Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review

This paper presents data from a transcutaneous vagus nerve stimulation experiment that point towards a blunted cardiac baroreceptor sensitivity (cBRS) in young males compared to females during electrical stimulation of the forearm and a rhythmic breathing task. Continuous electrocardiography, impedance cardiography and continuous blood-pressure recordings were assessed in a sex-matched cohort of twenty young healthy subjects. Electrical stimulation of the median nerve was conducted by using a threshold-tracking method combined with two rhythmic breathing tasks (0.1 and 0.2 Hz) before, during and after active or sham transcutaneous vagus nerve stimulation. Autonomic and hemodynamic parameters were calculated, and differences were analyzed by using linear mixed models and post hoc F-tests. None of the autonomic and hemodynamic parameters differed between the sham and active conditions. However, compared to females, male participants had an overall lower total cBRS independent of stimulation condition during nerve stimulation (females: 14.96 ± 5.67 ms/mmHg, males: 11.89 ± 3.24 ms/mmHg, p = 0.031) and rhythmic breathing at 0.2 Hz (females: 21.49 ± 8.47 ms/mmHg, males: 15.12 ± 5.70 ms/mmHg, p = 0.004). Whereas vagus nerve stimulation at the left inner tragus did not affect the efferent vagal control of the heart, we found similar patterns of baroreceptor sensitivity activation over the stimulation period in both sexes, which, however, significantly differed in their magnitude, with females showing an overall higher cBRS.

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Vagus nerve stimulation in chronic refractory epilepsy: chasing the cardiologist

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20211450 ◽

2021 ◽

Author(s):

Ansh Chaudhary ◽

Bhupendra Chaudhary

Keyword(s):

Electrical Stimulation ◽

Vagus Nerve ◽

Antiepileptic Drugs ◽

Nerve Stimulation ◽

Side Effect ◽

Neurological Disorder ◽

Vagus Nerve Stimulation ◽

Refractory Epilepsy ◽

Stimulation Of

Epilepsy the second most common chronic neurological disorder after stroke affect 0.5-2% population worldwide. Antiepileptic drugs though remain the corner stone in management of epilepsy in majority of patients but still 30% of patients continues to have seizure or experience unacceptable pharmacological side effect. Electrical stimulation of vagus nerve is an effective and promising neurophysiological treatment for patients with refractory epilepsy who are either unsuitable candidate of surgery or falls in category of surgically refractory epilepsy.

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Serum cytokine levels are modulated by specific frequencies, amplitudes, and pulse widths of vagus nerve stimulation

10.1101/2020.01.08.898890 ◽

2020 ◽

Author(s):

Téa Tsaava ◽

Timir Datta-Chaudhuri ◽

Meghan E. Addorisio ◽

Emily Battinelli Masi ◽

Harold A. Silverman ◽

...

Keyword(s):

Electrical Stimulation ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Inflammatory Cytokine ◽

Serum Cytokine ◽

Stimulation Parameters ◽

Cytokine Levels ◽

Selection Of ◽

Stimulation Of

ABSTRACTElectrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation. Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα), while other parameters selectively lowered serum TNFα levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.

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A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions

Journal of Neurophysiology ◽

10.1152/jn.00057.2020 ◽

2020 ◽

Vol 123 (5) ◽

pp. 1739-1755

Author(s):

Lorenza Colzato ◽

Christian Beste

Keyword(s):

Literature Review ◽

Vagus Nerve ◽

Brain Stimulation ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Cognitive Effects ◽

Future Directions ◽

Transcutaneous Vagus Nerve Stimulation ◽

Stimulation Technique ◽

Stimulation Of

Brain stimulation approaches are important to gain causal mechanistic insights into the relevance of functional brain regions and/or neurophysiological systems for human cognitive functions. In recent years, transcutaneous vagus nerve stimulation (tVNS) has attracted considerable popularity. It is a noninvasive brain stimulation technique based on the stimulation of the vagus nerve. The stimulation of this nerve activates subcortical nuclei, such as the locus coeruleus and the nucleus of the solitary tract, and from there, the activation propagates to the cortex. Since tVNS is a novel stimulation technique, this literature review outlines a brief historical background of tVNS, before detailing underlying neurophysiological mechanisms of action, stimulation parameters, cognitive effects of tVNS on healthy humans, and, lastly, current challenges and future directions of tVNS research in cognitive functions. Although more research is needed, we conclude that tVNS, by increasing norepineprine (NE) and gamma-aminobutyric acid (GABA) levels, affects NE- and GABA-related cognitive performance. The review provides detailed background information how to use tVNS as a neuromodulatory tool in cognitive neuroscience and outlines important future leads of research on tVNS.

