Psychiatry Research: Neuroimaging, 40:49-60 49 Elsevier

Family History and Brain Morphology in Schizophrenia: An M RI Study

Steven B. Schwarzkopf, Henry A. Nasrallah, Stephen C. Olson, Bernhard Bogerts, Judy A. McLaughlin, and Tanmoy Mitra

Received August 31, 1990; revised version received March 18, 1991; accepted March 31, 1991.

Abstract. This study examined neuroanatomical differences between male schizophrenic patients with a family history of psychosis (n ---- 16) and those without such a history (n ----- 15). Intracranial area, cerebral area, ventricular size, and cortical atrophy were assessed using magnetic resonance imaging (MRI). Third ventricular enlargement was more prevalent in patients than controls (n -- 15). Familial and nonfamilial patients differed significantly. Reduced cranial and cerebral areas without ventricular enlargement characterized familial patients, whereas nonfamilial patients showed marked lateral ventricular enlargement without a reduction in cranial/cerebral size.

Key Words. Schizophrenia, magnetic resonance imaging, family history.

Attempts to delineate schizophrenic subtypes have a long history, stimulated by marked clinical heterogeneity and the expectation that identifying homogeneous subgroups should yield theoretically and clinically relevant insights. Recently, "tradit ional" symptom-based classifications have been advanced with the use of more refined symptom assessments (Andreasen, 1985). Another approach has been to include neuroanatomical /neuropsychological test findings and neuroleptic response in defining subgroups (Crow, 1980). These classification schemes have been accompanied by more explicit hypotheses about the pathophysiology of specific patient subgroups. Classifying patients on the basis of family history of psychiatric illness has been proposed as a strategy to examine characteristics of patients with either mainly genetic or mainly environmental causes of illness (Murray et al., 1985; Lewis et al., 1987). This approach is based on evidence for the presence of both genetic and environmental factors in the etiology of schizophrenia (McNeil and Kaij, 1978; Kendler, 1983; Kety, 1983; Owen et al., 1988), as well as reports suggesting an "inverse relationship between indicators of brain pathology and family history" (Murray et al., 1988). Despite some theoretical and methodological objections to this

An earlier version of this report was presented at the Annual Meeting of the American Psychiatric Association, San Francisco, CA, May 1989.

Steven B. Schwarzkopf, M.D., is Neuroscience Research Fellow; Henry A. Nasrallah, M.D., is Professor and Chairman of Psychiatry; Stephen C. Olson, M.D., is Assistant Professor of Psychiatry; Judy A. McLaughlin, M.S., is Coordinator for the Schizophrenia Research Program; and Tanmoy Mitra, M.S., is in the Department of Psychiatry and The Neuroscience Program, The Ohio State University College of Medicine, Columbus, OH. Bernhard Bogerts, M.D., is in the Department of Psychiatry, University of Dusseldorf, Dusseldorf, Germany. (Reprint requests to Dr. S.B. Schwarzkopf, OSU Dept. of Psychiatry, 473 W. 12th Ave., Columbus, OH 43210-1228, USA.)

0165-1781/91/$03.50 © 1991 Elsevier Scientific Publishers Ireland Ltd.

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method (Eaves et al., 1986; McGuffin et al., 1987; Kendler, 1988), numerous studies have identified differences between familial and nonfamilial (sporadic) patients, including differences in brain morphology (for review, see Lyons et al., 1989).

Studies of brain morphology in familial and nonfamilial (sporadic) patients have most commonly assessed cerebral lateral ventricular size. A higher incidence of ventricular enlargement or larger ventricular size in nonfamilial patients has been reported by many investigators (Reveley et al., 1984; Oxiensterna et al., 1984; Romani et al., 1986; Turner et al., 1986). However, others have noted larger ventricular measures in familial patients (Nasrallah et al., 1983; Kaiya et al., 1989) or no differences between the groups (Pearlson et al., 1985; Farmer et al., 1987). Ventricular size differences between familial and nonfamilial patients therefore remain controversial.

In addition to the well-established finding of ventricular enlargement in schizophrenia, an overall decrease in brain size (Andreasen et al., 1986; Brown et al., 1986) and focal reductions of cerebral volume (Bogerts et al., 1985; Brown et al., 1986; Suddath et al., 1990) have been reported in schizophrenic patients. Overall reduction in brain size, however, has not been a consistent finding (Andreasen et al., 1990). In a preliminary study of schizophrenic and schizoaffective disorder patients, we found significantly smaller midline cerebral structures in familial patients compared to nonfamilial patients (NasraUah et al., 1988).

On the basis of previous studies, we examined differences between familial and sporadic patients on cerebral ventricular measures. In addition, we attempted to replicate our preliminary results showing reduced midsagittal cranial and cerebral measures in familial patients. We performed magnetic resonance imaging (MRI) scans on a new sample of male schizophrenic patients and controls, assessing lateral and third ventricular size, cortical atrophy, and cranial and cerebral area. Familial patients were compared to nonfamilial patients on these measures, and all patients were compared to controls.

Methods

Subjects. The sample included 31 male schizophrenic patients and 14 male controls, none from the original study. Patients were 18 to 50 years old, had illness onset before age 45, and met DSM-III-R (American Psychiatric Association, 1987) criteria for schizophrenia. Patients were excluded for a history of serious or debilitating medical illness (including seizure disorder), penetrating head injury, prolonged loss of consciousness, neurosurgery, metallic implants in the body, or past/present substance abuse. Most patients were stable outpatients in ongoing treatment, had chronic illness (mean length of illness -- 9 years), and were moderately impaired (mean global assessment rating = 61). Normal controls were volunteers who responded to advertisements and exhibited no psychopathology on a version of the Structured Clinical Interview for DSM-III-R (SCID-R; Spitzer et al., 1987) for controls.

Clinical Testing. Patients were interviewed using the Patient version of the Structured Clinical Interview for DSM-III-R (the SCID-P; Spitzer et al., 1987). The SCID-P, all available medical records, and informant data were reviewed by one of the investigators (S.C.O.), and diagnoses assigned according to DSM-III-R (American Psychiatric Associa- tion, 1987) criteria. Family history data were obtained from face-to-face interview (Family History Research Diagnostic Criteria [FH-RDC]; Endicott et al., 1985) with the patient's mother, or when she was not available, another close family member. Criteria described

51

by Reveley et al. (1984) were used to classify patients as family history positive (FH Pos) if a first or second degree relative had been hospitalized for affective disorder or schizophrenia. Patients not meeting this criterion were classified as family history negative (FH Neg). FH Pos patients were further categorized as either family history positive for schizophrenia (FH Pos SZ) or family history positive for affective illness only (FH Pos AFF). Age, height, and weight were recorded to assess possible confounding effects of body habitus in general.

Cranial and Cerebral Measures. Subjects underwent MRI scanning (Fig. 1) with a General Electric 1.5 tesla scanner using a T1 weighted pulse sequence (TI = 800 MS, TR = 1500 MS). Eight scans per subject were obtained about the midline with a slice thickness of 3 mm and an interslice distance of I mm. The slice passing through or closest to the septum pellucidum was identified as midsagittal. Patients also had a full coronal series (20-30 slices) with slice thickness of 0.5 cm and 0.5 cm interslice interval.

Fig. 1. Midsagittal magnetic resonance (MRI) scan

Midsagittal MRI images were magnified to approximately twice normal head size and traced by a researcher who was unaware of the subject's diagnosis or family history status. The following measurements were made using computerized planimetry (Fig. 2): (1) Cranial area: inner margin of marrow line, foramen magnum, and inferior boundary of the prefrontal lobe used as landmarks. (2) Cerebral area: outline of the sulci traced without smoothing. (3) Frontal area: defined as cerebral area anterior to a perpendicular drawn to the midpoint of the maximal length of the corpus callosum (Fig. 2).

For the frontal and cerebral areas, the two MRI images immediately adjacent to the midsagittal slice were traced, measured, and averaged. An average of the two parasagittal slices was used instead of a single midsagittal measure due to variability of these structures on the midsagittal slice. The reliability and rationale for these measures have been described previously (Andreasen et al., 1986; Coffman et al., 1989). Interrater reliability was high for all three area measures (intraclass correlations: cranial > 0.90, cerebral > 0.95, frontal > 0.80).

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Fig. 2. Tracing of midsagittal MRI scan

c,tllosa.l.~re~tal r - !

Ventr£cZo

Ce reb ra l J~icea

Ace&

Major landmarks include the inner margin of marrow line, the foramen magnum, and a perpendicular drawn to the midpoint of the maximal corpus caUosum length. MRI = magnetic resonance imaging.

