A histological study of the corpus callosum in chronic schizophrenia

Psvchiatr)' Research, 8 .251-260(1983)

Elsevier

251

A Histological Study of the Corpus Callosum in Chronic Schizophrenia Henry A . Nasrallah, Mona McCalley-Whitters, Llewellyn B . Bigelow, and Frederick P . Rauscher Received August 25, 1982; revised version received January l7, /983 ; accepted februarr l2,

198.3 . Abstract . As a followup to a post-mortem study of the brains of schizophrenic and control subjects where the corpus callosum was found to be significantly thicker anteriorly in early onset compared to late onset schizophrenia, histological sections of 18 schizophrenic, 7 manic-depressive, and I I medical ; surgical control subjects were prepared using a stain for glia and a stain for callosal fibers . A quantitative study of the concentration of glial cells and interhemispheric callosal fibers revealed no difference between groups . A neuropathologist unaware of the tissue origin rated the histological sections forgliosis . There was significantly more severe gliosis in the callosi of the late onset schizophrenics compared to early onset schizophrenics as well as the control group . These preliminary findings suggesting callosal pathology are discussed, and the need for further studies is stressed . Key Words . Schizophrenia . corpus callosum, histopathology, gliosis, cerebral ventricles . Over the past decade, the corpus callosum, which is the largest inter hemispheric commissure, has become an important brain area for psychiatric research,The main impetus for this trend came from the classic commissurotomy (split-brain) studies that revolutionized the scientific and philosophical views of brain function (Sperry, 1968 ; Gazzaniga, 1970) . The most important finding to come out of the split-brain studies (in which the corpus callosum and ; or other commissures were sectioned) is that the two cerebral hemispheres contain two separate and different spheres of consciousness, which are fully integrated via the corpus callosum and other commissures into one cohesive self (Gazzaniga and LeDoux, 1978) . In split-brain patients, each hemisphere exists as a separate self with its own perceptions, cognition . and emotions, and the right and left hemispheric spheres of consciousness may at times experience contradictory thoughts, feelings, and intentions (Sperry, 1977) . Surprisingly, patients with a sectioned corpus callosum appear hardly different from their preoperative selves, and

I Ienry A . Nasrallah . M .D ., is Associate Professor of Psychiatry, University of Iowa College of Medicine . and Chief, Psychiatry Service, VA Medical Center. Iowa City . IA, USA . Mona McCalley-Whitters, B .S, is Research t echnician . V A Medical Center. Iowa City_ IA, USA . l .lewellyn B . Bigelow, M .D ., is Director, W .A.W . Division, St Ehzabeths Hospital, Washington, DC, USA . Frederick P . Rauscher, M .D., is Assistant Professor of Psychiatry . Indiana Lniversity School of Medicine, and Staff Psychiatrist, VA Medical Center, Indianapolis, IN, IUSA . (Reprint requests to Dr . H .A . Nasrallah, Chief, Psychiatry Service VA Medical Center . Iowa City . IA 52241 . USA_) 0165-1781 83 0000-0000 $3 .00 ©

Elsevier Science Publishers

25 2 only specialized techniques such as tachistoscopte testing can detect that the right and left cerebral hemispheres arc functioning autonomously (Sperry et al ., 1969) . The importance of the corpus callosum for psychiatry became increasingly more apparent with the rapid developments in the field of cerebral lateralization and asymmetry of function of the cerebral hemispheres in relation to psychopathology (Gruzelier and Plor-Henry, 1979) . In 1972, Rosenthal and Bigelow reported that Loa quantitative study of 10 different brain regions in chronic schizophrenic subjects, only the corpus callosum was found to be significantly different (thicker) in the schizophrenic group compared to psychiatric controls . This finding has been repeatedly referred to in the literature as a possible indicator of interhemispheric dysfunction in schizophrenia (Nasrallah, 1982) . Subsequently, several studies of disrupted interhemispheric transfer of visual (Beaumont and Dimond, 1973 : Eaton et al ., 1979), tactile (Green . 1978; Dimond et al ., 1979 ; Cart, 1980), and auditory perceptions (Green and Kotenko, 1980) in schizophrenia intensified speculations that a diseased corpus callosum may play a central role in the production of schizophrenic symptoms . Dimond (1979) suggested that schizophrenia may he a disorder of cerebral disconnection and urged that histological studies of the corpus callosum be conducted (p . 60) . In the only other study of the corpus callosum in schizophrenia, we reported (Nasrallah et al ., 1979) no difference between schizophrenic and psychiatric control groups, but rioted a strong trend (p = 0 .08) for the early onset (before age 30, usually nonparanoid) schizophrenic subgroup to have a thicker corpus callosum than the late onset (after age 30, usually paranoid) schizophrenic subgroup . A reanalysis of the measurements (Bigelow et al . . 1983) revealed that the difference between early and late onset schizophrenia, as well as the difference between early onset schizophrenia and c ontrols . i s significant for the frontal but not posterior part of the corpus callosum . We present here a histological study of the corpus callosum in theabove-mentioned sample of schizophrenic subjects . The purpose of this investigation was to find if there were quantitative or qualitative histological differences in the callossi of schizophrenic patients as compared to psychiatric and nonpsychiatric control groups .

