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Increased prefrontal sulcal prominence in relatively young patients with unipolar major depression
PSYCHIATRY RESEARCH NEUROIMAGING ELSEVIER
Psychiatry Research: Neuroimaging67 (1996) 123-134
Increased prefrontal sulcal prominence in relatively young patients with unipolar major depression H e l i o Elkis a, L e e F r i e d m a n *b, P e t e r F. B u c k l e y h, H o n g S h i c k L e e c, C h r i s t i n e L y s b, B e n j a m i n K a u f m a n d, H e r b e r t Y . M e l t z e r b aDepartment of Psychiatry, University of Sao Paulo School of Medicine and Hospital do Servidor Publico Estadual, Sao Paulo, Brazil bDepartment of Psychiatry, Case Western Reserve University School of Medicine, Hanna Pavilion, First Floor Mail Room, 11100 Euclid Ave., Cleveland, OH 44106-5000, USA CDepartment of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea dDepartment of Radiology, Case Western Reserve University School of Medicine, Cleveland. OH. USA
Received 31 July 1995; revised 8 September 1995; accepted 8 October 1995
Abstract
Although several studies have reported ventricular enlargement and sulcal prominence in mixed samples of patients with affective disorders (unipolar and bipolar subtypes), it is not established if these findings extend to a homogeneous sample of relatively young patients with unipolar major depression ventricular:brain ratio (VBR) and prefrontal sulcal prominence (PSP). In the present study, measures of ventricle-brain ratio (VBR) and prefrontal sulcal prominence (PSP) were compared in patients with affeetive disorders (n = 24, mean age = 39), medical control subjects (n = 40), patients with schizophrenia (n = 101) on ventricular : brain ratio (VBR) and prefrontal sulcal prominence (PSP). No statistically significant differences were noted in VBR in the three groups. Both patient groups had significantly greater PSP than the medical control subjects but did not differ significantly from each other. The results of the present study extend the finding of prefrontal sulcal prominence, but not ventricular enlargement, to relatively young patients with unipolar depression. Furthermore, the results of the present study suggest that patients with schizophrenia and patients with affective disorders differ only slightly or not at all in brain morphology, at the level of resolution studied. Keywords: Affective disorder; Computed tomography; Schizophrenia; Ventricle-brain ratio
1. Introduction
It is well established that patients with schizophrenia have higher rates of ventriculomegaly and/or sulcal widening than do normal control subjects (for review, see Shelton and * Corresponding author, Tel.: +1 216 844-7485;fax: +1 216 844-7484.
Weinberger, 1986; Raz and Raz, 1990; Van Horn and McManus, 1992; Elkis et al., 1995). It is less well appreciated that many studies have reported ventricular enlargement and sulcal widening in affective disorders (for review, see Nasrallah et ai., 1989; Raz and Raz, 1990; Schlegel, 1991), suggesting that these types of abnormalities are not specific to schizophrenia. However, the majority of brain-imaging studies in affective disorders have
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been performed in mixed samples of patients with bipolar and unipolar disorders (Schlegel, 1991), and many studies are based on samples of patients over 50 years of age (Nasrallah et al., 1989). Thus, it is unclear if the finding of ventricular enlargement or sulcal widening extends to homogeneous groups of relatively young patients with unipolar depression (Nasrallah et al., 1990). Clarification of this question might have both clinical and theoretical implications, since unipolar depression is more common than bipolar depression (Weissman et al., 1991) and is usually thought of as a less severe form of depression. Furthermore, studies in young patients may be more easily interpretable than those in older patients, because they are less confounded by the effects of age (Murphy et al., 1992). The purpose of the present study was to compare a group of relatively young patients with unipolar major depression to nonpsychiatric controls and patients with schizophrenia on measures of ventricular enlargement and suleal widening. Our hypothesis was that the unipolar patients would show significantly more ventricular enlargement and sulcal widening than the control subjects, but that these abnormalities would be less pronounced than those in patients with schizophrenia.
2. Methods
2.1. Subjects Patients with unipolar major depression (n = 25), patients with schizophrenia (n = 110), and medical control subjects (n = 40) were compared on computed tomographic (CT) measures. CT scan studies were completed when the patients were inpatients at University Hospitals of Cleveland. Diagnoses were made according to DSM-III-R criteria (American Psychiatric Association, 1987) and were based on interviews that used the Schedule for Affective Disorders and Schizophrenia, Lifetime Version (Endicott and Spitzer, 1978), supplemented with additional questions from the Present State Examination (Wing et al., 1974). All diagnoses were made by consensus of a psychiatrist and other research personnel who collected the clinical data. Patients were excluded
if they had a current (within 6 months of study date) history of alcohol or drug abuse, or recent (within 6 months) exposure to electroconvulsive therapy. Subjects were excluded if they had a lifetime history of major systemic or neurological disorders that might affect the brain. None of the patients had been treated with steroids. All patients were between 18 and 65 years old. Of the 110 patients with schizophrenia and the 25 patients with unipolar depression who met the criteria mentioned above, nine patients with schizophrenia and one patient with unipolar major depression had specific abnormalities detected on CT scan examination (detailed below). The 10 patients with specific CT abnormalities were excluded from the main analysis, but their CT measurements are reported separately. A number of patients and control subjects had generalized findings on CT examination, such as 'ventricles mildly enlarged' or 'prominence of the sulci and fissures over the convexities, which is unusual for age'. Subjects (including controls, see below) with such findings were not excluded from the main analysis. For the main analysis, the patient sample consisted of 24 patients with unipolar major depression (8 males, 16 females) and 101 schizophrenics (73 males, 28 females). The mean (SD) age of the unipolar depressed patients was 38.7 (12.8) years, and the mean age of the schizophrenic patients was 32.0 (7.9) years. The patients with unipolar major depression had been ill for 9.0 (8.3) years, and the patients with schizophrenia had been ill 12.1 (6.7) years. The mean age at onset of illness for the unipolar depressed patients was 29.7 (11.6) years, whereas the mean age at onset for the schizophrenic patients was 19.9 (4.5) years. The medical control subjects presented to the emergency room of University Hospitals of Cleveland with the complaint of headache (n = 35), vertigo (n = 2) or symptoms of viral infection (n = 3). The mean age of the control group was 33.3 (10.4) years. No trauma patients (ineluding head trauma, of course) were included. All subjects (17 males, 23 females) had a complete physical examination and full blood laboratory tests at the time of CT scan. Only patients with
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normal blood laboratory results and normal physical examination were included. The medical charts of these subjects were reviewed and subjects were screened according to the same criteria as the psychiatric patients. All procedures were undertaken after subjects provided written consent. 2.2. CT scan measurements The CT scanner was a Siemens Somatom DR-H fourth generation scanner with a resolution matrix of 512 × 512 pixels and 960 projections per slice. Scan slices were 15° to the canthomeatal line at a thickness of 8 mm per slice. The window setting through the brain was 84 with a center of 35. After the interrater reliability study, which involved two raters (L.F. and C.L.), all CT measurements were made by a single rater (C.L.), who was unaware of subjects' diagnoses during the rating. 2.2.1. Ventricular measurements. Measurements of ventricle-brain ratio (VBR) were made with a compensating polar planimeter (Keuffel and Esser Co., Germany). The instrument was calibrated when the study began and checked repeatedly throughout the study. We used the method of Synek and Reuben (1976), as modified by Shelton et al. (1988). Measurements were made where the bodies of the lateral ventricles were most prominent. Since the planimeter is less accurate in measuring small structures, such as the body of lateral ventricles, the areas of the left and right bodies of the lateral ventricles were measured 10 times and averaged. The whole brain area was measured once. The left and right ventricular body measurements were added together, divided by the total brain area, and multiplied by 100 to give the VBR measurement. Each VBR was rated on two separate occasions; each rating was done without knowledge of the other rating. The final measure was the average of the two ratings. If the first two ratings differed by more than 30%, then the VBR was rated a third time, and the two closest measurements were averaged for a final VBR. An interrater reliability study was conducted with two raters measuring 23 scans. The intraclass correlation coefficient (ICC) (Bartko and Carpenter, 1976) was 0.93 (P < 0.001).
