Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice

Yap, Jonathan Y. Y.; Keatch, Charlotte; Lambert, Elisabeth; Woods, Will; Stoddart, Paul R.; Kameneva, Tatiana

doi:10.3389/fnins.2020.00284

Cited by 238 publications

(245 citation statements)

References 127 publications

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“…Despite its extensive use (Yap et al, 2020) and advantages, the lower sensitivity at the earlobe requires higher currents to produce a comparable subjective intensity. Future studies could apply additional control conditions (e.g.…”

Section: Discussionmentioning

confidence: 99%

Transcutaneous vagus nerve stimulation in humans induces pupil dilation and attenuates alpha oscillations

Sharon

Fahoum

Nir

2020

Preprint

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Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve Locus Coeruleus (LC) stimulation via the nucleus of the solitary tract (NTS) that receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline (NE) levels, whereas LC lesions suppress VNS therapeutic efficacy. Non-invasive transcutaneous VNS (tVNS) employs electrical stimulation targeting the auricular branch of the vagus nerve at the Cymba Conchae of the ear, but it remains unclear to what extent tVNS mimics VNS. Here, we investigated the short-term effects of tVNS in healthy human male volunteers (n=24) using high-density EEG and pupillometry during visual fixation at rest, comparing short (3.4s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4-5s after trial onset) that was significantly higher than following sham stimulation. We further quantified how tVNS modulates idle occipital alpha (8-13Hz) activity, identified in each participant using parallel factor analysis. We found that tVNS attenuates alpha oscillations to a greater extent than does sham stimulation. Thus, tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, supporting the hypothesis that it elevates noradrenaline and acetylcholine signaling and mimics invasive VNS.

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Section: Discussionmentioning

confidence: 99%

Transcutaneous vagus nerve stimulation in humans induces pupil dilation and attenuates alpha oscillations

Sharon

Fahoum

Nir

2020

Preprint

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“…The stimulation intensity, often determined by the patients themselves based on discomfort threshold, may be reported as amplitude (mA) and/or voltage (V). Reports go up to 60 mA or 24 V, but the final intensity setting is often not reported (29,30).…”

Section: Discussionmentioning

confidence: 99%

Feasibility of Non-Invasive Vagus Nerve Stimulation (gammaCore VET™) for the Treatment of Refractory Seizure Activity in Dogs

et al. 2020

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Idiopathic epilepsy is the most common chronic neurologic condition in dogs. Approximately 20-30% of those dogs are refractory to standard medical therapy and commonly experience side effects from antiepileptic drugs. Non-invasive vagus nerve stimulation (nVNS) has been frequently used in human medicine as an adjunct seizure therapy with low incidence of adverse events. Canine studies are limited to invasive surgical implants with no non-invasive evaluations currently published. We investigated the feasibility and efficacy of nVNS (gammaCore VET) as an adjunct treatment for refractory epilepsy in dogs. In total, 14 client-owned dogs completed the trial of either 8-or 16-week treatment periods during which they received 90-120 s stimulation three times per day in the region of the left cervical vagus nerve. Owners recorded seizure type (focal or generalized) and frequency as well as any adverse effects. Out of 14 dogs, nine achieved a reduction in seizure frequency and four were considered responders with a 50% or greater reduction in seizures from baseline to the final treatment period. However, there was no statistically significant difference in overall seizure frequency (p = 0.53) or percent change in seizure frequency between groups (p = 0.75). Adverse effects occurred in 25% of dogs originally enrolled, with reports of a hoarse bark and limb trembling, lethargy, behavioral changes, and an increase in seizure frequency. Non-invasive VNS was found to be safe and easy to administer with mild adverse events. It is considered a feasible treatment option as an adjunct therapy in refractory seizures and should be further investigated.

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“…In addition, citations of all selected studies were hand searched to identify additional studies. The citations of relevant reviews (Murray et al, 2016;Yap et al, 2020) were also searched to identify aVNS clinical RCTs. Through these citation searches, 5 additional studies were found.…”

Section: Search Methodsmentioning

confidence: 99%

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

Verma

Mudge

Kasole

et al. 2020

Preprint

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BackgroundThe 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.MethodsTo 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 ‘some’ or ‘high’ risk of bias, which makes interpreting their results in a broader context problematic.ResultsThe 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.DiscussionDrawing 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.ConclusionThe 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.

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Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice

Cited by 238 publications

References 127 publications

Transcutaneous vagus nerve stimulation in humans induces pupil dilation and attenuates alpha oscillations

Transcutaneous vagus nerve stimulation in humans induces pupil dilation and attenuates alpha oscillations

Feasibility of Non-Invasive Vagus Nerve Stimulation (gammaCore VET™) for the Treatment of Refractory Seizure Activity in Dogs

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

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