www.elsevier.com/locate/schres

Schizophrenia Research

Dysfunction of early-stage visual processing in schizophrenia:

harmonic analysis

Dongsoo Kima, Vance Zemona,b, Alice Sapersteina,

Pamela D. Butlera,c,*, Daniel C. Javitta,c

aProgram in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research,

140 Old Orangeburg Road, Orangeburg, NY, USAbFerkauf Graduate School of Psychology, Yeshiva University, 1300 Morris Park Ave. Bronx, NY, USA

cDepartment of Psychiatry, New York University School of Medicine, New York, NY, USA

Received 10 November 2003; received in revised form 11 October 2004; accepted 13 October 2004

Available online 15 December 2004

Abstract

Schizophrenia is associated with severe neurocognitive deficits that constitute a core feature of the disorder. Deficits have

been most extensively studied in relationship to higher-order processes. This study evaluated the integrity of early visual

processing in order to evaluate the overall pattern of visual dysfunction in schizophrenia. Steady-state visual-evoked potentials

(ssVEPs) were recorded over the occipital cortex (Oz) in patients with schizophrenia and schizoaffective disorder (N=26) and in

age-matched comparison volunteers (N=22). Two stimuli were used: windmill-dartboard and partial-windmill, which are

contrast-reversing (~4 Hz), radial patterns with dominant low spatial-frequency content. Each stimulus was presented for 1 min.

Fourier analysis was performed on the ssVEP data to extract the relevant temporal frequency (i.e., harmonic) components.

Magnitude-squared coherence (MSC) was computed to estimate the relative signal level for each frequency component. The

patients showed reduced amplitude and coherence of second harmonic responses in both conditions, but intact first harmonic

responses in the windmill-dartboard condition. This finding of a differential deficit may indicate a significant loss in the

magnocellular pathway, which contributes to the generation of the second harmonic component under these conditions. Early

sensory deficits may lead to impairments in subsequent stages of processing.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Harmonics; Lateral interaction; Visual-evoked potentials; Schizophrenia

0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.schres.2004.10.011

* Corresponding author. Cognitive Neuroscience and Schizo-

phrenia, Nathan S. Kline Institute for Psychiatric Research, 140

Old Orangeburg Road, Orangeburg, NY 10962, USA. Tel.: +1 845

398 6537; fax: +1 845 398 6545.

E-mail address: Butler@nki.rfmh.org (P.D. Butler).

1. Introduction

Schizophrenia is associated with severe neuro-

cognitive deficits that constitute a core feature of the

disorder. Deficits have been most extensively studied

in relationship to high-order processes, such as

76 (2005) 55–65

D. Kim et al. / Schizophrenia Research 76 (2005) 55–6556

executive functioning, working memory, attention,

and abstract reasoning (Goldberg and Gold, 1995;

Goldman-Rakic, 1994; Green, 1998; Weinberger and

Gallhofer, 1997). Perceptual dysfunction, however,

may also play a prominent pathophysiological role

and may provide important clues regarding underlying

etiology (Adler et al., 1999; Braff et al., 1991;

Cadenhead et al., 1998; Javitt et al., 1999). Deficits

in visual processing in schizophrenia have been well

documented and include increased visual thresholds

(Butler et al., 1996; Saccuzzo and Braff, 1986;

Slaghuis and Bakker, 1995) and greater sensitivity

to backward masking (Braff et al., 1991; Butler et al.,

1996; Green et al., 1999; Slaghuis and Bakker, 1995).

In addition, patients with schizophrenia have impaired

motion perception, spatial localization, and eye

tracking (Cadenhead et al., 1998; Chen et al., 2003;

O’Donnell et al., 1996). Recent studies show impaired

early-stage visual processing (Butler et al., 2001) and

visual object recognition in the patients with schizo-

phrenia (Doniger et al., 2002).

