TMS as a Tool for the Evaluation of Neuromodulatory Effects of Transcutaneous Vagus Nerve Stimulation

In the past two decades, vagus nerve stimulation (VNS)has become a valuable treatment option for patients with refractory epilepsy. However, VNS requires a surgical procedure associated with potential side effects. Therefore, the development of non-invasive devices that selectively target the vagus nerve fibers with a low risk profile has gained interest. Transcutaneous auricular VNS (tVNS) is such a non-invasive neurostimulation modality that targets the cutaneous receptive field of the auricular branch of the vagus nerve located in the outer ear. Up to date, tVNS has been investigated as a potential treatment for epilepsy with inconsistent results. The goal of this study is to investigate the effect of tVNS on cortical excitability. This will provide important insight into the underlying effects of this technique on brain neurophysiology. Cortical excitability will be investigated by combining transcranial magnetic stimulation with electromyography (TMS-EMG) and electroencephalography (TMS-EEG), evaluating changes in motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs).

In this prospective, single-blind, cross-over study, we will include 15 healthy male participants. They will undergo a TMS safety screening (TSS) questionnaire and clinical neurological examination before inclusion. Each participant will complete 2 sessions at least one week apart, one with active tVNS and one with sham tVNS.

The intervention is tVNS by means of the Nemos® device which stimulates the cymba conchae at the outer ear. Stimulation parameters are set to a frequency of 25 Hz, a pulsewidth of 250 µs, 7 s ON, 18 s OFF. The output current is ramped up until the user feels a tingling sensation at the stimulation site, but should remain subthreshold to painful stimulation. Stimulation is delivered during 60 min.Sham stimulation is achieved by placing the electrode on the earlobe instead of the cymba conchae.

Before and after the intervention 120 single TMS pulses, 120 paired pulses with an interstimulus interval of 3ms and 120 paired pulses with an interstimulus interval of 100ms will be delivered over the right motor hotspot. MEPs will be measured at the left first dorsal interosseus muscle. TEPs will be measured using a 64-channel TMS-compatible electrode cap. MEPS and TEPS will be preprocessed offline in Matlab. TEP and MEP morphology ( amplitude and latency) will be evaluated before and after the intervention to investigate changes in cortical excitability.