Sham tVNS Research Articles

Transcutaneous vagus nerve stimulation has no anti-inflammatory effect in diabetes

Chronic inflammation is associated with diabetes and contributes to the development and progression of micro- and macrovascular complications. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to reduce levels of circulating inflammatory cytokines in non-diabetics by activating the cholinergic anti-inflammatory pathway. We investigated the anti-inflammatory potential of tVNS as a secondary endpoint of a randomized controlled trial in people with diabetes (NCT04143269). 131 people with diabetes (type 1: n = 63; type 2: n = 68), gastrointestinal symptoms and various degrees of autonomic neuropathy were included and randomly assigned to self-administer active (n = 63) or sham (n = 68) tVNS over two successive study periods: (1) Seven days with four daily administrations and, (2) 56 days with two daily administrations. Levels of systemic inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α, IFN-γ) were quantified from blood samples by multiplex technology. Information regarding age, sex, diabetes type, and the presence of cardiac autonomic neuropathy (CAN) was included in the analysis as possible confounders. No differences in either cytokine were seen after study period 1 and 2 between active and sham tVNS (all p-values > 0.08). Age, sex, diabetes type, presence of CAN, and baseline levels of inflammatory cytokines were not associated with changes after treatment (all p-values > 0.07). A tendency towards slight reductions in TNF-α levels after active treatment was observed in those with no CAN compared to those with early or manifest CAN (p = 0.052). In conclusion, tVNS did not influence the level of systemic inflammation in people with diabetes.

Transcutaneous vagal nerve stimulation for treating gastrointestinal symptoms in individuals with diabetes: a randomised, double-blind, sham-controlled, multicentre trial

Aims/hypothesisDiabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study.MethodsThis study included adults (aged 20–86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function.ResultsSixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: −0.26 ± 0.64 vs −0.17 ± 0.62, p=0.44; GSRS: −0.35 ± 0.62 vs −0.32 ± 0.59, p=0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: −0.47 ± 0.78 vs −0.33 ± 0.75, p=0.34; GSRS: −0.46 ± 0.90 vs −0.35 ± 0.79, p=0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs −19 min, p=0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p>0.05). The tVNS was well-tolerated.Conclusions/interpretationCervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy.Trial registrationClinicalTrials.gov NCT04143269FundingThe study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045)Graphical

Integrative effects of transcutaneous auricular vagus nerve stimulation on esophageal motility and pharyngeal symptoms via vagal mechanisms in patients with laryngopharyngeal reflux disease.

Laryngopharyngeal reflux disease (LPRD) is primarily characterized by discomfort in the pharynx and has limited treatment options. This research aimed to assess the efficacy of transcutaneous auricular vagus nerve stimulation (tVNS) in patients with LPRD and delve into the potential underlying mechanisms. A total of 44 participants, diagnosed with LPRD were divided into two groups randomly. Twice-daily stimulation was delivered for 2 weeks for patients in experimental group, with stimulation ranging from 1.0 mA to 1.5 mA (n = 22), while the control group underwent sham tVNS (n = 22) with the same stimulation parameters and different anatomical location. The severity of symptoms and levels of anxiety and depression were monitored using questionnaires. High-resolution esophageal manometry data were collected, and the patients' autonomic function was assessed through heart rate variability analysis. There was a positive correlation between reflux symptom index (RSI) scores and low frequency/high frequency (LF/HF) ratio (r = 0.619; p < 0.001), Hamilton anxiety scale (HAMA) scores (r = 0.623; p < 0.001), and Hamilton depression scale (HAMD) scores (r = 0.593; p < 0.001). Compared to the pre-tVNS phase, RSI (p < 0.001), HAMA (p < 0.001), and HAMD (p < 0.001) scores were significantly reduced after 2 weeks of treatment. Additionally, the resting pressure of the upper esophageal sphincter (UESP; p < 0.05) and lower esophageal sphincter (LESP; p < 0.05) showed significant enhancement. Notably, tVNS led to an increase in root mean square of successive differences (RMSSD; p < 0.05) and high frequency (HF; p < 0.05) within heart rate variability compared to the pre-treatment baseline. Compared to the control group, RSI (p < 0.001), HAMA (p < 0.001), and HAMD (p < 0.001) scores in tVNS group were significantly lower at the end of treatment. Similarly, the resting pressure of UESP (p < 0.05) and LESP (p < 0.05) in tVNS group were significantly higher than that of control group. Notably, RMSSD (p < 0.05) and HF (p < 0.05) in tVNS group were significantly higher than that of control group. This study demonstrated that tVNS as a therapeutic approach is effective in alleviating LPRD symptoms. Furthermore, it suggests that improvements in esophageal motility could be associated with vagus nerve-dependent mechanisms.

