lack of association between prepulse inhibition and antisaccadic deficits in chronic schizophrenia:...

JOURNALOF

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Journal of Psychiatric Research 39 (2005) 227–240

PSYCHIATRIC

RESEARCH

Lack of association between prepulse inhibition andantisaccadic deficits in chronic schizophrenia: implications

for identification of schizophrenia endophenotypes

Veena Kumari a,*, Ulrich Ettinger b, Trevor J. Crawford c, Elizabeth Zachariah b,Tonmoy Sharma d

a Department of Psychology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UKb Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

c Mental Health & Neural Systems Research Unit, Department of Psychology, Lancaster University, Lancaster, UKd Clinical Neuroscience Research Centre, Dartford, Kent, UK

Received 4 April 2004; received in revised form 5 August 2004; accepted 20 August 2004

Abstract

Individuals with schizophrenia, compared to healthy individuals, are known to exhibit deficient prepulse inhibition (PPI) of the

startle response as well as reduced performance on the antisaccade task. There is evidence for genetic transmission of both PPI and

antisaccadic abnormalities in schizophrenia. It has been suggested that PPI and antisaccade measures identify separate endopheno-

types, on the basis of a lack of relationship between PPI and antisaccade deficits in patients with schizotypal personality disorder.

However, given that patients with schizotypal personality disorder are unlikely to manifest all the abnormalities associated with

schizophrenia, it is important to determine that there is no relationship present between these two abnormalities in people affected

with schizophrenia. The main objective of this investigation therefore was to establish the lack of the association between PPI and

antisaccade deficits in schizophrenia in two independent studies. Study 1 involved 39 patients with schizophrenia and 14 healthy

controls and study 2 involved 35 patients with schizophrenia and 22 healthy controls. PPI (uninstructed paradigm) of the acousti-

cally elicited startle (eye blink) was measured electromyographically. Antisaccadic eye movements (standard, non-overlap version)

were measured using infrared oculography. Patients displayed reduced PPI and a lower percentage of correct antisaccades relative to

healthy controls in both studies. As expected, no relationship occurred between PPI and the percentage of correct antisaccade

responses in either group. It is concluded that PPI and antisaccade abnormalities in schizophrenia represent separate endopheno-

types, reflecting the functions of different genetic aetiologies and different or only partially overlapping neural systems.

� 2004 Elsevier Ltd. All rights reserved.

Keywords: Schizophrenia; Prepulse inhibition; Antisaccade eye movements; Genetics; Endophenotypes

1. Introduction

Schizophrenia has long been conceptualised as a dis-

order of attention and information processing (Braff,

1993; Callaway and Naghdi, 1982). Prepulse inhibition

0022-3956/$ - see front matter � 2004 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jpsychires.2004.08.007

* Corresponding author. Tel.: +44 207 848 0233; fax: +44 207 708

3497.

E-mail address: [email protected] (V. Kumari).

(PPI) of the startle response and antisaccade eye move-

ments are two of the paradigms most commonly used to

demonstrate information processing deficits in schizo-

phrenia (reviews, Braff et al., 2001; Everling and Fischer,

1998; McDowell and Clementz, 2001), and have alsobeen considered important in studies of the genetics of

this disorder (Braff and Freedman, 2002).

PPI of the startle response refers to a reduction

in the amplitude of the response to a strong sensory

mailto:[email protected]

228 V. Kumari et al. / Journal of Psychiatric Research 39 (2005) 227–240

stimulus, the pulse, if this is preceded by 30–500 ms by

a weak stimulus, the prepulse (Graham, 1975). PPI is

believed to serve the function of reducing behavioural

interference that might otherwise occur from the simul-

taneous processing of the pulse and prepulse stimuli.

Since the first demonstration by Braff et al. (1978), alarge body of research carried out over the last 25

years in several independent laboratories confirms that

patients with schizophrenia show reduced PPI com-

pared to healthy non-psychiatric populations (review,

Braff et al., 2001). Recent studies examining the effects

of antipsychotic medication, whether typical or atypi-

cal, on PPI in schizophrenia patients have revealed

mixed evidence. Some studies (Kumari et al., 1999,2002; Leumann et al., 2002; Oranje et al., 2002) have

reported �normal-range� PPI in patients treated with

atypical antipsychotics or in patients treated effectively

with typical or atypical antipsychotic medication

(Weike et al., 2000) while others report no effect of typ-

ical or atypical antipsychotic medication (Duncan

et al., 2003a,b; Mackeprang et al., 2002; Parwani et al.,

2000) or of medication status (Perry et al., 2002). Onthe whole, the evidence so far seems to suggest a

graded response, i.e. increase in PPI from unmedicated

patients through those medicated with typical anti-

psychotics to patients medicated with atypical anti-

psychotics, rather than a complete normalization of

PPI by antipsychotic medications in schizophrenia.

There is, however, reliable evidence of reduced PPI in

the schizophrenia spectrum, especially in patients withschizoptypal personality disorder (Cadenhead et al.,

1993, 2000) and in the first-degree relatives of schizo-

phrenia patients with relatively high correlations

(r = 0.66) between PPI in sibling pairs (one proband

and one non-schizophrenic sibling) (Cadenhead et al.,

2000), suggesting that the PPI deficit represents, at

least in part, a trait marker of genetic risk for schizo-

phrenia that may be observed even in the absence ofa diagnosis of schizophrenia.

The antisaccade paradigm examines the conflict be-

tween a prepotent stimulus that produces a powerful

urge to saccade to the target, and the overriding goal

to look in the opposite direction. It requires the subject

to inhibit a reflexive saccade towards the target and in-

stead initiate a saccadic eye movement in the direction

opposite to the target. Studies have shown that patientswith schizophrenia (Broerse et al., 2001; Clementz and

Sweeney, 1990; Crawford et al., 2002; Everling and

Fischer, 1998; Hutton et al., 2002) generate a high per-

centage of errors on this task. Typical antipsychotics do

not appear to have a significant influence on antisac-

cade performance in schizophrenia (review, Ettinger

and Kumari, 2003) but recent studies using cross-sec-

tional (Chaudhry et al., 2002) as well as within-subjectsdesigns (Burke and Reveley, 2002) indicate some

improvement with atypical antipsychotics as noted ear-

lier for PPI. However, patients with schizotypal person-

ality disorder also, on average, generate a high

percentage of error on this task than healthy individu-

als (Cadenhead et al., 2002). In addition, there is con-

siderable evidence for genetic transmission of this

abnormality in schizophrenia from family and twinstudies (Clementz et al., 1994; Crawford et al., 1998;

Curtis et al., 2001; Ettinger et al., 2004; Malone and

Iacono, 2002; Ross et al., 1998; Thaker et al., 2000;

but see Brownstein et al., 2003). The relatives of pro-

bands with abnormal antisaccade performance are also

more likely to show this abnormality than relatives of

probands with normal performance (Crawford et al.,

1998; Curtis et al., 2001; McDowell and Clementz,1997). Furthermore, increased error rates are found in

first, but not second, degree relatives of schizophrenia

patients (McDowell and Clementz, 1997).

Endophenotypes play an important role in under-

standing not only the genetic but also the neurological

basis of schizophrenia (Braff and Freedman, 2002).

