Non-invasive Vagus Nerve Stimulation Research Articles

An update on migraine: Current and new treatment options.

Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both.

Noninvasive vagus nerve stimulation in spontaneous subarachnoid hemorrhage (VANQUISH): A randomized safety and feasibility study

Noninvasive vagus nerve stimulation in spontaneous subarachnoid hemorrhage (VANQUISH): A randomized safety and feasibility study

The Effects of Transcutaneous Auricular Vagus Nerve Stimulation on Language Retention in College-Aged Students

As our world is becoming more globally connected, the ability to speak another language is increasingly becoming a valuable skill. While there exist many training programs to help acquire a new language, this task becomes increasingly difficult with age—thus presenting the need for a novel method of intervention to assist in this process. Considering this increasing difficulty and poor outcomes of existing methods, a new biologically based intervention could be valuable for improving learning and memory. Previous research conducted in our lab has shown that noninvasive transcutaneous auricular vagus nerve stimulation (taVNS) is an effective intervention in memory-based reading comprehension and letter-sound learning (Thakkar et al., 2020;2023). TaVNS has also been shown to boost associative memory (Jacobs et al., 2015), spatial working memory (Sun et al., 2021), and emotional memory (Ventura-Bort et al., 2021). Despite this knowledge, little is known about taVNS and its effects on long-lasting language retention. Thus, this current study explores whether transcutaneous auricular vagus nerve stimulation can improve learning and retention of vocabulary words in a new language when paired with a training routine. Typically developing college-aged individuals were recruited through an online participant pool. All individuals were screened for age, IQ, reading, memory, and attention for inclusion in this study. The participants completed a one-hour training session in which they were presented with 30 Palauan nouns, the respective English translations, as well as images of the nouns. During this time, the participants received sham, 5 Hz, or 25 Hz stimulation to the posterior of the left tragus. Prior to training, participants completed a translation test to measure their existing knowledge of the Palauan language, and this test was repeated immediately after training and again seven days later to measure learning and retention. After analysis of the results, no effect was found for any stimulation group immediately after training. At retention, however, the 25 Hz taVNS group showed significantly greater performance than both the sham and 5 Hz taVNS groups on recall of material. There was also no statistical difference between the performance of the sham and 5 Hz taVNS groups. Lastly, the results further suggest that stimulation intensity does not impact the efficacy of the intervention. These data suggest that taVNS, regardless of stimulation intensity, may be used to help in the retention of novel words in a new language. These data will be important for ongoing research examining the uses of taVNS, its use as an intervention for learning and retention of a new language, as well as its potential uses in other areas of cognition.

Indomethacin-Responsive Headache Disorders.

This article describes the clinical features and treatment of the indomethacin-responsive headache disorders paroxysmal hemicrania and hemicrania continua. Both paroxysmal hemicrania and hemicrania continua are treated with indomethacin at the lowest clinically useful dose. It has recently become clear that some patients with either condition may respond to treatment with noninvasive vagus nerve stimulation, which can be both indomethacin sparing and, in some cases, headache controlling. Given the lifelong nature of both paroxysmal hemicrania and hemicrania continua, brain imaging with MRI is recommended when the conditions are identified, specifically including pituitary views. Paroxysmal hemicrania and hemicrania continua are indomethacin-responsive headache disorders that offer a rewarding and unique opportunity to provide marked clinical improvement when recognized and treated appropriately. These disorders share the final common pathway of the trigeminal-autonomic reflex, with head pain and cranial autonomic features, and are differentiated pathophysiologically by the pattern of brain involvement, which can be seen using functional imaging. They have distinct differential diagnoses to which the clinician needs to remain alert.

