ORIGINAL ARTICLES i

A Prospective Follow-up Study of Brain Morphology and Cognition in First-Episode Schizophrenic Patients: Preliminary Findings

Lynn E. DeLisi, William Tew, Shu-hong Xie, Anne L. Hoff, Michael Sakuma, Maureen Kushner, Gregory Lee, Karen Shedlack, Angela M. Smith, and Roger Grimson

Brain morphological abnormalities have been reported in several independent investigations of chronic schizophrenic patients. The present study is a prospective 4-year follow-up of first-epi- sode schizophrenic patients to determine whether some of these abnormalities may be a conse- quence of regional brain structural change over time after the onset of a first psychotic episode. Whole hemisphere, temporal lobes, superior temporal gyrus, hippocampus, caudate, corpus callosum, and lateral ventricles were measured in a series of MRl scans taken over a 4-year period in 20patients and five controls. Total volume reduction was noted in both hemispheres to a greater degree in patients than controls. When adjusted for total brain size, left ventricular enlargement occurred in patients, but not controls, over time. These preliminary data suggest that subtle cortical atrophy may be occurring over time after the onset of illness.

Key Words: First-episode schizophrenia, brain morphology, ventricular enlargement

BIOL PSYCHIATRY 1995;38:349-360

Introduction Evidence for the presence of structural brain pathology in chronic schizophrenia comes from several decades of post- mortem and in vivo brain imaging studies (reviewed in Shapiro 1993). The presence and extent to which specific anomalies occur in representative populations of schizo-

From the Departments of Psychiatry (LEdeL, WT, S-HX, MS, MK, GL, KS, AMS) and Preventive Medicine (RG), Health Sciences Center, State University of New York at Stony Brook, Stony Brook NY; and the Biological Psychiatry Research Unit, Napa State Hospital, Napa, CA (ALH).

Address reprint requests to Dr. Lynn E. DeLisi, Department of Psychiatry and Behav- ioral Science. Health Sciences Center, SUNY, Stony Brook, NY 1 t794.

Received March 2, 1994; revised October 19.1994.

phrenic patients, however, continues to be controversial, and their significance remains elusive. Although most in- vestigators interpret available evidence as suggesting that a developmental disturbance in brain growth causes a predis- position for eventually having schizophrenia (Akbarian et al 1993; Crow et al 1989a; Murray and Lewis 1987; Wein- berger 1987), the timing of the occurrence of each reported pathological distinction has not been determined. Nor has progressive brain change been ruled out.

The most replicated of findings in schizop.hrenia brain morphologic studies has been the presence of mild enlarge- ment of cerebral ventricles--mainly the lateral ventricles

© 1995 Society of Biological Psychiatry 0006-3223/95/$09.50 SSDI 0006-3223(94)00376-E

350 BIOL PSYCHIATRY L.E. DeLisi et al 1995:38:349-360

(including frontal, temporal and occipital horus) and the less-studied third ventricle (reviewed in Shelton et al 1986; Raz and Raz 1990). Other replicated findings associated with, although by no means specific to, schizophrenia are: reduction in temporal cortex (Dauphinais et al 1990; Rossi et al 1990; Suddath et al 1989; DeLisi et al 1991); reduced hippocampal (DeLisi et al 1988; Bogerts et al 1985, 1990a,b; Suddath et al 1990) and superior temporal gyrus size (B arta et al 1990; Shenton et a11992); more widespread cortical changes (Ron et al 1992; Zipursky et al 1992); and reduction of normal cerebral asymmetries (Brown et al 1986; Crow et al 1989a,b; Crow 1990; Crow et al 1992; Hoff et al 1992a; Falkai et al 1992; Rossi et al 1992). The corpus callosum has also been the focus of numerous studies, though no clear finding emerges from them as a whole (Reviewed in Hoff et al, 1994). All of these findings, while replicated in some, although not all studies, are not detect- able in all chronic schizophrenic patients when compared with controls, nor do they all cluster in individual patients; rather, they represent subtle significant deviations from population mean distributions of structural size. Studies of brain morphology in monozygotic twins discordant for schizophrenia show that much of the above inconsistent variance may be attributable to genetic factors (Reveley et al 1982, 1984) and that an individual with schizophrenia, when compared with his/her co-twin sharing identical genes, has evidence of all the above morphological changes, thus attributing them to the disease process itself (Suddath et al 1990). These studies do not, however, clarify whether the changes are developmental with occurrence prior to the illness onset, or progressively occurring after the onset of illness.