Identification of separate endophenotypes is very

important in the selection of neurobiological markersto be used in future genetic studies (Braff and Freed-

man, 2002; Cadenhead and Braff, 2002). PPI and anti-

saccade measures have recently been suggested

(Cadenhead and Braff, 2002; Cadenhead et al., 2002)

to identify separate endophenotypes, based on the

observation of no relationship between PPI and anti-

saccade deficit in patients with schizotypal personality

disorder (Cadenhead et al., 2002); out of 21 patients,only one patient had deficits on both PPI and antisac-

cade tasks, though seven patients had deficient PPI and

seven patients had antisaccade deficits. A related line of

enquiry has found PPI to be also independent of P50

gating, another measure of automatic inhibitory func-

tion, in healthy individuals (Schwarzkopf et al., 1993)

as well in patients with schizotypal personality disorder

(Cadenhead et al., 2002), suggesting divergence evenwithin the measures of automatic information process-

ing. However, given that patients with schizotypal per-

sonality disorder are unlikely to display all the

abnormalities associated with schizophrenia, and that

there may be a limited range of scores in healthy sam-

ples, it is important to determine the lack of associa-

tion between PPI and antisaccadic deficits in patients

with schizophrenia.The present investigation therefore assessed, for the

first time to our knowledge, PPI and antisaccade per-

formance in the same set of clinically stable chronic

schizophrenia patients in two independent studies (study

2 undertaken to confirm the findings of study 1). It was

hypothesised that the patient group, on average, will ex-

hibit reduced PPI and lower percentage of correct anti-

saccade responses, compared to the healthy controlgroup, but no relationship will be found between these

two measures in either group.

V. Kumari et al. / Journal of Psychiatric Research 39 (2005) 227–240 229

2. Materials and methods

2.1. Study 1

2.1.1. Participants and clinical assessments

Forty patients (all men; age-range 22–65 years)diagnosed as having schizophrenia by a psychiatrist

using the Structured Clinical Interview for DSM-IV

(SCID-P; First et al., 1995) took part. Startle data

for one patient were incomplete and thus unusable,

reducing the sample size to 39 patients (mean ± SD

age, 36.97 ± 8.95 years). Nineteen of these 39 patients

were on a range of oral or depot typical antipsychotics

and 20 patients on atypical antipsychotics (9 on ris-peridone, 5 on clozapine, 5 on olanzapine, 1 on quetia-

pine). Sixteen (of 39) patients were also receiving

anticholinergic medication (i.e. procyclidine in varying

doses). Thirty-two (of 39) patients were regular ciga-

rette smokers. Symptoms were rated using the positive

and negative syndrome scale (PANSS, Kay et al.,

1987; mean ± SD positive symptoms, 9.27 ± 2.89;

mean ± SD negative symptoms, 10.97 ± 3.92;mean ± SD general psychopathology, 28.15 ± 7.44).

The mean age at the illness onset was 25.05 years

(SD = 6.36). Twenty-five (of 39) patients also took part

in our previous studies: 12 patients on typical anti-

psychotics and 7 patients on risperidone were included

in Kumari et al. (Kumari et al., 2002) and 5 patients

on clozapine and one patient on quetiapine was in-

cluded in Kumari et al. (2000). Antisaccade data inall participants are examined and reported for the first

time.

Fifteen healthy controls (all men; age-range 20–60

years), screened for a history of, or current, mental

disorders (using SCID-NP; First et al., 1996), regular

medical prescription and presence of psychosis in their

first degree relatives, were recruited via advertisements

in local newspapers, for comparison purposes. Theseparticipants had not taken part in any of our previous

PPI studies. Startle data in one healthy control were

discarded due to very high and unstable baseline on

more than 50% trials reducing the sample size for

the control group to 14 (mean ± SD age,

33.71 ± 9.85 years). Three healthy controls were regu-

lar cigarette smokers. There was no restriction on

smoking intake for either patients or controls to avoida state of nicotine withdrawal, but care was taken to

avoid testing them within 30 min of smoking a ciga-

rette on PPI or antisaccade tasks, to avoid the poten-

tial effect of nicotine administration on task

performance (Depatie et al., 2002; Kumari et al.,

2001).

The study procedures were approved by the Ethical

Committee of the Institute of Psychiatry, London. Allparticipants gave their written informed consent after

the procedures had been fully explained to them.

2.1.2. Design

Measurements of PPI of the acoustic startle response

and antisaccadic eye movements were taken on the same

day, with counterbalanced task presentation across par-

ticipants in each group.

2.1.3. PPI: Paradigm, startle response measurement and

scoring

All participants were tested for intact auditory abili-

ties using an audiometer (Kamplex, AS7) at 40 dB [A]

(1000 Hz). No subject was excluded on this account.

Startle testing was carried out using a commercial com-

puterized human startle response monitoring system

(Mark II, SR-Lab, San Diego, California). This wasused to deliver acoustic startle stimuli, and record and

score the electromyographic (EMG) activity for 250

ms starting from the onset of the stimulus. Stimuli were

presented to participants through headphones (Tele-

phonics, TDH-39P). EMG recordings were taken with

participants sitting comfortably in a moderately lit

soundproof laboratory. The eye blink component of

the startle response was indexed by recording EMGactivity of the orbicularis oculi muscle directly beneath

the right eye, by positioning two miniature silver/silver

chloride electrodes filled with Dracard electrolyte paste

(SLE, Croydon, UK). The ground electrode was at-

tached behind the right ear on the mastoid.

The session began with a 5-min acclimatization

period consisting of 70-dB (A) continuous white noise.

The pulse-alone stimulus was a 40-ms presentation of115-dB (A) white noise and the prepulse stimulus a 20-

ms presentation of 85-dB (A) noise, both over 70-dB

(A) continuous background noise. Participants received

61 startle stimuli in all. Sixty trials, in 5 blocks of 12 tri-

als each, followed an initial pulse-alone trial. Each block

consisted of three pulse-alone trials, three prepulse trials

with a 30-ms prepulse-to-pulse (onset to onset) interval,

three prepulse trials with a 60-ms prepulse-to-pulseinterval, and three prepulse trials with a 120-ms pre-

pulse-to-pulse interval, presented to participants in a

pseudorandom order with a mean inter-trial-interval of

15 s (range 9–23). Participants were told that the exper-

iment was to measure their attention to a number of

noise-bursts, but no specific instructions were given as

to attend or ignore them. They were requested to keep

their eyes open during the experiment.The startle system recorded EMG activity for 250 ms

(sample interval 1 ms) from the onset of the pulse stim-

ulus. The amplification gain control for EMG signal was

kept constant for all participants. Recorded EMG activ-

ity was band-pass filtered, as recommended by the SR-

Lab. A 50-Hz filter was used to eliminate the 50-Hz

interference. EMG data were scored off-line, as in our

previous studies (Kumari et al., 1999, 2001, 2002, inpress) by the analytic program of this system for re-

sponse amplitude (in arbitrary Analog-to-Digit units).


Responses (<5%) were rejected if the onset and peak la-

tencies differed by more than 95 ms or when the baseline

values shifted by more than 50 units. PPI (over the entire

session) was computed as percentage reduction of the

amplitude over pulse-alone trials, i.e. PPI = ([a � b])/

a · 100, where ‘‘a’’ = amplitude averaged over allpulse-alone trials, and ‘‘b’’ = amplitude averaged over

all prepulse trials.

2.1.4. Antisaccade: paradigm, response measurement and

scoring

The visual stimuli were presented on a horizontal

light-emitting diode (LED) array, at 200 cm distance

from the participants. The target consisted of the lightfrom a single LED, subtending a visual angle of 0.15�.Head movements were minimised using a chin rest. Test-

ing took place in a quiet, darkened room. A nine-point

calibration (±20�, ±15�, ±10�, ±5�, 0�) was carried out

before antisaccade assessment. The antisaccade task

used ±15� targets, presented in a fixed, quasi-random or-

der. An antisaccade trial began with the target in the

centre of the subject�s visual field for 1000 ms and thesubject was instructed to focus his gaze on this target.

The target then abruptly jumped to a peripheral loca-

tion, along the horizontal plane, and remained there

for 1000 ms before it returned to the central position

for the next trial. Participants were required to inhibit

a reflexive saccade towards the peripheral target, and

to generate a saccadic eye movement to the mirror-im-

age projection of the target, in the opposite hemifield.Two blocks of eight such trials were performed, with

an equal number of leftward and rightward saccades,

and a brief break between blocks. Prior to the antisac-

cade task, reflexive saccade trials requiring participants

to follow a visual target were conducted to allow them

to adapt to the experimental procedures and the record-

ing device. Four practice antisaccade trials using each

target location were then carried out before the experi-mental trials, and could be repeated if necessary.

Recordings of eye position were made using infrared

oculography (Iris 6500, Skalar Medical, Delft, The

Netherlands; Reulen et al., 1988). Eye and target posi-

tion were logged by the eye-tracker. Signals were con-

verted from analogue to digital by a 4-channel

analogue-to-digital converter card with 12 bits resolu-

tion per channel and a sampling frequency of 500 Hz.Data were saved onto hard disk for further analysis.

Eye movement recordings, taken at the left eye, were

analyzed using a semi-automated procedure in the EYE-

MAP software package (AMTech GmbH, Weinheim,

Germany). Percentage of correct antisaccades was the

primary performance measure on this task, though we

also examined the latencies of correct antisaccades to

target presentation and the gain, i.e. eye amplitude di-vided by target amplitude, of correct antisaccades. The

criteria for the detection of saccades were a minimum

velocity of 30�/s; a minimum eye amplitude of 1.5�;and a minimum latency of eye movement to target pres-

entation of 100 ms. The percentage of correct responses

was calculated as the percentage of correct trials over to-

tal number of valid trials, excluding eye-blink trials and

artefacts. Eye-blinks were identified by inspection of theposition and velocity charts.

2.1.5. Data analysis

Firstly, to examine the difference between patients

and healthy controls in response amplitude and habitu-

ation over the pulse-alone trials, amplitude data were

subjected to a 2 (Group: patients, controls) · 5 (Block:

five blocks of three pulse-alone trials each) analysis ofvariance (ANOVA) with Group as a between-subjects

factor and Block as a within-subjects factor. A further

ANOVA on amplitude scores was carried out after split-

ting the patient group into two groups based on their

medication type (typical or atypical antipsychotics) with

3 (Group: patients on typical antipsychotics, patients on

atypical antipsychotics, healthy controls) · Block ANO-

VA, with Trial Type as a within-subjects factor andGroup as a between-subjects factor. PPI scores were

subjected to a 2 (Group) · 3 (Trial Type: prepulse trials

with 30-, 60-, and 120-ms prepulse-to-pulse intervals)

ANOVA with Trial Type as a within-subjects factor

and Group as a between-subjects factor. Given some

evidence (see Section 1) for differential effects of typical

and atypical antipsychotics in PPI in schizophrenia, the

effects were further evaluated after splitting the patientgroup into two groups based on their medication type

(typical or atypical antipsychotics) with 3 (Group: pa-

tients on typical antipsychotics, patients on atypical

antipsychotics, controls) · 3 (Trial Type) ANOVA with

Trial Type as a within-subjects factor and Group as a

between-subjects factor. All effects were reevaluated

with ANCOVAs, covarying for age, given the slight dif-

ference between the ages of patients and controls andthe report (Ellwanger et al., 2003) of a relationship be-

tween PPI of the acoustic startle response and age in

healthy controls. Latencies to response peak were ana-

lyzed by 2 (Group) · 4 (Trial Type: pulse-alone, 30,

60, 120 ms) ANOVAs, followed by ANCOVAs covary-

ing for age (Ellwanger et al., 2003). Significant main and

interaction effects from all ANOVAs/ANCOVAs were

followed up with lower order ANOVAs, ANCOVAs,and post hoc mean comparisons as appropriate.

The principle antisaccade measure, percentage of cor-

rect antisaccades, was examined with a one-way ANO-

VA with Group as the between-subjects factor. The

effects were reevaluated, as for PPI, to examine any ef-

fects attributable to the medication type (typical versus

atypical) as recent studies indicate low error rate on

antisaccade in patients treated with atypical antipsych-otics, relative to those treated with typical antipsychotics

(Burke and Reveley, 2002; Chaudhry et al., 2002). Gain


and latency measures were similarly analyzed as the er-

ror rate. A second series of analysis was carried out

using ANCOVAs with age entered as a covariate to par-

tial out any influence of age in group effect in antisac-

cade measures (Olincy et al., 1997).

The relationship of PPI to percentage of correct anti-saccades was initially evaluated using Spearman�s rank

order correlations, separately for patients and controls.

Next, the association between PPI and antisaccade

measures was examined employing a similar methodol-

ogy to that used by Cadenhead et al. (2002). PPI with

60-ms prepulse-to-pulse interval was chosen for this pur-

pose, as patients treated with typical or atypical anti-

psychotics showed reduced PPI at this interval relativeto controls (see Section 3). In this analysis, the mean

PPI with 60-ms prepulse-to-pulse intervals of healthy

controls minus 1 SD (mean = 50.21; SD = 20.08) was

used to define a deficit cut off score of 30.13 for PPI.

Similarly, the mean percent of correct antisaccade re-

sponses of controls minus 1 SD (mean = 83.49,

SD = 12.41) was used to define a deficit cut off score

of 71.08 for antisaccade. All analyses were performedusing SPSS (Version 10). The a level for significance

(two-tailed) was set at P = 0.05, unless specified

otherwise.

2.2. Study 2

This study was undertaken to confirm the findings of

study 1 in an independent sample involving patients ofboth sexes, and using an antisaccade task which had im-

proved reliability compared with the task used in study 1

(Ettinger, 2002). Specifically, the task used in study 2

had 60 trials with no within-session practice effects

(Ettinger et al., 2003a) whereas the task in study 1 had

only 16 trials, allowing the possibility that a lack of rela-

tionship between PPI and antisaccade deficits might

have been due to the low reliability of antisaccade per-formance with 16 trials. The only details described are

those that differed from study 1.