Methods Of the original sample of brains of chronic schizophrenic and manic patients, diagnosed by Research Diagnostic Criteria (Spitzer et al ., 1978) at St . Elizabeths Hospital . Washington. D .C ., which were used for the measurement of thickness (Bigelow et al ., 1983) . 25 brains were found to be suitably preserved for histological studies . The remaining samples had completely dried due to inadequate preservation . Eleven brains were those of early onset schizophrenics, seven were those of late onsett schizophrenics . and seven were those of manic-depressives . Brains of I I consecutively autopsied matched patients who died at the Unwersuy of Iowa Hospitals of medical or .surgical causes with no history of psychiatric illness and no gross neurological involvement were selected as a control group . Histological preparations for glial cell nuclei (hematoxylin-eosin stain) and for callosal fibers (Bielschowsky stain) were made from the anterior (just before the genu) and posterior (lustbefore the torn ix) parts of the corpus callosum of each subject (Fig . I) . It was decided that because a significant difference in amerior but not posterior callosal thickness was found between early and late onset schizophrenia, a histological comparison was necessary it) investigate possible histological differences between those two callosal regions .

253 Fig . 1 Sag itta I section of the brain showing the ante ri or and posterior regions of the corpus callosum where histological sections were obtianed

The histological slides were coded, and the following studies were done : I . A quantitative study of the concentration of glial cell nuclei and eallosal fibers (crosssections) in the corpus callosi tissue of schizophrenic and control brains was done bya research technician unaware of the tissues origin . A 10 x 10 grid (total area at high power - 0 .56 P2) was used in the microscope eye-piece, and the number of glial nuclei and callosal axons was counted in randomly preselected squares on the grid . The glial nuclei were easy to count, but the eallosal fiber cross-sections were numerous and at times extremely small and hard to count, producing less reliable results . 2 . A qualitative clinical pathological assessment of the same anterior and posterior callosal histological preparations was made by a neuropathologist unaware of the source of the slides or the purpose of the study . The neuropathologist rated each sample for gliosis (defined as an increase in the number of astrocytic and ; or glial cells Jihrils) as absent (0), mild (1), moderate (2), severe (3), or very severe (4) . The rating reflected the most severe degree of gliosis noted on each section . Statistical analysis for the mean concentration of glial cells and callosal fibers was done using analysis of variance (ANOV A) . The Mann-Whitney rank sum test (two-tailed) was used to find differences in gliosis ratings between groups . The mean rank was used for tied ratings .

