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

Abstract 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 reliably reflects pharmacological 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.