Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II

Nesbitt A.D., Marin J.C., Tompkins E., Ruttledge M.H., Goadsby P.J.

To report our initial experience with a novel device, designed to provide portable, noninvasive, transcutaneous stimulation of the vagus nerve, both acutely and preventively, as a treatment for cluster headache.Patients with cluster headache (11 chronic, 8 episodic), from 2 centers, including 7 who were refractory to drug treatment, had sufficient data available for analysis in this open-label observational cohort study. The device, known as the gammaCore, was used acutely to treat individual attacks as well as to provide prevention. Patient-estimated efficacy data were collected by systematic inquiry during follow-up appointments up to a period of 52 weeks of continuous use.Fifteen patients reported an overall improvement in their condition, with 4 reporting no change, providing a mean overall estimated improvement of 48%. Of all attacks treated, 47% were aborted within an average of 11 ± 1 minutes of commencing stimulation. Ten patients reduced their acute use of high-flow oxygen by 55% with 9 reducing triptan use by 48%. Prophylactic use of the device resulted in a substantial reduction in estimated mean attack frequency from 4.5/24 hours to 2.6/24 hours (p < 0.0005) posttreatment.These data suggest that noninvasive vagus nerve stimulation may be practical and effective as an acute and preventive treatment in chronic cluster headache. Further evaluation of this treatment using randomized sham-controlled trials is thus warranted.This study provides Class IV evidence that for patients with cluster headache, transcutaneous stimulation of the vagus nerve aborts acute attacks and reduces the frequency of attacks.

Ben‐Menachem E., Revesz D., Simon B.J., Silberstein S.

Vagus nerve stimulation (VNS) is effective in refractory epilepsy and depression and is being investigated in heart failure, headache, gastric motility disorders and asthma. The first VNS device required surgical implantation of electrodes and a stimulator. Adverse events (AEs) are generally associated with implantation or continuous on-off stimulation. Infection is the most serious implantation-associated AE. Bradycardia and asystole have also been described during implantation, as has vocal cord paresis, which can last up to 6 months and depends on surgical skill and experience. The most frequent stimulation-associated AEs include voice alteration, paresthesia, cough, headache, dyspnea, pharyngitis and pain, which may require a decrease in stimulation strength or intermittent or permanent device deactivation. Newer non-invasive VNS delivery systems do not require surgery and permit patient-administered stimulation on demand. These non-invasive VNS systems improve the safety and tolerability of VNS, making it more accessible and facilitating further investigations across a wider range of uses.

Fisher R.S., Eggleston K.S., Wright C.W.

Huang F., Dong J., Kong J., Wang H., Meng H., Spaeth R.B., Camhi S., Liao X., Li X., Zhai X., Li S., Zhu B., Rong P.

Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure. In this pilot randomized clinical trial, we compared the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS on patients with IGT. 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham taVNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc). 100 participants completed the study and were included in data analysis. Two female patients (one in the taVNS group, one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period. Our study suggests that taVNS is a promising, simple, and cost-effective treatment for IGT/ pre-diabetes with only slight risk of mild side-effects.

Cai P.Y., Bodhit A., Derequito R., Ansari S., Abukhalil F., Thenkabail S., Ganji S., Saravanapavan P., Shekar C.C., Bidari S., Waters M.F., Hedna V.S.