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2.2.2. Prefrontal sulcal prominence ratings. The degree of prefrontal sulcal prominence (PSP) was rated with an extensively modified version of the method previously used by our group (Friedman et al., 1991). That method was based on the method of Shelton et al. (1988). The purpose of the modifications was to enhance the objectivity of the rating and thus increase interrater reliability. Fig. 1 illustrates the rating levels, and Table 1 lists the criteria. The first step in the rating was to find the slice with the foramen of Monro. The foramen should be visibly connected to the frontal horns of the lateral ventricles. If the foramen of Monro was equally visible on two slices, the slice with the best representation (largest width) of the third ventricle was chosen for rating. The PSP was rated on the frontal cortical surface, anterior to the sylvian fissures bilaterally. The next step was to count the number of clearly visible sulci in the frontal area. If three or more sulci were clearly evident, then the PSP rating was > 1.0, and additional measurements, described below, were required. Otherwise, the PSP was 0.0 if there was no evidence of sulci in the frontal area or 0.5 if one or two sulci were clearly evident and all gyral surfaces were in contact with the skull. If the PSP was > 1.0, then the curved circumference of the frontal cortex between the left and right sylvian fissures was measured in mm with a flexible ruler (Alvin). The next step involved an assessment of the amount of frontal cortical tissue that was pulled away from the skull. A measuring magnifier (7 ×, Bausch and Lomb, Cat. No. 81-34-35) was used to measure the number of mm of each portion of the circumference pulled away. Any gyral surface that was clearly pulled away from the skull was included in the measurement. Skull portions that were over sulci were not considered for this measurement. Thus, the goal was to measure the number of mm of gyral surface pulled away from the skull. Next, the total number of mm of gyral surface (from all frontal gyri) pulled away (discontinuous) from the skull was summed. Finally, the percentage of the total curved circumference of the frontal cortex that was discontinuous to the gyral surface was computed. If this percentage was -~ 5%, the PSP score was 1.0. If the percentage was >5% and <20%, then the PSP score was 1.5. If
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Fig. 1. Illustration of the prefrontal sulcal prominence rating scale.
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Table 1 Brief description of the prefrontal suleal prominence rating scale Rating level
0.0 0.5 1.0 1.5 2.0 2.5 3.0
Description Sulci clearly visible
Gyral surface discontinuous with skull
None 1 or 2 >3 >3 >3 >3 >- 3
--<5% > 5% and < 20% > 20% and < 50% >50% and < 100% 100%
the percentage pulled away was > 20% and _<50%, then the PSP score was 2.0. If the percentage pulled away was > 50%, but < 100%, then the PSP score was 2.5. If 100% of the gyral surface was discontinuous with the skull, then the PSP score was 3.0. Each scan was rated twice by a single rater (C.L.) on separate days. The second rating was done without knowledge of the first. If the scores were >0.5 scale units apart, then the scans were rated a third time. The two ratings that were within 0.5 scale units were chosen. The final PSP score was the average of the two ratings. The ICC for two raters and 20 scans for PSP was 0.83.
2.3. Statistical analysis The first step in the analysis was the determination of the appropriateness of parametric statistics, including normality of distributions and homogeneity of variance across groups. It was concluded that a parametric analysis was appropriate. (The age distributions were skewed and were log-transformed.) Diagnostic differences and gender effects were tested with two-factor analysis of covariance (ANCOVA) with age as a covariate. Since the sample sizes of the cells in the ANCOVA were not balanced, the method of unweighted means was used for F tests (Searle, 1987). Post hoc comparisons were evaluated with the Scheff6 test. Correlational analyses used Spearman rank-order correlation coefficients (rs). All P values are two-tailed. Outliers were identified according to a standard
algorithm (SPSS, 1989). Subjects with values 1.5 x the interquartile range above the 75th percentile, or 1.5 x the interquartile range below the 25th percentile were considered as outliers. 3. Results
3.1. Age The diagnostic groups differed significantly in age (log-transformed) at the time of the CT scan ( F = 3.53, df= 2,162, P = 0.031). Post hoc tests revealed that the group of patients with unipolar major depression was significantly older than the group of patients with schizophrenia (P < 0.05). No other group differences were significant. Since age affects brain structure (Murphy et al., 1992), age was included as a covariate in all subsequent analyses.
3.2. Gender In the medical control group, 43% of the subjects were male; in the schizophrenic group, 72% of the subjects were male; and in the affective group, 33% of the subjects were male. There were significantly more males in the schizophrenic group than in either the medical control group (x 2 = 11.00, df= 1, P = 0.0009) or unipolar major depression group (X2 = 12.90, df= 1, P = 0.0003). The medical control group and the unipolar major depression group did not significantly differ on gender (X2 = 0.53, df= 1, P = 0.47). To control for gender effects, gender was included as a factor in the test of the effect of diagnosis.
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H. Elkis et al./ Psychiatry Research: Neuroimaging 67 (1996) 123-134
CONTROLS
3.3. Test of the diagnosis effect Figs. 2 and 3 provide histograms of VBR and PSP, respectively, for each group. The effects of diagnosis, gender, and their interaction were tested in a 3 x 2 analysis of covariance with age as a covariate. Table 2 presents the results. Age was a significant covariate for VBR but not for PSP. There were no significant diagnosis, gender, or interaction effects for VBR. Two controls and three patients with schizophrenia, all with VBR values > 12.0, were classified as outliers. After removal of these five subjects, the diagnosis effect was still not significant for VBR ( F = 1.97, df= 2,153, P = 0.143). For PSP, the diagnosis effect was highly significant, but the gender effects and the interaction were not significant. Post hoc tests revealed that both patient groups had significantly elevated PSP compared with the medical control group (P < 0.02), but the two patient groups were not
P E R C E N X
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significantly different (P = 0.92). The diagnosis factor accounted for 8.4% of the variance in PSP. The two patients with schizophrenia who had very low PSP scores (0.0 and 0.25) were classified as outliers with the SPSS algorithm. As would be expected upon examination of Fig. 3, removal of these subjects resulted in the schizophrenia group becoming more unlike the control group and more like the affective disorders group. Thus, the pattern of results that emerged with these subjects included was strengthened after their removal (diagnosis effect before removal: F = 7.41, df= 2,158, P = 0.001; diagnosis effect after removal: F = 8.47, df= 2,156, P < 0.001). The diagnosis effect on PSP was also tested with a dichotomous analysis. Subjects were divided into those with a PSP rating _<1.25 (low PSP) and those with a PSP rating > 1.25 (high PSP). The proportion of subjects with high PSP for each group was as follows: 0.28 (medical controls), 0.59 (patients with schizophrenia), and 0.67 (patients
1.02 (0.52)
Mean PSP (SD)
0.91 (0.55)
5.52 (2.43) 1.33 (0.49)
6.32 (2.61) 1.28 (0.40)
6.11 (2.22) 1.38 (0.58)
5.31 (1.64)
Males (n = 8)
!.39 (0.51)
6.65 (1.84)
Females (n = 16)
Unipolar depression (n = 24)
Note. VBR, ventricle-brain ratio; PSP, prefrontal sulcal prominence. *P < 0.05; **P < 0.001.
