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Normal eye tracking is associated with abnormal morphology of medial temporal lobe structures in schizophrenia
Schizophrenia Research . 8 (1992) 1-10 f; 1992 Elsevier Science Publishers B . V . All rights reserved 0920-9964,/92 ; $05 .00
SCHIZO 00251
Normal eye tracking is associated with abnormal morphology of medial temporal lobe structures in schizophrenia Deborah L . Levy,' ,b Bernhard Bogerts,` Gustav Degreef, a e Beth Dorogusker, t Christine Watemaux,a.b, g Manzar Ashtari,' Darlene Jody,' Stephen Geisler, d and Jeffrey A . Liebermana •` 'Mailman Research Center, M,Lean Hospital, Belmont . M.9, USA . 'Department o/ Psychiatry, Harvard Medical School, Boston, MA . LISA, `Department of Psychiatry, University of Dusseldorf Dusseldorf FRG, 'Hillside Hospital, a division of Long Island Jewish Medical Center, Glen Oaks, NY, USA, 'Department of Psychiatry, Albert Einstein College oJ'Medcine . Brmrr, NY, USA, 'Department of Psychiatry, Elizabeth General Hospital, Elizabeth, NJ, USA . sDeparrment of Biostatistics, Harvard School of Public Health, Boston, MA, USA, 'Department of Radiology. Long Island Jewish Medical Center, New Hyde Park, NY, USA, and'Sandor Institute, Hanover, NJ, USA
(Received 3 October 1991, revised received 25 April 1992 . accepted I I May 1992)
Eye tracking and brain morphology assessed by magnetic resonance imaging were examined in 48 patients in their first episode of schizophrenia and in 15 normal controls . Schizophrenic patients showed higher rates of eye tracking dysfunction and more abnormal brain morphology involving the lateral ventricles, medial temporal lobe (MTL) structures and the frontal-parietal cortex than controls . Enlargement of the lateral ventricles and global rating of abnormal brain morphology were significantly more prevalent in male schizophrenics than female schizophrenics . These findings indicate that abnormalities in a variety of brain regions are present in some schizophrenics during the period shortly after the first hospitalization and could not be a function of treatment or chronic illness . We found no relation between abnormal eye tracking and any single feature of abnormal brain morphology . However, normal eye tracking was significantly associated with MTL abnormalities in schizophrenics, reflecting an inverse association between quality of eye tracking and degree of abnormality in MTL structures . These results suggest that abnormal eye tracking is not mediated by the same processes that lead to structural brain anomalies in schizophrenia . as : Magnetic resonance imaging ; Eye tracking ; (Schizophrenia)
INTRODUCTION
An elevated prevalence of eye tracking abnormalities in schizophrenics has been replicated many times (see Lipton et al ., 1983 ; Holzman, 1985 ; Clementz and Sweeney . 1990 for reviews) . The psychological and biological characteristics that distinguish schizophrenics with eye tracking dysfunction (ETD) from schizophrenics with normal Correspondence to : Deborah L . Levy, Mailman Research Center, McLean Hospital, 115 Mill Street . Belmont, MA 02178, USA .
tracking, however, have not been elucidated . Brain morphology is a potentially informative source of data that may help both to clarify the basis for this heterogeneity among schizophrenics and to identify cerebral correlates of ETD . Four studies have used computerized tomography (CT) and one study has used magnetic resonance imaging (MRI) to examine the relation between lateral ventricle size and eye tracking in schizophrenics (Weinberger and Wyatt, 1982 ; Bartfai et al ., 1985 ; Stever et al ., 1986 ; Smeraldi et al ., 1987 ; Blackwood et al,, 1991b) . Significant associations have been reported between lateral ventricular enlargement (LVE) and both ETD
(Weinherger and Wyatt, 1982 : Blackwood et at., 1991b) and normal eye tracking (Smeraldi et al ., 1987) . In two other studies eye tracking and lateral ventricle size were found to be unrelated (Bartfai et al ., 1985 ; Siever et al ., 1986) . These inconsistencies are due at least in part to low statistical power to detect associations in small samples with a low prevalence of brain morphological abnormalities . More specifically, Weinberger and Wyatt (1982) reported a significant association between LVE and qualitative ratings of ETD . Nine of 14 (64%) patients with enlarged ventricles had ETD compared with six of 20 (30%) chronic schizophrenics with normal ventricles . Bartfai et al . (1985) described a tendency for 'worse SPEM [smooth pursuit eye movements]' to be related to 'larger ventricles' in 18 schizophrenics, but no specific brain morphological change was associated with ETD . Power to detect an association between specific features of brain morphology and eye tracking performance was reduced by lack of variability in the two measures . None of the schizophrenics met criteria for LVE and other morphological abnormalities were uncommon . In contrast, ETD was unusually prevalent (83% for a sinusoidal target and 92% for a triangular target), which may have been a function of relatively fast target speeds (26 .6 degjs for the constant velocity target ; 0 .55 Hz for the sinusoidal target) and the small amplitude of target movement (9 .5 degrees) . Smeraldi et al . (1987) examined ventricle-brain ratios (VBR) and qualitative ratings of eye tracking in 28 schizophrenics, 5 subjects with schizophrenia spectrum personality disorders and 53 controls . They reported a significant association between LVE and qualitatively normal tracking among the patients . Twelve of fourteen (86%) subjects with schizophrenia spectrum disorders and LVE had qualitatively normal eye tracking, compared to nine of nineteen (47 .4%) spectrum disorder subjects with lateral ventricles of normal size . Siever et al . (1986) found that VBR was not significantly correlated with qualitative rating of eye tracking in 14 acutely ill hospitalized schizophrenics . However, the authors noted that such an association may have been obscured by the paucity of ventricular enlargement in their sample ; only two subjects had enlarged ventricles (who also showed ETD) .
These four studies examined the relation between eye tracking and brain morphology, assessed by CT, primarily in relation to lateral ventricle size . Only the report by Blackwood et at . (1991b) examined multiple features of brain morphology in relation to eye tracking and used magnetic resonance to image the brain . They compared 31 schizophrenics with 28 normal controls and found that schizophrenics with ETD had significantly larger lateral ventricles than normal controls . Schizophrenics with normal eye tracking did not differ from controls in lateral ventricle size . Size of the cingulate cortex and medial temporal lobe structures was unrelated to eye tracking . The present study examines the relation between brain morphology assessed by MRI and eye tracking in first-episode schizophrenics and normal controls . Data on schizophrenics early in the course of illness minimizes the effects of chronicity, hospitalization and lengthy exposure to neuroleptic drug treatment . A significant association between ETD and specific features of abnormal brain morphology in first-episode patients would support a relation between both characteristics and the pathophysiology of the disorder itself, rather than with features of its progression and treatment .
