Subcortical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging study

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Subcortical and Temporal Structures in Affective Disorder and Schizophrenia: A Magnetic Resonance Imaging Study Victor W. Swayze, II, Nancy C. Andreasen, Randall, J. Alliger, William T.C. Yuh, and James C, ~Ehrhardt

Volumetric measurements of subcortical and temporal structures were done on a sample of 54 schizophrenic patients, who were compared with 48 bipolar patients and 47 normal controls. We observed the male schizophrenic patients to have significant enlargement in the putamen and lesser enlargement in the caudate. We found the right temporal lobe to be larger than the left across all diagnostic groups, although bipolar females failed to have this asymmetry. We did not replicate the finding of decreased hippocampal, amygdala, or temporal lobe volume in our schizophrenic patients. Nor did we find significant differences between our bipolar patients and controls in the structures measured, with the exception of the right hippocampus. Our findings are consistent with a developmental defect in pruning of subcortical brain regions or with a comiJensatory synaptic increase secondary to decreased input from other brain regions such as the prefrontal cortex or anterior temporal lobe structures. Coupled with the lack of temporal lobe asymmetry in bipolar females, these findings suggest that different types of genderspecific neurodevelopmental abnormalities may occur in affective versus schizophrenic psychosis, which may reflect the effects of hormonal influences on brain development in predisposed individuals. The past decade has been characterized by a resurgence of interest in neuropathology and in the anatomical substrates of psychopathology. A variety of brain regions have captured the attention of investigators, including the frontal system, temporolimbic regions, the basal ganglia, and asymmetries of the cerebral hemispheres. The bulk of this effort has been applied to the study of schizophrenia, with more modest application to bipolar illness. Postmortem studies have implicated the limbic system as a possible substrate for the cognitive and emotional abnormalities observed in patients suffering from schizophrenia; however, no adequate controlled postmortem studies in bipolar subjects examining the cerebral cortex or the basal ganglia have been done. Controlled studies of schizophrenia have reported reduction in the volume or +,hickness of the hippocampal formation, para-

From the Psychiatry Service (VWS) Veterans Affairs M~ical Center, The Mental Health Clinical Research Center (NLA, RJA) and the Department of Radiology (WTCY, JCE), The University of Iowa Hospitals and Clinics Iowa City, Iowa. Address reprint requests to Dr. V. W. Swayze, !I, PsychiatryService, Veterans Affairs Medical Center, iowa City, IA 52246. Received January 15, 1991, revised September 13, 1991. © 1992 Society of Biological Psychiatry

0006-3223/92/$05.00

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hippocampal gyms, and amygdala; cytoarchitectronic abnormalities in the entorhinal cortex or hippocampus; and decreased numbers of pyramidal cells in the CA! to CA4 subfields of the hippocampus (Scheibel and Kovelman 1981; Kovelman and Scheibel 1984; Bogerts et al 1985; Falkai and Bogerts 1986; Jakob and Beckanann 1986; Brown et al 1986; Colter et al 1987; Falkai et al 1988; Jeste and Lohr 1989; Bogerts et al 1990a; Arnold et al 1991; Conrad et al 1991). Not all of these findings have been replicated, however (Altschuler et al 1987, 1990; Christison et al 1989; Heckers et al 1990a, 1990b). Few specific anatomical abnormalities have been reported in the basal ganglia based on postmortem brain studies, although a study of the Vogt collection reported decreased volume of the internal segment of the globus pallidus (Bogerts et al 1985), and Stevens (1982) also noted some abnormalities in her neuropathologic studies. A svJdy of brains from Copenhagen reported reduced brain weight and reduced hemispheric, cortical, and central gray matter volumes in schizophrenic versus normal control brain tissue (Pakkenberg 1987). The internal pallidum was significantly smaller in both the right and left her,;spheres in schizophrenics compared with controls in the brain collection at the University of Diisseldorf (Bogerts et al 1990a). The nucleus accumbens has also been reported to be smaller in schizophrenics than in controls (Pakkenberg 1990). On ~he other hand, several functional imaging studies have suggested the possibility of hypermetabolic activity, including increased glucose utilization, cerebral blood flow, and De receptor density, in several subcortical brain regions (Wolkin et al 1985; Volkow et al 1986; Wong et al i986; Early et al 1987; Gur et al 1987; Early et al 1989). These functional studies may have structural implications, suggesting the possibility of a greater volume of gray matter in the basal ganglia, based on the following evidence suggest';ng a correlation between size and the level of metabolic activity: (1) A recent MRI study found proportionately greater gray-matter volume in women than in men when compared to their total brain size, although no absolute difference in gray-matter volume was found (Rusinek et al 1991); (2) studies of regional cerebral blood flow and metabolism have shown higher levels of gray matter activity in women than men (Gur et al 1982; Devous et ai 1986; Baxter et al 1987; Yoshii et al 1987, 1988). A substantial literature has also developed to suggest that cognitive and emotional dysfunctions could be based on structural or functional asymmetries of the cerebral hemispheres (Hor-Henry 1969a, 1969b, 1976). Much of this work is based on the wellestablished fact of hemispheric specialization. An anatomical basis for lateral difference concepts was discovered by Geschwind, who first showed that left hemisphere specialization for language was reflected in gross anatomical brain structure with a clear enlargement of the left planum temporale (Geschwind and Levitsky 1968). Postmortem studies of anatomical cerebral asymmetries in psychosis have been limited, although a relatively large functional literature supports this possibility. CT studies of the neuroanatomy of schizophrenia have been inconclusive. In affective illness the strongest evidence that structural abnormalities underly affective symptoms has been derived from the work of Robinson and colleagues. They have demonstrated that hemispherespecific stroke lesions may mimic or produce classic affective syndromes (Robinson and Szetela 1981; Robinson et al 1984; Robinson and Starkstein 1990). Postmortem tissue samples are relatively difficult to collect and usually are obtained from elderly individuals. It is important, therefore, to use neuroradiologic tools to assess brain anatomy in order to disentangle the effects of aging from the effects of the basic psychopathologic process. Magnetic resonance imaging (MRI) is ideally suited to examine possible neuroanatomical subsurates of psychopatholo~y in vivo.