5.56 (2.84)
Mean VBR (SD)
Females (n = 28)
Males (n = 73)
Males (n = 17)
Females (n = 23)
Schizophrenia (n = 101)
Medical controls (n = 40)
Table 2 Analysis of diagnosis, gender, and age effects on VBR and PSP
F
(df= 1,158) 5.42* 2.97
F
(df = 2,158) 0.78 0.04
F
(df= 1,158) 0.35 0.39
F
(df = 2,158) 1.12 7.41"*
Age as covariate
Diagnosis x gender interaction Gender
Diagnosis
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with affective disorders). Both patient groups had significantly more subjects with high PSP than did the control group (P < 0.005), but the patient groups did not differ from one another. Finally, the difference between patients with affective disorder and control subjects on PSP was tested with one additional analysis, designed to remove any doubt about the contribution of age to the effect. As noted above, the patients with affective disorders were not statistically significantly older (mean = 38.7 years, SD = 10.4) than the controls (mean = 33.3 years, SD = 12.8), but there was a trend for them to be older (t =-1.84, df= 62, P = 0.071). For the final analysis, the three oldest patients with affective disorder and the three youngest control subjects were excluded. Now the mean ages of the two groups were very close (patients: mean = 35.3 years, SD = 9.6; controis: m e a n = 3 4 . 4 years, S D = 10.1), and no statistical trend toward a mean difference was apparent (t =-0.34, df= 56, P = 0.734). The PSP scores of these two more closely matched groups were compared with a t test. The mean PSP in the affective disorder group (1.37, SD = 0.55) was significantly elevated compared with that in the control group (0.94, SD = 0.53; t = -2.9, df= 56, P = 0.005). This confirms that the differences between the affective disorder group and the control group were not related to any age difference.
3.4. Within-group correlations between age, age at onset, duration of illness, and PSP To examine further the significance of increased PSP in the clinical populations, we correlated PSP with age, age at onset, and duration of illness within each diagnostic group. A significant correlation was noted in the unipolar major depression group between PSP and age (rs = 0.45, P = 0.027). After Bonferroni correction for multiple correlations, this correlation was not statistically significant. No other significant correlations were noted in the affective disorder group. In the group of patients with schizophrenia, no significant correlations were noted.
and one of 25 (4%) patients with unipolar major depression had specific CT abnormalities. The following specific abnormalities were noted in patients with schizophrenia: vermian cerebellar abnormality (possible Dandy-Walker variant malformation) (n = 2); focal cerebellar signal attenuation (n = 1); extensive calcification of the falx (n = 2); hyperostosis of skull with extensive calcification of the falx (n = 1); dural calcification in the frontal-parietal convexity (n = 1); habenular commissure calcification (n = 1); and malformation of the auditory canals and cochlea (n = 1). One patient with unipolar major depression had a CT image compatible with empty sella. The rates in the two populations did not differ significantly (X2 = 0.52, df= 1, P = 0.47). The CT measures (VBR and PSP) of the nine schizophrenic patients with specific abnormalities were compared with those of the 101 schizophrenic patients without such abnormalities. The two groups were not significantly different on VBR (t = -1.23, df= 8.44, P = 0.25; separate variance estimates) or PSP (t = -0.77, df= 108, P = 0.44).
3.6. Generalized findings on CT examination Patients with clinical evaluations that noted generalized parenchymal loss or sulcal enlargement were included in the main analyses above. To assess the sensitivity of clinical CT evaluation, we also compared the rates of clinical generalized findings in the three diagnostic groups. In the group of medical controls, 8 of 40 (20%) subjects had generalized findings; in patients with schizophrenia, 50 of 101 (50%) had such findings; and in the group of patients with unipolar major depression, 4 of 24 (17%) had such findings. The rate for patients with schizophrenia was significantly higher than that in either medical controls (X2 = 10.3, df= 1, P = 0.001) or patients with unipolar major depression (X2 = 8.52, df= 1, P = 0.004). The rate in medical controls was not significantly different from that in patients with unipolar major depression (x2=0.11, df= 1, P = 0.74). 4. Discussion
3.5. Specific abnormalities on CT examination in the patient groups Nine of 110 (8%) patients with schizophrenia
The main finding of the present study was that relatively young patients with unipolar major de-
H. Elkis et al. / Psychiatry Research: Neuroimaging 67 (1996) 123-134
pression had increased PSP compared with controis. PSP was also increased in the schizophrenic patients relative to the controls, and the degree of PSP in the two patient groups did not differ. Although the finding of increased cortical sulcal prominence has been reported in patients with affective disorders generally, to our knowledge this is the first report of increased prefrontal sulcal prominence in a relatively young and homogeneous sample of patients with unipolar major depression. Coffey et al. (1993a) did control for age in their study, and reported decreased frontal lobe volume in depressed patients. However, the mean age of the patient group in their study was 61.3 years. The present findings, in a younger group of patients, more convincingly demonstrate that such abnormalities are not secondary to age and do not result from an interaction between age and diagnosis. As pointed out by Jeste et al. (1988), some investigators have assumed or promoted the notion that affective disorders are merely 'functional' abnormalities, without any 'organic' substrate. The findings of the present study do not support this notion. There has been a suggestion that the outcome of studies such as that presented here is influenced, in an important way, by the nature of the control group (Iacono et al., 1988; Smith et al., 1988). Iacono et al. (1988) and Smith et al. (1988) found different results in comparisons in which patients with schizophrenia were compared with 'medical' controls versus normal controls recruited from the community. They hypothesized that this may be due to the fact that medical control scans are typically screened for a normal evaluation. This would tend to decrease the VBR in the control group, and artifactually increase the differences between patients and controls. Although the present study employed a medical control group, the scans were not screened for the presence of global structural abnormalities, so there was no risk of such a bias. Furthermore, two meta-analyses failed to find any influence of this factor in studies of schizophrenia (Raz et al., 1988) or affective disorders (Elkis et al., 1995). Finally, this factor would tend to create an artificial significant difference between patients and controls, but in the present study, no significant difference in VBR was noted.
