Phasic, Event-Related Transcutaneous Auricular Vagus Nerve Stimulation Modifies Behavioral, Pupillary, and Low-Frequency Oscillatory Power Responses

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased frontal-midline theta and alpha power during the EST, whereas occipital alpha power was reduced during both the EST and PLRT. Our findings provide evidence that phasic taVNS systematically modulates behavioral, pupillary, and electrophysiological parameters of LC-NA activity during cognitive processing. Moreover, we demonstrate for the first time that the pupillary light reflex can be used as a simple and effective proxy of taVNS efficacy. These findings have important implications for the development of noninvasive neuromodulation interventions for various cognitive and clinical applications. SIGNIFICANCE STATEMENT taVNS has gained increasing attention as a noninvasive neuromodulation technique and is widely used in clinical and nonclinical research. Nevertheless, the exact mechanism of action of taVNS is not yet fully understood. By assessing physiology and behavior in a response conflict task in healthy humans, we demonstrate the first successful application of a phasic, noninvasive vagus nerve stimulation to improve cognitive control and to systematically modulate pupillary and electrophysiological markers of the noradrenergic system. Understanding the mechanisms of action of taVNS could optimize future clinical applications and lead to better treatments for mental disorders associated with noradrenergic dysfunction. In addition, we present a new taVNS-sensitive pupillary measure representing an easy-to-use biomarker for future taVNS studies.