Benefit of noninvasive vagus nerve stimulation in vaccine optimization for young children

Whether it is mandatory to vaccinate young children against SARS-CoV-2 and respiratory syncytial virus (RSV) is still an ongoing topic of debate. Indeed, vaccine acceptance for young children is either too low (in the case of COVID-19) or, in some cases, unattainable (with the demand far exceeding the capacity of production in the case of RSV vaccines in some countries). In addition, while vaccines do confer immunity, they can be complicated by inflammatory reactions to the vaccine itself. This inflammatory response is controlled by the nervous system, specifically the vagus nerve. Vagal tone optimization in and of itself confers some level of protection against viral infections such as SARS-CoV-2 or RSV, but the degree of protection has not been adequately evaluated. Even though additional studies are needed to validate a strategy of vagal optimization as an alternative to or co-treatment with vaccines, studies of noninvasive vagus nerve stimulation should be supported by public health agencies as an adjunctive tool providing young children with safe, ready-to-use immunization and protection from vaccine reactions. This recommendation is based on scientific, epidemiological, ethical, and economic considerations.

O126: Non-invasive vagus nerve stimulation to reduce ileus after colorectal surgery: randomised feasibility trial and efficacy assessment

Abstract Objective Ileus is characterised by intestinal dysmotility after surgery. In preclinical models, vagus nerve stimulation reduces intestinal inflammation, preventing smooth muscle dysfunction and accelerating the return of gut function. This study explored the efficacy and feasibility of a definitive trial and implementation of non-invasive, electrical, vagus nerve stimulation (nVNS). Design A participant-blinded, multi-centre, feasibility trial of self-administered nVNS was performed. Patients undergoing colorectal surgery were randomised to four groups of pre- and post-operative treatment (A: nVNS/nVNS; B: nVNS/Sham; C: Sham/nVNS; D: Sham/Sham). Feasibility outcomes were participant recruitment, compliance, and blinding. Clinical outcomes were intestinal function and adverse events. Interviews with patients and clinicians explored barriers to feasibility and implementation. In an independent cohort, the effects of nVNS on serum IL-1b, IL-6, and TNFa were quantified at baseline, 24-hours, and 72-hours after surgery. Results Ninety-seven out of 125 (77.6%) eligible patients took part. The median compliance was 19 out of 20 stimulations (IQR: 17-20). The median time to pass stool was 4 (3-5), 3 (2-4), 2.5 (2-3.5), and 3 (2-4) days for groups A-D, respectively. The incidence of adverse events was similar across groups. Trends toward reduced pro-inflammatory mediators were observed after nVNS. Interviews with patients (n=19) demonstrated their motivation to contribute actively to their recovery and interviews with clinicians (n=10) revealed strong reciprocal support. Conclusion This study confirms the safety, feasibility, and support for nVNS after surgery. Research on nVNS should progress from its current focus on pre-clinical models to powered, dedicated assessments of clinical effectiveness.

Increased cardiac vagal tone in childhood-only, adolescent-only, and persistently antisocial teenagers: the mediating role of low heart rate.

Cardiac vagal tone is an indicator of parasympathetic nervous system functioning, and there is increasing interest in its relation to antisocial behavior. It is unclear however whether antisocial individuals are characterized by increased or decreased vagal tone, and whether increased vagal tone is the source of the low heart rate frequently reported in antisocial populations. Participants consisted of four groups of community-dwelling adolescent boys aged 15.7 years: (1) controls, (2) childhood-only antisocial, (3) adolescent-only antisocial, and (4) persistently antisocial. Heart rate and vagal tone were assessed in three different conditions: rest, cognitive stressor, and social stressor. All three antisocial groups had both lower resting heart rates and increased vagal tone compared to the low antisocial controls across all three conditions. Low heart rate partially mediated the relationship between vagal tone and antisocial behavior. Results indicate that increased vagal tone and reduced heart rate are relatively broad risk factors for different developmental forms of antisocial behavior. Findings are the first to implicate vagal tone as an explanatory factor in understanding heart rate - antisocial behavior relationships. Future experimental work using non-invasive vagus nerve stimulation or heart rate variability biofeedback is needed to more systematically evaluate this conclusion.

