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MRI Brain Abnormalities in Chronic Schizophrenia:

One Process or More?



Bryan T. Woods, Deborah Yurgelun-Todd, Jill M. Goldstein, Larry J. Seidman, and Ming T. Tsuang

It has been suggested that schizophrenia is primarily a prefrontal-temporal-limbic circuitry disorder. Further, it has been argued that primary neurologic vulnerability to the illness is established only during early stages of brain development and is not progressive. We tested the hypothesis of whether brain volume losses in prefrontal and temporal-limbic regions have occurred either before or after brain growth was hypothesized to be complete in schizophrenia. Nineteen chronic schizophrenic patients and 19 age- and sex-matched normal controls underwent magnetic resonance imaging (MRI). All scans were segmented into gray and white matter and cerebrospinal fluid (CSF) compartments for the frontal and temporal lobes and posterior cerebral hemispheres. Multivariate analysis of variance was used to analyze absolute intracranial cerebrum and subregion volumes, i.e., gray, white and CSF, absolute tissue (i.e., gray plus white) volumes, and tissue to intracranial volume (TCV) ratios. Patients showed significant intracranial volume reductions only in the frontal lobes but highly significantly lower TCV ratios (i.e., greater relative tissue loss) in all three major regions. It is suggested that the observed decreases in frontal intracranial volumes reflect a pathologic process in schizophrenia that impacted the frontal regions before brain growth was complete. We hypothesize that the generalized lower patient TCV ratios are attributable to a process that affected the whole cerebrum over a time period after brain volume had reached its maximum levels.

Key Words: Schizophrenia, MRI, brain imaging, frontal lobes, temporal lobes BIOL PSYCHIATRY 1996;40:585-596

Introduction

The evidence for cerebral anatomic abnormalities in schizophrenic patients is very strong (Weinberger 1984). The occasional negative studies can reasonably be attributed to small sample size, unusual patient selection fac-

From the Departments of Neurology and Psychiatry. Texas A & M Medical School and Neurology Section, VA Medical Center, Temple, TX (BTW); Department of Psychiatry, Harvard Medical School and Brain Imaging Center and Mailman Research Center, McLean Hospital, Belmont, MA (DY - T); Harvard Institute of Psychiatric Epidemiology and Genetics (JMG, US, MTT); and Harvard Department of Psychiatry at Massachusetts Mental Health Center, Boston, MA, and Brockton-West Roxbury V A Medical Center, Brockton, MA (JMG, US, MTT); Neuropsychology Laboratory, Department of Psychiatry. Harvard Medical School,

© 1996 Society of Biological Psychiatry

tors, and possibly etiologic heterogeneity. Less unanimity exists for the localization and extent of the abnormalities, though the most frequently replicated findings are lateral ventricular enlargement and] medial temporal volume reduction. Even less settled are the issues of etiology and timing of the causative insults.

The case for a developmental origin of brain abnormalities in schizophrenia comes from both clinical and neu-

Massachusetts Mental Health Center, Boston, MA (JMG. US); and the Department of Epidemiology, Harvard School of Public Health. Boston, MA (MTT).

Address reprint requests to Dr. Bryan T. Woods, Neurology Section. VA Medical Center, 1901 S. 1st St., Temple, TX 76504.

Received September 28, 1994; revised July 24, 1995.

0006-3223/96/$15.00 ssm 0006-3223(95)00478-5

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ropathologic reports. Clinical imaging studies of newonset schizophrenic patients show some volume abnormalities are already present at this stage (DeLisi 1991a; Lieberman 1992). Neuropathological studies show an absence of gliosis in schizophrenic brains (Roberts 1991), and a loss of intemeurons in layer II of the cingulate gyrus and prefrontal cortex (Benes et al 1991). These findings have been interpreted as indicating occurrence of the anatomical changes, pre-illness, and probably in the perinatal period (Weinberger 1987; Murray et al 1992). A recent neuropathological study of postmortem material from schizophrenic patients that stained for the neuron-specific enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase (Akbarian et al 1993a,b), found evidence for decreased numbers of positive-staining cells in neocortex and increased numbers of positivestaining cells in subcortical white matter in both frontal and temporal regions. It was concluded that both regions showed a defect in prenatal neuronal migration.

The question of whether there may also be brain changes that take place after onset of illness has long been disputed. There is some positive evidence for such continuing pathological changes from both clinical and imaging studies. Recent clinical studies of schizophrenia indicate that many patients have a course in which they progressively deteriorate over the initial 5-10 years of illness, and then plateau (McGlashan 1988; Breier et al 1991). Several MRI cross-sectional studies have suggested that generalized loss of brain volume in schizophrenia is related to duration of illness (Gur et al 1991) and age (O'Callaghan et aI1992). Gur et al (1991) found that, after covarying for age, schizophrenic patients had a significant positive correlation of duration of illness and total CSF volume. O'Callaghan et al (1992) reported that cortical atrophy, but not ventricular size, showed a significantly greater positive correlation with age for patients than for controls. In contrast another recent large cross-sectional MRI study that carefully controlled for age effects failed to find any significant relationship between volume loss and duration of illness (Zipursky et al 1992).

