MEG-measured visually induced gamma-band oscillations in chronic schizophrenia: Evidence for impaired generation of rhythmic activity in ventral stream regions

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Abstract

Background

Gamma-band oscillations are prominently impaired in schizophrenia, but the nature of the deficit and relationship to perceptual processes is unclear.

Methods

16 patients with chronic schizophrenia (ScZ) and 16 age-matched healthy controls completed a visual paradigm while magnetoencephalographic (MEG) data was recorded. Participants had to detect randomly occurring stimulus acceleration while viewing a concentric moving grating. MEG data were analyzed for spectral power (1–100 Hz) at sensor- and source-level to examine the brain regions involved in aberrant rhythmic activity, and for contribution of differences in baseline activity towards the generation of low- and high-frequency power.

Results

Our data show reduced gamma-band power at sensor level in schizophrenia patients during stimulus processing while alpha-band and baseline spectrum were intact. Differences in oscillatory activity correlated with reduced behavioral detection rates in the schizophrenia group and higher scores on the “Cognitive Factor” of the Positive and Negative Syndrome Scale. Source reconstruction revealed that extra-striate (fusiform/lingual gyrus), but not striate (cuneus), visual cortices contributed towards the reduced activity observed at sensor-level in ScZ patients. Importantly, differences in stimulus-related activity were not due to differences in baseline activity.

Conclusions

Our findings highlight that MEG-measured high-frequency oscillations during visual processing can be robustly identified in ScZ. Our data further suggest impairments that involve dysfunctions in ventral stream processing and a failure to increase gamma-band activity in a task-context. Implications of these findings are discussed in the context of current theories of cortical-subcortical circuit dysfunctions and perceptual processing in ScZ.

Introduction

Recent evidence has highlighted the contribution of impaired perceptual processing towards behavioural and physiological deficits in schizophrenia (ScZ). This is supported through data from anatomy (Selemon et al., 1995), physiology (Rivolta et al., 2014, Sun et al., 2013, Grützner et al., 2013, Krishnan et al., 2005, Butler et al., 2007) and psychophysics (Butler et al., 2008, Uhlhaas and Silverstein, 2005, Uhlhaas and Mishara, 2007), which has highlighted that the earliest stages of auditory and visual processing might be compromised. As a result, dysfunctions in “higher” cortical regions that support more complex cognitive processes involved in executive functions and social cognition could be essentially due to deficits in bottom-up driven sensory activity (Javitt, 2009).

Abnormalities in rhythmic activity at low and high frequencies could provide a mechanism for dysfunctional perception in ScZ (Tan et al., 2013). Rhythmic activity at gamma-band frequencies has been shown to systematically correlate with stimulus parameters, such as contrast, size, or retinal location (Muthukumaraswamy and Singh, 2013). This has led to the conclusion that gamma-band activity may essentially be involved in feed-forward propagation of sensory activity along the visual hierarchy (Michalareas et al., 2016) which is consistent with the laminar expression profile (Markov et al., 2014). More specifically, high frequency oscillations occur predominantly in granular layers 3 and 4, while alpha (8–12 Hz)/beta (13–30 Hz) oscillations occur predominantly in infra-granular layers 5 and 6 (Bastos et al., 2015, van Kerkoerle et al., 2014). In addition to stimulus parameters, the amplitude and frequency of high-frequency oscillations in visual cortices can also be influenced by central states, such as attention. Initial evidence was provided by Fries and colleagues (Fries et al., 2001) who showed that 35–90 Hz activity in macaque visual area V4 strongly increased when behaviourally relevant stimuli were within the focus of attention. Moreover, attentional states and expectancy strongly impacts on activity prior to the onset of stimulus (Beck and Kastner, 2009, Corbetta and Shulman, 2002). Stimulus expectation is typically expressed in a decrease of power in the lower, in particular alpha-frequency range prior to stimulus onset and often predicts subsequent task performance (Thut et al., 2006, van Dijk et al., 2008). In contrast to lower frequencies, higher frequencies in the gamma-band range typically only increase in power shortly after the expected stimulus arrives (Bauer et al., 2014). Accordingly, it has been hypothesized that across areas in the visual processing hierarchy alpha-band oscillations are involved in feedback propagation of information flow while gamma-band activity are strongly involved in feed-forward mediated information processing of stimulus-related activity (Fries, 2015).

Several EEG/MEG-studies have provided preliminary evidence for the potential role of abnormal high-frequency oscillations in visual-perceptual deficits in ScZ (Spencer, 2008, Sun et al., 2013, Grützner et al., 2013). However, the underlying generators as well as the potential mechanisms remain unclear. One possibility is that impaired high-frequency oscillations in ScZ are the direct consequence of dysfunctions in neurobiological mechanisms that underlie the generation of rhythmic activity in sensory cortices (Tan et al., 2013). Gamma-band oscillations are critically dependent upon the balance between Excitation and Inhibition (E/I-balance) mediated by NMDA/AMPA-receptors and GABAergic interneurons in local circuits which determine the strength and duration of the oscillations (Wang and Buzsaki, 1996, Fuchs et al., 2007, Whittington et al., 1995, Carlen et al., 2012). In ScZ, there is extensive evidence for disturbance in these parameters (Uhlhaas and Singer, 2012) that include alterations in visual cortices, such as reductions in the mRNA of GAD67, an enzyme that synthesizes GABA (Hashimoto et al., 2003). Furthermore, Magnetic Resonance Spectroscopy (MRS)-measured reduction in GABA-levels was found to correlate with psychophysical impairment in orientation-specific surround suppression in ScZ patients (Yoon et al., 2010), suggesting a potential role in visual dysfunctions.

To address the possibility that visual cortices in ScZ are characterized by impairments in the generation of gamma-band oscillations and to elucidate potential correlations with impairments in alpha oscillations before and during stimulus processing, we employed a visual task that was designed to elicit robust high-frequency activity in the context of focused attention (Hoogenboom et al., 2006). Previous data showed excellent signal-to-noise ratio (SNR) for gamma-band oscillations and high reliability across measurements (Muthukumaraswamy et al., 2010). In combination with detailed source reconstruction of MEG-measured high-frequency oscillations, we expected novel insights into the contribution of brain areas and alpha oscillations towards impaired high-frequency oscillations in ScZ. Moreover, our analysis allowed the examination of alterations in rhythmic activity during the pre-stimulus baseline period, and its potential effects on subsequent task-induced activity. There is evidence suggesting a positive correlation between high pre-stimulus (baseline) alpha-band power over visual cortex and poor stimulus-detection performance (Romei et al., 2008, Romei et al., 2010). Accordingly, we analysed baseline and task induced oscillations at sensor-level and in virtual channels to examine this possibility.

Section snippets

Participants

Sixteen chronic schizophrenia (ScZ) patients (6 females, mean age 34 ± 10.6 years [standard deviation: STDEV]) were recruited from the in- and outpatients units of the Dept. of Psychiatry, affiliated hospital Hoechst, Frankfurt, Germany. All ScZ-patients met DSM-IV criteria for ScZ and were on stable antipsychotic treatment. Sixteen age-matched healthy controls (6 females, mean age 31 ± 8.0 years) were recruited from the local community. The study was carried out according to the Declaration of

Behavioural data

Performance on the moving grating task was different between the two groups (Table 2). Although ScZ patients and healthy controls (HC) were on average equally fast in responding, accuracy was significantly lower for the ScZ patients (p = 0.001).

Task-induced activity

Time-frequency responses (TFRs) of sensor-level data (Fig. 2A) revealed stimulus-induced increases in gamma and decreases in alpha band power, compared to baseline power, a pattern that was present for both groups. Topographic distributions of the maximum

Discussion

The current findings demonstrate that visual cortices in ScZ are involved in the failure to generate optimal amplitudes of gamma-band oscillations in ventral stream occipital areas. Previous findings with EEG and MEG reported reductions in the amplitude and phase of high-frequency oscillations during visual tasks at illness-onset and in chronic ScZ (Tan et al., 2013, Spencer, 2008, Sun et al., 2013, Grützner et al., 2013). However, because of the potential contribution of distinct and

Contributors

Tineke Grent-‘t-Jong contributed to analyses and write-up of the study.

Davide Rivolta contributed to design, recordings, analyses and write-up.

These two authors investigated equal amounts of work and time into the study and current manuscript and therefore share first authorship.

Andreas Sauer contributed to design and recordings.

Michael Grube, Wolf Singer, Michael Wibral and Peter Uhlhaas (leading investigator) are senior scientists who supervised the entire study, from design to final

Acknowledgments

The authors declare no competing financial interests. Davide Rivolta was supported by the LOWE grant Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF).

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