PsychiatryResearch: Neuroimaging, 35: 137-147
I37
Elsevier
Reduction in Temporal Lobe Size in Siblings With Schizophrenia: A Magnetic Resonance imaging Study I. Deborah Dauphinais, Lynn E. DeLisi, Timothy J. Crow, Kostas Atexandropoulos, Nigel Colter, Ivan Tuma, and Elliot S. Gershon Received February 28, 1990; revised version received August 1.5, 1990; accepted August 19, 1990. Abstract. Twenty-eight individuals with familial schizophrenia, from 16unrelated families (12 sibling pairs and 4 individuals whose siblings refused scanning), and 21 normal control subjects were examined by cerebral magnetic resonance imaging (MRI). Measurements of the cerebrum, temporal lobes, and cerebral lateral ventricles were obtained using consecutive coronal sections containing these structures. Temporal lobe volume was significantly decreased by approximately 10% in these early onset schizophrenic siblings compared with normal controls. These findings add to recent post-mortem and neuroradiological evidence for morphological alteration in the temporal lobes in schizophrenia. Key Words. Sch~oph~~a, familial, magnetic resonance imaging.
Radiologic and post-mortem studies have reported structural changes in the brains of adult schizophrenic subjects, including enlargement of the third and lateral ventricles (Johnstone et al., 1976; Shelton and Weinberger, 1986). The ventricular changes show some selectivity to the temporal horn region (Brown et al., 1986; Crow et al., 1989~) and add to other evidence of temporal lobe abnormalities reported from post-mortem examinations (Scheibel and Kovelman, 1981; Jakob and Beckmann, 1986; Altshuler et al., 1987; Jeste and Lohr, 1989; Falkai and Bogerts, 1990). Magnetic resonance imaging (MRI) has improved resolution and multiplane capacity compared with computed tomography (CT), thereby enabling the examination of limbic brain structures. The findings from cerebral MRI studies in schizophrenia have been diverse and inconsistent. Decreased size of the cranium, cerebrum, and frontal lobes in schizophrenic males (Andreasen et al., 1986); increased width of the anterior and middle regions of the corpus callosum in schizophrenic females (Nasrallah et al., 1986); increased length of the corpus callosum; enlargement of the septum
At the time this work was done, I. Deborah Dauphinais, M.D., and Lynn E. DeLisi, M.D., were in the Clinical Neurogenetics Branch, National Institute of Mental Health, Bethesda, MD. Dr. Dauphinais is now in the Continuing Care Service, Massachusetts Mental Health Center, Boston, MA. Dr. DeLisi is now in the Department of Psychiatry, State University of New York at Stony Brook, Stony Brook, NY. Timothy J. Crow, Ph.D., F.R.C.P., F.R.C.Psych., Kostas Alexandropoulos, M.D., Nigel Colter, and Ivan Tuma, M.D., are in the Division of Psychiatry, Clinical Research Centre and Northwick Park Hospital, Harrow, Middlesex, England. Elliot S. Gershon, M.D., is Chief, Clinical Neurogenetics Branch, National Institute of MentaI Health, Bethesda, MD. (Reprint requests to Dr. L.E. DeLisi, Dept. of Psychiatry, Heaith Sciences Center, T-10, SUNY Stony Brook, Stony Brook, NY 11794, USA.) 01651781/90/$03.50 @ 1990 Elsevier Scientific Publishers Ireland Ltd.
peilucidum (Mathew et ai., 1985); and enlargement of the lateral and third ventricles (Kelsoe et al., 1988) have all been reported. Other MRI studies show no differences in ventricle-to-brain ratio, bicaudate ratio, bifrontal ratio (Smith et al., 1987). cerebellar vermis and fourth ventricle size (Mathew and Partain, 1985) or III qualitative review of the periventricular structures (Johnstone et al., 1986,. Recent studies focused on temporal lobe structures have reported reduced total size of the temporal lobes (Suddath et al, t989), particularly on the left (Johnstone et al., 1989; Rossi et ai., 1989). In a preliminary analysis, we reported bilateral amygdala-hippocampal reductions in schizophrenic subjects (Dauphinais et al., 1987; DeLisi et al., 1988). Subsequent findings, from other groups, $>fbilateral hippocampal reductions in schizophrenic probands compared with their discordant monozygotic twins (Suddath et al., 1990) and reduction of medial limbic temporal lobe structures in schizophrenic subjects (Bogerts et al., 1990) have been reported. ‘The present study expands our preliminary reports to examine in detail structures of the temporal lobes and ventricular system in a cohort of siblings with familial schizophrenia. Methods Subjects. Twenty-eight individuals (15 men and 13 women) with a diagnosis of chronic schizophrenia or schizoaffective illness from 16 unrelated families were recruited for cerebral MRI studies. Subjects were recruited from a larger group of families in which more than one individual from the same generation is ill with schizophrenia (DeLisi et al., 1987). Diagnoses were made using modified Research Diagnostic Criteria (Spitzer et al., 1977; Mazure and Gershon, 1979) on the basis of structured interviews (modified Schedule for Affective Disorders and Schizophrenia; Spitzer and Endicott, 1978) combined with medical records and information from relatives. The mean (i SD) age of schizophrenic subjects was 32.4 ZIZ6.0 years (range 23-43 years) and the mean duration of illness was 12.8 f 5.8 years (range I-27 years). Ten subjects received a diagnosis of schizophrenia (9 chronic, 1 subacute), and 18 subjects were given a diagnosis of chronic schizoaffective disorder. All subjects also met DSM-MT-R criteria for schizophrenia (American Psychiatric Association, f987). One subject was hospitalized at the time of evaluation, 25 subjects were in outpatient treatment, and 2 were not in any treatment. The 26 patients in treatment were taking psychotropic medications at the time of the study. Four schizophrenic subjects had a history of drug abuse, one of alcoholism. and five of both drug abuse and alcoholism. Twenty-eight control subjects were recruited over a 16-month period and formed the group from which controls were selected for two separate comparisons between schizophrenic subjects and controis. Some of the controls were selected from a group of subjects examined with the same scanner for other research studies (e.g., Clinical Brain Disorders Branch, National Institute of Mental Health). The first control group for analysis #l consisted of 21 subjects; 10 were NIMH personnel and I1 were community volunteers. There were 12 men and 9 women (mean age = 36.5, SD = 8.1, range = 20-58 years). The second control group for analysis #2 was selected a few months later and consisted of 21 individuals (9 NIMH personnel and 12 community volunteers; 11 men and 10 women (mean age = 33.3, SD = 6.6 years, range = 21-45 years). Thirteen scans from the first control group were available on magnetic tape and thus were included in the second control group along with scans from eight newly recruited subjects. The community volunteers were interviewed and diagnosed in the same manner as the probands, found to be free of psychiatric and medical illness, and had no family history of schizophrenia or major affective disorder; NIMH personnel were screened for history of major medical and psychiatric illness. There was no significant difference between the schizophrenic and normal control subjects for height, age, or male-female ratio.
139 MRI Procedures. Cerebral scans were performed using a Picker Vista 0.5 Tesla superconducting magnet. Subjects were positioned for scanning by laser light to the canthomeatal line. A midsagittal pilot scan, followed by an inversion recovery sequence in the coronal plane, was obtained on each subject (inversion time [IR] = 600 ms, repetition time [TR] = 3583 ms, echo time [TE] = 30 ms). This Tl weighted sequence was selected to provide maximum differentiation of gray and white matter. Twelve contiguous coronal cuts were obtained, beginning at the anterior-most tip of the frontal lobe at lo-mm intervals. MRI Measurements and Analyses. Two independent sets of analyses were performed, one using measurements obtained from the radiographic films of the images (Analysis #I) and the other using measurements taken directly from magnetic tapes of the computerized images (Analysis #2).
