The Relationship Between Antisaccades, Smooth
Pursuit, and Executive Dysfunction in First-Episode
Samuel B. ...
addition, we examined the contribution of symptomatology to
oculomotor performance. In line with previous reports linking
vation that a common strategy employed is to follow a
predetermined search sequence beginning with the same
box. A higher ...
There were no significant correlations between antisaccade
errors and any of the syndrome scores in the patient group
impaired inhibition per se that is related to the ability to perform
the antisaccade task in schizophrenia (but see Crawfo...
normality exist in schizophrenia? A saccadic eye movement ...
Rosse RB, Schwartz BL, Kim SY, Deutsch SI (1993): Correlation between
antisaccade and Wisconsin Card Sorting Test performa...
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The Relationship Between Antisaccades, Smooth Pursuit, and ...

  1. 1. The Relationship Between Antisaccades, Smooth Pursuit, and Executive Dysfunction in First-Episode Schizophrenia Samuel B. Hutton, Vyv Huddy, Thomas R.E. Barnes, Trevor W. Robbins, Trevor J. Crawford, Christopher Kennard, and Eileen M. Joyce Background: Both oculomotor and neuropsychologic deficits have been used to support the hypothesis that schizophrenia is associated with prefrontal cortex dysfunction, but studies that have specifically investigated the relationships between these deficits have produced inconsistent findings. Methods: We measured both smooth pursuit and antisaccade performance in a large group (n ϭ 109) of patients with first-episode schizophrenia and a group of matched control subjects (n ϭ 59) and investigated the relationship between performance on these tasks and performance on a range of executive tasks. We additionally explored the relationship between these variables and measures of psychopathology at presentation and duration of untreated psychosis. Results: Antisaccade errors were significantly correlated with spatial working memory performance. Smooth pursuit gain did not correlate with any neuropsychologic measure. There were no reliable correlations between either oculomotor variables and measures of psychopathology and duration of untreated psychosis. Conclusions: These findings suggest that in schizophrenia working memory and antisaccade performance reflect the same abnormal prefrontal substrates and that smooth pursuit is mediated by a separate neural abnormality. Key Words: Antisaccade, executive function, oculomotor, schizo- phrenia, smooth pursuit, working memory N europathologic and neuroimaging studies suggest that prefrontal cortex dysfunction is a core feature of schizo- phrenia (for a review, see Weinberger et al 2001). Supportive behavioral evidence includes the finding of severe and enduring deficits on neuropsychologic tests of executive function thought to reflect the integrity of the prefrontal cortex (e.g., Gold et al 1997; Hutton et al 1998b). Schizophrenia is also associated with well-replicated impairments in smooth pursuit eye tracking (for a review, see Hutton and Kennard 1998), and these, too, have been linked to a dysfunctional prefrontal cortex (Levin 1984); however, studies of schizophrenia that have di- rectly examined smooth pursuit and executive functions in the same patients are equivocal, with some reporting positive corre- lations between measures of smooth pursuit and executive function (Bartfai et al 1985; Grawe and Levander 1995; Katsanis and Iacono 1991; Litman et al 1991; Park and Holzman 1993; Snitz et al 1999) and others finding either no correlations (Gambini and Scarone 1992; Tien et al 1996) or correlations between only a small subset of the measures taken (Friedman et al 1995; Radant et al 1997). The results of functional neuroimag- ing studies also argue against the hypothesis that pursuit and executive deficits share a common prefrontal substrate. Whereas tests of executive function such as the Wisconsin Card Sorting Task (WCST) typically activate the dorsolateral prefrontal cortex (Berman et al 1995), smooth pursuit performance activates a neural network that includes the frontal eye fields but not the DLPFC (Berman et al 1999; O’Driscoll et al 2002; Petit et al 1997; Petit and Haxby 1999; Rivaud et al 1994; Rosano et al 2002). Furthermore, there is no evidence that DLPFC lesions cause pursuit abnormalities in man (Gooding et al 1999; Heide et al 1996). Patients with schizophrenia also demonstrate saccadic abnor- malities, particularly on the antisaccade task (e.g., Crawford et al 1995a, 1995b; Hutton et al 1998a). This requires subjects to inhibit a reflexive saccade to a sudden-onset target in the periphery and initiate instead a