25 4 Results Table I shows the results of the quantitative study_ the mean number of glial cells and cal losal fibers in schizophrenia (early and late onset), manic-depressive illness, and the medical 'surgical control group . Nod ifferences were found between any of the groups . fable 2 shows the ncuropathologist's ghosts rating for each of the study groups (listed in decreasing order) . Significantly more severe gliosis was found in late onset schizophrenia compared to early onset schizophrenia (anteriorly and posteriorly) and compared to controls (anteriorly) . No other differences emerged between schizophrenia and other groups . However, like the late onset schizophrenics, the manicdepressive subjects had more gliosis antenorly than the controls, and more gliosis posteriorly than early onset schizophrenics . Figs . 20, 2b, 2e, and 2d demonstrate the histological sections with (a) absent . (h) mild, (e) moderate, and (d) severe gliosis in the H & E preparations of callosal tissue in this study . The thickness of each corpus callosum is shown in Table 2 to facilitate comparisons of the gross and histological features of each subject . Table 1 . Concentration of glial cells and callosal fibers in the study groups Glial cells Myelinated callosal fibers per unit area per unit area Age Anterior Posterior Anterior Posterior Diagnosis Early onset 65 . 64 9 .9 9 4 _ 12 8 .21 2 .5 10 .8 1 1 .5 13 .2 * 4 .9 schizophrenia Late onset 11 .8 + 1 .9 73 .3 * 12 .2 9 .5 t 2 .2 8 .1 + 2 .5 12 .5 ± 2 .5 schizophrenia Manic-depressive 70 .4-22 .5 10 .2'2 .2 7 .8-2 .0 10.6'1 .5 11 .5-3 .8 illness Medical/surgical 10 .8 ' 1 .8 8 .7 ± 1 .6 12 .0 - 1 .9 11 .0 - 2 .3 64 .4 2 . 111 controls Statistical analysis ,ANOVA

NS

NS

NS

NS

NS

Data are expressed as mean L SD .

Discussion This histological study was conducted mainly to investigate possible histopathological correlates of a thickened corpus callosum in early onset compared to late onset schizophrenia (Bigelow et al ., 1983)_ However, the finding of significantly more severe gliosis in the late onset group suggests that pathology may be associated with thinner rather than thicker callosal width . The much thicker corpus eallosi in the medical, surgical controls lends further support to this notion . the lack of difference among groups in the quantitative study may be due to the fact that the measurements were done in randomly selected areas of the stained sections

0

0 +1 0

0

(4 .4)

(6 .2)

(4 .6)

(5 .7)

(5 .0)

(4 .5) (6 .4)

(3 .6)

+3' +2 +2

+1

+1

*1'

+1

-1

0 0

0

(4 .6)

1 0

(3 .8)

(5 .2)

+1

-2

(5 .2) (3 .6) (44) (5 .0)

.3' '3 +2'

0 .019

Exact continge ncy table analysis

Manic-depression vs controls

Late onset schizophrenia vs . manic-depression

Early onset schizophrenia vs . manic- depression

Total schizophrenia vs . manic-depression

Total schizophrenia vs . controls

Early onset schizophrenia vs . controls

Late onset schizophrenia vs . controls

Early vs, late onset schizophrenia

n < 0 .04 NS NS NS NS NS <006

p < 0 .02

(9 .1) (11 4) ( 7 .2) ( 45)

NS NS

p<0 .02

p< 0-04 NS NS NS NS

0

(9 .4)

0 0 0

( 8 .2) (106) ( 9 .3) (10 .5) (9 .2) (11 .9)

0

0

0

.1

+1

+1

0 +2' +2 +2

+1

+2

0

0

0 0

+1

0

-1

+2 +2

Medical/ surgical controls (n-11) _ Anterior Posterior

+3' +3'

Manic-depression (n = 7) _ Anterior Posterior

Statistical analysis (rank sum test, 2-tailed)

Late onset schizophrenia (+'-7) Anterior Posterior +3' +3' (3 .5) +3' (40) -3' +3 (3 6) +3 +2' (3 .9) -2 (5 1) +2 (4 .5) 0 (5 .4) 0

1 . Corpora Amylacea with suspected atrophy were noted by the pathologist . 2 . Value in parentheses is the mean corpus callosum thickness tin mm) at the subject at that level_

0

+1

+2 +2

+1

+2

Posterior

(671' (47) (47)

Anterior

Early onset schizophrenia (n=11)

Table 2 . Neuropathologist's blind ratings of gliosis (from 0 to +4) in anterior and posterior histological sections (H & E stain) in the study groups

256 Fig . 2 . Four histological sections (H & E stain)

Figure 2a . Normal callosal tissue

Figure 2b . Mild gliosis

25 7

Figure 2c . Moderate gliosis

Figure 2d . Severe gliosis The four sections show nor mal(a), mild gItosis(b), moderate gliostsfc), and severe gliosis(d) . Moderate and severe gliosis (note increase i n fibrils) were more common in late onset schizophrenia than i n early onset schizophrenia or medical/surgical controls,