The Stony Brook Prospective Study of first-episode cases of schizophrenia was therefore designed to clarify the tim- ing of brain morphological anomalies associated with schizophrenia. Beginning in 1987, consecutive first admis- sions to a public catchment area hospital (Kings Park Psy- chiatric Center) who had a first episode of schizophrenia, schizoaffective, or schizophreniform disorder, were re- cruited for a longitudinal study. A total of 60 patients and 30 controls were evaluated from February 1987 through March 1991. To summarize our previous reports on this cohort, enlargement of the lateral ventricles (specifically, left greater than right) was detectable in those subjects that retained a diagnosis of schizophrenia, and size of ventricles was inversely correlated with age of onset and outcome-- the larger the ventricles at the time of a first episode, the earlier the age of onset of symptoms and the poorer the outcome (DeLisi et al 1991, 1992a,b). The occurrence of a developmental disturbance could be implied from the in- creased prevalence of a cavum septum in this cohort (DeLisi et al 1993), significantly smaller corpus callosum (Hoff et al, 1994) and evidence of reduced temporal lobe asymme-

tries in the female patients (Hoff et al 1992a; DeLisi et al 1994). A 2-year follow-up evaluation of 24 of the initial 30 patients revealed no overall change among patients in ven- tricular or temporal lobe size (DeLisi et al 1992a), although the variance in measured structure size over 2 years was larger in patients than controls.

It was of particular interest that in our initial studies (DeLisi et al 1991) the degree of enlargement of lateral ventricular size was not as great as that in chronic patients, and that reductions in the size of temporal lobes, superior temporal gyrus, and hippocampus were not detected. In fact, while temporal lobe size was identical in first-episode pa- tients and controls, the chronic patients (used as another comparison group) did show evidence of reduced left tem- poral lobe size and enlargement of the left caudate, which previously had been reported in chronic patients (DeLisi et al 1991; Jeruigan et al 1991; Breier et al 1992; Swayze et al 1992). Left temporal lobe size was also significantly corre- lated with duration of psychotic symptoms (DeLisi et al 1991).

Our studies of neuropsychological functioning, however, revealed that cognitive deficits equal to that of chronic patients were present at the first episode and appeared to improve at discharge or remain stable (DeLisi et al 1991; Hoff et al 1992a,b).

The above findings were suggestive that, although a sub- tle primary underlying (and possibly only microscopic) de- velopmental anomaly may lead to the development of schizophrenia, a progressive gross pathological disturbance may be taking place in parallel to the chronic clinical course of the illness. Since clinical deterioration with active posi- tive symptoms commonly occurs within the first five years of illness, we conducted the following serial examinations that prospectively follow these patients, with clinical, cog- nitive, and morphological evaluations 2, 3, and 4 years after the first hospital admission. These data presented below are from 20 of the original 30 first-episode patients described in DeLisi et al (1991).

Methods

Overall Study Design Patients and controls had magnetic resonance imaging (MRI) scans and neuropsychological tests within the first month of their first hospitalization for schizophrenia. Eval- uations were repeated 2, 3, and 4 years later. MRI scans collected on 20 first-episode psychotic patients and five controls (from a previous study of 30 patients and 20 con- trols) were available on magnetic storage tapes for analysis from the initial evaluation and one at least 4 years later. Seventeen of the 20 patients also had scans available from the second and third year of follow-up, two had additional scans at the second year (but not third), and only one of the

Brain Morphology and Cognition in Schizophrenics B1OL PSYCHIATRY 351 1995;38:349-360

20 had only initial and fourth-year scans completed. Of the 10 original patients who were unavailable at the 4-year follow-up, one was deceased (by homicide), one was in jail, two had moved out of driving distance, and six refused repeat scanning. Fifteen of the 20 original controls either refused repeat scans or were unavailable for further evalua- tions. One of the five available controls missed the fourth but returned for a fifth year follow-up. All initial scans from patients were performed within a month of the anniversary of the first admission date. Clinical and neuropsychological evaluations were performed during the same week of each MRI scan.