Early models of visual system dysfunction focused

on the psychophysically defined btransientQ and

bsustainedQ visual channels (Green et al., 1994;

Slaghuis and Curran, 1999). More recently, this

dichotomy has been supplanted by anatomically and

physiologically based distinctions between the mag-

nocellular and parvocellular visual pathways. These

pathways begin in the retina and project, by means of

the lateral geniculate nucleus (LGN), to the striate

cortex. Magnocellular cells show greater sensitivity

than parvocellular cells to low luminance contrast

(~1–10% contrast). Parvocellular neurons, in contrast,

do not start responding until stimuli reach higher

contrast (~10%; Kaplan, 1991; Tootell et al., 1998). In

addition, magnocellular cells are preferentially acti-

vated by relatively large (i.e., low spatial frequency)

stimuli, whereas parvocellular cells are activated more

strongly by stimulus elements that are relatively small

(i.e., have high spatial frequency). Finally, magnocel-

lular neurons are sensitive to motion but relatively

unresponsive to color contrast, whereas the opposite is

true of parvocellular cells. Magnocellular neurons

project preferentially to the dorsal visual stream

(bwhereQ pathway) and subserve motion processing,

spatial localization, and attentional organization. In

contrast, parvocellular neurons project preferentially

to the ventral visual stream (bwhatQ pathway) and

subserve object identification (Ungerleider and Mish-

kin, 1982).

Recording steady-state visual-evoked potentials

(ssVEPs), we have previously demonstrated that

patients with schizophrenia show reduced amplitude

responses to magnocellular–but not to parvocellular-

selective stimuli, suggesting physiological dysfunc-

tion preferentially in this visual pathway (Butler et al.,

2001). Furthermore, we have demonstrated that visual

backward masking deficits are observed when mag-

nocellular-selective, but not parvocellular-selective,

stimuli are used as masks supporting a role of

magnocellular-system dysfunction in the backward

masking deficits in schizophrenia (Butler et al., 2002;

Schechter et al., 2003).

This study further investigates early visual pro-

cessing dysfunction in schizophrenia using two

stimuli referred to as bwindmill-dartboardQ (WD)

and bpartial-windmillQ (PW; Fig. 1), which may be

useful in distinguishing magnocellular and parvocel-

lular dysfunction. These stimuli are used widely in

visual research and generate ssVEPs that index

activity within low-level regions of the visual pathway

(Grose-Fifer et al., 1994; Sokol et al., 1992; Zemon et

al., 1986b). Low spatial-frequency patterns (i.e., PW

stimulus) that contrast-reverse in time elicit VEPs

with a dominant second harmonic component and a

percept that includes apparent motion. The second

harmonic refers to the VEP response at twice the input

(fundamental) frequency. Second harmonic responses

which are preferentially elicited by achromatic

(McKeefry et al., 1996) and low spatial frequency

(Murray et al., 1983) stimuli are thought to be

mediated primarily by magnocellular system activity.

For instance, a previous study by Grose-Fifer et al.

(1994) has shown that the dominant second harmonic

response to the PW stimulus is largely attributable to

the low spatial-frequency content of this stimulus.

When the high spatial-frequency content was filtered

by blurring the stimulus, the second harmonic

component was relatively unaffected. In contrast, it

has been shown that to attain a sizable amplitude of

the first harmonic component in the response to the

WD stimulus, 10% or greater contrast is needed in

static regions of the pattern (Zemon and Ratliff,

1982). The first harmonic refers to the VEP response

at the stimulus input (fundamental) frequency. This

contrast dependency may indicate a dominant role of

Fig. 1. Partial-windmill (A) and windmill-dartboard (B,C) conditions. (A) The contrast of the first and third annuli was held constant at 0%,

whereas the pattern elements in the central disk and the second annulus contrast reverse at ~4 Hz to produce partial-windmill; (B,C) the

windmill-dartboard stimulus has two distinct phases: windmill, shown in (B), and dartboard, shown in (C). The contrast of the first and third

annuli was held constant at 32%. Contrast reversal (~4 Hz) of the pattern elements in the central disk and the second annulus resulted in the

change of appearance from a windmill to a dartboard.

D. Kim et al. / Schizophrenia Research 76 (2005) 55–65 57

the parvocellular pathway in the generation of the first

harmonic (Tootell et al., 1998). Thus, this study

assesses relative integrity of parvocellular and mag-

nocellular systems by comparison of first and second

harmonics of responses to WD and PW stimuli in

schizophrenia.

