Using TMS-EEG to study the intricate interplay between GABAergic inhibition and glutamatergic excitation during reactive and proactive motor inhibition

Background Combining Transcranial magnetic stimulation (TMS) with electroencephalography (EEG) enables assess TMS-evoked potentials (TEP) and estimate γ-aminobutyric acid (GABA) and glutamatergic neurotransmission across the entire motor inhibition network. The N45 and N100 TEP peaks are associated with GABAa and GABAb signaling, respectively, whereas the N15, P30 and P60 TEPs reflect glutamatergic neurotransmission. This study applied TMS-EEG to investigate modulation of TEP components during reactive and proactive inhibition and whether individual differences in GABA and glutamate signaling predict inhibitory performance. Methods Twenty-four healthy participants completed two TMS-EEG sessions, targeting either the left primary motor cortex (M1) or the pre-supplementary motor area (preSMA) at rest and during a stop-signal task. We compared TEP peak amplitudes across TMS (active/sham) and Trial Type (stop/go trials) and assessed their relationship with task performance. Results Participants with a higher N45 amplitude at rest over M1, reflecting increased GABAa signaling, demonstrated a faster stop-signal reaction time. TMS during motor inhibition revealed higher N15 amplitudes over preSMA, reflecting increased glutamatergic neurotransmission, for successful stops versus go trials. Similarly, N15 was higher for uncertain than certain go trials suggesting that an early excitatory signal from preSMA is crucial for both reactive and proactive motor inhibition. Conclusion Higher GABAa inhibitory signaling in M1 at rest is linked to faster reactive inhibition. The preSMA likely plays a key role in both reactive and proactive motor inhibition. Here we provide novel direct empirical insights into the underlying neurophysiological mechanisms, highlighting a functional relevance of early glutamatergic excitatory signals for successful motor inhibition.