Four-second trains of transcutaneous vagus nerve stimulation increase online corticospinal excitability and pupil size in humans

Transcutaneous vagus nerve stimulation (tVNS) has emerged as a method for interrogating the role of the locus coeruleus (LC) norepinephrine system in human behavior. Tuning of excitability in the corticospinal tract is central to many cognitive and motor processes, but little is known about how the LC contributes to this tuning. In particular, no existing studies have examined the effect of tVNS on corticospinal excitability "online" during active stimulation, where the largest effects on pupil size are observed. To address this question, we delivered repeated 4-s trains of tVNS and sham stimulation and elicited motor-evoked potentials (MEPs) during stimulation trains (online) and shortly after train offset (offline). Pupil size was concurrently recorded throughout each train. We discovered that tVNS significantly increases corticospinal excitability compared with sham stimulation, but only when measured online and not offline. The excitatory effects on corticospinal excitability were greater in the latter half of tVNS trains. Pupil size was also significantly increased by tVNS compared with sham; however, the effect on pupil size peaked earlier during the tVNS trains compared with corticospinal excitability. In line with these distinct temporal profiles, changes in corticospinal excitability and pupil size were not significantly correlated, likely reflecting differences in the anatomical circuits underpinning each effect. This work demonstrates for the first time that tVNS increases corticospinal excitability at rest, but the effect only emerges when corticospinal excitability is measured online during active tVNS. Implications for basic and clinical neuroscientific research are discussed.<b>NEW & NOTEWORTHY</b> Four-second trains of transcutaneous vagus nerve stimulation (tVNS) increase corticospinal excitability and pupil size compared with sham stimulation, but only "online" during active stimulation. Corticospinal excitability and pupil size show distinct temporal profiles of change in response to 4-s trains of tVNS. tVNS-induced changes in corticospinal excitability and pupil size are not correlated, which is likely reflective of the distinct anatomical circuits underpinning each effect.