Ventricular Measures. On the basis of an examination of the entire coronal series of MRI images, one of the investigators (B.B.) rated lateral and third ventricular size on a 3-point scale (0 = no enlargement, 1 = equivocal enlargement, 2 = definite enlargement). Overall cortical atrophy was also rated on a 3-point scale (0 = no atrophy, 1 = equivocal atrophy, 2 = definite atrophy). Assessments were made without knowledge of diagnostic or family history data.

Statistical Analysis. Group differences (controls, FH Pos patients, FH Neg patients) on potential confounders (age, height, and weight) were assessed using analysis of variance with two planned comparisons (controls vs. patients, FH Pos vs. FH Neg patients).

Group differences for cranial, cerebral, and frontal areas were also assessed using one-way analysis of variance (ANOVA). Two planned comparisons, dictated by a priori hypotheses, were tested (controls vs. patients, FH Pos vs. FH Neg patients). All area measures met criteria for use of parametric methods (Wilks Shapiro test for normality).

Qualitative measures of ventricular enlargement were assessed using nonparametric tests (Kruskal-Wallis, Wileoxon tests). As with the area measures, two planned comparisons were run, contrasting controls with patients and FH Pos patients to FH Neg patients. All p values were calculated using two-tailed testing, and all analyses were run using a standard statistical package (SAS Institute, 1985).

Results

No group differences were noted for age, height, race, or weight (Table 1). Mean differences present should have biased against significant findings since F H Pos pat ients were nonsignificantly older (making ventr icular enlargement more likely) and nonsignif icantly taller and heavier (potential ly biasing toward larger cerebral size in F H Pos patients). Midsagi t ta l area measures were nonsignif icantly smaller in pat ients as c o m p a r e d to controls (Table 2). When patients were divided by family his tory status (Table 2), F H Pos pat ients had consistent ly smaller mean areas than F H Neg patients. This difference was significant for cranial area (t9 < 0.02) and showed a s t rong trend in the predicted direction for cerebral area (p < 0.08). Fron ta l area measures were smaller in the F H Pos group, but this was not significant (p < 0.15). As shown in Fig. 3a and 3b, familial pat ients had smal ler mean cranial

Table 1. Comparison of potential confounding variables by group

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Controls All patients FH neg FH pos Variable (n = 15) (n = 31) (n = 15) (n = 16)

Age (yr) 29.60 31.65 30.60 32.63 (7.46) (5.81) (5.40) (6.18)

Height (cm) 179.55 177.95 176.72 179.10 (4.83) (7.54) (8.50) {6.58)

Weight (kg) 82.92 84.12 82.22 85.89 (17.62) (15.71 ) (12.95) (18.17)

Note. All values are means (SD). FH neg = negative family history of schizophrenia. FH pos = positive family history of schizophrenia.

Table 2. Cranial, cerebral, and ventricular measures by group

Controls All patients FH Neg FH Pos Variable (n = lS) (n = 31) (n = 15) (n = 16)

Cranial area (cm 2) 174.43 170.61 175.611 165.931 (13.46) (10.82) (8.62) (10.79)

Cerebral area (cm 2) 81.20 78.96 81.392 76.682 (8.34) (7.04) (7.16) (6.32)

Frontal area (cm 2) 37.57 36.28 37.21 35.40 (3.71) (3.25) (3.77) (2.48)

Lateral ventricle 0.93 0.97 1.403 0.563 (0.96) (0.87) (0.83) (0.73)

Third ventricle 0.204 0.584 0.67 0.50 (0.56) (0.81) (0.82) (0.82)

Cortical atrophy 0.33 0.32 0.33 0.31 (0.62) (0.601 (0.62) (0.60)

Note. All measures are means (SD). FH neg = negative family history of schizophrenia. FH pos = positive family history of schizophrenia. 1. p < 0.05 (F = 5.87, df = 1). 2. p < 0.10 (F = 3.22, df = 1). 3. p < 0.01, Wilcoxon test. 4. p < 0.10, Wilcoxon test.

and cerebral areas than controls or FH Neg patients. FH Neg patients had mean values very similar to controls. Although the data are not plotted, patients with a first degree relative with schizophrenia (n = 8) had the smallest area measures (cranial 161.6; cerebral 75.36; frontal 35.02).