Pairing transcutaneous vagus nerve stimulation with an intensive bimanual training in children and adolescents with cerebral palsy: study protocol of a randomized sham-controlled trial.

Gross motor function impairments and manual dexterity deficits are frequently observed in children and adolescents with Cerebral Palsy (CP), having a major impact on their activity level and autonomy. Improving manual dexterity and activity level of patients with CP is often the focus of rehabilitation. Novel and adjuvant treatment methods that could support the standard training also in chronic conditions are a research priority. The transcutaneous Vagus Nerve Stimulation (tVNS) is a non-invasive brain stimulation technique, which provides a bottom-up stimulation of subcortical and cortical brain structures, enhancing brain GABA and Noradrenaline levels. This technique may play a pivotal role in brain plasticity, which has not been tested in CP patients before. 44 children and adolescents with CP will be involved, treated in pairs in a randomized, double-blind, pre-post test study. The two groups will undergo the Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) for 2 consecutive weeks, with 3 h daily sessions for 5 days per week, for an overall time interval of 30 h; the training will be combined with the application for 75 min/day of active or sham tVNS, in separate, randomly allocated groups. The primary outcome measure will include the scores at the Assisting Hand Assessment and Box and Block Test, and at an ad-hoc visuomotor task evaluating manual visuomotor control. Secondary outcomes will include the scores at the Children's Hand Experience Questionnaire, Canadian Occupational Performance Measure, Melbourne Assessment of Unilateral Upper Limb Function, Gross Motor Function Measure, Vineland, Pediatric quality of life inventory. The evaluation points will include pre (T0), post (T1) and 3-month follow up (T2) assessments. Safety and tolerability will also be assessed. The results of this trial will assess whether tVNS can effectively boost the effects of an intensive two-week bimanual training, in improving manual dexterity in children and adolescents with cerebral palsy, ensuring safety and tolerability throughout the intervention period.Clinical trial registration: ClinicalTrials.gov, NCT06372028.

Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol

BackgroundOver 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5–15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI.DesignVINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI.DiscussionVINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT05514756. Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.)

Synergistic effects of transcutaneous vagus nerve stimulation and inhibitory control training on electrophysiological performance in healthy adults.

Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive nerve stimulation technique that exerts a positive "exogenous" online neuromodulatory effect on inhibitory control (IC). Additionally, IC training (ICT) is an effective approach for enhancing IC via the "endogenous" activation of brain regions implicated in this process. The aim of the present study was to examine the synergistic effects of tVNS and ICT on IC enhancement. For this, we measured the changes in neural activity in frontal, fronto-central, and central regions in the time domain of the N2 component and the frequency domain of alpha power during the stop signal task. A total of 58 participants were randomly divided into four groups that received five sessions of either ICT or sham ICT with either online tVNS or sham tVNS. No differences in N2 amplitude were detected after any of the interventions. However, N2 latency shortened after tVNS + ICT in frontal, fronto-central, and central regions. N2 latency shortened after the intervention of sham tVNS + ICT in frontal region. Moreover, alpha power after tVNS + ICT intervention was larger than those of the other interventions in frontal, fronto-central, and central regions. The obtained electrophysiological data suggested that combining tVNS with ICT has synergistic ameliorative effects on IC, and provide evidence supporting the IC-enhancing potential of tVNS combined with ICT.

Transauricular vagus nerve stimulation for patients with disorders of consciousness: A randomized controlled clinical trial.

