A systematic review of 15 preclinical and 3 human studies found that NMDA receptor antagonists reduce evoked gamma-band power and intertrial phase coherence in auditory processing, while sometimes increasing baseline gamma-band activity. These changes partially match the reductions in gamma-band spectral power and intertrial phase coherence observed in 37 studies of schizophrenia patients and 9 studies of early-stage psychosis. However, baseline gamma-band findings were inconsistent across studies, and a publication bias was noted in the schizophrenia patient literature. The results support the idea that NMDA receptor hypofunction contributes to altered excitation/inhibition balance and auditory gamma-band deficits in schizophrenia.
Ketamine, an NMDA receptor antagonist given at sub-anesthetic doses, flattens the aperiodic slope of brain activity and increases gamma-band power (30–90 Hz), especially in prefrontal and central regions. These effects correlate with gene expression of parvalbumin and GluN2D. A computational model of cortical layer 2/3 shows that reducing NMDA receptor activity in parvalbumin or somatostatin interneurons boosts pyramidal neuron firing, reproducing the gamma power increase but not the aperiodic slope change. This suggests parvalbumin and somatostatin interneurons drive the gamma power rise, while the aperiodic component involves other mechanisms, challenging current excitation/inhibition balance models.