saccade to the mirror image location. Antisaccade errors occur when participants fail to inhibit a reflexive saccade before making the correct saccade, and arguably this type of deficit is more likely to be related to DLPFC dysfunction than smooth pursuit. Both lesion and func- tional neuroimaging studies suggest that the antisaccade task makes significant demands on the DLPFC (Doricchi et al 1997; Fukushima et al 1994; Gooding et al 1999; Guitton et al 1985; McDowell et al 2002; Pierrot-Deseilligny et al 1991; Sweeney et al 1996). The majority of studies that have investigated the relation- ship between executive function and antisaccade errors in patients with schizophrenia have observed significant correla- tions (Crawford et al 1995a; Gooding and Tallent 2001; Karoumi et al 1998; Nieman et al 2000; Rosse et al 1993; Tien et al 1996), although there are exceptions (Radant et al 1997; Snitz et al 1999). Possible reasons for the discrepant findings of studies relating oculomotor and executive function include differences in illness chronicity or severity, effects of medication (Hutton et al 2001), and task differences. To address this further, we tested a large group (n ϭ 109) of patients following their first episode of schizophrenia to reduce the variance introduced by illness duration and long-term medication effects. We used both smooth pursuit and saccadic tasks to determine possible differences in the pattern of relationships with neuropsychologic tests. We predicted that antisaccade errors, but not smooth pursuit, would be associated with performance on executive tests. We included a test of working memory as well as an analog of the WCST. In From the Department of Psychology (SBH), University of Sussex, Brighton; Division of Neuroscience and Mental Health (VH, TREB, CK, EMJ), Imperial College Faculty of Medicine, Charing Cross Site, London; Department of Experimental Psychology (TWR), University of Cambridge, Cambridge; Department of Psychology (TJC), University of Lancaster, Fylde College, Lancaster, United Kingdom. Address reprint requests to Prof. Eileen M. Joyce, Division of Neuroscience and Mental Health, Imperial College Faculty of Medicine, Charing Cross Site, St. Dunstan’s Road, London, W6 8RP, UK; E-mail: Received March 11, 2004; revised June 11, 2004; accepted July 2, 2004. BIOL PSYCHIATRY 2004;56:553–5590006-3223/04/$30.00 doi:10.1016/j.biopsych.2004.07.002 © 2004 Society of Biological Psychiatry
  2. 2. addition, we examined the contribution of symptomatology to oculomotor performance. In line with previous reports linking negative symptoms to frontal dysfunction, we predicted that negative symptoms would correlate with antisaccade error rate. Methods and Materials Subjects The patients were recruited as part of the West London Study of first-episode schizophrenia (Hutton et al 1998a, 1998b; Joyce et al 2002). The patients eligible for the study were aged between 16 and 50 years, were presenting from the community to mental health services with a schizophreniform psychosis for the first time, and had received no more than 12 weeks of antipsychotic medication. Data from 109 patients were included here on the basis that they performed the oculomotor and neuropsychologic components of the study protocol. Symptoms were assessed at the time of recruitment with the Scales for the Assessment of Positive Symptoms (SAPS, Andreasen 1984b) and Negative Symptoms (SANS, Andreasen 1984a) and the Comprehensive Psychopathological Rating Scale (Asberg et al 1978). The diag- nosis was determined for each patient by applying DSM-IV criteria to the range of symptoms at regular review meetings held by two experienced clinicians (EMJ, TREB). Scores for positive, disorganization, and negative syndromes of schizophrenia (Liddle and Barnes 1990) were calculated for each patient (positive: sum of SAPS hallucinations and delusions global subscale scores; disorganization: sum of SAPS bizarre behavior and positive thought disorder global subscale scores; negative: sum of all SANS global subscale scores) and expressed as the ratio of the maximum possible score. The duration of untreated psychosis was established for each patient by reviewing relevant information in the case notes and questioning the patient and relatives or caregivers. A modified questionnaire (Loebel et al 1993) was used, relating to the onset of positive psychotic symptoms (Lieberman et al 1993). Following recruitment, the patients were tested when it was felt that they were able to cooperate with the testing procedures. Patients underwent ocu- lomotor and neuropsychologic testing within 2 weeks of each other in the majority of cases (82%). At the time