Steady state visual evoked potential abnormalities in schizophrenia

https://doi.org/10.1016/j.clinph.2004.09.016Get rights and content

Abstract

Objective

The steady state visual evoked potential (SSVEP) can be used to test the frequency response function of neural circuits. Previous studies have shown reduced SSVEPs to alpha and lower frequencies of stimulation in schizophrenia. We investigated SSVEPs in schizophrenia at frequencies spanning the theta (4 Hz) to gamma (40 Hz) range.

Methods

The SSVEPs to seven different frequencies of stimulation (4, 8, 17, 20, 23, 30 and 40 Hz) were obtained from 18 schizophrenia subjects and 33 healthy control subjects. Power at stimulating frequency (signal power) and power at frequencies above and below the stimulating frequency (noise power) were used to quantify the SSVEP responses.

Results

Both groups showed an inverse relationship between power and frequency of stimulation. Schizophrenia subjects showed reduced signal power compared to healthy control subjects at higher frequencies (above 17 Hz), but not at 4 and 8 Hz at occipital region. Noise power was higher in schizophrenia subjects at frequencies between 4 and 20 Hz over occipital region and at 4, 17 and 20 Hz over frontal region.

Conclusions

SSVEP signal power at beta and gamma frequencies of stimulation were reduced in schizophrenia. Schizophrenia subjects showed higher levels of EEG noise during photic stimulation at beta and lower frequencies.

Significance

Inability to generate or maintain oscillations in neural networks may contribute to deficits in visual processing in schizophrenia.

Introduction

Schizophrenia is associated with visual processing abnormalities. Patients with schizophrenia often experience subjective disturbances of visual perception such as alterations in color, brightness, motion, depth and shape, and visual hallucinations (Cutting and Dunne, 1986, Phillipson and Harris, 1985). Visual psychophysical measures have documented deficits affecting contrast sensitivity (Slaghuis, 1998), form discrimination (Brenner et al., 2003), motion perception (Chen et al., 1999, Chen et al., 2003, O'Donnell et al., 1996, Schwartz et al., 1999) and backward masking (Green et al., 1999). These deficits may be more severe for stimuli presented at high temporal rates (Butler et al., 2001, Schwartz et al., 1999, Slaghuis and Bishop, 2001) or which require rapid integration of visual information across time (Green et al., 1999, Schwartz et al., 1999). Functional neuroimaging techniques such as PET and fMRI have also shown altered visual cortex activation in schizophrenia (Foxe et al., 2001, Braus et al., 2002, Renshaw et al., 1994, Taylor et al., 1997).

The neural processes responsible for these deficits in visual processing are not well characterized. One possibility is that subjects with schizophrenia have altered oscillatory and resonance characteristics within visual neural networks. Cellular studies suggest that oscillations at gamma frequencies (25 Hz and above) occur when the firing patterns of spatially separated brain regions are synchronized, and that these oscillations are essential for perceptual binding, stimulus selection, and response selection (Engel et al., 1997, Singer, 1999). Electroencephalographic (EEG) oscillations in the gamma range have been associated with perception, visual awareness, and associative learning in humans (Singer, 1999, Tallon-Baudry and Bertrand, 1999). If such oscillatory activity is necessary for integration of information within the nervous system, then disturbances of these processes would result in perceptual and cognitive deficits. Abnormalities in the generation or maintenance of neural oscillations has been hypothesized to be responsible for a variety of symptoms in schizophrenia, a mental illness associated with pervasive disorganization of thought and behavior (Bressler, 2003, Kwon et al., 1999, Lee et al., 2003, Brenner et al., 2003, Green et al., 1999, Green et al., 2003, O'Donnell et al., 2002, Phillips and Silverstein, 2003).

In this study, steady state visual potentials (SSVEPs) were used to evaluate the ability of visual circuits to oscillate at gamma and lower frequencies in schizophrenia. The SSVEP is an electroencephalographic (EEG) response which is synchronized in frequency and phase to a temporally modulated visual stimulus (Regan, 1989). SSVEPs, therefore, can evaluate the oscillatory properties of visual circuits in schizophrenia. Unlike psychophysical measures of visual processing, SSVEPs can be obtained with minimal task demands. The SSVEP can be elicited by a wide range of stimulation frequencies, from 1 to 100 Hz in humans (Herrmann, 2001, Regan, 1989) and in animals (Rager and Singer, 1998). Although the generators of the SSVEP responses are still under investigation, several studies have shown the involvement of posterior cortical regions, primarily the occipital cortex (Pastor et al., 2003, Muller et al., 1997, Silberstein, 1995, Weinberg et al., 1989). The SSVEP at high temporal frequencies is thought to preferentially activate the magnocellular pathway, while responses at low frequencies are believed to activate the parvocellular pathway (Silberstein, 1995). The SSVEP is also influenced by cognitive operations. SSVEP power is increased by spatial attention (Morgan et al., 1996, Muller et al., 1998). Concurrent performance of cognitive tasks such as Wisconsin Card Sorting Test (WCST) have also been shown to modulate SSVEP responses (Silberstein et al., 1995).

SSVEP power varies with temporal frequency of stimulation, indicative of frequency tuning or resonance (Regan, 1989). Herrmann (2001) observed peak resonances in the SSVEP at 10, 20, 40 and 80 Hz in humans to unpatterned visual flicker. Pastor et al. (2003) reported greatest resonance at 15 Hz to flicker stimulation. SSVEP resonance is thought to result from a combination of resonances at local neural circuits and global resonance over the cortex (Silberstein et al., 1995). The resonance at 10 Hz is thought to relate to mechanisms producing alpha activity and the 40 Hz resonance may relate to gamma activity, which has a putative role in perceptual integration (Singer, 1999).

The SSVEP has previously been studied in schizophrenia at alpha and lower frequencies (less than 13 Hz). Rice et al. (1989) reported that subjects with schizophrenia have lower power at several stimulating frequencies between 4.8 and 12 Hz, including frequencies in alpha band, compared to healthy control subjects. These changes were most prominent at frontal electrode sites. Schizophrenia subjects also showed reduced alpha activity (7–13 Hz) during resting period, but the reduction in alpha activity was larger during photic stimulation compared to resting period (Rice et al., 1989). Subsequently, Jin et al. (1995a) showed that SSVEP reduction in schizophrenia occurred at higher alpha frequencies (12.5 Hz) and not at lower alpha frequencies (9.375 Hz). Using Statistical Parametric Mapping (SPM), Jin et al. (1995a), found that this reduction was most prominent at mid-frontal, central and parietal regions. Jin et al. (2000) used 1 Hz stimulation and evaluated harmonics in alpha frequencies. Schizophrenia subjects showed reduced power at 10, 11 and 12 Hz in all regions except centro-temporal regions. Clementz et al. (2004) used different periods of stimulation (2–6 s) to evaluate the time course of the SSVEP response to 6.4 Hz stimulation. SSVEP power was reduced, and the time taken for schizophrenia subjects to reach maximal response and the decay time for the response after termination of stimulus were delayed. In summary, both reduction of power and altered timing of the SSVEP have been reported in schizophrenia. Reduction of power has been most consistently reported in high alpha frequencies (10 Hz and above).

The specificity of reduced SSVEP at alpha frequencies to schizophrenia has also been investigated. Jin et al. (1997) evaluated SSVEP responses at alpha frequency (7.2–9.6 Hz) in subjects with schizophrenia, major depression and healthy subjects. Schizophrenia subjects showed significantly reduced SSVEP power which was prominent at frontal regions. In contrast, subjects with major depression showed increased power for the same stimuli.

Medication and clinical status may also affect the SSVEPs in the alpha range. Wada et al. (1995) found reduced responses at 10 Hz in unmedicated schizophrenia patients over the occipital region. In a study comparing clozapine responders and non-responders, subjects who showed diminished symptoms after treatment with clozapine showed an increase in SSVEP responses at alpha frequencies, compared to subjects with no clinical improvement (Jin et al., 1995b). A separate study showed that the increase in SSVEP responses in subjects taking clozapine was centered around 6.25 and 9.375 Hz and was prominent over the frontal and central regions (Jin et al., 1998).

Altered alpha frequency photic driving responses in schizophrenia have been attributed to abnormalities in the circuits that generate alpha activity, including thalamocortical circuits (Jin et al., 1997). To our knowledge, SSVEPs for higher frequencies of stimulation (15–40 Hz) in schizophrenia have not been evaluated. The first objective of the current study was to compare the SSVEP in schizophrenia and in healthy controls over a wide range of stimulation frequencies, including beta and gamma frequencies. Abnormalities in the SSVEP response at these frequencies would provide support for the role of disturbed high frequency neural synchronization in the pathophysiology of this disorder as suggested by several investigators (Bressler, 2003, Kwon et al., 1999, Lee et al., 2003, Green et al., 2003, O'Donnell et al., 2002, Phillips and Silverstein, 2003). Our second objective was to compare EEG noise or background activity near stimulation frequencies between schizophrenia and healthy control subjects. Recent studies have shown that EEG noise is increased in schizophrenia and their unaffected siblings (Winterer et al., 2000, Winterer et al., 2004).

Section snippets

Subjects

Eighteen subjects diagnosed with schizophrenia (7 females) and 33 healthy, non-psychiatric control subjects (15 females) participated in this study. The average age of schizophrenia group was 39.5 years (SD=7.6 years) and the age of the control group was 36 years (SD=9.9 years). Exclusion criteria for all subjects included history of electroconvulsive therapy, neurologic illness, alcohol use in the past 24 h, visual impairment, or head trauma. In addition, control subjects were excluded if there

Factor analysis

Factor analyses yielded either two or 3 components that accounted for at least 80% variance for each frequency of stimulation (Table 1). Electrode sites Fz and Oz showed high loadings (>0.75) on different factors at each frequency, and were therefore used to index activity for these two factors in subsequent analyses.

Resting condition

Table 2 shows the results of the ANOVAs on signal power and noise power values calculated from the resting condition at Oz and Fz. There was a main effect for frequency at Oz and

Discussion

SSVEPs were used to evaluate frequency response characteristics in schizophrenia and control subjects. During photic stimulation, both groups showed higher power at the stimulation frequency compared to resting period and this response was largest at posterior head regions (Fig. 1). Factor analysis was used to identify spatially independent factors during photic stimulation at each frequency of stimulation. At all stimulus frequencies, 2–3 factors accounted for at least 80% of the variance. One

Acknowledgements

We are grateful for support from NIMH 1 RO1 MH62150-01 (BFO) and the Indiana University Foundation (BFO). Andrew King assisted in data collection and processing. We thank the participants in the study.

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