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 (Ͻ50 ms after TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ϳ100 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 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 ␣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.

Investigating TMS–EEG Indices of Long-Interval Intracortical Inhibition at Different Interstimulus Intervals

“…While the mechanisms underlying the generation of each TEP peak are not completely understood, contributions from independent cortical mechanisms are likely [24,25,42]. For P30, several lines of evidence implicate a role of cortical excitatory processes associated with the TMS pulse, including observations that P30 amplitude correlates with MEP amplitude [43], that P30 and the MEP both demonstrate sigmoidal recruitment curves [32,44], that GABAergic potentiation does not modulate P30 amplitude [42] and that LICI of P30 correlates with LICI of the MEP [24].…”

“…For P30, several lines of evidence implicate a role of cortical excitatory processes associated with the TMS pulse, including observations that P30 amplitude correlates with MEP amplitude [43], that P30 and the MEP both demonstrate sigmoidal recruitment curves [32,44], that GABAergic potentiation does not modulate P30 amplitude [42] and that LICI of P30 correlates with LICI of the MEP [24]. Subsequently, LICI of P30 has been interpreted as a reflection of the cortical inhibitory processes underlying the reductions in MEP amplitude associated with LICI [24], which are thought to include activation of post-synaptic GABA B receptors [11,38].…”

“…While the mechanisms contributing to the P30 and N40 are poorly understood, strong evidence suggests that the N100 reflects activation of cortical inhibitory processes [for review, see; 21], most likely involving activation of the GABA B receptor [42]. As a reduction in N100 amplitude should therefore represent reduced inhibitory tone, the decreased N100 observed following LICI is counterintuitive.…”

Characterization of GABAB-receptor mediated neurotransmission in the human cortex by paired-pulse TMS–EEG

“…By combining high-density TMS-EEG with pharmacology we were recently able to demonstrate (Premoli et al, 2014) that specific components of (single-pulse) TEPs, i.e. the negative potentials at around 45 (N45) and 100 (N100) milliseconds post stimulus (Lioumis et al, 2009;Rogasch et al, 2013), can be linked to GABAAR-and GABABR-mediated neurotransmission, respectively.…”

Assessment and modulation of cortical inhibition using transcranial magnetic stimulation

“…Furthermore, because of possible 'filtering' of cortico-spinal synapses and the motor endplate, a direct correlation between MEP amplitude and cortical excitability remains controversial. Accordingly, efforts are currently focusing on a more direct analysis of cortical inhibition, which is independent of the stimulated area of the cortex, using TMS-evoked electroencephalographic (EEG) potentials (Rogasch and Fitzgerald, 2013;Premoli et al, 2014). This attempt is supported by other techniques, e.g.…”