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Alternative Paradigm of Selective Vagus Nerve Stimulation Tested on an Isolated Porcine Vagus Nerve

The Scientific World JOURNAL ◽

10.1155/2014/310283 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Polona Pečlin ◽

Janez Rozman

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Fibre Type ◽

Vagus Nerve Stimulation ◽

Experimental Testing ◽

Present Stage ◽

Stage Of Development ◽

Isolated Segment ◽

Left Vagus ◽

Stimulation Of

Alternative paradigm for spatial and fibre-type selective vagus nerve stimulation (VNS) was developed using realistic structural topography and tested in an isolated segment of a porcine cervical left vagus nerve (LVN). A spiral cuff (cuff) containing a matrix of ninety-nine electrodes was developed for selective VNS. A quasitrapezoidal stimulating pulse (stimulus) was applied to the LVN via an appointed group of three electrodes (triplet). The triplet and stimulus were configured to predominantly stimulate the B-fibres, minimizing stimulation of the A-fibres and by-passing the stimulation of the C-fibres. To assess which fibres made the most probable contribution to the neural response (NR) during selective VNS, the distribution of conduction velocity (CV) within the LVN was considered. Experimental testing of the paradigm showed the existence of certain parameters and waveforms of the stimulus, for which the contribution of the A-fibres to the NR was slightly reduced and that of the B-fibres was slightly enlarged. The cuff provided satisfactory fascicle discrimination in selective VNS as well as satisfactory fascicle discrimination during NR recording. However, in the present stage of development, fibre-type VNS remained rather limited.

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Vagal afferent fibers contribute to the anti-inflammatory reactions by vagus nerve stimulation in concanavalin A model of hepatitis in rats

Molecular Medicine ◽

10.1186/s10020-020-00247-2 ◽

2020 ◽

Vol 26 (1) ◽

Author(s):

Byung Gon Jo ◽

Seung-Hyung Kim ◽

Uk Namgung

Keyword(s):

Electrical Stimulation ◽

Vagus Nerve ◽

Concanavalin A ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Α7 Nachr ◽

Afferent Fibers ◽

Tnf Α ◽

Anti Inflammatory ◽

Hepatic Branch

Abstract Background Increasing number of studies provide evidence that the vagus nerve stimulation (VNS) dampens inflammation in peripheral visceral organs. However, the effects of afferent fibers of the vagus nerve (AFVN) on anti-inflammation have not been clearly defined. Here, we investigate whether AFVN are involved in VNS-mediated regulation of hepatic production of proinflammatory cytokines. Methods An animal model of hepatitis was generated by intraperitoneal (i.p.) injection of concanavalin A (ConA) into rats, and electrical stimulation was given to the hepatic branch of the vagus nerve. AFVN activity was regulated by administration of capsaicin (CAP) or AP-5/CNQX and the vagotomy at the hepatic branch of the vagus nerve (hVNX). mRNA and protein expression in target tissues was analyzed by RT-PCR, real-time PCR, western blotting and immunofluorescence staining. Hepatic immune cells were analyzed by flow cytometry. Results TNF-α, IL-1β, and IL-6 mRNAs and proteins that were induced by ConA in the liver macrophages were significantly reduced by the electrical stimulation of the hepatic branch of the vagus nerve (hVNS). Alanine transaminase (ALT) and aspartate transaminase (AST) levels in serum and the number of hepatic CD4+ and CD8+ T cells were increased by ConA injection and downregulated by hVNS. CAP treatment deteriorated transient receptor potential vanilloid 1 (TRPV1)-positive neurons and increased caspase-3 signals in nodose ganglion (NG) neurons. Concomitantly, CAP suppressed choline acetyltransferase (ChAT) expression that was induced by hVNS in DMV neurons of ConA-injected animals. Furthermore, hVNS-mediated downregulation of TNF-α, IL-1β, and IL-6 expression was hampered by CAP treatment and similarly regulated by hVNX and AP-5/CNQX inhibition of vagal feedback loop pathway in the brainstem. hVNS elevated the levels of α7 nicotinic acetylcholine receptors (α7 nAChR) and phospho-STAT3 (Tyr705; pY-STAT3) in the liver, and inhibition of AFVN activity by CAP, AP-5/CNQX and hVNX or the pharmacological blockade of hepatic α7 nAChR decreased STAT3 phosphorylation. Conclusions Our data indicate that the activity of AFVN contributes to hepatic anti-inflammatory responses mediated by hVNS in ConA model of hepatitis in rats.