2.2.1. Participants and clinical assessments

Thirty-five patients (23 men, 12 women, mean ± SD

age, 43.91 ± 11.06 years; range 22–65 years) diagnosed

as having schizophrenia by a psychiatrist using the

Structured Clinical Interview for DSM-IV (SCID-P;First et al., 1995) took part. All patients were stable

for six weeks or more on oral or depot typical antipsych-

otics. Twenty-five (of 35) patients were regular cigarette

smokers. Nine patients were taking an anticholinergic

(procyclidine in varying doses) in addition to antipsych-

otics. Symptoms were rated using the PANSS (Kay

et al., 1987): mean ± SD positive symptoms,

16.14 ± 7.70; mean ± SD negative symptoms,17.71 ± 5.28; mean ± SD general psychopathology,

36.40 ± 10.17. The mean age at the illness onset for 34

patients (age of onset could not be reliably established

for one patient) was 25.52 years (SD = 8.41).

Twenty-two healthy controls (11 men, 11 women;

mean ± SD age, 32.82 ± 12.14 years; range 20–60 years),

screened and recruited as healthy controls of study 1,

were tested for comparison purposes. Seven healthy con-trols were regular cigarette smokers. All schizophrenia

patients and 20 of 22 healthy controls were included in

our previous investigation (Kumari et al., 2004) of PPI

deficits in schizophrenia; eye movement data in relation

to PPI in all participants are reported for the first time.

2.2.2. PPI: paradigm, startle response measurement and

scoring

Participants received 85 startle stimuli in all. Eighty-

four trials, in four blocks of 21 trials each, followed an

initial pulse-alone trial. Each block consisted of three

pulse-alone trials, three prepulse trials with a 30-ms pre-

pulse-to-pulse interval, three prepulse trials with a 60-ms

prepulse-to-pulse interval, three prepulse trials with a

90-ms prepulse-to-pulse interval, three prepulse trials

with a 120-ms prepulse-to-pulse interval, three prepulsetrials with a 150-ms prepulse-to-pulse interval, and three

prepulse trials with a 1000-ms prepulse-to-pulse interval

presented to participants in a pseudorandom order with

a mean inter-trial-interval of 15 s (range 9–23). As noted

in Section 1, our main focus here was on PPI, so the data

on 1000-ms prepulse-to-pulse interval trials, which pro-

duced prepulse facilitation and did not reliably differen-

tiate patients from healthy controls (Kumari et al.,2004), are not included in any analysis. The session

lasted about 30 min.

2.3. Antisaccade: paradigm, response measurement and

scoring

Stimuli were displayed on a 17-in. monitor. A white

target of circular shape (approximately 0.3� of visual an-gle) was presented on a black background. Participants

sat in a comfortable chair at a distance of 57cm from the

monitor. Head movements were minimised using a chin-

rest. Testing took place in a quiet, darkened room. A

three-point calibration task (+12�, 0�, �12�; each stimu-

lus duration = 1000 ms) was carried out before the anti-

saccade task.

An antisaccade trial began with the target in the cen-tral location for a random duration of 1000–2000 ms.

The target then jumped to one of four peripheral loca-

tions (±6�, ±12�) where it remained for 1000 ms. Each

peripheral location was used 15 times, resulting in a to-

tal of 60 trials. The sequence of peripheral target presen-

tations was random. Four practice trials using each

target location once were carried out before the experi-

mental trials and could be repeated if necessary. Datarecording and scoring procedures were the same as de-

scribed for study 1.


2.4. Data analysis

To examine the difference between patients and con-

trols in response amplitude and habituation over the

pulse-alone trials, amplitude data were subjected to a 2

(Group: patients, controls) · 4 (Block: four blocks ofthree pulse-alone trials each) ANOVA: Group was ta-

ken as a between-subjects factor and Block as a with-

in-subjects factor. PPI scores (calculated as study 1)

were subjected to a 2 (Group) · 5 (Trial Type: prepulse

trials with 30-, 60-, 90-, 120-, and 150-ms prepulse-to-

pulse intervals) ANOVA with Trial Type as a within-

subjects factor and Group as a between-subjects factor.

The Group effect in PPI was reevaluated with ANCO-VA, covarying for age (Ellwanger et al., 2003). Latencies

to response peak were analyzed by 2 (Group) · 6 (Trial

Type: pulse-alone, 30, 60, 90, 120 and 150 ms) ANO-

VAs, followed by reevaluation of effects with ANCO-

VAs covarying for age (Ellwanger et al., 2003).

Significant main and interaction effects were followed

up with lower order ANOVAs, ANCOVAs, and post

hoc mean comparisons as appropriate.The percentage of correct antisaccades, gain and la-

tency measures were initially examined with one-way

ANOVAs with Group as the between-subjects measure,

and then with ANCOVAs covarying for age.

The relationship of PPI to percent of correct antisac-

cades was first evaluated using Spearman�s rank order

correlations, separately for patients and controls. Next,

the association between 60-ms PPI and percentage ofcorrect antisaccades in patients was examined employ-

ing a similar methodology as described for study 1. In

this analysis, the mean PPI with 60-ms prepulse-to-pulse

intervals of healthy controls minus 1 SD (mean = 33.44;

SD = 19.36) was used to define a deficit cut off score of

14.08 for PPI. Similarly, the mean percent of correct

antisaccade responses of controls minus 1 SD

(mean = 70.60, SD = 14.43) was used to define a deficitcut off score of 56.17 for antisaccade.

Table 1

Response amplitudes over the five blocks of three pulse-alone trials each and

controls in study 1

Typical group (N = 19)

mean (SEM)

Atypical group (N

mean (SEM)

Response amplitude (in A/D units)

Block 1 613.25 (106.62) 580.17 (82.29)

Block 2 500.16 (95.08) 453.38 (78.58)

Block 3 516.05 (100.27) 377.69 (71.54)

Block 4 456.11 (90.44) 405.55 (80.25)

Block 5 409.89 (86.89) 365.75 (77.75)

Latencies to response peak (in ms)

Pulse-alone 63.76 (1.54) 61.55 (1.29)

30-ms PPI 59.43 (1.55) 54.22 (1.47)

60-ms PPI 55.58 (1.10) 54.50 (1.60)

120-ms PPI 61.04 (2.23) 56.96 (1.93)

3. Results

3.1. Study 1

3.1.1. Amplitude and habituation of the startle response

Patients and controls did not differ for amplitude orhabituation over the entire session (Fs < 1 for Group

and Group · Block effects). There was a comparable le-

vel of habituation of the response over five blocks of

pulse-alone trials in both groups [Block: F(4,

204) = 20.04, P < 0.001; LinF(1,51) = 41.16, P < 0.001].

Co-varying for age did not change these effects and there

were still no main or interaction effects involving the

Group factor. Further analysis after splitting the groupinto patients on typical or atypical antipsychotics also

did not reveal any new effects: patients on typical anti-

psychotics, patients on atypical antipsychotics and

healthy controls had comparable response amplitudes

and habituation (see Table 1).

3.1.2. PPI

As expected, patients showed less PPI than healthycontrols [Group: F(1,51) = 4.05, P = 0.05]. There was

also a highly significant effect of Trial Type

[F(2,102) = 39.13, P < 0.001] with a linear trend

[F(1,51) = 54.95, P < 0.001] indicating significantly

greater PPI with 120-ms prepulse trials than with 30-

ms prepulse trials. The effect of Group slightly improved

(F(1,51) = 4.72, P = 0.04) after covarying for age.

