Investigating the effects of transcutaneous vagus nerve stimulation on motor cortex excitability and inhibition through paired-pulse transcranial magnetic stimulation

Transcutaneous Vagus Nerve stimulation (tVNS) has been proposed as a treatment for refining GABAergic transmission. While the effects of tVNS on behavioral performance in inhibitory control tasks have been already demonstrated, neurophysiological studies investigating its effects on GABA-mediated inhibition in the motor cortex provided contrasting findings. Concurrently, the influence of participants' sex and state conditions remains unexplored. Here we applied single- and paired-pulse TMS to the right or left primary motor cortex in two groups of participants. We measured corticospinal excitability (CSE), short and long intracortical inhibition (SICI and LICI), cortical silent period (cSP) and intracortical facilitation (ICF) indexes. These measures were taken, in a within-subject design, at a baseline session before tVNS and after delivering active or sham tVNS in the Cymba conchae of the left ear. To exploit state-dependent effects and assess the role of tVNS in motor learning, tVNS was applied during the execution of a computerized visuomotor task. In the left TMS group, we observed that the visuomotor performance improved across task blocks during active tVNS only, regardless of participant's sex. Interestingly, in both groups, we found a specific increase of SICI, a proxy of GABAa activity, after active versus sham-tVNS and baseline evaluations, which was specifically limited to female participants. No effects on CSE, ICF or GABAb-mediated intracortical inhibition indexes were observed. The results show specific effects of tVNS on motor learning and GABAa-mediated motor inhibition, providing supportive evidence for the application of tVNS as a coadjuvant treatment for disorders with altered inhibition mechanisms.