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Vagus nerve stimulation: quality control in thyroid and parathyroid surgery

The Journal of Laryngology & Otology ◽

10.1258/0022215001905067 ◽

2000 ◽

Vol 114 (2) ◽

pp. 125-127 ◽

Cited By ~ 7

Author(s):

A. W. Lambert ◽

C. Cosgrove ◽

J. Barwell ◽

S. Oxenham ◽

D. C. Wilkins

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Vocal Fold ◽

Contralateral Side ◽

Equipment Failure ◽

Parathyroid Surgery ◽

Initial Identification ◽

Vocal Fold Palsy ◽

Stimulation Of

This paper describes the use of the Neurosign 100 Nerve Monitor and vagus nerve stimulation in the identification and assessment of the integrity of the recurrent laryngeal nerve (RLN) during thyroid and parathyroid surgery.Vocal fold function was assessed pre- and post-operatively in all patients undergoing thyroid and parathyroid surgery. The nerve monitor, used in association with endotracheal electrodes, was used to confirm correct RLN identification and demonstrate its integrity at the completion of surgery.There were 21 unilateral and 19 bilateral neck explorations. In these 40 patients, 57 of 59 RLNs were identified. The nerve monitor demonstrated RLN continuity in all but one case (equipment failure: electrode misplacement) after initial identification. Vagus nerve stimulation was performed in 21 patients without adverse sequelae. Damage to the RLN was identified in one of these patients, in whom direct RLN stimulation close to the larynx had failed to indicate discontinuity. Post-operatively this patient had a transient unilateral vocal fold palsy.The use of the Neurosign 100 Nerve Monitor is no substitute for meticulous surgery. Stimulation of the vagus nerve may be a more sensitive means of assessing RLN integrity during thyroid and parathyroid surgery than stimulation of the RLN itself. Confirmation of RLN integrity allows the surgeon to proceed with confidence to the contralateral side of the neck during hazardous bilateral explorations.

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

10.1101/2020.08.25.265876 ◽

2020 ◽

Author(s):

Omer Sharon ◽

Firas Fahoum ◽

Yuval Nir

Keyword(s):

Electrical Stimulation ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Pupil Dilation ◽

Somatosensory Stimulation ◽

Alpha Oscillations ◽

Sham Stimulation ◽

Non Invasive ◽

Transcutaneous Vagus Nerve Stimulation

AbstractVagus 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), which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Non-invasive transcutaneous VNS (tVNS) employs electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent that tVNS mimics VNS remains unclear. 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. We compared 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, using parallel factor analysis, how tVNS modulates idle occipital alpha (8-13Hz) activity identified in each participant. We found greater attenuation of alpha oscillations by tVNS than by sham stimulation. This demonstrates that tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, thus supporting the hypothesis that tVNS elevates noradrenaline and other arousal-promoting neuromodulatory signaling, and mimics invasive VNS.Significance statementCurrent non-invasive brain stimulation techniques are mostly confined to modulating cortical activity, as is typical with transcranial magnetic or transcranial direct/alternating-current electrical stimulation. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to stimulate subcortical arousal-promoting nuclei, though previous studies yielded inconsistent results. Here we show that short (3.4s) tVNS pulses in naïve healthy male volunteers induced transient pupil dilation and attenuation of occipital alpha oscillations. These markers of brain arousal are in line with the established effects of invasive VNS on locus coeruleus-noradrenaline signaling, and support the notion that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying the means by which endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.

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Vagus nerve stimulation for primary headache disorders: An anatomical review to explain a clinical phenomenon

Cephalalgia ◽

10.1177/0333102419833076 ◽

2019 ◽

Vol 39 (9) ◽

pp. 1180-1194 ◽

Cited By ~ 13

Author(s):

Dylan Jozef Hendrik Augustinus Henssen ◽

Berend Derks ◽

Mats van Doorn ◽

Niels Verhoogt ◽

Anne-Marie Van Cappellen van Walsum ◽

...