This set of analyses compared patients to the first control group (see above). Measurements were made from the hard copies of two coronal cuts using the Joyce Loebl magiscan system. This system uses a light pen and outline tracking program to draw boundaries that are quantified by computer. Images were magnified X 3 for all measurements except the temporal horn of the lateral ventricle for which magnification was X IO. Contrast was fixed at 20 units and brightness at 10 units. Measurements were made of the cerebral hemispheres (excluding temporal lobes), temporal lobes, left and right amygdala-hippocampi (including the parahippocampal gyrus), cerebral lateral ventricles, temporal horns of the lateral ventricles, and third ventricle. The medial boundary of the temporal lobe was determined by a straight line drawn from the most medial edge of the lateral sulcus to the recess above the optic tract. Temporal lobe gray and white matter were separately measured using an automatic boundary function. The posterior cut visualized the pons at the interpenduncular fossa; the anterior cut was the next cut forward and was always that cut just posterior to the optic chiasm. Although measurements were made by three investigators (K.A., N.C., and I.T.), each structure was measured by only one investigator, and all measurements were done without knowledge of the identities and diagnostic status of the subjects. Reliabilities were assessed from a series of 18 images that were measured by two independent raters and ranged from 0.98 for the cerebral lateral ventricles to 0.60 for the temporal horns of the lateral ventricles. Statistical analysis for this set of measurements was carried out using an analysis of variance covarying for age and height. There were two between-subject factors (schizophrenic vs. control subjects; men vs. women) and two within-subject factors (left vs. right; anterior vs. posterior). All regions were examined, but only the significant results are reported in Table 1. Analysis #I.
#2. This set of analyses compared patients with the second group of controls. Magnetic tapes of the scans were obtained in Picker format (the standard format used by Picker Imaging systems) and converted into a format readable by the VAX computer (J. Cappelletti, LCM/NIMH, modified by T. Collins, private contractor). Measurements were made using a microVAX computer (program developed by H. Burrows, Ph.D., ETB/NINDS) by one investigator (I.D.D.) without knowledge of subject identity. Images were called to the computer monitor by code numbers and magnified X 2.5, producing an image slightly smaller than actual head size. Image contrast was enhanced to maximize visibility of anatomic borders. Boundaries were outlined with a cursor positioned with a hand-guided “mouse,” and area was computed automatically in pixels and converted to square centimeters. On three sequential coronal slices, the following structures were measured: cerebral hemispheres (including the temporal lobes), temporal lobes, and lateral ventricles. On the two more posterior of these slices, the left and right amygdala-hippocampi plus parahippocampal gyrus, the left and right amygdala-hippocampi, the left and right temporal horns of the lateral ventricles, and the third ventricle were measured. The most anterior cut measured was at the level of the optic chiasm; the middle and posterior cuts corresponded to the anterior and posterior cuts measured in Analysis #l. The amygdala and hippocampus were measured as a Analysis
I40
unit because there was no clear boundary between these structures. The lateral boundary 01 the parahippocampal gyrus was determined by a vertical line drawn from the edge of the amygdala-hippocampus. Areas of each structure were summed to give volume estimates. Fig. 1 illustrates the three coronal cuts used in our analyses, and Fig. 2 illustrates the boundaries ot the temporal lobe and medial limbic structures. Ventricle-to-brain ratios (VBRs) were determined by summing ventricular area on all three cuts and were expressed as a Lh ratio to summed cerebral area for these same cuts. The scans of three schizophrenic patients and one control were not measurable with thlb methodology because of blurring of the images on the screen which prevented clear
Table 1. Analysis #1 : Coronal area measurements in cm2 f SD Schizophrenics
Cerebral
hemispheres
Controls
Men (n= 15)
Women (n = 13)
Men (n = 12)
___Women (n = 9)
32.66 f 0.56
30.74 f 0.44
33.17 f 0.90
32.21 f 0.77
32.96 zk0.55
31.71 f 0.42
34.04 Ifi 0.60
31.61 i 0.64
33.51 f 0.46
31.68 * 0.41
34.51 9~0.72
32.96 f 0.79
33.27 f 0.47
31.89 + 0.40
34.00 f 0.46
31.74 f 0.69
excluding
temporal lobe la lP ra rp Temporal lobes’ la
11.46 + 0.56
10.80 f 0.38
12.67 i 0.56
12.12* 0.54
lP ra
11.68 f 0.55
10.91 + 0.31
12.89 f 0.62
11.59 f 0.50
12.57 f 0.50
11.48 + 0.42
13.56 f 0.66
12.79 + 0.58
12.10 + 0.40
12.10 + 0.40
13.48 f 0.66
12.75 + 0.54
rp Amygdala-hippocampus
plus
parahippocampalgyrus la
0.818 f 0.062
0.797 f 0.079
0.961 III 0.069
0.890 k 0.074
IP ra
0.501 f 0.046
0.416 f 0.045
0.557 f 0.063
0.456 rt0.036
0.837 f 0.078
0.923 f 0.093
1.019 f 0.091
0.912 rt0.091
rp
0.538 f-0.041
0.457 * 0.037
0.535 f 0.037
0.480 f 0.057
Cerebral lateral ventricles la
1.748 f 0.19
1.197
1.251 f 0.19
1.295 zt0.10
IP ra
1.555 f 0.18
1.124 f0.18
0.964 f 0.17
1.085 f 0.14
1.524 f 0.15
1.061 zlz 0.14
1.316 f 0.23
1.085 i 0.14
1.403 k 0.16
1.099 +I0.17
1.155 9~0.25
1.126 i 0.18
rp Temporal horns’
f 0.20
la
0.224 f 0.046
0.277 f 0.055
0.161 f 0.018
0.193 ri0.040
IP ra
0.139 + 0.022
0.076 f 0.010
0.093 f 0.023
0.085 f 0.016
0.211 f 0.050
0.225 +L0.059
0.195 f 0.030
0.203 9~0.044
0.101 f 0.016
0.102 f 0.018
0.079 k 0.015
0.085 f 0.019
a
0.083 zt0.043
0.066 f 0.029
0.052 f 0.020
0.053 rtr 0.016
P
0.074 f 0.038
0.058 f 0.072
0.062 k 0.035
0.079 zt0.028
rp Thirdventricle'
-
Note. Analysis of variance (ANOVA) factoring schizophrenics vs. controls and men vs. women with age and height as covariates. la = left anterior, Ip = left posterior. ra = right anterior, rp = right posterior. 1. Significant ANOVA values: Temporal lobes: F = 8.22; df = 1,42; p < 0.01. Temporal horns: F = 7.71; df = 1,26; p < 0.01. Third ventricle: F = 6.01: df = 1, 40; p < 0.02.
