Abstract
Neuronal activity in the brain reflects an excitation–inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. Here, we tested the effects of a single oral dose of two anti-glutamatergic drugs (dextromethorphan, an NMDA receptor antagonist; perampanel, an AMPA receptor antagonist) and an L-type voltage-gated calcium channel blocker (nimodipine) on transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) potentials (TEPs) and TMS-induced oscillations (TIOs) in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled crossover design. Single-pulse TMS was delivered to the hand area of left primary motor cortex. Dextromethorphan increased the amplitude of the N45 TEP, while it had no effect on TIOs. Perampanel reduced the amplitude of the P60 TEP in the non-stimulated hemisphere, and increased TIOs in the beta-frequency band in the stimulated sensorimotor cortex, and in the alpha-frequency band in midline parietal channels. Nimodipine and placebo had no effect on TEPs and TIOs. The TEP results extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA receptor-mediated glutamatergic excitation. In contrast, AMPA receptor-mediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations. This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation–inhibition balance.
Highlights
Neuronal activity in the brain reflects an excitation–inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders
Drugs were well tolerated by all subjects, apart from slight nausea and/or dizziness reported after perampanel and dextromethorphan intake
Post hoc paired t-tests demonstrated an resting motor threshold (RMT) increase after perampanel and nimodipine (1.04 ± 0.04; t15 = 2.91, p = 0.007), but not dextromethorphan (0.99 ± 0.07, t15 = 0.94, p = 0.36), compared with the non-significant RMT change under placebo of 0.97 ± 0.07
Summary
Neuronal activity in the brain reflects an excitation–inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. AMPA receptormediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation–inhibition balance. Time–frequency decomposition reveals TMS-induced oscillations (TIOs) which, in contrast to TEPs, display responses not time-locked to the TMS p ulse[9]. Their typical profile following M1 stimulation is characterized by an increase in the 8–30 Hz range in the first 200 ms, followed by alpha and beta desynchronization in the time window from 200 to 400 ms[10], and a subsequent late beta rebound after 400 ms[11]. The pathophysiology of many neurological and psychiatric conditions is linked to a dysfunction in the glutamatergic system, such as schizophrenia19, epilepsy[20] or amyotrophic lateral s clerosis[21]
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