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The present finding of increased sulcal prominence should be interpreted in light of the fact that increased sulcal prominence is also reported in other neurologic or psychiatric conditions such as Alzheimer's dementia (Fazekas et ai., 1989; Burns et al., 1991), Huntington's Disease (Starkstein et al., 1989), bulimia (Krieg et al., 1987), anorexia nervosa (Krieg et al., 1988), alcoholism (Lishman, 1990), and benzodiazepene abuse (Schmauss and Krieg, 1987). Thus, from a diagnostic viewpoint, the finding is nonspecific. Also, from an anatomical viewpoint the present finding is nonspecific, as only two brain areas were measured, the areas were quite large, and the results were based on CT rather than higher resolution magnetic resonance imaging (MRI). Furthermore, although the diagnosis effect on PSP was statistically significant, diagnosis accounted for < 10% of the variance in PSP. Nonetheless, an understanding of the causes of this increase in sulcal fluid space may provide additional insights into the pathophysiology and pathomorphology of depression. One possibility is that increased suical prominence is a reversible state-related phenomenon in affectiv¢ disorders (Nasrallah et al., 1989). Reversibility of global structural changes has been established in certain conditions, such as alcoholism (Ron et al., 1982), anorexia nervosa (Kohlmeyer et al., 1983; Artmann et al., 1985), and bulimia (Krieg et al., 1987). However, the mechanisms underlying these reversible structural changes have not been identified. Kellner et al. (1983) hypothesized that ventricular enlargement or sulcal prominence may result from hypercortisolemia secondary to abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis in depression. This notion is supported by findings such as positive correlations between VBR and urinaryfree cortisol (Schlegel et al., 1989), plasma cortisol (Schlegel et al., 1989), and postdexamethasone cortisol concentrations (Rao et al., 1989). However, in a recent and directly relevant study, which included serial MRI scans and dexamethasone suppression tests, Coffey et al. (1993b) found no evidence linking structural abnormalities to hypercortisolemia in depression. Alternatively, the structural abnormalities in affective disorders may reflect hypoplasia, dysplasia,
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permanent brain damage, or some combination thereof. These possibilities are currently under active investigation in schizophrenia research (O'CaUaghan et al., 1992; Cannon et al., 1993). The same strategies may need to be applied in affective disorders (Nasrallah, 1991). There is evidence that depression can result from brain damage. It has been associated with stroke (Schwartz et al., 1993), tumor, and head injury (Jeste et al., 1988). The finding of increased PSP in affective disorders is consistent with the recent finding of Coffey et al. (1993a) that inpatients with depression have a reduced frontal lobe volume compared with controls. The implication of the frontal lobe in depression is also very consistent with a common underlying prefrontal cortical pathophysiology for schizophrenia and affective disorders, as proposed by Swerdlow and Koob (1987) and Drevets and Raichle (1992). The finding of increased sulcal prominence in patients with affective disorders and schizophrenia is consistent with the notion that these disorders represent points along a pathophysiologic 'continuum'. The continuum model was suggested a number of years ago by Meltzer (1973, 1976), who reported neuromuscular abnormalities (e.g., increased serum creatine kinase activity, skeletal muscle fiber abnormalities, and subterminal motor nerve sprouting) in both schizophrenia and psychotic depression. Subsequently, other biological abnormalities have been found to be present in patients with both types of disorders. For example, abnormalities have been noted in both patient groups in HPA function (Carroll et al., 1968; Kaneko et al., 1992), regional cerebral blood flow (Dolan et al., 1992; Liddle et al., 1992), serum dopamine-B-hydroxylase activity (Meltzer, 1984), sleep (Hudson et al., 1993), and evoked potentials (Wexler, 1992). Furthermore, several previous imaging studies reported ventricular enlargement in both groups, although this was not seen in the present study (Raz and Raz, 1990; Elkis et al., 1995). Crow (1990) has recently proposed a continuum model of mood disorder and schizophrenia based on genetics. In conclusion, the results of the present study suggest that patients with schizophrenia differ from patients with affective disorders only slightly
or not at all in brain morphology, at the level of resolution studied. Whether such similarity is rooted in a common underlying pathophysiology or, alternatively, reflects a similar expression of pathophysiologically distinct processes remains unclear. Further studies of the underlying pathophysiology of these global brain changes are needed to elucidate the clinical and theoretical significance of the findings.
Acknowledgments This research was supported by grants from the National Institute of Mental Health (MH-411684 and MH-415494; Dr. Meltzer), from the National Alliance for Research in Schizophrenia and Depression (Dr. Friedman), from the Scottish Rite Foundation (Dr. Friedman), and from the Prentiss Foundation (Dr. Meltzer). Dr. Meltzer is a recipient of a U.S. Public Health Service Research Career Scientist Development Award (MH47808), and Dr. Elkis is a recipient of a postdoctoral scholarship from CNPq (Brasilia/Brazil).
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H. Elkis et al. I Psychiatry Research: Neuroimaging 67 (1996) 123-134 quantitative cerebral anatomy in depression. Biol Psychiatry 33, 442-449. Crow, T. (1990) The continuum of psychosis and its genetic origins: The Sixty-fifth Maudsley Lecture. Br J Psychiatry 156, 788-797. Dolan, R., Bench, C., Brown, R., Scott, L., Friston, K. and Frackowiak, R. (1992) Regional cerebral blood flow abnormalities in depressed patients with cognitive impairments. J Neurol Neurosurg Psychiatry 55, 768-773. Drevets, W. and Raichle, M. (1992) Neuroanatomicai circuits in depression: implications for treatment mechanisms. Psychopharmacol Bull 28, 261-274. Elkis, H., Friedman, L., Wise, A. and Meltzer, H.Y. (1995) Meta-anaiyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders: comparisons with controls or patients with schizophrenia. Arch Gen Psychiatry 52, 735-746. Endicott, J. and Spitzer, R. (1978) A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35, 837-844. Fazekas, F., Alavai, A., Chawluk, J.B., Zimmerman, R.A., Hackney, D., Bilaniuk, L., Rosen, M., Alves, W.M., Hurtig, H.I., Jamieson, D.G., Kushner, M.J. and Reivich, M. (1989) Comparison of CT, MR, and PET in Alzheimer's dementia and normal aging. J Nucl Med 30, 1607-1615. Friedman, L., Knutson, L., Shurell, M. and Meltzer, H. (1991) Prefrontal sulcal prominence is inversely related to response to ciozapine in schizophrenia. Biol Psychiatry 29, 865-877. Hudson, J., Lipinski, J., Keck, P., Aizley, H., Vucokovic, A., Zierk, K. and Pope, H., Jr. (1993) Polysomnographic characteristics of schizophrenia in comparison with mania and depression. Biol Psychiatry 34, 191-193. lacono, W.G., Smith, G., Moreau, M., Beiser, M., Fleming, J.A.E., Lin, T. and Flak, B. (1988) Ventricular and sulcal size at the onset of psychosis. Am J Psychiatry 145, 820-924. Jeste, D., Lohr, J. and Goodwin, F. (1988) Neuroanatomical studies of major affective disorders: a review and suggestions for further research. Br J Psychiatry 153, 444-459. Kaneko, M., Yokoyama, F., Hoshimo, Y., Takahagi, K., Murata, S., Watanabe, M. and Kumashiro, H. (1992) Hypothaiamic-pituitary-adrenal axis function in chronic schizophrenia: association with clinical features. Neuropsychobiology 25, 1-7. Kellner, C., Rubinow, D., Gold, P. and Post, R. (1983) Relationship of cortisol hypersecretion to brain CT scan alterations in depressed patients. Psychiatry Res 8, 191-197. Kohlmeyer, K., Lehmkuhl, G. and Pontska, F. (1983) Computed tomography of anorexia nervosa. Am J Neuroradiol 4, 437-438. Krieg, J.-C., Backmund, H. and Pirke, K.-M. (1987) Cranial computed tomography findings in bulimia. Acta Psychiatr Scand 75, 144-149. Krieg, J.-C., Pirke, K.-M., Lauer, C. and Backmund, H. (1988) Endocrine, metabolic, and cranial computed findings in anorexia nervosa. Biol Psychiatry 23, 377-387. Liddle, P., Friston, K., Frith, C. and Frackowiak, R. (1992)
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Cerebral blood flow and mental processes in schizophrenia. J R Soc Med 85, 224-227. Lishman, W. (1990) Alcohol and the brain. Br J Psychiatry 156, 635-644. Meltzer, H.Y. (1973) Skeletal muscle abnormalities in patients with affective disorders. J Psychiatr Res 10, 43-57. Meitzer, H.Y. (1976) Neuromuscular dysfunction in schizophrenia. Schizophr Bull 2, 106-135. Meltzer, H.Y. (1984) Serum dopamine-13-hydroxylase activity and lateral ventricular size in affective disorders and schizophrenia. Biol Psychiatry 19, 1395-1402. Murphy, D.G.M., DeCarli, C., Sehapiro, M.B., Rapoport, S.I. and Horwitz, B. (1992) Age-related differences in volumes of subcortical nuclei, brain matter and cerebrospinal fluid in healthy men as measured with magnetic resonance imaging. Arch Neurol 49, 839-845. Nasrailah, H. (1991) Neurodevelopmental aspects of bipolar affective disorders. Biol Psychiatry 29, I-2. Nasrallah, H., Coffman, J. and Olson, S. (1989) Structural brain-imaging findings in affective disorders: an overview. J Neuropsychiatry Clin Neurosci 1, 21-26. Nasrallah, H., Coffman, J. and Olson, S. (1990) CT and MRI findings in affective disorders: clinical and research implications. In: Cazzullo, C., Sacchetti, E., Conte, G., lnvernizzi, G. and Vita, A. (Eds.), Plasticity and Morphology of the Central Nervous System. Kluver Academic Publisher, London, pp. 53-62. O'Callaghan, E., Buckley, P., Redmond, O., Stack, J., Ennis, J. and Waddington, J. (1992) Abnormalities of cerebral structure on magnetic resonance imaging: interpretation in relation to the neurodevelopmental hypothesis. J R Soc Med 85, 227-231. Rao, V.P., Krishnan, K.R.R., Goli, V., Sauders, W.B., Ellinwood, E.H., Blazer, D.G. and Nemeroff, C.B. (1989) Neuroanatomical changes and hypothalamo-pituitaryadrenal axis abnormalities. Biol Psychiatry 26, 729-732. Raz, S. and Raz, N. (1990) Structural abnormalities in major psychosis: a quantitative review of the evidences from computerized images. Psychol Bull 108, 93-108. Raz, S., Raz, N. and Bigler, E.D. (1988) Ventriculomegaly in schizophrenia: is the choice of the controls important? Psychiatry Res 24, 71-77. Ron, M.A., Acker, W., Shaw, G.K. and Lishman, A.W. (1982) Computerized tomography of the brain in chronic alcoholism: a survey and follow-up study. Brain 105, 497-514. Schlegel, S. (1991) Computed tomography in affective disorders. In: Hauser, P. (Ed.), Brain Imaging in Affective Disorders. American Psychiatric Press, Washington, DC, pp. 1-24. Schlegel, S., yon Bardeleben, U., Wiedemann, K., Frommberger, U. and Holsboer, F. (1989) Computerized brain tomography measures compared with spontaneous and suppressed plasma cortisol levels in major depression. Psychoneuroendocrinology i 4, 209-216. Sehmauss, C. and Krieg, J.-C. (1987) Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers. Psychol Med 17, 869-873.
