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
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 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.
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 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
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
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
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.
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.
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 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
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
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
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
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
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).
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
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
S .020 Ϫ.048
C .155 Ϫ.051
S .158 Ϫ.262a
C .059 Ϫ.230
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
p Ͻ .05.
p Ͻ .002 (signiﬁcant following Bonferroni correction).
556 BIOL PSYCHIATRY 2004;56:553–559 S.B. Hutton et al
impaired inhibition per se that is related to the ability to perform
the antisaccade task in schizophrenia (but see Crawford et al
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
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