeim et al., 1990, 1993).

Table i Subject characteristics Variable

Age (years) Gender (M,F) Education (years) Bipolar (%) Psychotic (%) Age at onset (years) Duration of illness (years) Pco 2 Hemoglobin Systolic blood pressure

Manic patients

Depressed patients

Normal subjects

Mean

SD

Mean

Mean

SD

30.45 3 M, 8 F 11.90 100 45 20.18 10.27 40.71 13.52 125.09

11.54

29.82 4M, 7F

12.90

5.12 9.99 5.22 1.35 18.05

35.00 4M, 7F 14.91 36 45 22.36 12.55 36.85 13.64 122.40

8.72 9.45 4.32 1.78 8.64

40.75 13.35 112.18

2.71 14.46 13.28

83.82

16.82

76.10

12.25

72.18

8.12

3.23

SD 8.40 1.81

0 0

(mmHg) Diastolic blood pressure

(mmHg)

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E. Rubin et al./Psychiatry Research: Neuroimaging 61 (1995) 1-10

Subjects were studied under resting, supine conditions in a quiet, darkened room, with blinders placed over the eyes. A Novo Cerebrograph 32c (Novo Diagnostic Systems, Copenhagen, Denmark) was used, with head positioning established by orienting a helmet housing 32 scintillation detectors (16 per hemisphere) in relation to light markers that were aligned to the canthomeatal line. Extensive quality-control procedures were used, as documented elsewhere (Prohovnik, 1988). End-tidal Pco2 was continuously monitored during the l l-min measurement period. Clearance curves were analyzed with a six-unknown model (M2), which provides greater sensitivity under low flow conditions and more accurate artifact removal, and the traditional four-unknown model (MI) (Prohovnik et al., 1983, 1989). CBF values derived with the M 1 model were available for 29 of the 33 subjects. The correlation between M1 and M2 estimates of global CBF was 0.97, with a ratio of 0.95 of M2 relative to M 1 values. Consequently, the dependent variable submitted to analysis was the M2 initial slope index (ISI; Prohovnik et al., 1985). Anxiety of the subjects during the measurement was rated on a Likert scale ("none" to "very much"). All normal subjects were rated as minimally to moderately anxious. No extreme anxiety ratings were noted for any of the mood disorder subjects, though such ratings are problematic in the setting of manic agitation.

2.3. Statistical analyses Two statistical approaches were used. One relied on traditional univariate and multivariate analyses of covariance (ANCOVA) techniques, and the other utilized the Scaled Subprofile Model (SSM; Moeller et al., 1987; Sackeim et al., 1993). For the traditional approach, the three groups were compared in an ANCOVA on global CBF values (log-transformed), with group and gender as between-subject terms and PCO2 and age as covariates. Global CBF was defined as the average ISI value across all 32 brain regions. To examine alterations in topography, 32 regional ratio values (region/global) were submitted to a repeated measures multivariate ANCOVA (MANCOVA), with group and gender as between-subject factors,

hemisphere and brain region as repeated measures factors, and age and Pco 2 as covariates. The resuits of this analysis were contrasted with a similar MANCOVA using the absolute regional values as dependent measures and adding global CBF as a covariate. Two sets of SSM analyses were conducted. First, SSM was applied to the values at each of the 32 brain regions, following previously described methods (Sackeim et al., 1993). In a second analysis aimed at detecting patterns of lateral asymmetry, SSM was applied to laterality ratios (left/right) from the 16 pairs of homologous regions. This approach enhances identification of region-dependent flow asymmetries. The topographic structures identified by SSM are based on covariance patterns, and CBF in homologous brain regions is typically more highly correlated than in nonhomologous regions. Therefore, asymmetry patterns were likely to be suppressed when SSM was applied to the complete set of regional values, as in the first analysis. Each SSM analysis produced a score for each subject on a Global Scaling Factor (GSF), which represents individual differences in global values, stripped of the effects of differences in topography. These analyses also produced a set of Subject Scaling Factors (SSF), or network scores, which reflect the extent to which each subject manifested particular topographic patterns. Finally, the SSM analyses produced a set of weights for each brain region, characterizing the extent to which it contributed to the network or Group Invariant Structure (GIS). 3. Results

