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Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive form of electrical brain stimulation, has shown potent therapeutic potential for a wide spectrum of conditions. How taVNS influences the characterization of motion sickness - a long mysterious syndrome with a polysymptomatic onset - remains unclear. Here, to examine taVNS-induced effects on brain function in response to motion-induced nausea, 64-channel electroencephalography (EEG) recordings from 42 healthy participants were analyzed; collected during nauseogenic visual stimulation concurrent with taVNS administration, in a crossover randomized sham-controlled study. Cortical neuronal generators were estimated from the obtained EEG using exact low-resolution brain electromagnetic tomography (eLORETA). While both sham and taVNS increased insula activation during electrical stimulation, compared to baseline, taVNS additionally augmented middle frontal gyrus neuronal activity. Following taVNS, brain regions including the supramarginal, parahippocampal, and precentral gyri were activated. Contrasting sham, taVNS markedly increased activity in the middle occipital gyrus during stimulation. A repeated-measures ANOVA showed that taVNS reduced motion sickness symptoms. This reduction in symptoms correlated with taVNS-induced neural activation. Our findings provide new insights into taVNS-induced brain changes, during and after nauseogenic stimuli exposure, including accompanying behavioral response. Together, these findings suggest that taVNS has promise as an effective neurostimulation tool for motion sickness management., (© 2024. The Author(s).)

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Conventional treatments are ineffective in reversing disease progression. Recently, the therapeutic and rehabilitation potential of vagus nerve stimulation (VNS) in PD has been explored. However, the underlying mechanisms remain largely unknown. In this study, we investigated the neuroprotective effects of VNS in a lateral lesioned mice model of PD. Excluding controls, experimental mice received cuff electrode implantation on the left vagus nerve and 6-hydroxydopamine administration into the bilateral striatum. After ten days, electrical stimulation was delivered for 11 consecutive days onto PD animals. Behavioral tests were performed after stimulation. The expression of TH, Iba-1, GFAP, adrenergic receptors and cytokines in the SN and striatum was detected by immunofluorescence or western blotting. The activity of noradrenergic neurons in the locus coeruleus (LC) was also measured. Our results suggest that VNS improved behavioral performance in rod rotation, open field tests and pole-climbing tests in PD mice, accompanied by a decrease in the loss of dopaminergic neurons in the SN and increased TH expression in the striatum. Neuroinflammation-related factors, such as GFAP, Iba-1, TNF-α and IL-1β were also suppressed in PD mice after VNS compared to those without treatment. Furthermore, the proportion of c-Fos-positive noradrenergic neurons in the LC increased when animals received VNS. Additionally, the expression of the adrenergic receptor of α1BR was also upregulated after VNS compared to PD mice. In conclusion, VNS has potential as a novel PD therapy for neuroprotective effects, and indicate that activation of norepinephric neurons in LC may plays an important role in VNS treatment for PD., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Vagal nerve stimulator (VNS) implantation is a vital therapy for epilepsy refractory to other treatments; however, it is associated with a very high rate of voice changes. Relatively few of these patients are evaluated for vocal fold motion impairments. In this series, we evaluate 5 such patients with a novel phenotype of forced abduction with VNS stimulation., Methods: Retrospective case series., Results: Five patients with a VNS implant who underwent operative direct or in-office rigid laryngoscopy and had vocal fold motion impairment associated with VNS activation are included. All 5 patients had vocal fold mobility with VNS off and a fixed with activation. All patients exhibited vocal fold abduction with VNS activation. Patient 2 has since undergone laryngeal reinnervation, which helped her intermittent dysphonia but left a small glottic gap. A type 1 thyroplasty corrected this gap and improved her voice further. Patient 3 has undergone laryngeal reinnervation for which early results show improvement in perceptual and patient reported outcomes. Patients 4 and 5 have both undergone laryngeal reinnervation with improvement in voice., Conclusion: Previous reported cases of stimulated immobility associated with VNS use describe only adduction of the vocal fold. This series expands the previous work showing the VNS activation can also cause stimulated immobility in an abducted position, for which reinnervation and other medialization procedures offer promising treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To consider the possible role of the vagus nerve (VN) in the pathophysiology of sleep bruxism (SB) and introduce a multimodal protocol of transcutaneous auricular stimulation of the VN in the treatment of SB patients., Methods: Ten patients with SB underwent four sessions of electric transcutaneous auricular vagus nerve stimulation (ta-VNS) in specific auricular areas. The patients were advised to manually stimulate the same areas between sessions. Masticatory muscle activity and sleep parameters were measured by a polysomnography (PSG) before and after the treatment. Heart rate variability (HRV) parameters were measured during each stimulation., Results: PSG analysis revealed a statistically significant reduction in tonic SB index and tonic contraction time. HRV parameters showed a statistically significant increase in mean values of the vagal tone after each session of stimulation. No side effect was reported., Conclusion: The stimulation of the VN might have a role in the treatment of SB.

Increased sympathetic and reduced parasympathetic nerve activity is associated with disease progression and poor outcomes in patients with chronic heart failure. The demonstration that markers of autonomic imbalance and vagal dysfunction, such as reduced heart rate variability and baroreflex sensitivity, hold prognostic value in patients with chronic heart failure despite modern therapies encourages the research for neuromodulation strategies targeting the vagus nerve. However, the approaches tested so far have yielded inconclusive results. This review aims to summarize the current knowledge about the role of the parasympathetic nervous system in chronic heart failure, describing the pathophysiological background, the methods of assessment, and the rationale, limits, and future perspectives of parasympathetic stimulation either by drugs or bioelectronic devices., (© 2024. The Author(s).)