Vagus nerve stimulation (VNS) is currently FDA-approved for treatment of both medically refractory partial-onset seizures and severe, recurrent refractory depression which have failed to respond to medical interventions. Because of its ability to regulate mechanisms well-studied in neuroscience, such as norepinephrine and serotonin release, the vagus nerve may play an important role in regulating cerebral blood flow, edema, inflammation, glutamate excitotoxicity, and neurotrophic processes. There is strong evidence that these same processes are important in stroke pathophysiology. We reviewed the literature for the role of VNS in improving ischemic stroke outcomes by performing a systematic search for publications in Medline (1966-2014) with keywords “vagus nerve stimulation AND stroke” in subject headings and key words with no language restrictions. Of the 73 publications retrieved, we identified 7 studies from 3 different research groups that met our final inclusion criteria of research studies addressing the role of vagus nerve stimulation in ischemic stroke. Results from these studies suggest that VNS has promising efficacy in reducing stroke volume and attenuating neurological deficits in ischemic stroke models. Given the lack of success in Phase III trials for stroke neuroprotection, it is important to develop new therapies targeting different neuroprotective pathways. Further studies of the possible role of VNS, through normally physiologically active mechanisms, in ischemic stroke therapeutics should be conducted in both animal models and clinical studies. In addition, recent advent of a non-invasive, transcutaneous VNS could provide the potential for easier clinical translation.

Jaboli M., Bennell J., Epstein O.

Introduction Vagal dysfunction has been implicated in gastroparesis. Gut vagal afferents convey symptoms of nausea, bloating and early satiety but the nerve also has an antinociceptive function. GammaCore (electroCore, LLC: New Jersey) is a CE marked hand-held vagus nerve stimulator designed to selectively stimulate afferent vagal A-fibres. It is possible that in gastroparesis, stimulation of the vagus nerve as it traverses the neck might influence symptoms.Methods Fifteen patients with severe gastroparesis awaiting Enterra (Medtronic, Minnesota) implantation agreed to a short proof of concept assessment of nVNS. Each patient was supplied with a GammaCore device programmed to deliver 150 doses, each dose lasting 90 seconds. The electrodes on the GammaCore device were positioned in line with the right cervical vagus nerve and stimulation applied three times daily. The gastroparesis multi-symptom questionnaire, that includes the symptoms of nausea, vomiting, early satiety and bloating, was completed daily for the week prior to starting treatment and daily throughout the treatment period. Symptoms were scored on a Likert scale (1 = none and 5 = severe). Composite and individual symptom scores were summated for the week preceding treatment and the final two weeks of the treatment period.Results Only seven of the 15 patients complied with the treatment regimen. In six patients, the diary score cards were incomplete and two patients did not use the GammaCore.Conclusion In this group of severely ill patients awaiting Enterra implantation, half complied with the treatment regimen. Compliant patients scored improvement in nausea, early satiety and bloating, as well as the composite gastroparesis score. This short term proof of concept assessment suggests that nVNS influences symptoms conveyed by vagal afferents. It is possible that stimulation of both left and right vagus nerves, increased stimulation amplitude, and a longer period of treatment might improve responsiveness. Future clinical trials are warranted to elucidate safety, efficacy, dose response and compliance.Disclosure of Interest None Declared.

Levine Y.A., Koopman F., Faltys M., Zitnik R., Tak P.

Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) cause significant morbidity and mortality. Despite significant therapeutic advances, the medical need for patients with these disorders remains high. An important neural-immune regulatory mechanism termed the “inflammatory reflex,” and its efferent arm, the “cholinergic antiinflammatory pathway” regulate innate and adaptive immunity. An emerging body of evidence indicates that stimulation of this pathway with implantable medical devices is a feasible therapeutic approach in disorders of dysregulated inflammation. Herein we describe the underlying biology and the preclinical experiments done in standard animal models that provided the rationale for testing in clinical trials. The preclinical development approach comprised elements of classic drug and medical device development, yet had unique features and challenges. “Bioelectronic medicines” having ideal characteristics of both drugs and medical devices hold great conceptual promise for treatment of systemic diseases in the future. However studies being done today will help determine whether neurostimulation of the cholinergic antiinflammatory pathway (NCAP) has the potential in the nearer term to fulfill the needs of patients, caregivers and payers for an additional potential treatment option for inflammatory disorders, and might thus become one of the first feasible examples of a bioelectronic medicine.

Sun F.T., Morrell M.J.

