title: TMS-EEG signatures of GABAergic neurotransmission in the human cortex.
abstract: 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 α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) 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 α1-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.
authors.affiliation: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, 72076 Tübingen, Germany, International Max Planck Research School, 72076 Tübingen, Germany, Laboratory of Cognitive and Computational Neuroscience, Centre for Biomedical Technology, Universidad Politécnica de Madrid, 28660 Madrid, Spain, School of Psychology, University of East London, E15 4LZ London, United Kingdom, Department of Neurophysiology, Max Planck Institute for Brain Research, 60528 Frankfurt am Main, Germany, Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society, 60528 Frankfurt am Main, Germany, Functional and Restorative Neurosurgery, University Hospital Tübingen, Eberhard Karls University, 72076 Tübingen, Germany, and Department of Neurology, Goethe-University, 60528 Frankfurt am Main, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Premoli
authors.forename: Nazareth
authors.initials: N
authors.lastname: Castellanos
authors.forename: Davide
authors.initials: D
authors.lastname: Rivolta
authors.forename: Paolo
authors.initials: P
authors.lastname: Belardinelli
authors.forename: Ricardo
authors.initials: R
authors.lastname: Bajo
authors.forename: Carl
authors.initials: C
authors.lastname: Zipser
authors.forename: Svenja
authors.initials: S
authors.lastname: Espenhahn
authors.forename: Tonio
authors.initials: T
authors.lastname: Heidegger
authors.forename: Florian
authors.initials: F
authors.lastname: Müller-Dahlhaus
authors.forename: Ulf
authors.initials: U
authors.lastname: Ziemann
mesh_terms: D000328:Adult; D001931:Brain Mapping; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004569:Electroencephalography; D004576:Electromyography; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D018682:GABA Agents / Q000494:pharmacology; D006801:Humans; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D050781:Transcranial Magnetic Stimulation; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018682:GABA Agents; D005680:gamma-Aminobutyric Acid
keywords: GABA; electroencephalography; human cortex; inhibition; pharmaco-TMS-EEG; transcranial magnetic stimulation
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