Figure 1. Midsagittal slice of the brain
Lines indicate the planes for the coronal slices measured. Measurements were made from the 2 more posterior slices in Analysis #l and from all 3 slices in Analysis 82.
delineation of anatomic boundaries. This blurring was not evident on the films used for Analysis # 1. Reliability of measu~ments was determined for each structure, from the scans of six individuals, measured three separate times. Intraclass correlations for triplicate measures ranged from 0.93 to 0.98 for all structures except for the temporal horns of the lateral ventricles (intraclass correlations: left = 0.72, right = 0.50). A measurement of 0 pixels was assigned to the area of the temporal horn for subjects in which this structure was not visible. The remaining scans were measured in duplicate, and the mean value was used in data analysis. All analyses were performed using the Statistical Analysis System (SAS Institute, 1985). Table 2 shows the volume estimates obtained in Analysis #2. A General Linear Model (GLM) adjusting for height, age, gender, and diagnosis was performed. To analyze for a familial effect on brain structure size, a GLM adjusting for height, age, gender, and family was done. To look for an association of size of brain structures with history of alcoholism in this group of schizophrenic siblings, an additional GLM adjusting for height, age, gender, alcoholism, and diagnosis was performed. In addition, f tests were used to compare schizophrenic subjects with and without a history of substance abuse (n = 10 and n = 15, respectively) and schizophrenic subjects with and without a history of auditory hallucinations (n = 19 and n = 6, respectively). Side and side X diagnosis analyses were done using a multivariate analysis of variance (MANOVA) with repeated measures. Results
A significant reduction was found in the temporal lobes, bilaterally, in schizophrenic subjects compared with normal controls in both sets of analyses (see Tables 1 and 2). In Analysis #I, temporal lobe gray and white matter regions were measured
Figure 2. Coronal slice of the brain at a level 10 mm posterior to the optic chiasm
The figure demonstrates
how boundanes for the temporal lobes and medial limblc structures were determlned
separately, and a similar reduction m area was found in both regions. The temporal horns of the lateral ventricles and the third ventricle were found to be significantly enlarged in schizophrenic patients in Analysis #1 but not in Analysis #2. Significant differences in volume of the right amygdala-hippo~ampus plus parahippo~ampal gyrus and right amygdala-hippocampus were found between schizophrenic and normal control subjects in Analysis #2 but not in Analysis #I. The reduction in cerebral volume found in Analysis #2 appears to result from temporal lobe reduction, since a comparison of cerebral volume minus temporal lobe volume revealed no significant differences between patients and controls. There was no significant correlation of size of brain structures or VBR with age or years since onset of illness (left temporal lobe: Pearson’s r I= 0.16,~ ==0.44; right temporal lobe: r = -0.21, I) = 0.31; VBR: r r= 0.02, ~7 = 0.91 in either set of analyses. Nor were significant differences found in brain structure size between schizophrenic subjects with or without a history of substance abuse or auditory hallucinations. The results of the GLM performed to assess for effects of alcoholism on brain structure size revealed a significant effect for size of the right VBR (Type III sum of squares = 0.0002; F= 4.01; df= 1,44; p -= 0.0522) and the totai VBR (Type III sum of squares = 0.0002; F = 3.97; cif= 1, 44; p = 0.05331, but not for any of the temporaf lobe measurements. A familial efffect was noted only for size of the left cerebral hemisphere volume (Type III sum of squares = 5920.82; F =I. 4.49; # -= I, 31; p = 0.0112) and left plus right cerebral hemisphere area (Type III sum of squares = 19103.26; F= 3.69; c@==1. 31; p = 0.0221).
143 Correlations between the two sets of analyses showed measurements of the temporal lobe to be significantly correlated (right side: r = 0.48,~ < 0.006; left side: r = 0.79, p < O.OOOl),while measurements of the amygdala-hippocampi were not (r = 0.022, p > 0.5).
Repeated measures MANOVA (Analysis #2) revealed a main effect for side in both groups for the measurements of the cerebral hemispheres and temporal lobes Table 2. Analysis #2: Coronal measurements-Volume as the summed areas (cm3 f SD)
estimates expressed
Schizophrenics Men (n = 13)
Controls
Women (n = 12)
Men (n = 10)
Women (n = 10)
Cerebral hemispheres’ Left
177.75 k 10.38
168.72 k
Right
180.23 f 11.04
172.13 + 6.43
Left
39.80 f 5.75
38.71 f 4.14
43.90 f 5.02
41.90 + 6.75
Right
42.26 f 5.73
40.14 * 3.58
47.41 f 5.07
43.71 + 6.25
5.76
184.51 f 12.74
177.74 k 19.49
190.08 +
179.45 k 16.07
9.90
Temporal lobes
Amygdala-hippocampus parahippocampal
plus
gyrusl
Left
6.39 zt 1.09
6.13 f 0.81
7.05 zt 1.24
6.36 zt 1.24
Right
5.96 zt 0.82
6.07 k 0.88
7.00 + 1.03
6.47 zt 0.97
Left
4.04 It 0.88
3.76 k 0.82
4.33*
1.12
4.07 * 0.92
Right
3.64 f 0.77
3.59 f 0.57
4.15 It 0.88
4.01 k 0.76
Left
5.14 f 2.21
3.47 * 1.04
3.10 k 1.36
2.71 zt 0.99
Right
4.42 f 1.67
3.56 zt 1.53
3.38 f 1.42
2.81 * 1.04
Amygdala-hippocampus’
Cerebral lateral ventricles’
Ventricle to brain ratio (in %)I Left
2.86 f 1.18
2.06 f 0.61
1.70 zk 0.76
1.51 k 0.48
Right
2.44 k 0.88
2.06 f 0.87
1.80 f 0.81
1.54 f 0.45
Left
0.12 * 0.13
0.22 f 0.14
0.13 * 0.10
0.20 f 0.15
Right
0.21 f 0.12
0.24 k 0.16
0.19 f 0.11
0.23 f 0.14
0.86 f 0.32
0.63 f 0.98
0.71 f 0.15
0.605 zt 0.29
Temporal horn
Third ventricle
Note. Analyses of variance (ANOVAs) are based on the General Linear Model of SAS adjusting for height, age, gender, and diagnosis. 1. Significant ANOVA values: Cerebral hemispheres,
F = 4.06; df = 1,44;p < 0.05, left side. F = 6.07; of = 1, 44;p < 0.02, right side.
Temporal lobes:
F = 4.67: of = 1, 44; p < 0.04, left side. F = 7.54; df = 1, 44; p < O.tXt9.right side.
Amygdala-hippocampus/ parahippccampal gyrus:
F = 2.21; of = 1, 44; p < 0.15, left side. f = 7.94; of = 1, 44;p < 0.006, right side
Amygdala-hippocampus:
F=1.6l;df=l,44;p ieft, Lambda -r- 0.81, F= 9.92; dJ’= 1. 43; p c: 0.003: right temporal lobe I> left, Lambda == 0.8 1, F= 10.9; @= I, 43; p < 0.002). No side X diagnosis interactions were present, Indicating no abnormalities XI rtght-left asymmetries in these schizophrenic subjects. in Analysis #2 VBRs were calculated and found to be significantly larger in the schizophrenic subjects compared with normal controls. Thirteen of the schizophrenic subjects had (‘7‘ scans performed as part of an earlier study from our group (DeLisi et al.. 1986). The VBR measured by CT was compared with the VBR measured by MRI. A strong positive correlation was found when the two more anterior cuts measured by MRI. at the level of the frontal horns of the lateral ventricles. were compared with the axial CT cut of the frontal horns (I .z= 0.90. p = 0.000 1). The CT cut that maximally visualized the bodies and occipital horns of the lateral ventricles was compared with the third. more posterior MRI cut, at the level of the bodies of the lateral ventricles. and a significant correlation was again noted (r = 0.79. it = 0.0004)
Discussion The major finding of the present study is bilateral reduction in temporal lobe volume in schizophrenic subjects. This finding adds support to the other recent post-mortem and MRI studies that localize a site of pathology in schizophrenia to the temporal lobe. In a preliminary study of a subgroup of these scans using manually traced structural outlines and planimetry. we reported modest bilateral area reduction of the hippocampus-amygdala (DeLisi et al., 1988). Our present report fails to show a difference in one set of measurements (Table l), but did so (Table 2) in another. This discrepency may be due, in part, to the low reliability of measurements made of these small structures on MRI scans, as well as our inability to obtain thinner, more closely spaced slices through this region, as was done in the recent study by Bogerts et al. (1990). The differences in these structures seem to be subtle and were detected in a study of discordant monozygotic twins (Suddath et al., 1990) by using the well twin from each pair for comparison. It should be noted, however, that while reduction of the hippocampus (Jeste and Lohr, 1989; Falkai and Bogerts, 1990) and the parahippocampal gyrus (Brown et al., 1986) has been reported in post-mortem brains of schizophrenic patients, overall temporal lobe reduction has not been described in post-mortem studies. The present study in part confirms previous reports of ventricular enlargement in schizophrenia. In at least one post-mortem study, ventricular enlargement is shown to be greatest in the left temporal horn of the lateral ventricles (Crow et al., 1989a). In the present study, we report enlargement of the temporal horns of the lateral ventricles in one set of analyses with greater magnitude on the left side, particularly in the anterior slice (Table 1). Our finding of enlargement of the lateral ventricular system is present bilaterally and is also noted to be greater on the left side (Table 2). Also of note is the fact that the changes in the amygdala-hippocampus in Analysis #2 were greater on the right side. Similar findings were recently reported (Bogerts et al., 1990). A possible explanation is that this change reflects an altered disposition of these structures with respect to the coronal plane.