Disorders of consciousness (DoCs) are a frequent complication of brain injury disease, and effective treatments are currently lacking. Transauricular vagus nerve stimulation (tVNS) has been proposed as a promising therapeutic method for neurological disorders such as epilepsy and depression. In our previous study, we demonstrated that vagus nerve stimulation promoted recovery in rats with DoCs caused by traumatic brain injury. However, the clinical effect of vagus nerve stimulation on consciousness disorders is unclear. We aimed to investigate the therapeutic efficacy and safety of tVNS in patients with DoCs. We conducted a randomized, double-blinded, sham-controlled trial. Patients (N = 60) with DoCs, including minimally conscious state (MCS) and vegetative state/unresponsive wakefulness syndrome, were enrolled and randomized to groups receiving either active or sham tVNS. A frequency of 20 Hz and pulse wave of 200 us was used in the active-tVNS protocol, which was performed in the auricular branch of the vagus nerve in the left outer ear. The sham-tVNS protocol was the same as the active-tVNS protocol although without current input. Both groups of patients also received conventional treatments. Consciousness was evaluated according to the Coma Recovery Scale-Revised before and after the 4-week intervention. We also recorded the type and number of behavioral responses. Safety was primarily assessed according to the incidence of treatment-emergent adverse events. Each patient's heart rate and blood pressure were monitored during all treatment sessions. Ultimately, 57 patients completed the study: 28 patients underwent active tVNS and 29 patients underwent sham tVNS. No significant differences were observed in Coma Recovery Scale-Revised scores between the active- and sham-tVNS groups before the tVNS sessions. Compared with patients in the sham-tVNS group (9.28 ± 4.38), patients with DoCs treated with active tVNS showed improved consciousness (10.93 ± 4.99), although not statistically significant. Further analysis revealed obvious differences between patients with MCS receiving active and sham tVNS, but no significant difference in patients with vegetative state/unresponsive wakefulness syndrome in both groups. All side effects were considered common medical conditions with no obvious correlation to tVNS. These preliminary data provide early evidence that tVNS may be an effective and safe approach for promoting the recovery of consciousness, especially in patients with MCS. https://www.chictr.org.cn/edit.aspx?pid=175938&htm=4, identifier: ChiCTR2200066629.

Motor and Cognitive Modulation of a Single Session of Transcutaneous Auricular Vagus Nerve Stimulation in Post Stroke Patients: A Pilot Study.

Objective: The aim of the present study is to explore whether a single session of transcutaneous Vagus Nerve Stimulation (tVNS) can enhance the ipsilesional, and contralesional upper limb motor functions as well as cognitive functions in stroke patients. The effects of the stimulation were evaluated through two different tasks: the box and blocks test (BB), indexing manual dexterity, and the Go/No-go task, a visuomotor paradigm used to assess both motor readiness and response inhibition. Tests were administered without tVNS, during tVNS and during sham tVNS. Results: The BB showed a statistical difference for both contralesional side (p = 0.05) between Basal-Real condition (p = 0.042) and ipsilesional side (p = 0.001) between Basal-Real (p = 0.008) and for Real-Sham (p = 0.005). Any statistical difference was found for the mean latencies in the three conditions of the Go/No-go test. Conclusion: A single session of tVNS seems to improve upper limb motor functions but not cognitive functions in post-stroke patients, despite a positive trend was detected.

Impact of Transcutaneous Vagal Nerve Stimulation (Tvns) Priming on Therapy Outcomes for People With Aphasia

<h3>Research Objectives</h3> To investigate the impact of tVNS on therapy outcomes for aphasia. <h3>Design</h3> A double-blind, crossover intervention study design was used to allow for both within-subject and between-subject comparison of tVNS vs. sham condition. Participants were randomly assigned to either the active tVNS priming condition or the sham priming condition for the first half of treatment (5-6 weeks) and switched condition for the second half with the sham group then receiving active tVNS and the formerly active tVNS group receiving sham stimulation. <h3>Setting</h3> University of Maryland Hearing and Speech Clinic, College Park, MD. <h3>Participants</h3> Participants with aphasia due to stroke were recruited from the Washington, DC area; Participants were ineligible if they had certain medical conditions (eg. cancer) or implanted devices (e.g. pacemaker). Participants with a history of cardiac disease or seizures required medical clearance out of an abundance of caution. Participants were excluded for severe apraxia of speech, cognitive deficits and hearing loss. Eight participants (3m, 5f) with mild to moderate aphasia completed the study, 7 did not meet inclusion criteria, withdrew or were disrupted. No one dropped due to adverse events. Participants ranged from 22 to 75 years-old (avg. 52.9) and were between 7 months and 15 years post-onset. <h3>Interventions</h3> Participants received five minutes of either active or sham tVNS via an earbud prior to word-finding therapy. <h3>Main Outcome Measures</h3> The Western Aphasia Battery, Test of Word Finding in Adults, Boston Naming Test, F-A-S Task, Communication Confidence Rating Scale for Aphasia were completed at baseline, midterm, and post-treatment. <h3>Results</h3> Results are still being collected but suggest that tVNS priming may have only minimal impact on outcomes; recent work from other labs suggests that tVNS at the moment of encoding may have stronger impact, whereas priming may be more facilitative of retrieval. <h3>Conclusions</h3> TVNS is a low cost, safe, accessible modality with the potential to improve aphasia outcomes, but further work is needed to identify if and how it can be best used with this population. <h3>Author(s) Disclosures</h3> See individual author disclosures.

Meditative-based diaphragmatic breathing vs. vagus nerve stimulation in the treatment of fibromyalgia—A randomized controlled trial: Body vs. machine

Vagus nerve innervation via electrical stimulation and meditative-based diaphragmatic breathing may be promising treatment avenues for fibromyalgia. Explore and compare the treatment effectiveness of active and sham transcutaneous vagus nerve stimulation (tVNS) and meditative-based diaphragmatic breathing (MDB) for fibromyalgia. Participants enrolled from March 2019-October 2020 and randomly assigned to active tVNS (n = 28), sham tVNS (n = 29), active MDB (n = 29), or sham MDB (n = 30). Treatments were self-delivered at home for 15 min/morning and 15 min/evening for 14 days. Follow-up was at 2 weeks. Outpatient pain clinic in Oslo, Norway. 116 adults aged 18-65 years with severe fibromyalgia were consecutively enrolled and randomized. 86 participants (74%) had an 80% treatment adherence and 107 (92%) completed the study at 2 weeks; 1 participant dropped out due to adverse effects from active tVNS. Active tVNS is placed on the cymba conchae of the left ear; sham tVNS is placed on the left earlobe. Active MDB trains users in nondirective meditation with deep breathing; sham MDB trains users in open-awareness meditation with paced breathing. Primary outcome was change from baseline in ultra short-term photoplethysmography-measured cardiac-vagal heart rate variability at 2 weeks. Prior to trial launch, we hypothesized that (1) those randomized to active MDB or active tVNS would display greater increases in heart rate variability compared to those randomized to sham MDB or sham tVNS after 2-weeks; (2) a change in heart rate variability would be correlated with a change in self-reported average pain intensity; and (3) active treatments would outperform sham treatments on all pain-related secondary outcome measures. No significant across-group changes in heart rate variability were found. Furthermore, no significant correlations were found between changes in heart rate variability and average pain intensity during treatment. Significant across group differences were found for overall FM severity yet were not found for average pain intensity. These findings suggest that changes in cardiac-vagal heart rate variability when recorded with ultra short-term photoplethysmography in those with fibromyalgia may not be associated with treatment-specific changes in pain intensity. Further research should be conducted to evaluate potential changes in long-term cardiac-vagal heart rate variability in response to noninvasive vagus nerve innervation in those with fibromyalgia. https://clinicaltrials.gov/ct2/show/NCT03180554, Identifier: NCT03180554.

The use of transcutaneous Vagal Nerve Stimulation as an effective countermeasure for Simulator Adaptation Syndrome

This research focused on investigating the effectiveness of Transcutaneous Vagal Nerve Stimulation (tVNS) as compared to Galvanic Cutaneous Stimulation (GCS) at mitigating Simulator Adaptation Syndrome (SAS). Fifty drivers (mean age = 23.04 ± 17.71 years old, twenty-two men) participated in a driving simulation experiment. The total scores of the Simulator Sickness Questionnaire, head movements (body balance index), and driving performance variables were measured under five stimulation conditions: i) baseline (no stimulation delivered), ii) sham GCS, iii) sham tVNS, iv) active GCS, and v) active tNVS. The results showed that tVNS alleviated SAS and improved driving performance variables more effectively than GCS. We conclude that GCS and tVNS have similar neurological mechanisms to reduce SAS, providing possible explanations for the greater effectiveness of tVNS. We encourage the use of tVNS to decrease SAS.

The Role of Transcutaneous Vagal Nerve Stimulation in Cancer-Related Fatigue and Quality of Life in Breast Cancer Patients Receiving Radiotherapy: A Randomized, Double-Blinded and Placebo-Controlled Clinical Trial

<h3>Purpose/Objective(s)</h3> Cancer-related fatigue (CRF) is the most common symptom in breast cancer patients treated with radiotherapy (RT). Acupuncture was reported to be effective in the management of CRF due to enhanced vagus nerve activity and improved lymphopenia. We hypothesized that transcutaneous vagal nerve stimulation (tVNS) is effective for CRF in a more convenient and non-invasive way. <h3>Materials/Methods</h3> From April 2020 to December 2021, a total of 247 breast cancer patients receiving RT to the breast/chest wall ± regional lymph nodes were included in this study. Patients were randomized 2:1 to the tVNS group (n=163) or the sham tVNS group (stVNS group, n=84). The electrode clip was placed on the tragus with power on or off, once daily throughout RT. Both the patient and the assessing physician were blinded to the assignment. The primary endpoint was improvement of CRF in one month after RT (measured by the Brief Fatigue Inventory, BFI) and the change of lymphocytes during RT. Secondary endpoint included anxiety and depression (measured by Hospital Anxiety and Depression Scale, HADS), the sleep dysfunction (measured by Pittsburgh Sleep Quality Index, PSQI), and quality of life (measured by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire, EORTC QLQ-C30). ClinicalTrials.gov Identifier: NCT04563013. <h3>Results</h3> Baseline characteristics were well balanced between the two groups. In CRF improvement, the median (quartile) of BFI total score and comprehensive fatigue effect score of tVNS group was significantly lower than that in stVNS group (1.0 [0.3, 2.2] vs 1.7 [0.7, 3.6], <i>p</i>=0.015; 0.8 [0, 1.6] vs 1.4 [0.7, 3.8], <i>p</i>=0.005, respectively). The change in lymphocytes of tVNS group were significantly less than that in stVNS group from baseline to week 4 (median, -0.8 × 10⁹/L vs -1.0 × 10⁹/L, <i>p</i>=0.014), and to the end of RT (median, -0.9 × 10⁹/L vs -1.0 × 10⁹/L, <i>p</i>=0.004). In terms of psychological status, tVNS significantly lowered the total score (median, 3.0 vs 7.0, <i>p</i>=0.012) and the depression score (median, 1.0 vs 3.0, <i>p</i>=0.005) of HADS one month after RT. No significant difference in anxiety scores between the two groups (median, 2.0 vs 4.0, <i>p</i>=0.085). Patients in tVNS group had less sleep latency (median scores, 1.0 vs 2.0, <i>p</i>=0.042) and better social functioning (median scores, 100.0 vs 83.3, <i>p</i>=0.020) than stVNS group in one month after RT. No ear irritation or obvious changes in the external skin were observed. <h3>Conclusion</h3> tVNS can significantly improve the CRF, lymphopenia, and quality of life in breast cancer patients receiving RT.

Vagus nerve stimulation as a novel treatment for systemic lupus erythematous: study protocol for a randomised, parallel-group, sham-controlled investigator-initiated clinical trial, the SLE-VNS study

IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease. SLE is treated with immunosuppressants with suboptimal efficacy and high risk of serious side effects. Patients with SLE have increased risk...

A two-week course of transcutaneous vagal nerve stimulation improves global sleep: Findings from a randomised trial in community-dwelling adults.

Short sleep duration and poor sleep quality are common in the general population. This study tested if a 2-week course of daily transcutaneous vagal nerve stimulation (tVNS) improves sleep in community-dwelling adults. Participants were n=68 men and women aged 18-75years randomised into four groups: early and sham tVNS and late and sham tVNS. Early groups underwent daily 4h stimulation between Day 0 and 13, while late groups underwent daily 4h stimulation between Day 14 and 28. tVNS was performed with transcutaneous electrical nerve stimulation (TENS) on the left tragus, and sham tVNS (control conditions) was applied on the left earlobe. Sleep was measured with the Pittsburgh Sleep Quality Index. Analysis of prespecified contrasts (C), based on linear mixed modelling, revealed that for tVNS there were significant improvements in global sleep scores over time between Day 0 and Day 13 in the early stimulation phase (C=-1.90; 95% CI=-2.87 to -0.94), and between Day 14 and Day 28 in the late phase (C=-0.87; 95% CI=-1.41 to -0.32). No such differences were found under sham tVNS (applied early or late). However, global sleep scores showed no significant improvement under tVNS when compared against control groups during both the early (χ2=0.83, p=0.36), or late stimulation phase (χ2=0.24, p=0.63). We showed that two weeks of tVNS improves global sleep scores, but the change in sleep was not significantly different to control groups. Further studies are warranted to test the utility of tVNS in alleviating sleep complains in community-dwelling adults.

Training and Transfer Effects of Combining Inhibitory Control Training With Transcutaneous Vagus Nerve Stimulation in Healthy Adults.

Inhibitory control training (ICT) is a promising method to improve individual performance of inhibitory control (IC). Recent studies have suggested transcutaneous vagus nerve stimulation (tVNS) as a novel approach to affect cognitive function owing to its ability to modulate the locus coeruleus-noradrenaline system. To examine the synergistic effects of combining ICT with tVNS, 58 young males in college were randomly assigned to four groups: ICT + tVNS, ICT + sham tVNS, sham ICT + tVNS, and sham ICT + sham tVNS. Participants were instructed to complete three sessions that comprised pre-training tests, a training session, and post-training tests sequentially. Results showed that the ICT + tVNS group significantly improved training and near-transfer effects on the stop-signal and Go/No-go tasks, and these effects were larger than those of the other groups. However, none of the groups exhibited the far-transfer effect on the color-word Stroop task. These results suggest that tVNS augments the intervention effects of training and similar inhibition tasks to achieve the synergistic effect; however, it does not modulate the effects of non-training tasks and obtain the far-transfer effect. ICT combined with tVNS may be a valuable intervention for improving IC in healthy individuals in certain industries and offers novel research ideas for using tVNS for cognitive improvement.

Efficacy of transcutaneous vagus nerve stimulation as treatment for depression: A systematic review

• We conducted a systematic review to assess the efficacy of tVNS in depression. • Only two studies comparing tVNS with sham tVNS were included. • The studies included had several study limitations and imprecision. • It is uncertain whether tVNS reduces depressive symptoms and anxiety. • More studies are needed to explore the efficacy of tVNS in depression. Transcutaneous vagus nerve stimulation (tVNS) has been suggested as a treatment method for depression. A systematic review to systematically evaluate the efficacy of tVNS for the treatment of depression was conducted according to PRISMA guidelines. Primary outcomes were mortality, self-harm, depressive symptoms, and health-related quality of life (HRQoL). Secondary outcomes were anxiety symptoms, medication use, everyday functioning, complications, and patients’ experiences of treatment. Five databases were searched systematically. The included articles were critically appraised and certainty of evidence was assessed using GRADE. Two studies evaluating efficacy and a case series collecting data on complications were included. One randomized trial ( n = 37) and one cohort study ( n = 160) comparing tVNS with sham-tVNS reported significant reduction in the tVNS group of self-rated (SMD = -0.82, 95%-CI = -1.50, -0.15) but not clinician-rated depressive symptoms, after two weeks, and of both self-rated (SMD = -0.99, 95%-CI = -1.32, -0.66) and clinician-rated (SMD = -0.89, 95%-CI = -1.22, -0.57) depressive symptoms, after four weeks, respectively. Furthermore, the cohort study found reduction of both self-rated (SMD = -0.66, 95%-CI = -0.98, -0.34) and clinician-rated (SMD = -0.14, 95%-CI = -0.46, 0.17) anxiety symptoms. One case series ( n = 12), collecting data on complications, reported mild to moderate transient side effects. Available studies are few and heterogeneous, have major study limitations, problems with directness and imprecision. It is uncertain whether tVNS reduces depressive symptoms and anxiety. Although existing studies show promising results, further studies are needed to increase the certainty of evidence.

Recognizing emotions in bodies: Vagus nerve stimulation enhances recognition of anger while impairing sadness

According to the Polyvagal theory, the vagus nerve is the key phylogenetic substrate that supports efficient emotion recognition for promoting safety and survival. Previous studies showed that the vagus nerve affects people’s ability to recognize emotions based on eye regions and whole facial images, but not static bodies. The purpose of this study was to verify whether the previously suggested causal link between vagal activity and emotion recognition can be generalized to situations in which emotions must be inferred from images of whole moving bodies. We employed transcutaneous vagus nerve stimulation (tVNS), a noninvasive brain stimulation technique that stimulates the vagus nerve by a mild electrical stimulation to the auricular branch of the vagus, located in the anterior protuberance of the outer ear. In two sessions, participants received active or sham tVNS before and while performing three emotion recognition tasks, aimed at indexing their ability to recognize emotions from static or moving bodily expressions by actors. Active tVNS, compared to sham stimulation, enhanced the recognition of anger but reduced the ability to recognize sadness, regardless of the type of stimulus (static vs. moving). Convergent with the idea of hierarchical involvement of the vagus in establishing safety, as put forward by the Polyvagal theory, we argue that our findings may be explained by vagus-evoked differential adjustment strategies to emotional expressions. Taken together, our findings fit with an evolutionary perspective on the vagus nerve and its involvement in emotion recognition for the benefit of survival.

Motivational nondirective resonance breathing versus transcutaneous vagus nerve stimulation in the treatment of fibromyalgia: study protocol for a randomized controlled trial

BackgroundChronic widespread pain (CWP), including fibromyalgia (FM), affects one in every ten adults and is one of the leading causes of sick leave and emotional distress. Due to an unclear etiology and a complex pathophysiology, FM is a condition with few, if any, effective and safe treatments. However, current research within the field of vagal nerve innervation suggests psychophysiological and electrical means by which FM may be treated. This study will investigate the efficacy of two different noninvasive vagal nerve stimulation techniques for the treatment of FM.MethodsThe study will use a randomized, single-blind, sham-controlled design to investigate the treatment efficacy of motivational nondirective resonance breathing (MNRB™) and transcutaneous vagus nerve stimulation (Nemos® tVNS) on patients diagnosed with FM. Consenting FM patients (N = 112) who are referred to the Department of Pain Management and Research at Oslo University Hospital, in Oslo, Norway, will be randomized into one of four independent groups. Half of these participants (N = 56) will be randomized to either an experimental tVNS group or a sham tVNS group. The other half (N = 56) will be randomized to either an experimental MNRB group or a sham MNRB group. Both active and sham treatment interventions will be delivered twice per day at home, 15 min/morning and 15 min/evening, for a total duration of 2 weeks (14 days). Participants are invited to the clinic twice, once for pre- and once for post-intervention data collection. The primary outcome is changes in photoplethysmography-measured heart rate variability. Secondary outcomes include self-reported pain intensity on a numeric rating scale, changes in pain detection threshold, pain tolerance threshold, and pressure pain limit determined by computerized pressure cuff algometry, blood pressure, and health-related quality of life.DiscussionThe described randomized controlled trial aims to compare the efficacy of two vagal nerve innervation interventions, MNRB and tVNS, on heart rate variability and pain intensity in patients suffering from FM. This project tests a new and potentially effective means of treating a major public and global health concern where prevalence is high, disability is severe, and treatment options are limited.Trial registrationClinicalTrials.govNCT03180554. Registered on August 06, 2017.