ANOVA on PPI scores after dividing the patientsinto two groups (based on medication: typical or atypi-

cal antipsychotics; with two patient groups and a con-

trol group) revealed a significant Group · Trial Type

interaction [F(4,100) = 3.96, P = 0.005] with a strong

trend for the main effect of Group [F(2,50) = 3.04,

P = 0.06]. Subsequent analyses revealed significant

Group effects for 30-ms PPI[F(2,50) = 4.12, P = 0.03;

covarying for age, F(2,49) = 4.38, P = 0.02], 60-ms PPI[F(2,50) = 3.37, P = 0.04; covarying for age,

latencies to response peak in patients with schizophrenia and healthy

= 20) All patients (N = 39)

mean (SEM)

Controls (N = 14)

mean (SEM)

596.28 (66.08) 504.24 (93.97)

476.17 (60.69) 369.23 (64.66)

445.10 (60.31) 352.41 (75.76)

430.18 (59.63) 296.79 (52.91)

387.25 (57.49) 296.20 (71.10)

62.62 (1.00) 64.20 (1.99)

56.75 (1.13) 57.30 (1.88)

55.02 (0.97) 53.44 (0.92)

58.95 (1.49) 57.76 (1.63)

Table 3

Spearman�s rank order correlations between PPI and antisaccade

performance in patients with schizophrenia in study 1

30-ms 60-ms 120-ms

PPI

Trial type

30-ms –

60-ms 0.593** –

120-ms 0.530** 0.557** –

Antisaccade

Correct responses (%) 0.060 0.049 �0.062

** P < 0.001 level (two-tailed).


F(2,49) = 4.70, P = 0.01], but not for 120-ms PPI

[F = 1.63; covarying for age, F = 1.33]. Further post

hoc mean comparisons revealed that (i) with 30-ms pre-

pulse-to-pulse interval trials, patients given typical anti-

psychotics had reduced PPI compared to both healthy

controls [t(31) = 2.09, P = 0.04] and patients on atypicalantipsychotics [t(31) = 2.18, P = 0.04], and (ii) with 60-

ms prepulse-to-pulse interval trials, patients treated with

typical [t(31) = 2.41, P = 0.02] or atypical antipsychotics

[t(32) = 2.02, P = 0.05] had lower PPI than healthy con-

trols, but the typical and atypical medication groups did

not differ from each other (t < 1). Table 2 presents mean

(SEM) scores for PPI with 30-, 60-, and 120-ms pre-

pulse-to-pulse interval trials for patients (classified bymedication type) and healthy controls.

3.1.3. Latencies to response peak

The main effect of Trial Type was significant

[F(3,153) = 24.03, P < 0.001], indicating that latencies

to peak for trials with 30- and 60-ms prepulse-to-pulse

intervals were faster, whereas those for trials with 120-

ms prepulse-to-pulse intervals were slower relative tolatencies for pulse-alone trials (see Table 1). No effects

involving the Group factor were significant in any anal-

yses (i.e. patients versus healthy controls ANOVA, AN-

COVA with age as a covariate, or when the patient

sample was split into two groups based on their medica-

tion type and examined against each other and against

the control group).

3.1.4. Antisaccade

Patients had a lower percentage of correct responses

on the antisaccade task, relative to healthy controls

[F(1,51) = 9.46, P = 0.003; covarying for age:

F(1,50) = 8.40, P = 0.006] and this was true for patients

on typical antipsychotics [F(1,31) = 8.76, P = 0.006;

covarying for age: F(1,30) = 7.01, P = 0.01] as well as

on atypical antipsychotics [F(1,32) = 8.44, P = 0.007;covarying for age: F = (1,31) = 6.27, P = 0.02]. Patients

showed reduced gain relative to healthy controls [F(1,

51) = 6.25, P = 0.02; covarying for age: F(1,50) = 5.70,

P = 0.02] and this was also true for both typical

Table 2

Mean (SEM) PPI and antisaccade task performance in patients with schizop

Typical group (N = 19)

mean (SEM)

Atypical gro

mean (SEM

PPI

Trial type

30-ms �5.37 (12.30) 23.71 (5.60

60-ms 28.75 (6.54) 36.02 (4.59

120-ms 56.49 (4.44) 50.86 (6.14

Antisaccade

Correct responses (%) 61.66 (5.82) 61.77 (5.79

Latency (in ms) 339.10(19.00) 300.43 (13.6

Gain (%) 93.82 (6.39) 89.41 (6.19

[F(1,31) = 4.17, P = 0.05; covarying for age:

F(1,30) = 3.32, P = 0.08] and atypical antipsychotic

groups [F(1,32) = 6.64, P = 0.01; covarying for age:

F(1,31) = 5.31, P = 0.01]. Latency did not significantly

differentiate patients from healthy controls [see Table 2

for mean (SEM) antisaccadic task measures]. Patientson typical antipsychotics did not differ from those on

atypical antipsychotics for any antisaccade measures.

3.1.5. Relationship between PPI and antisaccade

performance

No relationship was found between PPI, at any pre-

pulse intervals tested, and percent of correct antisac-

cades in patients (see Table 3) or controls. Evaluationof these effects in separate groups of patients on typical

or atypical antipsychotics did not change the pattern of

effects described in Table 3.

Ten patients were identified with deficits on both PPI

and antisaccadic paradigms, 15 patients were identified

with deficient antisaccade performance but normal

PPI, 8 patients were identified with deficient PPI but

normal performance on the antisaccade task, and 6 pa-tients were identified with no (PPI or antisaccade) deficit

(see Table 4 for distribution of PPI scores and percent-

age of correct antisaccades in the patient group). The

observed frequencies (58.97% of the total population)

of patients with one deficit (either in PPI or on the anti-

saccade task) were significantly higher [X2(1) = 5.21,

hrenia and healthy controls in study 1

up (N = 20)

)

All patients (N = 39)

mean (SEM)

Controls (N = 14)

mean (SEM)

) 9.54 (4.70) 25.22 (3.05)

) 32.56 (3.95) 50.21 (5.37)

) 53.60 (3.80) 63.54 (4.62)

) 61.72 (4.05) 83.49 (3.32)

1) 319.27(11.86) 285.34 (13.49)

) 91.56 (4.39) 111.52 (5.17)


P = 0.02] than observed frequencies (25.64% of the total

population) of patients with deficits on both PPI and

antisaccade tasks.

Symptom levels in patients without PPI or antisac-

cade deficit (mean ± SD positive symptoms, 7.83 ±

1.17; mean ± SD negative symptoms, 8.67 ± 2.24;mean ± SD general psychopathology, 26.83 ± 9.64) were

not significantly different than those who had deficits on

either PPI or antisaccade paradigm (mean ± SD positive

symptoms, 9.17 ± 2.50; mean ± SD negative symptoms,

11.43 ± 4.05; mean ± SD general psychopathology:

29.04 ± 7.07) or deficits on both tasks (mean ± SD pos-

itive symptoms: 10.30 ± , SD = 4.08; mean ± SD nega-

tive symptoms: 11.30 ± 4.19; mean ± SD generalpsychopathology: 26.90 ± 7.41). Patients with only one

Table 4

PPI and antisaccade performance in 39 patients (all men) with

schizophrenia in study 1

Subject no. Percentage of

correct antisaccades

Percentage of

PPI (60-ms)

Medication type

(antipsychotics)