of testing, 53 patients were receiving typical antipsychotics, 36 were receiving atypical antipsychotics (risperidone or olanzapine), and 14 pa- tients were receiving no medication. In seven patients, eye movements were assessed without medications and neuropsy- chology after antipsychotic treatment commenced. Fifty-nine normal volunteers served as control subjects and were recruited from the same catchment area as the patients by advertising in local job centers and hospitals. Exclusion criteria were a history of psychiatric illness in the volunteer or a first-degree relative, presence of a medical illness that might impair cognitive function, and history of alcohol or drug abuse. Permission to conduct the study was obtained from the following local research ethics committees: Riverside; Merton, Sutton and Wandsworth; Kingston and Richmond; and Ealing, Hammer- smith and Fulham in London. All patients and control subjects gave written informed consent. All participants were paid a small honorarium for their time. Oculomotor Tests Oculomotor tests were described in detail in Hutton et al (1998a). In brief, eye movements were recorded in the dark with a Skalar IRIS infrared limbus reflection device. A hardware antialiasing filter (cut-off frequency 200 Hz) was used to filter eye position, and the sampling rate was 500 Hz. Stimulus display and data sampling were controlled by a PDP 11/73 computer or an IBM-compatible PC. Each paradigm was preceded by a calibra- tion trial in which nine light-emitting diode (LED) targets with known horizontal positions were illuminated sequentially, and the subject was asked to fixate each target in turn. Antisaccade Task The target display consisted of four red LED targets (diameter .25 degs) located 7.5 and 15 degrees either side of a central fixation LED. Each trial consisted of the following sequence: 1) A central fixation LED was illuminated at the beginning of each trial. 2) After 800 msec, the fixation LED was extinguished, and a peripheral target LED was simultaneously illuminated for 1000 msec and a 200-msec buzzer signal was initiated. Subjects were asked to direct their gaze as quickly and accurately as possible toward a position in space equally distant but in the opposite direction of the illuminated peripheral LED (i.e., to the mirror image location). An antisaccade error occurred when the subject was distracted by the target’s appearance and made a brief reflexive saccade toward it before correctly making a saccade in the opposite direction. Antisaccade errors were identified using custom software and expressed as a percentage of the total number of trials in which a recordable response was made. Smooth Pursuit Task The smooth pursuit stimulus was a bright red laser spot back projected onto the same translucent screen. The target oscillated horizontally with a triangular waveform of amplitude 22.5 degs. Four velocities—10, 20, 30, and 36 degs/sec, were used, and six full cycles were recorded at each velocity. Smooth pursuit analysis was performed using the Eyemap analysis package (Amtech, Heidelberg, Germany). Saccadic movements were identified and excluded from the analysis. In each half cycle, the portion of smooth pursuit eye movement having the highest velocity was identified and expressed as peak velocity gain (eye velocity/target velocity). This portion was always collected from the middle third of each half cycle to avoid acceleration and deceleration transients at the beginning and end of each ramp. Neuropsychologic Tests Neuropsychologic tests were described in detail in Hutton et al (1998b). The National Adult Reading Test (NART) was used to estimate premorbid IQ (Nelson and Willison 1991). Current IQ was estimated from four subtests of the Wechsler Adult Intelli- gence Scale—Revised (WAIS-R; Wechsler 1981) and was avail- able for 86 patients and 29 control subjects. Tests from the Cambridge Automated Neuropsychological Test Battery (Saha- kian and Owen 1992) were used as follows. Spatial span (Owen et al 1990): this measures the ability to remember the order of sequences of squares presented on the screen in increasing number. Pattern recognition memory (Sahakian et al 1988): 12 abstract visual stimuli are presented sequentially on the screen. Each stimulus is then presented along with a novel stimulus, and patients are asked to touch the familiar stimulus. This is repeated with 12 stimuli, giving a maximum possible score of 24. Spatial working memory (Owen et al 1990): patients are required to “open” sets of boxes, varying between three and eight in number, to find tokens. Errors are recorded when boxes in which tokens have been found are reopened. A measure of strategy use was calculated based on the obser- 554 BIOL PSYCHIATRY 2004;56:553–559 S.B. Hutton et al