METHODS Subjects
The patient sample consisted of 48 subjects (31 male, 17 female) who met Research Diagnostic Criteria (Spitzer et al . . 1978) for the diagnosis of schizophrenia or schizo-affective disorder (mainly schizophrenic) based on a SADS-L interview (Endicott and Spitzer, 1978) . All but one patient had been hospitalized for a first episode of psychosis and participated in a larger study on the psychobiology of first-episode schizophrenia (Lieberman et al 1992a), of which MRT scans and eye tracking were components . That one subject was treated as an outpatient . Median age was 24 .5 years (range : 16-36 years) . The normal control group consisted of 15 individuals (12 males, three females) who were screened for a personal or family history of schizophrenia, neurological disorder and substance abuse . Median age was 24 .0 years (range : 19-37 years) . The two groups did not differ in age
(Wilcoxon 2-sample test, Z = 0 .7033, ns) or gender distribution (y2,„=0 .64, ns) . Procedures Horizontal eye movements were recorded using infrared reflectometry . Signals from the photodetectors were amplified for sampling at rates of 250 timesjs/channel by analog-to-digital conversion to obtain angular eye position . Eye movements were calibrated to + 16 .25 degrees . A vertical signal detected blinks . The target, a cross subtending 1 .45 degrees of visual arc, was displayed on a rear projection screen 18 inches in front of the subject . The eye tracking task consisted of three trials in which the target moved sinusoidally at a frequency of 0 .4 Hz and aa peak-to-peak amplitude of 27 degrees . The duration of each trial was 30 s ; after 15 s the subject was re-alerted to the task . During the second trial the subject silently counted the number of times the target changed color, a procedure that optimizes performance (Shagass et al ., 1976 ; Holzman et al ., 1976) . A qualitative rating of normal or abnormal eye tracking was assigned to each record by one of the authors (DL) without knowledge of the subject's group membership or the MRI ratings using a modification of the scheme of Benitez (1970) . Testing was carried out in eight patients prior to neuroleptic drug treatment, in 21 medicated patients at discharge (median exposure : 2 months), and in 19 medicated patients within a median of 13 .6 months of their first hospital admission . Using date of admission as the criterion for onset of illness, median duration of illness at time of eye tracking was 4 .1 months . Median duration of exposure to neuroleptic drugs for all patients was 4 months . Medicated and unmedicated patients were analyzed as one group because qualitative ratings of eye tracking do not change as a result of neuroleptic drug treatment (Holzman et al ., 1974 ; Levy et al ., 1984 ; Rea et al ., 1989 ; Spohn et al ., 1988) . MRt scans were obtained using a SiemensMagnetom scanner operating at a field strength of 1 .0 tesla . A 50° flip angle 3-D gradient echo pulse sequence (Fast Low Angle Shot - FLASH) with a TR of 40 ms and a TE of 15 ms was used to acquire 63 contiguous 3 .1 mm thick sections of the brain in the coronal plane . The film hard copy of each scan was indepen-
dently evaluated qualitatively by two of the authors (BB and GD), who were blind to diagnosis and the eye tracking ratings . Each of four brain regions, the lateral ventricles, the third ventricle, frontalparietal cortex, and medial temporal lobe (MTL) structures, was classified as normal, questionable, or abnormal based on visual inspection . These ratings were made with knowledge of the subject's age . Criteria for abnormalities in each of these regions were as follows : (1) frontal-parietal cortex prominence of the cortical sulci, cortical subarachnoid space, and interhemispheric fissure ; (2) LYE increased size of the body, frontal or occipital horns of the lateral ventricles and/or blunting of the lateral angle of the lateral ventricles ; (3) increased width of the third ventricle ; (4) MTL structures - reduced size of the hippocampal formation, and/or dysplasia of the hippocampus with accompanying enlargement of the temporal horn of the lateral ventricle . Examples of the normal, questionable, and abnormal appearances of MTL structures are shown in Fig . 1 . Assessment of the hippocampus began posteriorly at the level of the pulvinar nucleus of the thalamus and included the most rostra) part of the hippocampal formation . A rating of `questionable' was assigned in cases where the degree of abnormality was insufficient to classify the region as unequivocally abnormal and too great to classify the region as unequivocally normal . Such equivocal changes may represent extremes of the normal range of variation or they may reflect genuinely abnormal findings, but their clinical significance is currently unclear . Therefore . `questionable' ratings were not combined with either `normal' or `abnormal' ratings in the statistical analyses . Instead, ratings were considered ordinal . For a more detailed discussion of delineation criteria and inter-rater reliability, see Lieberman et al . (1992b) . The MRI data were analyzed with respect to : (a) the prevalence of normal, abnormal and questionable ratings of each region ; (b) total abnormal brain morphology score (sum of the ordinal ratings in each region ; 0=normal, I = questionable, 2= abnormal) ; and (c) greatest abnormal brain morphology score (coded 0 if all regions were rated normal, I if no regions were rated abnormal, but at least one region was rated questionable, 2 if any one region was rated abnormal) . Median duration of illness at time of the MRI scan was 2 .7 months . Median length of neuroleptic
Fig . I . Qualitative ratings of medial temporal lobe structures . Arrows identify the medial temporal lobe structures . (A) Normal. (B) Questionable. (C) Abnormal . (A) Seventeen-year-old female schizophrenic subject . (B) Twenty-year-old male schizophrenic subject . (C) Eighteen-year-old female schizophrenic subject .
exposure was two months at the time of the MRI scan . Median interval between the eye tracking and MRI procedures was 59 days in the patients and 31 days in the controls . This difference was not statistically significant (Wilcoxon 2-sample test, Z = - 1 .4527, ns) . Because of artifact, the third ventricle and MTL could not be rated in one patient . Both qualitative and quantitative MRI data on the larger sample of patients have been presented elsewhere (Bogerts et al ., 1990; Dcgrcef et al ., 1992 ; Lieherman et al ., 1992a, 1992b) . Statistical methods The association between diagnosis and eye tracking was examined using a Yates' corrected Chi Square test (Siegel . 1956) . The association between diagnosis and MRI ratings was examined using logistic regression (Cox, 1980) . The association between
eye tracking and MRI ratings in schizophrenics was also examined using logistic regression . Logistic regression was used instead of chi-square analyses in order to make use of the ordinal nature of the MRI ratings (i .e . that an MRI rating of questionable falls between normal and abnormal) . Age and sex, in addition to MRI ratings, were considered as predictor variables in all the logistic regression analyses . Wald's chi-square statistic was used to test the significance of each of the predictor variables .
