Vagal nerve stimulation alters task-evoked pupillary responses in older adults but not younger adults in a single-blind sham-controlled crossover trial

Abstract

Introduction: The locus coeruleus (LC) undergoes age-related changes and is involved in Alzheimer\'s disease pathogenesis. Vagal nerve stimulation (VNS) may modulate LC activity and could be used therapeutically, but age-related differences in VNS responses remain unexplored. Methods: We used a single-blind, sham-controlled, crossover design in 41 participants (21 younger, 20 older adults). Participants completed a visual oddball task with pupillometry during transcutaneous auricular VNS (verum: cymba concha; sham: earlobe) with ~30-minute washout between conditions. Results: Older adults showed smaller baseline pupil diameter but larger normalized task-evoked responses than younger adults a priori. VNS produced age-specific effects: older adults demonstrated increased tonic pupil size throughout stimulation and reduced oddball-evoked responses, with stronger effects with more current. Younger adults showed no consistent VNS effects. Discussion: VNS affects LC-related physiological measures differently across age groups, with older adults showing more robust responses. These age-specific effects may reflect different baseline LC activity states.