  3. 3. vation that a common strategy employed is to follow a predetermined search sequence beginning with the same box. A higher score for this measure indicates a poorer strategy use. Planning (Owen et al 1990): in this modification of the Tower of London task (Shallice 1982) subjects move colored “balls” in an arrangement displayed on the screen to match a goal arrangement. Subjects are asked to attempt the solution in the minimum number of moves, which could be 2, 3, 4, or 5. A stringent measure of accuracy is provided by the proportion of problems solved in the minimum number of moves (i.e., the number of perfect solutions). Attentional set shifting (Owen et al 1991): subjects are required to learn a series of visual discriminations. One of two stimulus dimensions (shape or line) is relevant. Once correct responding is established, subjects are introduced to differ- ent exemplars of the same dimension for correct respond- ing, testing their ability to generalize the rule they have just learned (intradimensional shift [IDS]). At the later, extradi- mensional shift stage (EDS) the rule is reversed so that a previously irrelevant dimension now becomes relevant. This assesses the ability to inhibit the previously correct response set by shifting attention from one dimension to another. Thus, the EDS is analogous to the attentional shift involved in WCST performance. Statistics Duration of untreated psychosis data were log10 transformed because of skew. Correlation coefficients (Pearson’s r) were calculated between the oculomotor and neuropsychologic vari- ables for control subjects, and between oculomotor measures and neuropsychologic variables and clinical variables for pa- tients. Because of the large number of correlations, meaningful associations were determined by setting the significance level using the Bonferroni procedure. This resulted in a corrected critical p value for the control correlations of .003, and a corrected critical p value for the patient correlations of .002. Significant correlations were followed up with regression analy- ses. Comparison between patient and control groups were performed with the t test and the chi-squared test. Results The mean and SD of the syndrome scores of the patients, expressed as a proportion of maximum possible score were as follows: negative syndrome .39 (.26), positive syndrome .68 (.27), and disorganization syndrome .38 (.28). The mean, SD, and statistic for all measures common to patients and control subjects are reported in Table 1. There were no differences in age or gender ratio. Of the neuropsychologic tests, only the IQ scores were not significantly different in patients and control subjects. For the oculomotor variables, patients made significantly more errors on the antisaccade task and demonstrated significantly lower gain during smooth pursuit. Correlation Analysis Correlation coefficients (Pearson’s R) for control subjects and patients are presented in Table 2. In control participants, there were no significant correlations between any oculomotor and neuropsychologic variables. In patients, significant correlations were observed between antisaccade errors and spatial span, spatial working memory strategy, and spatial working memory errors. Antisaccade errors were also weakly associated with Tower of London perfect solutions and WAIS-IQ, but these correlations were not significant after the Bonferroni correction. To determine which variable provided the best prediction of antisaccade errors, spatial span, spatial working memory strat- egy, and spatial working memory errors were entered into a regression analysis using the stepwise procedure. Only spatial working memory errors emerged as a significant predictor (beta ϭ .36, t ϭ 3.94, p Ͻ .01), but the amount of variance in antisaccade performance that this measure accounted for was relatively small (R2 ϭ .128). Although the relationship between antisaccade errors and IQ did not survive Bonferroni correction, the magnitude of the correlation suggested that IQ may be a mediating variable; however, when the effect of full-scale IQ was partialled out in the 86 patients who had performed the WAIS-R, the association between working memory and antisaccade errors was, if any- thing, stronger (r ϭ .41, p Ͻ .001). Smooth pursuit velocity gain was weakly correlated with spatial span in the patients (r ϭ .194, p ϭ .049), but this correlation did not survive the Bonferroni correction. Table 1. Comparison Between Normal Control Subjects and Patients with Schizophrenia on Age, Sex Ratio, Neuropsychological, and