Elsevier

Neuropharmacology

Volume 62, Issue 3, March 2012, Pages 1504-1518
Neuropharmacology

Invited review
Gamma synchrony: Towards a translational biomarker for the treatment-resistant symptoms of schizophrenia

https://doi.org/10.1016/j.neuropharm.2011.02.007Get rights and content

Abstract

The lack of efficacy for antipsychotics with respect to negative symptoms and cognitive deficits is a significant obstacle for the treatment of schizophrenia. Developing new drugs to target these symptoms requires appropriate neural biomarkers that can be investigated in model organisms, be used to track treatment response, and provide insight into pathophysiological disease mechanisms. A growing body of evidence indicates that neural oscillations in the gamma frequency range (30–80 Hz) are disturbed in schizophrenia. Gamma synchrony has been shown to mediate a host of sensory and cognitive functions, including perceptual encoding, selective attention, salience, and working memory – neurocognitive processes that are dysfunctional in schizophrenia and largely refractory to treatment. This review summarizes the current state of clinical literature with respect to gamma-band responses (GBRs) in schizophrenia, focusing on resting and auditory paradigms. Next, preclinical studies of schizophrenia that have investigated gamma-band activity are reviewed to gain insight into neural mechanisms associated with these deficits. We conclude that abnormalities in gamma synchrony are ubiquitous in schizophrenia and likely reflect an elevation in baseline cortical gamma synchrony (‘noise’) coupled with reduced stimulus-evoked GBRs (‘signal’). Such a model likely reflects hippocampal and cortical dysfunction, as well as reduced glutamatergic signaling with downstream GABAergic deficits, but is probably less influenced by dopaminergic abnormalities implicated in schizophrenia. Finally, we propose that analogous signal-to-noise deficits in the flow of cortical information in preclinical models are useful targets for the development of new drugs that target the treatment-resistant symptoms of schizophrenia.

This article is part of a Special Issue entitled ‘Schizophrenia’.

Highlights

► Gamma-band responses (GBRs) are essential for cortical information processing. ► GBRs are widely disrupted in schizophrenia, across paradigms and brain regions. ► Gamma deficits have been linked to treatment-resistant disease symptoms. ► Analogous abnormalities have been reported in preclinical disease models. ► Abnormal gamma signal-to-noise represents a biomarker for drug development

Introduction

Schizophrenia is a debilitating neuropsychiatric illness with a prevalence of 1–2%. Core impairments include positive symptoms (hallucinations, delusions), negative symptoms (flat affect, impoverished speech, social deficits, anhedonia, avolition), and cognitive deficits (attention, working memory, executive function). Additionally, there are significant abnormalities in sensory and perceptual processing. Numerous antipsychotic medications are available and are characterized by a strong correlation between dose and dopamine D2 receptor affinity. This led to the “dopamine hypothesis,” which attributes disease pathogenesis to excess mesolimbic dopamine signaling. Whereas these drugs are effective in treating positive symptoms, they have little efficacy for negative and cognitive symptoms. These “treatment-resistant symptoms” are frequently associated, suggesting a potential pathophysiological link, and the severity of these deficits are the best predictors of long-term outcome (Barr et al., 2010, Green, 1996, Harvey et al., 1998, Milev et al., 2005, Park et al., 1999, Siegel et al., 2006).

Developing new therapies to target treatment-resistant symptoms requires identification of neural endophenotypes associated with these deficits (Braff and Light, 2005). Emerging evidence from EEG/MEG studies indicates that abnormal gamma range (30–80 Hz) synchrony may be such a biomarker, reflecting core pathophysiological features of schizophrenia including cognitive and perceptual abnormalities. Gamma oscillatory activity is thought to be a fundamental mechanism that integrates neural networks within and across brain structures, facilitating coherent sensory registration. In schizophrenia, gamma abnormalities have been reported in a variety of contexts, including in sensory-driven, cognitive, and resting-state paradigms. As reviewed below, these deficits are present at first-episode psychosis (Symond et al., 2005), in unmedicated patients (Gallinat et al., 2004), and, to a lesser degree, in unaffected relatives (Leicht et al., 2010a), suggesting that abnormal gamma synchrony is a heritable feature of schizophrenia. Gamma-band responses (GBRs) have been associated with symptom scales and cognitive performance, indicating that these measures are likely related to disease pathophysiology. Finally, abnormal GBRs have been reported in preclinical disease models, providing potential targets for treatment development.

Section snippets

Overview

Information processing is achieved in part by the coordinated firing of distinct neural populations (Buzsáki, 2006). Such synchrony is thought to be an emergent property of neural networks, generated by the temporal coordination between synaptic transmission and firing of individual neuronal populations. Hans Berger first described a dominant oscillation of ∼10 Hz, which he termed alpha (Berger, 1929). Berger and others coined terms still used today to designate brain activity within specific

Gamma oscillations in clinical studies of schizophrenia

This section reviews clinical evidence for gamma abnormalities in schizophrenia, focusing on the experimental paradigms that are most directly translatable to model organisms – resting, passive sensory, and a few cognitive paradigms.

Gamma oscillations in preclinical studies of schizophrenia

As in humans, gamma activity has been associated with a wide range of cognitive and sensory processes across species. For example, cats (Gray et al., 1989, Lakatos et al., 2004), rats (Sukov and Barth, 2001) and mice (Ehrlichman et al., 2009, Lazarewicz et al., 2010, Nase et al., 2003) show a peak in phase-locked gamma activity (∼40 Hz) within the first 100 ms of auditory or visual stimulation, following a time course similar to that observed in humans (Pantev et al., 1991, Shibata et al., 1999).

Synthesis: a model of gamma-band activity

Based on a comprehensive review of the literature, we suggest that there is reduced gamma signal-to-noise during cortical information processing in schizophrenia, a hypothesis previously suggested (Flynn et al., 2008, Kissler et al., 2000, Krishnan et al., 2005, Tseng et al., 2008, Williams et al., 2009b, Winterer et al., 2000, Winterer et al., 2004). There is strong evidence that pre-stimulus baseline gamma activity is elevated and that task-driven ‘evoked’ gamma-band responses are reduced in

Acknowledgments

The authors would like to thank Greg Carlson, Chang-Gyu Hahn, and Bruce Turetsky for helpful discussions regarding the content of this manuscript.

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