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To date, 11 magtietic resonance imaging (MRI) studies have been published that evaluate temporal lo[-e structure in schizophrenic and/or bipolar subjects versus normal controls. Five of the~e studies evaluated area measurements of the hippocampus, amygdala, or temporal lobe fDeLisi et al 1988; Hauser et al 1989a; Johnstone et al i989; Rossi et al 1990; Young et al 1991). Five used volumetric measurements of various temporal lobe structures (Kelso¢ et al 1988; Suddath et al 1989; Barta et ai 1990; Bogerts et al 1990b; Altshuler et all 1991), and one used both area and volumetric measurements (Suddat,h et al 1990). ~Smadditional study using both area and volumetric measurements compared schizophrenics to bipolar subjects but without a normal control group (Rossi et al 1991). These studies are reviewed in Table 1. Despite the differences in scanner and methodology used, the majority of the studies examining subjects with schizophrenia demonstrated that various aspects of the temporal lobe, hippocampus, and amygdala may be smaller in some schizophrenic samples versus normal controls. Three of these stucies investigated various aspects of temporal lobe structures in affective illness: one found significantly smaller temporal lobe to cerebral areas ratios (Hauser et al 1989a); the second found no significant differences in these subjects compared with controls (Johnstone et al 1989); and the third found both left and right temporal lobe volume to be significantly smaller in bipolars versus controls (Altshuler et al 1991). Two studies examined the volumes of the caudate ~nd the combined putamenglobus pallidus. One found no significant differences in these measurements (Kelsoe et al 1988); the other found the putamen-globus pallidus to be significantly larger bilaterally in schizophrenics versus controls (Jemigan et al 1991). We report here our efforts to systematically apply magnetic resonance imaging to the measurement of temporal and subcortical structures in a relatively large sample of schizophrenic and bipolar affective disorder subjects. We sought to determine whether there were specific abnormalities in temporal and subcortical nuclei that might influence mood and behavior (e.g., hippocampus, amygdala, caudate), and to determine whether overall abnormalities in temporal lobe size or temporal lobe asymmetry could be observed.

Methods

Patient Samples Patients in this study w©re recruited from admissions to The University of Iowa Hospitals and Clinics who met DSM-III criteria for schizophrenia or for bipolar affective disorder. The patients included in this sample are identical to those reported in other papers describing frontal lobe size, ventricular size, and areas of increased signal intensity in affective disorders and schizophrenia (Andreasen ¢t al 1990; Swayze et al 1990). The sample consisted of 55 schizophrenic patients and 48 patients suffering from bipolar affective disorder. These two groups were educationally ~imilar. The mean educational level for the schizophrenics was 13.32 (SD = 2.66), while that of the bipolars was 13.77 years (SD = 2.86). The sex ratios of the two samples were also similar. Thirty-six of the schizophrenics were men and 18 were women; 29 of the bipolars were men and 19 were women. Five of the schizophrenics were left handed and one was mixed; 5 of the bipolars were left handed and 4 were mixed. They were also similar in height and weight. One male schizophrenic had nearly complete agenesis of the corpus callosum and was excluded from the analysis. Clinically, this sample consisted of relatively young individuals who were typically

24

15

15 bipolar; 2 unipolar

21; 20 bipolar

Kelsoe et al 1988

Suddath et al 1989

Hauser et al 1989a

Johnstone et al 1989

21

21

15

14

18

Number of / Controls

24

Subjectsa

Delisi et al 1988

Som'ce

0.15 tesla scanner TR = 544 msec, TE = 44 msec 6-10 8-ram coronal slices

0.5 tesla scanner Inversion recovery; 1"I - 600 msec, TR = 3500 msec ! 2 l-cm coronal slices