Background: Contrast-induced acute kidney injury (CI-AKI) is manifested by a rapid decline in renal function occurring within 48-72 h in patients exposed to iodinated contrast media (CM). Although intravenous hydration is currently the effective method confirmed to prevent CI-AKI, it has several drawbacks. Some investigations have demonstrated the nephroprotective effects of vagus nerve stimulation (VNS) against kidney ischemia-reperfusion injury, but no direct research has investigated the use of VNS for treating CI-AKI. Additionally, most current VNS treatment applies invasive electrical stimulator implantation, which is largely limited by the complications. Our recent publications introduce the magnetic vagus nerve stimulation (mVNS) system pioneered and successfully used for the treatment of myocardial infarction. However, it remains uncertain whether mVNS can mitigate CI-AKI and its specific underlying mechanisms. Therefore, we herein evaluate the potential therapeutic effects of mVNS on CM-induced nephropathy in rats and explore the underlying mechanisms., Results: mVNS treatment was found to significantly improve the damaged renal function, including the reduction of elevated serum creatinine (Scr), blood urea nitrogen (BUN), and urinary N-acetyl-β-D-glucosaminidase (NAG) with increased urine output. Pathologically, mVNS treatment alleviated the renal tissue structure injury, and suppressed kidney injury molecule-1 (KIM-1) expression and apoptosis in renal tubular epithelial cells. Mechanistically, increased circulating plasma exosomal miR-365-3p after mVNS treatment enhanced the autophagy and reduced CM-induced apoptosis in renal tubular epithelial cells by targeting Ras homolog enriched in brain (Rheb)., Conclusions: In summary, we demonstrated that mVNS can improve CI-AKI through enhanced autophagy and apoptosis inhibition, which depended on plasma exosomal miR-365-3p. Our findings highlight the therapeutic potential of mVNS for CI-AKI in clinical practice. However, further research is needed to determine the optimal stimulation parameters to achieve the best therapeutic effects., (© 2024. The Author(s).)

Gouty inflammation, caused by uric acid crystal deposition, primarily affects tissues around the toe joints and triggers potent inflammatory responses. Current treatments focus on alleviating inflammation and pain using pharmaceutical agents, which can lead to side effects and complications. This has generated interest in non-pharmacological interventions, such as non-invasive vagus nerve stimulation (VNS). In this study, we explored the anti-inflammatory mechanisms of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of acute gout. Gouty inflammation was induced by injecting monosodium urate (MSU) crystals into the ankle joints of BALB/c mice. The effects of taVNS on the expression of inflammatory cytokines and chemokines in the ankle joint tissue were assessed using real-time quantitative PCR (qPCR), western blotting, histological assessments (H&E staining), and immunohistochemistry (IHC). The role of α7 nicotinic acetylcholine receptors (α7nAChR) was also evaluated by signal blocking. Our findings revealed that MSU significantly elevated gout-associated inflammatory cascades and mediators in the ankle joint. Notably, taVNS at 200 µA and 25 Hz effectively reduced these inflammatory responses, decreasing neutrophil infiltration and chemoattraction within the tissue. taVNS showed significant anti-inflammatory properties by suppressing neutrophil activity, offering a novel therapeutic approach for gout beyond conventional pharmacological methods. Additionally, taVNS holds potential for managing various chronic joint diseases. These results highlight taVNS as a promising non-pharmacological therapy for chronic inflammation., (© 2024. The Author(s).)

The efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive method to modulate physiological markers of noradrenergic activity of the Locus Coeruleus (LC), such as pupil dilation, is increasingly more discussed. However, taVNS studies show high heterogeneity of stimulation effects. Therefore, a taVNS setup was established here to test different frequencies (10 Hz and 25 Hz) and intensities (3 mA and 5 mA) during phasic stimulation (3 s) with time-synchronous recording of pupil dilation in younger adults. Specifically, phasic real taVNS and higher intensity led to increased pupil dilation, which is consistent with phasic invasive VNS studies in animals. The results also suggest that the influence of intensity on pupil dilation may be stronger than that of frequency. However, there was an attenuation of taVNS-induced pupil dilation when differences in perception of sensations were considered. Specifically, pupil dilation during phasic stimulation increased with perceived stimulation intensity. The extent to which the effect of taVNS induces pupil dilation and the involvement of sensory perception in the stimulation process are discussed here and require more extensive research. Additionally, it is crucial to strive for comparable stimulation sensations during systematic parameter testing in order to investigate possible effects of phasic taVNS on pupil dilation in more detail., (© 2024. The Author(s).)

Introduction: Deep brain stimulation (DBS) and vagus nerve stimulation (VNS) can improve motor function in patients with poststroke hemiplegia. No comparison study exists., Methods and Analysis: This is a randomised, double-blind, controlled clinical trial involving 64 patients who had their first stroke at least 6 months ago and are experiencing poststroke limb dysfunction. These patients must receive necessary support at home and consent to participate. The aim is to evaluate the effectiveness and safety of DBS and VNS therapies. Patients are excluded if they have implantable devices that are sensitive to electrical currents, severe abnormalities in their lower limbs or are unable to comply with the trial procedures. The study has two parallel, distinct treatment arms: the Stimulation Group and the Sham Group. Initially, the Stimulation Group will undergo immediate electrical stimulation postsurgery, while the Sham Group will receive non-stimulation 1 month later. After 3 months, these groups will swap treatments, with the Stimulation Group discontinuing stimulation and the Sham Group initiating stimulation. Six months later, both groups will resume active stimulation. Our primary outcomes will meticulously assess motor function improvements, using the Fugl-Meyer Assessment, and safety, monitored by tracking adverse reaction rates. Furthermore, we will gain a comprehensive view of patient outcomes by evaluating secondary measures, including clinical improvement (National Institutes of Health Stroke Scale), surgical complications/side effects, quality of life (36-item Short Form Questionnaire) and mental health status (Hamilton Anxiety Rating Scale/Hamilton Depression Rating Scale). To ensure a thorough understanding of the long-term effects, we will conduct follow-ups at 9 and 12 months postsurgery, with additional long-term assessments at 15 and 18 months. These follow-ups will assess the sustained performance and durability of the treatment effects. The statistical analysis will uncover the optimal treatment strategy for poststroke hemiplegia, providing valuable insights for clinicians and patients alike., Ethics and Dissemination: This study was reviewed and approved by the Ethical Committee of Chinese PLA General Hospital (S2022-789-01). The findings will be submitted for publication in peer-reviewed journals with online accessibility, ensuring adherence to the conventional scientific publishing process while clarifying how the research outcomes will be disseminated and accessed., Trial Registration Number: NCT06121947., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Treatment-resistant depression (TRD) is a condition in which patients suffering from depression no longer respond to common methods of treatment, such as anti-depressant medication. Neurosurgical procedures such as ablative surgery, deep brain stimulation, and vagus nerve stimulation have been used in efforts to overcome TRD., Objectives: This review aims to provide an overview of the side effects of neurosurgery performed in clinical studies related to depression., Methods: A literature search was conducted through PubMed, MEDLINE, EMBASE, Ovid, and ClinicalTrials.gov databases., Results: This review selected 10 studies for ablative surgery, 12 for deep brain stimulation, and 10 for vagus nerve stimulation, analyzing their side effect profiles of neurosurgery for TRD. The major side effects of each type of neurosurgery were identified, such as incontinence and confusion for ablative surgery, headaches and increased suicide ideation for deep brain stimulation, and voice hoarseness and dyspnea for vagus nerve stimulation., Conclusion: The review discusses the merits and demerits of neurosurgery as a treatment option for TRD. It also suggests new insights into decreasing the burden of these neurosurgical side effects so that they can be a viable, high-efficacy treatment method for TRD., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: To determine the effects of vagal nerve stimulation on cognition and epilepsy-associated psychosocial problems in patients with intractable epilepsy, and to assess their relation to seizure decline., Methods: The longitudinal study was conducted at Saad Al-Witry Neurosciences Hospital, Baghdad, Iraq, from December 2015 to December 2020, and comprised refractory epilepsy cases with implanted vagal nerve stimulation devices. They were subjected to pre- and post-implantation epilepsy protocol assessment with added neuropsychological evaluation using the Mini-Mental State Examination system. Each case was followed up for 2 years post-implantation. Descriptive data regarding patient records of age, seizure nature, mental functioning level, and vagal nerve stimulation insertion was noted. Data was analysed using SPSS 21., Results: Of the 150 patients, 75(50%) each were males and females, with 70(46.7%) aged <10 years at the time of surgery. Overall, 80(53.3%) patients had partial seizures with secondary generalisation, 70(46.7%) had refractory seizure attacks for <5 years, 78(52%) had attack frequency of 2-5 per day. All 150(100%) patients had had vagal nerve stimulation for >2 years. Post-intervention, 80(53.3%) patients had <2 attacks per day. Mini-Mental State Examination score was >25 in 35(23.3%) patients which post-intervention rose to 64(42.7%)., Conclusions: There was evidence of improvement with respect to patient characteristics predictive of vagal nerve stimulation-related cognition and neuropsychological responsiveness in refractory epilepsy.

