Elsevier

Clinical Neurophysiology

Volume 115, Issue 8, August 2004, Pages 1863-1874
Clinical Neurophysiology

Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing

https://doi.org/10.1016/j.clinph.2004.03.013Get rights and content

Abstract

Objective

Integration of sensory information by cortical network binding appears to be crucially involved in target detection. Studies in schizophrenia using functional and diffusion tensor neuroimaging, event-related potentials and EEG coherence indicate an impairment of cortical network coupling in this disorder. Previous electrophysiological investigations in animals and humans suggested that gamma activity (oscillations at around 40 Hz) is essential for cortical network binding. Studies in medicated schizophrenia provide evidence for a reduced gamma activity in the context of auditory stimulus processing. This is the first investigation of oscillatory activations in the gamma-band in an auditory oddball paradigm in unmedicated schizophrenic patients.

Methods

EEG gamma-band responses (GBRs) of 15 drug-free schizophrenic patients and 15 age- and gender-matched healthy controls were compared. A wavelet transform based on Morlet wavelets was employed for the calculation of oscillatory GBRs.

Results

In response to standard stimuli, early evoked GBRs (20–100 ms), which are supposed to reflect auditory cortex activation, did not show significant group differences. However, schizophrenic patients showed reduced evoked GBRs in a late latency range (220–350 ms), particularly after target stimuli. This deficit occurred over right frontal scalp regions. Furthermore, significant correlations were observed between oscillatory GBRs and clinical parameters in schizophrenic patients.

Conclusions

The results are consistent with a relative preserved stimulus processing in the auditory cortex as reflected by the early GBR. The reduced late GBR is compatible with an abnormal interaction within a frontal lobe network, as was postulated by previous neuroimaging studies.

Significance

The present study provides evidence for disturbed processing within frontal cortical regions in unmedicated schizophrenic patients as indicated by reduced evoked EEG GBRs.

Introduction

A basic question in brain function research is how the manifold parallel neuronal activations, necessary to process even a simple sensory stimulus, are integrated and bound together. For example, in an auditory oddball task, early stimulus classification has to be integrated with attention, working memory, response selection, and motor output within a time range of milliseconds. This is known as the binding problem (Engel et al., 2001, Singer and Gray, 1995). The temporal binding model assumes that integrative processes in the brain are closely related to precisely synchronized activity of different neurons within the same, or between different cortical areas. Synchrony was shown to enhance the salience of neural responses because correlated discharges (synchrony) have a stronger impact on neuronal populations than temporally disorganized inputs (Alonso et al., 1996, Singer, 1999). According to the binding concept, neuronal populations in a cortical network that are already synchronized entrain other neurons to become part of the same overall assembly which corresponds to the incorporation of some content (e.g. stimulus) into a broader context (decision making and response).

Synchrony of electromagnetic activity across a broad frequency spectrum has been demonstrated to be related to cortical information processing (Bressler et al., 1993, Winterer et al., 1999). A major focus of interest have been high frequency oscillations in the gamma-band (30–80 Hz, mainly around 40 Hz), which apparently play a crucial role in the integration of cortical processes (Basar-Eroglu et al., 1996, Joliot et al., 1994, Senkowski and Herrmann, 2002). It has been shown that oscillatory gamma-band responses (GBRs) can be synchronized over short and large distances, and thereby showing a distinct temporal relation to the underlying cerebral activity (Schurmann et al., 1997). Furthermore, GBRs have been related to various sensory and cognitive processes in widespread cortical regions including perceptual and associative learning (Gruber et al., 2002, Miltner et al., 1999), sensory/motor integration (Murthy and Fetz, 1992, Salenius et al., 1996), object representation (Tallon-Baudry and Bertrand, 1999) and selective attention processes (Fries et al., 2001, Herrmann and Knight, 2001).

With regard to schizophrenia, measurable neurophysiological correlates of regional and inter-regional synchrony are of major interest. This is because there are a number of indications that anatomical and functional connectivity is critically disturbed in schizophrenic patients. For instance, evidence exists that the demyelination of subfrontal white matter, which is thought to result in a disturbance of regional interaction, can be accompanied by psychotic symptoms (Hyde et al., 1992). Furthermore, diffusion tensor imaging (DTI), a relatively new technique assessing the integrity and possibly connectivity of white matter fibers in vivo, provided evidence for a disruption in the white matter of the prefrontal cortex (Buchsbaum et al., 1998), the posterior corpus callosum (Foong et al., 2000) and the uncinate fasciculus, which is the most prominent white matter tract connecting temporal and frontal brain regions (Kubicki et al., 2002). In line with this, functional neuroimaging and electrophysiological studies in schizophrenia suggest abnormalities in the interaction, i.e. functional connectivity or coherence between a number of brain areas, notably between prefrontal and temporal lobe structures (Fletcher et al., 1999, Ford et al., 2002, Friston and Frith, 1995, Norman et al., 1997, Winterer et al., 2003a). These studies focused on the interaction of regions, i.e. usually multisynaptic macrocircuits, rather than on deficits in isolated cortical areas. It is therefore of interest that recent work in schizophrenic patients also suggested a disturbance of synchrony in local prefrontal and temporal lobe microcircuits (Winterer et al., 2003b, Winterer et al., 2004).

So far, it is not well understood at which time point in the information processing stream deficits of synchrony or functional connectivity are most prominent in schizophrenia illness. Measuring task-related oscillatory GBRs may provide a new insight in the temporal aspects of regional and inter-regional information processing. GBRs can be roughly classified in early sensory oscillations with a likely origin in sensory areas, for example the auditory cortex (Pantev et al., 1991), and in late cognitive gamma responses which are intrinsically generated (Basar et al., 2001)—presumably from continuous large-scale cortical interactions (Engel and Singer, 2001, Varela et al., 2001). In this context, gamma activity was seen as a correlate of the binding of sensory cortical areas with high-order cortical networks (Basar et al., 2001, Schutt and Basar, 1992). Previous investigations in schizophrenic patients described disturbed GBRs during auditory oddball paradigm (Haig et al., 2000, Lee et al., 2001) in response to trains of clicks with varying repetition frequency (Kwon et al., 1999), and in response to ‘Gestalt’ stimuli (Spencer et al., 2003). The results suggest a decrease in the ability of neural networks to support synchronous neural activity, particularly at 40 Hz (for a recent review see Lee et al., 2003). The deficit in auditory stimulus processing was observed in the early (Lee et al., 2001; <100 ms post-stimuli) and the late gamma activities (Haig et al., 2000; 200–400 ms post-stimuli). However, since neuroimaging studies provided evidence that antipsychotic medication may enhance inter-regional connectivity in schizophrenia (Dolan et al., 1995), the results of previous studies may comprise some therapeutic effects because the included patients were treated with antipsychotics. The present study investigated GBRs in an auditory oddball paradigm in 15 drug-free schizophrenic patients and 15 age- and gender-matched healthy controls. With regard to local and inter-regional pathophysiology in schizophrenia we tested the following hypotheses:

  • (a)

    Cortical network processing is disturbed at early stages of information processing in schizophrenic patients. We expect to find abnormal early GBRs (at around 20–100 ms) in the primary auditory cortex.

  • (b)

    Impaired network processing in patients with schizophrenia also occurs at later stages of information processing. Therefore, we also expect to find decreased late GBRs (>200 ms).

Section snippets

Subjects

The study was approved by the Ethics Committee of the Benjamin-Franklin-University Hospital of the Free University of Berlin. All subjects gave written informed consent after the procedure was fully explained to them.

Schizophrenic patients

Fifteen patients (4 females, 11 males, 28.4±11.0 years) of the Department of Psychiatry, Benjamin-Franklin-University Hospital, Berlin, who met DSM-IV criteria for schizophrenia (American Psychiatric Association, 1994) were enrolled in the investigation. The diagnosis of

Reaction times and error rates

Mean reaction times in response to target stimuli did not differ significantly between schizophrenic patients (402±148 ms) and healthy controls (379±70 ms) (F(1,28)=0.387, P=0.539). Patients made more errors (omitted button press on target stimuli) (mean 5.2±10.9%) as compared to healthy controls (mean 0.6±1.5%), but these differences were not statistically significant (F(1,28)=2.77, P=0.107).

Analysis of event-related potentials (N1-, P3-component)

N1-component: The analysis of the N1-amplitudes (100–150 ms) at the midline electrodes Fz and Cz

Discussion

This study investigated oscillatory responses in the EEG gamma-band during an auditory oddball paradigm. GBRs of 15 drug-free schizophrenic patients and 15 age- and gender-matched healthy controls were compared. As a main result, we found reduced evoked GBRs for patients in a late latency range between 220 and 350 ms for the target stimuli over right frontal scalp regions. In addition, significant correlations were observed between oscillatory GBRs and clinical parameters in schizophrenic

Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (DFG: #Wi1316/2-2). Daniel Senkowski was funded by the Deutsche Forschungsgemeinschaft (DFG: #HE3353/1) and the Max Planck Society. We express our thanks to Maren Grigutsch for software development and insightful comments and to Niko A. Busch and Moritz Hanisch for their helpful comments on the manuscript.

References (84)

  • J Gallinat et al.

    Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing

    Biol Psychiatry

    (2003)
  • I.G Gurtubay et al.

    Gamma band activity in an auditory oddball paradigm studied with the wavelet transform

    Clin Neurophysiol

    (2001)
  • A.R Haig et al.

    Peak gamma latency correlated with reaction time in a conventional oddball paradigm

    Clin Neurophysiol

    (1999)
  • A.R Haig et al.

    Gamma activity in schizophrenia: evidence of impaired network binding?

    Clin Neurophysiol

    (2000)
  • C.S Herrmann et al.

    Mechanisms of human attention: event-related potentials and oscillations

    Neurosci Biobehav Rev

    (2001)
  • C.S Herrmann et al.

    Gamma responses and ERPs in a visual classification task

    Clin Neurophysiol

    (1999)
  • C.S Herrmann et al.

    Spatial versus object feature processing in human auditory cortex: a magnetoencephalographic study

    Neurosci Lett

    (2002)
  • K.H Lee et al.

    An integration of 40 Hz gamma and phasic arousal: novelty and routinization processing in schizophrenia

    Clin Neurophysiol

    (2001)
  • C Mulert et al.

    Reduced event-related current density in the anterior cingulate cortex in schizophrenia

    NeuroImage

    (2001)
  • M.I Posner et al.

    Attentional networks

    Trends Neurosci

    (1994)
  • J Röschke et al.

    Single trial analysis of event related potentials: a comparison between schizophrenics and depressives

    Biol Psychiatry

    (1996)
  • W.T Roth et al.

    Auditory event-related potentials in schizophrenia and depression

    Psychiatry Res

    (1981)
  • S Salenius et al.

    Human cortical 40 Hz rhythm is closely related to EMG rhythmicity

    Neurosci Lett

    (1996)
  • A Schutt et al.

    The effects of acetylcholine, dopamine and noradrenaline on the visceral ganglion of Helix pomatia. II. Stimulus evoked field potentials

    Comp Biochem Physiol C

    (1992)
  • D Senkowski et al.

    Effects of task difficulty on evoked gamma activity and ERPs in a visual discrimination task

    Clin Neurophysiol

    (2002)
  • W Singer

    Neuronal synchrony: a versatile code for the definition of relations?

    Neuron

    (1999)
  • M Sugiura et al.

    Different distribution of the activated areas in the dorsal premotor cortex during visual and auditory reaction-time tasks

    NeuroImage

    (2001)
  • C Tallon-Baudry et al.

    Oscillatory gamma activity in humans and its role in object representation

    Trends Cogn Sci

    (1999)
  • N Tzourio et al.

    Functional anatomy of human auditory attention studied with PET

    NeuroImage

    (1997)
  • A von Stein et al.

    Different frequencies for different scales of cortical integration: from local gamma to long range alpha/theta synchronization

    Int J Psychophysiol

    (2000)
  • P Wagner et al.

    A replication study on P300 single trial analysis in schizophrenia: confirmation of a reduced number of ‘true positive’ P300 waves

    J Psychiatr Res

    (2000)
  • G Winterer et al.

    Cortical activation, signal-to-noise ratio and stochastic resonance during information processing in man

    Clin Neurophysiol

    (1999)
  • G Winterer et al.

    Event-related potentials and genetic risk for schizophrenia

    Biol Psychiatry

    (2001)
  • G Winterer et al.

    Functional and effective frontotemporal connectivity and genetic risk for schizophrenia

    Biol Psychiatry

    (2003)
  • J.M Alonso et al.

    Precisely correlated firing in cells of the lateral geniculate nucleus

    Nature

    (1996)
  • Diagnostic and statistical manual of mental disorders

    (1994)
  • D.S Barth et al.

    Thalamic modulation of high-frequency oscillating potentials in auditory cortex

    Nature

    (1996)
  • C Basar-Eroglu et al.

    A compound P300-40 Hz response of the cat hippocampus

    Int J Neurosci

    (1991)
  • S.L Bressler et al.

    Episodic multiregional cortical coherence at multiple frequencies during visual task performance

    Nature

    (1993)
  • M Brosch et al.

    Stimulus-related gamma oscillations in primate auditory cortex

    J Neurophysiol

    (2002)
  • M.S Buchsbaum et al.

    MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia

    NeuroReport

    (1998)
  • R.J Dolan et al.

    Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia

    Nature

    (1995)
  • Cited by (0)

    View full text