RFSU LTS Eye tracking Twenty-three of 48 first-episode patients (47 .9%) and 115 (6 .7%) normal controls had qualitative
ratings of ETD ; this difference was statistically significant (Yates' corrected )(2lt,=6 .59, p=0 .01)Subjects with normal eye tracking did not differ in age from patients with ETD (t 161 ,=0 .93, ns) ; we also found no age difference between good and bad tracking schizophrenic patients (t f46J = 1 .49, as) . Although eye tracking deteriorates with age (Sharpe and Sylvester, 1978 ; Spooner et al ., 1980), the absence of an age effect undoubtedly reflects the young age of our subjects . There was also no relation between sex and eye tracking among patients (xf fl> =0 .27, ns) or among the total sample (x = ( , ) = 0_59, ns) . Brain morphology
Schizophrenic patients had a significantly higher mean total abnormal brain morphology score (sum of regional ratings) than normal controls . Table I presents these results . Significant differences were also obtained between the two groups when greatest abnormal brain morphology score (any one region rated abnormal vs any one region rated questionable vs all regions rated normal) was examined . The bottom panel of Table 2 presents the greatest abnormal brain morphology scores . Logistic regression was used to investigate the association between being schizophrenic and MRf ratings of normal, questionable, or abnormal . Schizophrenic subjects had a significantly higher rate of abnormal (27 .7%) and questionable (36 .2%) ratings of brain structure than normal controls (0% and 20%, respectively) (Wald x 2 11 ,=8 .03, p+0 .0046) when all regions were considered . Neither age (Wald Z2,,)=0 .51, ns) nor sex (Wald x= 11 ,=2 .62, ns) was a significant predictor of these ratings . Logistic regressions were used to investigate the association between a diagnosis of schizophrenia and a rating of normal, questionable, or abnormal brain morphology in each of three regions : the lateral ventricles, third ventricle, and MTL . Schizophrenic patients had a significantly higher rate of questionable and abnormal ratings of the lateral ventricles (20 .8% and 18 .8%, respectively) (Wald g z fl ,=4 .61,p=0 .032) and MTL structures (25 .5% and 12.8% . respectively) (Wald y - ( 11 =3 .9126, p= 0 .048) than normal controls (6 .7% and 0%, respectively) when age and sex were taken into account . The distributions of ratings for these regions are presented in Table 2 . These associations were her-
TABLE I Total abnormal brain morphology scores in firs!-episode schizophrenic and normal conirolsubject y Total abnormal brain morphology score Mean SD
Group
n
Schizophrenia Males Females Normal
47
1 .81,
31 16
2 .26" 0 .94
15
033
1 .99 2 .11 1 .39
0 .72
'Schizophrenics vs normal controls : Itsm-2 .81, p<0 .0068 . ° Male schizophrenics vs female schizophrenics : t,,=2 .25, p=0 .029 . derline significant without adjustments for age and sex . Sex approached statistical significance as a predictor of diagnosis (x2 t 1,=3 .47 . p=0 .063), reflecting the preponderance of males among the patient sample . There were no significant differences between normal controls and patients in ratings of the third ventricle with (Wald g 2 J17 = 0 .944 . p=0 .33) or without (Wald g 2 , 1) =1 .43 . p= 0 .23) adjustments for age and sex . Age was not a significant predictor for any region (all ps>0 .35) . Subjects with normal, questionable, and abnormal ratings did not differ in age in any of the three regions . again likely reflecting the young age of the sample (Jernigan et al ., 1990) . Because no control had a questionable or abnormal rating of the frontal-parietal cortex, a logistic regression could not be performed on ratings of this region . The results of a Fisher's Exact (Siegel, 1956) indicated a significantly higher rate of questionable (27 .1%) and abnormal (2 .1%) ratings of frontal-parietal cortex in patients than in controls (p=0 .034) . See Table 2 . Sex dif)PVenees
Male schizophrenic subjects differed from female schizophrenic subjects in two respects . First, male schizophrenics had a significantly higher total abnormal brain morphology score than female schizophrenics (see Table I ) . Second, male schizophrenics had a significantly higher rate of questionable (32 .3%) and abnormal (22 .6%) ratings of the lateral ventricles than female schizophrenics (0% and 11 .8%, respectively) (Fisher's Exact test, p= 0 .0053) . Male schizophrenics also had a higher prevalence of questionable and abnormal ratings of the third ventricle, frontal-parietal cortex, and
6 TABLE 2 Qualitative ratings of cortex, lateral ventricles, At TL structures, and greatest abnormal bruin murp ologv in first-episode sctuzop/renic and normal control subjects Cortex Group Schizophrenic Normal
n 48 15
Normal 34 15
Questionable 13 0
Abnormal 1 0
Normal 29 14
Questionable
Abnormal
Normal 29 14
Questionable 12 1
Lateral ventricles Group Schizophrenic Normal
n 48 15
10 1
9 0
MNTL Group Schizophrenic Normal
n 47 l5
Abnormal
6 0
Greatest abnormal brain morphology Group Schizophrenic Normal
n 47 l5
All normal l7 12
At least I questionable 17 3
MTL structures, than female schizophrenics, but these differences were not statistically significant . Relation between eye tracking and brain morphology Logistic regression was used to investigate the relation between eye tracking and MRT ratings in schizophrenics . Schizophrenics with normal eye tracking had significantly higher rates of questionable and abnormal ratings of MTL structures than subjects with ETD . reflecting an inverse relation between quality of tracking and degree of MTL abnormality . These data are presented in Table 3 . This relation holds with (Wald y 2 , 1) =3 .93, p=0 .047) or without (Wald y2(1)=4 .12, p=0 .041) adjustments for age and sex . All six patients with MTL abnor-
At least I abnormal 13 0
malities had normal tracking, as did 50% of patients with questionable ratings of MTL structures and 44 .8% of patients with ratings of normal MTL structures . Neither ratings of the frontalparietal cortex, lateral ventricles or third ventricle, nor the greatest abnormal brain morphology score, predicted eye tracking (all ps>0 .2) . Total abnormal brain morphology score also did not distinguish good trackers from bad trackers (t f4z ,= 0 .9995, ns) .
DISCUSSION
The high rates of ETD in diseases affecting the central nervous system (see Leigh and Zee, 1991)
TABLE 3 Qualitative ratings u) MTL structures and qualitative ratings
of normal
and abnormal eye tracking in first-episode schizophrenics
Eye tracking
n
Normal
Questionable
Abnormal
Normal Abnormal
25 22
13
6
6
l6
0
7
and the occurrence of both ETD (see Lipton et al ., 1983 ; Clementz and Sweeney, 1990) and a variety of aberrations in brain structure in schizophrenic patients (Johnstone et al ., 1976; Nasrallah et al ., 1986; Bogerts et al ., 1990) led us to expect that abnormal eye tracking would be associated with some feature of abnormal brain structure . However, both our results and those of Smeraldi et al . (1987) show a relation between normal eye tracking and some feature of abnormal brain morphology . Our data support MTL anomalies and their data support EVE . The results of both studies support a dissociation between qualitative measures of abnormal eye tracking and abnormal brain morphology and an association between normal eye tracking and abnormal brain structure . These findings suggest that whatever process grossly alters brain structure in schizophrenia is unrelated to the mechanisms involved in ETD . We cannot, of course, exclude the possibility that abnormalities in brain regions that were not examined (e .g . frontal eye fields, superior colliculus) . and which may play an important role in the mediation of eye movements, show a different pattern of association with eye tracking performance . The lower than expected co-occurrence of ETD and visible brain pathology raises the intriguing possibility that different etiological mechanisms are implicated in the pathogenesis of each phenomenon . Genetic factors seem to play a critical role in the transmission of both schizophrenia and ETD (Holzman et al . . 1988 ; Matthysse et al ., 1986) . Although still not settled definitively (see Lewis, 1990), certain abnormalities in brain morphology (detected on CT) may be less prevalent in schizophrenics who are at genetic risk than in schizophrenics who have no family history of the disorder (Reveley, et al ., 1982) . Specific brain morphological aberrations in the latter group may reflect environmental insults secondary to birth complications, viral factors, or other still unknown nongenetic causes (Cannon et al ., 1989 ; Rcveley, et al ., 1982) . Indeed, schizophrenics who have no family history of the disorder (who are presumably at low genetic risk) are more likely to be born during months associated with greater risk of perinatal morbidity and mortality (Kinney and Jacobsen, 1978), which might in turn be expected to result in neurologic sequelae, such as brain structural changes. The roles of genetic liability,
birth and obstetrical complications, and their interaction in influencing individual differences in patterns of normal and abnormal brain structure are currently being explored with respect to both MRI variables and eye tracking in these subjects . We found no association between eye tracking and enlargement of either the lateral ventricles or the third ventricle . Although this result parallels the findings for the lateral ventricles described by Sicver et al . (1986), whose sample of young, recent onset patients was similar to ours, and those of Bartfai et al . (1985), who studied a mixed group of first- and multi-episode schizophrenics, the negative findings of all three studies may reflect low statistical power secondary to relatively low rates of EVE . Our sample of first-episode patients did not show the significant association between LVE and ETD found by Blackwood et al . (1991b) or by Weinberger and Wyatt (1982) in chronic schizophrenics . Our Yates' corrected chi square analysis of the Weinberger and Wyatt (1982) data, however, does not show a statistically significant association between lateral ventricle size and eye tracking ( ;t 2 ( ,, = 2 .66, p=0 .10) . Our results showing an association between normal eye tracking and MTL abnormalities also contrast with those of Blackwood et al . (199Ib), who found no relation between eye tracking and area of MTL Structures . Two factors may account for the differences between our findings and those of Blackwood et al . (1991 b) . First, we used qualitative ratings of both eye tracking and brain morphology, whereas they treasured regional brain areas and distinguished good and had trackers based on a cutoff in the natural logarithm of the signal :noise ratio score. Second, our sample of first-episode schizophrenics had a significantly higher prevalence of abnormal eye tracking than normal control subjects . Their sample of schizophrenics did not differ from normal control subjects on a global quantitative measure of eye tracking proficiency, although a larger sample from which these patients were drawn did differ from controls (Blackwood et al ., 1991a) . The rates of ETD in first-episode schizophrenics and normal controls are consistent with figures reported in previous studies of chronic and acute schizophrenics and normal controls (Holzman et al ., 1974, 1977 ; Yee et al ., 1987 ; Siever et al ., 1986) and in the larger sample of first-episode patients from which this sample was drawn (Lieb-
erman ct al ., 1992a) . The presence of ETD in these patients, who had been ill and/or medicated for only a short time, indicates that neither chronic psychosis nor chronic exposure to neuroleptic drugs is a necessary condition for the presence of ETD and that ETD is present early in the course of schizophrenia . These results provide further . though indirect, support for the trait status of ETD in schizophrenics (Levy et al ., 1984 : Spohn and Larson, 1983) . The qualitative ratings of neuroanatomic regions yielded significant elevations in the prevalence of abnormal brain morphology in first-episode schizophrenics compared with controls in three of the four brain regions studied (the lateral ventricles, MTL structures, frontal-parietal cortex) . in the total abnormal brain morphology score . and in the greatest abnormal brain morphology score . These results suggest that a variety of anomalies in brain structure are present during the period shortly after the first hospitalization in a subgroup of schizophrenics and are unlikely to he a result of neuroleptic drug treatment (Weinberger, 1984) or chronic illness . Although these group differences are based on qualitative ratings of specific brain regions . they are consistent with quantitative data derived from the larger sample from which these first-episode patients are drawn (Lieberman et al ., 1992b ; Degreef et al ., 1992 ; Bogerts et al ., 1990), Although we did not find significantly elevated rates of third ventricular enlargement in schizophrenics compared with controls, such a group difference has been found in larger samples of patients and controls from which our groups were drawn . The absence of significant differences in this study likely reflects low statistical power to detect group differences in the prevalence of relatively uncommon brain abnormalities . The majority of CT scan studies have not shown an effect of gender on LVF (reviewed in Goetz and Van Kammen. 1986), but another review of CT studies (Raz and Raz, 1990) found a significant association between gender composition and effect size for ventriculomegaly . Our group found that males had a significantly larger mean ventricular volume than women, but there was no interaction of diagnosis with gender (Degreef et al ., 1992) . The similarity between our eye tracking and MRI results and those reported by other investigators indicate that
the relatively small control group did not prevent us from detecting group differences . Although abnormal brain morphology is more common in some regions than in others, and any single abnormal feature occurs in a minority of patients, no one region seems to be characteristically involved . This pattern parallels research findings showing that a variety of neurological signs, but no single type, account for the increased prevalence of neurological abnormalities in schizophrenics (and also in their first-degree relatives) (Woods et al ., 1986 : Kinney et al ., 1986, 1991) . The existing CT studies and our own MRI study were based on qualitative ratings of eye tracking . Similarly, classifications of brain regions based on visual inspection are inevitably less precise than quantitative measures of each structure, although qualitative ratings are significantly correlated with volume of the same region (Lieberman et al ., 1992b) . As the various quantitative features of ocular motor performance and volumetric regional brain measurements become available . we will have the opportunity to examine these variables in greater detail .
ACKNOWLEDGEMENTS
The authors thank Mrs . Rosalind Zitner . Mrs . Sabina Meyer .. and Mrs . Greta Schimmel for their assistance in data collection and Drs . Philip Holzman . Dennis Kinney . Martha Shenton and Deborah Yurgelun-Todd for their helpful comments on the manuscript . This work was supported in part by IJSPHS grants MH-41646, MH-00537 . MH-41960, MH-31154, MH- 31340 .
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10 movement disorder and its psychobiotogic correlates in unmedicated schizophrenics . Biol . Psychiatry 21 . 1167-1174 . Smeraldi, E ., Gambini, 0 . . Bellodi . L ., Sacchetti . E., Vita, A ., di Rosa, M ., Macciardi, F., Cazzullo . C.L . (1987) Combined measure of smooth pursuit eye movements and ventriclebrain ratio in schizophrenic disorders . Psychiatry Res . 21, 293-301 . Spitzer. R .L ., Endicott, J . and Rohbinss, E . (1978) Research diagnostic criteria . Arch . .Gen Psychiatry 35, 773-782 . Spohn, H .S . and Larson, J . (1983) Is eye tracking dysfunction specific to schizophrenia? Schizophr . Bull . 9, 50-55 . Spohn, H .E . . Coyne, L . and Spray, J . (1988) The effect of ncuroleptics and tardive dyskinesia on smooth-pursuit eye movements in chronic schizophrenics . Arch . Gen . Psychiatry 45, 833 -840 . Spooner, J .W ., Sakala, S .M ., Batch, R .W . (1980) Effect of aging on eye tracking . Arch . Neurol . 37, 575-576 .
Weinberger . D .R . (1984) Computed tomography (CT) findings in schizophrenia : Speculation on the meaning of it all . 1 . Psychiatric Res . 18, 477-490 . Weinherger, D .R . and Wyatt, R .J . (1982) Cerebral ventricular size : A biological marker for subtyping chronic schizophrenia . In E . Usdin ; and J . Handin, (Eds) . Biological Markers in Psychiatry and Neurology . Oxford : Pergamon, pp.505-512 . Woods, B .T., Kinney, D .K ., Yurgelun-Todd, D .A . (1986) Neurological abnormalities in schizophrenic patients and their families : 1 . Comparison of schizophrenic . bipolar, and substance abuse patients and normal controls- Arch . Gen . Psychiatry 43, 657- 663 . Yce, R ., Batch, R .W . . Marder, S ., Levy. D .L ., Sakala, S .M . and Honruhia, V . (1987) Eye movements in schizophrenia . Invest . Ophthalmol . Vis . Sci . 28, 366-374 .
SCHIZO 00251
Normal eye tracking is associated with abnormal morphology of medial temporal lobe structures in schizophrenia Deborah L . Levy,' ,b Bernhard Bogerts,` Gustav Degreef, a e Beth Dorogusker, t Christine Watemaux,a.b, g Manzar Ashtari,' Darlene Jody,' Stephen Geisler, d and Jeffrey A . Liebermana •` 'Mailman Research Center, M,Lean Hospital, Belmont . M.9, USA . 'Department o/ Psychiatry, Harvard Medical School, Boston, MA . LISA, `Department of Psychiatry, University of Dusseldorf Dusseldorf FRG, 'Hillside Hospital, a division of Long Island Jewish Medical Center, Glen Oaks, NY, USA, 'Department of Psychiatry, Albert Einstein College oJ'Medcine . Brmrr, NY, USA, 'Department of Psychiatry, Elizabeth General Hospital, Elizabeth, NJ, USA . sDeparrment of Biostatistics, Harvard School of Public Health, Boston, MA, USA, 'Department of Radiology. Long Island Jewish Medical Center, New Hyde Park, NY, USA, and'Sandor Institute, Hanover, NJ, USA
(Received 3 October 1991, revised received 25 April 1992 . accepted I I May 1992)
Eye tracking and brain morphology assessed by magnetic resonance imaging were examined in 48 patients in their first episode of schizophrenia and in 15 normal controls . Schizophrenic patients showed higher rates of eye tracking dysfunction and more abnormal brain morphology involving the lateral ventricles, medial temporal lobe (MTL) structures and the frontal-parietal cortex than controls . Enlargement of the lateral ventricles and global rating of abnormal brain morphology were significantly more prevalent in male schizophrenics than female schizophrenics . These findings indicate that abnormalities in a variety of brain regions are present in some schizophrenics during the period shortly after the first hospitalization and could not be a function of treatment or chronic illness . We found no relation between abnormal eye tracking and any single feature of abnormal brain morphology . However, normal eye tracking was significantly associated with MTL abnormalities in schizophrenics, reflecting an inverse association between quality of eye tracking and degree of abnormality in MTL structures . These results suggest that abnormal eye tracking is not mediated by the same processes that lead to structural brain anomalies in schizophrenia . as : Magnetic resonance imaging ; Eye tracking ; (Schizophrenia)
INTRODUCTION
An elevated prevalence of eye tracking abnormalities in schizophrenics has been replicated many times (see Lipton et al ., 1983 ; Holzman, 1985 ; Clementz and Sweeney . 1990 for reviews) . The psychological and biological characteristics that distinguish schizophrenics with eye tracking dysfunction (ETD) from schizophrenics with normal Correspondence to : Deborah L . Levy, Mailman Research Center, McLean Hospital, 115 Mill Street . Belmont, MA 02178, USA .
tracking, however, have not been elucidated . Brain morphology is a potentially informative source of data that may help both to clarify the basis for this heterogeneity among schizophrenics and to identify cerebral correlates of ETD . Four studies have used computerized tomography (CT) and one study has used magnetic resonance imaging (MRI) to examine the relation between lateral ventricle size and eye tracking in schizophrenics (Weinberger and Wyatt, 1982 ; Bartfai et al ., 1985 ; Stever et al ., 1986 ; Smeraldi et al ., 1987 ; Blackwood et al,, 1991b) . Significant associations have been reported between lateral ventricular enlargement (LVE) and both ETD
(Weinherger and Wyatt, 1982 : Blackwood et at., 1991b) and normal eye tracking (Smeraldi et al ., 1987) . In two other studies eye tracking and lateral ventricle size were found to be unrelated (Bartfai et al ., 1985 ; Siever et al ., 1986) . These inconsistencies are due at least in part to low statistical power to detect associations in small samples with a low prevalence of brain morphological abnormalities . More specifically, Weinberger and Wyatt (1982) reported a significant association between LVE and qualitative ratings of ETD . Nine of 14 (64%) patients with enlarged ventricles had ETD compared with six of 20 (30%) chronic schizophrenics with normal ventricles . Bartfai et al . (1985) described a tendency for 'worse SPEM [smooth pursuit eye movements]' to be related to 'larger ventricles' in 18 schizophrenics, but no specific brain morphological change was associated with ETD . Power to detect an association between specific features of brain morphology and eye tracking performance was reduced by lack of variability in the two measures . None of the schizophrenics met criteria for LVE and other morphological abnormalities were uncommon . In contrast, ETD was unusually prevalent (83% for a sinusoidal target and 92% for a triangular target), which may have been a function of relatively fast target speeds (26 .6 degjs for the constant velocity target ; 0 .55 Hz for the sinusoidal target) and the small amplitude of target movement (9 .5 degrees) . Smeraldi et al . (1987) examined ventricle-brain ratios (VBR) and qualitative ratings of eye tracking in 28 schizophrenics, 5 subjects with schizophrenia spectrum personality disorders and 53 controls . They reported a significant association between LVE and qualitatively normal tracking among the patients . Twelve of fourteen (86%) subjects with schizophrenia spectrum disorders and LVE had qualitatively normal eye tracking, compared to nine of nineteen (47 .4%) spectrum disorder subjects with lateral ventricles of normal size . Siever et al . (1986) found that VBR was not significantly correlated with qualitative rating of eye tracking in 14 acutely ill hospitalized schizophrenics . However, the authors noted that such an association may have been obscured by the paucity of ventricular enlargement in their sample ; only two subjects had enlarged ventricles (who also showed ETD) .