0.5 tesla scanner Inversion recovery; TR = 3583 reset, T! = 600 msec 12 l-cm coronal slices 0.5 tesla scanner Inversion recovery; TI - 600 msec, TE -30 msec 12 l-cm coronal slices

0.5 tesla scanner 12 l-cm coronal slices

Imaging techniques

Area ratios for temporal lobe to cerebrum, hippocampal complex to temporal lobe, hippocampal complex to cerebrum, and temporal lobe white to gray matter. All coronal temporal lobe and temporal horn areas. Slice with largest area for each structure was reported.

Volumes of total temporal lobe, total gray matter, and total white matter.

Areas on 2 slices through the hippocampus/amygdala complex, parahippocampa! gyms, and both structures combined (total limbic complex). Temporal lobe volume. Amygdala-hippocampal volume.

Bilateral temporal lobe measurements used

Table 1. Magnetic Resonance Imaging Studies o f Temporal Lobe Structure in Schizophrenia and Bipolar Disorder

Schizophrenic group had smaller total right temporal lobe, right temporal lobe gray matter, and left temporal lobe gray matter volumes. Affective disorder group had significantly smaller temporal lobe to cerebral area ratio; left side only when age/education used in ANCOVA Left temporal lobe is smaller than right in schizophrenics. Result reversed in controls and affecfive patients.

No differences noted.

Total limbic complex is smaller bilaterally on anterior slice and on the right in the posterior slice in schizophrenics

Significant results when compared with controls

t~

17

15 (discordant monozygotic twins)

15

35

Rossi et ai 1990

Suddath et al 1990

Barta et al 1990

Bogerts et al 1990

25

15

1.5 tesla scanner Spin echo; Tit = 800

15 cotwin'

1.0 tesla scanner Tl-weighted; TR = 40 msec, TE = 15 msec 63 3-ram coronal slices

3-mm interleaved slices

msec

1.5 tesla scanner Tl-weighted; TR = 800 m,~c, TE = 20

30 5 - m m slices

msec, T E = 20 msec

0.5 tesla scanner Spin echo; TR = 450 msec, TE = 30 msec 7 8-ram coronal slices

13 Coronal sections depicting temporal lobes at their maximum extent (usually section 4, but section 5 was also measured). Total gray and white matter volumes. Area and volume measurements of hippocampus, gray and white matter, amygdala, and temporal horns on part or all of six slices. Amygdala volume was the sum of the volumes of two largest slices. Superior temporal gyral volume was measured on three slices. Temporal lobe volume was measured on nine consecutive coronal slices. Hippocampus and amygdala were measured as one structure but divided into two portions at the mamillary bodies. Temporal horn was divided in two portions at the slice posterior to the mamillary bodies.

(continued)

Left hippocampal portion and total hippocampus/amygdala are smaller in male schizophrenics. Left anterior temporal horn portion and left total temporal horn are larger in male and female schizophrenics respectively.

Left amygdala, right temporal lobe and right superior temporal gyms were significantly smaller in schizophrenics vs. controls.

Total left gray matter volume was smaller in schizophrenics; bilateral hippocampal area and volume less in schizophrenics.

Left temporal lobe area was smaller on both sections evaluated in schizophrenics.

t~

.¢

mm

m

f~ f~

10; 16 bipolars

31

Rossi et al 1991

Young e,t al 1991

33

None

10

0.08 tesla scanner SR sequence with TR = 800 msec, flip angle = 60°; 10 8mm slices. SR sequence with TR = 500 msec, flip angle = 90°; 10 12mm slices

15 5-mm coronal slices 2-mm interslice gap

msec

0.5 tesla scanner Inversion recovery; TI - 600 msec, TR3500 msec 12 10-mm coronal slices 0.5 tesla scanner spin echo; TR = 2400 msec, TE = 120

Imaging techniques

~l'his study included 6 of the bipolar subjects studied by Hauser et al 1989.

°Subjects are schizophrenic unless other',~:~,',- ~oted.

10 bipolarsb

Number of Subjects° / Controls

Altshuler et al 1991

Source

Table 1. Continued

Ratios of the temporal lobe, hippocampus, amygdala, parahippocampal gyros, and caudate nucleus areas to intracranial area using predetermined representative slices selected from a neuroanatomical atlas.

Temporal lobes were measured on five consecutive slices.

Temporal lobe was measured on 5-6 consecutive slices.

Bilateral temporal lobe measurements used

Temporal lobe was smaller in schizophrenics in two slice areas on the right and four on the left and had reduced total volume compared with bipolars. (Results did not change when covaried for midsagittal brain area.) None of these ratio measurements were significant for schizophrenics. The absolute right-left difference for the amygdala was significant in controls vs. schizophrenics.

