Non-invasive vagus nerve stimulation (nVNS) is effective in several types of headache disorders. We sought to unravel the mechanism of how nVNS exhibits this efficacy. This study used a randomized, single-blind, sham-controlled, crossover-design, and comprised three projects with three independent cohorts of healthy participants. Project I (n=15) was explorative. Six quantitative sensory test (QST) parameters, including mechanical pain threshold (MPT), were measured over the left V1 dermatome and forearm, and compared before and after unilateral nVNS. Projects II (n=20) and III (n=21) were online pre-registered . QST parameters were compared over the left (Project II) or bilateral V1 and V3 dermatomes (Project III), respectively, in addition to the left forearm as a control. A secondary analysis of heart rate variability (HRV) using a historical control group was used to control for systemic effects of nVNS. Verum-nVNS induced trigeminal-specific modulation of pain threshold (i.e., MPT) over the left V1 in Project I, left V1 and V3 in Project II, and bilateral V1 and V3 in Project III. Data pooled from Project II and III demonstrated greater increase of MPT in the V1 vs. V3 dermatome. There were no differences associated with sham-nVNS in any projects. HRV parameters did not change after nVNS. Our results provide functional evidence of a long hypothesized functional trigemino-vagal system in humans and may explain why nVNS is effective in some headache but not in somatic pain disorders. Since unilateral nVNS modulated the trigeminal thresholds bilaterally, this effect is probably indirect through a central top-down mechanism.Copyright © 2022 International Association for the Study of Pain.