Transcutaneous vagus nerve stimulation modulates attentional resource deployment towards social cues

Transcutaneous vagus nerve stimulation (tVNS) has been shown to promote inferences of emotional states based on eye-related information provided by facial expressions of emotions. Eye gaze direction can influence the allocation of attentional sources when processing facial emotional stimuli. Here we sought for further evidence indicating whether tVNS effects would be specific to emotional expressions or to gaze - both socially relevant stimuli - and whether they reflect the enhancement of attention. In two separate sessions receiving either active or sham tVNS, forty-three healthy young volunteers completed a Rapid Serial Visual Presentation task in which participants identified the gender of a target face (T1) with direct (salient social cue) or averted gaze (subtler social cue) with different emotional expressions or a neutral expression, and then judged the orientation of a landscape (T2) that appeared at different temporal lags after T1. Active tVNS, compared to sham stimulation, enhanced conditional T2 accuracy for both neutral and emotional faces and independently of the temporal lag, but only when gaze was directed at the participant. This suggests that tVNS modulates attention to a direct gaze (salient social cue) irrespective of the expressed emotion. We interpret that the effects of tVNS seem to reflect enhanced perception of gaze direction, which in turn attracts attention, making the observer more sensitive and increasing the impact of the socially relevant facial cue. We conclude that tVNS is a promising technique for enhancing social information processing in healthy humans.

SPARC: Respiratory‐Gated Transcutaneous Vagus Nerve Stimulation Modulates Gastric Function in Functional Dyspepsia

The vagus nerve plays an important role in both sensory and motor aspects of gastric physiology. Both animal and human studies suggest that accommodation reflex consists of a vagovagal reflex pathway. Thus, modulating vagal efference may be promising to increase gastric hypomotility for gastroparesis or functional dyspepsia.Transcutaneous vagus nerve stimulation (tVNS) of the auricular branch of the vagus nerve is a promising non‐invasive neuromodulatory therapy for numerous disorders. We have demonstrated that tVNS targets nucleus tractus solitarii, and medullary efferent parasympathetic (vagal) nuclei (Sclocco et al. 2019). Our group showed that neural target‐engagement can be enhanced by gating stimulation to the exhalation phase of respiration, via Respiratory‐gated Auricular Vagal Afferent Nerve Stimulation (RAVANS).In this ongoing study, we evaluate nine (9) functional dyspepsia (FD) patients with both brain fMRI and 4D cine MRI of the stomach during a test meal challenge and concurrent RAVANS or Sham tVNS, to investigate effects on gastric emptying. MRI examinations were performed immediately following ingestion of a food‐based MRI contrast test meal (470ml, pineapple‐based with high manganese content), using 4D cine MRI. Each subject was scanned 15, 65, and 80 minutes post‐meal (T0, T1, T2), while experiencing active RAVANS (300μs pulse width, 1.5s stimulation trains delivered at 100Hz in the cymba concha of the left ear) or Sham (no current) on two different visits (randomized order). Abdominal MRI images were segmented to isolate the stomach, meal and air contents (semi‐automated, based on image contrast) for each subject and post‐meal time point, and volumetric indices of gastric accommodation and emptying were calculated.In FD patients, the ratio between total gastric volume and ingested volume – a proxy for gastric accommodation – was significantly higher during RAVANS compared to Sham (RAVANS: 1.46 ± 0.45, mean ± SD; Sham: 1.18 ± 0.34; p‐val = 0.024). Furthermore, the percent reduction in meal volumes during RAVANS were significantly higher compared to Sham from T0 to T1 (RAVANS: −18.18 ± 11.70%; Sham: −10.40 ± 7.47%; p‐val = 0.032), and from T0 to T2 (RAVANS: −32.68 ± 10.56%; Sham: −24.24 ± 13.63%; p‐val = 0.047).These results support the hypothesis that RAVANS can successfully modulate gastric accommodation and emptying in FD patients. Future investigations will link fMRI response to RAVANS with gut motility to investigate the brain‐gut axis underlying tVNS‐modulated gastric physiology.Support or Funding InformationWe thank the following organizations for funding support: US National Institutes of Health (NIH), Office Of The Director (OT2‐OD023867); National Institute of Biomedical Imaging and Bioengineering (R21‐EB024701); National Center for Complementary and Integrative Health, NIH (R61‐AT009306, P01‐AT006663, R01‐AT007550); National Institute of Diabetes and Digestive and Kidney Diseases (R21‐DK116029).(a) Mosaic image of abdominal 3D MRI data with air (yellow) and meal (red) segmentations; (b) 3D reconstruction of the gastric volume; (c) 3D gastric reconstruction mapping the average displacement on the stomach surface.Figure 1