3.1. Global and topographic effects: traditional analyses The ANCOVA on global CBF did not yield any effects involving diagnostic group. As seen in Table 2, manic patients had only slightly higher global CBF compared with depressed patients or normal control subjects. There was a main effect of gender ( F = 6.15; df= 1, 25; P = 0.02), with females being characterized by higher global CBF. There was also a significant effect of the covariate Pco2 (F= 11.54; df= 1, 25; P = 0.002). In the MANCOVA on the 32 regional ratio

E. Rubin et al. / Psychiatry Research: Neuroimaging 61 (1995) 1-10 Table 2 Cerebral blood flow (CBF) parameters Variable

Global CBF (ISI) Left hemisphere CBF Right hemisphere CBF GSF Score on SSF 1 (32-region analysis) Score on SSF 2 (32-region analysis) Score on SSF 3 (32-region analysis) Score on depression profile Score on laterality SSF2 (16 left / right paired regions)

Manic patients

Depressed patients

Normal subjects

Mean

SD

Mean

SD

Mean

SD

58.67 100.65 99.35 55.28 -8.47

10.76 1.29 1.29 8.4 26.66

55.74 99.92 100.08 56.75 -5.44

5.44 0.74 0.74 7.75 17.45

56.90 100.21 99.79 55.80 13.91

7.59 0.69 0.69 7.62 17.65

3.09

22.92

2.89

14.03

-5.97

12.43

-!.17

20.41

0.31

15.33

0.86

15.73

-15.43 -4.22

70.61 19.19

-7.91 -7.24

44.78 14.35

23.34 11.45

37.65 14.95

Note. Left and right hemisphere CBF values were normalized by global mean CBF (top row). ISI, initial slope index; GSF, Global Scaling Factor; SSF, Subprofile Scaling Factor (topographic pattern derived from Scaled Subprofile Model; see text).

values, there was a main effect of brain region ( F = 5.23; df= 15, 11; P < 0.005). The only other significant effects involved the interactions between hemisphere and age (F = 4.24; df= 1, 25; P = 0.05), and between brain region and Pco2 ( F = 4.71; df= 15, 11; P < 0.01). The only effect to approach significance involving diagnostic group was the group × hemisphere interaction ( F = 2.81; df= 2, 25; P = 0.08). This marginal interaction suggested that laterality differences characterized the groups. The ordering of means indicated that manic patients had the highest average CBF and depressed patients had the lowest CBF in the left hemisphere; this ordering was reversed for the right hemisphere (Table 2). However, when difference scores were computed on normalized hemispheric asymmetry values [left- rightl/global, one-sample t tests indicated that none of the groups departed from zero. Pairwise comparison of the groups in these difference scores also did not yield a significant effect. As an alternative approach, a MANCOVA was also performed on the 32 absolute regional values, with group and sex as between-subject terms, hemisphere and region as within-subject factors, and age, Pco2, and global CBF as covariates. There

were no significant effects involving diagnostic group.

3.2. Global and topographic effects: SSM There were no differences among the groups in GSF, SSM's estimate of region-independent global CBF (Table 2). Three topographic patterns accounted for 54.7% of the variance in CBF values that was both subject- and region-dependent. Subject scores on these networks accounted for 39.4% of the variance in raw global CBF. Correlations were computed between the region weights in the patterns obtained here and the weights in the three patterns obtained in a previous study of larger and independent samples of depressed patients and normal control subjects (Sackeim et al., 1990). The first SSM-derived pattern (SSF0 in both studies described a similar topography (r = 0.81; df= 30; P < 0.0001) and reflected a classic anteroposterior dimension, with higher CBF in selective frontal and anterior temporal regions than in more posterior regions (Fig. 1). The second pattern to emerge in this study had similar weights to the third pattern in our earlier study (r = 0.63; df= 30; P < 0.0001). In the present study, this pattern reflected a complex pattern of lateral asymmetries,

E. Rubin et al. / Psychiatry Research." Neuroimaging 61 (1995) 1-10

~,.I

I I

2.8

2.6 2.4 2,2

--

2.0

Fig. 1. Illustration of region weights on the first topographic pattern identified in the 32-region analysis using the Scaled Subprofile Model. This pattern reflected an anteroposterior gradient, with higher cerebral blood flow in frontal and anterior temporal regions. Table 2 presents the scores of the groups on this pattern (Subprofile Scaling Factor 1).