25 8 and that counting cross-sections of callosal fibers with diameters less than 1

µ is

difficult and not reliable . On the other hand, the clinical neuropathologist's assessment is made after scanning the entire section, noting patterns of gliosis in some regions and not others, and detecting the increase in astrocytic fibrils which are not detected in the quantitative approach used in this study . the finding of increased gliosis in the corpus callosum is consistent with other reports (Fisman, 1975 : Stevens, 1982) of increased gliosis in various regions of the brains of chronic schizophrenic patients . A viral encephalopathy was suggested by Stevens (1982) as a possible etiology for increased gliosis in schizophrenia . The finding in this study that gliosis was significantly more frequent in late onset (usually paranoid) as compared to early onset (usually nonparanoid) schizophrenia is consistent with reports of a higher frequency of abnormal electroencephalographic (EEG) activity in paranoid than in nonparanoid schizophrenia (I lays, 1977), which suggests organic (rather than genetic) etiology in late onset schizophrenia . In addition, the finding of neuropathological abnormalities in the corpus callosum of schizophrenic patients is consistent with the notions of disrupted interhemispheric integration in schizophrenia (Gruzelier and Flor-Henry, 1979 ; Nasrallah, 1982) and with reports of impaired callosal transfer in schizophrenic patients (Jones and Miller, 1981 ; Gulman et al ., 1982) . Disruption of the anterior corpus callosum by tumors has been shown to be associated with delusions and hallucinations (Nasrallah and McChesney . 1981) compared to controls . However . significant clinical depression was also noted with callosal tumors . There are other possible interpretations of the data in this study . The advanced age of the patients (1 able I), though not significantly different from controls, suggests the possible contribution of aging to the increased gliosis . The frequent observations of corpora amylacea (Table 2), which are associated with degenerative changes in the aging brain, appear to support this possibility . However, it should be noted that Stevens (1982) found that corpora amylaeea in the brains of schizophrenic patients were disproportionately greater than would be expected for their ages . The data here still show that the late onset schizophrenic and the manic-depressive groups, both of whom had a high degree of ghosts compared to early onset schizophrenics and controls, had a higher mean age at death than the early onset schizophrenic or control groups (Table I) . The similarity in gliosis between late onset schizophrenia and manic-depression either suggests that the finding is not specific or that there was a diagnostic overlap between the two groups due to their clinical similarities . A potential source of variance in this study is the fact that the control group cailosi were preserved in formalin for a much shorter period of time (up to I year) compared to the schizophrenic patients (2 to 8 years) . Although formalin fixation has been shown not to alter brain structures significantly (Small and Peterson, 1982), more comparable fixation periods would be preferable . An interesting implication of this study is the possible association of callosal thinning and gliosis with cerebral ventricular enlargement . Over the past few years . several reports have described significant enlargement on computed tomography (CT scans) in the cerebral ventricles of chronic schizophrenic patients (Johnstone et al . . 1976 ; Weinherger et al ., 1979 ; Nasrallah et al ., 1982a) and manic patients as well

259 (Nasrallah et al ., 1982b) . -Shinning of the corpus callosum (which is the roof of the lateral ventricles) and delayed myelination of corpus callosum fibers are known to occur in progressive hydrocephalus, and are associated with lateral ventricular enlargement (Milhorat, 1972 ; Gadson et at ., 1979) . Miller and Sethi (1971) hypothesized that as the lateral ventricles increased in size due to the pressure of cerebrospinal fluid build-up in children with hydrocephalus . the corpus callosum would be mechanically stretched, resulting in partial callosal dysfunction . Whether a similar phenomenon occurs in schizophrenic and manic patients remains to be studied . Finally . a possible explanation of the data is that the increased gliosis found in late onset schizophrenia may, in this particular sample of patients (most of whom were born in the early 1900s), he related to the encephalitis epidemic earlier in this century . Psychiatric sequelae of viral encephalitis include schizophrenia-like and manic-like psychoses . and a viral hypothesis of schizophrenia has been proposed (-Iorrey and Peterson, 1976) . We are currently studying a younger post-mortem sample of schizophrcnic patients in order to avoid the possible confounding effects of aging and the encephalitis epidemic . Acknowledgment . Dr . Michael Noel Hart, neuropathologist . provided culuable assistance .

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