The WD and PW stimuli may also be used to

investigate lateral interactions within visual cortex

that play a role in modulating afferent input (Zemon

and Ratliff, 1982; Zemon et al., 1986b). Two types of

nonlinear lateral interactions (i.e., long-range and

short-range) have been observed in response to WD

and PW stimuli. The long-range interaction can be

examined by looking at the ratio of the second

harmonic response elicited by WD stimulation com-

pared to the second harmonic response elicited by PW

stimulation. An attenuation of the second harmonic

response to WD stimulation relative to the second

harmonic response to PW stimulation indicates intact

long-range interactions. Conversely, the short-range

interaction is reflected in the first harmonic compo-

nent of the response to WD stimulation (Zemon and

Ratliff, 1982). The short-range and long-range inter-

actions both appear to be inhibitory in origin (Victor

and Zemon, 1985; Zemon and Ratliff, 1982, 1984). In

addition, it has been suggested that the short-range

and long-range lateral interactions are of GABAergic

inhibitory origin (Hirsch and Gilbert, 1991; Zemon et

al., 1986a; Zemon and Ratliff, 1982). Short-range

interactions appear to reflect the extent of dendritic

fields of inhibitory interneurons within primary visual

cortex which range from 200 to 300 Am (Somogyi et

al., 1982). Long-range horizontal connections in the

primary visual cortex extend up to 8 mm (Gilbert and

Wiesel, 1989; Hirsch and Gilbert, 1991). Thus, WD

and PW stimuli also permit analysis of early cortical

mechanisms involved in modulating the afferent input

to the cortex.

As with previous work in our laboratory, the

primary dependent measures in this study are

neurophysiological, and no task (other than fixating

a point on a CRT monitor) was involved (Butler et

al., 2001). Also, recording time was brief (1 min for

each stimulus), minimizing the degree to which

differential fatigue or lack of cooperation might have

contributed to the results. The present methods thus

provide an objective and noninvasive approach to

assessing the integrity of early visual processing in

schizophrenia.

2. Method

2.1. Participants

Twenty-six inpatients (21 males, 5 females) meet-

ing DSM-IV criteria for schizophrenia (n=17) and

schizoaffective disorders (n=9) at the Nathan Kline

Institute for Psychiatric Research provided written

informed consent after the procedures had been fully

explained. Diagnoses were obtained by means of chart

review, consultation with the treating psychiatrists,

and the Structured Clinical Interview for DSM-IV

(SCID). Patients were excluded if they had any

D. Kim et al. / Schizophrenia Research 76 (2005) 55–6558

neurological or ophthalmologic disorders that might

affect performance. Eight patients were taking atyp-

ical antipsychotics (olanzapine) and 18 were receiving

typical antipsychotic medications. The mean chlor-

promazine-equivalent dose was 1050.42 mg/day

(range=334–2004, S.D.=404).

Twenty-two comparison volunteers (10 males, 12

females), age-matched to the patients, provided

written informed consent after the procedures had

been fully explained. Comparison volunteers with a

history of psychiatric, neurological, and/or ophthal-

mologic disorders were excluded.

The patient and comparison groups did not differ

significantly in age (patient, mean=38.7 years,

S.D.=10.5, N=26; comparison, mean=39.2 years,

S.D.=10.7, N=22), although socioeconomic status, as

measured with the four-factor Hollingshead scale

(Hollingshead and Redlich, 1958), was significantly

lower for the patients (mean=26.6, S.D.=11.4) than for

the comparison subjects (mean=48.1, S.D.=14.1)

(t=�5.6, df=43, pb0.0005). Scores for general psy-

chopathology (BPRS), negative symptoms, and pos-

itive symptoms were mean=32.9, S.D.=8.9; mean=

26.6, S.D.=13.4; mean=7.8, S.D.=3.9, respectively.

All participants were tested in binocular and

monocular conditions (dominant and nondominant

eyes). Eye dominance was determined by asking

each participant to look through a narrow tube. The

eye selected for viewing was judged to be the

dominant one.

All participants showed better than 20/40 (=0.5)

vision for all three eye conditions. The patients had

lower visual acuity than did the controls for eye

condition. However, only the nondominant condition

showed a significant group difference (t=3.2, df=46,

p=0.003). Control analyses were, therefore, per-

formed to evaluate potential contribution of

between-group acuity to observed between-group

differences.