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Schwartz, J.A., Speed, N.M., Brumberg, J.A., Brewer, T.L., Brown, M. and Greden, J.F. (1993) Depression and stroke rehabilitation. Biol Psychiatry 33, 694-699. Scarle, S.R. (1987) Linear Models for Unbalanced Data. Wiley, New York, p. 536. Shelton, R.C., Karson, C.N., Doran, A.R., Pickar, D., Bigelow, L.B. and Weinberger, D.R. (1988) Cerebral structural pathology in schizophrenia: evidence for a selective prefrontal cortical defect. Am J Psychiatry 145, 154-163. Shelton, R.C. and Weinberger, D.R. (1986)X-ray computerized tomography studies in schizophrenia: a review and synthesis. In: Nasrallah, H.A. and Weinberger, D.R. (Eds.), Handbook of Schizophrenia: The Neurology of Schizophrenia. Vol. 1. Elsevier, New York, pp. 207-250. Smith, G.N., Iacono, W.G., Moreau, M., Tallman, K., Beiser, M. and Flak, B. (1988) Choice of comparison group and findings of computerised tomography in schizophrenia. Br J Psychiatry 153, 667-674. SPSS, Inc. (1989)SPSS.PC+ Update for V3.0 and 3.1. SPSS, Inc., Chicago. Starkstein, S.E., Folstein, S.E., Brandt, J., Pearison, G.D., McDonnell, A. and Folstein, M. (1989) Brain atrophy in Huntington's Disease. Neuroradiology 31, 156-159.
Swerdlow, N.R. and Koob, G.F. (1987) Dopamine, schizophrenia, mania, and depression: toward a unified hypothesis of cortico-striato-pallido-thalamic function. Behav Brain Sci 10, 197-245. Synek, V. and Reuben, J.R. (1976) The ventricular-brain ratio using planimetric measurement of EMI scans. Br J Radiology 49, 233-237. Van Horn, J.D. and McManus, I.C. (1992) Ventricular enlargement in schizophrenia: a recta-analysis of studies of the ventricle:brain ratio (VBR). Br J Psychiatry 160, 687-697. Weissman, M.M., Bruce, M.L., Leaf, P.J., Florio, L.P. and Holzer, C. 111 (1991) Affective disorders. In: Robins, L.N. and Regier, D.A. (Eds.), Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. Free Press, New York, pp. 53-80. Wexler, B.E. (1992) Beyond the Kraepelinean dichotomy. Biol Psychiatry 31,539-541. Wing, J.K., Cooper, J.E. and Sartorius, N. (1974) The Measurement and Classification of Psychiatric Symptoms. Cambridge University Press, London.
Psychiatry Research: Neuroimaging67 (1996) 123-134
Increased prefrontal sulcal prominence in relatively young patients with unipolar major depression H e l i o Elkis a, L e e F r i e d m a n *b, P e t e r F. B u c k l e y h, H o n g S h i c k L e e c, C h r i s t i n e L y s b, B e n j a m i n K a u f m a n d, H e r b e r t Y . M e l t z e r b aDepartment of Psychiatry, University of Sao Paulo School of Medicine and Hospital do Servidor Publico Estadual, Sao Paulo, Brazil bDepartment of Psychiatry, Case Western Reserve University School of Medicine, Hanna Pavilion, First Floor Mail Room, 11100 Euclid Ave., Cleveland, OH 44106-5000, USA CDepartment of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea dDepartment of Radiology, Case Western Reserve University School of Medicine, Cleveland. OH. USA
Received 31 July 1995; revised 8 September 1995; accepted 8 October 1995
Abstract
Although several studies have reported ventricular enlargement and sulcal prominence in mixed samples of patients with affective disorders (unipolar and bipolar subtypes), it is not established if these findings extend to a homogeneous sample of relatively young patients with unipolar major depression ventricular:brain ratio (VBR) and prefrontal sulcal prominence (PSP). In the present study, measures of ventricle-brain ratio (VBR) and prefrontal sulcal prominence (PSP) were compared in patients with affeetive disorders (n = 24, mean age = 39), medical control subjects (n = 40), patients with schizophrenia (n = 101) on ventricular : brain ratio (VBR) and prefrontal sulcal prominence (PSP). No statistically significant differences were noted in VBR in the three groups. Both patient groups had significantly greater PSP than the medical control subjects but did not differ significantly from each other. The results of the present study extend the finding of prefrontal sulcal prominence, but not ventricular enlargement, to relatively young patients with unipolar depression. Furthermore, the results of the present study suggest that patients with schizophrenia and patients with affective disorders differ only slightly or not at all in brain morphology, at the level of resolution studied. Keywords: Affective disorder; Computed tomography; Schizophrenia; Ventricle-brain ratio
1. Introduction
It is well established that patients with schizophrenia have higher rates of ventriculomegaly and/or sulcal widening than do normal control subjects (for review, see Shelton and * Corresponding author, Tel.: +1 216 844-7485;fax: +1 216 844-7484.
Weinberger, 1986; Raz and Raz, 1990; Van Horn and McManus, 1992; Elkis et al., 1995). It is less well appreciated that many studies have reported ventricular enlargement and sulcal widening in affective disorders (for review, see Nasrallah et ai., 1989; Raz and Raz, 1990; Schlegel, 1991), suggesting that these types of abnormalities are not specific to schizophrenia. However, the majority of brain-imaging studies in affective disorders have
0925-4927/96/$15.00 © 1996 Elsevier ScienceIreland Ltd. All rights reserved PH S0925-4927(96)02744-8
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been performed in mixed samples of patients with bipolar and unipolar disorders (Schlegel, 1991), and many studies are based on samples of patients over 50 years of age (Nasrallah et al., 1989). Thus, it is unclear if the finding of ventricular enlargement or sulcal widening extends to homogeneous groups of relatively young patients with unipolar depression (Nasrallah et al., 1990). Clarification of this question might have both clinical and theoretical implications, since unipolar depression is more common than bipolar depression (Weissman et al., 1991) and is usually thought of as a less severe form of depression. Furthermore, studies in young patients may be more easily interpretable than those in older patients, because they are less confounded by the effects of age (Murphy et al., 1992). The purpose of the present study was to compare a group of relatively young patients with unipolar major depression to nonpsychiatric controls and patients with schizophrenia on measures of ventricular enlargement and suleal widening. Our hypothesis was that the unipolar patients would show significantly more ventricular enlargement and sulcal widening than the control subjects, but that these abnormalities would be less pronounced than those in patients with schizophrenia.