Significant group differences were found for lateral ventricular measures (Table 2). Although controls did not differ significantly from patients, nonfamilial patients had significantly more enlargement compared to familial patients (Wilcoxon test, p < 0.01). In contrast to lateral ventricular findings, the patient group showed a strong trend for increased third ventricular enlargement compared to controls (Wilcoxon test, p < 0.09); this being significant at the 0.05 level using one-tailed testing. There was no tendency for familial and nonfamilial patients to differ on this measure (Wilcoxon test, p < 0.50), unlike the pattern for the lateral ventricular measures. Fig. 4b shows the low incidence of third ventricular enlargement in

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Fig. 3. Cranial (a) and cerebral (b) area measurements by group

a

.o

o

180.0

177.5

175.0

172.5

170.0

t 67.5

165.0

1 62.5

160.0

1 57.5

t 55.0 Controls All Patients FH Neg F'H Pas

Group

b

u

o

w

Controls i

All Potients FH Neg Group

m

FH Pos

Controls: n = 15, all patients: n = 31, FH neg patients: n = 15, FH pos patients: n = 16. Values indicated are means and standard errors. FH neg = negative family history of schizophrenia. FH pos = positive family history of schizophrenia.

controls (6.7% definite, 6.7% equivocal), despite this group's high incidence of lateral ventricular abnormality. Therefore, although lateral ventricular enlargement occurred frequently in schizophrenic patients, its high incidence in controls made it a nonspecific finding. The increased incidence of third ventricular enlargement in schizophrenic patients and the relative lack of this abnormality in controls made it a more specific but less sensitive finding.

No differences were noted on ratings of cortical atrophy between patients and controls, or between familial and nonfamilial patients (Table 2).

Discussion

The current study is consistent with the majority of reports showing an excess of cerebral abnormalities in schizophrenia. Results also suggest differences in brain

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60%

40%

morphology between patients with and without a family history of psychosis. Familial patients exhibited a reduction of cranial and cerebral area when compared to controls and nonfamilial (sporadic) schizophrenic patients. Nonfamilial patients lacked evidence of cerebral hypoplasia, but had significantly more lateral ventricular enlargement than familial patients. Both patient groups exhibited greater third ventricular enlargement than controls. Despite the high incidence of lateral ventricular enlargement in the patient group, controls in this study exhibited an equally high frequency of this abnormality, making lateral ventricular enlargement a nonspecific finding. This contrasted with the third ventricular findings, which showed infrequent enlargement in the controls.

Support for a decrease in overall brain size in schizophrenic patients comes from a variety of sources. Evidence includes findings from neuroimaging studies (Pearlson et al., 1985; Andreasen et al., 1986), brain weight data from autopsy material (Brown et al., 1986), and head size measurements of children born to schizophrenic mothers

Fig. 4. Lateral (a) and third (b) ventricular enlargement findings

100%

80%

20%

O% Controls All Patients FH Neg FH Pos

(N-15) (N-31) (N-15) (N-16)

m Definite Enlargement ~ Equiv. Enlargement

lOO% ~ b r

80% ! Third Ventricle

r

0% ± ~ Controls All Pstients FH Neg FH Poe

(N.15) (N-31} (N-15) (Nole)

Definite Enlargement ~ Equiv. Enlargement

Parenthesized values indicate sample size and number of subjects with particular rating (definite/equivocal enlargement) in each group. Percentage of combined equivocal and definite enlargement is shown at top of bars.

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(McNeil, 1988). This has not been a consistent finding, however, with some investiga- tors unable to replicate positive results (Andreasen et al., 1990). The present finding of reduced cranial and cerebral areas in familial patients suggests that hypoplasia may be present in patients with a high degree of genetic loading but absent or too subtle to detect in patients with less or no genetic vulnerability. This may explain some of the inconsistencies in the literature regarding cerebral size in schizophrenia. The validity of this finding is strengthened by the observation that effect size (mean differences between familial and nonfamilial groups) increased as the definition of family history was narrowed (FH Pos --" FH Pos SZ ~ FH Pos SZ in first degree relative). Whether schizophrenia is characterized by a continuum of genetic and environmental liabilities (McGuffin et al., 1987) or by discrete groups with predomi- nantly genetic versus predominantly environmental origins of illness, our findings support hypoplasia of cranial and cerebral structures as a marker of genetic liability. The reduction of cranial and cerebral size, and the lack of significant cortical atrophy, suggest a developmental abnormality rather than an atrophic process.