2.2. Apparatus

The VENUS system (Neuroscientific, Farming-

dale, NY), an all-inclusive system for creating,

modifying, and generating visual stimuli for recording

of brain electrophysiological and psychophysical

responses, was used for this study. The display was

a 14-in. Princeton Ultrasynch RGB monitor, and the

raster was set to a 16�16 cm square. The frame rate

was ~119 Hz. The space-average luminance was

approximately 100 cd/m2.

2.3. Stimuli

Two stimuli were used: windmill-dartboard and

partial-windmill (Fig. 1). The stimulus display

subtended a visual angle of 88 at the viewing

distance of 114 cm. Both stimuli consist of a central

disc (radius: 0.948) and three contiguous annuli

(radius: first ring: 1.8758; second ring: 2.8138; andthird ring: 3.758), radially divided into light and dark

segments. For both stimuli, the dynamic regions

(central disc and second annulus) are sinusoidally

contrast-reversed (from �32% to +32%) at ~4 Hz.

Each stimulus was presented for 1 min, and the same

pattern was presented repetitively throughout the

duration of the run.

2.3.1. Partial-windmill condition

In the partial-windmill (PW) condition, the first

and third annuli are set at zero contrast and thus

contain a uniform field set at the mean luminance

level. The central disc and second annulus contain

light and dark elements that contrast-reverse, which

produces the percept of apparent motion and yields a

VEP that contains a dominant second harmonic in

addition to a smaller fourth harmonic component.

2.3.2. Windmill-dartboard condition

In the windmill-dartboard (WD) condition, the

central disk and second annulus were contrast

reversed, while the first and third annuli were

fixed in contrast at the peak value of the dynamic

regions (32%). As a result, the percept alternates

between that of a windmill and that of a dartboard,

and the resulting VEP contains a dominant first

harmonic in addition to an attenuated second

harmonic component.

2.4. Visual-evoked potentials

Visual-evoked potentials (VEPs) were recorded

from the occipital site (Oz) relative to the vertex

reference site by means of gold-cup electrodes. The

ground electrode was placed at the parietal site (Pz).

The raw EEG was amplified (by 10,000), filtered with

D. Kim et al. / Schizophrenia Research 76 (2005) 55–65 59

a bandpass of 0.1–100Hz and digitized at a rate of

four times the monitor frame rate (~476 Hz).

Frequency analysis was performed for each epoch.

Amplitude and phase measures at the fundamental

(stimulus) frequency (~4 Hz) and at other harmonic

components were extracted by means of a discrete

Fourier transform (Regan, 1989).

Magnitude-squared coherence (MSC) was com-

puted to estimate the signal level for each frequency

component (Zemon et al., 1999). MSC is the ratio of

signal power to signal+noise power for a given

frequency component. When there is no noise, it is

deemed pure signal (MSC=1). The MSC decreases

from 1 and theoretically falls to 0 as the signal

decreases leaving only noise. Estimates of MSC are

biased by an amount that depends on sample size:

bias=1/q. In this study, q=10. Therefore, bias level

was 0.1.

2.5. Procedure

The participants were tested monocularly (domi-

nant and nondominant eye) and binocularly after they

were light-adapted to the mean luminance of the

display for several minutes. They were seated in a

dimly lit room and instructed to fixate on the small dot

placed in the center of the display during each run.

The experimenter monitored the gaze of each partic-

ipant during each run to ensure steady fixation. Any

runs in which gaze was unsteady were rejected, and

those runs were then repeated. In addition, if the EEG

trace contained sizable deflections from baseline or

other noise activity, the run was rejected and then

repeated. Brief rest periods were provided between

runs. The order of presentation of the two stimuli (PW

and WD) and eye conditions (binocular, dominant,

and nondominant) were counterbalanced to control for

a possible order effect.

2.6. Statistical analysis

Demographic comparisons were analyzed between

groups by means of two-tailed t tests. ssVEP MSC

responses were analyzed using repeated measures

analyses of variance with factors as described below.