Subject Characteristics

The patients consisted of 15 males and five females with a mean age at the onset of the study of 27.3 +/-8 (SD) and a mean duration of psychotic symptoms prior to hospitaliza- tion of 12.2 months +/-22 (SD) (median = 2.5 months). At the first admission, their diagnoses by DSM-III-R (APA 1987) criteria consisted of 11 schizophreniform, four schizophrenia, and five schizoaffective disorder (four with less than 6 months of illness). On 4-year follow-up, diag- noses were: 10 with chronic schizophrenia; eight schizoaf- fective disorder; one schizophreniform disorder, recovered; and one major depression, recurrent with schizotypal per- sonality disorder. Six had frequent alcohol and/or drug use prior to the first hospitalization (although not related to it), while only one continued this use after hospitalization. For the total group, mean number of hospitalizations was 2.5 +/- 1.7 (13 having been rehospitalized at least once), and mean total time spent in hospital was 5.3 +/- 4.3 months, and mean time on neuroleptics was 35.6 +/ - 15.3 months at the 4-year follow-up. Six patients had been on lithium, seven overlapping patients on antidepressants, and 10 on minor tranquilizers for some portion of the time. Controls were three males and two females, mean age at study onset of 28.2 +/ - 6 (SD) years. None had medical problems, alcohol or drug abuse, nor were taking long-term medica- tions.

Clinical Evaluations

All subjects were interviewed annually by the same clinical researcher (MK) using a structured research format. For diagnostic information, an interval modified Schedule for Affective Disorders and Schizophrenia (SADS; Spitzer and Endicott 1978), The Brief Psychiatric Rating Scale (BPRS; Overall and Gorham 1963), the Scale for the Assessment of Positive Symptoms (SAPS), and The Scale for Assessment of Negative Symptoms (SANS; Andreasen 1982, 1984) plus outpatient and hospital records were compiled. The additional annual follow-up packet consisted of several questionnaires and included a cumulative record of all hos-

pitalizations with dates of admission and discharge, list of all medications taken with dose and dates, and the Global Assessment Scale (GAS; Endicott et al 1976). All ratings were performed throughout the follow-up period by one trained rater for reliability (MK). Diagnoses were per- formed prospectively at each follow-up period by a psychi- atrist (LED) using the above information, but without knowledge of individual brain imaging or neuropsycholo- gical data. Best estimate diagnoses were made using DSM- III-R criteria, based on cumulative lifetime information up to that point (interviews, hospital and clinical records, as well as information from family members).

Neuropsychological Evaluations

Neuropsychologic evaluations were performed to detect whether any cognitive change was related to structural change. No specific aspect of cognitive functioning was hypothesized to be a specific sign of change; thus, as com- prehensive a set of tests as possible was performed. Thus, the battery of neuropsychological tests used in our previous studies was administered to both patients and controls on a yearly basis. This battery has been described elsewhere (Hoff et al 1992a,b). Neuropsychological summary scales were created using internal consistency reliability proce- dures (coefficient alphas ranged from 0.67-0.89). Z trans- formed scores were created for each subject using means and standard deviations from normal controls (n = 57). Scores were summed and averaged to create scales reflect- ing functional domains. There were nine summary scales: Language, Executive, Verbal Memory, Spatial Memory, Concentration/Speed, Sensory/Perceptual, Left and Right Hemisphere, and a Global factor.

MRI Scan Parameters

GE Signa scanner with 1.5 Tesla magnet was used with spin-echo, T-1 (sagittal, axial, and coronal) and T-2 (axial) sequences. The following parameters were determined as the best available when the study began in 1987 and were thus continued in the longitudinal study: All coronal, sagit- tal, and axial slices had a matrix of 256 × 256, 5 mm slice thickness with 2 mm gap, and FOV:24. For sagittal and coronal slices the TR was 600 and TE 25 and NEX 2. For axial slices the TR was 2000, TE 25/80 and NEX 1.

