Auricular Vagus Neuromodulation - A Systematic Review on Quality of Evidence and Clinical Effects

Background: The auricular branch of the vagus runs superficial to the surface of the skin, making it a favorable target for non-invasive techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. Unfortunately, often with conflicting results. Methods: To investigate the conflicting results, we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) using the established Cochrane Risk of Bias tool as a framework. The Risk of Bias tool is intended to identify deviations from an ideal RCT that may cause the effect of an intervention to be overestimated or underestimated. As is common for early-stage studies, the majority of aVNS studies were assessed as having 9some9 or 9high9 risk of bias, which makes interpreting their results in a broader context problematic. Results: The reported trial outcomes were qualitatively synthesized across studies. There is evidence of a modest decrease in HR during higher stimulation current amplitudes. Findings on heart rate variability (HRV) conflicted between studies and were hindered by trial design including inappropriate washout periods and multiple methods used to quantify HRV. There is early-stage evidence to suggest aVNS may reduce circulating levels or endotoxin induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs on implantable VNS, albeit with concerns over quality of blinding. aVNS showed preliminary evidence of ameliorating pathological pain but not induced pain. Discussion: Drawing on the fundamentals of neuromodulation, we establish the need for direct measures of neural target engagement in aVNS. Firstly, for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target engagement. Secondly, direct measures of target engagement, along with consistent evaluation of the double blind, must be used to improve the design of controls in the long term - a major source of concern identified in the Cochrane analysis. Lastly, we list common improvements for the reporting of results that can be addressed in the short term. Conclusion: The need for direct measures of neural target engagement and consistent evaluation of the double blind is applicable to other paresthesia-inducing neuromodulation therapies and their control designs. We intend for this review to contribute to the successful translation of neuromodulation therapies such as aVNS.