Preventive noninvasive vagal nerve stimulation reduces insufficient sleep-induced depression by improving the autonomic nervous system

BackgroundDepression is closely linked to an imbalance in the autonomic nervous system (ANS). However, the role of this imbalance in mediating the effects of sleep deprivation (SD) and vagus nerve stimulation (VNS) on emotional well-being is not fully understood. MethodsA population-based analysis was conducted to explore the relationship between sleep duration, depression scores, and heart rate variability (HRV). Additionally, the chronic SD mouse model was established to assess the impact of preventive transcutaneous auricular VNS (taVNS) on pathological and behavioral changes. ResultsOur study found a significant link between sleep duration, depression severity, and HRV. Shorter sleep duration was associated with higher depression scores and lower RMSSD (a measure of HRV). In our rat model, insufficient sleep consistently impaired HRV. This effect was mitigated by taVNS, accompanied by corresponding changes in levels of IL-1β and IL-6, astrocyte and microglia activation, and tail suspension times. ConclusionsUsing VNS as a preventive treatment for depression-risk individuals with insufficient sleep shows promise. It not only broadens the potential applications of VNS but also sheds light on its mechanism—particularly its role in enhancing vagal nerve function and balancing the ANS, as evidenced by HRV measurements.

Non-Pharmacological Treatments in Paediatric Migraine.

Psychological, social, and biological aspects contribute synergistically to the maintenance and chronicity of pain in primary headaches. An integrated intervention seems to be the most appropriate in the management of these conditions, taking advantage not only of pharmacological strategies, but also of different approaches according to the global assessment and patient necessities. In this perspective, non-pharmacological treatments are becoming increasingly used to overcome these issues also in paediatric migraine treatment. Particularly, nutraceuticals, non-invasive neuromodulation, and behavioural approaches are well tolerated and of potential interest. This paper aims to present the main approaches reported in the literature in the management of migraine in children and adolescents presenting an up-to-date review of the current literature. We therefore performed a narrative presentation for each of these three categories: nutraceuticals (riboflavin; magnesium; melatonin; vitamin D; coenzyme Q10; and polyunsaturated fatty acid); non-invasive neuromodulation (trigeminal nerve stimulator; non-invasive vagal nerve stimulation; transcranial magnetic stimulation; and remote electrical neuromodulation), and behavioural therapies (biofeedback; cognitive behavioural therapy; and mindfulness-based therapy). These approaches are increasingly seen as a valid treatment option in primary headache management also in paediatrics, avoiding medication overuse and drug treatment contraindications.

Heart rate variability and cold-induced vascular dilation after stimulation of two different areas of the ear: a prospective, single-blinded, randomized crossover study

BackgroundBoth noninvasive transauricular vagus nerve stimulation (taVNS) and traditional medical practice (TMP), such as auriculotherapy, use the auricle as a starting point for stimulation, but with two different conceptual frameworks: taVNS depends on vagal afferences to account for its effects, whereas TMP requires stimulation of the ear with high topographical accuracy regardless of the afferent nerves. The aim of this study was to measure heart rate variability (HRV) and cold water–induced vasodilation (CIVD) after puncturing two different ear points with the same afference but that should have opposite effects according to TMP.MethodsTen healthy subjects were investigated in this single-blinded crossover study over three sessions. In the first session, sympathetic activation was performed via cold water immersion of the right hand, with recordings taken from multiple fingers. HRV was assessed in the time domain (square root of the mean squared differences of NN intervals (RMSSD)) and frequency domain (low (LF) and high frequencies (HF)). In the second and third sessions, the same skin immersion test was performed, and mechanical stimulation was applied to the ear at two different points on the internal surface of the antitragus, one with alleged parasympathetic activity and the other with alleged sympathetic activity. The stimulation was done with semipermanent needles.ResultsStimulation of the point with alleged parasympathetic activity immediately resulted in a significant decrease in RMSSD in 75% of the subjects and in LF in 50% of the subjects, while stimulation of the point with alleged sympathetic activity resulted in an increase in HF and RMSSD in 50% of the subjects. Stimulation of these points did not affect the CIVD reflex. The 20 min cold water immersion induced an immediate decrease in LF and the LF/HF ratio and an increase in HF. The skin temperature of the nonimmersed medius significantly decreased when the contralateral hand was immersed, from 34.4 °C to 31.8 °C.ConclusionsStimulation of two different ear points innervated by the same afferent nerves elicited different HRV responses, suggesting somatotopy and a vagal effect beyond vagal afferences. These results are not in accordance with the claims of TMP.Trial registrationNCT04130893 (18/10/2019) clinicaltrials.com.