Paired associative stimulation (PAS) is a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS). PAS can induce long-term potentiation (LTP)-like plasticity in humans, manifested as motor-evoked potential (MEP) enhancement. We have developed a variant of PAS ("high-PAS"), which consists of high-frequency PNS and high-intensity TMS and targets spinal plasticity and promotes rehabilitation after spinal cord injury (SCI). Vagus nerve stimulation (VNS) promotes LTP-like plasticity and enhances recovery in SCI and stroke in humans and animals when combined with repetitive motor training. We combined high-PAS with simultaneous noninvasive transcutaneous auricular VNS (aVNS) to determine if aVNS enhances the extent of PAS-induced MEP amplitude increase. Sixteen healthy participants were stimulated for 20 min in four different sessions (PAS, PAS + aVNS, PAS + shamVNS, and aVNS) in a randomized single-blind setup. MEPs were measured before, immediately after, and at 30, 60, and 90 min post-stimulation. Stimulation protocols with PAS significantly potentiated MEPs (p = 0.005) when compared with aVNS (p = 0.642). Although not significant, MEP enhancement observed after PAS (43.5%) is further increased by aVNS (49.7%) and electrical earlobe stimulation (63.9%). Our aVNS setup failed to significantly enhance the effect of PAS, but sham VNS revealed a trend towards enhanced plasticity. Optimization of auricular VNS stimulation setup is required for possible tests of patients with SCI., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: To assess the impact of vagus nerve stimulation (VNS) on quality of life contributors such as rescue medications., Methods: Using the seizure diary application SeizureTracker™ database, we examined trends in rescue administration frequency before and after the first recorded VNS magnet swipe in patients with drug-resistant epilepsy who had 1) At least one VNS magnet swipe recorded in the diary, and 2) Recorded usage of a benzodiazepine rescue medication (RM) within 90 days prior to the first swipe. A paired Wilcoxon rank-sum test was used to assess changes in RM usage frequency between 30-, 60-, 90-, 180- and 360-day intervals beginning 30 days after first magnet swipe. Longitudinal changes in RM usage frequency were assessed with a generalized estimating equation model., Results: We analyzed data of 95 patients who met the inclusion criteria. Median baseline seizure frequency was 8.3 seizures per month, with median baseline rescue medication usage frequency of 2.1 administrations per month (SD 3.3). Significant reductions in rescue medication usage were observed in the 91 to 180 day interval after first VNS magnet swipe, and at 181 to 360 days and at 361 to 720 days, with the magnitude of reduction increasing over time. Decreases in rescue medication usage were sustained when controlling for patients who did not record rescue medication use after the first VNS magnet swipe (N=91). Significant predictors of reductions in rescue medication included baseline frequency of rescue medication usage and time after first VNS magnet swipe., Significance: This retrospective analysis suggests that usage of rescue medications is reduced following the start of VNS treatment in patients with epilepsy, and that the magnitude of reduction may progressively increase over time., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [SW, CRM & PM reported personal fees (speakers bureau) from LivaNova outside the submitted work. R.M. is the cofounder/owner of Seizure Tracker, LLC, which has received funding from Courtagen, Engage Therapeutics, Greenwich Biosciences, Neurelis, UCB, Xenon Pharmaceuticals, and grants from TuberousSclerosis Alliance. SC is the co-founder/owner of EpilepsyAI, LLC, which has received funding from Neurelis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential Competing Interest.]., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