Subjects were positioned in the scanner so that the in- fraorbital-meatal line was perpendicular to the table. The head was stabilized with foam to prevent lateral motion and velcro tape placed across the forehead. Lazer light cross- hairs were used to center on the nasion as the zero point of the head. Sagittal slices were then acquired by scanning left and fight 50 centimeters. For axial acquisition, the midline sagittal was used as a guide and the cursor was lined up with the long axis of the cerebrum, parallel to frontal lobes, and

352 BIOL PSYCHIATRY L.E, DeLisi et al 1995:38:349-360

scans were completed from the foramen magnum to the vertex. Coronals were also acquired, using the midline sa- gittal as a guide, and an angle parallel to the brain stem and spinal cord used. Scans proceed from the most posterior portion of the brain through the tip of the frontal lobe. For subsequent scans, additional adjustments were made based on the original scans for each sequence. Slice levels and angles were matched to previous ones and may be altered from the standard protocol if necessitated by the head posi- tion from previous scans.

Analyses

Measurements of whole brain, lateral ventricles, temporal lobes, superior temporal gyrus, and the hippocampus/ amygdala complex were performed from the coronal, cau- date nucleus from axial, and corpus callosum from the mid- sagittal plane on a SUN Workstation using the ANALYZE software (Mayo Clinic).

REGION OF INTEREST MEASUREMENTS. (measure- ment reliability data follows descriptions):

1. Whole brain. These measurements were performed on both sagittal and coronal slices. The midline sagittal slice where the spinal cord, nose, and corpus callosum were maximally visible was used to outline brain tissue using the outer surface of the cortex and excluding brain stem, spinal cord, and cerebrospinal (CSF) space between sulci. Coronal slices included the whole brain from frontal to occipital poles. These brain areas were circumscribed using double magnification. Measurements began with the first posterior slice in which cerebral hemispheres were visible and left and right hemispheres were traced individually. Tracing began from the center of the hemispheres, including the cerebellum, excluding the brain stern and CSF between outer sulci. Measurements extended through to the anterior end of the cerebrum until both hemispheres were no longer visible (approximately 22 slices).

2. Lateral ventricles. Tracings began at the first anterior coronal slice where lateral ventricles were first visible on left or right. As the slices advanced posteriorly, the septum pellucidum, body of the caudate nucleus, thalamus, basal ganglia, and the third ventricle became visible. Measure- ments were terminated at the most posterior slice in which the lateral ventricles on both sides disappeared. Approxi- mately 12 slices were used. Seven of the 20 patients and one control had a detectable cavum septum peUucidum on one to two coronal slices. Although it was not included in the measurements of left and right ventricles, had it been, it was unlikely to have an effect on the results, since its area was calculated at less than 2 mm 2.

3. Temporal lobe. Approximately l0 coronal slices per subject, magnified by three, were used. Measurements began posteriorly, with the first visualization of the superior

and inferior colliculi. This was an approximate landmark only, since the temporal lobes are not midline structures. If the subject's head was slightly tilted, compensation for the tilt was made by measuring temporal lobes on the slice above or below this landmark on either side. Tracing began medially for both left and right temporal lobes at the lowest most medial end of the lateral sulcus (circular sulcus, as viewed in DeArmond et al 1989) circumscribing the outer surface, ending at a line drawn connecting the base of the stem of the lobes. Measurement proceeded anteriorly until temporal lobes were no longer visible on either side.

4. Superior temporal gyrus. Coronal measurements were taken from the first anterior slice in which the temporal lobes were visible, using similar landmarks as above for the temporal lobe slices. Tracing began at the lowest, most medial end of the lateral sulcus and circumscribed the most superior gyrus of the temporal lobe along the superior tem- poral sulcus and medial to the stem. This measurement includes both white and grey matter.

5. Hippocampus/amygdala. These structures were mea- sured together as one complex, since the distinction was not clearly defined on all scans. Approximately six coronal slices contained these structures for each individual. Each was magnified by 3 for measurements. The most anterior slice was defined at the level where the stem of the temporal lobes first appeared. The hippocampus was considered no longer visible for measurements at the level in which the crux of the fornix and the inferior colliculus first appeared.