Eye Movement Measures Controls Mean (SD) Patients Mean (SD) Statistic Sex ratio (male/female) 42/17 86/23 Chi Square(1) ϭ 1.3, ns Age (years) 26.1 (5.2) 25.3 (7.3) t(166) ϭ Ϫ.7, ns Neuropsychological Measures NART IQ 104.0 (10.4) 100.8 (10.4) t(141) ϭ Ϫ1.8, ns WAIS-R IQ 97.1 (13.4) 94.0 (14.6) t(113) ϭ Ϫ1.0, ns Spatial Span 6.6 (1.3) 5.6 (1.4) t(162) ϭ Ϫ4.6, p Ͻ .01 SWM strategy score 30.1 (5.5) 34.7 (4.5) t(163) ϭ 5.9, p Ͻ .01 SWM errors (6 and 8 Box) 17.0 (13.2) 29.4 (18.8) t(163) ϭ 4.4, p Ͻ .01 Planning (perfect solutions) 9.3 (1.9) 7.5 (2.0) t(161) ϭ Ϫ5.5, p Ͻ .01 Attentional set shift (errors) 14.8 (8.9) 21.5 (11.2) t(163) ϭ 3.9, p Ͻ .01 Pattern recognition memory 22.5 (1.9) 20.6 (2.8) t(161) ϭ Ϫ4.7, p Ͻ .01 Oculomotor Measures Smooth pursuit velocity gain .95 (.06) .87 (.10) t(156) ϭ Ϫ5.3, p Ͻ .01 Antisaccade errors .20 (.17) .42 (.26) t(166) ϭ 5.9, p Ͻ .01 NART, National Adult Reading Test; WAIS-R, Wechsler Adult Intelligence Scale–Revised; SWM, spatial working memory. S.B. Hutton et al BIOL PSYCHIATRY 2004;56:553–559 555
  4. 4. There were no significant correlations between antisaccade errors and any of the syndrome scores in the patient group (positive [r ϭ Ϫ1.77]; negative [r ϭ .097]; disorganization [r ϭ Ϫ.098]; all ps Ͼ .05). Smooth pursuit gain was not associated with positive (r ϭ Ϫ.92) or negative (r ϭ .043) syndrome scores (all ps Ͼ.3). There was a weak association between disorganization syndrome and pursuit gain (r ϭ .208, p Ͻ .05), but this did not survive the Bonferroni correction. Duration of untreated psycho- sis (log10) did not correlate with either smooth pursuit (r ϭ .09, ns) or antisaccade errors (Ϫ.067, ns). Discussion In a group of 109 patients with first-episode schizophrenia, analysis of clinical, neuropsychologic, and oculomotor measures yielded two main findings. First, three neuropsychologic measures correlated significantly with antisaccade error rate: spatial span, spatial working memory strategy score, and spatial working mem- ory errors. Second, there were no correlations between any neuro- psychologic measure and smooth pursuit gain. In a matched control group of 59 normal volunteers, there were no significant correla- tions between any measures, indicative of a lack of heterogeneity with respect to performance in this population. The three separate neuropsychologic measures that were significantly correlated with antisaccade performance have pre- viously been shown to be intercorrelated in our patient popula- tion (Joyce et al 2002). This is consistent with theoretical accounts of working memory (Baddeley 1986) that predict that superior short-term memory capacity or the use of an efficient search strategy will improve performance on the spatial working memory task. Indeed, the regression analysis revealed that spatial working memory errors was the best predictor of antisac- cade performance, almost certainly because this is the measure that reflects most directly the integrity of working memory processes. Thus, out of a range of measures reflecting different facets of executive and oculomotor function, we found a highly specific association between antisaccade errors and spatial work- ing memory. Performance on tasks that load less on working memory and more on executive processes of planning or attentional set inhibition and shifting did not correlate with antisaccade errors. There have been few previous studies directly examining the relationship between antisaccade performance and working memory in schizophrenia. Snitz et al (1999) failed to find an association using a spatial delayed-response working memory task in a group of inpatients; however, Gooding and Tallent (2001), using a more demanding version of this working memory task, found a significant association when they tested community patients who possibly displayed a greater range of functioning. Only one other study has examined the relationship between antisaccade performance and working memory in patients with first-episode schizophrenia, and, again using a spatial delayed- response task, a significant relationship was found (Nieman et al 2000). Our findings confirm and extend this finding because we examined much larger patient and control groups and our spatial working memory task differed in that it required the retention of a number of spatial locations simultaneously and the revision of this information in working memory while executing the task. We also employed other tasks of executive function that allow us to examine the relevant cognitive processes contributing to antisaccade performance more precisely. Our findings support the growing consensus that it is the working memory aspect of executive