The results of longitudinal imaging studies have also been mixed. Studies using CT, which cover a greater duration of illness because of longer availability of the technique, have not resolved the question of whether volume loss is progressive or not, since both negative (Nasrallah et al 1986; Illowsky et a11988; Vita et a11988; Abi-Dargham et al 1991) and positive (Kemali et a11989; Woods et al 1990; Schwarzkopf et al 1990) studies have been reported.

Longitudinal studies using MRI are still in their early stages. Lieberman et al (1992) found a nonsignificant trend for chronic schizophrenics to have a higher prevalence of morphologic brain abnormalities than acute pa-

B. T. Woods et al

tients; however, they raised the possibility that this trend might be accounted for by the poorer prognosis associated with the presence of brain abnormalities at initial diagnosis and a subsequent "selection out" of the patients with fewer brain abnormalities. DeLisi et al (1991a), using a similar design, found that chronic, but not acute, schizophrenic patients showed a significant reduction in temporal lobe volume as compared to age-matched controls. Interestingly, at a 2-year follow-up of the acute patients, in which both good-outcome and poor-outcome patients were restudied, there was an overall trend to increased ventricular enlargement, with several patients showing a greater than 20% increase in ventricular size (DeLisi et al 1991b).

It is evident that early and late changes are not mutually exclusive, and it is quite possible that both occur in the same patients by different mechanisms. There is a longstanding neuroradiological observation (Davidoff-DykeMasson syndrome) that offers the possibility of distinguishing brain volume loss beginning in early life from that occurring after brain growth is complete. Studies of patients with cerebral hemiatrophy occurring in early life show that the intracranial cavity is smaller on the side where the brain is atrophic, although the skull may be thicker (Taveras and Wood 1976; Zilkha 1980; Woods and Yurgelun-Todd 1991). This occurs because, barring the uncommon event of a pathologic premature fusion of skull sutures, regional brain growth drives regional intracranial cavity growth during development. Thus, an early impairment of brain growth will result in a correspondingly smaller intracranial cavity; however, since intracranial cavity expansion is not reversible after skull sutures fuse, regional loss of brain tissue volume after growth is complete will not cause a decrease in intracranial volume, but rather a compensatory increase in regional cerebrospinal fluid (CSF) space. It follows then that reductions in overall or regional intracranial volume in schizophrenic patients relative to controls are likely to be the result of events that had their onset during the period of brain growth, while decreases in the ratio of brain tissue volume to intracranial volume (TCY ratio) imply a tissue loss that occurred after brain growth and development were essentially completed (i.e., by the middle of the second decade oflife). Finally, a combination of both reduced intracranial volume and a reduced TCY ratio is evidence for a process (or processes) that operated both during and after the period of brain growth.

The current study measured differences in intracranial volume and in brain tissue to cranial volume (TCY) ratio for the whole cerebrum and several subregions implicated in schizophrenia, e.g., frontal, temporal, ventricles, striatum, and pallidum. This study is a first step in beginning to determine whether patients showed evidence for gener-

MRI in Schizophrenia

alized or regional brain volume loss that occurred either before or after brain growth was complete, or both.

Methods

Magnetic Resonance Imaging

All MRI scans were carried out on a single General Electric Signa 1.5 Tesla system with shielded gradients and quadrature detection coils. Images were acquired using an inversion recovery sequence in the coronal plane perpendicular to the individual canthomeatal line. Slices were acquired from just behind the occipital pole to just ahead of the frontal pole, and were 5-6 mm thick (depending on individual head anteroposterior length) with no interslice interval. All images were analyzed on an auxiliary console using a method that is a variant of an approach originally described for computed tomography (CT) scans (Pfefferbaum et al 1986) and modified for MRI (Lim et al 1989) that segments a brain image into gray, white, and CSF components. The process began with an operator using a cursor to outline the cerebrum and surrounding CSF on each coronal image of a complete front-to-back contiguous series, by tracing along the inner surface of the skull or dura mater, the upper surface of the tentorium, and the medial surface of the temporal lobes; the brainstem was transected at the mesencephalic-diencephalic junction. These outlined regions of interest (ROls) summed over all images constituted the cerebral intracranial volume.

For each image the outlined cerebral ROI was then duplicated on a split screen, with one image displayed with subjectively optimal gray-scale windowing and leveling, and the other image windowed to one (i.e., windowed so that all pixels were black or white). The level of the black-white image was then varied by the operator so as to optimally match the shape of the resulting silhouette to the appropriate tissue compartment on the adjacent gray-scale image. This level is the intensity threshold for the boundary separating two tissue components. The same process was used for both the CSF-gray boundary and the graywhite boundary, and all pixels in the outlined ROI were categorized into one of the three components depending on their intensity values vis-a-vis the thresholds. The thresholds established in this way for each individual slice were used for all subsequent measurements on that slice. The whole process was carried out independently by two raters blind to diagnosis and to one another's results.