Neurostimulation is now an established therapy for the treatment of movement disorders, pain, and epilepsy. While most neurostimulation systems available today provide stimulation in an open-loop manner (i.e., therapy is delivered according to preprogrammed settings and is unaffected by changes in the patient’s clinical symptoms or in the underlying disease), closed-loop neurostimulation systems, which modulate or adapt therapy in response to physiological changes, may provide more effective and efficient therapy. At present, few such systems exist owing to the complexities of designing and implementing implantable closed-loop systems. This review focuses on the clinical experience of four implantable closed-loop neurostimulation systems: positional-adaptive spinal cord stimulation for treatment of pain, responsive cortical stimulation for treatment of epilepsy, closed-loop vagus nerve stimulation for treatment of epilepsy, and concurrent sensing and stimulation for treatment of Parkinson disease. The history that led to the development of the closed-loop systems, the sensing, detection, and stimulation technology that closes the loop, and the clinical experiences are presented.

Rong P., Liu A., Zhang J., Wang Y., He W., Yang A., Li L., Ben H., Li L., Liu H., Wu P., Liu R., Zhao Y., Zhang J., Huang F., et. al.

Abstract This trial was designed to test the safety and effectiveness of transcutaneous auricular vagus nerve stimulation (ta-VNS) for patients with refractory epilepsy. Pre-trial：144 patients were randomly assigned to ta-VNS group (n=98) or transcutaneous auricular non-vagus nerve stimulation (tn-VNS) control group (n=46). Treatment was conducted twice per day for 24 weeks. After 8, 16 and 24 weeks of treatment，the patients were evaluated according to the Modified Engel Scale (four classes). After 8 weeks，according to the medical ethic design, patients in tn-VNS group were switched into ta-VNS group uniquely. After 8 weeks’ treatment 41.0% and 27.5% of patients from ta-VNS and tn-VNS groups, respectively, experienced reduction in seizure frequency that reached I, II and III levels according to the standards of the Modified Engel Scale compared with the baselines, indicating significant difference in seizure reduction between the two groups. After 24 weeks of treatment, ta-VNS patients had a 47.7% reduction, and tn-VNS, with an additional 16 weeks of treatment, reached 47.5% in reduction. After 8 weeks’ treatment, the percentages of average seizure frequency in ta-VNS and tn-VNS were reduced by 42.6% and 11.5% respectively, providing a statistically significant difference in the results between the two groups (P<0.05). In addition, there were significant improvements in electroencephalograph (EEG) and the quality of daily life of the patients after treatment. The results show that this ta-VNS treatment can effectively reduce the frequency of seizures and improve the patient's quality of life. This may be an effective treatment for refractory epilepsy. At the same time，it is also safe，economic, and widely applicable.

Howland R.H.

The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuro-endocrine-immune axis to maintain homeostasis through its afferent and efferent pathways. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve, including manual or electrical stimulation. Left cervical VNS is an approved therapy for refractory epilepsy and for treatment-resistant depression. Right cervical VNS is effective for treating heart failure in preclinical studies and a phase II clinical trial. The effectiveness of various forms of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve. VNS deserves further study for its potentially favorable effects on cardiovascular, cerebrovascular, metabolic, and other physiologic biomarkers associated with depression morbidity and mortality.

Goadsby P., Grosberg B., Mauskop A., Cady R., Simmons K.

Background We sought to assess a novel, noninvasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraine. Methods Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain. Results Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching ( n = 1), raspy voice ( n = 1) and redness at the device site ( n = 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%). Conclusions nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients.

Howland R.H.

The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuro-endocrine-immune axis. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve. Left cervical VNS is an approved therapy for refractory epilepsy and treatment-resistant depression. Right cervical VNS has proven effective for treating heart failure in preclinical studies and a Phase II clinical trial. The effectiveness of noninvasive transcutaneous VNS for epilepsy, depression, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, and cardiovascular, cerebrovascular, and metabolic syndromes might be mediated by the vagus nerve. Transcutaneous VNS deserves further study as an antidepressant therapy and for its potential effect on physiological biomarkers associated with depression morbidity and mortality.