function that is relevant for antisaccade performance. The antisaccade task requires inhibi- tion of a reflex saccade toward the target and the planning and execution of an eye movement to the mirror image location, while keeping the requirements or context of the task in mind. In schizophrenia, other studies, as well as ours, that have included several executive tests have found that it is those tests loading most heavily on working memory processes that correlate most strongly and most consistently with antisaccade error rates. Thus, two recent studies have shown that errors on a memory-load continuous performance task, in which subjects need to update continually a series of digits in working memory while attending and responding to a current digit, are significantly associated with antisaccade errors, whereas errors on the Stroop and Trail Making Test are not (Broerse et al 2001; Nieman et al 2000). This finding appears paradoxical at first because these latter two tasks require the inhibition of a prepotent response for accurate performance in the same way as the antisaccade task requires the suppression of a reflex saccade toward the target; however, computational models of working memory predict inhibition errors similar to those demonstrated in the antisaccade task via a failure of proper maintenance of adequate task representations that are required for correct task performance, or “context maintenance” (Cohen and Servanschreiber 1992). Increasing working memory load has been shown to increase antisaccade errors in dual-task paradigms (Mitchell et al 2002; Roberts et al 1994), providing direct evidence. We have previously shown that in oculomotor tasks that shared the requirement for inhibition of a reflex saccade, performance was affected by the concurrent cognitive demands of the tasks (Hutton et al 2002). Thus, it appears that it is impaired working memory capacity rather than Table 2. Correlations (Pearson’s R) Between Oculomotor and Neuropsychologic Profile Measures in First-Episode Schizophrenia Patients and Matched Control Subjects Smooth Pursuit Gain Antisaccade Errors NART IQ S .020 Ϫ.048 C .155 Ϫ.051 WAIS-R IQ S .158 Ϫ.262a C .059 Ϫ.230 Spatial Span S .194a Ϫ.295b C Ϫ.162 Ϫ.026 Spatial Working Memory Strategy Score S Ϫ.176 .307b C .028 .152 Spatial Working Memory Errors S Ϫ.169 .358b C .133 .154 Planning: Perfect Solutions S .161 Ϫ.211a C .165 .080 Attentional Set-Shift Errors S Ϫ.059 .155 C .088 Ϫ.019 Pattern Recognition Memory S Ϫ.025 Ϫ.102 C Ϫ.071 .000 C, control subjects; NART, National Adult Reading Test; S, schizophrenia patients; WAIS-R, Wechsler Adult Intelligence Scale–Revised a p Ͻ .05. b p Ͻ .002 (significant following Bonferroni correction). 556 BIOL PSYCHIATRY 2004;56:553–559 S.B. Hutton et al
  5. 5. impaired inhibition per se that is related to the ability to perform the antisaccade task in schizophrenia (but see Crawford et al 2002). In this respect, the finding that the WCST and antisaccade performance are correlated in four out of five studies is particu- larly interesting (Crawford et al 1995a; Karoumi et al 1998; Radant et al 1997; Rosse et al 1993; Tien et al 1996). The key executive process embedded in the WCST is the inhibition of a previously learned response and the shifting of cognitive set to facilitate a different response; however, this is a procedurally complex task that requires the operation of a number of cognitive processes simultaneously (Park 1997). Furthermore, the inhibitory require- ments of the WCST follow the brief learning of a response set, the strength of which is much less than the potent, almost reflexive, responses that need to be overcome in the Stroop and the Trail Making Test. Indeed, recent studies suggest that in schizophre- nia, the working memory component of the WCST may be paramount to performance (Gold et al 1997; Hartman et al 2003; Park 1997). Although we did not use the WCST, we did use an attentional set-shifting task that decomposes the processing elements of the WCST over a number of stages, thereby mini- mizing the load on working memory. This task thus allows separate examination of rule learning and abstraction, rule reversal, and attentional set shifting–response inhibition. When we examined key indices of response inhibition–set shifting ability, we found no association with antisaccade errors. An alternative interpretation of our finding is that antisaccade errors and working memory impairment are both proxy mea- sures for illness severity and therefore intercorrelate. This is unlikely because we found that the association was not mediated by general intellectual ability (premorbid or current) or by symptom severity at