Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing
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)
- et al.
Gamma-band responses in the brain: a short review of psychophysiological correlates and functional significance
Int J Psychophysiol
(1996) - et al.
Gamma, alpha, delta, and theta oscillations govern cognitive processes
Int J Psychophysiol
(2001) - et al.
Enhancement of auditory sensory gating and stimulus-bound gamma band (40 Hz) oscillations in heavy tobacco smokers
Neurosci Lett
(2002) - et al.
Temporal binding and the neural correlates of sensory awareness
Trends Cogn Sci
(2001) - et al.
P300 in schizophrenia: confirmation and statistical validation of temporal region deficit in P300 topography
Biol Psychiatry
(1988) - et al.
P300 topographic asymmetries are present in unmedicated schizophrenics
Electroencephalogr Clin Neurophysiol
(1993) - et al.
Time course of human 40 Hz EEG activity accompanying P3 responses in an auditory oddball paradigm
Neurosci Lett
(1997) - et al.
Abnormal cingulate modulation of fronto-temporal connectivity in schizophrenia
NeuroImage
(1999) - et al.
Reduced communication between frontal and temporal lobes during talking in schizophrenia
Biol Psychiatry
(2002) - et al.
Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia
NeuroImage
(2002)