There are many treatment options available for patients with medically refractory epilepsy including antiseizure medications, surgery, devices and ketogenic diet therapy. Ketogenic diet therapy has been shown to be a safe and effective treatment option in adult and pediatric patients. In order to obtain maximal clinical effectiveness and tolerability of any treatment option, adjustments are often necessary. This article outlines the "fine-tuning" options available for antiseizure medications, vagus nerve stimulation and ketogenic diet therapies and demonstrates that ketogenic diet therapies offer a wider array of personalizing and fine-tuning options., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Drug-resistant epilepsy (DRE) affects one-third of patients with focal epilepsy. A large portion of patients are not candidates for epilepsy surgery, thus alternative options, such as vagus nerve stimulation (VNS), are proposed. Our objective is to study the effect of vagus nerve stimulation on lesional versus non-lesional epilepsies., Methods: This is a retrospective cohort study in a single center in London, Ontario, which includes patients with DRE implanted with VNS, implanted between 1997-2018 and the date of analysis is December 2023., Participants: Patients implanted with VNS were classified by lesional (VNS-L) and non-lesional (VNS-NL) based on their MRI head findings. We further subdivided the VNS groups into patients with VNS alone versus those who also had additional epilepsy surgeries., Results: A total of 29 patients were enrolled in the VNS-L, compared to 29 in the VNS-NL. The median age of the patients in the study was 31.8 years, 29.31 % were men (N = 17). 41.4 % (n = 12) of the patients were VNS responders (≥50 % seizure reduction) in the VNS-L group compared to 62.0 % (n = 18) in the VNS-NL group (p = 0.03). When other epilepsy surgeries were combined with VNS in the VNS-L group, the median rate of seizure reduction was greater (72.4 (IQR 97.17-45.88) than the VNS-NL group 53.9 (IQR 92.22-27.92); p = 0.27)., Conclusions: VNS is a therapeutic option for patients with lesional epilepsy, with slightly inferior results compared to patients with non-lesional epilepsy. Patients implanted with VNS showed higher seizure reduction rates if they had previous epilepsy surgeries. This study demonstrates that VNS in lesional epilepsies can be an effective treatment., 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 © 2024. Published by Elsevier Inc.)

Epilepsy associated with high-titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug-resistant epilepsy associated with GAD65-IgG. We retrospectively identified 15 patients with drug-resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L -1 ) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I-II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure-free at last follow-up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases., (© 2024 International League Against Epilepsy.)

Transcutaneous auricular vagus nerve stimulation (taVNS) is an emerging neuromodulation technology that has been reported to be beneficial in the treatment of diseases by several studies, but its exact mechanism of action is still unclear. It has been demonstrated that taVNS can influence interoceptive signals. Notably, the processing of interoceptive signals is directly related to many diseases, such as depression, anxiety, and insomnia. The insula and the medial prefrontal cortex (MPFC) communicate during the bottom-up transmission of taVNS-induced signals, and both play a role in interoceptive signal processing. By focusing on the insula and MPFC, our research pioneers detail the potential interactions between interoceptive signal processing and the neuromodulation effects of taVNS, providing novel insights into the neurobiological mechanisms of taVNS. Two functional connectivity (FC) analyses (region of interest-based and seed-based) were used in this study. We observed that negative connectivity between the insula and the MPFC was significantly weakened following taVNS, while there were no statistical changes in the sham group. Our findings elucidate potential mechanisms linking vagal activity with intrinsic FC among specific brain regions and networks. Specifically, our results indicate that taVNS may enhance the ability to flexibly balance interoceptive awareness and cognitive experiences by modulating the FC between the insula and MPFC. The modulation effects may impact body-brain interactions, suggesting the mechanism of taVNS in therapeutic applications.

Objective: This study explored intraneural stimulation of the right thoracic vagus nerve (VN) in sexually mature male minipigs to modulate safe heart rate and blood pressure response., Material and Methods: We employed an intraneural electrode designed for the VN of pigs to perform VN stimulation (VNS). This was delivered using different numbers of contacts on the electrode and different stimulation parameters (amplitude, frequency, and pulse width), identifying the most suitable stimulation configuration. All the parameter ranges had been selected from a computational cardiovascular system model., Results: Clinically relevant responses were observed when stimulating with low current intensities and relatively low frequencies delivered with a single contact. Selecting a biphasic, charge-balanced square wave for VNS with a current amplitude of 500 μA, frequency of 10 Hz, and pulse width of 200 μs, we obtained heart rate reduction of 7.67 ± 5.19 beats per minute, systolic pressure reduction of 5.75 ± 2.59 mmHg, and diastolic pressure reduction of 3.39 ± 1.44 mmHg., Conclusion: Heart rate modulation was obtained without inducing any observable adverse effects, underlining the high selectivity of the intraneural approach., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Injection of polyinosinic:polycytidylic acid (poly(I:C)) into experimental animals induces neuroimmunological responses and thus has been used for the study of neurological disorders such as anxiety, depression, and chronic fatigue. Here, we investigated the effects of vagus nerve stimulation (VNS) on poly(I:C)-induced neuroinflammation and associated behavioral consequences in rats. The microglia in the prefrontal cortex (PFC) displayed the activated form of morphology in poly(I:C)-injected rats and changed to a normal shape after acute VNS (aVNS). Production of phospho-NF-κB, phospho-IκB, IL-1β, and cleaved caspase 3 was elevated by poly(I:C) and downregulated by aVNS. In contrast, phospho-Akt levels were decreased by poly(I:C) and increased by aVNS. Neuronal production of fractalkine (CX3CL1) in the PFC was markedly reduced by poly(I:C), but recovered by aVNS. Fractalkine interaction with its receptor CX3CR1 was highly elevated by VNS. We further demonstrated that the pharmacological blockade of CX3CR1 activity counteracted the production of IL-1β, phospho-Akt, and cleaved form of caspase 3 that was modulated by VNS, suggesting the anti-inflammatory effects of fractalkine-CX3CR1 signaling as a mediator of neuron-microglia interaction. Behavioral assessments of pain and temperature sensations by von Frey and hot/cold plate tests showed significant improvement by chronic VNS (cVNS) and forced swimming and marble burying tests revealed that the depressive-like behaviors caused by poly(I:C) injection were rescued by cVNS. We also found that the recognition memory which was impaired by poly(I:C) administration was improved by cVNS. This study suggests that VNS may play a role in regulating neuroinflammation and somatosensory and cognitive functions in poly(I:C)-injected animals., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite its efficacy in human epidermal growth factor receptor 2 positive cancer treatment, trastuzumab-induced cardiotoxicity (TIC) has become a growing concern. Due to the lack of cardiomyocyte regeneration and proliferation in adult heart, cell death significantly contributes to cardiovascular diseases. Cardiac autonomic modulation by vagus nerve stimulation (VNS) has shown cardioprotective effects in several heart disease models, while the effects of VNS and its underlying mechanisms against TIC have not been found. Forty adult male Wistar rats were divided into 5 groups: (i) control without VNS (CSham) group, (ii) trastuzumab (4 mg/kg/day, i.p.) without VNS (TSham) group, (iii) trastuzumab + VNS (TVNS) group, (iv) trastuzumab + VNS + mAChR blocker (atropine; 1 mg/kg/day, ip, TVNS + Atro) group, and (v) trastuzumab + VNS + nAChR blocker (mecamylamine; 7.5 mg/kg/day, ip, TVNS + Mec) group. Our results showed that trastuzumab induced cardiac dysfunction by increasing autonomic dysfunction, mitochondrial dysfunction/dynamics imbalance, and cardiomyocyte death including apoptosis, autophagic deficiency, pyroptosis, and ferroptosis, which were notably alleviated by VNS. However, mAChR and nAChR blockers significantly inhibited the beneficial effects of VNS on cardiac autonomic dysfunction, mitochondrial dysfunction, cardiomyocyte apoptosis, pyroptosis, and ferroptosis. Only nAChR could counteract the protective effects of VNS on cardiac mitochondrial dynamics imbalance and autophagy insufficiency. Therefore, VNS prevented TIC by rebalancing autonomic activity, ameliorating mitochondrial dysfunction and cardiomyocyte death through mAChR and nAChR activation. The current study provides a novel perspective elucidating the potential treatment of VNS, thus also offering other pharmacological therapeutic promises in TIC patients., 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 © 2024. Published by Elsevier Inc.)

