Neural network dynamics underlying gamma synchronization deficits in schizophrenia

Gamma band (40-Hz) activity is associated with many sensory and cognitive functions, and is critical for cortico-cortical transmission and the integration of information across neural networks. The capacity to support gamma band activity can be indexed by the auditory steady-state response (ASSR); schizophrenia patients have selectively reduced synchrony to 40-Hz stimulation. While 40-Hz ASSR is a translatable electroencephalographic biomarker with emerging utility for therapeutic development for neuropsychiatric disorders, the spatiotemporal dynamics underlying the ASSR have not yet been characterized. In this study, a novel Granger causality analysis was applied to assess the propagation of gamma oscillations in response to 40-Hz steady-state stimulation across cortical sources in schizophrenia patients (n=426) and healthy comparison subjects (n=293). Results revealed distinct, hierarchically sequenced temporal and spatial response dynamics underlying gamma synchronization deficits in patients. During the response onset interval, patients exhibited abnormal connectivity of superior temporal and frontal gyri, followed by decreased information flow from superior temporal to middle cingulate gyrus. In the later (300-500 ms) interval of the ASSR response, patients showed significantly increased connectivity from superior temporal to middle frontal gyrus followed by broad failures to engage multiple prefrontal brain regions. In conclusion, these findings reveal the rapid disorganization of neural circuit functioning in response to simple gamma-frequency stimulation in schizophrenia patients. Deficits in the generation and maintenance of gamma-band oscillations in schizophrenia reflect a fundamental connectivity abnormality across a distributed network of temporo-frontal networks.