1 20.00a 62.25 Typical

2 21.43a 9.41a Typical

3 25.00a 35.94 Atypical

4 25.00a 27.78a Atypical

5 26.67a 32.30 Atypical

6 31.25a 33.08 Typical



9 35.71a 20.50a Typical

10 35.71a 31.38 Atypical

11 37.50a �39.16a Typical

12 42.86a 83.40 Typical


14 50.00a 1.52a Typical

15 53.33a 50.72 Typical


17 57.14a 38.68 Atypical

18 60.00a 75.40 Typical

19 64.29a 62.32 Atypical


21 66.67a 48.19 Typical

22 66.67a 56.32 Typical

23 66.67a 65.25 Atypical

24 68.75a 61.30 Atypical

25 68.75a 41.95 Atypical

26 75.00 3.07a Typical

27 75.00 5.95a Typical

28 78.57 3.67a Typical

29 78.57 29.03a Typical

30 84.62 2.99a Atypical

31 85.71 25.87a Typical

32 86.67 55.09 Atypical

33 86.67 25.01a Atypical

34 93.33 38.65 Typical

35 100.00 34.32 Atypical

36 100.00 32.85 Atypical

37 100.00 70.66 Typical

38 100.00 18.41a Typical

39 100.00 31.91 Atypical

a Below the cut off defining deficient performance.

deficit (PPI or antisaccade) also had very comparable

symptom levels to patients with deficits on both para-

digms (means and SDs already presented).

3.2. Study 2

3.2.1. Amplitude and habituation of the startle response

Patients and controls did not differ for amplitude or

habituation over the entire session (Fs < 1 for Group

and Group · Block effects). There was comparable level

of habituation of the response over five blocks of pulse-

alone trials in both groups (Block: F(3,165) = 16.63,

P < 0.001; LinF(1,55) = 34.71, P < 0.001; see Table 5].

3.2.2. PPI

As expected, patients showed less PPI than controls

[Group: F(1,55) = 5.57, P = 0.02]. There was also a

highly significant effect of Trial Type [F(4,220) = 44.82,

P < 0.001] and a significant Group · Trial Type interac-

tion [F(4,220) = 4.08, P < 0.003] which upon further

analyses showed that all but 30-ms PPI trials signifi-

cantly differentiated the two groups (see Table 6). Theeffect of Group remained significant [F(1,54) = 3.89,

P = 0.05) after covarying for age.

3.2.3. Latencies to response peak

For the latencies to response peak, there was a main

effect of Trial Type [F(5,275) = 4.13, P = 0.001] indicat-

ing faster latencies to response onset for trials preceded

by the prepulse relative to latencies for pulse-alone trials(see Table 5). No effects involving the Group factor were

significant in any analyses of latencies to response onset

or peak.

3.2.4. Antisaccade

Patients had a lower percentage of correct antisac-

cade responses than controls [F(1,55) = 13.12,

P < 0.001] and this effect remained significant after co-varying for age [F = (1,54) = 4.73, P = 0.03]. Patients

also showed trends for reduced gain (under-shooting)

relative to controls [F(1,55) = 3.34, P = 0.07; co-varying

for age: F(1,54) = 3.26, P = 0.08] and increased latency

[F(1,55) = 10.63, P = 0.008; co-varying for age: F(1,

54) = 3.65, P = 0.06].

3.2.5. Association between PPI and antisaccade

performance

As seen in study 1, no relationship was found be-

tween PPI at any prepulse intervals tested and percent-

age of correct antisaccades in patients or controls (see

Table 7).

Ten patients were identified with deficits on both PPI

and antisaccadic paradigms. Fourteen patients were

identified with deficits on either antisaccade task orPPI but not on both paradigms, and 11 patients were

identified with no (PPI or antisaccade) deficit (see Table

Table 5

Response amplitudes over the four blocks of three pulse-alone trials

each and latencies to response peak in patients with schizophrenia (all

on typical antipsychotics) and healthy controls in study 2

Patients (N = 35)

mean (SEM)

Controls (N = 22)

mean (SEM)

Response amplitude (in A/D units)

Block 1 492.23 (69.30) 477.79 (101.08)

Block 2 364.69 (50.66) 418.38 (101.70)

Block 3 307.51 (40.06) 342.64 (88.85)

Block 4 326.72 (48.15) 336.38 (82.90)

Latencies to response peak (in ms)

Pulse-alone 72.74 (2.09) 69.15 (1.82)

30-ms PPI 67.63 (2.40) 62.90 (2.12)

60-ms PPI 71.05 (2.51) 62.56 (1.97)

90-ms PPI 69.80 (2.18) 66.20 (2.37)

120-ms PPI 71.99 (2.44) 65.93 (2.29)

150-ms PPI 68.94 (2.70) 62.79 (1.88)

Table 6

Mean (SEM) PPI and antisaccade task performance in patients with

schizophrenia (all on typical antipsychotics) and healthy controls in

study 2

Patients (N = 35)

mean (SEM)

Controls (N = 22)

mean (SEM)

PPI

Trial Type

30-ms 12.04 (3.76) 12.28 (4.52)

60-ms 18.46 (3.65) 35.44 (4.13)

90-ms 28.47 (3.30) 45.34 (4.20)

120-ms 29.96 (3.87) 44.29 (3.94)

150-ms 31.33 (3.82) 42.72 (4.06)

Antisaccade

Correct responses (%) 51.51 (3.70) 70.60 (3.08)

Latency (in ms) 379.35 (16.78) 304.12 (11.48)

Gain (%) 76.70 (3.78) 98.44 (4.36)

Table 7

Spearman�s rank order correlation coefficients for relationship between PPI a

controls in study 2

30 60

PPI Patients

Trial Type

30-ms (30) –

60-ms (60) 0.570** –

90-ms (90) 0.600** 0.728**

120-ms (120) 0.506* 0.697**

150-ms (150) 0.347* 0.603**

Antisaccade

Correct responses (%) 0.132 0.067

PPI Controls

30-ms (30) –

60-ms 0.502* –

90-ms 0.522* 0.780**

120-ms 0.486*

150-ms 0.656** 0.653**

Antisaccade

Correct responses (%) �0.285 �0.199

* P < 0.05 level (two-tailed).** P < 0.001 level (two-tailed).


8 for distribution of scores). As in study 1, there were

more patients (40% of the total population) with deficit

on either PPI or antisaccade task than with deficits on

both tasks (28.57% of the population), though the differ-

ence in observed frequencies in this study was not

significant.Symptom levels in patients without PPI or antisac-

cade deficit (mean ± SD positive symptoms,

19.27 ± 8.25; mean ± SD negative symptom,

16.36 ± 4.48; mean ± SD general psychopathology:

37.45 ± 9.70) were comparable to those who had deficits

on either PPI or antisaccade task (mean ± SD positive

symptoms: 15.21 ± 8.60; mean ± SD negative symp-

toms, 17.64 ± 4.62; mean ± SD general psychopathol-ogy, 34.29 ± 12.06) or deficits on both tasks

(mean ± SD positive symptoms, 15.21 ± 8.60;

mean ± SD negative symptom: 19.30 ± 6.88; mean ± SD

general psychopathology, 34.00 ± 8.19). Patients with

only one deficit (PPI or antisaccade) also had very com-

parable symptom levels to patients with deficits on both

paradigms (means and SDs already presented).