6. The head of the caudate nucleus. Measurements of this structure were taken from the T-1 axial slices for all slices where it was clearly visible (2-3) on either left or right side (below the frontal horns of the lateral ventricles),

7. Corpus callosum. Using facial landmarks, the medial, sagittal slice of the brain was used to outline the total area.

8. The space between the cerebral cortex and inner border of the skull was measured on the coronal images delineating the inferior boundary by drawing a line connect- ing the lowest boundary on both sides, excluding the cere- bellum.

All measurements were performed by the same individ- ual for each structure in order to eliminate errors due to multiple rater measurement variance. In addition, to reduce the intrarater variance for within subject comparisons (which were the most crucial), the series of scans for each individual were measured together in the same measure- ment session for each structure in random order. In this way doubtful regions were handled in a consistent manner from year to year of the study within individuals. All measure- ments were performed by computer engineers or graduate students specifically trained in the brain neuroanatomy. In addition, each rater was blind to whether the subject was a patient or control, how many of each were present, and the reason for evaluating the scans (i.e., that there could be

Brain Morphology and Cognition in Schizophrenics BIOL PSYCHIATRY 353 1995;38:349 360

progressive change over time). The intrarater ICC for each structure performed on approximately 25 scans 2 months apart was as follows: whole brain (coronal), 0.95; lateral ventricles, > 0.99; temporal lobe, 0.97; superior temporal gyrus, > 0.99; hippocampus, 0.76; caudate, 0.96; and corpus callosum, 0.95. Since the lowest reliability was with the hippocampus, measurements were taken twice and the mean value used in analyses. It is assumed that reliability was increased with the performance of measurements con- secutively in one time period in the series of scans from the same individual.

For each slice, area measurements were converted from pixels to millimeters 2 according to the formula: Area (ram 2) = measured pixels x FOV ht./image ht. x FOV length/image length, where FOV ht. = 240 mm, FOV length = 240 mm, and image ht. = 256 pixels as per our present protocol. All slice measurements were summed and multiplied by the slice thickness plus gap (7 mm) to obtain a total volume.

STATISTICAL ANALYSES. Measurements for each structure and their ratios to whole brain size were plotted versus time for each individual separately. Linear regres- sion was then performed to examine the rate of change in each structure over time. The slope of the regression line for each individual subject on each measurement of a region of interest (for both absolute value and ratio to whole brain size) was calculated, and these slopes were used in all analy- ses. Analyses were performed to determine whether the mean slope for all patients and controls separately was significantly different from a zero slope using the Wilcoxon sign ranks one sample test within the univariate procedure on SAS (Statistical Analysis Software). Mann-Whitney tests were used to determine whether slopes for patients were significantly different from those of controls.

Nonparametric exploratory correlations were performed (Spearman's r) to look for relationships between the change in MRI variables and the change in cognitive measures as well as other clinical indices.

Results

Analysis of the rate of structure change (slopes; Figure 1, Table 1) revealed significant decreases in corpus callosum, left and right temporal lobes, left and right superior tem- poral gyrus, left and right hippocampus/amygdala, right caudate, and both cerebral hemispheres in the patients. Sig- nificant reduction was not seen for any structure in the controls. The rate of change of the right cerebral hemi- sphere, but not the left, was significantly greater in patients than controls, while the left caudate decreased more in controls than patients. Both were significant even when corrected for the number of comparisons made (n = 13). No

other structural change was significantly different between patients and controls.

Since change in individual structures could be a function of more generalized real cortical change or some unknown artifactual whole brain size change, the rate of change for individual structures was also examined as a ratio to whole brain size (Table 2). In these analyses, there was a trend for corpus callosum to enlarge in controls, but not patients. The left lateral ventricle appeared enlarged when viewed as a ratio to whole brain size in patients, but not controls, and the caudate changed significantly more in controls than patients bilaterally. All other structures remained unchanged.

In order to determine whether actual number of slices where structures appeared could account for any of the results, total number of slices measured for each subject for each structure was tabulated. No slice number differences were present for any measured structure or either hemi- sphere between patients and controls.

Measurement of the coronal space between cerebral hemispheres and inner skull examined over time showed a nonsignificant inverse correlation in patients where, the larger the change in the space between brain and cerebrum, the smaller the whole brain (Spearman r = -.21); however, the space measurements were technically difficult to per- form, as clear boundaries could not be ascertained in several cases. In order to further determine the validity of the mea- sured coronal hemispheric change over time, coronal widths were obtained for each scan year by extending a line con- necting the angles between both ears. There was no change in these widths over time in patients or controls.