Volumes were smaller bilaterally in bipolar subjects.

Significant results when compared with controls ..¢

t,o I,,J

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1992;31:221-24o

seriously ill with multiple l~rior hospitalizations; on the other hand, few required chronic institutionalization. Schizophrenics had a mean age of onset of 2i.44 (SD = 4.44), the number of previous hospitalizations was 6.62 (SD = 5.70), the months of previous hospitalization were 12.26 (SD = 21.53). The mean age of onset for the bipolars was 22.86 years (SD = 7.82), the number of previous hospitalizations was 5.89 (SD = 6.15,~, the months of previous hospitalization were 9.07 (SD = 10.75). The two groups were similar in age. The mean age of the schizophrenic men was 32.28 years, while that of the women was 35.39 years. The mean age of the bipolar men was 33.41 years, while that of the women was 34.63 years. The mean height of the schizophrenic subjects was 174.35 (SD = 76.3) and 164.38 (SD - 9.36) cm for males and females, respectively. The mean height of the bipolar subjects was 176.9 (SD ffi 6.98) and 163.08 (SD = 6.03) cm for males and females, respectively.

Control Subjects Control subjects consisted of 47 healthy volunteers recruited from Iowa City and nearby communities. They were selected in order to obtain a control sample that would be educationally similar to the two patient samples. Their mean educational achievement was 14.17 (SD = 2.26). They were also selected in order to approximate the sex ratio of the patients as closely as possible. Twenty-eight were men and 19 were women. None were left handed and four were mixed. Their height and weight were also equivalent to that of the patient groups. Controls were initially screened with a psychiatric and medical history. Potential control subjects were excluded if they had a history of alcohol or other substance abuse, or a past history of any major mental illness, such as schizophrenia, affective disorder, anxiety disorder, eating disorder, or any other problem leading to psychiatric treatment or the prescription of psychoactive medication. Individuals with a history of serious medical illness or neurological disorder were also excluded. All patients and control subjects gave informed consent.

Clinical Assessment Patients were assessed with the Core Assessment Battery of The University of Iowa Mental Health Clinical Research Center. The standard clinical interview in this battery is the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen 1985). Material covered in the interview permits assessment and diagnosis of schizophrenia and related spectrum conditions, bipolar and unipolar affective disorders and related spectrum conditions, and various forms of alcoholism and other substance abuse. It can be used to make diagnoses with Research Diagnostic Criteria, DSM-III or DSM-m-R criteria. Diagnoses in the present study were based on DSM-III criteria.

MR! Scanning Subjects were evaluated using a 0.5 Tesla MRI scanner (Picker Corp, Cleveland, OH) from The University of Iowa Department of Radiology. Because our major emphasis in this study was measurement of small subcortical gray matter structures (i.e., the caudate, putamen, amygdala, and hippocampus) as well as overall temporal lobe size and asymmetry, we used coronal sections as these permit the best visualization of the structures.

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Figure 1. Representative tracings of structures seen on the MRI.

Our scanning sequence began with a midsagittal scout in order to identify the location of structures that would be measured on the coronal sections. We used this scout film to position our coronal cuts by selecting a reference point in the center of the brain in order to correct as much as possibie for variation in head size. The optic chiasm, which is clearly visualized on the midsagittal scout, was used as the central reference point for the first coronal image. This cut, perpendicular to the midsagittal scout, was designated as CO. Three cuts were then obtained anterior to this reference cut and four posterior to it. These eight cuts were obtained at l-cm intervals with no gaps between slices. Because we were interested in obtaining maximal gray-white contrast, we chose to use an inversion recovery sequence in this study with a TI of 600 msec and a TR of 1600 msec. This inversion recovery sequence lends itself well to morphometric studies designed to measure specific brain structures as it provides excellent definition of gray matter, white matter, and cerebral spinal fluid.

Measurement and Evaluation of Scans For the majority of the analyses reported in this study, measures were obtained by working with the MRI films. Each individual coronal slice was enlarged using an overhead projector. Relevant structures were then traced on the projected images and measured by a planimeter. Figure 1 shows a representative tracing of the structures seen on the eight slices. Structures such as the caudate nucleus, putamen, hippocampus, and temporal lobes were typically seen on multiple slices. The area of individual structures was measured on the multiple slices in which they were seen and the volume thereafter calculated by summing the areas and multiplying by slice thickness. Thus, the measures reported in this text are all tissue volumes in cubic centimeters, apart from the amygdala, which was typically only seen in a single slice ~nd for which only area measurements could be

