Promoting long-term inhibition of human fear responses by non-invasive transcutaneous vagus nerve stimulation during extinction training

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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Transcutaneous Vagus Nerve Stimulation

European Neurological Review ◽

10.17925/enr.2011.06.04.254 ◽

2011 ◽

Vol 6 (4) ◽

pp. 254 ◽

Cited By ~ 43

Author(s):

Jens Ellrich ◽

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Drug Resistant ◽

Non Invasive ◽

Transcutaneous Vagus Nerve Stimulation ◽

The Common ◽

Myelinated Fibres ◽

Drug Resistant Epilepsy ◽

Intended Use

Invasive vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. Besides its recognised clinical efficacy, there are major drawbacks, such as invasiveness and a great many side effects. Therefore there is a medical demand for transcutaneous VNS (t-VNS®), which combines selective, non-invasive access to vagus nerve afferents with a low risk profile. Both treatments excite thick myelinated fibres of vagus nerve branches that project to the nucleus of the solitary tract in the brainstem. Preclinical data emphasise the equivalent anticonvulsive effects of both methods. Based upon the common mode of action and the first clinical data, the t-VNS device received Conformité Européenne (CE) approval. Besides the approved intended use for drug-resistant epilepsy and depression, a future clinical trial will address the efficacy of t-VNS in chronic pain.

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Direct and Transcutaneous Vagus Nerve Stimulation for Treatment of Tinnitus: A Scoping Review

Frontiers in Neuroscience ◽

10.3389/fnins.2021.680590 ◽

2021 ◽

Vol 15 ◽

Author(s):

Natalia Yakunina ◽

Eui-Cheol Nam

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Neural Plasticity ◽

Vagus Nerve Stimulation ◽

Human Subjects ◽

Acoustic Stimulation ◽

Non Invasive ◽

Transcutaneous Vagus Nerve Stimulation ◽

Alternative Approach ◽

Tinnitus Treatment

Recent animal research has shown that vagus nerve stimulation (VNS) paired with sound stimuli can induce neural plasticity in the auditory cortex in a controlled manner. VNS paired with tones excluding the tinnitus frequency eliminated physiological and behavioral characteristics of tinnitus in noise-exposed rats. Several clinical trials followed and explored the effectiveness of VNS paired with sound stimuli for alleviating tinnitus in human subjects. Transcutaneous VNS (tVNS) has received increasing attention as a non-invasive alternative approach to tinnitus treatment. Several studies have also explored tVNS alone (not paired with sound stimuli) as a potential therapy for tinnitus. In this review, we discuss existing knowledge about direct and tVNS in terms of applicability, safety, and effectiveness in diminishing tinnitus symptoms in human subjects. This review includes all existing clinical and neuroimaging studies of tVNS alone or paired with acoustic stimulation in tinnitus patients and outlines the present limitations that must be overcome to maximize the potential of (t)VNS as a therapy for tinnitus.

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Effect of Transcutaneous Vagus Nerve Stimulation in Dysphagia After Lateral Medullary Infarction: A Case Report

American Journal of Speech-Language Pathology ◽

10.1044/2019_ajslp-18-0262 ◽

2019 ◽

Vol 28 (4) ◽

pp. 1381-1387

Author(s):

Ying Yuan ◽

Jie Wang ◽

Dongyu Wu ◽

Dahua Zhang ◽

Weiqun Song

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Rating Scale ◽

Tube Feeding ◽

Nasogastric Feeding ◽

Lateral Medullary Infarction ◽

Severe Dysphagia ◽

Transcutaneous Vagus Nerve Stimulation ◽

Medullary Infarction

Purpose Severe dysphagia with weak pharyngeal peristalsis after dorsal lateral medullary infarction (LMI) requires long-term tube feeding. However, no study is currently available on therapeutic effectiveness in severe dysphagia caused by nuclear damage of vagus nerve after dorsal LMI. The purpose of the present investigation was to explore the potential of transcutaneous vagus nerve stimulation (tVNS) to improve severe dysphagia with weak pharyngeal peristalsis after dorsal LMI. Method We assessed the efficacy of 6-week tVNS in a 28-year-old woman presented with persisting severe dysphagia after dorsal LMI who had been on nasogastric feeding for 6 months. tVNS was applied for 20 min twice a day, 5 days a week, for 6 weeks. The outcome measures included saliva spitted, Swallow Function Scoring System, Functional Oral Intake Scale, Clinical Assessment of Dysphagia With Wallenberg Syndrome, Yale Pharyngeal Residue Severity Rating Scale, and upper esophagus X-ray examination. Results After tVNS, the patient was advanced to a full oral diet without head rotation or spitting. No saliva residue was found in the valleculae and pyriform sinuses. Contrast medium freely passed through the upper esophageal sphincter. Conclusion Our findings suggest that tVNS might provide a useful means for recovery of severe dysphagia with weak pharyngeal peristalsis after dorsal LMI. Supplemental Material https://doi.org/10.23641/asha.9755438

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The Transcutaneous Vagus Nerve Stimulation Device of the Nu-Calm-Solace Lifesciences Gives an Output Signal that is a Multifractal: Is there a Support in the Treatment of the Atrial Fibrillation?