These four studies examined the relation between eye tracking and brain morphology, assessed by CT, primarily in relation to lateral ventricle size . Only the report by Blackwood et at . (1991b) examined multiple features of brain morphology in relation to eye tracking and used magnetic resonance to image the brain . They compared 31 schizophrenics with 28 normal controls and found that schizophrenics with ETD had significantly larger lateral ventricles than normal controls . Schizophrenics with normal eye tracking did not differ from controls in lateral ventricle size . Size of the cingulate cortex and medial temporal lobe structures was unrelated to eye tracking . The present study examines the relation between brain morphology assessed by MRI and eye tracking in first-episode schizophrenics and normal controls . Data on schizophrenics early in the course of illness minimizes the effects of chronicity, hospitalization and lengthy exposure to neuroleptic drug treatment . A significant association between ETD and specific features of abnormal brain morphology in first-episode patients would support a relation between both characteristics and the pathophysiology of the disorder itself, rather than with features of its progression and treatment .
METHODS Subjects
The patient sample consisted of 48 subjects (31 male, 17 female) who met Research Diagnostic Criteria (Spitzer et al . . 1978) for the diagnosis of schizophrenia or schizo-affective disorder (mainly schizophrenic) based on a SADS-L interview (Endicott and Spitzer, 1978) . All but one patient had been hospitalized for a first episode of psychosis and participated in a larger study on the psychobiology of first-episode schizophrenia (Lieberman et al 1992a), of which MRT scans and eye tracking were components . That one subject was treated as an outpatient . Median age was 24 .5 years (range : 16-36 years) . The normal control group consisted of 15 individuals (12 males, three females) who were screened for a personal or family history of schizophrenia, neurological disorder and substance abuse . Median age was 24 .0 years (range : 19-37 years) . The two groups did not differ in age
(Wilcoxon 2-sample test, Z = 0 .7033, ns) or gender distribution (y2,„=0 .64, ns) . Procedures Horizontal eye movements were recorded using infrared reflectometry . Signals from the photodetectors were amplified for sampling at rates of 250 timesjs/channel by analog-to-digital conversion to obtain angular eye position . Eye movements were calibrated to + 16 .25 degrees . A vertical signal detected blinks . The target, a cross subtending 1 .45 degrees of visual arc, was displayed on a rear projection screen 18 inches in front of the subject . The eye tracking task consisted of three trials in which the target moved sinusoidally at a frequency of 0 .4 Hz and aa peak-to-peak amplitude of 27 degrees . The duration of each trial was 30 s ; after 15 s the subject was re-alerted to the task . During the second trial the subject silently counted the number of times the target changed color, a procedure that optimizes performance (Shagass et al ., 1976 ; Holzman et al ., 1976) . A qualitative rating of normal or abnormal eye tracking was assigned to each record by one of the authors (DL) without knowledge of the subject's group membership or the MRI ratings using a modification of the scheme of Benitez (1970) . Testing was carried out in eight patients prior to neuroleptic drug treatment, in 21 medicated patients at discharge (median exposure : 2 months), and in 19 medicated patients within a median of 13 .6 months of their first hospital admission . Using date of admission as the criterion for onset of illness, median duration of illness at time of eye tracking was 4 .1 months . Median duration of exposure to neuroleptic drugs for all patients was 4 months . Medicated and unmedicated patients were analyzed as one group because qualitative ratings of eye tracking do not change as a result of neuroleptic drug treatment (Holzman et al ., 1974 ; Levy et al ., 1984 ; Rea et al ., 1989 ; Spohn et al ., 1988) . MRt scans were obtained using a SiemensMagnetom scanner operating at a field strength of 1 .0 tesla . A 50° flip angle 3-D gradient echo pulse sequence (Fast Low Angle Shot - FLASH) with a TR of 40 ms and a TE of 15 ms was used to acquire 63 contiguous 3 .1 mm thick sections of the brain in the coronal plane . The film hard copy of each scan was indepen-
dently evaluated qualitatively by two of the authors (BB and GD), who were blind to diagnosis and the eye tracking ratings . Each of four brain regions, the lateral ventricles, the third ventricle, frontalparietal cortex, and medial temporal lobe (MTL) structures, was classified as normal, questionable, or abnormal based on visual inspection . These ratings were made with knowledge of the subject's age . Criteria for abnormalities in each of these regions were as follows : (1) frontal-parietal cortex prominence of the cortical sulci, cortical subarachnoid space, and interhemispheric fissure ; (2) LYE increased size of the body, frontal or occipital horns of the lateral ventricles and/or blunting of the lateral angle of the lateral ventricles ; (3) increased width of the third ventricle ; (4) MTL structures - reduced size of the hippocampal formation, and/or dysplasia of the hippocampus with accompanying enlargement of the temporal horn of the lateral ventricle . Examples of the normal, questionable, and abnormal appearances of MTL structures are shown in Fig . 1 . Assessment of the hippocampus began posteriorly at the level of the pulvinar nucleus of the thalamus and included the most rostra) part of the hippocampal formation . A rating of `questionable' was assigned in cases where the degree of abnormality was insufficient to classify the region as unequivocally abnormal and too great to classify the region as unequivocally normal . Such equivocal changes may represent extremes of the normal range of variation or they may reflect genuinely abnormal findings, but their clinical significance is currently unclear . Therefore . `questionable' ratings were not combined with either `normal' or `abnormal' ratings in the statistical analyses . Instead, ratings were considered ordinal . For a more detailed discussion of delineation criteria and inter-rater reliability, see Lieberman et al . (1992b) . The MRI data were analyzed with respect to : (a) the prevalence of normal, abnormal and questionable ratings of each region ; (b) total abnormal brain morphology score (sum of the ordinal ratings in each region ; 0=normal, I = questionable, 2= abnormal) ; and (c) greatest abnormal brain morphology score (coded 0 if all regions were rated normal, I if no regions were rated abnormal, but at least one region was rated questionable, 2 if any one region was rated abnormal) . Median duration of illness at time of the MRI scan was 2 .7 months . Median length of neuroleptic
Fig . I . Qualitative ratings of medial temporal lobe structures . Arrows identify the medial temporal lobe structures . (A) Normal. (B) Questionable. (C) Abnormal . (A) Seventeen-year-old female schizophrenic subject . (B) Twenty-year-old male schizophrenic subject . (C) Eighteen-year-old female schizophrenic subject .
exposure was two months at the time of the MRI scan . Median interval between the eye tracking and MRI procedures was 59 days in the patients and 31 days in the controls . This difference was not statistically significant (Wilcoxon 2-sample test, Z = - 1 .4527, ns) . Because of artifact, the third ventricle and MTL could not be rated in one patient . Both qualitative and quantitative MRI data on the larger sample of patients have been presented elsewhere (Bogerts et al ., 1990; Dcgrcef et al ., 1992 ; Lieherman et al ., 1992a, 1992b) . Statistical methods The association between diagnosis and eye tracking was examined using a Yates' corrected Chi Square test (Siegel . 1956) . The association between diagnosis and MRI ratings was examined using logistic regression (Cox, 1980) . The association between
eye tracking and MRI ratings in schizophrenics was also examined using logistic regression . Logistic regression was used instead of chi-square analyses in order to make use of the ordinal nature of the MRI ratings (i .e . that an MRI rating of questionable falls between normal and abnormal) . Age and sex, in addition to MRI ratings, were considered as predictor variables in all the logistic regression analyses . Wald's chi-square statistic was used to test the significance of each of the predictor variables .