most marked in temporal and parietal cortex. The third-emerging pattern in this study resembled the second pattern in our prior investigation (r = 0.80; df= 30; P < 0.0001). In the earlier study and subsequent work, this pattern was found to be abnormally expressed in patients with major depressive disorder (Sackeim et al., 1990, 1993). This pattern reflected CBF reductions in selective frontal, superior temporal, and anterior parietal regions. The ANCOVAs conducted on subject scores on each of these networks revealed a significant main effect of diagnostic group for the first pattern ( F = 3.63; df= 2, 25; P < 0.05) (Table 2: SSFI, 32-region analysis). Post hoc comparisons, using t tests on least-squares adjusted means, indicated that normal control subjects differed from depressed patients (P < 0.02) and tended to differ from

manic patients (P = 0.07), while the clinical groups did not differ. Relative to both clinical groups, normal control subjects had an accentuated pattern of higher CBF in anterior cortical regions. This effect was further tested by computing ratios of the average CBF in the 10 frontal regions relative to the average in the 22 remaining posterior regions. An ANCOVA on these anterior/posterior ratio scores also produced a main effect of diagnostic group ( F = 4.37; df= 2, 25; P = 0.02). Post hoc comparisons indicated that normal control subjects had higher frontal ratio scores than either manic patients (P = 0.008) or depressed patients (P = 0.08), and the two clinical groups did not differ. The ANCOVAs conducted on subject scores on the remaining two networks from the 32-region

E. Rubin et al. / Psychiatry Research: Neuroimaging 61 (1995) 1-10

analysis did not produce effects involving diagnostic group. When subjects were scored for their loading on the "depression profile", as identified in previous research (Sackeim et al., 1990), there were also no significant effects involving diagnostic groups (P = 0.12). However, as indicated in Table 2, normal control subjects and manic patients had the most extreme scores on this profile, with depressed patients being intermediate. Comparison of normal control subjects and manic patients in covariate-adjusted means suggested that this difference may have been reliable (t = 2.11, df= 20, P < 0.05).

3.3. Laterality effects: SSM SSM was also applied to the laterality ratio scores (left/right for each of 16 paired regions). Three networks were identified. The networks accounted for 41.8% of the variability that was subject, region, and asymmetry dependent. The ANCOVAs conducted on the subject scores on these asymmetry patterns yielded a marginal main effect of group for the second network (F = 3.31; df= 2, 25; P = 0.05). No other effects involving group approached significance. Each of the three laterality networks was complex, involving shifting patterns of asymmetry (left > right or right > left) that varied on a regional basis, within a given brain lobe. For example, of the six frontal and anterior temporal regions, four loaded highly on the second laterality pattern, with two regions characterized by greater flow in the left hemisphere and two regions characterized by greater flow in the right hemisphere. Post hoc comparisons of subject scores on the second laterality network indicated that depressed patients differed significantly from normal control subjects (P < 0.05), while manic patients tended to differ from normal subjects (P = 0.07), and the two clinical groups did not differ from each other. To help clarify regional contributions to the group differences on the second laterality network, ANCOVAs were conducted on the difference scores (left - right) at the 16 brain regions. The groups differed only at a detector over the inferior frontal cortex (F = 5.43; df= 2, 25; P = 0.01). In this region, depressed patients had higher CBF in the right than in the left hemisphere, whereas

manic patients and normal control subjects showed the opposite pattern. Post hoc comparisons indicated that the depressed patients differed from the other two groups (P's _< 0.008). 4. Discussion

We used two statistical approaches to compare global and regional CBF in relatively young, minimally medicated manic, depressed, and normal adults. There were only 11 subjects per group, severely limiting statistical power. On the other hand, this study focused on the largest sample of minimally medicated manic patients yet to be included in a functional brain-imaging study. We used traditional multivariate statistics as well as SSM, a procedure designed to separate global from topographic effects and to score individuals in their manifestations of multiple topographic patterns. The groups did not differ in global CBF or in GSF (SSM's measure of global effects stripped of the contributions of topographic patterns). The traditional multivariate statistical approach also failed to reveal group differences in topographic effects. While there was a suggestion that the groups differed in laterality effects averaged across hemispheres, this suggestion was not sustained by within-group or discrete between-group comparisons. Furthermore, the groups did not differ in GSF when SSM was applied to regional laterality ratios. In this context, the GSF corresponds to a global measure of hemispheric differences, stripped of the influence of topographic variation in laterality patterns. The SSM analysis applied to the 32 regional values indicated that both clinical groups had reduced manifestations of an anteroposterior gradient. Compared with normal control subjects, the clinical samples had reduced CBF in selective frontal and anterior temporal regions relative to more posterior regions of the cortex. These regional changes diminished the normal degree of hyperfrontality, an effect confirmed by deriving a traditional measure of hyperfrontality: the ratio of CBF in frontal regions to the rest of the cortex. When SSM was applied to the analysis of laterality differences at 16 homologous brain regions, there was

