Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Author: Yap JYY1, Keatch C2, Lambert E3,4, Woods W3, Stoddart PR1,2, Kameneva T2,4,5 Affiliation: <sup>1</sup>ARC Training Centre in Biodevices, Swinburne University of Technology, Hawthorn, VIC, Australia. <sup>2</sup>Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, VIC, Australia. <sup>3</sup>School of Health Sciences, Swinburne University of Technology, Hawthorn, VIC, Australia. <sup>4</sup>Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC, Australia. <sup>5</sup>Department of Biomedical Engineering, The University of Melbourne, Parkville, VIC, Australia. Conference/Journal: Front Neurosci. Date published: 2020 Apr 28 Other: Volume ID: 14 , Pages: 284 , Special Notes: doi: 10.3389/fnins.2020.00284. eCollection 2020. , Word Count: 308 Several studies have illustrated that transcutaneous vagus nerve stimulation (tVNS) can elicit therapeutic effects that are similar to those produced by its invasive counterpart, vagus nerve stimulation (VNS). VNS is an FDA-approved therapy for the treatment of both depression and epilepsy, but it is limited to the management of more severe, intervention-resistant cases as a second or third-line treatment option due to perioperative risks involved with device implantation. In contrast, tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. Although it has been shown that tVNS elicits hypo- and hyperactivation in various regions of the brain associated with anxiety and mood regulation, the mechanism of action and influence of stimulation parameters on clinical outcomes remains predominantly hypothetical. Suppositions are largely based on correlations between the neurobiology of the vagus nerve and its effects on neural activity. However, tVNS has also been investigated for several other disorders, including tinnitus, migraine and pain, by targeting the vagus nerve at sites in both the ear and the neck. As most of the described methods differ in the parameters and protocols applied, there is currently no firm evidence on the optimal location for tVNS or the stimulation parameters that provide the greatest therapeutic effects for a specific condition. This review presents the current status of tVNS with a focus on stimulation parameters, stimulation sites, and available devices. For tVNS to reach its full potential as a non-invasive and clinically relevant therapy, it is imperative that systematic studies be undertaken to reveal the mechanism of action and optimal stimulation modalities. Copyright © 2020 Yap, Keatch, Lambert, Woods, Stoddart and Kameneva. KEYWORDS: neuromodulation; neurostimulation; transcutaneous; vagus nerve; vagus nerve stimulation PMID: 32410932 PMCID: PMC7199464 DOI: 10.3389/fnins.2020.00284