RFSU LTS Eye tracking Twenty-three of 48 first-episode patients (47 .9%) and 115 (6 .7%) normal controls had qualitative
ratings of ETD ; this difference was statistically significant (Yates' corrected )(2lt,=6 .59, p=0 .01)Subjects with normal eye tracking did not differ in age from patients with ETD (t 161 ,=0 .93, ns) ; we also found no age difference between good and bad tracking schizophrenic patients (t f46J = 1 .49, as) . Although eye tracking deteriorates with age (Sharpe and Sylvester, 1978 ; Spooner et al ., 1980), the absence of an age effect undoubtedly reflects the young age of our subjects . There was also no relation between sex and eye tracking among patients (xf fl> =0 .27, ns) or among the total sample (x = ( , ) = 0_59, ns) . Brain morphology
Schizophrenic patients had a significantly higher mean total abnormal brain morphology score (sum of regional ratings) than normal controls . Table I presents these results . Significant differences were also obtained between the two groups when greatest abnormal brain morphology score (any one region rated abnormal vs any one region rated questionable vs all regions rated normal) was examined . The bottom panel of Table 2 presents the greatest abnormal brain morphology scores . Logistic regression was used to investigate the association between being schizophrenic and MRf ratings of normal, questionable, or abnormal . Schizophrenic subjects had a significantly higher rate of abnormal (27 .7%) and questionable (36 .2%) ratings of brain structure than normal controls (0% and 20%, respectively) (Wald x 2 11 ,=8 .03, p+0 .0046) when all regions were considered . Neither age (Wald Z2,,)=0 .51, ns) nor sex (Wald x= 11 ,=2 .62, ns) was a significant predictor of these ratings . Logistic regressions were used to investigate the association between a diagnosis of schizophrenia and a rating of normal, questionable, or abnormal brain morphology in each of three regions : the lateral ventricles, third ventricle, and MTL . Schizophrenic patients had a significantly higher rate of questionable and abnormal ratings of the lateral ventricles (20 .8% and 18 .8%, respectively) (Wald g z fl ,=4 .61,p=0 .032) and MTL structures (25 .5% and 12.8% . respectively) (Wald y - ( 11 =3 .9126, p= 0 .048) than normal controls (6 .7% and 0%, respectively) when age and sex were taken into account . The distributions of ratings for these regions are presented in Table 2 . These associations were her-
TABLE I Total abnormal brain morphology scores in firs!-episode schizophrenic and normal conirolsubject y Total abnormal brain morphology score Mean SD
Group
n
Schizophrenia Males Females Normal
47
1 .81,
31 16
2 .26" 0 .94
15
033
1 .99 2 .11 1 .39
0 .72
'Schizophrenics vs normal controls : Itsm-2 .81, p<0 .0068 . ° Male schizophrenics vs female schizophrenics : t,,=2 .25, p=0 .029 . derline significant without adjustments for age and sex . Sex approached statistical significance as a predictor of diagnosis (x2 t 1,=3 .47 . p=0 .063), reflecting the preponderance of males among the patient sample . There were no significant differences between normal controls and patients in ratings of the third ventricle with (Wald g 2 J17 = 0 .944 . p=0 .33) or without (Wald g 2 , 1) =1 .43 . p= 0 .23) adjustments for age and sex . Age was not a significant predictor for any region (all ps>0 .35) . Subjects with normal, questionable, and abnormal ratings did not differ in age in any of the three regions . again likely reflecting the young age of the sample (Jernigan et al ., 1990) . Because no control had a questionable or abnormal rating of the frontal-parietal cortex, a logistic regression could not be performed on ratings of this region . The results of a Fisher's Exact (Siegel, 1956) indicated a significantly higher rate of questionable (27 .1%) and abnormal (2 .1%) ratings of frontal-parietal cortex in patients than in controls (p=0 .034) . See Table 2 . Sex dif)PVenees
Male schizophrenic subjects differed from female schizophrenic subjects in two respects . First, male schizophrenics had a significantly higher total abnormal brain morphology score than female schizophrenics (see Table I ) . Second, male schizophrenics had a significantly higher rate of questionable (32 .3%) and abnormal (22 .6%) ratings of the lateral ventricles than female schizophrenics (0% and 11 .8%, respectively) (Fisher's Exact test, p= 0 .0053) . Male schizophrenics also had a higher prevalence of questionable and abnormal ratings of the third ventricle, frontal-parietal cortex, and
6 TABLE 2 Qualitative ratings of cortex, lateral ventricles, At TL structures, and greatest abnormal bruin murp ologv in first-episode sctuzop/renic and normal control subjects Cortex Group Schizophrenic Normal
n 48 15
Normal 34 15
Questionable 13 0
Abnormal 1 0
Normal 29 14
Questionable
Abnormal
Normal 29 14
Questionable 12 1
Lateral ventricles Group Schizophrenic Normal
n 48 15
10 1
9 0
MNTL Group Schizophrenic Normal
n 47 l5
Abnormal
6 0
Greatest abnormal brain morphology Group Schizophrenic Normal
n 47 l5
All normal l7 12
At least I questionable 17 3
MTL structures, than female schizophrenics, but these differences were not statistically significant . Relation between eye tracking and brain morphology Logistic regression was used to investigate the relation between eye tracking and MRT ratings in schizophrenics . Schizophrenics with normal eye tracking had significantly higher rates of questionable and abnormal ratings of MTL structures than subjects with ETD . reflecting an inverse relation between quality of tracking and degree of MTL abnormality . These data are presented in Table 3 . This relation holds with (Wald y 2 , 1) =3 .93, p=0 .047) or without (Wald y2(1)=4 .12, p=0 .041) adjustments for age and sex . All six patients with MTL abnor-
At least I abnormal 13 0
malities had normal tracking, as did 50% of patients with questionable ratings of MTL structures and 44 .8% of patients with ratings of normal MTL structures . Neither ratings of the frontalparietal cortex, lateral ventricles or third ventricle, nor the greatest abnormal brain morphology score, predicted eye tracking (all ps>0 .2) . Total abnormal brain morphology score also did not distinguish good trackers from bad trackers (t f4z ,= 0 .9995, ns) .
