Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review

Redgrave, Jessica; Day, Douglas G.; Leung, Harvey; Laud, Peter J.; Ali, Ahmed Said; Lindert, Ralf; Majid, Arshad

doi:10.1016/j.brs.2018.08.010

Cited by 193 publications

(153 citation statements)

References 47 publications

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“…The recommended duration of stimulation is 2 min and can be administered several times (up to 12 times) a day (Holle-Lee & Gaul, 2016). Recognised side-effects of tVNS can include local skin irritation from electrode placement, headache and nasopharyngitis (Redgrave et al 2018). A common sideeffect of cervical tVNS is painless, mild facial twitching (Holle-Lee & Gaul, 2016).…”

Section: Introductionmentioning

confidence: 99%

The anatomical basis for transcutaneous auricular vagus nerve stimulation

et al. 2019

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The array of end organ innervations of the vagus nerve, coupled with increased basic science evidence, has led to vagus nerve stimulation (VNS) being explored as a management option in a number of clinical disorders, such as heart failure, migraine and inflammatory bowel disease. Both invasive (surgically implanted) and non‐invasive (transcutaneous) techniques of VNS exist. Transcutaneous VNS (tVNS) delivery systems rely on the cutaneous distribution of vagal afferents, either at the external ear (auricular branch of the vagus nerve) or at the neck (cervical branch of the vagus nerve), thus obviating the need for surgical implantation of a VNS delivery device and facilitating further investigations across a wide range of uses. The concept of electrically stimulating the auricular branch of the vagus nerve (ABVN), which provides somatosensory innervation to several aspects of the external ear, is relatively more recent compared with cervical VNS; thus, there is a relative paucity of literature surrounding its operation and functionality. Despite the increasing body of research exploring the therapeutic uses of auricular transcutaneous VNS (tVNS), a comprehensive review of the cutaneous, intracranial and central distribution of ABVN fibres has not been conducted to date. A review of the literature exploring the neuroanatomical basis of this neuromodulatory therapy is therefore timely. Our review article explores the neuroanatomy of the ABVN with reference to (1) clinical surveys examining Arnold’s reflex, (2) cadaveric studies, (3) fMRI studies, (4) electrophysiological studies, (5) acupuncture studies, (6) retrograde tracing studies and (7) studies measuring changes in autonomic (cardiovascular) parameters in response to auricular tVNS. We also provide an overview of the fibre composition of the ABVN and the effects of auricular tVNS on the central nervous system. Cadaveric studies, of which a limited number exist in the literature, would be the ‘gold‐standard’ approach to studying the cutaneous map of the ABVN; thus, there is a need for more such studies to be conducted. Functional magnetic resonance imaging (fMRI) represents a useful surrogate modality for discerning the auricular sites most likely innervated by the ABVN and the most promising locations for auricular tVNS. However, given the heterogeneity in the results of such investigations and the various limitations of using fMRI, the current literature lacks a clear consensus on the auricular sites that are most densely innervated by the ABVN and whether the brain regions secondarily activated by electrical auricular tVNS depend on specific parameters. At present, it is reasonable to surmise that the concha and inner tragus are suitable locations for vagal modulation. Given the therapeutic potential of auricular tVNS, there remains a need for the cutaneous map of the ABVN to be further refined and the effects of various stimulation parameters and stimulation sites to be determined.

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Section: Introductionmentioning

confidence: 99%

The anatomical basis for transcutaneous auricular vagus nerve stimulation

et al. 2019

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“…We have recently shown invasive VNS to have beneficial effects on human executive functions, specifically working memory (Sun et al, 2017b ), suggesting that VNS might be useful in the treatment of cognitive impairment. Considering the costs and risks involved in invasive stimulation, it is of great interest to determine whether a safer non-invasive stimulation, transcutaneous vagus nerve stimulation (tVNS; Badran et al, 2018b ; Redgrave et al, 2018 ), has similar potential for enhancing executive functions.…”

Section: Introductionmentioning

confidence: 99%

Reduced Frontal Nogo-N2 With Uncompromised Response Inhibition During Transcutaneous Vagus Nerve Stimulation—More Efficient Cognitive Control?

Pihlaja

Failla

Peräkylä

et al. 2020

Front. Hum. Neurosci.

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We have previously shown invasive vagus nerve stimulation to improve attention and working memory and alter emotion-attention interaction in patients with refractory epilepsy, suggesting that VNS might be useful in the treatment of cognitive impairment. The current research focuses on whether non-invasive, transcutaneous vagus nerve stimulation (tVNS) has similar effects to VNS. Furthermore, we aimed to assess whether tVNS has an impact on cognitive control in general or on underlying brain physiology in a task that mimics everyday life demands where multiple executive functions are engaged while encountering intervening emotional stimuli. Event-related potentials (ERP) evoked in such a task, specifically centro-parietal P3 and frontal N2 were used as biomarkers for attention allocation and cognitive control required to carry out the task. A single-blinded, sham-controlled, within-subject study on healthy subjects ( n = 25) was conducted using Executive Reaction Time Test (RT-test), a Go/NoGo task engaging multiple executive functions along with intervening threat-related distractors while EEG was recorded. tVNS at the left tragus and sham stimulation at the left ear lobe was alternately delivered throughout the task. To assess the impact of tVNS on neural activity underlying attention and cognitive control, centro-parietal P3 and frontal N2 peak amplitudes were measured in Go and NoGo conditions. Task performance was assessed with RTs and different error types reflecting cognitive control in general and distinct executive functions, such as working memory and response inhibition.No significant effects due to tVNS on performance in the Executive RT-test were observed. For N2 there was a main effect of stimulator status and a significant interaction of trial type (Go, NoGo) and stimulator status. Post hoc analysis revealed that tVNS resulted in a significant reduction of frontal N2 only in the NoGo condition. No significant effects were observed for P3 nor were there any effects of emotion. Diminished NoGo-N2 potential along with unaltered task performance during tVNS suggests fewer cognitive control resources were required to successfully withhold a prepotent response. Though caution is warranted, we suggest that tVNS may lead to more efficient neural processing with fewer resources needed for successful cognitive control, providing promise for its potential use in cognitive enhancement.

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“…Non-invasive transcutaneous vagal nerve stimulation (tVNS) applies electrical current at a high frequency (typically 25Hz) through the left ear, targeting the auricular branch of the vagus nerve at the Cymba Conchae (Figure1) (for anatomic evidence see Van Bockstaele et al, 1999;Bermejo et al, 2017). tVNS has been shown to mimic the anticonvulsive and antidepressant effects of invasive VNS (Stefan et al, 2012;He et al, 2013;Hein et al, 2013;Bauer et al, 2016;Rong et al, 2016;Trevizol et al, 2016) and proved to be safe and tolerable (Redgrave et al, 2018). Beyond its clinical efficacy, there is growing interest in using tVNS in healthy individuals for basic neuroscience research (Van Leusden et al, 2015), but previous studies are inconsistent in determining to what extent tVNS mimics invasive VNS with respect to the effects on EEG or pupil dilation that could suggest LC-NE involvement (Ventura-Bort et al, 2018;Warren et al, 2018;Keute et al, 2019).…”

Section: Introductionmentioning

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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Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review

Cited by 193 publications

References 47 publications

The anatomical basis for transcutaneous auricular vagus nerve stimulation

The anatomical basis for transcutaneous auricular vagus nerve stimulation

Reduced Frontal Nogo-N2 With Uncompromised Response Inhibition During Transcutaneous Vagus Nerve Stimulation—More Efficient Cognitive Control?

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

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