The finding of greater lateral ventricular enlargement in nonfamilial patients is consistent with many but not all previous reports (for review, see Murray et al., 1988). Although there was a significant difference between the patient groups on lateral ventricular measures, this was not observed for the third ventricle. Therefore, lateral, but not third ventricular enlargement, differentiated familial and nonfamilial patients. This finding supports the view of some investigators, who speculate that third ventricular enlargement is more specific to the pathology of schizophrenia than lateral ventricular enlargement (Boronow et al., 1985; Shelton and Weinberger, 1986; Kanba et al., 1987).

Findings in our control group are consistent with the view that lateral ventricular enlargement is a nonspecific finding related to cerebral insult in general. In our controls, we found a high incidence of lateral ventricular enlargement without concomitant third ventricular enlargement. This finding may represent nonspecific environmental insults in psychiatrically well adults. Reports showing differences in ventricular measures between medical controls and "normal" controls (Smith et al., 1988) support a higher incidence of nonspecific lateral ventricular enlargement in the normal population than was previously thought. On the other hand, controls with enlarged ventricles may not be completely typical, since this group showed subtle clinical deviations that were statistically significant (Olson et al., 1990).

Ventricular findings support previous speculation that nonfamilial schizophrenic patients require nonspecific environmental insults to develop illness. These findings are also in agreement with reports indicating lateral ventricular enlargement as a sequela of brain insult (Reveley et al., 1984; Schulsinger et al., 1984; Pearlson et al., 1985). Third ventricular enlargement, on the other hand, may be a pathological characteristic common to both familial and nonfamilial schizophrenia.

Limitations of the current study include weaknesses inherent in the family history method of classification, the use of area and qualitative brain measures rather than volumetric estimates, the lack of female subjects, and modest sample size.

The familial/sporadic categorization risks classifying familial patients as

57

nonfamilial, given most reasonable models of genetic transmission. Cases classified as nonfamilial could have genetic loading due to polygenic inheritance, lack of penetrance of major genes, recessive genes, and quality of data regarding diagnoses in relatives, including difficulty in identifying spectrum cases, sibship size differences, and relatives not having passed through the age of risk (Kendler, 1987). Familial cases could be expected to be more reliably classified. The primary consequence of misclassification would be a dramatic decrease in statistical power (Kendler, 1987; Lyons et al., 1990), making detection of significant differences more difficult (high likelihood of type II error). However, there should not be a bias toward finding spuriously significant results (type I error). Despite the probable lack of robust statistical power, the use of the strategy is supported by many investigators reporting differences between familial and nonfamilial patients (for recent review, see Lyons et al., 1989). While this may be due to excess reporting of positive findings, it may also be due to a large effect size detectable despite misclassifications.

Previous studies have established the increased sensitivity of more quantitative brain measures (Reveley, 1985; Raz et al., 1987). Volumetric measures, therefore, should be the most sensitive in detecting significant differences. The use of area and qualitative measures, as compared to volumetric measures, should not bias toward spuriously positive results. We are currently in the process of determining total cerebral and ventricular volumes for the present sample and for a new sample of patients and controls. The new sample includes female subjects, this being critical to the generalizability of results (Seeman, 1985; Lyons et al., 1989).

Conclusions

The current findings add to evidence supporting excess brain abnormalities in schizophrenia. Results indicate the nonspecific nature of lateral ventricular enlargement and support a greater specificity of third ventricular enlargement for the neuropathology of schizophrenia. Further, the results suggest distinct morphological patterns in patients with and without a family history of psychosis. Nonfamilial patients were characterized by excessive lateral ventricular enlargement without cranial or cerebral size reduction, while familial patients exhibited reduced midsagittal cranial and cerebral areas with infrequent lateral ventricular enlargement. These patterns suggest a genetically determined hypoplasia of neural structures in familial patients that is absent or more subtle in nonfamilial patients. Findings also suggest that nonfamilial patients may experience more environmental brain insults, which may be necessary for the development of psychosis and result in lateral ventricular enlargement. Whether a qualitative "split" between genetic and nongenetic schizophrenia is present, or a continuum of genetic and environmental liability exists, further use of the familial/sporadic approach seems justified in exploring the genetic and environmental features of the illness.

Acknowledgment. Melvin L. Moeschberger, Ph.D., provided valuable statistical consultation. The study was supported by a research grant from the Board of Regents of Ohio to H.A. Nasrallah, M.D.

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