The role of GABAAergic neurotransmission in the human brain probed by paired-pulse TMS-EEG

Abstract

Cortical inhibitory processes can be measured by paired-pulse transcranial magnetic stimulation (TMS). Until recently, short-interval intracortical inhibition (SICI) and longinterval intracortical inhibition (LICI) were quantified as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments consider them as a measure of GABAA and GABAB receptor-mediated neurotransmission, respectively. The effect of SICI on TMS-evoked EEG potentials (TEPs) and its pharmacological properties using combined TMS and electroencephalography (TMS-EEG) have not been systematically studied. Thus, the present study aims to investigate the physiological underpinnings of TEPs modulated by SICI, to examine its pharmacological characteristics and to compare SICI with a separate paired-pulse paradigm LICI. Sixteen healthy male subjects participated in three sessions of the pseudo-randomized, placebo-controlled, double-blinded crossover study. Paired-pulse TMS was tested over the left motor cortex and the evoked brain responses were recorded by a high-density 64-channel EEG. Neuroactive drugs acting as positive modulator at GABAA-(diazepam, 20mg) or as specific agonist at GABAB (baclofen, 50mg) receptors were applied, probing the pharmacological characteristics of SICI. We analyzed the effects of a conditioning stimulus (CS) applied 2 ms prior to a test stimulus (TS) on TEPs. Here, SICI was calculated as the difference between pairedpulse TEPs (corrected for late EEG responses evoked by the conditioning pulse) and single-pulse TEPs. Cluster-based permutation analysis showed that SICI before drugintake significantly suppressed late TEPs (N100 and P180, both p < 0.001). Whereas diazepam reduced SICI of the N100 over the non-stimulated hemisphere (p = 0.03), baclofen increased SICI of the N100 over frontal sites of both hemispheres (p = 0.007). The comparison of the effects of two paired-pulse paradigms with differing interstimulus intervals (ISI), SICI (ISI = 2 ms) and LICI (ISI = 100 ms), showed a largely similar modulation on TEPs irrespective of the interstimulus interval. These findings demonstrate for the first time that cortical inhibitory mechanisms are explained insufficiently by TMS-EMG studies testing corticospinal activity; TEPs of SICI and LICI cannot be deduced directly from MEP amplitudes. Furthermore, we demonstrated a tight interaction between GABAergic receptor subtypes controlling the balance between inhibitory and excitatory activity at the level of human cortex. The modulation by paired-pulse paradigms increases our knowledge of TMS-EEG measurements identifying functional abnormalities with altered inhibitory mechanisms.