Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve Locus Coeruleus (LC) stimulation via the nucleus of the solitary tract (NTS) that receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline (NE) levels, whereas LC lesions suppress VNS therapeutic efficacy. Non-invasive transcutaneous VNS (tVNS) employs electrical stimulation targeting the auricular branch of the vagus nerve at the Cymba Conchae of the ear, but it remains unclear to what extent tVNS mimics VNS. Here, we investigated the short-term effects of tVNS in healthy human male volunteers (n=24) using high-density EEG and pupillometry during visual fixation at rest, comparing short (3.4s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4-5s after trial onset) that was significantly higher than following sham stimulation. We further quantified how tVNS modulates idle occipital alpha (8-13Hz) activity, identified in each participant using parallel factor analysis. We found that tVNS attenuates alpha oscillations to a greater extent than does sham stimulation. Thus, tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, supporting the hypothesis that it elevates noradrenaline and acetylcholine signaling and mimics invasive VNS.
bioRxiv Subject Collection: Neuroscience