4. Discussion

The present investigation assessed, for the first time

to our knowledge, PPI and antisaccade performance in

the same group of patients with schizophrenia in two

independent studies, and examined the relationship be-

tween abnormalities on these two tasks. Supportingthe hypothesis, both studies revealed a lack of associa-

tion between PPI and antisaccade abnormalities in schiz-

ophrenia. Patients of both studies showed, on average,

nd antisaccade performance in patients with schizophrenia and healthy

90 120 150

–

0.814** –

0.760** 0.846** –

�0.033 0.157 0.120

–

0.701** 0.843** –

0.752** 0.832** –

�0.101 �0.129 �0.263

Table 8

PPI and antisaccade performance in 35 patients with schizophrenia (all

on typical antipsychotics) in study 2

Subject no. Percentage of

correct antisaccades

Percentage of

PPI (60-ms)

Sex

1 5.08a 0.24a Male

2 7.89a 31.33 Female

3 13.73a �3.84a Male

4 25.86a �11.68a Male

5 28.57a �29.46a Male

6 28.81a 41.82 Male

7 32.65a 33.53 Male

8 34.69a 25.13 Male

9 35.71a 31.12 Male

10 36.36a 7.51a Male

11 38.18a 44.26 Female

12 42.11a 24.26 Female

13 44.00a �6.58a Male

14 44.23a 33.56 Male

15 46.30a 30.85 Female

16 50.85a 34.91 Female

17 51.11a 43.76 Female

18 51.85a �31.72a Male

19 54.35a 12.77a Female

20 55.00a 7.44a Female

21 55.93a 6.89a Male

22 58.00 29.29 Male

23 60.00 45.42 Female

24 65.31 25.91 Male

25 65.45 18.08 Male

26 67.80 28.81 Male

27 69.49 23.77 Male

28 71.67 22.76 Female

29 72.88 52.69 Male

30 76.36 20.01 Male

31 76.79 �23.78a Male

32 78.95 33.13 Female

33 81.03 13.32a Male

34 84.75 35.74 Female

35 91.23 �5.55a Male

a Below the cut off defining deficient performance.


reduced PPI in a passive paradigm (i.e. no instructions

to attend the prepulses) as well as a lower percentage

of correct antisaccade responses on the antisaccade task,

relative to healthy controls. Previous studies had ad-

dressed PPI and antisaccade performance in schizophre-

nia in separate investigations and had found, as in the

present study, that patients, on average, display deficits

on both these tasks. The observation of a lack of associ-ation between deficits on PPI and antisaccade task in the

present study can be viewed as extending previous

observations (Cadenhead et al., 2002) of no relationship

between PPI and antisaccade performance in patients

with schizotypal personality disorder, to patients with

schizophrenia.

The findings of this investigation support the sugges-

tion (Braff and Freedman, 2002; Cadenhead and Braff,2002) that PPI and antisaccade paradigms identify sep-

arate schizophrenia endophenotypes. One explanation

for this lack of association between passive PPI and

antisaccade abnormalities in the present sample, as sug-

gested and discussed previously by Braff and Freedman

(2002) and Cadenhead and Braff (2002), is that these

measures primarily utilize different or only partially

overlapping neural networks and involve a different level

(automatic/controlled) of information processing, as de-tailed further.

Neuroimaging studies in healthy human participants

have revealed activation in the striatum (Kumari et al.,

2003a), thalamus (using active PPI paradigm requiring

attention to prepulses, Hazlett et al., 2001; using passive

PPI paradigm, Kumari et al., 2003a) and parietal re-

gions (Hazlett et al., 1998; Kumari et al., 2003a) in asso-

ciation with PPI. Prefrontal cortex has been seenactivated with active PPI (Hazlett et al., 1998) but not

with passive PPI (Kumari et al., 2003a). All regions

noted in association with PPI have also shown hypoac-

tivation with PPI in patients with schizophrenia (Hazlett

et al., 1998; Kumari et al., 2003a). Increased error rate

on the antisaccade task is found to be associated with le-

sions to the dorsolateral prefrontal cortex (DLPFC)

(Fukushima et al., 1994; Gaymard et al., 1998; Pierrot-Deseilligny et al., 1991) and the anterior cingulate

(Milea et al., 2003), but not to the globus pallidus/puta-

men (Vermersch et al., 1996) or posterior parietal cortex

(Pierrot-Deseilligny et al., 1991). Neuroimaging studies

have also produced evidence for the involvement of

DLPFC (McDowell et al., 2002; Muri et al., 1998; Swee-

ney et al., 1996), frontal eye field (with likely involve-

ment in pre-saccadic inhibitory processes) (Cornelissenet al., 2002; O�Driscoll et al., 1995; Sweeney et al.,

1996;) and striatal regions (Crawford et al., 1996;

O�Driscoll et al., 1995; Raemaekers et al., 2002; Sweeney

et al., 1996) in antisaccade performance. Interestingly,

increased error rate on the antisaccade task correlates

with poor working memory in schizophrenia (Nieman

et al., 2000), which is also known to be heavily depend-

ent on DLPFC function (Smith and Jonides, 1997). Sim-ilarly, in patients with Parkinson�s disease antisaccade

error rates are correlated with performance on a puta-

tive �frontal� lobe task such as the Wisconsin Card Sort-

ing test, supporting the view that basal ganglia

impairment alone is not responsible for the antisaccade

abnormality (Broerse et al., 2001). These various lines of

evidence, taken together, suggest that the frontal lobe, in

particular DLPFC, activity might be critical for the tra-ditional antisaccade paradigm performance, which in-

volves suppression of a reflexive saccade in favour of

an antisaccade (Pierrot-Deseilligny et al., 2003). Con-

versely, thalamic activity might be more critical (Kumari

et al., 2003a) than DLPFC activity for passive PPI, gi-

ven the involuntary, automatic nature of this task. There

are no published studies of PPI in patients with lesions

to the frontal lobe. It would be valuable for future stud-ies to examine passive as well as active PPI in patients

with frontal lobe lesions. It is possible that attentional


modulation of active PPI (Hazlett and Buchsbaum,

2001) and antisaccade PPI would be affected by damage

to the frontal lobe, but passive PPI would remain intact

or relatively less affected. However, it is plausible that

PPI or antisaccade deficits in individual schizophrenia

patients may be caused by dysfunctions in different re-gions given the involvement of multiple neural regions

in normal range PPI and antisaccade performance and

the genetic aetiology of these deficits may also be heter-

ogeneous within the schizophrenia population.

The lack of a positive correlation between PPI and

antisaccade deficits seen in the present sample of medi-

cated patients is unlikely to be explained by medication

effects. Both PPI and antisaccade deficits were observedin earlier studies of patients medicated with typical anti-

psychotics, before the advent of atypical antipsychotics

(reviews, Braff et al., 2001; Everling and Fischer, 1998).

As mentioned in Section 1, some studies (Kumari et al.,

1999, 2002; Leumann et al., 2002; Oranje et al., 2002)

suggest, at best, a small positive effect (but sufficient

to bring the patient group, on average, within the nor-

mal range) of atypical antipsychotics on PPI while oth-ers (Duncan et al., 2003a,b; Mackeprang et al., 2002;

Parwani et al., 2000; Perry et al., 2002) report no effect

of antipsychotic medication, whether typical or atypical,

on PPI in schizophrenia patients. There are only few

data specifically examining the effects of antipsychotic

medication on antisaccade performance in schizophre-

nia. The evidence available so far suggests that typical

antipsychotics do not have any noticeable effects (re-view, Ettinger and Kumari, 2003) while atypical anti-

psychotics might produce some improvement in

antisaccade performance in schizophrenia (Burke and

Reveley, 2002; Chaudhry et al., 2002). In this investiga-

tion (study 1), however, we focused on the PPI param-

eters (i.e. 60-ms prepulse-to-pulse intervals) that

revealed deficits in patients regardless of whether they

were being treated with typical or atypical antipsychot-ics and did not find a significant difference in antisac-

cade performance of patients treated with typical and

atypical antipsychotics. Smoking/nicotine has similar

(i.e. beneficial) effects on both PPI (Kumari et al.,

2001) and antisaccadic performance (Depatie et al.,

2002) in schizophrenia and is thus unlikely to confound

our observations. Likewise, anticholinergic medication

has similar (mild detrimental) effects on both PPI (Ku-mari et al., 2003b) and antisaccade error rate (Ettinger

et al., 2003b) in patients with schizophrenia. Impor-

tantly, no patient included in this study was taking

drugs, such as anxiolytics, which are known to disrupt

antisaccade performance (Green and King, 2000; Green

et al., 1998), but not to affect PPI (Abduljawad et al.,

1997). One issue that might have influenced the results

of study 2 and other relevant studies involving subjectsof both sexes concerns the effects of sex in PPI and anti-

saccade performance. Previous studies (e.g. Aasen et al.,

in press; Kumari et al., 2003c, 2004; Swerdlow et al.,

1993, 1999) have observed lower PPI in healthy women

compared to healthy men when women are tested with-

out regard to where they are in their menstrual cycle.

This observation is explained, at least in part, by the

association between high estrogen phases and low PPIin healthy women (Swerdlow et al., 1997; Jovanovic

et al., 2004). Women included in study 2 (study 1 did

not include women) were tested without regard to their

menstrual cycle phases: healthy women showed the ex-

pected pattern of effect (i.e. lower PPI than men) but

this was not seen in the patient group (if anything, af-

fected women showed more PPI than affected men with

30-ms prepulse trials) as reported elsewhere (Kumariet al., 2004). The effect of sex in antisaccade perform-

ance in schizophrenia of healthy populations has not

been as intensively investigated as in PPI. There are

some data showing more accurate antisaccade perform-

ance in healthy men than healthy women tested without

regard to their menstrual cycle phases (Crawford et al.,

1998) but a significant sex effect in antisaccade perform-

ance was not seen in controls (data not shown) or pa-tients in this study (study 2; see Table 8). The results

of the two studies presented in this report demonstrate

that patients with schizophrenia, as a group, have PPI

and antisaccade deficits which are independent of each

other not only in men (study 1) but also in mixed gender

patient groups (study 2). However, given the evidence of

clear changes in PPI over the menstrual cycle in women

(Swerdlow et al., 1997; Jovanovic et al., 2004), a carefulassessment of menstrual cyclity would be desirable in

studies of this kind. Future studies should, therefore,

confirm the lack of association between PPI and anti-

saccade measures in healthy women and women with

schizophrenia taking their menstrual cycle phases and

hormonal status into account.

There are other aspects of this investigation that de-

serve some comment. Firstly, in both studies, there weresome patients who had deficits on both PPI and antisac-

cade paradigms, other patients had deficient antisaccade

performance but normal PPI or deficient PPI but nor-

mal performance on the antisaccade task, and still oth-

ers who were identified with no PPI or antisaccade

deficit (see Tables 4 and 8). Our observations of a lack

of either deficit in a proportion of patients in both stud-

ies is akin to those of Palmer et al. (1997) who notednormal range performance on a number of neuropsy-

chological measures in a proportion of patients with

schizophrenia.

Secondly, we employed the standard, non-overlap

version of the �step� kind, i.e. the peripheral target ap-

pears the moment the central target disappears (no-

gap, non-overlap), antisaccade task in both studies. A

previous study (McDowell et al., 1999) has shown thatthe �far overlap� version of the antisaccade task provides

larger separations (5–6 sigma) than �near overlap�


version between the patient and healthy control groups.

It is therefore possible that a greater proportion of pa-

tients would have been classified as showing deficient

antisaccade performance had we used the �far over-lap�version of the antisaccade task.

Thirdly, the presence of PPI and/or antisaccade defi-cit seemed unrelated to the severity of symptoms in both

studies. Our observations showing a lack of correspond-

ence between PPI or antisaccade deficit and symptoms

have empirical support from previous studies. Although

some data indicate a modestly negative relationship be-

tween PPI and symptoms of schizophrenia (Braff et al.,

1999), most studies do not find such a relationship (re-

view; Braff et al., 2001). A similar picture has emergedfor the antisaccade deficit. Both acutely ill and remitted

patients display deficits on the antisaccade task (Curtis

et al., 2001) and, as for PPI, a modest negative relation-

ship has been seen between antisaccade performance

and symptoms in some, but not all, studies (review,

Ettinger and Kumari, 2003). Concerning the trait nature

of these tasks, excellent temporal stability in healthy hu-

mans has been demonstrated for both PPI (Abel et al.,1998; Cadenhead et al., 1999) and antisaccade tasks

(Ettinger et al., 2003a). Our observations, taken together

with previous relevant data in patients with schizophre-

nia and their relatives, suggest that PPI and antisaccade

abnormalities represent, at least in part, trait-like deficits

in schizophrenia which might be more stable than the

symptoms which fluctuate.

In conclusion, this study found a lack of associationbetween PPI and antisaccade abnormalities in schizo-

phrenia. This observation indicates the divergence of

two inhibitory deficits in schizophrenia, one operating

at the automatic processing level (i.e. PPI), and the other

(i.e. antisaccade) at the volitional level (Callaway and

Naghdi, 1982). The evidence for genetic transmission

of PPI and antisaccade abnormalities (cited in Section

1) but a lack of association between them (Cadenheadet al., 2002; present results), taken together, supports

the suggestion (Braff and Freedman, 2002; Cadenhead

and Braff, 2002) that these two abnormalities represent

separate endophenotypes. Identification of useful endo-

phenotypes has important implications for the field of

genetic research for schizophrenia. An endophenotype

is phenotypically simpler than the complex clinical phe-

notype, with the latter being the result of an interactionbetween the genetic and environmental influences and

likely to vary between affected individuals (Gottesman

and Gould, 2003). The genes, discovered by the linkage

and candidate gene approaches, therefore should be

more strongly associated with an endophenotype than

the illness itself. As suggested by Braff and Freedman

(2002), functional abnormalities capable of detecting

genetically mediated deficits (i.e. endophenotypes) mustnow be used to provide a powerful focussed approach to

search for schizophrenia genes.

Acknowledgements

Financial support by the Wellcome Trust, UK

(067427/427/Z/02/Z; Senior Fellowship in Basic Biomed-

ical Science to Dr Kumari), and the National Alliance

for Research on Schizophrenia and Depression, USA(Young Investigator Award to Dr Kumari). Ulrich

Ettinger holds a Richard H. Tomlinson Post-doctoral

Research Fellowship. We are grateful to Sinead McCabe

for her help with manuscript preparation.

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