Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: An electrophysiological study in healthy volunteers

Abstract

Background Benefits of cervical non-invasive vagus nerve stimulation (nVNS) devices have been shown in episodic cluster headache and preliminarily suggested in migraine, but direct evidence of vagus nerve activation using such devices is lacking. Vagal somatosensory evoked potentials (vSEPs) associated with vagal afferent activation have been reported for invasive vagus nerve stimulation (iVNS) and non-invasive auricular vagal stimulation. Here, we aimed to show and characterise vSEPs for cervical nVNS. Methods vSEPs were recorded for 12 healthy volunteers who received nVNS over the cervical vagus nerve, bipolar electrode/DS7A stimulation over the inner tragus, and nVNS over the sternocleidomastoid (SCM) muscle. We measured peak-to-peak amplitudes (P1-N1), wave latencies, and N1 area under the curve. Results P1-N1 vSEPs were observed for cervical nVNS (11/12) and auricular stimulation (9/12), with latencies similar to those described previously, whereas SCM stimulation revealed only a muscle artefact with a much longer latency. A dose-response analysis showed that cervical nVNS elicited a clear vSEP response in more than 80% of the participants using an intensity of 15 V. Conclusion Cervical nVNS can activate vagal afferent fibres, as evidenced by the recording of far-field vSEPs similar to those seen with iVNS and non-invasive auricular stimulation.

Keywords: Neuromodulation; VNS; dose-response analysis; evoked potential; headache.

Figure 1.

Stimulation conditions (a) at M2-Cz after nVNS over the right paramedian cervical region (first active condition); (b) at M2-Cz after bipolar stimulation over the right inner tragus (second active condition); (c) at M2-Cz after nVNS over the right SCM muscle (control condition). nVNS: non-invasive vagus nerve stimulation; SCM: sternocleidomastoid. Stimulations were performed bilaterally, with recordings performed at different electrode positions according to the side of stimulation, but only right stimulation and M2-Cz are depicted in this figure.

Figure 2.

Traces in M1-Cz for (a) nVNS over the left paramedian cervical region (first active condition; top) and bipolar stimulation over the left inner tragus (second active condition; bottom) up to 15 ms in a single participant; (b) nVNS over the left paramedian cervical region (first active condition; top) and nVNS over the left SCM muscle (control condition; bottom) up to 35 ms in a single participant; and (c) nVNS over the left paramedian cervical region (first active condition) up to 35 ms in all 12 participants (blue lines) and average (black line). nVNS: non-invasive vagus nerve stimulation; SCM: sternocleidomastoid.

Figure 3.

(a) Proportion of participants who had an identifiable response (at least unilaterally) using each preprogramed stimulation intensity (chi-square analysis considering all intensities); (b) logarithmic dose-response curve. AUC: area under the curve. *p < 0.05; **p < 0.01. A responder was defined as a participant who demonstrated at least one measurable electrophysiological signal (after left or right stimulation at any intensity) that was easily distinguishable from the baseline noise.