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Dysfunction of early-stage visual processing in schizophrenia: harmonic analysis
Schizophrenia Research 76 (2005) 55 – 65 www.elsevier.com/locate/schres
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 a
Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY, USA b Ferkauf Graduate School of Psychology, Yeshiva University, 1300 Morris Park Ave. Bronx, NY, USA c Department 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
1. Introduction * Corresponding author. Cognitive Neuroscience and Schizophrenia, 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: [email protected] (P.D. Butler). 0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2004.10.011
Schizophrenia is associated with severe neurocognitive deficits that constitute a core feature of the disorder. Deficits have been most extensively studied in relationship to high-order processes, such as
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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 schizophrenia (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 magnocellular 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 activated 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, magnocellular 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 Mishkin, 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 parvocellularselective stimuli, suggesting physiological dysfunction preferentially in this visual pathway (Butler et al., 2001). Furthermore, we have demonstrated that visual backward masking deficits are observed when magnocellular-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 processing 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 parvocellular 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
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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.
the parvocellular pathway in the generation of the first harmonic (Tootell et al., 1998). Thus, this study assesses relative integrity of parvocellular and magnocellular 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 compared 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 component of the response to WD stimulation (Zemon and Ratliff, 1982). The short-range and long-range interactions 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) meeting 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
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neurological or ophthalmologic disorders that might affect performance. Eight patients were taking atypical antipsychotics (olanzapine) and 18 were receiving typical antipsychotic medications. The mean chlorpromazine-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 ophthalmologic 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 psychopathology (BPRS), negative symptoms, and positive 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, performed to evaluate potential contribution of between-group acuity to observed between-group differences.
raster was set to a 1616 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; and third 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.
2.2. Apparatus 2.4. Visual-evoked potentials The VENUS system (Neuroscientific, Farmingdale, 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
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
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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 computed 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 (dominant 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 participant 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 combined because there was no significant difference
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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 interactions. 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 (schizophrenia/control) and within-subject factor of harmonic 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 significant group x harmonic interaction ( F=10.5, df=1,46, p=0.002), reflecting differential generation of harmonics across groups. Post hoc ANOVAs demonstrated 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 threeeye conditions. There was no significant main effect of eye condition (dominant, nondominant, and binocular), and no significant groupeye interaction. The between-group difference in second harmonic generation 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
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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).
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 difference 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 groupeye 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 stimulus 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 groupharmonic interaction ( F=5.6, df=1,46, p=0.023), supporting the
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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 groupstimulus condition interaction ( 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 harmonics 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, schizophrenia, 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
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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 schizoaffective disorder ( p=0.2) or between patients with schizophrenia and patients with schizoaffective disorder ( 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 generation 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 schizophrenia 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
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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 demonstrated 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 detection 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 differentiating 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 emission 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 connections 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 heavily 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 parvocellular, 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 controls. 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
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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 magnocellularly driven attentional capture predominating over parvocellularly driven attentional capture (Steinman 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 presented 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
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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 combined. A secondary analysis evaluated relative deficits. No significant differences were detected between patients with schizophrenia versus schizoaffective disorder. However, patients with schizoaffective disorder 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
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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 Burroughs Wellcome Translational Scientist Award (to DCJ). We thank Dr. Glenn Wylie for helpful comments on the manuscript.
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Slaghuis, W.L., Curran, C.E., 1999. Spatial frequency masking in positive- and negative-symptom schizophrenia. J. Abnorm. Psychology 108, 42 – 50. Slaghuis, W.L., Thompson, A.K., 2003. The effect of peripheral visual motion on focal contrast sensitivity in positiveand negative-symptom schizophrenia. Neuropsychologia 41, 968 – 980. Sokol, S., Zemon, V., Moskowitz, A., 1992. Development of lateral interactions in the infant visual system. Vis. Neurosci. 8, 3 – 8. Somogyi, P., Freund, T.F., Cowey, A., 1982. The axo-axonic interneuron in the cerebral cortex of the rat, cat and monkey. Neuroscience 7, 2577 – 2607. Steinman, B.A., Steinman, S.B., Lehmkuhle, S., 1997. Transient visual attention is dominated by the magnocellular stream. Vision Res. 37, 17 – 23. Tootell, R.B., Hadjikhani, N.K., Vanduffel, W., Liu, A.K., Mendola, J.D., Sereno, M.I., Dale, A.M., 1998. Functional analysis of primary visual cortex (V1) in humans. Proc. Natl. Acad. Sci. U. S. A. 95, 811 – 817. Ungerleider, L., Mishkin, M., 1982. Two cortical visual system. In: Ingle, D., Goodale, M.A., Mansfield, R.J.W. (Eds.), Analysis of Visual Behavior. MIT Press, Cambridge, MA, pp. 549 – 580. Victor, J.D., Zemon, V., 1985. The human visual evoked potential: analysis of components due to elementary and complex aspects of form. Vision Res. 25, 1829 – 1842. Weinberger, D.R., Gallhofer, B., 1997. Cognitive function in schizophrenia. Int. Clin. Psychopharmacol. 12 (Suppl. 4), S29 – S36. Zemon, V., Ratliff, F., 1982. Visual evoked potentials: evidence for lateral interactions. Proc. Natl. Acad. Sci. U. S. A. 79, 5723 – 5726. Zemon, V., Ratliff, F., 1984. Intermodulation components of the visual evoked potential: responses to lateral and superimposed stimuli. Biol. Cybern. 50, 401 – 408. Zemon, V., Kaplan, E., Ratliff, R., 1986a. The role of GABAmediated intracortical inhibition in the generation of visual evoked potentials. In: Cracco, R., Bodis-Wollner, I. (Eds.), Evoked Potentials: Frontiers of Clinical Neuroscience, vol. 3. Alan R. Liss, INC., New York, pp. 287 – 295. Zemon, V., Victor, J.D., Ratliff, F., 1986b. Functional subsystems in the visual pathways of humans characterized using evoked potentials. In: Cracco, R., Bodis-Wollner, I. (Eds.), Evoked Potentials: Frontiers of Clinical Neuroscience, vol. 3. Alan R. Liss, New York, pp. 203 – 210. Zemon, V., Buckley, S., Fitzgerald, K., Gordon, J., Hartmann, E., Meyer, A., 1999. Objective determination of signal from noise in swept-parameter transient visual evoked potentials (VEPs). Invest. Ophthalmol. Visual. Sci. 40/4, S824.
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 a
Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY, USA b Ferkauf Graduate School of Psychology, Yeshiva University, 1300 Morris Park Ave. Bronx, NY, USA c Department 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
1. Introduction * Corresponding author. Cognitive Neuroscience and Schizophrenia, 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: [email protected] (P.D. Butler). 0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2004.10.011
Schizophrenia is associated with severe neurocognitive deficits that constitute a core feature of the disorder. Deficits have been most extensively studied in relationship to high-order processes, such as
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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 schizophrenia (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 magnocellular 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 activated 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, magnocellular 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 Mishkin, 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 parvocellularselective stimuli, suggesting physiological dysfunction preferentially in this visual pathway (Butler et al., 2001). Furthermore, we have demonstrated that visual backward masking deficits are observed when magnocellular-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 processing 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 parvocellular 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
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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.
the parvocellular pathway in the generation of the first harmonic (Tootell et al., 1998). Thus, this study assesses relative integrity of parvocellular and magnocellular 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 compared 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 component of the response to WD stimulation (Zemon and Ratliff, 1982). The short-range and long-range interactions 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) meeting 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
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neurological or ophthalmologic disorders that might affect performance. Eight patients were taking atypical antipsychotics (olanzapine) and 18 were receiving typical antipsychotic medications. The mean chlorpromazine-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 ophthalmologic 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 psychopathology (BPRS), negative symptoms, and positive 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, performed to evaluate potential contribution of between-group acuity to observed between-group differences.
raster was set to a 1616 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; and third 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.
2.2. Apparatus 2.4. Visual-evoked potentials The VENUS system (Neuroscientific, Farmingdale, 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
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
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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 computed 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 (dominant 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 participant 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 combined because there was no significant difference
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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 interactions. 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 (schizophrenia/control) and within-subject factor of harmonic 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 significant group x harmonic interaction ( F=10.5, df=1,46, p=0.002), reflecting differential generation of harmonics across groups. Post hoc ANOVAs demonstrated 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 threeeye conditions. There was no significant main effect of eye condition (dominant, nondominant, and binocular), and no significant groupeye interaction. The between-group difference in second harmonic generation 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
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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).
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 difference 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 groupeye 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 stimulus 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 groupharmonic interaction ( F=5.6, df=1,46, p=0.023), supporting the
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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 groupstimulus condition interaction ( 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 harmonics 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, schizophrenia, 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
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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 schizoaffective disorder ( p=0.2) or between patients with schizophrenia and patients with schizoaffective disorder ( 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 generation 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 schizophrenia 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
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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 demonstrated 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 detection 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 differentiating 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 emission 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 connections 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 heavily 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 parvocellular, 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 controls. 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
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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 magnocellularly driven attentional capture predominating over parvocellularly driven attentional capture (Steinman 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 presented 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
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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 combined. A secondary analysis evaluated relative deficits. No significant differences were detected between patients with schizophrenia versus schizoaffective disorder. However, patients with schizoaffective disorder 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
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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 Burroughs Wellcome Translational Scientist Award (to DCJ). We thank Dr. Glenn Wylie for helpful comments on the manuscript.
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