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obtained. We have assessed the reliability of these measurement techniques and found it to be excellent. Interrater reliability, based on the assessment of 20 patients by two independent raters, was above 0.9 and typically above 0.95. This high level of reliability was achieved by developing an instruction manual that specified the rules to be used in deciding difficult boundary problems. (The manual is available upon request.) This study was begun in 1986, and all of the measurements reported in this paper were completed in 1989 and were based on manual planimetry. Subsequent studies are being done with semiautomated tracing and segmentation techniques. Results Our analyses of temporal structure focused on two major areas: volume of subcortical structures and differences in temporal asymmetry. We have chosen to report the measures of subcortical structures using independent comparison between schizophrenics and normal controls and bipolars and normal controls. We chose this approach because our a priori hypotheses, which were shaped by the neuropathologic literature, were limited to predictions about relationships between schizophrenics and controls. We hypothesized that we would find a decreased size in the hippocampus, and possibly the amygdala, in schizophrenic patients in comparison to normal individuals. We also anticipated possible decreases in caudate size in schizophrenia. On the other hand, we had no a priori hypotheses about the size of these structures in bipolar illness. Table 2 summarizes the volume means and standard deviations of the subcortical brain structures of the schizophrenic patients in this study as compared to the normal controls. The schizophrenic patients do differ significantly on several measures; specifically, both the right and left putamen are significantly larger in the schizophrenic patients, and there is a trend toward enlargement of the caudate. These findings occur principally in the male patients. On the other hand, the a priori predictions of decreased hippocampal or amygdala size are not confirmed. The findings for the bipolar patients are summarized in Table 3. Here we observe no significant differences between patients and controls except for one variable, the volume of the right hippocampus. Because the boundaries of the hippocampus and amygdala are sometimes difficult to determine, we also generated a combined variable that includes volume of both the amygdala and hippocampus summed together. When this variable was examined, no differences were seen. The second area of focus in the present study was temporal lobe size. Our multiple cuts permitted us to assess temporal lobe volume, as the temporal lobes could be clearly seen on five or six consecutive cuts, and in most cases five cuts were measured in this study. The data for temporal lobe size are summarized in Table 4. In all three groups the temporal lobe volume is consistently larger on the right side than on the left. There appear to be interesting differences between the diagnostic groups in the balance of leftright asymmetry between the sexes. Within the bipolar group, the difference between right and left temporal volume is markedly greater in the males than in the females by a ratio of 6 to 1 cc; within the schizophrenic group the difference is relatively greater for females, with a ratio of approximately 3 to 5; within the normal group the differences are nearly equal between sexes, with a ratio of 4 to 3. Because of these potential differences, we analyzed these data with a diagnosis by sex by hemisphere mixed-model analysis of variance (ANOVA). The ANOVA yielded a significant three-way interaction (F[2,142] = 3.18, p < 0.044). This indicates that the

230

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Table 2. Subcortical Brain Structures in Schizophrenic Patients (n = 53) and Control Subjects (n = 47) Schizophrenics Parameter

g

Right caudate Males 2.92 ' Females 2.59 Total 2.81 Left caudate Males 3.00 Females 2.66 Total 2.89 Right putamen Males 5.32 Females 4.69 Total .5. i2 Left putamen Males 5. ! 3 Females ,t, 57 Total 4,95 Right hippocampus Males 1,48 Females 1,29 Total 1.42 Left Hippocampus Males 1.46 Females ! .42 Total 1.45 Right amygdala Males 2.19 Females 2.10 Total 2,16 Left amygdala Males 2.16 Females 2. I 0 Total 2.14 Right amygdala/hippocampus Males 3.67 Females 3.39 Total 3.58 Left amygdala/hippocampus Males 3.62 Females 3.52 Total 3.59

Controls

SD

g

SD

t

p

0.76 0.64 0.74

2.61 2.57 2.60

0.47 0.52 0.48

1.99 0.08 1.75

0.05 ! 7 0.9402 0.0828

0.66 O.66 0.67

2.71 2.62 2.68

0.47 0.50 0.48

1.94 O.21 !. 85

0.0572 0.8352 0.0674

0.94 0.90 0.97

4.80 4.57 4.70

0.67 0.71 0.69

2.52 0.45 2.51

0.0144 0.6539 0.0140

0.95 0.91 0.97

4.68 4.47 4.59

0.84 0.82 0.83

2.01 O.35 1.98

0.0498 O.7309 0.0501

0.61

i.49

0.35

-0.05

0.38 0.55

1.44 1.47

0,38 0.36

- 1.21 -0.54

0.9630 0.2358 0.5943

0,48 0,34 0.44

1.47 ! .40 !.44

0.36 0.47 0.41

-0. I I 0.09 0.02

0.9102 0.9277 0.9873

0,61 0,69 0,63

2.14 1,88 2,03

0,75 0,38 0,63

0.33 I. 12 1.00

0.7417 0.2722 0.3182

0,55 0.64 0,57

2.14 1.97 2.07

0.80 0.47 0.69

0.13 0.71 0.58

0.8990 0.4818 0.5665

0.81 0.83 0.82

3.62 3.33 3.50

0.77 0.53 0.69

O.25 0.25 0.51

0.8003 0.7974 0.6102

0.78 0.73 0.76

3.61 3.37 3.51

0.88 0.59 0.78

0.05 0.66 0.48

0.9607 0.5114 0.6318

interaction o f two variables changes at different levels of a third variable (see Figure 2). Because out interest was to focus on hemispheric differences, the t w o - w a y interactions o f potential interest were diagnosis by hemisphere or sex by hemisphere. The diagnosis by hemisphere interaction was not significant for either sex; however, there was a significant sex by hemisphere interaction for bipolar patients only (F[1,142] - 6.85, p < 0.01). Further analysis o f this interaction found male bipolars to have significantly larger right temporal lobes c o m p a r e d to their left temporal lobes (F[1,142] = 21.35, p <

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Table 3. Subcortical Brain Structures in Bipolar Patients (n = 48) and Control Subjects (n = 47) Bipolars Parameter

~

Right caudate Males 2.59 Females 2.39 Total 2.51 Left caudate Males 2.69 Females 2.46 Total 2.60 Right putamen Males 4.98 Females 4.62 Total 4.84 Left putamen Males 4.80 Females 4.62 Total 4.73 Right hippocampus Males 1.32 Females 1.29 Total 1.31 Left hippocampus Males 1.38 Females 1.27 Total 1.34 Right amygdala Males 2.36 Females 2.01 Total 2.22 Left amygdala Males 2.23 Females 2.06 Total 2.16 Right amygdale/hippocampus Males 3.68 Females 3.30 Total 3.53 Left amygdala/hippocampus Males 3.61 Females 3.34 Total 3.50

Controls SD

~

SD

t

p

0.67 0.53 0.62

2.61 2.57 2.60

0.47 0.52 0.48

- O. 17 - 1.08 - 0.77

O.8650 0.2844 0.44.!4

0.63 0.47 0.58

2.71 2.62 2.68

0.47 0.50 0.48

- 0.18 - 1.02 - 0.73

0.8584 0.3141 0.4705

0.69 0.91 0.80

4.80 4.57 4.70

0.67 0.71 0.69

1.02 0.21 0.88

0.3129 0.8346 0.3793

0.77 0.82 0.78

4.68 4.47 4.59

0. ~4 0.82 0.83

O.59 0.57 0.83

0.5547 0.5734 0.4067

0.37 0.41 0.38

1.49 1.44 1.47

0.35 0.38 0.36

- 1.79 - I. 19 - 2.14

0.0796 0.2435 0.0350

0.40 0.35 0.38

1.47 1.41 1.44

0.36 0.47 0.41

-0.87 -0.97 - 1.29

0.3862 0.3406 0.1999

0.68 0.59 0.66

2.14 1.88 2.03

0.75 0.38 0.63

1.21 0.78 1.43

0.2313 0.4433 0.1569

0.67 0.65 0.66

2.14 1.97 2.07

0.80 0.47 0.69

0.45 0.51 0.67

0.3517 0.6105 0.5046

0.71 0.75 0.74

3.62 3.33 3.50

0.77 0.53 0.69

0.30 - 0.14 0.18

0.7662 0.8926 0.8575

0.68 0.70 0.70

3.61 3.37 3.51

0.88 0.59 0.78

0.00 - O. 16 - 0.08

0.9994 0.8707 0.9396

0.001). Significant main effects were found for sex (F[1,142] = 12.14, p < 0.001) and hemisphere (F[1,142] = 4 0 . 7 8 , p < 0.0001).

Discussion This study has attempted to evaluate the previous findings of reduced size of temporal lobe structures in schizophrenia and bipolar disorder that have been reported in the

232

V.W. Swayze et al

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Table 4. Temporal Lobe Size in Schizophrenia and Bipolar Affective Disorder Bipolar patients

Schizophrenic patients

Control subjects

Male Female Total Male Female Total Male Female Total (n = 29) (n = 19) (n = 48) (n = 36) (n = 17) (n = 53) (n = 28) (n = 19) (n = 47) Right temporal lobe Mean SD Left temporal lobe Mean SD