Transcutaneous auricular vagus nerve stimulation for the treatment of myoarthropatic symptoms in patients with craniomandibular dysfunction – a protocol for a randomized and controlled pilot trial

BackgroundTemporomandibular disorders (TMD) are a collective term for pain and dysfunction of the masticatory muscles and the temporomandibular joints. The most common types of TMD are pain-related, which may impact the psychological behavior and quality of life. Currently, the most popular methods for the treatment of TMD patients are occlusal splint therapy, often in combination with physical- and/or pharmacotherapy. However, due to the complexity of etiology, the treatment of chronic TMD remains a challenge. Recently, CE-certified systems for non-invasive VNS (transcutaneous auricular vagus nerve stimulation, taVNS) have become available and show positive effects in the treatment of chronic pain conditions, like migraine or fibromyalgia, with which TMD shares similarities. Therefore, it is the main purpose of the study to evaluate the feasibility of daily taVNS against chronic TMD and to assess whether there is an improvement in pain severity, quality of life, and kinetic parameters.MethodsThis study is designed as a single-blinded, double-arm randomized controlled trial (RCT) in a 1:1 allocation ratio. Twenty adult patients with chronical TMD symptoms will be enrolled and randomized to stimulation or sham group. In the stimulation group, taVNS is performed on the left tragus (25 Hz, pulse width 250 µs, 28 s on/32 s off, 4 h/day). The sham group will receive no stimulation via a non-functional identical-looking electrode. Validated questionnaire data and clinical parameters will be collected at the beginning of the study and after 4 and 8 weeks. The compliance of a daily taVNS of patients with chronical TMD will be evaluated via a smartphone app recording daily stimulation time and average intensity. Additionally, the treatment impact on pain severity and quality of life will be assessed with different questionnaires, and the effect on the mandibular mobility and muscle activity will be analyzed.DiscussionThis is the first clinical trial to assess the feasibility of taVNS in patients with chronic TMD symptoms. If taVNS improves the symptoms of TMD, it will be a significant gain in quality of life for these chronic pain patients. The results of this pilot study will help to determine the feasibility of a large-scale RCT.Trial registrationThis study has been registered in the DRKS database (DRKS00029724).

Effects of non-invasive vagus nerve stimulation on clinical symptoms and molecular biomarkers in Parkinson's disease.

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson's disease (PD) patients. In a subgroup of patients, we measured selected neurotrophins, inflammatory markers and markers of oxidative stress in serum. Thirty-three PD patients with freezing of gait (FOG) were randomized to either active nVNS or sham nVNS. After baseline assessments, patients were instructed to deliver six 2 min stimulations (12 min/day) of the active nVNS/sham nVNS device for 1 month at home. Patients were then re-assessed. After a one-month washout period, they were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters (speed, stance time and step length) were observed with active nVNS. While serum tumor necrosis factor- α decreased, glutathione and brain-derived neurotrophic factor levels increased significantly (p < 0.05) after active nVNS treatment. Here we present the first evidence of the efficacy and safety of nVNS in the treatment of gait in PD patients, and propose that nVNS can be used as an adjunctive therapy in the management of PD patients, especially those suffering from FOG. Clinical trial registration: identifier ISRCTN14797144.

Non-Invasive Vagal Nerve Stimulation Pre-Treatment Reduces Neurological Dysfunction After Closed Head Injury in Mice.

Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1β) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1β activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.