In the primary analyses, data from patients with

schizophrenia and schizoaffective disorder were com-

bined because there was no significant difference

between these groups. In addition, two covariate

analyses were performed to examine the potential

contribution of the visual acuity difference observed

between the patients and controls. Post hoc one-way

ANOVAs and two-tailed t tests were applied when the

ANOVAs revealed significant main effects or inter-

actions. Data were analyzed for normality by means

of the Kolmogorov–Smirnov test and for equality of

variance by using Levene’s test. No deviations from

normality or equality of variance were observed.

3. Results

3.1. Partial-windmill condition

Between-group analyses of ssVEP responses

(MSC) were analyzed using a repeated measures

ANOVA with between-subject factor of group (schiz-

ophrenia/control) and within-subject factor of har-

monic level (first vs. second). In the PW condition

(see Fig. 2), the primary neural response occurred at

the second harmonic of the presented stimulus, as

reflected in the highly significant main effect of

harmonic across groups ( F=293.8, df=1,46,

p=0.0001). There was also a significant main effect

of group (F=10.1, df=1,46, p=0.003) and a signifi-

cant group x harmonic interaction (F=10.5, df=1,46,

p=0.002), reflecting differential generation of har-

monics across groups. Post hoc ANOVAs demon-

strated no significant difference between groups in

first harmonic generation (F=0.1, df=1,46, p=0.8),

but a significant between-group difference in second

harmonic generation (F=11.6, df=1,46, p=0.001).

The MSC score of the second harmonic for patients

was about 72% of comparison values across all three-

eye conditions. There was no significant main effect

of eye condition (dominant, nondominant, and binoc-

ular), and no significant group�eye interaction. The

between-group difference in second harmonic gener-

ation remained highly significant even following

covariation for potential between-group differences

in visual acuity (F=7.0, df=1,46, p=0.011).

3.2. Windmill-dartboard condition

In the WD condition, the primary neural response

was at the first harmonic (see Fig. 2), as reflected in a

Fig. 2. Mean magnitude-squared coherence (MSC) scores for partial-windmill (upper) and windmill-dartboard (lower) conditions. BI: binocular

eye condition; DO: dominant eye condition; ND: nondominant eye condition. Controls: comparison subjects (N=22); Scz patients:

schizophrenia patients (N=26). MSC was computed to estimate the signal level for each frequency component. MSC=signal power/signal+noise

power. Therefore, 1=pure signal; 0=no signal. Bias level was set on 0.1 (using 10 epochs). aSignificant difference between groups (t=2.8–4.1,

df=46, pb0.01); bsignificant difference between groups (t=2.2–2.6, df=46, pb0.05).

D. Kim et al. / Schizophrenia Research 76 (2005) 55–6560

significant main effect of harmonic (F=58.1, df=1,46,

p=0.0001). As in the PW condition, there was a

significant group effect (F=5.9, df=1,46, p=0.018),

and a significant group x harmonic interaction

(F=6.6, df=1,46, p=0.013). Post hoc ANOVAs

demonstrated no significant difference between

groups in first harmonic generation (F=0.3, df=1,46,

p=0.6), but a highly significant between-group differ-

ence in second harmonic generation ( F=18.9,

df=1,46, p=0.0001). The MSC score of the second

harmonic for patients was about 62% of comparison

values across all three-eye conditions. There was no

significant main effect of eye condition and no

significant group�eye interaction. As in the PW

condition, the between-group difference in second

harmonic generation remained highly significant even

following covariation for potential between-group

differences in visual acuity ( F=13.8, df=1,46,

p=0.001).

3.3. Cross-condition comparisons

In controls, the first harmonic response in the WD

condition was of approximately equal amplitude to the

second harmonic response in the PW condition,

providing an opportunity for evaluation of differential

deficits free of amplitude confound. A repeated

measure ANOVA with within-group factors of stim-

ulus type and eye condition was performed to

examine the differential deficits in first harmonic of

WD and second harmonic of PW. There was a

significant main effect of group (F=4.4, df=1,46,

p=0.041) and a significant group�harmonic interac-

tion (F=5.6, df=1,46, p=0.023), supporting the

D. Kim et al. / Schizophrenia Research 76 (2005) 55–65 61

observation of a selective impairment of second

harmonic responses to WD/PW stimuli.

3.4. Long-range lateral interactions

To examine the long-range lateral interactions,

amplitudes of the second harmonic component for

both PW and WD conditions were examined. There

was no significant group�stimulus condition inter-

action (F=2.7, df=1,46, p=0.11), showing that the

ratio of the second harmonic for the PW and WD

condition did not differ between groups.

3.5. Fourth harmonic

Two repeated measures ANOVAs were performed

to look at between-group difference in fourth har-

monics of WD and PW conditions. In the WD

condition, there was a significant main effect of group

(F=4.5, df=1,46, p=0.04), but no group x eye

condition interaction. There was also a significant

main effect of group (F=8.1, df=1,46, p=0.007) in the

PW condition. The MSC scores of the fourth

harmonics for patients in WD and PW conditions

were both about 68% of comparison values across all

three-eye conditions.

3.6. Patients with schizophrenia versus schizoaffective

disorder

There were 17 patients with schizophrenia, 9

patients with schizoaffective disorder, and 22 controls.

A MANOVA was performed to discover possible

between-group differences in harmonics generated by

PW and WD conditions. A multivariate analysis based

on the general linear model was performed to explore

the effects of group membership (control, schizophre-

nia, schizoaffective) and eye condition (dominant,

nondominant, binocular) on the six relevant response

measures (WD first, second, third, fourth and PW

second, fourth harmonic components). There was a

main effect of group membership (F=7.1, df=2,45,

p=0.002), but there was no interaction effect of group

by eye condition (F=1.8, df=4,88, p=0.14). Main

effect of eye condition was significant when all six

response measures were included (F=4.7, df=2,44,

p=0.014), and when only the PW measures were

analyzed (F=4.7, df=2,45, p=0.014), but not when

the WD measures were analyzed separately (F=1.7,

df=2,45, p=0.2).

In the PW condition, there was a significant main

effect of group in second harmonic generation across

all three-eye conditions: binocular (F=7.1, df=2,45,

p=0.002), nondominant (F=7.8, df=2,45, p=0.001),

and dominant (F=5.3, df=2,45, p=0.008). Scheffe’s

post hoc test revealed a significant difference between

controls and patients with schizophrenia ( p=0.002),

but not between controls and patients with schizo-

affective disorder ( p=0.2) or between patients with

schizophrenia and patients with schizoaffective dis-

order ( p=0.09) across all eye conditions.

In the WD condition, as in the PW condition, there

was a significant main effect of group in second

harmonic generation for binocular (F=6.1, df=2,45,

p=0.005) and nondominant eye conditions (F=8.7,

df=2,45, p=0.001), but not for first harmonic gen-

eration for all eye conditions. Scheffe’s post hoc test

revealed a significant difference between controls and

patients with schizophrenia ( p=0.007), but not

between controls and patients with schizoaffective

disorder ( p=0.1) or between patients with schizo-

phrenia and patients with schizoaffective disorder

( p=0.9) for all eye conditions.

4. Discussion

Although there has been increasing focus on the

study of visual processing deficits in schizophrenia

(Braus et al., 2002; Brenner et al., 2003; Keri et al.,

2004; Li, 2002; Schwartz et al., 1999; Slaghuis and

Thompson, 2003), underlying neurophysiological

mechanisms remain to be determined. This is the first

study to analyze dysfunction of the visual system in

schizophrenia using pan-harmonic analysis of

ssVEPs. Two types of stimuli were used—WD and

PW. Harmonics were extracted using Fourier analysis,

and responses were analyzed across groups to

compare first versus second harmonics. Integrity of

lateral interactions was analyzed using ratios of

responses to the harmonics. The primary findings

are that patients with schizophrenia show significantly

decreased magnitude of second harmonic responses in

both the PW and WD conditions, but intact first

harmonic responses indicating a deficit in early visual

processing. The differential deficit is apparent even

D. Kim et al. / Schizophrenia Research 76 (2005) 55–6562

under conditions in which controls show similar

magnitude responses, and so cannot be attributed to

psychometric artifact. Lateral interactions in the

primary visual cortex, however, appear to be intact.

On the perceptual level, the present results may be

relevant to recent studies showing impaired motion

detection in schizophrenia (Braus et al., 2002; Brenner

et al., 2003; Li, 2002). Impairments in motion

detection have been increasingly observed (Braus et

al., 2002; Chen et al., 1999; Li, 2002; O’Donnell et

al., 1996). However, the underlying substrates have

yet to be fully defined. Motion detection is decoded

primarily in dorsal stream visual areas, such as MT

(V5), but depends upon inputs primarily from the

magnocellular visual system. Behavioral studies alone

cannot determine whether motion detection deficits

observed in schizophrenia reflect dysfunction of

cortical motion areas or of low-level projection

systems.

Recent functional imaging studies have demon-

strated decreased activation in MT during motion

detection in schizophrenia, but no between-group

difference in activation of primary visual areas. This

finding has been interpreted as reflecting dysfunction

primarily within higher-order cortical motion detec-

tion regions (Braus et al., 2002). In contrast, the

finding in this study of impaired ssVEP activity to

the present stimuli indicates dysfunction within early

visual regions (precortical or V1). The failure to

detect changes within primary cortex in functional

imaging studies may reflect difficulty in differentiat-

ing motion-related from feature-related activity

within primary visual cortex using anatomically (as

opposed to neurophysiologically) based imaging, or

may indicate that functional imaging signals, in

general, reflect integrity of input as well as of local

processing (Logothetis, 2002). Thus, impaired MT

activation noted in functional imaging experiments

may reflect impaired input into higher visual regions,

rather than impaired local detection. Positron emis-

sion tomography (PET) studies in controls have

shown motion-dependent alteration in activation of

primary visual areas with incoherent motion stimuli

(McKeefry et al., 1997). Whether activation deficits

to such stimuli can be observed in schizophrenia

remains to be determined.

Long- and short-range lateral inhibitory connec-

tions within cortex play a critical role in sculpting

ssVEP responses to WD and PW stimuli (Zemon and

Ratliff, 1982, 1984). In particular, attenuation of the

second harmonic component in the WD as compared

to the PW condition and generation of a first harmonic

component by WD stimulation are thought to depend

on long-range and short-range lateral interactions

within the cortex, respectively (Grose-Fifer et al.,

1994; Sokol et al., 1992; Zemon and Ratliff, 1982).

Although second harmonic responses were reduced to

both PW and WD stimuli, the relative ratio was

unchanged, suggesting that deficits in long-range

lateral inhibitory activity cannot account for the

present pattern of results. The normal first harmonic

in patients demonstrates that they also have intact

short-range inhibitory activity.

Exact mechanisms underlying the differential

deficit in second versus first harmonic response

remain to be determined, but may involve differential

magnocellular versus parvocellular involvement in

schizophrenia. As noted above, second harmonic

responses are thought to depend preferentially on

functioning of the magnocellular visual pathways,

whereas first harmonic responses depend more heav-

ily upon parvocellular processing (Grose-Fifer et al.,

1994; McKeefry et al., 1996; Murray et al., 1983;

Zemon and Ratliff, 1982). Prior electrophysiological

(Butler et al., 2001; Doniger et al., 2002; Foxe et al.,

2001) and psychophysical (Keri et al., 2004;

Schechter et al., 2003; Schwartz et al., 1999; Slaghuis

and Thompson, 2003) studies have demonstrated

greater impairment in magnocellular, than parvocel-

lular, functioning in schizophrenia. The present results

would thus be consistent with those prior findings.

Alternatively, deficits in nonlinear mechanisms

present in cortex, such as shunting inhibition which

are important in producing responses at higher

harmonics or temporal frequencies (Carandini and

Heeger, 1994) would also result in greater attenuation

of higher harmonic responses in patients than con-

trols. Other types of studies, such as ones that utilize

two-sinusoid stimulation, may serve as effective

probes of nonlinear cortical mechanisms and thus

may provide additional information (Zemon and

Ratliff, 1984). Whatever the underlying mechanism,

the differential involvement of second versus first

harmonic responses nevertheless excludes nonspecific

factors, such as attention or cooperation in producing

the observed deficits in schizophrenia, and supports

D. Kim et al. / Schizophrenia Research 76 (2005) 55–65 63

prior studies demonstrating early visual processing

deficits in schizophrenia.

Although attentional mechanisms are known to be

impaired in schizophrenia, an underlying assumption

of much research is that deficits are driven by such

btop downQ mechanisms. In this study, it is unlikely

that attentional deficits contributed strongly to the

observed results. First, there was no behavioral

component in the study other than fixation on the

center of the display. Second, the results would show

deficits in generation of first as well as second

harmonics if there were gross attentional disturbances

(e.g., failure to maintain fixation on the screen).

Instead, this study argues that visual attentional

impairments may be bbottom-up,Q due to failure of

basic neurophysiological processes within early visual

areas. The magnocellular system, in particular,

appears to mediate automatic capture of attention by

salient (e.g., moving, flickering) stimuli, with magno-

cellularly driven attentional capture predominating

over parvocellularly driven attentional capture (Stein-

man et al., 1997). Magnocellular neurons project

preferentially to the dorsal stream, and parvocellular

neurons project preferentially to the ventral stream.

Magnocellular inputs to the dorsal stream cross over

to ventral stream areas and also play a critical role in

organizing activity within ventral stream, object

recognition areas (Doniger et al., 2000, 2002; Lamme

and Roelfsema, 2000; Schroeder et al., 1998). Patients

with schizophrenia actually show decreased, rather

than increased, distractibility to visual stimuli pre-

sented outside the focus of attention (Slaghuis and

Thompson, 2003), consistent with magnocellular

dysfunction. Magnocellular dysfunction also appears

to contribute to impaired recognition of both moving

(Schwartz et al., 1999) and fragmented (Doniger et al.,

2002) stimuli and impaired visual organization. The

present data are thus consistent with a model in which

impaired magnocellular input into the dorsal visual

stream leads to dysfunctional modulation of ventral

stream object recognition processes (Doniger et al.,

2002).

A limitation of this study is that all patients were

receiving antipsychotic medication at the time of

testing. Thus, a medication effect cannot be excluded.

Dopamine is well known to be present in the visual

system and has an impact on visual processing

including spatial frequency tuning (Bodis-Wollner

and Tzelepi, 1998). However, it is highly unlikely

that such effects play a role in the generation of

second harmonic but not first harmonic responses.

Furthermore, acute haloperidol administration had no

effect on the generation of ssVEPs (Jibiki et al.,

1993). Several visual backward masking studies also

did not find a difference in backward masking

performance in the same patients tested on and off

medication (Braff and Saccuzzo, 1982; Butler et al.,

1996, 2002; Green et al., 1999). In this study, no

significant correlations were found between CPZ

equivalents and first and second harmonics. Thus, it

is unlikely that the differential deficits shown in this

study are due to a medication effect.

For the primary analysis, results from patients with

schizophrenia and schizoaffective disorder were com-

bined. A secondary analysis evaluated relative deficits.

No significant differences were detected between

patients with schizophrenia versus schizoaffective

disorder. However, patients with schizoaffective dis-

order did not on their own differ significantly from

controls. The lack of difference may reflect differential

underlying pathophysiology, heterogeneity within the

schizoaffective group, or simply the small number of

patients studied with schizoaffective disorder. Patients

with schizophrenia and schizoaffective disorder were

also not matched for severity of illness. These issues

can be further clarified in future studies.

In summary, this study confirms prior reports of

early visual processing deficits in schizophrenia using

novel visual stimuli. Patients showed a differential

deficit with intact first harmonic responses to WD

stimuli but impaired second harmonic responses to

both PW and WD conditions. These stimuli therefore

may be useful in characterizing visual processing

deficits in schizophrenia and may suggest differential

involvement of magnocellular and paravocellular

systems. These deficits may contribute significantly

to subsequent stages, such as conscious motion

detection, attentional capture, and stimulus-driven

perceptual organization.

Acknowledgments

Presented in part at the 32nd annual meeting of the

Society for Neuroscience, Orlando, FL, Nov. 2–7,

2002 and at the 9th International Congress on

D. Kim et al. / Schizophrenia Research 76 (2005) 55–6564

Schizophrenia Research, Colorado Springs, CO,

March 29–April 2, 2003. This work was supported

by USPHS grants RO1 MH66374 (PDB), R37

MH49334, and K02 MH01439 (DCJ), and a Bur-

roughs Wellcome Translational Scientist Award (to

DCJ). We thank Dr. Glenn Wylie for helpful com-

ments on the manuscript.

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