Transcutaneous auricular vagus nerve stimulation demonstrates effects on pupil responses in Parkinson's disease

Background: The locus coeruleus-norepinephrine (LC-NE) system is affected early in Parkinson's disease (PD) and is associated with various non-motor symptoms. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising non-invasive approach for improving PD symptoms, and it has been hypothesized that its action is linked to the LC-NE brainstem system; however, its neurophysiological mechanisms remain poorly understood. Objective: Given the close relationship between LC-NE activity and pupil dynamics, pupillometry may provide a non-invasive measure of LC-related activity during taVNS. This monocentric, single-blinded, sham-controlled study investigated the impact of taVNS on pupillary response as an indicator of taVNS effects at the level of the brainstem. Methods: Twenty-one patients with PD and 18 age-matched healthy controls were included. Real and sham stimulation were applied in a randomized cross-over design, and pupil size was continuously recorded. A local-global auditory processing task, which elicits arousal-related responses to auditory irregularities, was incorporated as a control condition to evaluate pupil responsiveness associated with LC-NE system activity. Results: Real taVNS elicited greater pupil dilation than sham stimulation, with a significant effect emerging 2710--3640 ms after stimulation onset in patients with PD. In contrast, no significant difference was found between real and sham stimulation in healthy controls. The local-global auditory processing task elicited larger pupil responses to deviant than non-deviant stimuli in both groups, indicating intact LC-NE reactivity. Conclusion: TaVNS elicited a significant pupillary response in individuals with PD but not in healthy older adults, providing evidence of physiological responsiveness to taVNS in PD.