The next step was outlining smaller ROls for subsequent segmentation. The independently outlined structures were the separate left and right cerebral hemispheres, anterior (predominantly prefrontal) frontal lobes, major

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frontal subdivisions (dorsolateral, dorsomedial, and orbitofrontal regions), temporal lobes and temporal horns, corpus striatum, ventral pallidum, and lateral ventricles. The primary anatomic guides for this process were the coronal brain sections in the atlas of Matsui and Hirano (1978). The posterior cerebral region volumes were not measured independently but were derived from the cerebral hemispheric volumes less the sum of the ipsilateral frontal and temporal volumes.

The structure boundaries were traced as follows. First, all external borders were traced along the inner border of the skull/dura mater. Second, the inferior and medial borders of the temporal lobes and posterior cerebrum followed the tentorium and medial brain border so as to exclude the cranial nerves, and the brainstem was transected at the mesencephalic-diencephalic junction. Third, the posterior boundary of the frontal lobes was the rearmost slice passing fully through the genu of the corpus callosum. Fourth, the posterior boundary for the temporal lobes was the rearmost slice passing fully through the splenium of the corpus callosum, the superolateral boundary was the Sylvian fissure, and the superomedial boundary was a line drawn from the medialmost point of the Sylvian fissure straight down to the hippocampal fissure. Fifth, the ventral pallidum (Alheid and Heimer 1988) was bounded by the triangle formed by the anterior commissure superiorly, the third ventricle medially, and the inferior margin of the cerebrum. Finally, the corpus striatum included the head of the caudate, the putamen, and that part of the body of the caudate that was included on the putminal slices.

It should be noted that the posterior boundaries we utilized to delineate the frontal and temporal lobes are not the true posterior anatomical boundaries of either region. In particular the frontal regions are largely prefrontal, and exclude the precentral and most of the premotor regions.

With one exception, all of these structures were measured on more than one slice. For reasons of anatomical landmark reliability, the subdivisions of the frontal lobes were outlined on the single slice that formed the posterior boundary of the frontal lobe. On this slice the anatomic division between dorsomedial and dorsolateral regions was the superior frontal sulcus, and the boundary between dorsolateral and orbitofrontal regions was the anterior ramus of the lateral sulcus (Nieuwenhuys et al 1988).

In order to assess measurement reliability across both rater and subjects, nine control subjects were scanned twice on separate days, and two raters independently thresholded and outlined all slices of both studies for each subject. The intraclass coefficients (ICC) (Fleiss 1983) between raters for the same scans were: 0.99 for gray matter, white matter, and total intracranial volume; 0.94 for CSF; 0.80 for corpus striatum; and 0.46 for ventral

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pallidum. Between scans, the ICCs were as follows: gray matter, 0.92 for raters 1 and 2; white matter, 0.79 for raters 1 and 2; CSF, 0.87 for rater 1 and 0.89 for rater 2; and total intracranial volume, 0.99 for both raters.

Subjects

A total of 17 patients (14 men, 3 women) meeting DSM-III-R (American Psychiatric Association 1987) criteria for schizophrenia (SCZ), two women meeting criteria for schizoaffective disorder, and 19 healthy controls (14 men, 5 women) were quantitatively evaluated with MRI. The schizophrenic patients were a subsample of consecutive admissions of 50 schizophrenic and schizoaffective patients from four area hospitals who were recruited for a study of the heterogeneity of schizophrenia (M. T. Tsuang, principal investigator). Twenty consecutive patients who had agreed to participate in the larger study were asked to have an MRI study as well, and all agreed. One patient exceeded the weight limit of the scanner and was replaced by the next consecutive patient, who also agreed to participate. Ultimately, 19 patients were included in the MRI scan group, since one scan was rendered unusable by severe movement artifact.

Patients had to be proficient in English, not have any lifetime history of DSM-III-R substance dependence nor any history of DSM-III-R substance abuse in the last 6 months, have no history of neurologic disease or injury with persistent central nervous system (CNS) damage, not have undergone electroconvulsive therapy in the last 6 months, and not have any systemic medical illness affecting brain function. DSM-III-R diagnoses were made on the basis of a consensus by three senior investigators, all of whom evaluated material from a structured psychiatric interview, the Schedule for Affective Disorder and Schizophrenia (SADS) (Spitzer and Endicott 1978), from an interview with the currently treating clinician, and from a systematic review of past and present medical records. Reliability of diagnoses was high, with a K of 0.80 reflecting 11 agreements and only one disagreement between the consensus diagnosis and two expert diagnosticians who made independent clinical assessments. Fifteen of the 17 SCZ patients met DSM-III-R criteria for nonparanoid subtype, while two were paranoid subtype. The patients who received MRI scans did not differ from those who did not receive MRI on demographic, clinical, or neuropsychologic criteria (Seidman et al 1994).

Subjects and controls were between the ages of 20 and 55 years. Mean ages in years (with standard deviations in parentheses) were as follows: schizophrenic (SCZ) men, 34.4 (9.2); control (CTL) men, 34.6 (9.7); SCZ/schizoaffective women, 35.2 (6.7); and CTL women, 34.6 (6.7).

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Age did not differ significantly for patients versus controls, nor when stratified by sex. Subjects were all white non-Hispanics and had a mean education level of 12.6 years. More complete demographic and neuropsychologic data on these subjects has been previously reported (Seidman et aI1994). Control subject scans were selected from a larger panel of available normal control studies conducted on the same MRI system. Controls were selected on the basis of sex and age by someone who was blind to scan results. The control pool consisted of hospital maintenance workers, clerical staff, health professions students, and professional staff members. Their estimated mean education level was 15 years.

Data Analysis

The independent variables for all analyses were diagnosis (SCZ, CTL) and hemisphere (left, right). Dependent variables were either the absolute volumes or the TCV ratios of the ROIs. Absolute volumes comprised total intracranial volumes (i.e., gray + white matter + CSF) for the frontal, temporal, and posterior cerebral regions and the frontal subregions; brain tissue (i.e., gray + white) for the cerebrum; the CSF segment of the ROI for the temporal horns and lateral ventricles; and the gray matter segment of the ROI for the corpus striatum and ventral pallidum. TCV ratios were the sum of the gray and white matter segments for each ROI divided by the sum of the gray and white matter and CSF volumes for the same ROI. In the case of frontal subregions, where measurements were on a single slice, volumes rather than areas were nevertheless used as the unit of measurement because slice thickness was 5 mm for some patients and 6 mm for others. Due to partial volume effects, different slice thicknesses will result in slightly different measurements for the same scan, even if the center of the slice is identical, although phantom measurements on our system indicated that these differences would be less than 1%.

All analyses employed either analyses of variance (ANOV A) or multivariate analysis of variance (MANOVA) (Abacus Concepts 1989). Separate MANOV As were utilized for the dependent variables that were measurements of absolute volumes and those that were ratios of measured volumes. The major cerebral regions (frontal, temporal, and posterior) were analyzed separately from the specific anatomic structures (frontal subregions, lateral ventricles, temporal horns, corpus striatum, and ventral pallidum) and from the cerebral segments (gray, white, and CSF). Moreover, because two of the female patients were diagnosed as schizoaffective rather than schizophrenic, all of the analyses were also run excluding these two patients and their matched controls; however,

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Table I. Means and Standard Deviations of Cerebral Regions and Tissue Compartments for Patients and Controls

Patients Controls
Region Left Right Left Right
Cerebrum total 568.6 (68.6) 568.0 (69.2) 589.7 (60.2) 593.6 (60.1)
Gray 322.6 (50.7) 322.1 (50.0) 355.1 (36.9) 355.8 (35.9)
White 163.5 (18.8) 165.8 (20.0) 168.1 (23.0) 168.8 (27.4)
CSF 81.5 (20.3) 80.1 (20.0) 66.6 (14.1) 69.1 (11.5)
Frontal total 99.3 (12.3) 106.1 (13.5) 1l0.3 (8.7) 116.3 (13.8)
Gray 57.7 (12.1) 62.6 (11.7) 67.1 (9.3) 71.9 (12.3)
White 28.6 (7.0) 28.1 (7.4) 31.4 (5.4) 30.9 (7.3)
CSF 13.2 (4.6) 15.4 (5.3) 12.0 (3.5) 13.5 (4.1)
Temporal total 86.8 (13.5) 93.5 (11.6) 88.0 (6.9) 93.5 (7.6)
Gray 57.1 (9.7) 60.8 (9.1) 62.6 (8.1) 64.7 (7.7)
White 18.6 (4.5) 21.1 (4.5) 18.2 (3.3) 20.9 (5.0)
CSF 11.1 (2.9) 11.6 (2.8) 7.1 (2.6) 8.0 (2.3)
Posterior total 382.4 (48.3) 368.3 (48.7) 391.3 (41.4) 383.7 (41.0)
Gray 207.8 (33.8) 198.7 (35.4) 225.4 (23.2) 219.2 (24.1)
White 116.3 (13.0) 116.6 (12.4) 118.5 (17.3) 117.0 (17 .0)
CSF 57.3 (14.9) 53.0 (15.4) 47.5 (10.8) 47.5 (8.2)
Lateral ventricles 10.6 (4.5) 9.3 (4.1) 7.2 (3.8) 8.3(1.7)
Temporal horns 0.4 (0.3) 0.3 (0.2) 0.1 (0.1) 0.2 (0.1)
Corpus striatum 8.1 (2.1) 8.2 (1.3) 8.6 (1.9) 8.7 (1.7)
Ventral pallidum 0.6 (0.1) 0.6 (0.1) 0.6 (0.1) 0.6 (0.1)
Frontal subregions 28.6 (3.5) 29.5 (3.6) 28.5 (2.4) 29.5 (3.0)
Dorsolateral 13.2 (2.6) 13.5 (2.1) 14.3 (2.5) 14.3 (2.6)
Dorsomedial 5.8 (1.1) 6.3 (2.0) 5.8 (1.5) 5.9 (2.0)
Orbital 9.6 (1.7) 9.7 (1.8) 8.5 (1.4) 9.0(1.5)
CSF = cerebrospinal fluid. this did not significantly alter the outcome of any of the comparisons, so only the results for the full group of 19 patients are presented.

Because there is some controversy in the literature about the use of ratio measurements, such as the TCV (Arndt et al 1991; Mathalon et al 1993), the regional volumes and tissue compartments were also analyzed while covarying for the appropriate intracranial volume (e.g., frontal brain tissue volumes for patients and controls were compared after covarying for frontal intracranial volume). This did not change the results in any significant way, thus only the TCV results are presented.

Results

Absolute Volume Analyses

Table 1 shows the absolute value means and standard deviations for each structure and compartment, by hemisphere, for both patients and controls. The patients' mean cerebral hemisphere volumes were 3.9% smaller than those of the controls; however, ANOVA of cerebral hemisphere volume showed that the effect of diagnosis fell short of statistical significance (F = 2.58; df 1, 72; p :::; 0.12), and there was no significant effect of side or an interaction of side and diagnosis. ANOV A of cerebral hemispheric brain tissue volume showed a significant

reduction for the patients (F = 7.46; p :::; 0.01). MANOV A of gray and white matter and CSF as dependent variables also showed a significant main effect of diagnosis (Wilks' Lambda 0.750; F = 7.77; df 3,70; p :::; 0.0001). The patients had significantly less gray matter (F = 10.76; p :::; 0.002) and more CSF (F = 11.23; p :::; .002) than the controls, but the white matter differences were not significant.

MANOV A with the intracranial volumes of the temporal, frontal, and posterior brain subregions revealed a significant overall effect of diagnosis (Wilks' Lambda .891; F = 2.84; df 3, 70; P :::; 0.05). The overall effect of side and the interaction effect of side and diagnosis were not significant. Looking at the individual comparisons, the patient group had a significantly smaller frontal intracranial volume than the controls (F = 6.42; df 1, 72; p :::; 0.02) but no significant differences for temporal or posterior region volumes (Figure 1).

MANOV A with the frontal subregions, lateral ventricles, temporal horns, corpus striatum, and ventral pallidum as dependent variables showed an overall significant effect for diagnosis (Wilks' Lambda 0.723; F = 3.61; df 7,66; P :::; 0.005). The patients had significantly larger orbitofrontal intracranial volume (F = 6.02; df 1, 72; p :::; 0.02), a trend to a smaller dorsolateral frontal intracranial volume (F = 3.01; df 1, 72; p :::; 0.10), and significantly larger

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Figure 1. Differences in regional intracranial volumes and tissue to intracranial volume (TCV) ratios between patients and controls, expressed as percent decreases from control values. **** = p :s 0.0001; *** = p :s 0.001; * = p :s 0.05.

Frontal

lateral ventricles (F = 5.92; df 1, 72; p ::s; 0.02) and temporal horns (F = 18.23; df 1, 72; p ::s; 0.0001). The dorsomedial frontal, corpus striatum, and ventral pallidum volumes were not significantly different between patients and controls. None of the regions showed a significant effect of side nor diagnosis by side interaction.

Brain Ratio Analyses

ANOV A of the TCV ratios for cerebral hemispheres demonstrated significant differences between patients and controls with patients having a lower TCV ratio than controls (F = 23.08; df 1, 72; p ::s; 0.0001). There was no significant main effect for side or interaction. MANOV A of the temporal, frontal, and posterior brain region TCV ratios showed a significant overall effect for diagnosis (Wilks' Lambda .602; F = 15.44; df 3, 70; p ::s; 0.0001) but no significant effect of side or interaction. The patients' TCV ratios were significantly lower than those of the controls for the temporal region (F = 46.54; df 1, 72; p ::s; 0.0001), the frontal region (F = 12.35; df 1, 72; p ::s; 0.001), and the posterior cerebral region (F = 14.21; df 1, 72;p::S; 0.001), also shown in Figure Lit was possible that

these results were due to the larger lateral ventricles of the patients. Thus, ventricular volume was subtracted from the CSF volume, the TCV ratios were reanalyzed, and the results were essentially unchanged.

Given that a subgroup of the patients and controls had scans with slices that were 6 mm rather than 5 mm thick, results for both absolute volumes and TCV ratios were reanalyzed with slice thickness as a variable. No significant direct effect nor interactions were found.