DISCUSSION
The high rates of ETD in diseases affecting the central nervous system (see Leigh and Zee, 1991)
TABLE 3 Qualitative ratings u) MTL structures and qualitative ratings
of normal
and abnormal eye tracking in first-episode schizophrenics
Eye tracking
n
Normal
Questionable
Abnormal
Normal Abnormal
25 22
13
6
6
l6
0
7
and the occurrence of both ETD (see Lipton et al ., 1983 ; Clementz and Sweeney, 1990) and a variety of aberrations in brain structure in schizophrenic patients (Johnstone et al ., 1976; Nasrallah et al ., 1986; Bogerts et al ., 1990) led us to expect that abnormal eye tracking would be associated with some feature of abnormal brain structure . However, both our results and those of Smeraldi et al . (1987) show a relation between normal eye tracking and some feature of abnormal brain morphology . Our data support MTL anomalies and their data support EVE . The results of both studies support a dissociation between qualitative measures of abnormal eye tracking and abnormal brain morphology and an association between normal eye tracking and abnormal brain structure . These findings suggest that whatever process grossly alters brain structure in schizophrenia is unrelated to the mechanisms involved in ETD . We cannot, of course, exclude the possibility that abnormalities in brain regions that were not examined (e .g . frontal eye fields, superior colliculus) . and which may play an important role in the mediation of eye movements, show a different pattern of association with eye tracking performance . The lower than expected co-occurrence of ETD and visible brain pathology raises the intriguing possibility that different etiological mechanisms are implicated in the pathogenesis of each phenomenon . Genetic factors seem to play a critical role in the transmission of both schizophrenia and ETD (Holzman et al . . 1988 ; Matthysse et al ., 1986) . Although still not settled definitively (see Lewis, 1990), certain abnormalities in brain morphology (detected on CT) may be less prevalent in schizophrenics who are at genetic risk than in schizophrenics who have no family history of the disorder (Reveley, et al ., 1982) . Specific brain morphological aberrations in the latter group may reflect environmental insults secondary to birth complications, viral factors, or other still unknown nongenetic causes (Cannon et al ., 1989 ; Rcveley, et al ., 1982) . Indeed, schizophrenics who have no family history of the disorder (who are presumably at low genetic risk) are more likely to be born during months associated with greater risk of perinatal morbidity and mortality (Kinney and Jacobsen, 1978), which might in turn be expected to result in neurologic sequelae, such as brain structural changes. The roles of genetic liability,
birth and obstetrical complications, and their interaction in influencing individual differences in patterns of normal and abnormal brain structure are currently being explored with respect to both MRI variables and eye tracking in these subjects . We found no association between eye tracking and enlargement of either the lateral ventricles or the third ventricle . Although this result parallels the findings for the lateral ventricles described by Sicver et al . (1986), whose sample of young, recent onset patients was similar to ours, and those of Bartfai et al . (1985), who studied a mixed group of first- and multi-episode schizophrenics, the negative findings of all three studies may reflect low statistical power secondary to relatively low rates of EVE . Our sample of first-episode patients did not show the significant association between LVE and ETD found by Blackwood et al . (1991b) or by Weinberger and Wyatt (1982) in chronic schizophrenics . Our Yates' corrected chi square analysis of the Weinberger and Wyatt (1982) data, however, does not show a statistically significant association between lateral ventricle size and eye tracking ( ;t 2 ( ,, = 2 .66, p=0 .10) . Our results showing an association between normal eye tracking and MTL abnormalities also contrast with those of Blackwood et al . (199Ib), who found no relation between eye tracking and area of MTL Structures . Two factors may account for the differences between our findings and those of Blackwood et al . (1991 b) . First, we used qualitative ratings of both eye tracking and brain morphology, whereas they treasured regional brain areas and distinguished good and had trackers based on a cutoff in the natural logarithm of the signal :noise ratio score. Second, our sample of first-episode schizophrenics had a significantly higher prevalence of abnormal eye tracking than normal control subjects . Their sample of schizophrenics did not differ from normal control subjects on a global quantitative measure of eye tracking proficiency, although a larger sample from which these patients were drawn did differ from controls (Blackwood et al ., 1991a) . The rates of ETD in first-episode schizophrenics and normal controls are consistent with figures reported in previous studies of chronic and acute schizophrenics and normal controls (Holzman et al ., 1974, 1977 ; Yee et al ., 1987 ; Siever et al ., 1986) and in the larger sample of first-episode patients from which this sample was drawn (Lieb-
erman ct al ., 1992a) . The presence of ETD in these patients, who had been ill and/or medicated for only a short time, indicates that neither chronic psychosis nor chronic exposure to neuroleptic drugs is a necessary condition for the presence of ETD and that ETD is present early in the course of schizophrenia . These results provide further . though indirect, support for the trait status of ETD in schizophrenics (Levy et al ., 1984 : Spohn and Larson, 1983) . The qualitative ratings of neuroanatomic regions yielded significant elevations in the prevalence of abnormal brain morphology in first-episode schizophrenics compared with controls in three of the four brain regions studied (the lateral ventricles, MTL structures, frontal-parietal cortex) . in the total abnormal brain morphology score . and in the greatest abnormal brain morphology score . These results suggest that a variety of anomalies in brain structure are present during the period shortly after the first hospitalization in a subgroup of schizophrenics and are unlikely to he a result of neuroleptic drug treatment (Weinberger, 1984) or chronic illness . Although these group differences are based on qualitative ratings of specific brain regions . they are consistent with quantitative data derived from the larger sample from which these first-episode patients are drawn (Lieberman et al ., 1992b ; Degreef et al ., 1992 ; Bogerts et al ., 1990), Although we did not find significantly elevated rates of third ventricular enlargement in schizophrenics compared with controls, such a group difference has been found in larger samples of patients and controls from which our groups were drawn . The absence of significant differences in this study likely reflects low statistical power to detect group differences in the prevalence of relatively uncommon brain abnormalities . The majority of CT scan studies have not shown an effect of gender on LVF (reviewed in Goetz and Van Kammen. 1986), but another review of CT studies (Raz and Raz, 1990) found a significant association between gender composition and effect size for ventriculomegaly . Our group found that males had a significantly larger mean ventricular volume than women, but there was no interaction of diagnosis with gender (Degreef et al ., 1992) . The similarity between our eye tracking and MRI results and those reported by other investigators indicate that
the relatively small control group did not prevent us from detecting group differences . Although abnormal brain morphology is more common in some regions than in others, and any single abnormal feature occurs in a minority of patients, no one region seems to be characteristically involved . This pattern parallels research findings showing that a variety of neurological signs, but no single type, account for the increased prevalence of neurological abnormalities in schizophrenics (and also in their first-degree relatives) (Woods et al ., 1986 : Kinney et al ., 1986, 1991) . The existing CT studies and our own MRI study were based on qualitative ratings of eye tracking . Similarly, classifications of brain regions based on visual inspection are inevitably less precise than quantitative measures of each structure, although qualitative ratings are significantly correlated with volume of the same region (Lieberman et al ., 1992b) . As the various quantitative features of ocular motor performance and volumetric regional brain measurements become available . we will have the opportunity to examine these variables in greater detail .
ACKNOWLEDGEMENTS
The authors thank Mrs . Rosalind Zitner . Mrs . Sabina Meyer .. and Mrs . Greta Schimmel for their assistance in data collection and Drs . Philip Holzman . Dennis Kinney . Martha Shenton and Deborah Yurgelun-Todd for their helpful comments on the manuscript . This work was supported in part by IJSPHS grants MH-41646, MH-00537 . MH-41960, MH-31154, MH- 31340 .
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