2. Methods
2.1. Subjects Patients with unipolar major depression (n = 25), patients with schizophrenia (n = 110), and medical control subjects (n = 40) were compared on computed tomographic (CT) measures. CT scan studies were completed when the patients were inpatients at University Hospitals of Cleveland. Diagnoses were made according to DSM-III-R criteria (American Psychiatric Association, 1987) and were based on interviews that used the Schedule for Affective Disorders and Schizophrenia, Lifetime Version (Endicott and Spitzer, 1978), supplemented with additional questions from the Present State Examination (Wing et al., 1974). All diagnoses were made by consensus of a psychiatrist and other research personnel who collected the clinical data. Patients were excluded
if they had a current (within 6 months of study date) history of alcohol or drug abuse, or recent (within 6 months) exposure to electroconvulsive therapy. Subjects were excluded if they had a lifetime history of major systemic or neurological disorders that might affect the brain. None of the patients had been treated with steroids. All patients were between 18 and 65 years old. Of the 110 patients with schizophrenia and the 25 patients with unipolar depression who met the criteria mentioned above, nine patients with schizophrenia and one patient with unipolar major depression had specific abnormalities detected on CT scan examination (detailed below). The 10 patients with specific CT abnormalities were excluded from the main analysis, but their CT measurements are reported separately. A number of patients and control subjects had generalized findings on CT examination, such as 'ventricles mildly enlarged' or 'prominence of the sulci and fissures over the convexities, which is unusual for age'. Subjects (including controls, see below) with such findings were not excluded from the main analysis. For the main analysis, the patient sample consisted of 24 patients with unipolar major depression (8 males, 16 females) and 101 schizophrenics (73 males, 28 females). The mean (SD) age of the unipolar depressed patients was 38.7 (12.8) years, and the mean age of the schizophrenic patients was 32.0 (7.9) years. The patients with unipolar major depression had been ill for 9.0 (8.3) years, and the patients with schizophrenia had been ill 12.1 (6.7) years. The mean age at onset of illness for the unipolar depressed patients was 29.7 (11.6) years, whereas the mean age at onset for the schizophrenic patients was 19.9 (4.5) years. The medical control subjects presented to the emergency room of University Hospitals of Cleveland with the complaint of headache (n = 35), vertigo (n = 2) or symptoms of viral infection (n = 3). The mean age of the control group was 33.3 (10.4) years. No trauma patients (ineluding head trauma, of course) were included. All subjects (17 males, 23 females) had a complete physical examination and full blood laboratory tests at the time of CT scan. Only patients with
H. Elkis et al. / Psychiatry Research: Neuroimaging 67 (1996) 123-134
normal blood laboratory results and normal physical examination were included. The medical charts of these subjects were reviewed and subjects were screened according to the same criteria as the psychiatric patients. All procedures were undertaken after subjects provided written consent. 2.2. CT scan measurements The CT scanner was a Siemens Somatom DR-H fourth generation scanner with a resolution matrix of 512 × 512 pixels and 960 projections per slice. Scan slices were 15° to the canthomeatal line at a thickness of 8 mm per slice. The window setting through the brain was 84 with a center of 35. After the interrater reliability study, which involved two raters (L.F. and C.L.), all CT measurements were made by a single rater (C.L.), who was unaware of subjects' diagnoses during the rating. 2.2.1. Ventricular measurements. Measurements of ventricle-brain ratio (VBR) were made with a compensating polar planimeter (Keuffel and Esser Co., Germany). The instrument was calibrated when the study began and checked repeatedly throughout the study. We used the method of Synek and Reuben (1976), as modified by Shelton et al. (1988). Measurements were made where the bodies of the lateral ventricles were most prominent. Since the planimeter is less accurate in measuring small structures, such as the body of lateral ventricles, the areas of the left and right bodies of the lateral ventricles were measured 10 times and averaged. The whole brain area was measured once. The left and right ventricular body measurements were added together, divided by the total brain area, and multiplied by 100 to give the VBR measurement. Each VBR was rated on two separate occasions; each rating was done without knowledge of the other rating. The final measure was the average of the two ratings. If the first two ratings differed by more than 30%, then the VBR was rated a third time, and the two closest measurements were averaged for a final VBR. An interrater reliability study was conducted with two raters measuring 23 scans. The intraclass correlation coefficient (ICC) (Bartko and Carpenter, 1976) was 0.93 (P < 0.001).
125
2.2.2. Prefrontal sulcal prominence ratings. The degree of prefrontal sulcal prominence (PSP) was rated with an extensively modified version of the method previously used by our group (Friedman et al., 1991). That method was based on the method of Shelton et al. (1988). The purpose of the modifications was to enhance the objectivity of the rating and thus increase interrater reliability. Fig. 1 illustrates the rating levels, and Table 1 lists the criteria. The first step in the rating was to find the slice with the foramen of Monro. The foramen should be visibly connected to the frontal horns of the lateral ventricles. If the foramen of Monro was equally visible on two slices, the slice with the best representation (largest width) of the third ventricle was chosen for rating. The PSP was rated on the frontal cortical surface, anterior to the sylvian fissures bilaterally. The next step was to count the number of clearly visible sulci in the frontal area. If three or more sulci were clearly evident, then the PSP rating was > 1.0, and additional measurements, described below, were required. Otherwise, the PSP was 0.0 if there was no evidence of sulci in the frontal area or 0.5 if one or two sulci were clearly evident and all gyral surfaces were in contact with the skull. If the PSP was > 1.0, then the curved circumference of the frontal cortex between the left and right sylvian fissures was measured in mm with a flexible ruler (Alvin). The next step involved an assessment of the amount of frontal cortical tissue that was pulled away from the skull. A measuring magnifier (7 ×, Bausch and Lomb, Cat. No. 81-34-35) was used to measure the number of mm of each portion of the circumference pulled away. Any gyral surface that was clearly pulled away from the skull was included in the measurement. Skull portions that were over sulci were not considered for this measurement. Thus, the goal was to measure the number of mm of gyral surface pulled away from the skull. Next, the total number of mm of gyral surface (from all frontal gyri) pulled away (discontinuous) from the skull was summed. Finally, the percentage of the total curved circumference of the frontal cortex that was discontinuous to the gyral surface was computed. If this percentage was -~ 5%, the PSP score was 1.0. If the percentage was >5% and <20%, then the PSP score was 1.5. If
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Fig. 1. Illustration of the prefrontal sulcal prominence rating scale.
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Table 1 Brief description of the prefrontal suleal prominence rating scale Rating level
0.0 0.5 1.0 1.5 2.0 2.5 3.0
Description Sulci clearly visible
Gyral surface discontinuous with skull
None 1 or 2 >3 >3 >3 >3 >- 3
--<5% > 5% and < 20% > 20% and < 50% >50% and < 100% 100%
the percentage pulled away was > 20% and _<50%, then the PSP score was 2.0. If the percentage pulled away was > 50%, but < 100%, then the PSP score was 2.5. If 100% of the gyral surface was discontinuous with the skull, then the PSP score was 3.0. Each scan was rated twice by a single rater (C.L.) on separate days. The second rating was done without knowledge of the first. If the scores were >0.5 scale units apart, then the scans were rated a third time. The two ratings that were within 0.5 scale units were chosen. The final PSP score was the average of the two ratings. The ICC for two raters and 20 scans for PSP was 0.83.
2.3. Statistical analysis The first step in the analysis was the determination of the appropriateness of parametric statistics, including normality of distributions and homogeneity of variance across groups. It was concluded that a parametric analysis was appropriate. (The age distributions were skewed and were log-transformed.) Diagnostic differences and gender effects were tested with two-factor analysis of covariance (ANCOVA) with age as a covariate. Since the sample sizes of the cells in the ANCOVA were not balanced, the method of unweighted means was used for F tests (Searle, 1987). Post hoc comparisons were evaluated with the Scheff6 test. Correlational analyses used Spearman rank-order correlation coefficients (rs). All P values are two-tailed. Outliers were identified according to a standard
algorithm (SPSS, 1989). Subjects with values 1.5 x the interquartile range above the 75th percentile, or 1.5 x the interquartile range below the 25th percentile were considered as outliers. 3. Results
3.1. Age The diagnostic groups differed significantly in age (log-transformed) at the time of the CT scan ( F = 3.53, df= 2,162, P = 0.031). Post hoc tests revealed that the group of patients with unipolar major depression was significantly older than the group of patients with schizophrenia (P < 0.05). No other group differences were significant. Since age affects brain structure (Murphy et al., 1992), age was included as a covariate in all subsequent analyses.
3.2. Gender In the medical control group, 43% of the subjects were male; in the schizophrenic group, 72% of the subjects were male; and in the affective group, 33% of the subjects were male. There were significantly more males in the schizophrenic group than in either the medical control group (x 2 = 11.00, df= 1, P = 0.0009) or unipolar major depression group (X2 = 12.90, df= 1, P = 0.0003). The medical control group and the unipolar major depression group did not significantly differ on gender (X2 = 0.53, df= 1, P = 0.47). To control for gender effects, gender was included as a factor in the test of the effect of diagnosis.
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H. Elkis et al./ Psychiatry Research: Neuroimaging 67 (1996) 123-134
CONTROLS
3.3. Test of the diagnosis effect Figs. 2 and 3 provide histograms of VBR and PSP, respectively, for each group. The effects of diagnosis, gender, and their interaction were tested in a 3 x 2 analysis of covariance with age as a covariate. Table 2 presents the results. Age was a significant covariate for VBR but not for PSP. There were no significant diagnosis, gender, or interaction effects for VBR. Two controls and three patients with schizophrenia, all with VBR values > 12.0, were classified as outliers. After removal of these five subjects, the diagnosis effect was still not significant for VBR ( F = 1.97, df= 2,153, P = 0.143). For PSP, the diagnosis effect was highly significant, but the gender effects and the interaction were not significant. Post hoc tests revealed that both patient groups had significantly elevated PSP compared with the medical control group (P < 0.02), but the two patient groups were not
P E R C E N X
40 35 30 25 2O 15 10 5 0 O0
0 25
0 50
0 75
1 O0
12 5
15 0
1 75
2 O0
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30 25. 20. 15. I0i
0 O0
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0 50
0 75
1 O0
1 25
1 50
AFFECTIVES P E R C E
4o 35 30 25 20
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i
0 25
I
0 50
I
0 75
,
1
1 00
1 25
I
1 50
I
,
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Fig. 3. Frequency (%) histograms of prefrontal sulcal prominence for each group. iR
IEt
,llb__= SCHIZOPHRENICS
,
p2oJ
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roll
I
0
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.
.
.
.
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AFFECTIVES
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Fig. 2. Frequency (%) histograms of ventricle:brain ratio for each group.
significantly different (P = 0.92). The diagnosis factor accounted for 8.4% of the variance in PSP. The two patients with schizophrenia who had very low PSP scores (0.0 and 0.25) were classified as outliers with the SPSS algorithm. As would be expected upon examination of Fig. 3, removal of these subjects resulted in the schizophrenia group becoming more unlike the control group and more like the affective disorders group. Thus, the pattern of results that emerged with these subjects included was strengthened after their removal (diagnosis effect before removal: F = 7.41, df= 2,158, P = 0.001; diagnosis effect after removal: F = 8.47, df= 2,156, P < 0.001). The diagnosis effect on PSP was also tested with a dichotomous analysis. Subjects were divided into those with a PSP rating _<1.25 (low PSP) and those with a PSP rating > 1.25 (high PSP). The proportion of subjects with high PSP for each group was as follows: 0.28 (medical controls), 0.59 (patients with schizophrenia), and 0.67 (patients
1.02 (0.52)
Mean PSP (SD)
0.91 (0.55)
5.52 (2.43) 1.33 (0.49)
6.32 (2.61) 1.28 (0.40)
6.11 (2.22) 1.38 (0.58)
5.31 (1.64)
Males (n = 8)
!.39 (0.51)
6.65 (1.84)
Females (n = 16)
Unipolar depression (n = 24)
Note. VBR, ventricle-brain ratio; PSP, prefrontal sulcal prominence. *P < 0.05; **P < 0.001.
5.56 (2.84)
Mean VBR (SD)
Females (n = 28)
Males (n = 73)
Males (n = 17)
Females (n = 23)
Schizophrenia (n = 101)
Medical controls (n = 40)
Table 2 Analysis of diagnosis, gender, and age effects on VBR and PSP
F
(df= 1,158) 5.42* 2.97
F
(df = 2,158) 0.78 0.04
F
(df= 1,158) 0.35 0.39
F
(df = 2,158) 1.12 7.41"*
Age as covariate
Diagnosis x gender interaction Gender
Diagnosis
4~
I
o~ x.i
.z:
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with affective disorders). Both patient groups had significantly more subjects with high PSP than did the control group (P < 0.005), but the patient groups did not differ from one another. Finally, the difference between patients with affective disorder and control subjects on PSP was tested with one additional analysis, designed to remove any doubt about the contribution of age to the effect. As noted above, the patients with affective disorders were not statistically significantly older (mean = 38.7 years, SD = 10.4) than the controls (mean = 33.3 years, SD = 12.8), but there was a trend for them to be older (t =-1.84, df= 62, P = 0.071). For the final analysis, the three oldest patients with affective disorder and the three youngest control subjects were excluded. Now the mean ages of the two groups were very close (patients: mean = 35.3 years, SD = 9.6; controis: m e a n = 3 4 . 4 years, S D = 10.1), and no statistical trend toward a mean difference was apparent (t =-0.34, df= 56, P = 0.734). The PSP scores of these two more closely matched groups were compared with a t test. The mean PSP in the affective disorder group (1.37, SD = 0.55) was significantly elevated compared with that in the control group (0.94, SD = 0.53; t = -2.9, df= 56, P = 0.005). This confirms that the differences between the affective disorder group and the control group were not related to any age difference.
3.4. Within-group correlations between age, age at onset, duration of illness, and PSP To examine further the significance of increased PSP in the clinical populations, we correlated PSP with age, age at onset, and duration of illness within each diagnostic group. A significant correlation was noted in the unipolar major depression group between PSP and age (rs = 0.45, P = 0.027). After Bonferroni correction for multiple correlations, this correlation was not statistically significant. No other significant correlations were noted in the affective disorder group. In the group of patients with schizophrenia, no significant correlations were noted.
and one of 25 (4%) patients with unipolar major depression had specific CT abnormalities. The following specific abnormalities were noted in patients with schizophrenia: vermian cerebellar abnormality (possible Dandy-Walker variant malformation) (n = 2); focal cerebellar signal attenuation (n = 1); extensive calcification of the falx (n = 2); hyperostosis of skull with extensive calcification of the falx (n = 1); dural calcification in the frontal-parietal convexity (n = 1); habenular commissure calcification (n = 1); and malformation of the auditory canals and cochlea (n = 1). One patient with unipolar major depression had a CT image compatible with empty sella. The rates in the two populations did not differ significantly (X2 = 0.52, df= 1, P = 0.47). The CT measures (VBR and PSP) of the nine schizophrenic patients with specific abnormalities were compared with those of the 101 schizophrenic patients without such abnormalities. The two groups were not significantly different on VBR (t = -1.23, df= 8.44, P = 0.25; separate variance estimates) or PSP (t = -0.77, df= 108, P = 0.44).
3.6. Generalized findings on CT examination Patients with clinical evaluations that noted generalized parenchymal loss or sulcal enlargement were included in the main analyses above. To assess the sensitivity of clinical CT evaluation, we also compared the rates of clinical generalized findings in the three diagnostic groups. In the group of medical controls, 8 of 40 (20%) subjects had generalized findings; in patients with schizophrenia, 50 of 101 (50%) had such findings; and in the group of patients with unipolar major depression, 4 of 24 (17%) had such findings. The rate for patients with schizophrenia was significantly higher than that in either medical controls (X2 = 10.3, df= 1, P = 0.001) or patients with unipolar major depression (X2 = 8.52, df= 1, P = 0.004). The rate in medical controls was not significantly different from that in patients with unipolar major depression (x2=0.11, df= 1, P = 0.74). 4. Discussion
3.5. Specific abnormalities on CT examination in the patient groups Nine of 110 (8%) patients with schizophrenia
The main finding of the present study was that relatively young patients with unipolar major de-
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pression had increased PSP compared with controis. PSP was also increased in the schizophrenic patients relative to the controls, and the degree of PSP in the two patient groups did not differ. Although the finding of increased cortical sulcal prominence has been reported in patients with affective disorders generally, to our knowledge this is the first report of increased prefrontal sulcal prominence in a relatively young and homogeneous sample of patients with unipolar major depression. Coffey et al. (1993a) did control for age in their study, and reported decreased frontal lobe volume in depressed patients. However, the mean age of the patient group in their study was 61.3 years. The present findings, in a younger group of patients, more convincingly demonstrate that such abnormalities are not secondary to age and do not result from an interaction between age and diagnosis. As pointed out by Jeste et al. (1988), some investigators have assumed or promoted the notion that affective disorders are merely 'functional' abnormalities, without any 'organic' substrate. The findings of the present study do not support this notion. There has been a suggestion that the outcome of studies such as that presented here is influenced, in an important way, by the nature of the control group (Iacono et al., 1988; Smith et al., 1988). Iacono et al. (1988) and Smith et al. (1988) found different results in comparisons in which patients with schizophrenia were compared with 'medical' controls versus normal controls recruited from the community. They hypothesized that this may be due to the fact that medical control scans are typically screened for a normal evaluation. This would tend to decrease the VBR in the control group, and artifactually increase the differences between patients and controls. Although the present study employed a medical control group, the scans were not screened for the presence of global structural abnormalities, so there was no risk of such a bias. Furthermore, two meta-analyses failed to find any influence of this factor in studies of schizophrenia (Raz et al., 1988) or affective disorders (Elkis et al., 1995). Finally, this factor would tend to create an artificial significant difference between patients and controls, but in the present study, no significant difference in VBR was noted.
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The present finding of increased sulcal prominence should be interpreted in light of the fact that increased sulcal prominence is also reported in other neurologic or psychiatric conditions such as Alzheimer's dementia (Fazekas et ai., 1989; Burns et al., 1991), Huntington's Disease (Starkstein et al., 1989), bulimia (Krieg et al., 1987), anorexia nervosa (Krieg et al., 1988), alcoholism (Lishman, 1990), and benzodiazepene abuse (Schmauss and Krieg, 1987). Thus, from a diagnostic viewpoint, the finding is nonspecific. Also, from an anatomical viewpoint the present finding is nonspecific, as only two brain areas were measured, the areas were quite large, and the results were based on CT rather than higher resolution magnetic resonance imaging (MRI). Furthermore, although the diagnosis effect on PSP was statistically significant, diagnosis accounted for < 10% of the variance in PSP. Nonetheless, an understanding of the causes of this increase in sulcal fluid space may provide additional insights into the pathophysiology and pathomorphology of depression. One possibility is that increased suical prominence is a reversible state-related phenomenon in affectiv¢ disorders (Nasrallah et al., 1989). Reversibility of global structural changes has been established in certain conditions, such as alcoholism (Ron et al., 1982), anorexia nervosa (Kohlmeyer et al., 1983; Artmann et al., 1985), and bulimia (Krieg et al., 1987). However, the mechanisms underlying these reversible structural changes have not been identified. Kellner et al. (1983) hypothesized that ventricular enlargement or sulcal prominence may result from hypercortisolemia secondary to abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis in depression. This notion is supported by findings such as positive correlations between VBR and urinaryfree cortisol (Schlegel et al., 1989), plasma cortisol (Schlegel et al., 1989), and postdexamethasone cortisol concentrations (Rao et al., 1989). However, in a recent and directly relevant study, which included serial MRI scans and dexamethasone suppression tests, Coffey et al. (1993b) found no evidence linking structural abnormalities to hypercortisolemia in depression. Alternatively, the structural abnormalities in affective disorders may reflect hypoplasia, dysplasia,
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permanent brain damage, or some combination thereof. These possibilities are currently under active investigation in schizophrenia research (O'CaUaghan et al., 1992; Cannon et al., 1993). The same strategies may need to be applied in affective disorders (Nasrallah, 1991). There is evidence that depression can result from brain damage. It has been associated with stroke (Schwartz et al., 1993), tumor, and head injury (Jeste et al., 1988). The finding of increased PSP in affective disorders is consistent with the recent finding of Coffey et al. (1993a) that inpatients with depression have a reduced frontal lobe volume compared with controls. The implication of the frontal lobe in depression is also very consistent with a common underlying prefrontal cortical pathophysiology for schizophrenia and affective disorders, as proposed by Swerdlow and Koob (1987) and Drevets and Raichle (1992). The finding of increased sulcal prominence in patients with affective disorders and schizophrenia is consistent with the notion that these disorders represent points along a pathophysiologic 'continuum'. The continuum model was suggested a number of years ago by Meltzer (1973, 1976), who reported neuromuscular abnormalities (e.g., increased serum creatine kinase activity, skeletal muscle fiber abnormalities, and subterminal motor nerve sprouting) in both schizophrenia and psychotic depression. Subsequently, other biological abnormalities have been found to be present in patients with both types of disorders. For example, abnormalities have been noted in both patient groups in HPA function (Carroll et al., 1968; Kaneko et al., 1992), regional cerebral blood flow (Dolan et al., 1992; Liddle et al., 1992), serum dopamine-B-hydroxylase activity (Meltzer, 1984), sleep (Hudson et al., 1993), and evoked potentials (Wexler, 1992). Furthermore, several previous imaging studies reported ventricular enlargement in both groups, although this was not seen in the present study (Raz and Raz, 1990; Elkis et al., 1995). Crow (1990) has recently proposed a continuum model of mood disorder and schizophrenia based on genetics. In conclusion, the results of the present study suggest that patients with schizophrenia differ from patients with affective disorders only slightly
or not at all in brain morphology, at the level of resolution studied. Whether such similarity is rooted in a common underlying pathophysiology or, alternatively, reflects a similar expression of pathophysiologically distinct processes remains unclear. Further studies of the underlying pathophysiology of these global brain changes are needed to elucidate the clinical and theoretical significance of the findings.
Acknowledgments This research was supported by grants from the National Institute of Mental Health (MH-411684 and MH-415494; Dr. Meltzer), from the National Alliance for Research in Schizophrenia and Depression (Dr. Friedman), from the Scottish Rite Foundation (Dr. Friedman), and from the Prentiss Foundation (Dr. Meltzer). Dr. Meltzer is a recipient of a U.S. Public Health Service Research Career Scientist Development Award (MH47808), and Dr. Elkis is a recipient of a postdoctoral scholarship from CNPq (Brasilia/Brazil).
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