145 Differences in some of the results occurred between our two sets of analyses and may be due to several factors. The control groups overlapped, but differed between the two analyses with only 13 of 28 total control subjects common to both. This change in control groups may contribute to the difference in our findings, although a more likely explanation is that correlations for measurements of the smaller, more irregularly shaped brain structures (amygdala and hippocampus) were lower than for the larger, more clearly defined brain structures (temporal lobes). We do not think that these differences resulted from actual measurement methodology (Analysis #l used radiographic films and Analysis #2 used computer tapes of the images) since at least with the larger areas (temporal lobes) both types of measurements were highly correlated. The significance of gross anatomical differences in schizophrenia remains controversial. It has been presented that brain structural differences in schizophrenia are a result of neurodevelopmental dysfunction prenatally or in early life (Crow, 1984; Weinberger, 1987; Crow et al., 1989~) and that these differences may be present before the onset of illness. The present study only examined chronic schizophrenic subjects. In a more recent study of newly diagnosed first episode schizophreniform subjects (DeLisi et al., in press), significant ventricular enlargement was found while temporal lobe reduction was not. Chronic schizophrenic subjects were found to have greater ventricular enlargement than the first episode patients and smaller left temporal lobes. Thus, the timing of the occurrence of brain morphological changes in schizophrenia, and whether they are progressive, has not been resolved. In some studies (e.g., Crow et al., 19896) morphological changes have been detected which are greater in early onset cases. In the present series age of onset was early at approximately 20 years. This may possibly be relevant to the fact that the temporal lobe changes are greater in this than other studies. In summary, we have investigated a series of chronic schizophrenic subjects with a familial tendency for illness, and report the presence of bilateral reduction of temporal lobe size and ventricular enlargement (also bilateral but greater on the left). Our findings are not correlated with age, years since onset of illness, presence of auditory hallucinations, or history of substance abuse. The& findings relate to a group of chronic schizophrenic subjects; determination of the timing of these events awaits studies of at-risk and newly diagnosed subjects, The authors are grateful to Julie Guroff and Diane Kazuba for technical assistance; Elizabeth Maxwell, M.S.W., for assistance with the recruitment and diagnosis of subjects; Lynn R. Goldin, Ph.D., and Christopher Frith, Ph.D., for consultation on statistical analysis; and Thomas Chase, M.D., for allowing us the use of his image analysis system at the National Institutes of Health. The authors are also grateful for the financial support received from the Public Health Service (I.D.D., NRSA Fellowship), the British Council (LT.), and the Greek Ministry of Health (A.K.). Acknowledgments.
References Altshuler, L.L.; Conrad, A.; Kovelman, J.A.; and Scheibel, A. Hippocampal pyramidal cell orientation in schizophrenia: A controlled neurohistologic study of the Yakovlev collection. Archives of General Psychiatry, 44:1094-1098, 1987. American Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: APA, 1987.
Andteasen, N.; Nastallah, H.A.; Dunn. V.; Oison, S.C.: Grove, W.M.; Ehrhardt, J.C’.. Coffman. J.A.; and Ctossett, J.H.W. Structural abnormalities in the frontal system in schizophrenia: A magnetic resonance imaging study. Archivc~s of General f.sychiotrr. 43: 1% 144, 1986. Bogerts. B.; Ashtari, M.; Degreet. G.: Alvlr, J.M.J.; Bilder, R.M.; and Lieberman, .1.X. Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenics. Psychiatry Research: Neuroimuging, 35: 1- 13, 1990. Brown, R.; Colter, N.; Corsellis, J.A.N.; Crow, T.J.; Frith, C.D.; Jagoe, R., Johnstone. E.C.; and Marsh 1.. Postmortem evidence of structural brain changes in schizophrenia: Differences in brain weight, temporal horn area and patahippocampal gytus compared with affective disorder. Archives of‘ General f.rychiatr_v. 43:36-42, 1986. Crow, T.J. A re-evaluation of the viral hypothesis: 1s psychosis a result of rettoviral integration at a site close to the cerebral dominance gene? Britlrh Journal u/’ Ps\*chiatry. 145:243-253, 1984. Crow, T.J.; Ball, J.; Bloom, S.; Brown, R.; Btuton, C.J.; Colter, N.; Frith, CD.; Owens, D.G.C.; and Roberts G.W. Schizophrenia as an anomaly of development of cerebral asymmetry. Archives of General Psychiatry, 46: 1145-I 150, 1989a. Crow, T.J.; Colter, N.; Ftith, C.D.; Johnstone, E.C.; and Owens, D.G.C. Developmental arrest of cerebral asymmetries in early onset schizophrenia. Psychiatry Research, 29:247-253, 19896. Dauphinais, l.D.; DeLisi, L.E.; Hauser, P.; and Gershon, E.S. Limbic system structural brain abnormalities in schizophrenia by magnetic resonance imaging. Presented at the 140th Annual Meeting of the American Psychiatric Association, Chicago, IL, May 1987. DeLisi, L.E.; Dauphinais, l.D.; and Gershon, E.S. Petinatal complications and reduced size of brain limbic structures in familial schizophrenia. Schizophrenia Bulletin, 14: 185-191, 1988. DeLisi, L.E.; Goldin, L.R.; Hamovit, J.R.: Maxwell, M.E.; Kurtz, D.; and Getshon, E.S. A family study of the association of increased ventricular size with schizophrenia. Archives qf General Ps_ychiatry,43: 148-153, 1986. DeLisi, L.E.; Goldin, L.R.; Maxwell, M.E.; Kazuba, D.M.; and Getshon, E.S. Clinical features of illness in siblings with schizophrenia or schizoaffective disorder. Archives o/ General Psychiatry, 44:89 l-896, 1987. DeLisi, L.E.; Hoff, A.L.; Schwartz. J.E.; Shields, G.W.; Halthorne, S.N.; Gupta, S.M., Henn, F.A.; and Anand. A.K. Brain morphology in first episode psychotic patients: A quantitative magnetic resonance imaging study. Biological Psychiatry, in press. Falkai, P., and Bogerts, B. Motphomettic evidence for developmental disturbances in the brains of schizophrenic patients. Presented at the 5th Biennial Winter Workshop on Schizophrenia, Badgastein, Austria, January 1990. Jakob, H., and Beckmann, H. Prenatal developmental disturbances in the limbic allocottex in schizophrenics. Journal of Neural Transmission, 65:303-326, 1986. Jeste, D.V., and Loht, J.B. Hippocampal pathologic findings in schizophrenia. Archives of General Psychiatry, 46:1019-1024, 1989. Johnstone, E.C.; Crow, T.J.; Frith, C.D.; Husband, J.; and Kreel, L. Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Loncet, 11:924-926, 1976. Johnstone, E.C.; Crow, T.J.; MacMillan, J.F.; Owens, D.G.C.; Byddet, G.M.; and Steiner, R.E. A magnetic resonance imaging study of early schizophrenia. Journal qf Neurology, Neurosurgery and Psychiatry, 49: 136-139, 1986. Johnstone, E.C.; Owens, D.G.C.; Crow, T.J.; Ftith, CD.; Alexandtopoulos, K.; Bydder, G.; and Colter, N. Temporal lobe structure as determined by nuclear magnetic resonance in schizophrenia and bipolar affective disorder. Journal of Neurology, Neurosurgery and Psychiatry, 52:736-741, 1989. Mathew, R.J., and Pattain, C.L. Midsagittal sections of the cetebellar vermis and fourth ventricle obtained with magnetic resonance imaging of schizophrenic patients. American Journal of Ps_vchiatry, 142:970-971. 1985.
