Non-invasive Vagus Nerve Stimulation Research Articles

A Critical Review of Noninvasive Brain Stimulation Technologies in Alzheimer's Dementia and Primary Progressive Aphasia.

Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer's disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer's Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters.

Parameter optimization of non-invasive vagus nerve stimulation for second language learning in typically developing young adults

Although the ability to acquire a second language (L2) and attain fluency in that language is beneficial for a growing number of people, it is significantly more difficult to acquire such skills in adulthood. While traditional in-person and computer training programs can aid in this process, learning is often slow and retention is quite poor. A method for driving long-lasting neural plasticity during language learning would be valuable for those who need or want to achieve fluency in a second language later in life. However, little is known about the effect of neuromodulation methods on language learning. In the current study, we investigated the effect of non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) on vocabulary word-learning in healthy young adults. Importantly, we approached this research question by investigating two key parameters of taVNS, stimulation frequency (Experiment 1) and current intensity (Experiment 2). Typically developing young adults completed a 1-h training session in which they learned 30 concrete, Palauan nouns while receiving real or sham stimulation to the left posterior tragus (Experiment 1) or stimulation at various intensities (Experiment 2). Participants completed a Palau-to-English translation test immediately after training and seven days later to quantify learning and retention. The results largely revealed that high frequency stimulation above sensory threshold improved retention of learned words. These results suggest that taVNS may improve retention of vocabulary words in a second language and that stimulation frequency may impact efficacy.

Effects of Transcutaneous Auricular Vagus Nerve Stimulation on the P300: Do Stimulation Duration and Stimulation Type Matter?

Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has attracted increasing interest as a neurostimulation tool with potential applications in modulating cognitive processes such as attention and memory, possibly through the modulation of the locus-coeruleus noradrenaline system. Studies examining the P300 brain-related component as a correlate of noradrenergic activity, however, have yielded inconsistent findings, possibly due to differences in stimulation parameters, thus necessitating further investigation. In this event-related potential study involving 61 participants, therefore, we examined how changes in taVNS parameters, specifically stimulation type (interval vs. continuous stimulation) and duration, influence P300 amplitudes during a visual novelty oddball task. Although no effects of stimulation were found over the whole cluster and time window of the P300, cluster-based permutation tests revealed a distinct impact of taVNS on the P300 response for a small electrode cluster, characterized by larger amplitudes observed for easy targets (i.e., stimuli that are easily discernible from standards) following taVNS compared to sham stimulation. Notably, our findings suggested that the type of stimulation significantly modulated taVNS effects on the P300, with continuous stimulation showing larger P300 differences (taVNS vs. sham) for hard targets and standards compared to interval stimulation. We observed no interaction effects of stimulation duration on the target-related P300. While our findings align with previous research, further investigation is warranted to fully elucidate the influence of taVNS on the P300 component and its potential utility as a reliable marker for neuromodulation in this field.

Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model.

Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α1-, α2-, or β-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the β-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS. These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through β-adrenergic receptor activation.

Transcutaneous auricular vagus nerve stimulation to acutely reduce emotional vulnerability and improve emotional regulation in borderline personality disorder (tVNS-BPD): study protocol for a randomized, single-blind, sham-controlled trial

BackgroundBorderline personality disorder (BPD) is considered a disorder of emotion regulation resulting from the expression of a biologically determined emotional vulnerability (that is, heightened sensitivity to emotion, increased emotional intensity/reactivity, and a slow return to emotional baseline) combined with exposure to invalidating environments. Vagal tone has been associated with activity in cortical regions involved in emotion regulation and a lower resting state of vagal tone has been observed in BPD patients relative to healthy controls. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to reduce temper outbursts in adults with Prader-Willi Syndrome, to enhance recognition of emotions in healthy students, and to improve depressive and anxiety symptoms. Furthermore, a single session of taVNS has been shown to acutely alter the recognition of facial expressions of negative valence in adolescents with MDD and increase emotion recognition in controls. However, the effect of taVNS on emotional vulnerability and regulation in individuals diagnosed with BPD has not been investigated. Our aims are to determine if taVNS is effective in acutely reducing emotional vulnerability and improve emotional regulation in BPD patients.MethodsForty-two patients will be randomized to a single session of taVNS or sham-taVNS while going through an affect induction procedure. It will consist of the presentation of one neutral and three negative affect-evoking 4-min-long videos in sequence, each of which is followed by a 4-min post-induction period during which participants will rate the quality and intensity of their current self-reported emotions (post-induction ratings) and the perceived effectiveness in managing their emotions during the video presentation. The rating of the current self-reported emotions will be repeated after every post-induction period (recovery ratings). Mixed models with individuals as random effect will be used to investigate the ratings at each stage of the study, taking into account the repeated measures of the same individuals at baseline, pre-induction, post-induction, and recovery.DiscussionThe study has potential to yield new insights into the role of vagal tone in emotion dysregulation in BPD and offer preliminary data on the effectiveness of taVNS as a possible non-invasive brain stimulation to treat a core symptom of BPD.Trial registrationClinicalTrials.gov NCT05892900. Retrospectively registered on Jun 07, 2023.