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E. Rubin et al./Psychiatry Research: Neuroiraaging 61 (1995) 1-10

an indication that both clinical groups were abnormal in manifestation of a specific laterality pattern. This pattern was complex and involved shifting laterality gradients in frontal and anterior temporal cortex. The only indication to emerge in this study that manic and depressed patients differed from each other in cortical CBF patterns was an exploratory analysis of laterality effects at each of the 16 homologous brain regions. There was a suggestion that at a particular inferior frontal region depressed patients were characterized by higher CBF on the right, while both manic patients and control subjects had higher relative CBF in the left homologous region. A recent report on five patients with primary mania noted a similar finding, with left > than right rCBF for the temperobasal region (Migliorelli et al., 1993). The apparent discrepancy between our studies in regional localization may reflect differences in scanning and analytic procedures. Metabolic abnormalities in the inferior frontal cortex have also been previously noted in depression, though the sign and lateralization of this effect remains controversial (e.g., Mayberg et al., 1990; Bromfield et al., 1992; Drevets et al., 1992). A major limitation of our study was the use of the lateral probe technique, which only quantifies cortical rCBF, with limited spatial resolution (Sackeim et al., 1990; Nobler et al., 1994). This study constitutes the first attempt to identify independent sets of laterality covariance patterns in functional imaging data. The statistical validity of the patterns that we obtained with SSM was underscored by the proportion of variance they accounted for that was subject, brain region, and asymmetry dependent. Perhaps a surprising result of this analysis was the fact that each of the three laterality patterns to emerge involved complex, shifting mosaics, with the direction of lateralized effects often reversing in neighboring brain regions. Such an outcome clearly needs to be studied within larger normal control samples, but it suggests that lateralization of functional activity in the resting state is complex and that attempts to characterize lateralized differences in terms of hemispheres or even lobes may be inappropriate. One caveat in the interpretation of our findings is that the CBF measurement procedure may itself

generate anxiety and, as a consequence, alter resting CBF values (reviewed in Mathew and Wilson, 1990). CBF changes related to the anxiety generated by procedures similar to ours have been noted with normal subjects (Risberg et al., 1977; Warach et al., 1987). Such effects are typically associated with the first exposure to the laboratory setting and are detected as mild global elevations of cortical CBF. In our study, global CBF and its counterpart in SSM, GSF, did not differ significantly across the diagnostic groups. Our global values might have concealed the combined effects on CBF due to mood disorder and state anxiety. However, if greater anxiety is assumed to have occurred in the patient groups, the elimination of global elevations due to anxiety would only accentuate our regional findings, which primarily reflected rCBF decreases. Moreover, SSM explicitly separates global effects from regional determinations. It is also possible that patients with different mood disorders could experience different levels of acute anxiety in response to the laboratory setting, potentially confounding attempts to describe CBF changes as characteristic of the depressed or manic state. To our knowledge, this possibility has not been studied, nor is there a reliable means of measuring anxiety in the setting of manic agitation. It is noteworthy, however, that except for one agitated manic patient who nonetheless completed the measurement, anxiety in our subjects was rated as mild to moderate, and all cooperated with the procedure. Our capacity to detect topographic abnormalities was greater with application of SSM than with a traditional multivariate approach. Particularly under low power circumstances, this advantage of SSM may reflect its attempt to first isolate consistent topographic effects before inquiring whether groups differ in manifesting these patterns. In contrast, the traditional approaches determine whether there are consistent group differences in mean profiles under circumstances where there is considerable random variability in regional values. Overall, the basic findings of this study suggest that manic and depressed patients do not differ in global CBF. A variety of investigators have suggested that rCBF or rCMR~I u is reduced in anterior cortical regions of patients with major

