Effects of pharmacological modulation of cortical excitability on resting-state EEG PAC in humans

Electroencephalography (EEG) signal is driven by oscillations arising from the synchronized activity of cortical neuronal populations. Phase-amplitude coupling (PAC) refers to the interaction whereby the amplitude of higher-frequency oscillations is systematically modulated by the phase of slower rhythms. It has been suggested that the excitation/inhibition (E/I) balance, which is often disrupted in neuropsychiatric and neurodegenerative disorders, plays a critical role in shaping PAC, although direct evidence in humans remains limited. In this study, we investigated the effects of pharmacologically modulated E/I balance on PAC using resting-state EEG (rs-EEG) data. Specifically, we analyzed the impact of anti-glutamatergic drugs, dextromethorphan (NMDA receptor antagonist) and perampanel (AMPA receptor antagonist), as well as nimodipine (L-type voltage-gated calcium channel blocker) on PAC in a double blind, placebo-controlled experiment. Analysis revealed a significant decrease in PAC following administration of dextromethorphan and perampanel, while nimodipine and placebo showed no effects. By showing that PAC is sensitive to pharmacological modulation consistent with shifts in cortical E/I balance, this study confirms its physiological relevance and supports its use as a biomarker of excitability disturbances and cortical dysfunction across neurological and psychiatric disorders.