73.26 6.78

64.29 7.20

69.71 8.18

69.34 9.54

67.84 7.45

68.86 8.88

68.89 808

64.47 8.47

67. I I 8.44

67.49 7.85

63.71 7.45

65.99 7.84

66.30 6.36

62.93 6.77

65.22 6.62

64.01 7.36

61.64 6.92

63.05 7.21

neuropathologic and magnetic resonance imaging literature. In addition~ it evaluated th~ size of several structures of the basal ganglia that have received limited attention to date. We utilized large samples of schizophrenic and bipolar subjects and educationally similar normal controls for this study. Bipolars were examined to determine whether they might also have temporal lobe or subcortical abnormalities when compared with controls. Through measuring temporal lobe volume on sequential coronal cuts in the present study, we have observed a consistent left versus right asymmetry, with the right temporal lobe having a larger volume in all groups. This is consistent with previous reports of temporal lobe measurements in normal subjects. In addition to the finding that the size of the planum temporale is larger on the left, angiographic studies have suggested that the posterior portion of the right temporal lobe is larger since the artery arches higher in the right Sylvian fissure (LeMay and Culebras 1972). This angiographic work and the evaluation of postmortem tissue led to the observation that the entire temporal lobe may be larger on the right (LeMay 1986). Three previous MRI studies that measured temporal lobe volume in normal subjects have confirmed this observation (Jack et al 1988, 1989; Suddath et al 1989). These differences are assumed to reflect differing underlying structural specialization of the left hemisphere versus the right hemisphere for language and other functions. A significant finding in this study is an unusual interaction between diagnosis, sex, and asymmetry of temporal lobe size. We have observed a difference in the temporal lobe volume asymmetry for male bipolar patients but not for female bipolar patients. This was not reported in a preliminary MRI study, although the sample was probably too small to detect any sex difference (Altshuler et al 1991). Recent evidence suggests that there may be a difference in cortical localization for areas serving particular motor skills and that this may be due to the activation effects of sex hormones (Kimura 1983; Hampson and Kimura 1988). Studies in the rat have shown that there is an inverse relationship of cerebral cortical thickness to the number of estrogen receptors that the cortex contains. M~les have a thicker cortex in .*beright hemisphere with a lower number of estrogen receptors than in the left hemisphere. The opposite is true for the female, in which the cortex is thicker on the left with fewer estrogen receptors than in the right cortex (Sandhu et al 1986). In humans, a significantly greater number of females have a larger planum temporale in the right hemisphere than do males, although both sexes still have a predominance of a larger planum in the left hemisphere (Wada et al 1975). Highly significant sexual dimorphisms have been found in cell groups in the preoptic-anterior hypothalamic area, and a dark-

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staining region of the bed nucleus of the stria terminalis are larger in men than in women in terms of total volume (Swaab and Fliers 1985; Allen et al 1989; Allen and Oorski 1990). Differences in the midsagittal area of the massa intermedia and anterior commissure have t~een reported, with women having both increased area of the massa intennedia and greater cross-sectional area of the anterior commissure (Allen and Oorski 1986, 1987). Studies of multiple area, shape, length, and thickness measurements of the corpus callosum as ev~.luate¢ in the midsagittal plane both in postmortem studies and with MRI have reported various findings of sex differences, but the results are inconsistent (De LacosteUtamsing and Halloway 1982; Nasrallah et al 1986; Hauser et al 1989b; Witelson 1989; De Lacoste et al 1990; Allen et al 1991). Our failure to find specific abnormalities of hippocampus and amygdala in schizo-

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phrenic subjects is not entirely surprising, considering two recent postmortem studies that have not confirmed reduced hippocampal size when care has been taken to control for or eliminate potential errors secondary to brain shrinkage (Heckers et al 1990a; Altshuler et a! 1990). Although it is possible that patients with less severe types of schizophrenia may have fewer morphologic changes, our sample, although not chronically institutionalized, was sufficiently seriously ill to require multiple hospitalizations. Our subjects were similar in age and du,'ation of illness to patients studied at the National Institute of Mental Health (NIMH) whe showed morphologic abnormalities (Suddath et al 1989, 1990). Our study, however, should not be construed as disconfirming the earlier postmortem studies or previous MRI findings. From its inception MRI has had impressive anatomical resolution, but first generation MRI cannot "see" the brain with the same level of precision as can be done in postmortem anatomical studies or in microscopic neuropathologic investigations. Our particular study had significant limitations similar to those reported by a group at NIMH (Kelsoe et al 1988), as both were based on relatively thick (l-cm) slices and both used manual planimetric measurement techniques. The use of thick slices and the resulting partial volume effects reduce the sensitivity of finding subtle differences in small, irregularly shaped structures. In addition, our amygdala/hippocampal measurements only used 3-4 slices because of concerns about standardization of boundaries; this produces undersampling of total amygdala/hippocampal volume. These limitations may account for our inability to detect decreased hippocampal size. We have observed a significant enlargement of the putamen and the caudate in our male schizophrenic patients. This finding was not anticipated, but recently two other groups observed similar enlargement of portions of the basal ganglia (Heckers et al 1991; Jernigan et al 1991). Because of the involvement of these basal ganglia structures in a variety of circuits that mediate cognition and behavior, this finding is potentially interesting. What might explain this finding, and why does it appear to be limited to male patients? Both the finding of abnormal asymmetry in female bipolars and the increased basal ganglia size in male schizophrenia patients could be accounted for by some type of neurodevelopmental abnormality that is mediated through eithvr genetic or external environmental influences. Because both of these disorders have an age of onset in the late teens and early 20's and as gender differences have been noted, the findings could potentially be explained as due to a neurodevelopmenmi anomaly that is hormonally mediated. One likely possibility is an abnormality in "synaptic pruning" (Huttenlocher 1979; Huttenlocher et al 1982; Rakic et al 1986). It is now relatively well established that synaptic density increases during early childhood and then subsequently declines as axons and dendrites are selectively eliminated, a process that occurs during childhood and adolescence and is potentially hormonally mediated. Increased synaptic density could be reflected in the overall size of structures. An alternate possibility is that the increased size of these basal ganglia structures represents increased synaptic density developed as a compensatory response to decreased input from anterior temporal, frontal, or thalamic regions. A number of studies in different animal species have indicated that sex hormones are involved in many aspects of neuronal, dendritic, and synaptic growth and elimination, depending on the developmental time ped¢~l, the anatomical region, and the animal species (MacLusky and Naftolin 1981; Arnold and Gorski 1984). For example, it is presumed