MANOV A of the ratios of white matter to intracranial volume, and gray matter to intracranial volume, showed a significant overall main effect for diagnosis (Wilks' Lambda 0.757; F = 11.40; df 2,71; p ::s; 0.0001), but a negligible effect for side and a minimal interaction. On the individual comparisons, the patients had a significantly smaller gray matter ratio than controls (F = 16.31; df 1, 72; p ::s; 0.0001), but no significant difference for white matter.

Discussion

Initial MRI reports on intracranial size in schizophrenic patients utilized area measurements on a single slice

MRI in Schizophrenia

(Andreasen 1986, 1990; Pear1son et a11989; Schwarzkopf et al 1991), but a number of recent MRI studies used overall intracranial volume in schizophrenic patients and controls (Woods and Yurgelun- Todd 1991; Gur et al1991, 1994; Jernigan et a11991; Pearlson et a11991; Zipursky et al 1991, 1992; Brier et al 1992; Harvey et al 1993; Schlaepfer et a11994; Andreasen et al1994). Andreasen et al (1986) found a significant decrease in intracranial area on a midsagittal slice, and Pearlson et al (1989) found a similar significant result using an axial slice; however, in a repeat study Andreasen et al (1990) failed to replicate their earlier result. Subsequently, only one of the 11 studies that compared intracranial volumes reported a significantly lower volume in patients (Gur et al 1994), although in the other 10 volumetric studies, the average patient intracranial volumes were smaller than controls. Thus, our study, which found patients to have a nonsignificant 3.9% reduction in total intracranial volume, is consistent with these other investigations.

We found a significant reduction in prefrontal intracranial volume in schizophrenic patients, which is consistent with a number of recent studies (Breier 1992; Zipursky et al 1992; Ron et al 1993; Andreasen 1994; Schlaepfer 1994). In particular, a recent MRl study by Lim and colleagues (1995) found that congenital rubella patients and rubella patients with schizophrenia-like symptoms matched to schizophrenics had significantly smaller intracranial volume, particularly in the prefrontal region, compared to matched normal controls. These findings suggested that a developmental lesion limited full brain growth, especially in prefrontal brain regions (Lim et al 1995). Although segmentation of intracranial volumes into gray and white matter and CSF is now standard for MRI volumetric studies, the use of this information in data analysis in the current study differs in two ways from earlier studies: use of proportions (TCV ratios) and analysis of the proportions in brain subregions. With the exception of the reports by Gur et al (1991, 1994), other studies have analyzed the segmented components after covariation for intracranial volume rather than analyzing them as proportions. Although Gur et al (1991, 1994) looked at the ratio of CSF volume to brain volume and the current study looked at the ratio of brain volume to intracranial volume (TCV), the analyses are comparable since the Gur et al (1994) ratio is arithmetically interconvertible with TCV.

It should be noted that there has been some controversy in the literature about whether and how to control for head size in imaging studies of schizophrenia, with Arndt et al (1991) arguing that head-size correction lowers measurement reliability, and Mathalon et al (1993) demonstrating that head-size correction improves criterion validity. Mathalon et al (1993) commented that "proportional

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scores ... may convey important information that would not be appreciated from residual scores." The authors find the Mathalon et al argument for head-size correction compelling, and furthermore found that using covariance rather than proportions did not significantly change any of the results in the current study.

The current study differs from Gur et al (1991, 1994) to the extent that they looked at whole brain proportions. In addition, as distinct from the other studies, we corrected for regional head size rather than overall head size. Since our study showed that prefrontal intracranial volume differs significantly between patients and controls, while overall intracranial volume did not, controlling for regional intracranial size should adjust for more of the variance in brain tissue volume than simply controlling for overall head size.

As discussed in the introduction, the interpretation of our results is guided by the principle that brain growth drives intracranial growth. There are; however, a number of important caveats regarding the permissible inferences that can be made from this principle. First, the presence of pathologically reduced intracranial volume in patients compared with controls is positive evidence for a process that has interfered with brain growth; however, the absence of a reduction in intracranial volume does not exclude all functionally significant developmental abnormalities, only those that impede brain growth. For example, if growth in some areas is excessive and in other areas is deficient, the net overall increase in intracranial volume due to brain growth may stay within the normal range, while brain function may be impaired.

Second, since intracranial volume in patients is compared to that of controls, the controls need to be appropriately matched for relevant variables for inferences about cortical differences to be valid. Sex and measures of body size (height, weight) have been found to correlate with head size, presumably because increased body size requires increased brain tissue, at least in primary somatosensory and motor regions. However, although height might fully account for sex differences in overall head size in normal subjects (Zipursky et al 1991), this might not hold equally true for all subregions and it seemed safest to match patient and control groups for sex, as was done in the current study. Moreover, although head size and height correlate well under ideal conditions, pathological conditions may disrupt this relationship in various ways. On the one hand, early nutritional deprivation, which may predispose to schizophrenia (Susser et al 1992), tends to spare brain (and thus head size) growth relative to height (Rudolph et al 1991). On the other hand, as noted by Pearlson et al (1991), it has been classically suggested that schizophrenia reduces head size more than height, and the data of Schwarzkopf et al (1991) indicate that head size

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reduction in schizophrenia is associated with a positive family history, implying a genetic origin. It follows that if one matches schizophrenic patients who have been nutritionally deprived in early life, to controls on height, or covariates for height, then head size will be overcorrected.