Dual-mode electromagnetic-triboelectric-piezoelectric multifunctional self-charging energy system for efficient capture of kinetic energy

This study presents an innovative dual-mode electromagnetic-triboelectric-piezoelectric multifunctional self-charging energy system (MS-CES) that integrates two different operating modes of electromagnetic generators for contact-separation (CS-EMG) and non-contact (NC-EMG), as well as a triboelectric nanogenerator (TENG) and a piezoelectric nanogenerator (PENG). The system has an energy management circuit that efficiently captures and converts kinetic energy from the environment. We investigate the output performance of each unit of the MS-CES under different vibration frequencies and amplitudes. The units work together through a compact mechanical structure design to achieve high voltage output while shortening charging time based on improved space utilization, thus gaining more efficient energy storage. Polyacrylonitrile (PAN) powder and barium titanate (BTO) composite nanofibre membrane (PAN/BTO) as PENG material further enhances the system's output performance. The system provides a continuous power source for the vibration sensors. It enables human-computer interaction with mobile phones and computers via Bluetooth modules, enabling real-time monitoring and analysis of vibration parameters. Furthermore, we have validated the feasibility of using the MS-CES to power a noninvasive vagus nerve stimulation device, providing new technological means for monitoring and treatment in the medical field.

Neurorehabilitation with vagus nerve stimulation: a systematic review.

To systematically review vagus nerve stimulation (VNS) studies to present data on the safety and efficacy on motor recovery following stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). Data sources: PubMed, EMBASE, SCOPUS, and Cochrane. Clinical trials of VNS in animal models and humans with TBI and SCI were included to evaluate the effects of pairing VNS with rehabilitation therapy on motor recovery. Two reviewers independently assessed articles according to the evaluation criteria and extracted relevant data electronically. Twenty-nine studies were included; 11 were animal models of stroke, TBI, and SCI, and eight involved humans with stroke. While there was heterogeneity in methods of delivering VNS with respect to rehabilitation therapy in animal studies and human non-invasive studies, a similar methodology was used in all human-invasive VNS studies. In animal studies, pairing VNS with rehabilitation therapy consistently improved motor outcomes compared to controls. Except for one study, all human invasive and non-invasive studies with controls demonstrated a trend toward improvement in motor outcomes compared to sham controls post-intervention. However, compared to non-invasive, invasive VNS, studies reported severe adverse events such as vocal cord palsy, dysphagia, surgical site infection, and hoarseness of voice, which were found to be related to surgery. Our review suggests that VNS (non-invasive or invasive) paired with rehabilitation can improve motor outcomes after stroke in humans. Hence, VNS human studies are needed in these populations (referring to SCI and TBI?) or just SCI. There are risks related to device implantation to deliver invasive VNS compared to non-invasive VNS. Future human comparison studies are required to study and quantify the efficacy vs. risks of paired VNS delivered via different methods with rehabilitation, which would allow patients to make an informed decision. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=330653.

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.

Efficacy of Vagal nerve stimulation on anxiety among elderly retired teachers during COVID-19 pandemic.

Excessive fear, worry and behavioral disturbances define anxiety, with particular significance attributed to vagal nerve, a crucial transmitter of information to the brain regions governing anxiety. Highlighting the importance of vagal nerve, transcutaneous auricular vagal nerve stimulation (TaVNS) emerges as a tolerable and safe technique. The success of non-invasive vagal nerve stimulation in alleviating anxiety underscores the pivotal role of the vagal nerve. The purpose of this study was to assess the effectiveness of physiotherapy interventions in mitigating anxiety among retired teachers during the COVID-19 pandemic, emphasizing the relevance of targeting the vagal nerve for improved mental well-being. 60 retired teachers diagnosed with anxiety were chosen through random allocation. Participants were divided into two groups: Group A (Experimental group) received transcutaneous auricular vagal nerve stimulation (TaVNS), and Group B (Control group) underwent the Jacobson relaxation technique. Intervention period spanned 4 weeks, with four sessions per week, lasting 30 minutes. The outcome measures included Generalized Anxiety Disorder-7 (GAD-7) questionnaire and salivary cortisol levels. Following the 4-week intervention, both groups exhibited a significant reduction in Generalized Anxiety Disorder-7 (GAD-7) scores and salivary cortisol levels (P < 0.001). Notably, Group A demonstrated a significantly higher effectiveness rate compared to Group B. The study concludes that transcutaneous auricular vagal nerve stimulation (TaVNS) is effective in reducing anxiety among retired teachers. Transcutaneous auricular vagal nerve stimulation (TaVNS) proves to be a powerful and effective intervention in alleviating anxiety among retired teachers, emphasizing its potential significance in enhancing mental well-being.

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.