Ben-Menachem E., Rydenhag B., Silander H.

Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of drug-resistant epilepsy. A new VNS system ("FitNeS"; manufactured by BioControl Medical (B.C.M.) Ltd., Yehud, Israel) was implanted in 5 patients with refractory focal epilepsy. The system is composed of a programmable pulse generator and a cuff electrode that is able to provide unidirectional stimulation, both of which are implanted in the left chest and in the neck, respectively. FitNeS is based on the CardioFit vagus nerve stimulation system, which is intended for the treatment of heart failure and which is currently in a randomized controlled phase III clinical trial. Long-term stimulation in the 5 patients resulted in a 50% seizure reduction in 2 patients, 25% in 2 patients, and no effect in one patient, with few reports concerning side effects. There were no complaints of hoarseness at levels of stimulation below 2mA nor were there any reports of dysphagia or cough. The lack of perceived stimulation effects might finally allow for the design of a truly blinded randomized controlled study to evaluate the efficacy of VNS compared to placebo.

Kraus T., Kiess O., Hösl K., Terekhin P., Kornhuber J., Forster C.

AbstractBackground It has recently been shown that electrical stimulation of sensory afferents within the outer auditory canal may facilitate a transcutaneous form of central nervous system stimulation. Functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) effects in limbic and temporal structures have been detected in two independent studies. In the present study, we investigated BOLD fMRI effects in response to transcutaneous electrical stimulation of two different zones in the left outer auditory canal. It is hypothesized that different central nervous system (CNS) activation patterns might help to localize and specifically stimulate auricular cutaneous vagal afferents. Methodology 16 healthy subjects aged between 20 and 37 years were divided into two groups. 8 subjects were stimulated in the anterior wall, the other 8 persons received transcutaneous vagus nervous stimulation (tVNS) at the posterior side of their left outer auditory canal. For sham control, both groups were also stimulated in an alternating manner on their corresponding ear lobe, which is generally known to be free of cutaneous vagal innervation. Functional MR data from the cortex and brain stem level were collected and a group analysis was performed. Results In most cortical areas, BOLD changes were in the opposite direction when comparing anterior vs. posterior stimulation of the left auditory canal. The only exception was in the insular cortex, where both stimulation types evoked positive BOLD changes. Prominent decreases of the BOLD signals were detected in the parahippocampal gyrus, posterior cingulate cortex and right thalamus (pulvinar) following anterior stimulation. In subcortical areas at brain stem level, a stronger BOLD decrease as compared with sham stimulation was found in the locus coeruleus and the solitary tract only during stimulation of the anterior part of the auditory canal. Conclusions The results of the study are in line with previous fMRI studies showing robust BOLD signal decreases in limbic structures and the brain stem during electrical stimulation of the left anterior auditory canal. BOLD signal decreases in the area of the nuclei of the vagus nerve may indicate an effective stimulation of vagal afferences. In contrast, stimulation at the posterior wall seems to lead to unspecific changes of the BOLD signal within the solitary tract, which is a key relay station of vagal neurotransmission. The results of the study show promise for a specific novel method of cranial nerve stimulation and provide a basis for further developments and applications of non-invasive transcutaneous vagus stimulation in psychiatric patients.

Morris G.L., Gloss D., Buchhalter J., Mack K.J., Nickels K., Harden C.

To evaluate the evidence since the 1999 assessment regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients >12 years.We reviewed the literature and identified relevant published studies. We classified these studies according to the American Academy of Neurology evidence-based methodology.VNS is associated with a >50% seizure reduction in 55% (95% confidence interval [CI] 50%-59%) of 470 children with partial or generalized epilepsy (13 Class III studies). VNS is associated with a >50% seizure reduction in 55% (95% CI 46%-64%) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies). VNS is associated with an increase in ≥ 50% seizure frequency reduction rates of ≈ 7% from 1 to 5 years postimplantation (2 Class III studies). VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies). Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio 3.4, 95% CI 1.0-11.2). VNS is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy. VNS may have improved efficacy over time.VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after VNS implantation.

