Moving beyond belief: A narrative review of potential biomarkers for transcutaneous vagus nerve stimulation

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive neurostimulation technique that is currently being tested as a potential treatment for a myriad of neurological and psychiatric disorders. However, the working mechanisms underlying tVNS are poorly understood and it remains unclear whether stimulation activates the vagus nerve for every participant. Finding a biological marker of tVNS is imperative, as it can help guide research on clinical applications and can inform researchers on optimal stimulation sites and parameters to further optimize treatment efficacy. In this narrative review, we discuss five potential biomarkers for tVNS and review currently available evidence for these markers for both invasive and tVNS. While some of these biomarkers hold promise from a theoretical perspective, none of the potential biomarkers provide clear and definitive indications that tVNS increases the vagal activity or augments activity in the locus coeruleus-noradrenaline network. We conclude the review by providing several recommendations for how to tackle the challenges and opportunities when researching potential biomarkers for the effects of tVNS.