Austin Cardiology ◽

10.26420/austincardiol.2017.1013 ◽

2017 ◽

Vol 2 (2) ◽

Author(s):

Elio Conte

Keyword(s):

Atrial Fibrillation ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Output Signal ◽

Vagus Nerve Stimulation ◽

Transcutaneous Vagus Nerve Stimulation

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Long Term Effects of Low Frequency (10 Hz) Vagus Nerve Stimulation on EEG and Heart Rate Variability in Crohn's Disease: A Case Report

Brain Stimulation ◽

10.1016/j.brs.2014.08.001 ◽

2014 ◽

Vol 7 (6) ◽

pp. 914-916 ◽

Cited By ~ 26

Author(s):

Didier Clarençon ◽

Sonia Pellissier ◽

Valérie Sinniger ◽

Astrid Kibleur ◽

Dominique Hoffman ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Crohn’S Disease ◽

Case Report ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Low Frequency ◽

Long Term Effects

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Non-invasive vagus nerve stimulation reduced neuron-derived IL-1β and neuroinflammation in acute ischemic rat brain

Hemorrhagic Stroke ◽

10.1016/j.hest.2021.06.003 ◽

2021 ◽

Author(s):

Lisa Y Yang ◽

Kiran Bhaskar ◽

Jeffrey Thompson ◽

Kelsey Duval ◽

Michel Torbey ◽

...

Keyword(s):

Vagus Nerve ◽

Rat Brain ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Non Invasive

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Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion

Psychological Medicine ◽

10.1017/s0033291720005073 ◽

2021 ◽

pp. 1-11

Author(s):

Magdalena Ferstl ◽

Vanessa Teckentrup ◽

Wy Ming Lin ◽

Franziska Kräutlein ◽

Anne Kühnel ◽

...

Keyword(s):

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Positive Mood ◽

Credible Interval ◽

Cognitive Effort ◽

Mood States ◽

Non Invasive ◽

Lower Baseline ◽

Open Question

Abstract Background Mood plays an important role in our life which is illustrated by the disruptive impact of aberrant mood states in depression. Although vagus nerve stimulation (VNS) has been shown to improve symptoms of depression, the exact mechanism is still elusive, and it is an open question whether non-invasive VNS could be used to swiftly and robustly improve mood. Methods Here, we investigated the effect of left- and right-sided transcutaneous auricular VNS (taVNS) v. a sham control condition on mood after the exertion of physical and cognitive effort in 82 healthy participants (randomized cross-over design) using linear mixed-effects and hierarchical Bayesian analyses of mood ratings. Results We found that 90 min of either left-sided or right-sided taVNS improved positive mood [b = 5.11, 95% credible interval, CI (1.39–9.01), 9.6% improvement relative to the mood intercept, BF10 = 7.69, pLME = 0.017], yet only during the post-stimulation phase. Moreover, lower baseline scores of positive mood were associated with greater taVNS-induced improvements in motivation [r = −0.42, 95% CI (−0.58 to −0.21), BF10 = 249]. Conclusions We conclude that taVNS boosts mood after a prolonged period of effort exertion with concurrent stimulation and that acute motivational effects of taVNS are partly dependent on initial mood states. Collectively, our results show that taVNS may help quickly improve affect after a mood challenge, potentially by modulating interoceptive signals contributing to the reappraisal of effortful behavior. This suggests that taVNS could be a useful add-on to current behavioral therapies.

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Vagus nerve stimulation for drug-resistant epilepsy

Practical Neurology ◽

10.1136/practneurol-2019-002210 ◽

2019 ◽

Vol 20 (3) ◽

pp. 189-198 ◽

Cited By ~ 1

Author(s):

Laura Pérez-Carbonell ◽

Howard Faulkner ◽

Sean Higgins ◽

Michalis Koutroumanidis ◽

Guy Leschziner

Keyword(s):

Vagus Nerve ◽

Seizure Frequency ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Therapeutic Option ◽

Drug Resistant ◽

Drug Resistant Epilepsy ◽

Randomised Controlled

Vagus nerve stimulation (VNS) is a neuromodulatory therapeutic option for drug-resistant epilepsy. In randomised controlled trials, VNS implantation has resulted in over 50% reduction in seizure frequency in 26%–40% of patients within 1 year. Long-term uncontrolled studies suggest better responses to VNS over time; however, the assessment of other potential predictive factors has led to contradictory results. Although initially designed for managing focal seizures, its use has been extended to other forms of drug-resistant epilepsy. In this review, we discuss the evidence supporting the use of VNS, its impact on seizure frequency and quality of life, and common adverse effects of this therapy. We also include practical guidance for the approach to and the management of patients with VNS in situ.

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