Keyword(s):

Vagus Nerve ◽

Trigeminal Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Primary Headache ◽

Solitary Tract ◽

Headache Disorders ◽

Primary Headache Disorders ◽

Non Invasive ◽

Stimulation Of

Background Non-invasive stimulation of the vagus nerve has been proposed as a new neuromodulation therapy to treat primary headache disorders, as the vagus nerve is hypothesized to modulate the headache pain pathways in the brain. Vagus nerve stimulation can be performed by placing an electrode on the ear to stimulate the tragus nerve, which contains about 1% of the vagus fibers. Non-invasive vagus nerve stimulation (nVNS) conventionally refers to stimulation of the cervical branch of the vagus nerve, which is made up entirely of vagal nerve fibers. While used interchangeably, most of the research to date has been performed with nVNS or an implanted vagus nerve stimulation device. However, the exact mechanism of action of nVNS remains hypothetical and no clear overview of the effectiveness of nVNS in primary headache disorders is available. Methods In the present study, the clinical trials that investigated the effectiveness, tolerability and safety of nVNS in primary headache disorders were systematically reviewed. The second part of this study reviewed the central connections of the vagus nerve. Papers on the clinical use of nVNS and the anatomical investigations were included based on predefined criteria, evaluated, and results were reported in a narrative way. Results The first part of this review shows that nVNS in primary headache disorders is moderately effective, safe and well-tolerated. Regarding the anatomical review, it was reported that fibers from the vagus nerve intertwine with fibers from the trigeminal, facial, glossopharyngeal and hypoglossal nerves, mostly in the trigeminal spinal tract. Second, the four nuclei of the vagus nerve (nuclei of the solitary tract, nucleus ambiguus, spinal nucleus of the trigeminal nerve and dorsal motor nucleus (DMX)) show extensive interconnections. Third, the efferents from the vagal nuclei that receive sensory and visceral input (i.e. nuclei of the solitary tract and spinal nucleus of the trigeminal nerve) mainly course towards the main parts of the neural pain matrix directly or indirectly via other vagal nuclei. Conclusion The moderate effectiveness of nVNS in treating primary headache disorders can possibly be linked to the connections between the trigeminal and vagal systems as described in animals.

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The Instant Effects of Continuous Transcutaneous Auricular Vagus Nerve Stimulation at Acupoints on the Functional Connectivity of Amygdala in Migraine without Aura: A Preliminary Study

Neural Plasticity ◽

10.1155/2020/8870589 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Wenting Luo ◽

Yue Zhang ◽

Zhaoxian Yan ◽

Xian Liu ◽

Xiaoyan Hou ◽

...

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Random Order ◽

Brain Regions ◽

Vital Role ◽

Auricular Acupuncture ◽

Fmri Study ◽

The Right ◽

Episodic Migraineurs

Background. A growing body of evidence suggests that both auricular acupuncture and transcutaneous auricular vagus nerve stimulation (taVNS) can induce antinociception and relieve symptoms of migraine. However, their instant effects and central treatment mechanism remain unclear. Many studies proved that the amygdalae play a vital role not only in emotion modulation but also in pain processing. In this study, we investigated the modulation effects of continuous taVNS at acupoints on the FC of the bilateral amygdalae in MwoA. Methods. Thirty episodic migraineurs were recruited for the single-blind, crossover functional magnetic resonance imaging (fMRI) study. Each participant attended two kinds of eight-minute stimulations, taVNS and sham-taVNS (staVNS), separated by seven days in random order. Finally, 27 of them were included in the analysis of seed-to-voxel FC with the left/right amygdala as seeds. Results. Compared with staVNS, the FC decreased during taVNS between the left amygdala and left middle frontal gyrus (MFG), left dorsolateral superior frontal gyrus, right supplementary motor area (SMA), bilateral paracentral lobules, bilateral postcingulum gyrus, and right frontal superior medial gyrus, so did the FC of the right amygdala and left MFG. A significant positive correlation was observed between the FC of the left amygdala and right SMA and the frequency/total time of migraine attacks during the preceding four weeks. Conclusion. Continuous taVNS at acupoints can modulate the FC between the bilateral amygdalae and pain-related brain regions in MwoA, involving the limbic system, default mode network, and pain matrix, with obvious differences between the left amygdala and the right amygdala. The taVNS may produce treatment effects by modulating the abnormal FC of the amygdala and pain networks, possibly having the same central mechanism as auricular acupuncture.

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