Non-invasive vagus nerve stimulation therapy for severe pharmacoresistant restless legs syndrome: efficacy and tolerance at 6 months

Non-invasive vagus nerve stimulation therapy for severe pharmacoresistant restless legs syndrome: efficacy and tolerance at 6 months

Vagus nerve stimulation inhibits cortical spreading depression via glutamate-dependent TrkB activation mechanism in the nucleus tractus solitarius.

Vagus nerve stimulation (VNS) was recently found to inhibit cortical spreading depression (CSD), the underlying mechanism of migraine aura, through activation of the nucleus tractus solitarius (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DRN). The molecular mechanisms underlying the effect of VNS on CSD in these nuclei remain to be explored. We hypothesized that VNS may activate glutamate receptor-mediated tropomyosin kinase B (TrkB) signaling in the NTS, thereby facilitating the noradrenergic and serotonergic neurotransmission to inhibit CSD. To investigate the role of TrkB and glutamate receptors in non-invasive VNS efficacy on CSD, a validated KCl-evoked CSD rat model coupled with intra-NTS microinjection of selective antagonists, immunoblot and immunohistochemistry was employed. VNS increased TrkB phosphorylation in the NTS. Inhibition of intra-NTS TrkB abrogated the suppressive effect of VNS on CSD and CSD-induced cortical neuroinflammation. TrkB was found colocalized with glutamate receptors in NTS neurons. Inhibition of glutamate receptors in the NTS abrogated VNS-induced TrkB activation. Moreover, the blockade of TrkB in the NTS attenuated VNS-induced activation of the LC and DRN. VNS induces the activation of glutamate receptor-mediated TrkB signaling in the NTS, which might modulate serotonergic and norepinephrinergic innervation to the cerebral cortex to inhibit CSD and cortical inflammation.

Effect of different non-pharmacologic placebo treatments on migraine prevention: a network meta-analysis of randomized controlled trials.

Placebo control plays an important role in evaluating the effectiveness of interventions. Specifying differential effects of various placebo controls on migraine prevention would be essential in the explanation of preventive treatment for migraine and the indirect comparison between different prophylactic therapeutics. To access the impact of different non-pharmacologic placebo types on different outcomes in migraine patients. We searched PubMed, Cochrane Controlled Register of Trials, Embase, and Web of Science databases from the date of creation to June 19, 2023. Randomized controlled trials of migraine that included sham intervention of acupuncture or cognitive behavioural therapy (CBT) or non-invasive Vagus Nerve Stimulation (nVNS) or repetitive Transcranial Magnetic Stimulation (rTMS) or transcranial Direct Current Stimulation (tDCS) were conducted. The primary outcome was the migraine days, and the secondary outcomes were the number of migraine attacks, headache days, headache frequency, and responder's rate. Placebo effects were assessed using five individual placebos for network meta-analysis, using mean differences to measure the relative effect of pair-wise comparisons between interventions. A total of 50 trials with 4880 subjects were included. Twenty-seven trials were evaluated for low risk of bias. The results of indirect comparisons show that sham rTMS and sham tDCS had optimal and similar effects in reducing migraine days; sham acupuncture has the greatest effect on reducing the number of migraine attacks and relieving headache frequency; sham rTMS had a highly significant advantage in reducing headache days compared with the other placebo controls. Based on the network meta-analysis results, we found that sham acupuncture had the greatest effect on migraine prophylaxis. The strong placebo effect of sham acupuncture should be considered when assessing the therapeutic effect.

