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

Abstract

Background: The auricular branch of the vagus nerve runs superficially, which makes it a favorable target for non-invasive stimulation techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. These trials often report conflicting results for the same indication.Methods: Using the Cochrane Risk of Bias tool we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) to identify the factors that led to these conflicting results. The majority of aVNS studies were assessed as having “some” or “high” risk of bias, which makes it difficult to interpret their results in a broader context.Results: There is evidence of a modest decrease in heart rate during higher stimulation dosages, sometimes at above the level of sensory discomfort. Findings on heart rate variability conflict between studies and are hindered by trial design, including inappropriate washout periods, and multiple methods used to quantify heart rate variability. There is early-stage evidence to suggest aVNS may reduce circulating levels and endotoxin-induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ameliorated pathological pain but not evoked pain.Discussion: Based on results of the Cochrane analysis we list common improvements for the reporting of results, which can be implemented immediately to improve the quality of evidence. In the long term, existing data from aVNS studies and salient lessons from drug development highlight the need for direct measures of local neural target engagement. Direct measures of neural activity around the electrode will provide data for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target activation. Furthermore, direct measures of target engagement, along with consistent evaluation of blinding success, must be used to improve the design of controls—a major source of concern identified in the Cochrane analysis. The need for direct measures of neural target engagement and consistent evaluation of blinding success is applicable to the development of other paresthesia-inducing neuromodulation therapies and their control designs.

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis

“…Another goal of our study was to explore the relationship between the study characteristics and the frequency of adverse events. Because there are no guidelines for taVNS clinical trials, there is a large interstudy heterogeneity in study methodology, device type, electrode design, and stimulation parameters 17 . Stimulation parameters vary among studies, with different stimulation frequencies, pulse widths, polarities, stimulation times, and utilized pulse types 13 .…”

“…Many authors consider taVNS a safer substitute for the previous surgical device 4,[14][15][16][17] . Thus far, taVNS use has been studied in many conditions such as epilepsy, tinnitus, depression, stroke, Alzheimer's disease 18 .…”

Non-Invasive Transcutaneous Vagus Nerve Stimulation for the Treatment of Fibromyalgia Symptoms: A Study Protocol

“…However, to the best of our knowledge, the potential of non-invasive auricular and cervical vagus nerve stimulation under repeated sessions to improve fibromyalgia symptoms has not been evaluated in randomized, sham-controlled clinical studies. Auricular and cervical transcutaneous vagus nerve stimulation (tVNS), two non-invasive low-intensity electric stimulation procedures [ 32 , 33 ], have however been explored with respect to their potential to modulate the activity of this nerve in other clinical settings [ 20 , 34 , 35 , 36 , 37 ], and the effectiveness of these non-invasive methods might not differ significantly from those of invasive stimulation, while non-invasiveness provides an advantageous safety profile [ 14 , 19 , 38 , 39 , 40 ].…”

Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study

“…In fact, the pressure applied on each auricle with the needle applicator on the selected acupoints was constantly painful by itself, and then, it could yield the same subjective perception as true needles to the patients with hypoxic-ischemic encephalopathy. Moreover, undertaking the sham stimulation outside the auricular region innervated by the ABVN, such as the ear lobe, called “location sham,” was recently advised against (Rangon, 2018 ; Borges et al, 2021 ; Verma et al, 2021 ). The patients, their physicians, and nursing staff were blind about randomization because the ears were hidden by the opaque Band-Aid throughout the hospitalization.…”