E. Rubin et al. / Psychiatry Research: Neuroimaging 61 (1995) 1-10

depression (Baxter et al., 1985, 1989; Martinot et al., 1990), who are characterized by flattened manifestation of an anteroposterior gradient (Buchsbaum et al., 1984, 1986). The fact that we obtained a similar deficit in patients studied while they were in manic episodes suggests that this functional abnormality may be common to severe mood disorders, independent of the valence of the affective state. Similarly, the SSM identification of an abnormal laterality pattern suggested commonality across depressed and manic states. When we compared the previously identified "depression profile" observed in elderly unipolar and bipolar patients in episodes of major depression to the topographic abnormalities studied here, we found indications that young bipolar manic patients may be similarly abnormal in manifestation of this pattern. These results suggest that similar abnormalities of cortical rCBF may characterize patients in both depressed and manic states. Determining whether such abnormalities reflect state or trait disturbances is a critical issue. In previous work, we found that the abnormal "depression profile" was stable when patients were studied both in depressed and euthymic states (Nobler et al., 1994). If the same pattern pertains to manic patients, this abnormality may constitute a general trait marker of severe mood disorder in both unipolar and bipolar patients. Whether such apparently stable cortical flow abnormalities in mood disorders are associated with anatomical or functional abnormalities of subcortical structures described in similar patient samples (e.g., Krishnan et al., 1992) remains to be explored. Acknowledgments This research was supported in part by grants from the National Institute of Mental Health (MH-35636), the Dana Foundation, and the National Alliance for Research in Schizophrenia and Depression (NARSAD). We thank Amy Wu, M.D., for assistance with the data analyses. References Baxter, L., Phelps, M., Mazziotta, J., Schwartz, J., Gerner, R.,

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Selin, C. and Sumida, R. (1985) Cerebral metabolic rates for glucose in mood disorders. Arch Gen Psychiatry 42, 441-447. Baxter, L., Schwartz, J., Phelps, M., Mazziotta, J., Guze, B., Selin, C., Gerner, R. and Sumida, R. (1989) Reduction of prefrontal glucose metabolism common to three types of depression. Arch Gen Psychiatry 46, 243-250. Blackburn, I., London, J. and Ashworth, C. (1977) A new scale for measuring mania. Psychol Med 7, 453-458. Bromfield, E., Altshuler, L., Leiderman, D., Balish, M., Ketter, T., Devinsky, O., Post, R. and Theodore, W. (1992) Cerebral metabolism and depression in patients with complex partial seizures. Arch Neurol 49, 617-623. Buchsbaum, M.S., DeLisi, L.E., Holcomb, H.H., Cappelletti, J., King, A.C., Johnson, J., Hazlett, E., DowlingZimmerman, S., Post, R.M., Morihisa, J., Carpenter, W., Cohen, R., Pickar, D., Weinberger, D.R., Margolin, R. and Kessler, R.M. (1984) Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders. Arch Gen Psychiatry 41, !159-1166. Buchsbaum, M.S., Wu, J., DeLisi, L.E., Holcomb, H., Kessler, R., Johnson, J., King, A.C., Hazlett, E., Langston, K. and Post, R. (1986) Frontal cortex and basal ganglia metabolic rates assessed by positron emission tomography with [laF]2-deoxyglucose in affective illness. J Affective Disord 10, 137-152. 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, 3628-3641. Endicott, J. and Spitzer, R. (1978) A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35, 837-844. Hamilton, M. (1967) Development of a rating scale for primary depression. Br J Soc Clin Psychol 6, 278-296. Kishimoto, H., Takazu, O., Ohno, S., Yamagnchi, T., Fujita, H., Kuwahara, H., Ishii, T., Matsushita, M., Yokoi, S. and Iio, M. (1987) IIC-glucose metabolism in manic and depressed patients. Psychiatry Res 22, 81-88. Krishnan, K., McDonald, W., Escalona, P., Doraiswamy, P., Na, C., Husain, M., Figiel, G., Boyko, O., Ellinwood, E. and Nemeroff, C. (1992) Magnetic resonance imaging of the caudate nuclei in depression. Arch Gen Psychiatry 49, 553-557. Martinot, J.L., Hardy, P., Feline, A., Huret, J.D., Mazoyer, B., Attar-Levy, D., Pappata, S. and Syrota, A. (1990) Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am J Psychiatry 147, 1313-1317. Mathew, R.J. and Wilson, W.H. (1990) Anxiety and cerebral blood flow. Am J Psychiatry 147, 838-849. Mayberg, H.S., Starkstein, S E., Sadzot, B., Preziosi, T., Andrezejewski, P.L., Dannals, R.F., Wagner, H.N. and Robinson, R.G. (1990) Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson's disease. Ann Neurol 28, 57-64. Migliorelli, R.; Starkstein, S., Teson, A., de Quiros, G., Vazquez, S.E., Leiguarda, R. and Robinson, R.G. (1993)

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