Introduction: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain., Materials and Methods: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT., Results: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS., Conclusions: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT00113453., Competing Interests: Conflict of Interest Mark S. George is currently Principal Investigator on multisite clinical trials in contract with LivaNova and Neurolief; is editor-in-chief of Brain Stimulation, an Elsevier journal; has received consulting fees from Sooma, Neurolief, Mictrotransponder, and Abbott (Boston Scientific); has Intellectual Property pending with the MUSCFoundation for Research related to transcutaneous auricular vagus nerve stimulation (taVNS) and infant feeding, taVNS, and motor recovery; participates on a Data Safety Monitoring Board or Advisory Board for Microtransponder, Brainsway (no compensation), and Magnus Medical (no compensation); and has received transcranial magnetic stimulation equipment from Magstim on loan. All other authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Preeclampsia is a serious obstetric complication. Currently, there is a lack of effective preventive approaches for this disease. Recent studies have identified transcutaneous auricular vagus nerve stimulation (taVNS) as a potential novel non-pharmaceutical therapeutic modality for preeclampsia. In this study, we investigated whether taVNS inhibits apoptosis of placental trophoblastic cells through ROS-induced UPR mt . Our results showed that taVNS promoted the release of acetylcholine (ACh). ACh decreased the expression of UPR mt by inhibiting the formation of mitochondrial ROS (mtROS), presumably through M3AChR. This reduced the release of pro-apoptotic proteins (cleaved caspase-3, NF-κB-p65, and cytochrome C) and helped preserve the morphological and functional integrity of mitochondria, thus reducing the apoptosis of placental trophoblasts, improving placental function, and relieving preeclampsia. Our study unravels the potential pathophysiological mechanism of preeclampsia. In-depth characterization of the UPR mt is essential for developing more effective therapeutic strategies for preeclampsia targeting mitochondrial function., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Background: Alcohol use disorder (AUD) poses a significant global health challenge. Traditional management strategies often face high relapse rates, leading to a need for innovative approaches. Mindfulness-based relapse prevention (MBRP) has emerged as a promising intervention to enhance cognitive control, reduce cue-related craving and improve interoceptive processing. Neuroimaging studies suggest that mindfulness training can modulate brain networks associated with these factors, potentially improving treatment outcomes for AUD. Neuroimaging studies suggest that mindfulness training can modulate brain networks linked to these brain functions, potentially improving treatment outcomes for AUD. However, it is unclear how MBRP links to neurophysiological measures such as frontal midline theta oscillations (FMΘ) and whether the beneficial effects of MBRP can be increased by enhancing FMΘ. Here, we will use two different forms of neuromodulation to target and enhance these oscillations, and evaluate their impact on the effectiveness of MBRP., Methods: This study will employ a four-arm randomized controlled trial to evaluate the synergistic effects of MBRP augmented with transcutaneous vagus nerve stimulation (tVNS) or closed-loop amplitude-modulated transcranial alternating current stimulation (CLAM-tACS) on cognitive control, cue reactivity and interoceptive processing in AUD patients. Participants will undergo six weekly group MBRP sessions and daily individual mindfulness practices. Assessments will include an inhibition task, cue-induced craving task, and heartbeat discrimination task, alongside heart rate variability and 32-channel EEG recordings. Participants will be assessed pre and post treatment, with a three-month follow-up to evaluate long-term effects on abstinence and alcohol consumption., Discussion: This study will not only elucidate the causal link between FMΘ and efficacy of MBRP, but contribute to a better understanding of how combined psychological and neuromodulation interventions can improve treatment outcomes for AUD, potentially leading to more effective therapeutic strategies. This study also seeks to explore individual differences in response to treatment, which could inform future approaches to AUD management., Trial Registration: This study received approval by the Charité-Universitätsmedizin Berlin Institutional Review Board (EA1/030/23, 10.11.2023). It was registered on ClinicalTrials.gov (NCT06308484)., (© 2024. The Author(s).)

