CONTROLLING PHASIC NEUROMODULATION IN HUMANS: DRIVING PUPIL DILATION WITH RAPID, TRANSCUTANEOUS STIMULATION OF THE VAGUS NERVE

Phasic responses of brainstem arousal systems, particularly the locus coeruleus–noradrenergic (LC-NA) system, drive dilations of the pupil. In mice, rapid vagus nerve stimulation drives LC-NA responses and dilates the pupil in a duration-dependent manner. Here, we measured and characterized pupil dilations evoked by rapid, transcutaneous vagus nerve stimulation (tVNS) in humans using pulse trains of different durations.
We systematically evaluated the effects of specific tVNS on pupil dilation at “rest” in N=20 participants. Active tVNS was applied to cymba conchae of the outer left ear and sham stimulation was applied to either earlobe or scapha of the same ear, as different control sites. Pulsed electrical stimulation was delivered at 25 Hz frequency and a pulse width of 400μs. The stimulus amplitude was calibrated for each participant and site to ~80% of the individual pain threshold (active: 2.17±0.18 mA; scapha: 1.55±0.14 mA; earlobe: 2.12±0.17 mA). We systematically varied the durations of stimulation pulse trains (0.52s, 1s, 3s, 5s; 4-8 s inter-stimulus intervals).
Active tVNS dilated the pupil in a stimulation duration-dependent manner. Stimulation at both sham sites also dilated the pupil. However, for earlobe sham lasting 3s, the dilations had a smaller amplitude than dilations evoked by active tVNS of the same pulse train duration.
We conclude that tVNS of 3s is a promising approach for manipulating pupil-linked, phasic arousal. Pupil dilations during sham stimulation may reflect non-specific stimulation effects, possibly related to sensation.