An examination of the slope of change for each cognitive functioning of the patients revealed no significant deteriora- tion in language, verbal memory, sensory perception, left hemisphere functioning, spatial memory, and executive function, while there was significant improvement over time in concentration/speed (p = .03), right hemispheric function (p = .002), and overall global functioning (p = .035) (Table 3). None of the tests of cognitive performance were correlated with clinical outcome, except the change in spa- tial memory positively correlated (Spearman r = .67, p = .009) and the change in language inversely correlated (r = - . 70 ,p = .005) with the Global Assessment Score.

The correlations of the change in all brain measures with change in neuropsychological measures revealed significant negative correlations of left hemispheric function with left and right hemispheric size, so that the greater the reduction in the size of the left hemisphere, the smaller the improvement in left hemispheric functioning (Table 4); however, there was a lack of correction with right hemispheric functioning. There were no trends for MRI structural change to be correlated with any pharmacologic treatment. Since all of the correlations do not reach statistical significance when corrected for the number of tests performed, they are considered only exploratory in nature.

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Table 1. Four-Year Fo l low-up of Fi rs t -Episode Schizophrenia

Brain Morphology: Rate of Change

+ Rate of change (cm/yr _ SD)

Patients Controls

Corpus callosum (cm 2) -0.05 ± 0.10" Lateral ventricles

Left +0.08 ± 0.32 Right +0.02 _+ 0.30

Temporal lobes

Left -0.76 ± 1.50" Right -0.79 ± 1.54"

Sup temporal gyms

Left -0.18 ± 0.30 ~ Right -0.17 + 0.41"

Hippocampus/amygdala

Left -0.05 + 0.08" Right -0.05 ± 0.08"

Caudate

Left a -0.02 -+ 0.05

Right ~ -0.04 ± 0.06- Cerebral hemispheres

Left -7.07 ± 7.40' Right c -7.18 ± 6.80'

-0.02 _+ 0.01

+0.07 + 0.15

+0.09 _+ 0.23

-0.53 ± 1.02 -0.79 ± 1.04

-0.17 ± 0.28 -0.09 ± 0.31

-0.10 ± 0.08 -0.08 ± 0.10

-0.07 -+ 0.04

-0.08 -+ 0.03

-3.13 ± 2.37 -2.31 + 1.95

"p < .05; #p < .01 ; 'p < .0001 (Wilcoxon sign ranks one sample test). Up < .05; "p = .057;Sp = .03, pts. vs. controls (Mann-Whitney test).

BIOL PSYCHIATRY 1995 ;38:349-360

357

Table 2. Four-Year Fo l low-up of Fi rs t -Episode Schizophrenia

Brain Morphology: Rate of Change per Total Brain Vo lume

Rate of change (cmVtotal brain volume/yr ± SD)

Patients Controls

Corpus callosum (cm2)" 1.88 -+ 9.2 4.66 ± 2.2 ~

Lateral ventricles" Left 1.29 4- 2.5" 0.52 ± 1.6

Right 0.74 -+ 2.6 0.83 -+ 1.6

Temporal lobes Left -0.09 ± 12.5 -3.57 ± 8.0 Right -0.65 ± 12.5 -3.16 ± 11.7

Sup temporal gyrus" Left -0.30 ± 2.5 -1.57 ± 3.0

Right -0.21 ± 3.4 -0.09 ± 2.8

Hippocampus/amygdala b

Left -1.10 ± 6.9 -7.46 ± 7.3 Right -0.80 ± 7.4 -3.99 ± 7.3

Caudate ~ Left" 0.44 ± 4.1 -7.69 _+ 7.0 d

Right' -1.36 ± 4.7 -8.11 ± 6,1 a

"× 1/10,000. ~'× 1/100,000. 'p < .04, patients vs. controls (Mann-Whitney test). '~p =.06; "p < .05 (Wilcoxon sign ranks one sample test).

however, do not reach statistical significance when correct- ing for the number of tests performed.