Objective: To investigate the effect of 20/4Hz transcutaneous auricular vagus nerve stimulation (taVNS) on anxiety symptoms in Parkinson's disease (PD) and the potential neural mechanism., Methods: In the current randomized, double-blind, sham-controlled trial, 30 PD patients with anxiety (PD-A), 30 PD patients without anxiety (PD-nA), and 30 healthy controls (HCs) were enrolled. PD-A patients were randomly (1:1) allotted to real taVNS stimulation group (RS) or sham stimulation group (SS) to explore the efficacy of a two-week treatment of taVNS to promote anxiety recovery. Simultaneously, all participants were measured activation in the bilateral prefrontal cortex during verbal fluency task (VFT) using functional near-infrared spectroscopy., Results: PD-A patients showed significantly decreased oxyhemoglobin in the left triangle part of the inferior frontal gyrus (IFG) during VFT, which was negatively related to the severity of anxiety symptoms. After two-week treatment of taVNS, the interaction of group and time had significant effect on HAMA scores (F = 18.476, p < 0.001, η 2  = 0.398). In RS group, compared with baseline, HAMA scores decreased significantly in the post-treatment and follow-up condition (both p < 0.001). Meanwhile, in RS group, HAMA scores were lower than those in SS group in the post-treatment and follow-up condition (p = 0.006, <0.001, respectively). Furthermore, the 20/4Hz taVNS remarkably ameliorated anxiety symptoms in PD patients, directly correlated with the increased activation of the left triangle part of the IFG during VFT in RS group., Conclusion: Our results depicted that taVNS could ameliorate the anxiety symptoms of PD-A patients and regulated the function of the left triangle part of the IFG., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Electroceuticals, through the selective modulation of peripheral nerves near target organs, are promising for treating refractory diseases. However, the small sizes and the delicate nature of these nerves present challenges in simplifying the fixation and stabilizing the electrical-coupling interface for neural electrodes. Herein, we construct a robust neural interface for fine peripheral nerves using an injectable bio-adhesive hydrogel bioelectronics. By incorporating a multifunctional molecular regulator during network formation, we optimize the injectability and conductivity of the hydrogel through fine-tuning reaction kinetics and multi-scale interactions within the conductive network. Meanwhile, the mechanical and electrical stability of the hydrogel is achieved without compromising its injectability. Minimal tissue damage along with low and stable impedance of the injectable neural interface enables chronic vagus neuromodulation for myocardial infarction therapy in the male rat model. Our highly-stable, injectable, conductive hydrogel bioelectronics are readily available to target challenging anatomical locations, paving the way for future precision bioelectronic medicine., (© 2024. The Author(s).)

Rationale: The brain-computer interface (BCI) is core tasks in comprehensively understanding the brain, and is one of the most significant challenges in neuroscience. The development of novel non-invasive neuromodulation technique will drive major innovations and breakthroughs in the field of BCI. Methods: We develop a new noninvasive closed-loop acoustic brain-computer interface (aBCI) for decoding the seizure onset based on the electroencephalography and triggering ultrasound stimulation of the vagus nerve to terminate seizures. Firstly, we create the aBCI system and decode the onset of seizure via a multi-level threshold model based on the analysis of wireless-collected electroencephalogram (EEG) signals recorded from above the hippocampus. Then, the different acoustic parameters induced acoustic radiation force were used to stimulate the vagus nerve in a rat model of epilepsy-induced by pentylenetetrazole. Finally, the results of epileptic EEG signal triggering ultrasound stimulation of the vagus nerve to control seizures. In addition, the mechanism of aBCI control seizures were investigated by real-time quantitative polymerase chain reaction (RT-qPCR). Results: In a rat model of epilepsy, the aBCI system selectively actives mechanosensitive neurons in the nodose ganglion while suppressing neuronal excitability in the hippocampus and amygdala, and stops seizures rapidly upon ultrasound stimulation of the vagus nerve. Physical transection or chemical blockade of the vagus nerve pathway abolish the antiepileptic effects of aBCI. In addition, aBCI shows significant antiepileptic effects compared to conventional vagus nerve electrical stimulation in an acute experiment. Conclusions: Closed-loop aBCI provides a novel, safe and effective tool for on-demand stimulation to treat abnormal neuronal discharges, opening the door to next generation non-invasive BCI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Chronic inflammation is associated with diabetes and contributes to the development and progression of micro- and macrovascular complications. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to reduce levels of circulating inflammatory cytokines in non-diabetics by activating the cholinergic anti-inflammatory pathway. We investigated the anti-inflammatory potential of tVNS as a secondary endpoint of a randomized controlled trial in people with diabetes (NCT04143269). 131 people with diabetes (type 1: n = 63; type 2: n = 68), gastrointestinal symptoms and various degrees of autonomic neuropathy were included and randomly assigned to self-administer active (n = 63) or sham (n = 68) tVNS over two successive study periods: (1) Seven days with four daily administrations and, (2) 56 days with two daily administrations. Levels of systemic inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α, IFN-γ) were quantified from blood samples by multiplex technology. Information regarding age, sex, diabetes type, and the presence of cardiac autonomic neuropathy (CAN) was included in the analysis as possible confounders. No differences in either cytokine were seen after study period 1 and 2 between active and sham tVNS (all p-values > 0.08). Age, sex, diabetes type, presence of CAN, and baseline levels of inflammatory cytokines were not associated with changes after treatment (all p-values > 0.07). A tendency towards slight reductions in TNF-α levels after active treatment was observed in those with no CAN compared to those with early or manifest CAN (p = 0.052). In conclusion, tVNS did not influence the level of systemic inflammation in people with diabetes., (© 2024. The Author(s).)

The research in neuroimmunomodulation aims to shed light on the complex relationships that exist between the immune and neurological systems and how they affect the human body. This multidisciplinary field focuses on the way immune responses are influenced by brain activity and how neural function is impacted by immunological signaling. This provides important insights into a range of medical disorders. Targeting both brain and immunological pathways, neuroimmunomodulatory approaches are used in clinical pain management to address chronic pain. Pharmacological therapies aim to modulate neuroimmune interactions and reduce inflammation. Furthermore, bioelectronic techniques like vagus nerve stimulation offer non-invasive control of these systems, while neuromodulation techniques like transcranial magnetic stimulation modify immunological and neuronal responses to reduce pain. Within the context of aging, neuroimmunomodulation analyzes the ways in which immunological and neurological alterations brought on by aging contribute to cognitive decline and neurodegenerative illnesses. Restoring neuroimmune homeostasis through strategies shows promise in reducing age-related cognitive decline. Research into mood disorders focuses on how immunological dysregulation relates to illnesses including anxiety and depression. Immune system fluctuations are increasingly recognized for their impact on brain function, leading to novel treatments that target these interactions. This review emphasizes how interdisciplinary cooperation and continuous research are necessary to better understand the complex relationship between the neurological and immune systems.