Effect of Vagal Nerve Stimulation and Jacobson Relaxation Technique on Agoraphobia among Post Neurological Ill-Patients: A Pilot Study

Background: This study was developed to determine the effectiveness of transcutaneous auricular vagus nervestimulation and Jacobson relaxation technique on agoraphobia among subjects with post neurological ill-patients.Purpose: The purpose of the study is to compare and evaluate the effectiveness of two non-pharmacologicalmethods of treatment for Agoraphobia patients with Post neurological ill-patients.Methods: The research project was conducted as a pilot study in a private hospital in Chennai. The experimentalgroup (group A) received transcutaneous auricular vagus nerve stimulation for approximately 20 minutes (30seconds ON and 5 minutes OFF) and a conventional Jacobson relaxation technique for 10 minutes. Group B gotconventional cognitive behavioral therapy (20 minutes) and the Jacobson relaxation technique (10 minutes).Following the four-week treatment period, a post-test analysis was performed using the Severity measure ofagoraphobia.Results: The study found that there is a positive impact of transcutaneous auricular vagus nerve stimulation andJacobson relaxation technique on agoraphobia in post neurological ill patients. The analysis obtained a mean valueof about 18 and an SD of 26 for group A, whereas group B revealed 24.8 ± 4.40, mean ± SD, and a significant Pvalue of &lt;0.001.Conclusion: When compared to group B, those in group A who received transcutaneous auricular vagus nervestimulation improved more significantly when dealing with agoraphobia of post neurological ill patients. As aresult, non-invasive transcutaneous auricular vagus nerve stimulation and Jacobson relaxation technique havebeen proven to be effective approaches for preventing agoraphobia.

Effect of non-invasive transcutaneous auricular vagus nerve stimulation on cerebral motor excitability-Study protocol for a randomized, sham controlled trial.

www.drks.de, number: DRKS00029937.

Effects of a single session of noninvasive auricular vagus nerve stimulation on sports performance in elite athletes: an open-label randomized controlled trial

ABSTRACT Objectives The purpose of this study was to investigate the efficacy of noninvasive auricular vagus nerve stimulation (AVNS) on sports performance. Methods The intervention group (n = 30) received a single session of AVNS, while the control group (n = 30) received a single session of sham AVNS. Pre- and post-treatment isometric quadriceps muscle strength, heart rate, lower extremity balance, and grip strength were measured. Results It was ascertained that the differences in heart rate (−0.73 pulse/min, p = 0.032) and modified Star Balance Test scores (anterior 2.72 cm, p = 0.000, posterolateral 3.65 cm, p = 0.000 and posteromedial 2.43 cm, p = 0.000) before and after AVNS were significant in subjects in the experimental group. The results of the one-way ANOVA analysis show that the differences obtained in all measurement parameters are not statistically significant (p > 0.05). Considering the partial eta squared (η2) obtained from the measurements, a small descriptive effect in favor of experimental group was obtained for the quadriceps strength (0.016) and anterior balance (0.054) measurements. Conclusion This study demonstrates that a single AVNS session compared to sham AVNS shows a modest benefit though not statistically significant improvement in athletic performance. Single-use of AVNS seems not effective in improving athletic performance. Clinical trial registration www.clinicaltrials.gov identifier NCT05436821.

Advances in Non-Invasive Neuromodulation: Designing Closed-Loop Devices for Respiratory-Controlled Transcutaneous Vagus Nerve Stimulation.

Studies suggest non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) as a potential therapeutic option for various pathological conditions, such as epilepsy and depression. Exhalation-controlled taVNS, which synchronizes stimulation with internal body rhythms, holds promise for enhanced neuromodulation, but there is no closed-loop system in the literature capable of performing such integration in real time. In this context, the objective was to develop real-time signal processing techniques and an integrated closed-loop device with sensors to acquire physiological data. After a conditioning stage, the signal is processed and delivers synchronized electrical stimulation during the patient's expiratory phase. Additional modules were designed for processing, software-controlled selectors, remote and autonomous operation, improved analysis, and graphical visualization. The signal processing method effectively extracted respiratory cycles and successfully attenuated signal noise. Heart rate variability was assessed in real time, using linear statistical evaluation. The prototype feedback stimulator device was physically constructed. Respiratory peak detection achieved an accuracy of 90%, and the real-time processing resulted in a small delay of up to 150 ms in the detection of the expiratory phase. Thus, preliminary results show promising accuracy, indicating the need for additional tests to optimize real-time processing and the application of the prototype in clinical studies.