Discussion

The present analysis of a series of structural brain measure- ments during a 4-year period subsequent to a first psychotic episode suggests that some general cortical brain change may be taking place to a greater extent than that which normally occurs; however, this finding was uncorrelated with change in cognitive functioning, clinical outcome, or pharmacologic treatment and was tempered by the small number of controls for comparison.

Significant change was noted in the size of several struc- tures, when the change in these structures was not compared

Table 3. 4 -Year Fol low-up of Firs t -Episode Schizophrenia

Cogn i t ive Funct ioning Patients Only

Rate of change (Z scores/yr ± SD) p

Language 0.0443 _+ 0.117 .179 Executive 0.1943 ± 0,403 .094

Verbal memory -0.0764 ± 0.238 .252

Spatial memory 0.1179 ± 0.217 .062

Concentration/speed 0.1429 _+ 0.219 .030* Sensory perception 0.1092 + 0.285 .175

Left hemisphere 0.0207 _+ 0.141 .590 Right hemisphere 0.1439 ± 0.135 .002**

Global 0.0879 ± 0.140 .035*

358 B1OL PSYCHIATRY L.E. DeLisi et al 1995;38:349-360

Table 4. Slope Correlational Analysis (Exploratory)

LHEMISPH RHEMISPH CC LVENT RVENT LCAUD RCAUD LTEMP RTEMP LSTG RSTG LHIPP RHIPP

Mo. in hosp. +.22 +. 12 - .06 - .08 -.42" - .06 - . 18 +.03 +.37 - .06 +.33 - .02 +. 11

4-Yr GAS - .04 +.03 +.22 - . 13 - .09 - . 12 - .20 +.05 - .09 +.34 - . 15 +.42 U -.31 Age @ 1st symp. +.12 +.18 +.05 +.43" +,55 h - .46 b +.01 - .27 - .35 +.17 - .10 +.07 - .30

Duration of symptoms: - .16 - .15 +.18 +.33 +,19 - .42- - .15 +.23 - .02 .08 .25 - .17 +.40"

Duration of neuroleptics: - .32 - .23 +.10 +.02 - .12 -.21 -.31 - . 10 +.13 +.14 +.26 - .13 - .08

Duration of lithium: - . 15 - .39 +.06 -.41" - .41" +.25 +.04 +. 15 +.20 +.02 +.26 +. 15 - .24

Neuropsychology Language - .22 - . 10 +.01 +.30 +. 14 - .02 - . 15 +.03 +.25 +. 12 +.24 +.21 +. 14

Executive +.28 +.07 +.09 - .24 - .53 - . 17 - .62 ~ +.56 ~ +.35 +.36 +.08 +.48 +. 12 Verbal memory - .29 - .44 +.21 +.17 - .17 +.02 +.04 +.37 +.45 +.03 +.31 - .15 - .33

Spat ia lmemory +.25 +.35 +.51" - .09 - .19 -.41 - .55 h +.25 -.21 +.29 - .35 +.38 - .13

Concentration +. 14 - .09 - .04 - .09 -.48" - .29 - .54 h +.05 +.47" +.30 +.51" +. 16 +.33

Left hemisphere function - .58 b - .70 ' +.23 +.36 +.05 - . 17 - .03 +.31 +.31 +.33 +.74' +.02 - .07

Right hemisphere function +.00 +.03 +.19 - .24 - .38 - .08 - .6F ' - .07 - .12 +.25 +.09 +.24 - .03

Sensory perception -.21 - ,24 +.21 +.09 - .20 +. 11 - .30 -.01 - .06 +. 15 +. 17 - .07 - .19

Global +.08 - .06 +.35 - . 13 -.51" - .30 - .75 ' +.41 +.33 +.43 +.26 +.47" +.02

The rate of change (slope) for MR! variables was compared with the rate of change of neuropsychological variables, the total months in hospital during the 4 years of follow-up, the Global Assessment Score (GAS) at the 4th-year follow-up evaluation, the age at which the first symptoms appeared, and the time from that age to the first MRI and neuropsychological evaluation.