The relationship of socioeconomic status (SES) and level of educational attainment to head size had also been disputed. It is widely agreed that the educational attainment and SES of schizophrenic patients might be lowered by their illness, so that SES of the family of origin rather than of the patients themselves should be matched. Although these data were not collected in this study, there is some controversy over its significance. Pearlson et al (1989) found that intracranial area had a significant positive relationship to SES in their controls; however, the two studies of intracranial area by Andreasen et al (1986, 1990) suggested that using control groups of different SES did not result in a change in mean intracranial volume of the controls. Moreover, more recently LaFosse et al (1994) found no significant relationship between intracranial volume and familial SES in either their controls or their patients. Given the debate in the field, our study needs to be replicated with subjects matched for parental SES.

A third caveat for interpretation of our results rests on the assumption that a reduced TCV ratio is an indicator of a loss of brain tissue occurring after the completion of brain growth, only if the reduced TCV ratio is due to increased CSF space around the brain. This is so because in normal subjects the ventricles stay the same absolute size during the developmental time period in which the brain is getting larger; however, they begin to enlarge in later life (Pfefferbaum 1994), making it apparent that normal brain growth cannot reduce ventricular size but brain atrophy can increase it. Accordingly, ventricular enlargement caused by a non-progressively early-life lesion would persist even if brain growth resumed; however, increased CSF space between the brain outer surface and the inner table of the skull caused by an early-life nonprogressive lesion would tend to be "filled up" by subsequent brain growth. Thus, a reduced TCV ratio due to ventricular enlargement could be due to an early or later lesion (or both).

Fourth, since the relative impact of a single time-limited pathologic process on intracranial volume, as opposed to TCV ratio, will vary depending on whether brain growth is continuing or complete, the results for different brain regions could vary, depending on the growth timetable of the regions affected by the lesion. Thus, if a lesion occurred when growth was complete posteriorly but still continuing anteriorly, the posterior region might show only a reduction in TCV ratio, while the anterior region showed only a reduction in intracranial volume.

Fifth, white matter growth due to myelination continues

B. T. Woods et al

past the third decade (Yakovlev and Lecours 1967), long after gray matter expansion stops and begins to reverse itself, presumably due to dendritic pruning (Huttenlocher 1979) and apoptosis (programmed cell death) (Kerr et al 1972; Carson et al 1993). Since total brain growth continues only as long as the sum of the two is positive (Pfefferbaum et al 1994), a "developmental" pathologic process causing enhanced gray matter volume loss might begin, while net brain volume was still increasing, and continue until net brain volume begins to decrease. Thus a single chronic disorder extending over a large part of the developmental time period could result in a combination of both a reduced TCV ratio and reduced intracranial volume, producing the same pattern as two lesions, one early and one late. (It is perhaps simply a matter of semantics whether volume loss due to pathologically excessive neuronal pruning is termed a developmental disorder while excessive cell loss due to some other mechanism is called a neuronal degeneration; however, the terms have strong historic overtones, and in this report the terms atrophy and degeneration have been avoided in favor of the more neutral and descriptive term volume loss.)

Sixth, the assumption that reduced brain growth leads to reduced intracranial volume comes from patients with reduced development of whole hemispheres, and the extension of the principle to the temporal lobes, where only a small part of the surface abuts against the convexity of the skull may not be valid in schizophrenia. Thus, no inference is being made from the results of this study that the temporal lobes are developmentally normal, only that the frontal lobes are not. This is an important point, since several neuropathological studies have suggested that the temporal lobes as well as the frontal lobes are associated with developmental abnormalities in schizophrenia (Akbarian et al 1993a, 1993b; Arnold et al 1991; Conrad et al 1991).

Bearing these caveats in mind, the observed significant decrease in patient intracranial volume in the frontal (predominantly prefrontal) region is attributable to reduced brain growth, while the failure to find a significant difference in intracranial volumes in the posterior regions of the brain (which represent two thirds of the total volume measured) indicates that this pathological restriction of brain growth was regionally localized. Although the volume reduction is not limited to the frontal region (9.4% vs. 3.3%), the loss gradient is potentially important because it is consistent with recent work by Lim and colleagues (1995), discussed above, demonstrating a slowing of brain growth particularly in prefrontal regions.