Agetsuma M., Hatakeyama A., Yamada D., Kuniishi H., Ito C., Takeuchi E., Tsuji S., Tsutsumi M., Ichiki T., Otomo K., Yoshioka T., Kobayashi T., Noritake A., Aoki Y., Nemoto T., et. al.

Albayrak S., Aydin B., Özen G., Yalçin F., Balık M., Yanık H., Urgen B.A., Veldhuizen M.G.

ABSTRACTIntroductionChemosensory food signals are carried by the vagus nerve (VN) from the gut to the brain and these signals contribute to communicating fullness and caloric value of the consumed food in regulatory and reward‐related contexts. Here, we aimed to explore whether neural responses to flavor can be modulated through noninvasive VN stimulation, which can be done transcutaneously (transcutaneous vagus nerve stimulation [tVNS]) on the outer ear via the auricular branch of VN. The ideal stimulation location on the outer ear for tVNS is not agreed on but two candidate locations are cymba conchae and tragus.MethodsIn this study, we explore the optimal stimulation location for tVNS (cymba conchae, tragus, and cymba conchae and tragus) and timing of tVNS relative to chocolate milk presentation (during, after) in a within‐participants design (15 participants). We examined various measures of efficacy; event‐related potential from electroencephalogram, eye‐blink rate, perceptual and hedonic aspects of flavor, swallowing behavior, and consumption behavior.ResultsWe observed no effect of stimulation location on any of the dependent variables. Unexpectedly, we observed a large effect of food consumption on spontaneous eye‐blink rate.ConclusionIn conclusion, overall we did not observe a clear optimal ear location for tVNS‐induced modulation of neurophysiological, perceptual, and behavioral variables. Future studies may confirm whether spontaneous eye‐blink rate can be a sensitive proxy for food reward‐related phasic dopamine shifts.

Jigo M., Carmel J.B., Wang Q., Rodenkirch C.

Monti D.A., Wintering N., Vedaei F., Steinmetz A., Mohamed F.B., Newberg A.B.

PurposeA growing number of research studies have explored the potential effects of vagus nerve stimulation (VNS) on brain physiology as well as clinical effects particularly related to stress and anxiety. However, there currently are limited studies showing functional changes during different frequencies of stimulation and laterality effects transcutaneous auricular VNS (TaVNS). In this study, we evaluated whether TaVNS alters functional connectivity in the brain of healthy controls. We hypothesized that TaVNS would significantly alter connectivity in areas involved with emotional processing and regulation including the limbic areas, insula, frontal lobe regions, and cerebellum.MethodsWe enrolled 50 healthy controls. Participants were placed in the MRI scanner with MRI compatible ear buds that provided TaVNS. Subjects underwent TaVNS in the left, right, and both ears in a randomized manner during the MRI session. Stimulation was provided for 5 min on and then there was a 5 min off period in between. To evaluate the primary outcome of neurophysiological effects, all participants received blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) during the TaVNS on and off states.ResultsThe results demonstrated significant changes in functional connectivity during TaVNS that differed depending on the frequency of stimulation and which ear was stimulated. In general, areas of the brain that had altered functional connectivity included the frontoparietal regions, limbic regions, insula, and cerebellum. Interestingly, cognitive areas were also involved including parts of the temporal lobe, salience network, and default mode network.ConclusionThis study is an initial step toward understanding the functional connectivity changes associated with TaVNS. The findings indicate significant brain changes, particularly in areas that are involved with emotional processing and regulation, as well as cognition. Future studies can expand on this data and focus on specific patient populations to determine the effects of TaVNS.

Zanello M., Voges B., Chelvarajah R., Sen A., Petelin Gadže Ž., Penchet G., De Benedictis A., Fornaro R., Iwasaki M., Iijima K., Jiltsova E., Mrak G., Barrit S., Moiraghi A., Landi A., et. al.

AbstractObjectiveVagus nerve stimulation (VNS) is an established therapy for drug‐resistant epilepsy (DRE) and is indicated for implantation on the left vagus nerve‐only. In rare cases right‐sided VNS may be the only option. With only seven published cases in the literature, data on safety and effectiveness of right‐sided VNS is very limited.MethodsAn anonymous 38‐item questionnaire was sent to expert surgeons implanting VNS for DRE. The questions covered demographics and clinical characteristics, the reason for right‐sided implantation and both neurological and surgical outcomes of right‐sided VNS.ResultsThe survey captured 38 cases of right‐sided VNS (18 females, mean age at surgery of 28.0 ± 16.3 years). Right‐sided VNS was performed because of VNS lead deficiency (n = 20), anatomical constraints (n = 8), infection of a left‐sided VNS site (n = 9), and presence of a left ventricular shunt (n = 1). Thirty‐two patients (84%) had a preoperative cardiac assessment. Three patients presented postoperative cardiac side‐effects. Right‐sided VNS was stopped at last follow‐up in three patients: due to deep infection (n = 1), due to dyspnea (n = 1), and due to sleep apnea syndrome (n = 1). Twenty‐one patients (55%) were responders to right‐sided VNS and the mean reduction of seizure frequency under right‐sided VNS was 56.2 ± 18.8%. Focusing on seizure frequency reduction between right‐sided VNS and left‐sided VNS: 20 patients experienced similar effectiveness, 1 experienced lesser effectiveness, and 2 patients experienced greater effectiveness with right‐sided VNS.InterpretationThis multicenter case series significantly augments the available literature on right‐sided VNS. This suggests comparable effectiveness to left‐sided VNS but potentially lower tolerability. Further studies are warranted to better evaluate safety and efficacy of right‐sided VNS.

Muniyandi M., Chelvanayagam K., Salam S.A., Vadamalai S., Rajsekar K., Ramachandran R.

Zhou W., Jia L., Yue L., Hu L.

Xu Z.Y., Fang J.J., Fan X.Q., Xu L.L., Jin G.F., Lei M.H., Wang Y.F., Liu J.B., Dong F., Jiang L.R., Guo Y.

Thakkar V.J., Crupper J.E., Engelhart A.S., Centanni T.M.

Sönmez Ö., Holstein E., Puschmann S., Schmitt T., Witt K., Thiel C.M.

AbstractTranscutaneous vagus nerve stimulation (tVNS) offers a non‐invasive method to enhance noradrenergic neurotransmission in the human brain, thereby increasing cognitive control. Here, we investigate if changes in cognitive control induced by tVNS are mediated through locus coeruleus‐induced modifications of neural activity in the anterior cingulate cortex. Young healthy participants engaged in a simple cognitive control task focusing on response inhibition and a more complex task that involved both response inhibition and working memory, inside a magnetic resonance imaging scanner. The tasks were executed using a randomized within‐subject design, with participants undergoing auricular tVNS and sham stimulation in separate sessions. tVNS significantly changed performance in the simple control task reflected in a greater propensity to respond. Furthermore, we observed a significant increase in neural activity in the anterior cingulate cortex during the simple cognitive control task under tVNS. Functional connectivity analyses revealed positive coupling between neural activity in the locus coeruleus and anterior cingulate cortex, however, this was not modulated by tVNS. The findings suggest that non‐invasive stimulation of the vagus nerve can modulate neural activity in the anterior cingulate cortex. While these neural effects suggest an impact of tVNS in a key region involved in conflict monitoring and cognitive control, the behavioral effects are more indicative of a shift in response bias rather than enhanced cognitive control.

Kang S., Santhosh R., Fuentes S., Kaye A.D.

Han Z., Zhang C., Cheng K., Chen Y., Tang Z., Chen L., Ni J., Wang Z.

Russo M.A., Chakravarthy K., Kinfe T.M.

Staats P.S., Blake J.

Shen J.W., Starling A.J.