147 Mathew, R.J.; Partain, C.L.; Prakash, R.; Kulkarni, M.V.; Logan, T.P.; and Wilson, W.H. A study of the septum pellucidum and corpus callosum in schizophrenia with MR imaging. Acta Psychiatrica
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72:414-421, 1985.
Kelsoe, J.R.; Cadet, J.L.; Pickar, D.; and Weinberger, D.R. Quantitative neuroanatomy in schizophrenia: A controlled magnetic resonance imaging study. Archives of General Psychiatry,
45533-541,
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Mazure, C., and Gershon, ES. Blindness and reliability in lifetime psychiatric diagnosis. Archives of General Psychiatry,
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Nasrallah, H.A.; Andreasen, N.C.; Coffman, J.A.; Olson, S.C.; Dunn, V.D.; Ehrhardt, J.C.; and Chapman, S.M. A controlled magnetic resonance imaging study of corpus callosal thickness in schizophrenia. Biological Psychiatry, 211274-282, 1986. Rossi, A.; Stratta, P.; D’Albenzio, L.; Tartaro, A.; Schiazza, G.; DiMichele, V.; Ceccoli, S.; and Casacchia, M. Reduced temporal lobe area in schizophrenia by magnetic resonance imaging: Preliminary evidence. Psychiatry Research, 29:261-263, 1989. SAS Institute Inc. Statistical Analysis System (Version 5). Cary, NC: SAS Institute Inc., 1985. Scheibel, A.B., and Kovelman, J.A. Disorientation of the hippocampal pyramidal cell and its processes in the schizophrenic patient. Letter to the editor. Biological Psychiatry, 16:101102, 1981.
Shelton, R.C., and Weinberger, D.R. X-ray computerized tomography in schizophrenia: A review and synthesis. In: Nasrallah, H.A., and Weinberger, D.R., eds. Handbook of Schizophrenia. Vol. 1. Amsterdam: Elsevier Science Publishers, 1986. pp. 207-250. Smith, R.C.; Baumgartner, R.; and Calderon, M. Magnetic resonance imaging studies of the brains of schizophrenic patients. Psychiatry Research, 20:3346, 1987. Spitzer, R.L.; Endicott, J.; and Robins, E. Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. 3rd ed. New York: New York State Psychiatric Institute, 1977. Spitzer, R.L., and Endicott, J. Schedule for Affective Disorders and Schizophrenia (SADS). New York: New York State Psychiatric Institute, 1978. Suddath, R.L.; Casanova, M.F.; Goldberg, T.E.; Daniel, D.G.; Kelsoe, J.R.; and Weinberger, D.R. Temporal lobe pathology in schizophrenia: A quantitative magnetic resonance imaging study. American Journal of Psychiatry, 146:464472, 1989. Suddath, R.L.; Christison, G.W.; Torrey, E.F.; Casanova, M.F.; and Weinberger, D.R. Anatomic abnormalities in the brains of monozygotic twins discordant for schizophrenia. New England Journal of Medicine, 322:789-94, 1990. Weinberger, D.R. Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry, 44:660-669, 1987.
I37
Elsevier
Reduction in Temporal Lobe Size in Siblings With Schizophrenia: A Magnetic Resonance imaging Study I. Deborah Dauphinais, Lynn E. DeLisi, Timothy J. Crow, Kostas Atexandropoulos, Nigel Colter, Ivan Tuma, and Elliot S. Gershon Received February 28, 1990; revised version received August 1.5, 1990; accepted August 19, 1990. Abstract. Twenty-eight individuals with familial schizophrenia, from 16unrelated families (12 sibling pairs and 4 individuals whose siblings refused scanning), and 21 normal control subjects were examined by cerebral magnetic resonance imaging (MRI). Measurements of the cerebrum, temporal lobes, and cerebral lateral ventricles were obtained using consecutive coronal sections containing these structures. Temporal lobe volume was significantly decreased by approximately 10% in these early onset schizophrenic siblings compared with normal controls. These findings add to recent post-mortem and neuroradiological evidence for morphological alteration in the temporal lobes in schizophrenia. Key Words. Sch~oph~~a, familial, magnetic resonance imaging.
Radiologic and post-mortem studies have reported structural changes in the brains of adult schizophrenic subjects, including enlargement of the third and lateral ventricles (Johnstone et al., 1976; Shelton and Weinberger, 1986). The ventricular changes show some selectivity to the temporal horn region (Brown et al., 1986; Crow et al., 1989~) and add to other evidence of temporal lobe abnormalities reported from post-mortem examinations (Scheibel and Kovelman, 1981; Jakob and Beckmann, 1986; Altshuler et al., 1987; Jeste and Lohr, 1989; Falkai and Bogerts, 1990). Magnetic resonance imaging (MRI) has improved resolution and multiplane capacity compared with computed tomography (CT), thereby enabling the examination of limbic brain structures. The findings from cerebral MRI studies in schizophrenia have been diverse and inconsistent. Decreased size of the cranium, cerebrum, and frontal lobes in schizophrenic males (Andreasen et al., 1986); increased width of the anterior and middle regions of the corpus callosum in schizophrenic females (Nasrallah et al., 1986); increased length of the corpus callosum; enlargement of the septum
At the time this work was done, I. Deborah Dauphinais, M.D., and Lynn E. DeLisi, M.D., were in the Clinical Neurogenetics Branch, National Institute of Mental Health, Bethesda, MD. Dr. Dauphinais is now in the Continuing Care Service, Massachusetts Mental Health Center, Boston, MA. Dr. DeLisi is now in the Department of Psychiatry, State University of New York at Stony Brook, Stony Brook, NY. Timothy J. Crow, Ph.D., F.R.C.P., F.R.C.Psych., Kostas Alexandropoulos, M.D., Nigel Colter, and Ivan Tuma, M.D., are in the Division of Psychiatry, Clinical Research Centre and Northwick Park Hospital, Harrow, Middlesex, England. Elliot S. Gershon, M.D., is Chief, Clinical Neurogenetics Branch, National Institute of MentaI Health, Bethesda, MD. (Reprint requests to Dr. L.E. DeLisi, Dept. of Psychiatry, Heaith Sciences Center, T-10, SUNY Stony Brook, Stony Brook, NY 11794, USA.) 01651781/90/$03.50 @ 1990 Elsevier Scientific Publishers Ireland Ltd.