presentation. The failure to find robust correlations between smooth pursuit performance and any executive neuropsychologic measure, in the context of a significant association with antisaccades, sug- gests that the smooth pursuit and antisaccade tasks differ in terms of the involvement of higher cognitive processes that implicate prefrontal cortex function. Although some studies have reported a significant association between WCST and pursuit performance (Grawe and Levander 1996; Katsanis and Iacono 1991; Litman et al 1991), others have not (Friedman et al 1995; Gambini and Scarone 1992; Radant et al 1997; Tien et al 1996). Studies employing a variety of other executive tests report equivocal or inconsistent findings (Friedman et al 1995; Grawe and Levander 1995; Katsanis and Iacono 1991; Litman et al 1991; Park and Holzman 1993; Radant et al 1997; Snitz et al 1999). The suggestion of independence is consistent with evidence that there are separable neural substrates mediating antisaccade and smooth pursuit. Lesion and functional neuroimaging studies in humans consistently suggest that smooth pursuit is mediated by a relatively discrete network critically involving the frontal eye fields of the frontal cortex (Berman et al 1999; O’Driscoll et al 2002; Petit et al 1997; Petit and Haxby 1999; Rivaud et al 1994; Rosano et al 2002), whereas antisaccade performance appears to be mediated by a number of frontal areas including those involved in oculomotor control (e.g., frontal eye fields) and those involved in cognitive function (e.g., dorsolateral prefrontal cor- tex; Doricchi et al 1997; Fukushima et al 1994; Gooding et al 1999; Guitton et al 1985; McDowell et al 2002; Pierrot-Deseilligny et al 1991; Raemaekers et al 2002; Sweeney et al 1996). One implication of our findings is that antisaccade performance may be another example of how a dysfunctional dorsolateral prefron- tal cortex can give rise to impairments on tasks dependent on working memory. Smooth pursuit, on the other hand, may reflect abnormalities in a different frontal area or even in nonfrontal areas. For example, studies of motion perception (Chen et al 1999) and step-ramp pursuit tasks (Sweeney et al 1998) implicate abnormalities in the frontal eye fields or projections to the frontal eye fields from areas involved in motion perception such as the middle and superior temporal cortex. It also remains possible that other measures of pursuit performance such as predictive pursuit or the number of corrective or intrusive saccades would have correlated with measures of executive dysfunction. Future studies addressing this issue should aim to take multiple mea- sures of pursuit performance. Correlations between oculomotor performance and clinical assessments were also nonsignificant. The lack of a relation between smooth pursuit and the severity of symptomatology at study entry is perhaps surprising given studies suggesting that smooth pursuit performance is associated with negative symp- toms (e.g., Katsanis and Iacono 1991; Ross et al 1996); however, these studies tested patients who had been ill for some time, and the fact that we used first-episode patients may explain the discrepancy. Two other studies of patients with first-episode schizophrenia also failed to observe correlations between symp- toms and smooth pursuit function (Gooding et al 1994; Iacono et al 1992). We have also found that negative symptoms can change over the first year of the illness, suggesting that, in our patients, negative symptoms at onset are not indicative of the enduring negative symptoms seen in groups of patients with more estab- lished illness. Our findings support suggestions that although symptoms may fluctuate during the course of the illness, working memory and oculomotor deficits may be relatively stable endo- phenotypes of schizophrenia. In conclusion, we have demonstrated a significant relation- ship between antisaccade errors and spatial working memory performance in a large group of patients with first-episode schizophrenia, suggesting that a shared abnormal neural sub- strate underlies both impairments. This is most likely to be the dorsolateral prefrontal cortex. Reductions in smooth pursuit velocity gain were unrelated to any neuropsychologic variable, suggesting that this may reflect an abnormality within a neural network most likely involving the frontal eye fields but not the dorsolateral prefrontal cortex. This research was supported by Wellcome Trust grants 042025 and 052247. We thank B. Puri, M. Chapman, and S. Mutsatsa for their help in recruiting the patients and H. Watt for statistical advice. 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