Gamma Oscillations and Excitation/Inhibition Imbalance: Parallel Effects of NMDA Receptor Antagonism and Psychosis.

Abnormalities in the 40-Hz auditory steady-state response (ASSR), a measure of gamma-band brain activity, appear in schizophrenia and in animal models with reduced NMDA receptor function. This study compared 40-Hz ASSR deficits in schizophrenia patients to those induced by ketamine (an NMDA receptor antagonist) in healthy participants. Schizophrenia patients showed increased prestimulus broadband gamma power and reduced evoked power, total power, and phase-locking factor, replicating prior work, but no phase delay. Ketamine similarly increased prestimulus gamma power and reduced evoked power, total power, and phase-locking factor, while also advancing the ASSR phase. Direct comparison revealed significant differences only in phase, suggesting NMDA receptor hypofunction contributes to gamma oscillation abnormalities in schizophrenia.

Study at a glance

Abstract

Auditory steady-state response (ASSR) abnormalities in the 40-Hz (gamma band) frequency have been observed in schizophrenia and in rodent studies of NMDA receptor (NMDAR) hypofunction. However, the extent to which 40-Hz ASSR abnormalities in schizophrenia resemble deficits in 40-Hz ASSR induced by acute administration of ketamine, an NMDAR antagonist, is not yet known. To address this knowledge gap, we conducted parallel electroencephalography studies: a crossover, placebo-controlled ketamine drug challenge study with healthy participants (study 1) and a comparison of patients with schizophrenia and healthy control participants (study 2). Time-frequency analysis of the ASSR was used to calculate baseline, broadband gamma power, evoked power, total power, phase-locking factor, and phase-locking angle. Relative to healthy control participants, patients with schizophrenia exhibited increases in prestimulus broadband gamma power and reductions in 40-Hz ASSR evoked power, total power, and phase-locking factor, replicating previous studies. However, we failed to replicate previous findings of 40-Hz ASSR phase delay in schizophrenia. Relative to placebo, ketamine increased prestimulus broadband gamma power; reduced 40-Hz ASSR evoked power, total power, and phase-locking factor; and advanced the phase of the 40-Hz ASSR. Normalized by their respective control groups/conditions, direct comparison of these measures between schizophrenia and ketamine data only revealed significant differences in phase, supporting the role of NMDAR hypofunction in mediating gamma oscillation abnormalities in schizophrenia.