The patients in this study also differed from controls in having a lower brain tissue to intracranial volume ratio in all brain regions, though most dramatically in the temporal

MRI in Schizophrenia

regions. On more detailed analysis, these significant decreases in brain tissue are almost entirely due to reductions in gray matter volume. We assume that decreases in the (TCV) ratio in patients, which arise from a loss of cortical tissue represent significantly increased patient regression from the maximum tissue volumes attained during development. Further, these differences, which persist after ventricular volumes are excluded, appear to reflect the effects of a process that had its impact some time after completion of maximum brain growth. Thus, in this patient group the positive evidence for significant underdevelopment of brain tissue is largely restricted to the prefrontal regions, while that for significant losses of pre-existing tissue volume implicates the whole cerebrum.

It could be that both the reduced intracranial volume and the relative increases in CSF space reflected by the TCV ratio, originated from a single process; however, the process would have to have covered a time period before and after completion of brain growth and had a spatial (anteroposterior) gradient of severity. That is, if it is assumed that proportional increases in CSF space and decreases in gray matter of the frontal regions and posterior cerebrum indicate that observed brain tissue volume has receded from previously attained maximum levels, it can be shown that the observed data are inconsistent with a single process whose duration of operation was restricted to the perinatal period. Complete MRI data on normal developmental changes in intracranial volume with age are not yet available, since the study of Pfefferbaum et al (1994) measured sulcal CSF volume on a subset of slices that excluded the frontal and occipital poles; however, there are published standards for the normal growth of head circumference. Using these data, the intracranial volume for the controls in our study, and the geometric relationship by which cerebral intracranial volume (CV) increases as a cubic function of circumference (C), it is possible to calculate that CV = approx. 0.007 C3. Using this formula, one can then make a rough estimate of the earliest age at which a single non-progressive brain insult could have both prematurely arrested intracranial volume growth and reduced the brain tissue to intracranial volume ratio.

In the male patient group, cerebral intracranial volume is reduced 56 mL (4.6%), which corresponds to a circumferential reduction of 0.85 em, If one looks at a standard head circumference growth chart, which shows mean male head circumference leveling off at 55.75 em at age 18, then a 0.85 em reduction in circumference corresponds to the mean normal male head circumference reached at age 14.5. (Combined charts are not available, but for women the shape of the curve is the same.) Thus, based on the maximum cerebral intracranial volume attained, the hypothetical single lesion in these patients could not have

BIOL PSYCHIATRY 1996;40:585-596

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occurred much earlier than age 14. Even if the male patient frontal intracranial volume loss of 10.1 % is extrapolated to the whole cerebrum, the results correspond to the mean male head circumference reached at age 12. In other words, if a single short-duration process caused both the intracranial volume loss and the TCV ratio reduction, that process had to occur before brain growth was complete but long after the perinatal period. Thus, the data do not allow rejection of a single-process model, but do appear to exclude a perinatal time limit for operation of such a single process.

The data presented in this study regarding tissue volume and intracranial volume are consistent with at least two models. A two-process model takes into account studies that have indicated that many schizophrenic patients have suffered cerebral damage apparently limited to the pre- or perinatal period. It postulates one process that occurs early in life, very possibly in the pre- or perinatal period, and results in decreased growth in the frontotemporal (limbic) regions and predisposes to the emergence of clinically overt schizophrenia. A second process has its onset some time after the point of maximum brain growth reached in early adolescence, affects the whole cerebrum, and leads to the development of overt illness in later adolescence or early adult life.

A single-process model that fits the current data requires a slow loss of brain tissue (primarily gray matter) that begins before the net increase in brain size is complete, continues after it is complete, and has its greatest impact in the anteriorly located frontotemporal regions. A process resulting in excessive dendritic pruning (Huttenlocher 1979) and apoptosis (Kerr et al 1972) would be consistent with this model. It is of note that apoptosis does not result in gliosis (Carson et al 1993), so the absence of gliosis in areas of cell loss in postmortem material from schizophrenic patients (Roberts 1991) does not exclude this process as a possible agent of tissue volume loss occurring after maximum intracranial volume expansion.

It is of interest that when Gur et al (1994) separated their schizophrenic patients into three diagnostic subgroups, and looked at absolute intracranial and brain volumes, sulcal CSF to brain ratios, and ventricle to brain ratios (VBR), there were different patterns of abnormalities. The negative symptom patients showed normal intracranial and brain tissue volumes but a significant increase in CSF to brain ratio and ventricle to brain ratio. The "Schneiderian" patients showed reduced intracranial volume and brain volume, but no elevation of either sulcal CSF to brain ratio of VBR. The paranoid patients had lower intracranial volume, normal brain volume and VBR, and a reduced sulcal CSF to brain ratio. This dissociation of findings by subgroup also implies the existence of more than one process causing measurable brain volume abner-

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mali ties in schizophrenia. Our patient group showed the abnormalities characteristic of the negative symptom and the Schneiderian patients in the Gur study (1994); however, the sample was too small to subdivide by clinical subtype or other important characteristics for understanding the heterogeneity of schizophrenia, such as sex (Goldstein et al 1989, 1994).

Although the simultaneous observation of changes in regional intracranial volumes and tissue volumes does not

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