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that dendrites have more bifurcations and a greater number of spines in the preoptic nucleus of the hypothalamus as a result of exposure to increased testosterone levels during the prenatal sensitive period in the male Macaque monkey (Ayoub et al 1983). Following castration in male rats, a substantial decrease in dendritic field extent and a loss of synaptic terminals occur in the spinal nucleus of the bulbocavernosus; in female rats without sufficient androgen exposure, partial pruning or elimination of neurons, dendritic fields, and synapses occurs spontaneously in perinatal development of this nucleus. However, androgen exposure in female rats attenuates this elimination of neurons (Breedlove and Arnold 1983; Nordeen et al 1985). There is also increasing evidence that androgen is converted to estrogen by way of a microsomal enzyme system called the aromatase complex located in various brain re~ions of primate and subprimate species. This includes the hypothalamus, amygda~a, hippocampus, and association cortices (Toran-Allerand 1984; MacLusky et al 1986, 1987; Clark et al 1988). It is clear that estrogen influences sex differences in synaptogenesis by its ability to increase the number of synapses and to increase cell growth and proliferation of axons (Naftolin et al 1990). As pointed out in the introduction, gray-matter volume appears to be proportional to various metabolic parameters, and therefore our findings in the schizophrenic patients are consistent with the earlier positron emission tomography (PET) studies suggesting increased glucose utilization, cerebral blood flow, and D2 receptor density in the basal ganglia (Wolkin et al 1985; Volkow e~ al 1986; Wong et al 1986; Gur et al 1987; Early et ai 1989). Because most indices of brain metaboiic activity are reflective of synaptic activity (Schwartz et al 1979; Mata et al 1980), these results would be consistent with a neurodevelopmental failure of pruning or with a compensatory synaptic increase in basal ganglia structures. These results are also consistent with the substantial literature on hypofrontality as reviewed recently by Buchsbaum (1990) and Berman and Weinberger (1990), as well as some of the theoretical literature suggesting a relative imbalance in the circuits that connect the prefrontal cortex and the basal ganglia (Weinberger 1987; Early et al 1989; Andrea~en et al 1989a, 1989b; Hoffman and Dobscha 1989). The findings in the bipolar patients are more difficult to account for, but are consistent with a similar explanation. The reported gender differences in several subcortical nuclei and commissures, coupled with the literature describing gender differences caused by the effect of sex hormones on cortical development, are consistent with this finding. In this context, the decreased size of the right hippocampus is puzzling, particularly as the effect appears to be contributed primarily by the males, who have relatively large right temporal lobes. Given the number of statistical tests performed, we suspect the hippocampal finding could be due to a Type I error. Both the results in bipolar patients, as well as those in schizophrenic patients, should be viewed with caution and should be tested in adGitional replication studies. New software now available for reconstructing MRI images permits the imaging of considerably thinner contiguous slices. One study has already been published using 3. lmm contiguous slices whicl~ showed that schizophrenic males have significantly smaller left hippocampal volumes than male controls. Left anterior temporal horn in males and overall left temporal horn volume in females was significantly greater in the schizophrenics than in the controls (Bogerts et al 1990b). Further investigations using thin slices that have greater contrast between gray and white matter will test for the presence or absence of abnormalities in subcortical regions with much more power than was available in the present study. These thin slices can be used to produce detailed volume renderings of

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the brain that can then be used to define the anatomical boundaries of structures such as the frontal and temporal lobes with greater precision than has previously been possible (Levin et al 1989). We currently have such studies underway. This research was supported in part by NIMH Grants MH31593, MH40856, and MHCRC 43271; The Nellie Ball Trust Fund, Iowa State Bank & Trust Company, Trustee; and a Research Scientist Award, MH00625.

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