Non-invasive vagus nerve stimulation with the gammaCore® in healthy subjects: is there electrophysiological evidence for activation of vagal afferents ?

Abstract:
Background
Non-invasive vagus nerve stimulation (nVNS) with the gammaCore® improves migraine and cluster headache. Animal experiments suggest that nVNS acts via stimulation of vagal afferents, but proof in humans is lacking. Vagal somatosensory evoked potentials (vSEP) are identified after invasive VNS or transcutaneous stimulation of auricular vagal branches, but late components could be muscle artifacts.
Objective
To search in healthy volunteers for reliable vSEP during nVNS with the gammaCore®
Methods
In 12 healthy subjects (7males) evoked potentials were recorded at A1/A2 (ref Cz) and C3/C4 (ref F3/F4) during 2-minute stimulation over left/right cervical vagus nerve with the gammaCore® (25Hz, 6-24V) and during stimulation over the inner tragus with a monopolar stimulator (2Hz, 50 stimuli, mean intensity 8mA).
Results
We identified 3 reproducible peaks P1, N1, P2 in 10 patients on the side of the gammaCore® stimulation at mean latencies of 2.05ms, 5.20ms and 9.13ms. P1-N1 amplitude increased significantly (p<0.01) with increasing voltage from 0.04μV to 0.52μV (C3/C4) and from 0.13µV to 2.04μV (A1/A2) respectively at 10V and 30V. Inner tragus stimulation elicited P1, N1, P2 peaks with shorter mean latencies (2.21ms, 3.72ms, 5.71ms) and a mean P1-N1 amplitude (A1/A2) of 5.0µV. When the gammaCore® was placed over the sternocleidomastoid muscle, there were no reproducible evoked potentials.
Conclusion
Non-invasive transcutaneous stimulation of the cervical vagus nerve with the gammaCore® elicits evoked potentials similar to those found with implanted electrodes or stimulation of Arnold’s nerve in the outer ear. The gammaCore®-evoked potentials increase in amplitude with stimulation intensity and disappear when the stimulator is positioned over neck muscles, suggesting that they are not muscle artifacts. Their short latency is compatible with their generation at the level of the foramen jugulare. The therapeutic effects reported with the gammaCore® in primary headaches can thus be mediated by genuine activation of vagus nerve afferents.