Aims: Transcutaneous auricular vagus nerve stimulation (taVNS) is widely used to treat a variety of disorders because it is noninvasive, safe, and well tolerated by awake patients. However, long-term and repetitive taVNS is difficult to achieve in awake mice. Therefore, developing a new taVNS method that fully mimics the method used in clinical settings and is well-tolerated by awake mice is greatly important for generalizing research findings related to the effects of taVNS. The study aimed to develop a new taVNS device for use in awake mice and to test its reliability and effectiveness., Methods: We demonstrated the reliability of this taVNS device through retrograde neurotropic pseudorabies virus (PRV) tracing and evaluated its effectiveness through morphological analysis. After 3 weeks of taVNS application, the open field test (OFT) and elevated plus maze (EPM) were used to evaluate anxiety-like behaviors, and the Y-maze test and novel object recognition test (NORT) were used to evaluate recognition memory behaviors, respectively., Results: We found that repetitive taVNS was well tolerated by awake mice, had no effect on anxiety-like behaviors, and significantly improved memory., Conclusion: Our findings suggest that this new taVNS device for repetitive stimulation of awake mice is safe, tolerable, and effective., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: Vagus nerve stimulation (VNS) is clinically useful for treating epilepsy, depression, and chronic pain. Currently, cervical VNS (cVNS) treatment is well-established, while auricular VNS (aVNS) is under development. Vagal stimulation regulates functions in diverse brain regions; therefore, it is critical to better understand how electrically-evoked vagal inputs following cVNS and aVNS engage with different brain regions., Objective: As vagus inputs are predominantly transmitted to the nucleus of tractus solitarius (NTS), we directly compared the activation of NTS neurons by cVNS or aVNS and the brain regions directly projected by the activated NTS neurons in mice., Methods: We adopted the targeted recombination in active populations method, which allows for the activity-dependent, tamoxifen-inducible expression of mCherry-a reporter protein-in neurons specifically associated with cVNS or aVNS., Results: cVNS and aVNS induced comparable bilateral mCherry expressions in neurons within the NTS, especially in its caudal section (cNTS). However, the numbers of mCherry-expressing neurons within different subdivisions of cNTS was distinctive. In both cVNS and aVNS, anterogradely labeled mCherry-expressing axonal terminals were similarly observed across different areas of the forebrain, midbrain, and hindbrain. These terminals were enriched in the rostral ventromedial medulla, parabrachial nucleus, periaqueductal gray, thalamic nuclei, central amygdala, and the hypothalamus. Sex difference of cVNS- and aVNS-induced labeling of NTS neurons was modest., Conclusion: The central projections of mCherry-expressing cNTS terminals are comparable between aVNS and cVNS, suggesting that cVNS and aVNS activate distinct but largely overlapping projections into the brain through the cNTS., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Vagus nerve stimulation (VNS) is an effective neuromodulatory treatment for patients with drug resistant epilepsy who cannot undergo curative surgical resection. Safety information states that the use of radiofrequency ablation devices may damage the VNS generator and leads. However, documented cases are scarce. This 62-year-old patient with bitemporal lobe epilepsy treated with VNS underwent radiofrequency ablation of an atrial fibrillation without any perioperative or postoperative complications., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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.

Abstract: Vagus nerve stimulation (VNS), an implantable neurostimulator, provides a valuable long-term treatment option for patients with difficult-to-treat depression. It has been reported that previous response to electroconvulsive therapy (ECT) might predict a better response to VNS and that VNS could reduce or eliminate the need for maintenance ECT in some patients. We present the case of a patient who received a total of more than 120 sessions of ECT over the course of 13 years because of a major depressive disorder, with favorable response but without achieving full remission. After implantation of VNS, ECT was discontinued, and her depressive symptoms improved, achieving remission within 12 months. This case supports VNS as an alternative to maintenance ECT in patients with difficult-to-treat depression who have shown previous response to ECT treatment., Competing Interests: H.M.-W. and K.D. have received honoraria for attending advisory board meetings and giving presentations at Continuing Professional Development meetings by the manufacturer of implanted VNS devices, LivaNova. P.S. received honorarium and travel expenses for lecturing about ECT at Livanova Campus, Düsseldorf, 2019, and Livanova Satelite Symposium ECNP, Paris, 2017. C.M. and J.O. have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The mechanisms of action of Vagus Nerve Stimulation (VNS) and the biological prerequisites to respond to the treatment are currently under investigation. It is hypothesized that thalamocortical tracts play a central role in the antiseizure effects of VNS by disrupting the genesis of pathological activity in the brain. This pilot study explored whether in vivo microstructural features of thalamocortical tracts may differentiate Drug-Resistant Epilepsy (DRE) patients responding and not responding to VNS treatment. Eighteen patients with DRE (37.11 ​± ​10.13 years, 10 females), including 11 responders or partial responders and 7 non-responders to VNS, were recruited for this high-gradient multi-shell diffusion Magnetic Resonance Imaging (MRI) study. Using Diffusion Tensor Imaging (DTI) and multi-compartment models - Neurite Orientation Dispersion and Density Imaging (NODDI) and Microstructure Fingerprinting (MF), we extracted microstructural features in 12 subsegments of thalamocortical tracts. These characteristics were compared between responders/partial responders and non-responders. Subsequently, a Support Vector Machine (SVM) classifier was built, incorporating microstructural features and 12 clinical covariates (including age, sex, duration of VNS therapy, number of antiseizure medications, benzodiazepine intake, epilepsy duration, epilepsy onset age, epilepsy type - focal or generalized, presence of an epileptic syndrome - no syndrome or Lennox-Gastaut syndrome, etiology of epilepsy - structural, genetic, viral, or unknown, history of brain surgery, and presence of a brain lesion detected on structural MRI images). Multiple diffusion metrics consistently demonstrated significantly higher white matter fiber integrity in patients with a better response to VNS (p FDR < 0.05) in different subsegments of thalamocortical tracts. The SVM model achieved a classification accuracy of 94.12%. The inclusion of clinical covariates did not improve the classification performance. The results suggest that the structural integrity of thalamocortical tracts may be linked to therapeutic effectiveness of VNS. This study reveals the great potential of diffusion MRI in improving our understanding of the biological factors associated with the response to VNS therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexandre Berger was an employee of Synergia Medical SA. The firm was not involved in the study design, data collection and analysis, interpretation of the data, the writing of the article, or the decision to submit it for publication. The remaining 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Percutaneous neuromodulation is emerging as a promising therapeutic approach for atrial fibrillation (AF). This article explores techniques such as ganglionated plexi (GP) ablation, and vagus nerve stimulation, pinpointing their potential in modulating AF triggers and maintenance. Noninvasive methods, such as transcutaneous low-level tragus stimulation, offer innovative treatment pathways, with early trials indicating a significant reduction in AF burden. GP ablation may address autonomic triggers, and the potential for GP ablation in neuromodulation is discussed. The article stresses the necessity for more rigorous clinical trials to validate the safety, reproducibility, and efficacy of these neuromodulation techniques in AF treatment., Competing Interests: Disclosure Nil., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: Diarrhea is commonly associated with irritable bowel syndrome, inflammatory bowel disease, microscopic colitis, and other gastrointestinal dysfunctions. Spontaneously occurring idiopathic chronic diarrhea is frequent in rhesus macaques, but has not been used as a model for the investigation of diarrhea or its treatment. We characterized this condition and present preliminary data demonstrating that left vagal nerve stimulation provides relief., Methods: Stool consistency scores were followed for up to 12 years. Inflammation was assessed by plasma C-reactive protein, [ 18 F]fluorodeoxyglucose (FDG) uptake, measured by positron emission tomography (PET), multiplex T cell localization, endoscopy and histology. The vagus was stimulated for 9 weeks in conscious macaques, using fully implanted electrodes, under wireless control., Key Results: Macaques exhibited recurrent periods of diarrhea for up to 12 years, and signs of inflammation: elevated plasma C-reactive protein, increased bowel FDG uptake and increased mucosal T helper1 T-cells. The colon and distal ileum were endoscopically normal, and histology revealed mild colonic inflammation. Application of vagal nerve stimulation to conscious macaques (10 Hz, 30 s every 3 h; 24 h a day for 9 weeks) significantly reduced severity of diarrhea and also reduced inflammation, as measured by FDG uptake and C-reactive protein., Conclusions and Inferences: These macaques exhibit spontaneously occurring diarrhea with intestinal inflammation that can be reduced by VNS. The data demonstrate the utility of this naturally occurring primate model to study the physiology and treatments for chronic diarrhea and the neural control circuits influencing diarrhea and inflammation that are not accessible in human subjects., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Bilateral transcutaneous auricular vagus nerve stimulation (taVNS) - a non-invasive neuromodulation technique - has been investigated as a safe and feasible technique to treat many neuropsychiatric conditions. such as epilepsy, depression, anxiety, and chronic pain. Our aim is to investigate the effect of taVNS on neurophysiological processes during emotional and Go/No-Go tasks, and changes in frontal alpha asymmetry. We performed a randomized, double-blind, sham-controlled trial with 44 healthy individuals who were allocated into two groups (the active taVNS group and the sham taVNS group). Subjects received one session of taVNS (active or sham) for 60 min. QEEG was recorded before and after the interventions, and the subjects were assessed while exposed to emotional conditions with sad and happy facial expressions, followed by a Go/No-Go trial. The results demonstrated a significant increase in N2 amplitude in the No-Go condition for the active taVNS post-intervention compared to the sham taVNS after adjusting by handedness, mood, and fatigue levels (p = 0.046), significantly reduced ERD during sad conditions after treatment (p = 0.037), and increased frontal alpha asymmetry towards the right frontal hemisphere during the emotional task condition (p = 0.046). Finally, we observed an interesting neural signature in this study that suggests a bottom-up modulation from brainstem/subcortical to cortical areas as characterized by improved lateralization of alpha oscillations towards the frontal right hemisphere, and changes in ERP during emotional and Go/No-Go tasks that suggests a better subcortical response to the tasks. Such bottom-up effects may mediate some of the clinical effects of taVNS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Drug-resistant epilepsy (DRE) poses significant challenges in terms of effective management and seizure control. Neuromodulation techniques have emerged as promising solutions for individuals who are unresponsive to pharmacological treatments, especially for those who are not good surgical candidates for surgical resection or laser interstitial therapy (LiTT). Currently, there are three neuromodulation techniques that are FDA-approved for the management of DRE. These include vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Device selection, optimal time, and DBS and RNS target selection can also be challenging. In general, the number and localizability of the epileptic foci, alongside the comorbidities manifested by the patients, substantially influence the selection process. In the past, the general axiom was that DBS and VNS can be used for generalized and localized focal seizures, while RNS is typically reserved for patients with one or two highly localized epileptic foci, especially if they are in eloquent areas of the brain. Nowadays, with the advance in our understanding of thalamic involvement in DRE, RNS is also very effective for general non-focal epilepsy. In this review, we will discuss the underlying mechanisms of action, patient selection criteria, and the evidence supporting the use of each technique. Additionally, we explore emerging technologies and novel approaches in neuromodulation, such as closed-loop systems. Moreover, we examine the challenges and limitations associated with neuromodulation therapies, including adverse effects, complications, and the need for further long-term studies. This comprehensive review aims to provide valuable insights on present and future use of neuromodulation., (© 2024. Fondazione Società Italiana di Neurologia.)

Objective: To evaluate differences in upper-extremity (UE) segment-specific (proximal or distal segment) recovery after vagus nerve stimulation (VNS) paired with UE rehabilitation (Paired-VNS) compared with rehabilitation with sham-VNS (Control). We also assessed whether gains in specific UE segments predicted clinically meaningful improvement., Design: This study reports on a secondary analysis of Vagus nerve stimulation paired with rehabilitation for UE motor function after chronic ischemic stroke (VNS-REHAB), a randomized, triple-blinded, sham-controlled pivotal trial. A Rasch latent regression was used to determine differences between Paired-VNS and Controls for distal and proximal UE changes after in-clinic therapy and 3 months later. Subsequently, we ran a random forest model to assess candidate predictors of meaningful improvement. Each item of the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT) was evaluated as a predictor of response to treatment., Setting: Nineteen stroke rehabilitation centers in the USA and UK., Participants: Dataset included 108 participants (N=108) with chronic ischemic stroke and moderate-to-severe UE impairments., Interventions: Not applicable., Main Outcome Measures: FMA-UE and WMFT., Results: Distal UE improvement was significantly greater in the Paired-VNS group than in Controls immediately after therapy (95% confidence interval, 0.27-0.73; P≤.001) and after 3 months (95% confidence interval, 0.16-0.75; P=.003). Both groups showed similar improvement in proximal UE at both time points. A subset of both distal and proximal items from the FMA-UE and WMFT were predictors of meaningful improvement., Conclusions: Paired-VNS improved distal UE impairment in chronic stroke to a greater degree than intensive rehabilitation alone. Proximal improvements were equally responsive to either treatment. Given that meaningful UE recovery is predicted by improvements across both proximal and distal segments, Paired-VNS may facilitate improvement that is otherwise elusive., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints., Materials and Methods: The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient's hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH., