Invited reviewGamma synchrony: Towards a translational biomarker for the treatment-resistant symptoms of 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.
References (217)
- et al.
Gamma-band electroencephalographic oscillations in a patient with somatic hallucinations
Lancet
(1998) - et al.
Neuregulin 1-erbB4 pathway in schizophrenia: from genes to an interactome
Brain Res. Bull.
(2010) - et al.
Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory
Schizophr. Res.
(2010) - et al.
Gamma, alpha, delta, and theta oscillations govern cognitive processes
Int. J. Psychophysiol.
(2001) - et al.
Working memory related gamma oscillations in schizophrenia patients
Int. J. Psychophysiol.
(2007) - et al.
Are oscillatory brain responses generally reduced in schizophrenia during long sustained attentional processing?
Int. J. Psychophysiol.
(2009) - et al.
Early cognitive and language skills are linked to resting frontal gamma power across the first 3 years
Behav. Brain Res.
(2008) - et al.
Response to the first stimulus determines reduced auditory evoked response suppression in schizophrenia: single trials analysis using MEG
Clin. Neurophysiol.
(2001) - et al.
Event-related potential abnormalities in schizophrenia: a failure to “gate in” salient information?
Schizophr. Res.
(2009) - et al.
Sensory gating revisited: relation between brain oscillations and auditory evoked potentials in schizophrenia
Schizophr. Res.
(2008)