"p -< .1. bp < .05, 'p <-.0l. ~p --<.001.

with total brain size. On the other hand, an increase in the left lateral ventricle of patients and not controls was ob- served only after correcting for total brain size, while a decrease in temporal lobe, superior temporal gyrus, and medial temporal lobe structures was no longer apparent. Thus the increase in ventricular size in the present study, combined with the decrease in hemispheric size suggests the appearance of either cortical or subcortical atrophy rather than primary enlargement of the ventricles.

Nevertheless, the changes observed during the 4 years of follow-up were small and only suggestive. It is possible that this time span is too short and that gross morphological pa- thology is not evident until much later on in years, i.e., 10 or more. Alternatively, the cohort studied may never develop the changes noted in other studies or only a subgroup will and can not be distinguished from the others at this early stage. Alter- natively, there could be small changes in almost all patients, but they may not be significant compared with controls in some studies due to the large variance in size of these struc- tures among unrelated individuals. It was only with MZ twin studies comparing those discordant for schizophrenia, where the genetic variance is controlled, that these differences have been clearly measurable and shown to be present in the major- ity of ill subjects (Suddath et al 1990).

It could be said that relatively thick slices through the

temporal lobe will not detect the subtle changes occurring in schizophrenia and may account for our negative findings when comparing the scans at the first episode with control scans; however, while we failed to find temporal lobe or hippocampal reduction in first-episode schizophrenia, we did find these in chronic cases using an identical scanning procedure (DeLisi et al 1991) and another MRI protocol with even thicker slices (Dauphinais et a11990; DeLisi et al 1988).

Numerous technical difficulties exist in performing serial human MRI studies over long periods of time. These range from physiological changes and movement artifacts in the subjects to scanner parameter variability and measurement inaccuracies. Some of these are carefully controlled in the present study (i.e., by daily phantom scanning, subject alignment according to previous scans, and measurement reliability studies), while others may be unavoidable (i.e., subject weight and hydration changes, head tilt); however, if these mask changes present in schizophrenia, it is ques- tionable whether such subtle abnormalities have any patho- logical significance. Certainly they are not of the magnitude detected in Alzheimer's or Huntington's disease, where degeneration can be seen on MRI scans despite variable scanning techniques or patient position in the scanner.

The relationship of cognitive function to structure is not

Brain Morphology and Cognition in Schizophrenics B1OL PSYCHIATRY 359 1995;38:349-360

clearly defined and is controversial. It is of interest that neur- opsychological functioning did not worsen over time, and most cognitive performance did not correlate with any struc- tural brain changes, and given the exploratory nature of the analyses, some were probably spurious. Nevertheless, it was of interest that the greater the decrease in the size of the brain, the less of an improvement in left hemispheric functioning.

The change in the size of the right ventricle was signifi- cantly correlated with a later age of onset, with a trend on the left. This might suggest that although ventricular enlarge- ment can be detected at the first hospitalization (DeLisi et al 1991), and thus be actively occurring early on, if the onset was at a later age, the process might be more likely to be active subsequent to the first hospitalization; however, no correlation was present with duration of illness. Alternative- ly, early and late onsets could reflect different pathologic processes. The significance of these correlations will remain uncertain until future studies can replicate these results.

It is of interest that the corpus callosum became signifi- cantly larger in controls, but not patients. Two previous reports in the literature describe similar changes in normal adult subjects over time (Cowell et al 1992; Pujol et al

1993). It is possible that schizophrenic patients have a re- duction in the rate of normal growth of the corpus callosum which presumably is related to increased myelination rather than actual axon number, although this has not been shown. It is unclear why the caudate nucleus decreased in controls, but not patients. Could there be a normal decline in caudate size during the third to fourth decade of life (ages of present subjects)? If so, this may not occur in patients for some unknown reason and thus explain why chronic patients will appear to have significantly larger caudate nuclei than con- trols as previously published (e.g., Breier et al 1992).

The patients in the present study, as well as additional first-episode patients will be continued in further follow-up studies to try to resolve the above uncertainties. A larger group of both patients and controls will be followed for a longer time period to determine more definitively whether progressive brain change is characteristic of schizophrenia.

This project is partially supported by NIMH RO 1844245 and a NARSAD Junior Investigator Award to ALH. We thank Dr. Gene Gindi, and The Department of Radiology, SUNY Stony Brook for their continued support during this project.

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