peilucidum (Mathew et ai., 1985); and enlargement of the lateral and third ventricles (Kelsoe et al., 1988) have all been reported. Other MRI studies show no differences in ventricle-to-brain ratio, bicaudate ratio, bifrontal ratio (Smith et al., 1987). cerebellar vermis and fourth ventricle size (Mathew and Partain, 1985) or III qualitative review of the periventricular structures (Johnstone et al., 1986,. Recent studies focused on temporal lobe structures have reported reduced total size of the temporal lobes (Suddath et al, t989), particularly on the left (Johnstone et al., 1989; Rossi et ai., 1989). In a preliminary analysis, we reported bilateral amygdala-hippocampal reductions in schizophrenic subjects (Dauphinais et al., 1987; DeLisi et al., 1988). Subsequent findings, from other groups, $>fbilateral hippocampal reductions in schizophrenic probands compared with their discordant monozygotic twins (Suddath et al., 1990) and reduction of medial limbic temporal lobe structures in schizophrenic subjects (Bogerts et al., 1990) have been reported. ‘The present study expands our preliminary reports to examine in detail structures of the temporal lobes and ventricular system in a cohort of siblings with familial schizophrenia. Methods Subjects. Twenty-eight individuals (15 men and 13 women) with a diagnosis of chronic schizophrenia or schizoaffective illness from 16 unrelated families were recruited for cerebral MRI studies. Subjects were recruited from a larger group of families in which more than one individual from the same generation is ill with schizophrenia (DeLisi et al., 1987). Diagnoses were made using modified Research Diagnostic Criteria (Spitzer et al., 1977; Mazure and Gershon, 1979) on the basis of structured interviews (modified Schedule for Affective Disorders and Schizophrenia; Spitzer and Endicott, 1978) combined with medical records and information from relatives. The mean (i SD) age of schizophrenic subjects was 32.4 ZIZ6.0 years (range 23-43 years) and the mean duration of illness was 12.8 f 5.8 years (range I-27 years). Ten subjects received a diagnosis of schizophrenia (9 chronic, 1 subacute), and 18 subjects were given a diagnosis of chronic schizoaffective disorder. All subjects also met DSM-MT-R criteria for schizophrenia (American Psychiatric Association, f987). One subject was hospitalized at the time of evaluation, 25 subjects were in outpatient treatment, and 2 were not in any treatment. The 26 patients in treatment were taking psychotropic medications at the time of the study. Four schizophrenic subjects had a history of drug abuse, one of alcoholism. and five of both drug abuse and alcoholism. Twenty-eight control subjects were recruited over a 16-month period and formed the group from which controls were selected for two separate comparisons between schizophrenic subjects and controis. Some of the controls were selected from a group of subjects examined with the same scanner for other research studies (e.g., Clinical Brain Disorders Branch, National Institute of Mental Health). The first control group for analysis #l consisted of 21 subjects; 10 were NIMH personnel and I1 were community volunteers. There were 12 men and 9 women (mean age = 36.5, SD = 8.1, range = 20-58 years). The second control group for analysis #2 was selected a few months later and consisted of 21 individuals (9 NIMH personnel and 12 community volunteers; 11 men and 10 women (mean age = 33.3, SD = 6.6 years, range = 21-45 years). Thirteen scans from the first control group were available on magnetic tape and thus were included in the second control group along with scans from eight newly recruited subjects. The community volunteers were interviewed and diagnosed in the same manner as the probands, found to be free of psychiatric and medical illness, and had no family history of schizophrenia or major affective disorder; NIMH personnel were screened for history of major medical and psychiatric illness. There was no significant difference between the schizophrenic and normal control subjects for height, age, or male-female ratio.
139 MRI Procedures. Cerebral scans were performed using a Picker Vista 0.5 Tesla superconducting magnet. Subjects were positioned for scanning by laser light to the canthomeatal line. A midsagittal pilot scan, followed by an inversion recovery sequence in the coronal plane, was obtained on each subject (inversion time [IR] = 600 ms, repetition time [TR] = 3583 ms, echo time [TE] = 30 ms). This Tl weighted sequence was selected to provide maximum differentiation of gray and white matter. Twelve contiguous coronal cuts were obtained, beginning at the anterior-most tip of the frontal lobe at lo-mm intervals. MRI Measurements and Analyses. Two independent sets of analyses were performed, one using measurements obtained from the radiographic films of the images (Analysis #I) and the other using measurements taken directly from magnetic tapes of the computerized images (Analysis #2).
This set of analyses compared patients to the first control group (see above). Measurements were made from the hard copies of two coronal cuts using the Joyce Loebl magiscan system. This system uses a light pen and outline tracking program to draw boundaries that are quantified by computer. Images were magnified X 3 for all measurements except the temporal horn of the lateral ventricle for which magnification was X IO. Contrast was fixed at 20 units and brightness at 10 units. Measurements were made of the cerebral hemispheres (excluding temporal lobes), temporal lobes, left and right amygdala-hippocampi (including the parahippocampal gyrus), cerebral lateral ventricles, temporal horns of the lateral ventricles, and third ventricle. The medial boundary of the temporal lobe was determined by a straight line drawn from the most medial edge of the lateral sulcus to the recess above the optic tract. Temporal lobe gray and white matter were separately measured using an automatic boundary function. The posterior cut visualized the pons at the interpenduncular fossa; the anterior cut was the next cut forward and was always that cut just posterior to the optic chiasm. Although measurements were made by three investigators (K.A., N.C., and I.T.), each structure was measured by only one investigator, and all measurements were done without knowledge of the identities and diagnostic status of the subjects. Reliabilities were assessed from a series of 18 images that were measured by two independent raters and ranged from 0.98 for the cerebral lateral ventricles to 0.60 for the temporal horns of the lateral ventricles. Statistical analysis for this set of measurements was carried out using an analysis of variance covarying for age and height. There were two between-subject factors (schizophrenic vs. control subjects; men vs. women) and two within-subject factors (left vs. right; anterior vs. posterior). All regions were examined, but only the significant results are reported in Table 1. Analysis #I.
#2. This set of analyses compared patients with the second group of controls. Magnetic tapes of the scans were obtained in Picker format (the standard format used by Picker Imaging systems) and converted into a format readable by the VAX computer (J. Cappelletti, LCM/NIMH, modified by T. Collins, private contractor). Measurements were made using a microVAX computer (program developed by H. Burrows, Ph.D., ETB/NINDS) by one investigator (I.D.D.) without knowledge of subject identity. Images were called to the computer monitor by code numbers and magnified X 2.5, producing an image slightly smaller than actual head size. Image contrast was enhanced to maximize visibility of anatomic borders. Boundaries were outlined with a cursor positioned with a hand-guided “mouse,” and area was computed automatically in pixels and converted to square centimeters. On three sequential coronal slices, the following structures were measured: cerebral hemispheres (including the temporal lobes), temporal lobes, and lateral ventricles. On the two more posterior of these slices, the left and right amygdala-hippocampi plus parahippocampal gyrus, the left and right amygdala-hippocampi, the left and right temporal horns of the lateral ventricles, and the third ventricle were measured. The most anterior cut measured was at the level of the optic chiasm; the middle and posterior cuts corresponded to the anterior and posterior cuts measured in Analysis #l. The amygdala and hippocampus were measured as a Analysis
I40
unit because there was no clear boundary between these structures. The lateral boundary 01 the parahippocampal gyrus was determined by a vertical line drawn from the edge of the amygdala-hippocampus. Areas of each structure were summed to give volume estimates. Fig. 1 illustrates the three coronal cuts used in our analyses, and Fig. 2 illustrates the boundaries ot the temporal lobe and medial limbic structures. Ventricle-to-brain ratios (VBRs) were determined by summing ventricular area on all three cuts and were expressed as a Lh ratio to summed cerebral area for these same cuts. The scans of three schizophrenic patients and one control were not measurable with thlb methodology because of blurring of the images on the screen which prevented clear
Table 1. Analysis #1 : Coronal area measurements in cm2 f SD Schizophrenics
Cerebral
hemispheres
Controls
Men (n= 15)
Women (n = 13)
Men (n = 12)
___Women (n = 9)
32.66 f 0.56
30.74 f 0.44
33.17 f 0.90
32.21 f 0.77
32.96 zk0.55
31.71 f 0.42
34.04 Ifi 0.60
31.61 i 0.64
33.51 f 0.46
31.68 * 0.41
34.51 9~0.72
32.96 f 0.79
33.27 f 0.47
31.89 + 0.40
34.00 f 0.46
31.74 f 0.69
excluding
temporal lobe la lP ra rp Temporal lobes’ la
11.46 + 0.56
10.80 f 0.38
12.67 i 0.56
12.12* 0.54
lP ra
11.68 f 0.55
10.91 + 0.31
12.89 f 0.62
11.59 f 0.50
12.57 f 0.50
11.48 + 0.42
13.56 f 0.66
12.79 + 0.58
12.10 + 0.40
12.10 + 0.40
13.48 f 0.66
12.75 + 0.54
rp Amygdala-hippocampus
plus
parahippocampalgyrus la
0.818 f 0.062
0.797 f 0.079
0.961 III 0.069
0.890 k 0.074
IP ra
0.501 f 0.046
0.416 f 0.045
0.557 f 0.063
0.456 rt0.036
0.837 f 0.078
0.923 f 0.093
1.019 f 0.091
0.912 rt0.091
rp
0.538 f-0.041
0.457 * 0.037
0.535 f 0.037
0.480 f 0.057
Cerebral lateral ventricles la
1.748 f 0.19
1.197
1.251 f 0.19
1.295 zt0.10
IP ra
1.555 f 0.18
1.124 f0.18
0.964 f 0.17
1.085 f 0.14
1.524 f 0.15
1.061 zlz 0.14
1.316 f 0.23
1.085 i 0.14
1.403 k 0.16
1.099 +I0.17
1.155 9~0.25
1.126 i 0.18
rp Temporal horns’
f 0.20
la
0.224 f 0.046
0.277 f 0.055
0.161 f 0.018
0.193 ri0.040
IP ra
0.139 + 0.022
0.076 f 0.010
0.093 f 0.023
0.085 f 0.016
0.211 f 0.050
0.225 +L0.059
0.195 f 0.030
0.203 9~0.044
0.101 f 0.016
0.102 f 0.018
0.079 k 0.015
0.085 f 0.019
a
0.083 zt0.043
0.066 f 0.029
0.052 f 0.020
0.053 rtr 0.016
P
0.074 f 0.038
0.058 f 0.072
0.062 k 0.035
0.079 zt0.028
rp Thirdventricle'
-
Note. Analysis of variance (ANOVA) factoring schizophrenics vs. controls and men vs. women with age and height as covariates. la = left anterior, Ip = left posterior. ra = right anterior, rp = right posterior. 1. Significant ANOVA values: Temporal lobes: F = 8.22; df = 1,42; p < 0.01. Temporal horns: F = 7.71; df = 1,26; p < 0.01. Third ventricle: F = 6.01: df = 1, 40; p < 0.02.
Figure 1. Midsagittal slice of the brain
Lines indicate the planes for the coronal slices measured. Measurements were made from the 2 more posterior slices in Analysis #l and from all 3 slices in Analysis 82.
delineation of anatomic boundaries. This blurring was not evident on the films used for Analysis # 1. Reliability of measu~ments was determined for each structure, from the scans of six individuals, measured three separate times. Intraclass correlations for triplicate measures ranged from 0.93 to 0.98 for all structures except for the temporal horns of the lateral ventricles (intraclass correlations: left = 0.72, right = 0.50). A measurement of 0 pixels was assigned to the area of the temporal horn for subjects in which this structure was not visible. The remaining scans were measured in duplicate, and the mean value was used in data analysis. All analyses were performed using the Statistical Analysis System (SAS Institute, 1985). Table 2 shows the volume estimates obtained in Analysis #2. A General Linear Model (GLM) adjusting for height, age, gender, and diagnosis was performed. To analyze for a familial effect on brain structure size, a GLM adjusting for height, age, gender, and family was done. To look for an association of size of brain structures with history of alcoholism in this group of schizophrenic siblings, an additional GLM adjusting for height, age, gender, alcoholism, and diagnosis was performed. In addition, f tests were used to compare schizophrenic subjects with and without a history of substance abuse (n = 10 and n = 15, respectively) and schizophrenic subjects with and without a history of auditory hallucinations (n = 19 and n = 6, respectively). Side and side X diagnosis analyses were done using a multivariate analysis of variance (MANOVA) with repeated measures. Results
A significant reduction was found in the temporal lobes, bilaterally, in schizophrenic subjects compared with normal controls in both sets of analyses (see Tables 1 and 2). In Analysis #I, temporal lobe gray and white matter regions were measured
Figure 2. Coronal slice of the brain at a level 10 mm posterior to the optic chiasm
The figure demonstrates
how boundanes for the temporal lobes and medial limblc structures were determlned
separately, and a similar reduction m area was found in both regions. The temporal horns of the lateral ventricles and the third ventricle were found to be significantly enlarged in schizophrenic patients in Analysis #1 but not in Analysis #2. Significant differences in volume of the right amygdala-hippo~ampus plus parahippo~ampal gyrus and right amygdala-hippocampus were found between schizophrenic and normal control subjects in Analysis #2 but not in Analysis #I. The reduction in cerebral volume found in Analysis #2 appears to result from temporal lobe reduction, since a comparison of cerebral volume minus temporal lobe volume revealed no significant differences between patients and controls. There was no significant correlation of size of brain structures or VBR with age or years since onset of illness (left temporal lobe: Pearson’s r I= 0.16,~ ==0.44; right temporal lobe: r = -0.21, I) = 0.31; VBR: r r= 0.02, ~7 = 0.91 in either set of analyses. Nor were significant differences found in brain structure size between schizophrenic subjects with or without a history of substance abuse or auditory hallucinations. The results of the GLM performed to assess for effects of alcoholism on brain structure size revealed a significant effect for size of the right VBR (Type III sum of squares = 0.0002; F= 4.01; df= 1,44; p -= 0.0522) and the totai VBR (Type III sum of squares = 0.0002; F = 3.97; cif= 1, 44; p = 0.05331, but not for any of the temporaf lobe measurements. A familial efffect was noted only for size of the left cerebral hemisphere volume (Type III sum of squares = 5920.82; F =I. 4.49; # -= I, 31; p = 0.0112) and left plus right cerebral hemisphere area (Type III sum of squares = 19103.26; F= 3.69; c@==1. 31; p = 0.0221).
143 Correlations between the two sets of analyses showed measurements of the temporal lobe to be significantly correlated (right side: r = 0.48,~ < 0.006; left side: r = 0.79, p < O.OOOl),while measurements of the amygdala-hippocampi were not (r = 0.022, p > 0.5).
Repeated measures MANOVA (Analysis #2) revealed a main effect for side in both groups for the measurements of the cerebral hemispheres and temporal lobes Table 2. Analysis #2: Coronal measurements-Volume as the summed areas (cm3 f SD)
estimates expressed
Schizophrenics Men (n = 13)
Controls
Women (n = 12)
Men (n = 10)
Women (n = 10)
Cerebral hemispheres’ Left
177.75 k 10.38
168.72 k
Right
180.23 f 11.04
172.13 + 6.43
Left
39.80 f 5.75
38.71 f 4.14
43.90 f 5.02
41.90 + 6.75
Right
42.26 f 5.73
40.14 * 3.58
47.41 f 5.07
43.71 + 6.25
5.76
184.51 f 12.74
177.74 k 19.49
190.08 +
179.45 k 16.07
9.90
Temporal lobes
Amygdala-hippocampus parahippocampal
plus
gyrusl
Left
6.39 zt 1.09
6.13 f 0.81
7.05 zt 1.24
6.36 zt 1.24
Right
5.96 zt 0.82
6.07 k 0.88
7.00 + 1.03
6.47 zt 0.97
Left
4.04 It 0.88
3.76 k 0.82
4.33*
1.12
4.07 * 0.92
Right
3.64 f 0.77
3.59 f 0.57
4.15 It 0.88
4.01 k 0.76
Left
5.14 f 2.21
3.47 * 1.04
3.10 k 1.36
2.71 zt 0.99
Right
4.42 f 1.67
3.56 zt 1.53
3.38 f 1.42
2.81 * 1.04
Amygdala-hippocampus’
Cerebral lateral ventricles’
Ventricle to brain ratio (in %)I Left
2.86 f 1.18
2.06 f 0.61
1.70 zk 0.76
1.51 k 0.48
Right
2.44 k 0.88
2.06 f 0.87
1.80 f 0.81
1.54 f 0.45
Left
0.12 * 0.13
0.22 f 0.14
0.13 * 0.10
0.20 f 0.15
Right
0.21 f 0.12
0.24 k 0.16
0.19 f 0.11
0.23 f 0.14
0.86 f 0.32
0.63 f 0.98
0.71 f 0.15
0.605 zt 0.29
Temporal horn
Third ventricle
Note. Analyses of variance (ANOVAs) are based on the General Linear Model of SAS adjusting for height, age, gender, and diagnosis. 1. Significant ANOVA values: Cerebral hemispheres,
F = 4.06; df = 1,44;p < 0.05, left side. F = 6.07; of = 1, 44;p < 0.02, right side.
Temporal lobes:
F = 4.67: of = 1, 44; p < 0.04, left side. F = 7.54; df = 1, 44; p < O.tXt9.right side.
Amygdala-hippocampus/ parahippccampal gyrus:
F = 2.21; of = 1, 44; p < 0.15, left side. f = 7.94; of = 1, 44;p < 0.006, right side
Amygdala-hippocampus:
F=1.6l;df=l,44;p ieft, Lambda -r- 0.81, F= 9.92; dJ’= 1. 43; p c: 0.003: right temporal lobe I> left, Lambda == 0.8 1, F= 10.9; @= I, 43; p < 0.002). No side X diagnosis interactions were present, Indicating no abnormalities XI rtght-left asymmetries in these schizophrenic subjects. in Analysis #2 VBRs were calculated and found to be significantly larger in the schizophrenic subjects compared with normal controls. Thirteen of the schizophrenic subjects had (‘7‘ scans performed as part of an earlier study from our group (DeLisi et al.. 1986). The VBR measured by CT was compared with the VBR measured by MRI. A strong positive correlation was found when the two more anterior cuts measured by MRI. at the level of the frontal horns of the lateral ventricles. were compared with the axial CT cut of the frontal horns (I .z= 0.90. p = 0.000 1). The CT cut that maximally visualized the bodies and occipital horns of the lateral ventricles was compared with the third. more posterior MRI cut, at the level of the bodies of the lateral ventricles. and a significant correlation was again noted (r = 0.79. it = 0.0004)
Discussion The major finding of the present study is bilateral reduction in temporal lobe volume in schizophrenic subjects. This finding adds support to the other recent post-mortem and MRI studies that localize a site of pathology in schizophrenia to the temporal lobe. In a preliminary study of a subgroup of these scans using manually traced structural outlines and planimetry. we reported modest bilateral area reduction of the hippocampus-amygdala (DeLisi et al., 1988). Our present report fails to show a difference in one set of measurements (Table l), but did so (Table 2) in another. This discrepency may be due, in part, to the low reliability of measurements made of these small structures on MRI scans, as well as our inability to obtain thinner, more closely spaced slices through this region, as was done in the recent study by Bogerts et al. (1990). The differences in these structures seem to be subtle and were detected in a study of discordant monozygotic twins (Suddath et al., 1990) by using the well twin from each pair for comparison. It should be noted, however, that while reduction of the hippocampus (Jeste and Lohr, 1989; Falkai and Bogerts, 1990) and the parahippocampal gyrus (Brown et al., 1986) has been reported in post-mortem brains of schizophrenic patients, overall temporal lobe reduction has not been described in post-mortem studies. The present study in part confirms previous reports of ventricular enlargement in schizophrenia. In at least one post-mortem study, ventricular enlargement is shown to be greatest in the left temporal horn of the lateral ventricles (Crow et al., 1989a). In the present study, we report enlargement of the temporal horns of the lateral ventricles in one set of analyses with greater magnitude on the left side, particularly in the anterior slice (Table 1). Our finding of enlargement of the lateral ventricular system is present bilaterally and is also noted to be greater on the left side (Table 2). Also of note is the fact that the changes in the amygdala-hippocampus in Analysis #2 were greater on the right side. Similar findings were recently reported (Bogerts et al., 1990). A possible explanation is that this change reflects an altered disposition of these structures with respect to the coronal plane.
145 Differences in some of the results occurred between our two sets of analyses and may be due to several factors. The control groups overlapped, but differed between the two analyses with only 13 of 28 total control subjects common to both. This change in control groups may contribute to the difference in our findings, although a more likely explanation is that correlations for measurements of the smaller, more irregularly shaped brain structures (amygdala and hippocampus) were lower than for the larger, more clearly defined brain structures (temporal lobes). We do not think that these differences resulted from actual measurement methodology (Analysis #l used radiographic films and Analysis #2 used computer tapes of the images) since at least with the larger areas (temporal lobes) both types of measurements were highly correlated. The significance of gross anatomical differences in schizophrenia remains controversial. It has been presented that brain structural differences in schizophrenia are a result of neurodevelopmental dysfunction prenatally or in early life (Crow, 1984; Weinberger, 1987; Crow et al., 1989~) and that these differences may be present before the onset of illness. The present study only examined chronic schizophrenic subjects. In a more recent study of newly diagnosed first episode schizophreniform subjects (DeLisi et al., in press), significant ventricular enlargement was found while temporal lobe reduction was not. Chronic schizophrenic subjects were found to have greater ventricular enlargement than the first episode patients and smaller left temporal lobes. Thus, the timing of the occurrence of brain morphological changes in schizophrenia, and whether they are progressive, has not been resolved. In some studies (e.g., Crow et al., 19896) morphological changes have been detected which are greater in early onset cases. In the present series age of onset was early at approximately 20 years. This may possibly be relevant to the fact that the temporal lobe changes are greater in this than other studies. In summary, we have investigated a series of chronic schizophrenic subjects with a familial tendency for illness, and report the presence of bilateral reduction of temporal lobe size and ventricular enlargement (also bilateral but greater on the left). Our findings are not correlated with age, years since onset of illness, presence of auditory hallucinations, or history of substance abuse. The& findings relate to a group of chronic schizophrenic subjects; determination of the timing of these events awaits studies of at-risk and newly diagnosed subjects, The authors are grateful to Julie Guroff and Diane Kazuba for technical assistance; Elizabeth Maxwell, M.S.W., for assistance with the recruitment and diagnosis of subjects; Lynn R. Goldin, Ph.D., and Christopher Frith, Ph.D., for consultation on statistical analysis; and Thomas Chase, M.D., for allowing us the use of his image analysis system at the National Institutes of Health. The authors are also grateful for the financial support received from the Public Health Service (I.D.D., NRSA Fellowship), the British Council (LT.), and the Greek Ministry of Health (A.K.). Acknowledgments.
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