TMS-EEG Signatures of GABAergic Neurotransmission in the Human Cortex

Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess
human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs).
It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (�50 ms after TMS),
whereas GABA-B receptors (GABABR) play a role for later TEPs (at�100 ms after TMS). However, the physiological underpinnings of
TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects
using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine
acting as allosteric-positive modulator at �1, �2, �3, and �5 subunit-containing GABAARs) and zolpidem (a positive modulator
mainly at the�1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a
GABABRagonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude
of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem
increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the
N45 represents activity of �1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel
window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia.