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Nearly 1% of the global population suffers from epilepsy. Drug-resistant epilepsy (DRE) affects one-third of epileptic patients who are unable to treat their condition with existing drugs. For the treatment of DRE, neuromodulation offers a lot of potential. The background, mechanism, indication, application, efficacy, and safety of each technique are briefly described in this narrative review, with an emphasis on three approved neuromodulation therapies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS), and closed-loop responsive neurostimulation (RNS). Neuromodulatory approaches involving direct or induced electrical currents have been developed to lessen seizure frequency and duration in patients with DRE since the notion of electrical stimulation as a therapy for neurologic diseases originated in the early nineteenth century. Although few people have attained total seizure independence for more than 12 months using these treatments, more than half have benefitted from a 50% drop in seizure frequency over time. Although promising outcomes in adults and children with DRE have been achieved, challenges such as heterogeneity among epilepsy types and etiologies, optimization of stimulation parameters, a lack of biomarkers to predict response to neuromodulation therapies, high-level evidence to aid decision-making, and direct comparisons between neuromodulatory approaches remain. To solve these existing gaps, authorize new kinds of neuromodulation, and develop personalized closed-loop treatments, further research is needed. Finally, both invasive and non-invasive neuromodulation seems to be safe. Implantation-related adverse events for invasive stimulation primarily include infection and pain at the implant site. Intracranial hemorrhage is a frequent adverse event for DBS and RNS. Other stimulation-specific side-effects are mild with non-invasive stimulation., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) stimulating the auricular branch of the vagus nerve along a well-defined neuroanatomical pathway, has promising therapeutic efficacy. Potentially, taVNS can modulate autonomic responses. Specifically, taVNS can induce more consistent parasympathetic activation and may lead to increased heart rate variability (HRV). However, the effects of taVNS on HRV remain inconclusive. Here, we investigated changes in HRV due to brief alteration periods of parasympathetic-vagal cardiac activity produced by taVNS on the cymba as opposed to control administration via the helix., Materials and Methods: We compared the effect of 10 min of active stimulation ( i.e ., cymba conchae) to sham stimulation ( i.e ., helix) on peripheral cardiovascular response, in 28 healthy young adults. HRV was estimated in the time domain and frequency domain during the overall stimulation., Results: Although active-taVNS and sham-taVNS stimulation did not differ in subjective intensity ratings, the active stimulation of the cymba led to vagally mediated HRV increases in both the time and frequency domains. Differences were significant between active-taVNS and both sham-taVNS and resting conditions in the absence of stimulation for various HRV parameters, but not for the low-frequency index of HRV, where no differences were found between active-taVNS and sham-taVNS conditions., Conclusion: This work supports the hypothesis that taVNS reliably induces a rapid increase in HRV parameters when auricular stimulation is used to recruit fibers in the cymba compared to stimulation at another site. The results suggest that HRV can be used as a physiological indicator of autonomic tone in taVNS for research and potential therapeutic applications, in line with the established effects of invasive VNS. Knowledge of the physiological effect of taVNS short sessions in modulating cardiovagal processing is essential for enhancing its clinical use., Competing Interests: Mariella Pazzaglia is an Academic Editor for PeerJ., (© 2022 Forte et al.)

Transcutaneous auricular vagus nerve stimulation (taVNS) can improve autonomic nerve function and is currently undergoing extensive clinical research; however, its efficacy heterogeneity has caused great controversy. Heart rate variability (HRV), a biomarker reflecting autonomic function, exhibits a time-varying pattern with circadian rhythms, which may be the main reason for the inconsistent stimulation effects. To test this conjecture, we performed isochronous acute stimulation experiments at intervals of 12 h. The results showed that HRV indicators representing vagal nerve activity significantly increased when stimulation was performed in the morning, and the enhancement of high frequency continued into the recovery period. However, the evening stimulation did not yield similar results. In addition, we found that improvements in the measures of autonomic balance were more pronounced in the presence of lower vagal activity. By increasing the stimulation duration, we also found that the effect of taVNS on HRV was not regulated by duration; in other words, HRV changes only had the best effect at the beginning of stimulation. These studies allowed us to determine the optimal stimulation phase and duration and potentially screen the optimal candidates for taVNS., Competing Interests: The authors have declared that no competing interests exist.

Objective. Vagus nerve stimulation (VNS) is Food and Drug Administration-approved for epilepsy, depression, and obesity, and stroke rehabilitation; however, the morphological anatomy of the vagus nerve targeted by stimulatation is poorly understood. Here, we used microCT to quantify the fascicular structure and neuroanatomy of human cervical vagus nerves (cVNs). Approach. We collected eight mid-cVN specimens from five fixed cadavers (three left nerves, five right nerves). Analysis focused on the 'surgical window': 5 cm of length, centered around the VNS implant location. Tissue was stained with osmium tetroxide, embedded in paraffin, and imaged on a microCT scanner. We visualized and quantified the merging and splitting of fascicles, and report a morphometric analysis of fascicles: count, diameter, and area. Main results. In our sample of human cVNs, a fascicle split or merge event was observed every ∼560 µ m (17.8 ± 6.1 events cm -1 ). Mean morphological outcomes included: fascicle count (6.6 ± 2.8 fascicles; range 1-15), fascicle diameter (514 ± 142 µ m; range 147-1360 µ m), and total cross-sectional fascicular area (1.32 ± 0.41 mm 2 ; range 0.58-2.27 mm). Significance. The high degree of fascicular splitting and merging, along with wide range in key fascicular morphological parameters across humans may help to explain the clinical heterogeneity in patient responses to VNS. These data will enable modeling and experimental efforts to determine the clinical effect size of such variation. These data will also enable efforts to design improved VNS electrodes., (Creative Commons Attribution license.)

Introduction: Vagus nerve stimulation (VNS) is a mainstay treatment in people with medically refractive epilepsy with a growing interest to identify biomarkers that are predictive of VNS efficacy. In this review, we looked at electroencephalography (EEG) and heart rate variability (HRV) parameters as potential biomarkers., Methodology: A comprehensive search of several databases limited to the English language and excluding animal studies was conducted. Data was collected from studies that specifically reviewed preoperative EEG and HRV characteristics as predictive factors of VNS outcomes., Results: Ten out of 1078 collected studies were included in this review, of which EEG characteristics were reported in seven studies; HRV parameters were reported in two studies, and one study reported both. For EEG, studies reported a lower global rate of synchronization in alpha, delta, and gamma waves as predictors of the VNS response. The P300 wave, an evoked response on EEG, had conflicting results. Two studies reported high P300 wave amplitudes in nonresponders and low amplitudes in responders, whereas another study reported high P300 wave amplitudes in responders. For HRV, one study reported high-frequency power as the only parameter to be significantly lower in responders. In contrast, two studies from the same authors showed that HRV parameters were not different between responders and nonresponders., Conclusion: HRV parameters and EEG characteristics including focal seizures and P300 wave have been reported as potential biomarkers for VNS outcomes in people with medically refractive epilepsy. However, the contradictory findings imply a need for validation through clinical trials., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Vagus nerve stimulation (VNS) is a neuromodulation therapy for children with drug-resistant epilepsy (DRE). The efficacy of VNS is heterogeneous. A prediction model is needed to predict the efficacy before implantation., Methods: We collected data from children with DRE who underwent VNS implantation and received regular programming for at least 1 year. Preoperative clinical information and scalp video electroencephalography (EEG) were available in 88 children. Synchronization features, including phase lag index (PLI), weighted phase lag index (wPLI), and phase-locking value (PLV), were compared between responders and non-responders. We further adapted a support vector machine (SVM) classifier selected from 25 clinical and 18 synchronization features to build a prediction model for efficacy in a discovery cohort (n = 70) and was tested in an independent validation cohort (n = 18)., Results: In the discovery cohort, the average interictal awake PLI in the high beta band was significantly higher in responders than non-responders (p < 0.05). The SVM classifier generated from integrating both clinical and synchronization features had the best prediction efficacy, demonstrating an accuracy of 75.7%, precision of 80.8% and area under the receiver operating characteristic (AUC) of 0.766 on 10-fold cross-validation. In the validation cohort, the prediction model demonstrated an accuracy of 61.1%., Conclusion: This study established the first prediction model integrating clinical and baseline synchronization features for preoperative VNS responder screening among children with DRE. With further optimization of the model, we hope to provide an effective and convenient method for identifying responders before VNS implantation., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: Vagus Nerve Stimulation (VNS) paired with rehabilitation delivered by the Vivistim® Paired VNS™ System was approved by the FDA in 2021 to improve motor deficits in chronic ischemic stroke survivors with moderate to severe arm and hand impairment. Vagus nerve stimulators have previously been implanted in over 125,000 patients for treatment-resistant epilepsy and the surgical procedure is generally well-tolerated and safe. In this report, we describe the Vivistim implantation procedure, perioperative management, and complications for chronic stroke survivors enrolled in the pivotal trial., Methods: The pivotal, multisite, randomized, triple-blind, sham-controlled trial (VNS-REHAB) enrolled 108 participants. All participants were implanted with the VNS device in an outpatient procedure. Thrombolytic agents were temporarily discontinued during the perioperative period. Participants were discharged within 48 hrs and started rehabilitation therapy approximately 10 days after the Procedure., Results: The rate of surgery-related adverse events was lower than previously reported for VNS implantation for epilepsy and depression. One participant had vocal cord paresis that eventually resolved. There were no serious adverse events related to device stimulation. Over 90% of participants were taking antiplatelet drugs (APD) or anticoagulants and no adverse events or serious adverse events were reported as a result of withholding these medications during the perioperative period., Conclusions: This study is the largest, randomized, controlled trial in which a VNS device was implanted in chronic stroke survivors. Results support the use of the Vivistim System in chronic stroke survivors, with a safety profile similar to VNS implantations for epilepsy and depression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Postpartum depression has a high prevalence in the United States (~13 %) and often goes undertreated/untreated. We conducted a multicenter, open-label, proof-of-concept trial to assess the Nēsos wearable, non-invasive, transcutaneous auricular vagus nerve stimulation (taVNS) system for the treatment of major depressive disorder with peripartum onset (PPD)., Methods: Women (n = 25), ages 18 to 45, within 9 months postpartum, and diagnosed with PPD were enrolled at 3 sites. The study included 6 weeks open-label therapy and 2 weeks observation. Efficacy outcomes included change from baseline (CFB) in Hamilton Rating Scale for Depression (HAMD17) total scores, HAM-D17 response and remission, and patient and clinician global impression of change (PGIC, CGIC) scores. Analysis included descriptive statistics and mixed-effects models for repeated measures., Results: The most common AEs (≥5 %) were discomfort (n = 5), headache (n = 3), and dizziness (n = 2); all resolved without intervention. No serious AEs or deaths occurred. Baseline mean HAM-D17 score was 18.4. Week 6 least squares (LS) mean CFB in HAM-D17 score was -9.7; 74 % achieved response and 61 % achieved remission. At week 6, at least some improvement was reported by 21 of 22 (95 %) clinicians on CGIC and 22 of 23 (96 %) participants on PGIC., Limitations: This was a single-arm, open-label study, and enrollment was limited to participants with mild-to-moderate peripartum depression., Conclusion: Results from this proof-of-concept study suggest that the Nēsos taVNS system is well tolerated and may be an effective non-invasive, non-pharmacological treatment for major depressive disorder with peripartum onset. Further evaluation in larger sham-controlled studies is needed., Clinicaltrials: govNCT03972995., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has received tremendous attention as a potential neuromodulator of cognitive and affective functions, which likely exerts its effects via activation of the locus coeruleus-noradrenaline (LC-NA) system. Reliable effects of taVNS on markers of LC-NA system activity, however, have not been demonstrated yet., Methods: The aim of the present study was to overcome previous limitations by pooling raw data from a large sample of ten taVNS studies (371 healthy participants) that collected salivary alpha-amylase (sAA) as a potential marker of central NA release., Results: While a meta-analytic approach using summary statistics did not yield any significant effects, linear mixed model analyses showed that afferent stimulation of the vagus nerve via taVNS increased sAA levels compared to sham stimulation (b = 0.16, SE = 0.05, p = 0.001). When considering potential confounders of sAA, we further replicated previous findings on the diurnal trajectory of sAA activity., Conclusion(s): Vagal activation via taVNS increases sAA release compared to sham stimulation, which likely substantiates the assumption that taVNS triggers NA release. Moreover, our results highlight the benefits of data pooling and data sharing in order to allow stronger conclusions in research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-invasive vagus nerve stimulation (nVNS) using a hand-held stimulator placed on the neck is an FDA-approved treatment for primary headache disorders. The safety of nVNS is unknown in stroke patients., Objective: To assess the safety and feasibility of nVNS for the acute treatment of stroke., Methods: TR-VENUS (clinicaltrials.gov identifier NCT03733431) was a randomized, sham-controlled, open-label, multicenter trial conducted in patients with acute ischemic stroke (IS) or intracerebral hemorrhage (ICH). Patients were randomly assigned to standard-dose nVNS, high-dose nVNS, or sham stimulation. The primary endpoint was a composite safety outcome defined as bradycardia or reduction in mean arterial blood pressure during treatment or progression of neurological or death within 24 h of treatment. The feasibility endpoints were the proportion of eligible subjects receiving nVNS within 6 h of symptom onset and the proportion completing all pre-specified treatment doses. Efficacy assessments included infarct growth from baseline to 24 h after treatment., Results: Sixty-nine patients (61 IS, 8 ICH) completed the study. The composite safety outcome was achieved in 32.0% in sham and 47.7% in nVNS group (p = 0.203). Treatment was initiated in all but two randomized patients. All dosed subjects received 100% of prespecified stimulations. A non-significant reduction in infarct growth was observed in the high-dose nVNS group (184.2% in sham vs. 63.3% in high-dose nVNS; p = 0.109)., Conclusions: The results of this study suggest that nVNS may be safe and feasible in the setting of acute stroke. These findings support further development of nVNS as a potential treatment for acute ischemic stroke., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ethem Murat Arsava Dr Arsava receives honoraria from Fresenius Kabi, Bayer AG, Daiichi-Sankyo, Pfizer, Sanofi, Abbott, and Nutricia. He serves on the advisory boards of Abbott, Daiichi-Sankyo, Bayer AG, Pfizer, Fresenius Kabi, and Nutricia. Mehmet Akif Topcuoglu Dr Topcuoglu receives honoraria from Fresenius Kabi, Daiichi-Sankyo, Sanofi, and Abbott. He serves on the advisory boards for Abbott, Fresenius Kabi, Daiichi-Sankyo, and Pfizer. Hakan Ay Hakan Ay is an employee of Takeda Pharmaceutical Company and holds an academic appointment at the Massachusetts General Hospital, Harvard Medical School. The remaining authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There are 9.9 million new cases of dementia in the world every year. Short-term conversion rate from mild cognitive impairment (MCI) to dementia is between 20% and 40%, but long-term in 5-10 years ranges from 60% to 100%. It is particularly important to prevent or prolong the development of MCI into dementia. Both auriculotherapy and vagus nerve stimulation are effective on improving cognitive functions. However, there is no double blinded randomized clinical trial to support the effectiveness of transcutaneous electrical stimulation of auricular acupoints in patients with MCI., Methods: This randomized controlled trial involved patients with MCI, aged from 55 to 75 years old. Patients were randomly allocated to transcutaneous auricular vagus nerve stimulation (taVNS) group or sham taVNS group. In the taVNS group, two auricular acupoints were stimulated, including heart (concha, CO 15 ) and kidney (CO 10 ), which are in the distribution of vagus nerve. While in the sham taVNS group, two other auricular acupoints were stimulated, including elbow (scaphoid fossa, SF 3 ) and shoulder (SF 4,5 ), which are out of the distribution of vagus nerve. The primary outcome was the Montreal cognitive assessment-basic, MOCA-B. The secondary outcomes included auditory verbal learning test-HuaShan version (AVLT-H), shape trails test A&B (STT-A&B), animal fluence test (AFT), Boston naming test (BNT), Pittsburgh sleep quality index (PSQI), rapid eye movement sleep behavior disorder screening questionnaire (RBDSQ), Epworth sleepiness scale (ESS) and functional activities questionnaire (FAQ). These outcome measures were taken at baseline, 24 weeks later., Results: After 24 weeks of intervention, the data of 52 patients were intended for analysis. After intervention, there was significant difference in the overall scores of MoCA-B between taVNS group and sham taVNS group (p = 0.033 < 0.05). In taVNS group, compared with before intervention, the overall scores of MOCA-B increased significantly after intervention (p < 0.001). As for N5 and N7, the two sub-indicators of AVLT-H, in taVNS group, compared with before intervention, both N5 and N7 increased significantly after intervention (both ps < 0.001). As for STTB, in taVNS group, compared with before intervention, STTB was significantly reduced after intervention (p = 0.016). For BNT, in taVNS group, compared with before intervention, BNT increased significantly after intervention (p < 0.001). In taVNS group, compared with before intervention, PSQI, RBDSQ, ESS and FAQ decreased significantly after intervention (p = 0.002, 0.025, <0.001, 0.006 respectively). 1 patient with a history of tympanic membrane perforation in taVNS group was reported with mild adverse reactions which disappeared a week after termination of taVNS. The intervention of taVNS is effective on increasing the overall scores of MoCA-B, N5 and N7., Conclusion: The clinical trial demonstrated that taVNS can improve cognitive performance in patients with MCI. This inexpensive, effective and innovative method can be recommended as a therapy for more patients with MCI in the prevention or prolonging of its development into dementia, but it is still required to be further investigated., Trial Registration: http://www.chictr.org.cn. (ID: ChiCTR2000038868)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) as a newly developed technique involves stimulating the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear, with resulting activation of vagal connections to central and peripheral nervous systems. Increasing evidence indicates that maladaptive neural plasticity may underlie the pathology of several pediatric neurodevelopmental and psychiatric disorders, such as autism spectrum disorder, attention deficit hyperactivity disorder, disruptive behavioral disorder and stress-related disorder. Vagal stimulation may therefore provide a useful intervention for treating maladaptive neural plasticity. In the current review we summarize the current literature primarily on therapeutic use in adults and discuss the prospects of applying taVNS as a therapeutic intervention in specific pediatric neurodevelopmental and other psychiatric disorders. Furthermore, we also briefly discuss factors that would help optimize taVNS protocols in future clinical applications. We conclude from these initial findings that taVNS may be a promising alternative treatment for pediatric disorders which do not respond to other interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Zhang, Zhou, Kendrick and Zhao.)

Background: As one of the most common stroke sequelae, poststroke cognitive impairment significantly impacts 17.6%-83% of survivors, affecting their rehabilitation, daily living and quality of life. Improving cognitive abilities among patients in stroke recovery is therefore critical and urgent. Transcutaneous auricular vagus nerve stimulation (TAVNS) is a non-invasive, safe, cost-effective treatment with great potential for improving the cognitive function of poststroke patients. This clinical research will evaluate the effectiveness, and help elucidate the possible underlying mechanisms, of TAVNS for improving poststroke cognitive function., Methods and Analysis: A single-centre, parallel-group, allocation concealment, assessor-blinded randomised controlled clinical trial. We will allocate 88 recruited participants to the TAVNS or sham group for an intervention that will run for 8 weeks, 5 days per week with twice daily sessions lasting 30 min each. Blood tests will be performed and questionnaires issued at baseline and 8-week and 12 week follow-ups. Primary outcomes will be changes in cognitive function scores. Secondary outcomes will be changes in activities of daily living, quality of life and serum oxidative stress indicators., Ethics and Dissemination: The Ethics Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine has approved the protocol (No. HN-LL-YJSLW-2022200). Findings will be published in peer-reviewed academic journals and presented at scientific conferences., Trial Registration Number: ChiCTR2200057808., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Noninvasive vagus nerve stimulation (nVNS) is effective in several types of headache disorders. We sought to unravel the mechanism of how nVNS exhibits this efficacy. This study used a randomized, single-blind, sham-controlled, crossover design and comprised 3 projects with 3 independent cohorts of healthy participants. Project I (n = 15) was explorative. Six quantitative sensory test parameters, including mechanical pain threshold (MPT), were measured over the left V1 dermatome and forearm and compared before and after unilateral nVNS. Projects II (n = 20) and III (n = 21) were preregistered online ( https://osf.io/r4jb9 ). Quantitative sensory test parameters were compared over the left (Project II) or bilateral V1 and V3 dermatomes (Project III), respectively, in addition to the left forearm as a control. A secondary analysis of heart rate variability (HRV) using a historical control group was used to control for systemic effects of nVNS. Verum-nVNS induced trigeminal-specific modulation of pain threshold (ie, MPT) over the left V1 in Project I, left V1 and V3 in Project II, and bilateral V1 and V3 in Project III. Data pooled from Projects II and III demonstrated a greater increase in MPT in the V1 vs V3 dermatome. There were no differences associated with sham-nVNS in any projects. Heart rate variability parameters did not change after nVNS. Our results provide functional evidence of a long hypothesized functional trigemino-vagal system in humans and may explain why nVNS is effective in some headache disorders but not in somatic pain disorders. Because unilateral nVNS modulated the trigeminal thresholds bilaterally, this effect is probably indirect through a central top-down mechanism., (Copyright © 2022 International Association for the Study of Pain.)

Objective: To examine the brain effects of transcutaneous auricular vagus nerve stimulation (taVNS) treatment of recurrent depression based on the functional brain network by using resting-state functional magnetic resonance imaging (fMRI)., Methods: Twenty-five patients with recurrent depression were enrolled in a single-arm trial of taVNS treatment for eight weeks. Clinical results were assessed by 17-item Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Scale (HAMA), Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), and Ruminative Response Scale (RRS) scales. Resting-state fMRI was conducted to explore the brain effects before and after treatment. For the functional connectivity (FC) analysis, the bilateral nucleus accumbens, globus pallidus, caudate, and putamen were selected as seeds. Finally, the correlations between FC and the clinical scale scores were calculated., Results: After treatment, the patients' scores of HAMD-17, HAMA, SDS, SAS, and RRS were significantly decreased ( < 0.05). FC was considerably decreased between the following areas: the left globus pallidus and the right postcentral gyrus, inferior parietal gyrus, the right globus pallidus and the left superior marginal gyrus, postcentral gyrus, superior parietal gyrus, inferior parietal gyrus, precuneus, right postcentral gyrus, superior marginal gyrus, and inferior parietal gyrus, between the right caudate and the right lingual gyrus, calcarine gyrus, and cerebellum. Changes in FC between the right globus pallidus and the left inferior parietal gyrus, between the left globus pallidus and the right postcentral gyrus were negatively correlated with HAMD-17 scores change before and after treatment (before, = 0.003, = -0.6; after, 0.009,= -0.54). The change of FC between the right globus pallidus and the right postcentral gyrus was negatively correlated with the change in SDS (= 0.026,= -0.474). The difference in FC between the right globus pallidus and the right postcentral gyrus was negatively correlated with the change in SAS (= 0.016,= -0.513)., Conclusions: Recurrent depression could be effectively treated with taVNS. The changes in brain FC involving the basal ganglia, default mode, and sensorimotor networks provide insight into the effects of taVNS treatment on recurrent depression.

Background: Mood plays an important role in our life which is illustrated by the disruptive impact of aberrant mood states in depression. Although vagus nerve stimulation (VNS) has been shown to improve symptoms of depression, the exact mechanism is still elusive, and it is an open question whether non-invasive VNS could be used to swiftly and robustly improve mood., Methods: Here, we investigated the effect of left- and right-sided transcutaneous auricular VNS (taVNS) v. a sham control condition on mood after the exertion of physical and cognitive effort in 82 healthy participants (randomized cross-over design) using linear mixed-effects and hierarchical Bayesian analyses of mood ratings., Results: We found that 90 min of either left-sided or right-sided taVNS improved positive mood [ b = 5.11, 95% credible interval, CI (1.39-9.01), 9.6% improvement relative to the mood intercept, BF 10 = 7.69, p LME = 0.017], yet only during the post-stimulation phase. Moreover, lower baseline scores of positive mood were associated with greater taVNS-induced improvements in motivation [ r = -0.42, 95% CI (-0.58 to -0.21), BF 10 = 249]., Conclusions: We conclude that taVNS boosts mood after a prolonged period of effort exertion with concurrent stimulation and that acute motivational effects of taVNS are partly dependent on initial mood states. Collectively, our results show that taVNS may help quickly improve affect after a mood challenge, potentially by modulating interoceptive signals contributing to the reappraisal of effortful behavior. This suggests that taVNS could be a useful add-on to current behavioral therapies.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences., (© 2022 International League Against Epilepsy.)

Introduction: Systemic 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 of mortality, organ damage and debilitating treatment-resistant fatigue. Autonomic nervous system dysfunction (AD) is present in approximately half of the patients and may promote autoimmunity by weakening the vagally mediated anti-inflammatory reflex. Recent studies suggest that transcutaneous vagus nerve stimulation (tVNS) has few side effects and beneficial effects on fatigue, pain, disease activity and organ function. This study investigates whether adjuvant tVNS improves measures of fatigue (primary end point), AD, clinical disease activity, inflammation, pain, organ function and quality of life.Hence, this study will contribute to the understanding of AD as a potentially important precursor of fatigue, disease activity, progression and complications in SLE, and how tVNS mechanistically may attenuate this. As adjuvant tVNS use may reduce the need for traditional immunosuppressive therapy, this trial may prompt a shift in the treatment of SLE and potentially other autoimmune disorders., Methods and Analysis: Eighty-four patients with SLE with fatigue and AD will be randomised 1:1 to active or sham tVNS in this double-blinded parallel-group study. In period 1 (1 week), participants will receive a 4 min tVNS 4 times daily and report on fatigue daily. After a 2-week pause, period 2 (8 weeks) will entail tVNS twice daily and participants will report on fatigue, pain and disease activity weekly. Secondary end points will be assessed before and after each period and after 1 week in period 2., Ethics and Dissemination: The study is approved by the Danish Medical Research Ethical Committees (case no: 2120231) and results will be published in international peer-reviewed journals., Trial Registration Number: NCT05315739., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Alzheimer's Disease (AD) is the leading cause of dementia and, at the time of diagnosis, half of AD patients display at least one neuropsychiatric symptom (NPS). However, there is no effective therapy for NPSs; furthermore, current treatments of NPSs accelerate cognitive decline. Due to the ineffectiveness and negative consequences of current treatments for NPSs, new approaches are strongly needed. Currently, indications for vagal nerve stimulation (VNS) include epilepsy, stroke rehabilitation and major depression but not NPSs or AD. Therefore, we investigated whether chronic VNS can treat NPSs in a rat model of AD. Here, we report the intracerebroventricular injection of amyloid-β (Aβ) results in depression-like behaviors and memory impairment in rats. Chronic VNS (0.8 mA, 500 μs, 30 Hz, 5 min/day) showed strong antidepressant and anxiolytic effects, and improved memory performance. Additionally, the anxiolytic effect of VNS was retained in the non-Aβ-treated rats. VNS also decreased aggressiveness and increased locomotor activity in both Aβ-treated and non-Aβ-treated rats. Recent studies showed VNS alters glutamatergic receptor levels, thus levels of GluA1, GluN2A, and GluN2B were determined. A significant reduction in GluN2B levels was seen in the hippocampus of VNS-treated groups which may relate to the anxiolytic effects and increased locomotor activity of VNS. In conclusion, VNS could be an effective treatment of NPSs, especially depression and anxiety, in AD patients without impairing cognition., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Vagus nerve stimulation (VNS) is a neuromodulation therapy for a broad and expanding set of neurologic conditions. However, the mechanism through which VNS influences central nervous system circuitry is not well described, limiting therapeutic optimization. VNS leads to widespread brain activation, but the effects on behavior are remarkably specific, indicating plasticity unique to behaviorally engaged neural circuits. To understand how VNS can lead to specific circuit modulation, we leveraged genetic tools including optogenetics and in vivo calcium imaging in mice learning a skilled reach task. We find that VNS enhances skilled motor learning in healthy animals via a cholinergic reinforcement mechanism, producing a rapid consolidation of an expert reach trajectory. In primary motor cortex (M1), VNS drives precise temporal modulation of neurons that respond to behavioral outcome. This suggests that VNS may accelerate motor refinement in M1 via cholinergic signaling, opening new avenues for optimizing VNS to target specific disease-relevant circuitry., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: For the past 20 years vagus nerve stimulation (VNS) has been an approved invasive treatment option for treatment-resistant depression (TRD) across Europe. In contrast to more common treatments, such as ECT, knowledge about VNS is low both in the general population and among professionals., Methods: In this narrative review, we provide a clinically and scientifically sound overview of VNS. Hypotheses on the mechanism of action as well as the current evidence base on efficacy are presented. Perioperative management, adverse event profile and follow-up including dose titration are described. A comparison of international guideline recommendations on VNS is also provided. Furthermore, we formulate criteria that are helpful in the selection of appropriate patients., Results: Electrical impulses are transmitted afferently via the vagus nerve and stimulate a neuromodulatory cerebral network via different pathways. Many studies and case series demonstrated the efficacy of VNS as an adjuvant procedure for TRD. The effect occurs with a latency period of 3-12 months and possibly increases with the duration of VNS. If stimulation recommendations are followed, side effects are tolerable for most patients., Conclusion: The use of VNS is an approved, effective and well-tolerated long-term therapy for chronic and treatment-resistant depression. Further sham-controlled studies over a longer observational period are desirable to improve the evidence., (© 2022. The Author(s).)

Introduction: The Neurovisceral Integration Model (NIM) proposes a complex interplay of visceral and neural structures that are crucial for adaptive responses to environmental demands. The aim of the present study was to investigate this circuitry using experimental manipulation via transcutaneous auricular vagus nerve stimulation (tVNS), measures of peripheral autonomic nervous system (ANS) activity and prefrontal cortex (PFC) oxygenation, quantified using functional near-infrared spectroscopy (fNIRS)., Methods: In a sample of n = 30 adolescents (age 14-17 years), tVNS versus sham stimulation was applied each during a 15-minute stimulation phase in a within-subject-cross-randomized-design. Mean oxygenation of the PFC and functional connectivity were assessed using fNIRS. Additionally, heart rate variability (HRV), heart rate (HR), electrodermal activity (EDA), and saliva alpha-amylase (sAA) were assessed to quantify peripheral ANS activity., Results: Using linear mixed-effects models, HRV increased (p < .0001) and HR (p < .0001) decreased during tVNS compared to sham. No effect on EDA or sAA was observed. PFC oxygenation increased over time under tVNS compared to sham (p = .017). The relative increase in HRV and decrease in HR was associated with increased oxygenation of the PFC (HR: p < .0001; HRV: p = .007). Exploratory analyses illustrated, that under tVNS, PFC connectivity increased compared to sham., Conclusion: The present study supports the NIM by showing that tVNS influences ANS activity and that relative changes in PFC oxygenation contribute to these effects. Implications of these findings and directions for further research are discussed., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Opioid Use Disorder (OUD) is a serious public health problem, and the behavioral and physiological effects of opioid withdrawal can be a major impediment to recovery. Medication for OUD is currently the mainstay of treatment; however, it has limitations and alternative approaches are needed., Objective: The purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on behavioral and physiological manifestations of acute opioid withdrawal., Methods: Patients with OUD undergoing acute opioid withdrawal were randomly assigned to receive double blind active tcVNS (N = 10) or sham stimulation (N = 11) while watching neutral and opioid cue videos. Subjective opioid withdrawal, opioid craving, and anxiety were measured using a Visual Analogue Scale (VAS). Distress was measured using the Subjective Units of Distress Scale (SUDS), and pain was measured using the Numerical Rating Scale (NRS) for pain. Electrocardiogram signals were measured to compute heart rate. The primary outcomes of this initial phase of the clinical trial (ClinicalTrials.gov NCT04556552) were heart rate and craving., Results: tcVNS compared to sham resulted in statistically significant reductions in subjective opioid withdrawal (p = .047), pain (p = .045), and distress (p = .004). In addition, tcVNS was associated with lower heart rate compared to sham (p = .026). Craving did not significantly differ between groups (p = .11)., Conclusions: tcVNS reduces behavioral and physiological manifestations of opioid withdrawal, and should be evaluated in future studies as a possible non-pharmacologic, easily implemented approach for adjunctive OUD treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The active and sham vagus nerve stimulation devices used in this research were provided in-kind by electroCore, Inc. J. D. Bremner has received grant funding support in the past from electroCore and currently serves on the Scientific Advisory Board for Evren Technologies, Inc. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Alcohol use disorder (AUD) is a relapsing-remitting condition characterized by excessive and/or continued alcohol consumption despite harmful consequences. New adjuvant tools, such as noninvasive brain stimulation techniques, might be helpful additions to conventional treatment approaches or even provide an alternative option for patients who fail to respond adequately to other treatment options. Here, we discuss the potential use of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON intervention in AUD. Compared with other techniques, atVNS has the advantage of directly stimulating nuclei that synthesize GABA and catecholamines, both of which are functionally altered by alcohol intake in AUD patients. Pharmacological options targeting those neurotransmitters are widely available, but have relatively limited beneficial effects on cognition, even though restoring normal cognitive functioning, especially cognitive control, is key to maintaining abstinence. Against this background, atVNS could be a particularly useful add-on because there is substantial meta-analytic evidence based on studies in healthy individuals that atVNS can enhance cognitive control processes that are crucial to regaining control over drug intake. We discuss essential future research on using atVNS as an ADD-ON intervention in AUD to enhance clinical and cognitive outcomes by providing a translational application. Given that this novel technique can be worn like an earpiece and can be employed without medical supervision/outside the clinical settings, atVNS could be well integratable into the daily life of the patients, where the task of regaining control over drug intake is most challenging., (© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objective: Respiratory-gated Auricular Vagal Afferent Nerve stimulation (RAVANS) is a safe nonpharmacological approach to managing chronic pain. The purpose of the current study was to examine (1) the feasibility and acceptability of RAVANS, combined with mindful meditation (MM) for chronic low back pain (CLBP), (2) the potential synergy of MM+RAVANS on improving pain, and (3) possible moderators of the influence of MM+RAVANS on pain., Design: Pilot feasibility and acceptability study., Setting: Pain management center at large academic medical center., Subjects: Nineteen adults with CLBP and previous MM training., Methods: Participants attended two sessions during which they completed quantitative sensory testing (QST), rated pain severity, and completed a MM+stimulation session. Participants received RAVANS during one visit and sham stimulation during the other, randomized in order. Following intervention, participants repeated QST., Results: MM+RAVANS was well tolerated, acceptable, and feasible to provide relief for CLBP. Both MM+stimulation sessions resulted in improved back pain severity, punctate pain ratings, and pressure pain threshold. Individuals with greater negative affect showed greater back pain improvement from MM+RAVANS while those with greater mindfulness showed greater back pain improvement from MM+sham., Conclusions: Results suggest that for CLBP patients with prior MM training, the analgesic effects of MM may have overshadowed effects of RAVANS given the brief single session MM+RAVANS intervention. However, those with greater negative affect may benefit from combined MM+RAVANS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective . Auricular vagus nerve stimulation (aVNS) has recently emerged as a promising neuromodulation modality for blood pressure (BP) reduction due to its ease of use although its efficacy is still limited compared to direct baroreflex stimulation. Previous studies have also indicated that synaptic depression of nucleus tractus solitarius (NTS) in the baroreflex pathway depends on stimulus frequency. However, the nature of this frequency dependence phenomenon on antihypertensive effect has been unknown for aVNS. We aimed to investigate the antihypertensive effect of aVNS considering frequency-dependent depression characteristic in the NTS synapse. We explored NTS activation and BP reduction induced by aVNS and by direct secondary neuron stimulation (DS). Approach . Both protocols were performed with recording of NTS activation and BP response with stimulation for each frequency parameter (2, 4, 20, 50, and 80 Hz). Main results . The BP recovery time constant was significantly dependent on the frequency of DS and aVNS (DS-2 Hz: 8.17 ± 4.98; 4 Hz: 9.73 ± 6.3; 20 Hz: 6.61 ± 3.28; 50 Hz: 4.93 ± 1.65; 80 Hz: 4.00 ± 1.43, p < 0.001, Kruskal-Wallis (KW) H-test/aVNS-2 Hz: 4.02 ± 2.55; 4 Hz: 8.13 ± 4.05; 20 Hz: 6.40 ± 3.16; 50 Hz: 5.18 ± 2.37; 80 Hz: 3.13 ± 1.29, p < 0.05, KW H-test) despite no significant BP reduction at 2 Hz compared to sham groups ( p > 0.05, Mann-Whitney U-test). Significance . Our observations suggest that the antihypertensive effect of aVNS is influenced by the characteristics of frequency-dependent synaptic depression in the NTS neuron in terms of the BP recovery time. These findings suggest that the antihypertensive effect of aVNS can be improved with further understanding of the neurological properties of the baroreflex associated with aVNS, which is critical to push this new modality for clinical interpretation., (© 2022 IOP Publishing Ltd.)

Purpose of Review: To summarize current evidence and recent developments in the surgical treatment of drug-resistant generalized epilepsy., Recent Findings: Current surgical treatments of drug-resistant generalized epilepsy include vagus nerve stimulation (VNS), deep brain stimulation (DBS) and corpus callosotomy (CC). Neurostimulation with VNS and/or DBS has been shown to be effective in reducing seizure frequency in patients with generalized epilepsy. DBS for generalized epilepsy is primarily consisted of open-loop stimulation directed at the centromedian (CM) nucleus in the thalamus, though closed-loop stimulation and additional targets are being explored. CC can be effective in treating some seizure types and can be performed using traditional surgical techniques or with the less invasive methods of laser ablation and radiosurgery. This current literature supports the use of VNS, DBS and CC, alone or in combination, as palliative treatments of drug-resistant generalized epilepsy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epilepsy is a neurological disorder with abnormal brain activity. It causes convulsions or periods of unusual behavior, sensations, and sometimes loss of awareness. Drug-resistant epilepsy (DRE) affects an estimated 15%-20% of patients with epilepsy. Vagus nerve stimulation (VNS) is a type of neuromodulation. VNS therapy is an adjunctive neurostimulation treatment for DRE patients who are unsuitable for respective surgery or have experienced unsuccessful surgery. VNS involves the use of a device to stimulate the vagus nerve with electrical impulses. VNS is not a cure for epilepsy, and most epilepsy patients can still experience seizures or use epilepsy medication after the procedure. However, 60%-70% of patients can have over 50% reduction in seizures 5 years after the VNS procedure. Seizure intensity may also reduce. VNS is safe with tolerable side effects in most cases. The mechanism of VNS action against epilepsy is still not accurately verified. Some people believe that VNS therapy improves their mood, memory, or alertness and may also help reduce depression. VNS therapy is also expected to work in other indications, including psychiatric, gastrointestinal, endocrinological, and immunological disorders.

The vagus nerve is a key physical constituent of the gut-brain axis. Increasing attention has recently been paid to the role that the gut, and the microorganisms inhabiting it, play in emotion and cognition. Animal studies have revealed the importance of the vagus nerve in mediating communication between the gut microbiome and the central nervous system, resulting in changes in emotional behaviour. This has renewed interest in understanding the role of vagal signalling in human emotion, particularly since human studies have also shown that alterations in gut microbiome composition can affect emotion. While stimulating the vagus nerve can help treat some cases of severe depression, here we investigate whether vagal afferent signalling can influence emotional processing in healthy subjects. We use the dot-probe task to determine the effect of transcutaneous vagus nerve stimulation on attentional biases towards emotional stimuli in 42 volunteers. Participants received both active and sham treatments using a within-subject design. We show that transcutaneous vagus nerve stimulation reduces the emotional bias towards faces expressing sadness and happiness, indicating a decrease in emotional reactivity. While our novel findings reveal the effect that vagal signalling can have on emotional biases in healthy subjects, future studies should seek to develop our understanding of the ways in which the microbiome interacts with, and stimulates, the vagus nerve. Since we find a reduction in emotional bias, most notably towards sadness, this may partly account for the effective use of vagus nerve stimulation in treatment-resistant depression. While its clinical application currently involves surgical stimulation, our results support the potential benefit of transcutaneous vagus nerve stimulation as a non-invasive, intermittent adjunctive therapy for patients with depression, given its frequent association with emotional biases., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Several types of palliative surgery to treat drug-resistant epilepsy (DRE) have been reported, but the evidence that is available is insufficient to help physicians redirect patients with DRE to the most appropriate kind of surgery., Methods: A systematic search in the PubMed and Scopus databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to compare different clinical features, outcomes, and complications of adult patients submitted to callosotomy, vagal nerve stimulation, multiple subpial transections, deep brain stimulation, or responsive neurostimulation., Results: After 3447 articles were screened, 36 studies were selected, including the data of 1628 patients: 76 were treated with callosotomy, 659 were treated with vagal nerve stimulation, 416 were treated with deep brain stimulation, and 477 were treated with responsive neurostimulation. No studies including patients treated with multiple subpial transections met the inclusion criteria. The global weighted average seizure frequency reduction was 50.23%, and the global responder rate was 52.12%. There were significant differences among the palliative surgical procedures in term of clinical features of patients and epilepsy, seizure frequency reduction, and percentage of responders. Complications were differently distributed as well., Conclusions: Our analysis highlights the necessity of prospective studies, possibly randomized controlled trials, to compare different forms of palliative epilepsy surgery. Moreover, by identifying the outcome predictors associated with each technique, the best responder may be profiled for each procedure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This paper reviews the many functions of the vagus nerve, to understand how they interact in daily life and what might be accomplished by therapeutical electrical stimulation. A short historical introduction on the discovery and name-giving of the cranial nerves numbers 9-12 is followed by an overview of the functions that are under lower brain stem control: heart (rate, contractility), intestine (swallowing, peristalsis and glands secretions, feeling of satiety), lungs (bronchoconstriction, lung-irritant and stretch receptor signaling), blood pressure (by vascular wall stress sensing) and blood gases by specialized receptors. Key in the review is the physiology behind beat-by-beat heart rate variations, how everyday life is reflected in its variability, from exciting moments to quiet sleep, with the 'common faint' or vasovagal collapse as extreme example. Next, the recently proposed role of the vagus nerve in limiting inflammation is discussed. This has led to adoption of an earlier developed technique for epilepsy treatment, i.e., electrical stimulation of one vagus nerve bundle in the neck, but now for immune diseases like rheumatoid arthritis and the scope is even widening to depression and cluster headache. However, the problem in application of whole vagus nerve stimulation is the lack of specificity: there is no way to titrate the stimulation to an observable effect variable. All nerves in the bundle, incoming and outgoing, can be 'hit', leading to side-effects which limit the intended application., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Norepinephrine (NE) driven noninvasive vagus nerve stimulation (nVNS), which improves attention and reduces reaction time, augments learning. Equally important, endogenous NE mediated arousal is highly dependent on the valence (positive or negative) of the exogenous stimulus. But to date, no study has measured valence specific effects of nVNS on both functional magnetic resonance imaging (fMRI) anticipation task response and reaction time in healthy individuals. Therefore, the aim of this pilot study was to assess whether nVNS vs sham modulates valence cortical anticipation task response and reaction time in a normative sample., Methods: Participants received right sided transcutaneous cervical nVNS (N = 12) or sham (N = 12) stimulation during a 3T fMRI scan. Subjects first performed a continuous performance task (CPT) and then a cued anticipation task to images of positively and negatively valenced events during fMRI. Reaction times to cues and Blood oxygen level dependent (BOLD) response were examined over phase to identify effects of nVNS/sham over time., Results: nVNS reduced reaction time for all valenced image anticipation trials. With the fMRI anticipation task, we observed a valence-specific effect; nVNS increased responsivity to images with negative valence and decreased responsivity to images with positive valence, whereas sham showed an inverse valence response., Conclusions: nVNS was linked to reduced reaction time during the anticipation task. In tandem, nVNS consistently enhanced responsivity to negatively valenced images and diminished responsivity to positively valenced images, suggesting specific nVNS driven endogenous neurotransmitter signaling may contribute., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Atrial fibrillation is an "invisible killer" of human health. It often induces high-risk diseases, such as myocardial infarction, stroke, and heart failure. Fortunately, atrial fibrillation can be diagnosed and treated early. Low-level vagus nerve stimulation (LL-VNS) is a promising therapeutic method for atrial fibrillation. However, some fundamental challenges still need to be overcome in terms of flexibility, miniaturization, and long-term service of bioelectric stimulation devices. Here, we designed a closed-loop self-powered LL-VNS system that can monitor the patient's pulse wave status in real time and conduct stimulation impulses automatically during the development of atrial fibrillation. The implant is a hybrid nanogenerator (H-NG), which is flexible, light weight, and simple, even without electronic circuits, components, and batteries. The maximum output of the H-NG was 14.8 V and 17.8 μA (peak to peak). In the in vivo effect verification study, the atrial fibrillation duration significantly decreased by 90% after LL-VNS therapy, and myocardial fibrosis and atrial connexin levels were effectively improved. Notably, the anti-inflammatory effect triggered by mediating the NF-κB and AP-1 pathways in our therapeutic system is observed. Overall, this implantable bioelectronic device is expected to be used for self-powerability, intelligentization, portability for management, and therapy of chronic diseases., (Copyright © 2022 Science China Press. Published by Elsevier B.V. All rights reserved.)

Background: Pursuing goals is compromised when being confronted with interfering information. In such situations, conflict monitoring is important. Theoretical considerations on the neurobiology of response selection and control suggest that auricular transcutaneous vagus nerve stimulation (atVNS) should modulate conflict monitoring. However, the neurophysiological-functional neuroanatomical underpinnings are still not understood., Methods: AtVNS was applied in a randomized crossover study design (n = 45). During atVNS or sham stimulation, conflict monitoring was assessed using a Flanker task. EEG data were recorded and analyzed with focus on theta and alpha band activity. Beamforming was applied to examine functional neuroanatomical correlates of atVNS-induced EEG modulations. Moreover, temporal EEG signal decomposition was applied to examine different coding levels in alpha and theta band activity., Results: AtVNS compromised conflict monitoring processes when it was applied at the second appointment in the crossover study design. On a neurophysiological level, atVNS exerted specific effects because only alpha-band activity was modulated. Alpha-band activity was lower in middle and superior prefrontal regions during atVNS stimulation and thus lower when there was also a decline in task performance. The same direction of alpha-band modulations was evident in fractions of the alpha-band activity coding stimulus-related processes, stimulus-response translation processes, and motor response-related processes., Conclusions: The combination of prior task experience and atVNS compromises conflict monitoring processes. This is likely due to reduction of the alpha-band-associated inhibitory gating process on interfering information in frontal cortices. Future research should pay considerable attention to boundary conditions affecting the direction of atVNS effects., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Invasive and transcutaneous vagus nerve stimulation [(t)-VNS] have been used to treat epilepsy, depression and migraine and has also shown effects on metabolism and body weight. To what extent this treatment shapes neural networks and how such network changes might be related to treatment effects is currently unclear. Using a pre-post mixed study design, we applied either a tVNS or sham stimulation (5 h/week) in 34 overweight male participants in the context of a study designed to assess effects of tVNS on body weight and metabolic and cognitive parameters resting state (rs) fMRI was measured about 12 h after the last stimulation period. Support vector machine (SVM) classification was applied to fractional amplitude low-frequency fluctuations (fALFF) on established rs-networks. All classification results were controlled for random effects and overfitting. Finally, we calculated multiple regressions between the classification results and reported food craving. We found a classification accuracy (CA) of 79 % in a subset of four brainstem regions suggesting that tVNS leads to lasting changes in brain networks. Five of eight salience network regions yielded 76,5 % CA. Our study shows tVNS' post-stimulation effects on fALFF in the salience rs-network. More detailed investigations of this effect and their relationship with food intake seem reasonable for future studies., (© 2021. The Author(s).)

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neuromodulatory technique that is thought to activate the Locus Coeruleus-Noradrenaline (LC-NA) system. Standard taVNS protocols consist of the administration of intermittent or continuous stimulation over long periods. However, there is currently a limited understanding of the temporal dynamics of taVNS modulation of cognitive processes, as well as its mechanisms of action. We argue that novel stimulation approaches, informed by established theories of the LC-NA system, are needed to further our understanding of the neurocognitive underpinnings of taVNS. In this pre-registered study, we tested whether an "event-related" taVNS protocol can modulate the LC-NA system. In a within-subject design (single session) we delivered brief trains of taVNS (3 s) during an auditory oddball paradigm. The taVNS was time-locked to the target stimuli presentation and randomly interleaved with sham stimulation. Response times (RT) and stimuli-driven pupillary diameter (PD) were used as indices of LC-NA activity. Results revealed that active taVNS increased RT to targets, as compared to sham trials. Notably, in line with current theories of LC-NA functioning, taVNS modulation of target-related pupil dilation depended on pre-stimulation PD, an index of baseline LC-NA activity. In particular, active (vs. sham) taVNS was associated with smaller pupil dilation in trials where the baseline PD was small. These results demonstrate, for the first time, the effectiveness of brief event-related taVNS in the modulation of cognitive processes and highlight the importance of using pupil size as an index of tonic and phasic LC-NA activity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To analyze the efficacy and safety of high-frequency VNS versus control (low-frequency VNS or no VNS) in patients with DRE using data from randomized controlled trials (RCTs). An electronic literature search was conducted on PubMed, EMBASE, and Cochrane Controlled Register of Trials (CENTRAL); 12 RCTs reporting seizure frequency or treatment response in studies containing a high-frequency VNS treatment arm (conventional VNS or transcutaneous VNS [tVNS]) compared to control (low-frequency VNS or no VNS) were included. Seizure frequency, treatment response (number of patients with ≥ 50% reduction in seizure frequency), quality of life (QOL), and adverse effects were analyzed. Seizure frequency was reported in 9 studies (718 patients). Meta-analysis with random-effects models favored high-frequency VNS over control (standardized mean difference = 0.82, 95%-CI = 0.39-1.24, p < .001). This remained significant for subgroup analyses of low-frequency VNS as the control, VNS modality, and after removing studies with moderate-to-high risk of bias. Treatment response was reported in 8 studies (758 patients). Random-effects models favored high-frequency VNS over control (risk ratio = 1.57, 95%-CI = 1.19-2.07, p < .001). QOL outcomes were reported descriptively in 4 studies (363 patients), and adverse events were reported in 11 studies (875 patients). Major side effects and death were not observed to be more common in high-frequency VNS compared to control. High-frequency VNS results in reduced seizure frequency and improved treatment response compared to control (low-frequency VNS or no VNS) in patients with drug-resistant epilepsy. Greater consideration for VNS in patients with DRE may be warranted to decrease seizure frequency in the management of these patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the clinical effect of transcutaneous auricular vagus nerve nerve stimulation (taVNS) on disorders of consciousness (DOC) patients with Coma Recovery Scale-Revised (CRS-R) and cerebral cortex activity by electroencephalogram (EEG) detection., Methods: Randomized controlled methods were used to evaluate the clinical effect of taVNS on patients with DOC. Twelve patients with initial CRS-R of 6-10 were randomly divided into the treatment group of taVNS and control group of transcutaneous non-auricular vague nerve stimulation (tnVNS). According to clinical diagnosis, the treatment group was divided into vegetative state (VS) group and minimally conscious state (MCS) group., Results: The energy of delta and beta bands is positively correlated with the brain activity of patients. taVNS has different regulatory effects on patients with different conscious States. In taVNS group, the energy of delta band in local brain regions changed significantly. Significant changes in brain connection activity were limited to local brain regions. While in patients with MCS in the taVNS group, delta and beta band energy significantly changed in multiple brain regions and cross-brain connection activity also changed significantly., Conclusion: These findings suggest that taVNS may be a related extra method for arousing patients' awakening by improving brain connection activity. And the effect is remarkable in MCS patients.

Aim: Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention., Methods: After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period., Results: Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, -0.83; p  = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p  = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported., Conclusions: These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy. Trial Registration: ClinicalTrials.gov (NCT03716505).

The vagus nerve, the great wanderer, is involved in numerous processes throughout the body and vagus nerve stimulation (VNS) has the potential to modulate many of these functions. This wide-reaching capability has generated much interest across a range of disciplines resulting in several clinical trials and studies into the mechanistic basis of VNS. This review discusses current preclinical and clinical evidence supporting the efficacy of VNS in different diseases and highlights recent advancements. Studies that provide insights into the mechanism of VNS are considered., (© 2022 The Author(s).)

Background and Study Aims:  Vagus nerve stimulation (VNS) has been employed worldwide as an adjunctive therapy in drug-resistant epilepsy patients. However, the mechanisms of VNS action potentially increase the risk of obstetric complications. The study presents the long-term single-center experience with pregnancies and childbirth in women with VNS for refractory epilepsy based on prospectively collected epileptologic data and a retrospective analysis of pregnancy, childbirth, and data about long-term child development., Material and Methods:  From a group of patients with VNS implanted for refractory epilepsy between October 1999 and January 2018, all the women of childbearing age (younger than 40 years) were identified. After checking their hospital records for data about any pregnancies, the women with confirmed childbirth during active VNS stimulation and their general practitioners were interviewed based on a prepared questionnaire regarding their gynecologic history, the course of pregnancy and childbirth, gestational week, birth weight and length, any congenital anomalies of the child, and the child's psychomotor development, school performance, and somatic health problems., Results:  From the group of 257 patients implanted with VNS for refractory epilepsy, 4 women (1.5%) became pregnant and gave birth (all on polypharmacotherapy). The mean interval from VNS implantation to birth was 44.3 months. Slight seizure worsening during the last trimester was reported in one woman. In one patient, acute caesarean section was required due to placental separation. Planned birth induction and caesarean section were used in the other two women because of their seizure disorder. No malfunction of the stimulation system was detected during pregnancy or after birth. No congenital malformations were observed. The two children who were of school age at the time of this study require special schooling., Conclusions:  The study results confirmed a high rate of obstetric interventions in patients with VNS. Although no teratogenic effect of VNS has been proven, the higher incidence of children exposed to VNS needing special education requires attention., Competing Interests: None declared., (Thieme. All rights reserved.)

Numerous studies confirm that the vagus nerve stimulation (VNS) is an efficient, indirect neuromodulatory therapy with electrically induced current for epilepsy that cannot be treated by epilepsy surgery and is therapy-refractory and for drug therapy-refractory depression. VNS is an established, evidence-based and in the long-term cost-effective therapy in an interdisciplinary overall concept.Long-term data on the safety and tolerance of the method are available despite the heterogeneity of the patient populations. Stimulation-related side effects like hoarseness, paresthesia, cough or dyspnea depend on the stimulation strength and often decrease with continuing therapy duration in the following years. Stimulation-related side effects of VNS can be well influenced by modifying the stimulation parameters. Overall, the invasive vagus nerve stimulation may be considered as a safe and well-tolerated therapy option.For invasive and transcutaneous vagus nerve stimulation, antiepileptic and antidepressant as well as positive cognitive effects could be proven. In contrast to drugs, VNS has no negative effect on cognition. In many cases, an improvement of the quality of life is possible.iVNS therapy has a low probability of complete seizure-freedom in cases of focal and genetically generalized epilepsy. It must be considered as palliative therapy, which means that it does not lead to healing and requires the continuation of specific medication. The functional principle is a general reduction of the neuronal excitability. This effect is achieved by a slow increase of the effectiveness sometimes over several years. Responders are those patients who experience a 50% reduction of the seizure incidence. Some studies even reveal seizure-freedom in 20% of the cases. Currently, it is not possible to differentiate between potential responders and non-responders before therapy/implantation.The current technical developments of the iVNS generators of the new generation like closed-loop system (cardiac-based seizure detection, CBSD) reduce also the risk for SUDEP (sudden unexpected death in epilepsy patients), a very rare, lethal complication of epilepsies, beside the seizure severity.iVNS may deteriorate an existing sleep apnea syndrome and therefore requires possible therapy interruption during nighttime (day-night programming or magnet use) beside the close cooperation with sleep physicians.The evaluation of the numerous iVNS trials of the past two decades showed multiple positive effects on other immunological, cardiological, and gastroenterological diseases so that additional therapy indications may be expected depending on future study results. Currently, the vagus nerve stimulation is in the focus of research in the disciplines of psychology, immunology, cardiology as well as pain and plasticity research with the desired potential of future medical application.Beside invasive vagus nerve stimulation with implantation of an IPG and an electrode, also devices for transdermal and thus non-invasive vagus nerve stimulation have been developed during the last years. According to the data that are currently available, they are less effective with regard to the reduction of the seizure severity and duration in cases of therapy-refractory epilepsy and slightly less effective regarding the improvement of depression symptoms. In this context, studies are missing that confirm high evidence of effectiveness. The same is true for the other indications that have been mentioned like tinnitus, cephalgia, gastrointestinal complaints etc. Another disadvantage of transcutaneous vagus nerve stimulation is that the stimulators have to be applied actively by the patients and are not permanently active, in contrast to implanted iVNS therapy systems. So they are only intermittently active; furthermore, the therapy adherence is uncertain., Competing Interests: H. Möbius erhielt Unterstützung in Form von Reisekosten im Rahmen eines OP-Kurses durch Fa. Inspire medical., (Thieme. All rights reserved. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Posttraumatic stress disorder (PTSD) remains one of the most prevalent diagnoses of World Trade Center (WTC) 9/11 responders. Transcutaneous auricular vagus nerve stimulation (taVNS) is a potential treatment for PTSD, as it can downregulate activity in the brain, which is known to be related to stress responses and hyperarousal. To understand barriers and facilitators to engagement in mental health care and the feasibility and acceptability of using the taVNS device as a treatment for PTSD symptoms, a focus group was conducted among patients from the Queens WTC Health Program who had elevated symptoms of PTSD. The focus group discussion was recorded, transcribed, and analyzed. Three themes and subthemes emerged: (1) the continued prevalence of mental health difficulties and systematic challenges to accessing care; (2) positive reception toward the taVNS device as a potential treatment option, including a discussion of how to increase usability; and (3) feedback on increasing the feasibility and acceptance of the research methodology associated with testing the device in a pilot clinical trial. The findings highlight the need for additional treatment options to reduce PTSD symptoms in this population and provide key formative phase input for the pilot clinical trial of taVNS.

Objective. Transcutaneous vagus nerve stimulation (tVNS) is a form of non-invasive brain stimulation that delivers a sequence of electrical pulses to the auricular branch of the vagus nerve and is used increasingly in the treatment of a number of health conditions such as epilepsy and depression. Recent research has focused on the efficacy of tVNS to treat different medical conditions, but there is little conclusive evidence concerning the optimal stimulation parameters. There are relatively few studies that have combined tVNS with a neuroimaging modality, and none that have attempted simultaneous magnetoencephalography (MEG) and tVNS due to the presence of large stimulation artifacts produced by the electrical stimulation which are many orders of magnitude larger than underlying brain activity. Approach. The aim of this study is to investigate the utility of MEG to gain insight into the regions of the brain most strongly influenced by tVNS and how variation of the stimulation parameters can affect this response in healthy participants. Main results. We have successfully demonstrated that MEG can be used to measure brain response to tVNS. We have also shown that varying the stimulation frequency can lead to a difference in brain response, with the brain also responding in different anatomical regions depending on the frequency. Significance. The main contribution of this paper is to demonstrate the feasibility of simultaneous pulsed tVNS and MEG recording, allowing direct investigation of the changes in brain activity that result from different stimulation parameters. This may lead to the development of customised therapeutic approaches for the targeted treatment of different conditions., (© 2022 IOP Publishing Ltd.)

Objective: To explore the modulation of transcutaneous auricular vagus nerve stimulation (taVNS) on default mode network (DMN) in patients with primary insomnia (PI)., Methods: A total of 22 PI patients (one patient dropped off and two patients were excluded) were included and treated with taVNS. The bilateral auricular points of Xin (CO 15 ) and Shen (CO 10 ) were selected and treated with disperse-dense wave at frequency of 4 Hz/20 Hz, the intensity was based on the patient's tolerance. taVNS was given once in the morning and once in the evening for 30 minutes each time. The treatment lasted for at least 5 days a week for 4 weeks. At the same time, 16 healthy subjects matched with gender and age were recruited. The Pittsburgh sleep quality index (PSQI) score was evaluated before and after treatment in PI patients. The resting-state functional magnetic resonance imaging (rs-fMRI) data of PI patients before and after treatment and healthy subjects at baseline period were collected to observe the effect of taVNS on the functional connection (FC) between posterior cingulate cortex (PCC) and whole brain., Results: After treatment, the total score of PSQI in PI patients was lower than that before treatment ( P <0.01). Compared with healthy subjects, the FC of the left PCC was increased either with the left orbital superior frontal gyrus or with left middle frontal gyrus ( P <0.001), and the FC between right PCC and left middle frontal gyrus was increased in PI patients before treatment ( P <0.001). Compared before treatment, the FC between left PCC and left middle frontal gyrus was decreased ( P <0.05), and the FC of the right PCC was decreased either with the right medial prefrontal cortex or with the left middle frontal gyrus in PI patients after treatment ( P <0.001, P <0.01)., Conclusion: taVNS can modulate the FC between anterior and posterior DMN, and between DMN and cognitive control network of PI patients, which may be one of the brain effect mechanisms of taVNS in the treatment of PI patients.

Introduction: Vagus nerve stimulation (VNS) is a neuromodulation therapy that can reduce the seizure burden of children with medically intractable epilepsy. Despite the widespread use of VNS to treat epilepsy, there are currently no means to preoperatively identify patients who will benefit from treatment. The objective of the present study is to determine clinical and neural network-based correlates of treatment outcome to better identify candidates for VNS therapy., Methods and Analysis: In this multi-institutional North American study, children undergoing VNS and their caregivers will be prospectively recruited. All patients will have documentation of clinical history, physical and neurological examination and video electroencephalography as part of the standard clinical workup for VNS. Neuroimaging data including resting-state functional MRI, diffusion-tensor imaging and magnetoencephalography will be collected before surgery. MR-based measures will also be repeated 12 months after implantation. Outcomes of VNS, including seizure control and health-related quality of life of both patient and primary caregiver, will be prospectively measured up to 2 years postoperatively. All data will be collected electronically using Research Electronic Data Capture., Ethics and Dissemination: This study was approved by the Hospital for Sick Children Research Ethics Board (REB number 1000061744). All participants, or substitute decision-makers, will provide informed consent prior to be enrolled in the study. Institutional Research Ethics Board approval will be obtained from each additional participating site prior to inclusion. This study is funded through a Canadian Institutes of Health Research grant (PJT-159561) and an investigator-initiated funding grant from LivaNova USA (Houston, TX; FF01803B IIR)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It has been suggested that vagus nerve stimulation (VNS) may enhance attention and working memory. The neuromodulator effects of VNS are thought to activate the release of neurotransmitters involving cognition and to promote neuronal plasticity. Therefore, VNS has been studied for its effects on attention and working memory impairment in neuropsychiatric disorders., Objectives: This study aimed to assess the effects of VNS on attention and working memory among patients with neuropsychiatric disorders, examine stimulation parameters, provide mechanistic hypotheses, and propose future studies using VNS., Materials and Methods: We conducted a systematic review using electronic databases MEDLINE (Ovid), Embase (Ovid), Cochrane library, and PsycINFO (Ovid). Narrative analysis was used to describe the therapeutic effects of VNS on attention and working memory, describe stimulation parameters, and propose explanatory mechanisms., Results: We identified 20 studies reporting VNS effects on attention and working memory in patients with epilepsy or mood disorders. For epilepsy, there was one randomized controlled trial from all 18 studies. It demonstrated no statistically significant differences in the cognitive tasks between active and control VNS. From a within-subject experimental design, significant improvement of working memory after VNS was demonstrated. One of three nonrandomized controlled trials found significantly improved attentional performance after VNS. The cohort studies compared VNS and surgery and found attentional improvement in both groups. Nine of 12 pretest-posttest studies showed improvement of attention or working memory after VNS. For mood disorders, although one study showed significant improvement of attention following VNS, the other did not., Conclusions: This review suggests that, although we identified some positive results from eligible studies, there is insufficient good-quality evidence to establish VNS as an effective intervention to enhance attention and working memory in persons with neuropsychiatric disorders. Further studies assessing the efficacy of such intervention are needed., (Copyright © 2021 International Neuromodulation Society. All rights reserved.)

Although transcutaneous auricular vagus nerve stimulation (taVNS) is thought to increase central noradrenergic activity, findings supporting such mechanism are scarce and inconsistent. This study aimed to investigate whether taVNS modulates indirect markers of phasic and tonic noradrenergic activity. Sixty-six healthy participants performed a novelty auditory oddball task twice on separate days: once while receiving taVNS (left cymba concha), once during sham (left earlobe) stimulation. To maximize potential effects, the stimulation was delivered continuously (frequency: 25 Hz; width: 250 μs) at an intensity individually calibrated to the maximal level below pain threshold. The stimulation was administered 10 min before the oddball task and maintained throughout the session. Event-related pupil dilation (ERPD) to target stimuli and pre-stimulus baseline pupil size were assessed during the oddball task as markers of phasic and tonic noradrenergic activity, respectively. Prior to and at the end of stimulation, tonic pupil size at rest, cortisol, and salivary alpha-amylase were assessed as markers of tonic noradrenergic activity. Finally, we explored the effect of taVNS on cardiac vagal activity, respiratory rate, and salivary flow rate. Results showed a greater ERPD to both target and novelty compared to standard stimuli in the oddball task. In contrast to our hypotheses, taVNS did not impact any of the tested markers. Our findings strongly suggest that continuous stimulation of the cymba concha with the tested stimulation parameters is ineffective to increase noradrenergic activity via a vagal pathway., (© 2021 Society for Psychophysiological Research.)

Background and Objective: The cardiac autonomic nervous system (CANS) plays an important role in the pathophysiology of atrial fibrillation (AF). Cardiovascular disease can cause an imbalance within the CANS, which may contribute to the initiation and maintenance of AF. Increased understanding of neuromodulation of the CANS has resulted in novel emerging therapies to treat cardiac arrhythmias by targeting different circuits of the CANS. Regarding AF, neuromodulation therapies targeting the vagus nerve have yielded promising outcomes. However, targeting the vagus nerve can be both pro-arrhythmogenic and anti-arrhythmogenic. Currently, these opposing effects of vagus nerve stimulation (VNS) have not been clearly described. The aim of this review is therefore to discuss both pro-arrhythmogenic and anti-arrhythmogenic effects of VNS and recent advances in clinical practice and to provide future perspectives for VNS to treat AF., Materials and Methods: A comprehensive review of current literature on VNS and its pro-arrhythmogenic and anti-arrhythmogenic effects on atrial tissue was performed. Both experimental and clinical studies are reviewed and discussed separately., Results: VNS exhibits both pro-arrhythmogenic and anti-arrhythmogenic effects. The anatomical site and stimulation settings during VNS play a crucial role in determining its effect on cardiac electrophysiology. Since the last decade, there is accumulating evidence from experimental studies and randomized clinical studies that low-level VNS (LLVNS), below the bradycardia threshold, is an effective treatment for AF., Conclusion: LLVNS is a promising novel therapeutic modality to treat AF and further research will further elucidate the underlying anti-arrhythmogenic mechanisms, optimal stimulation settings, and site to apply LLVNS., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)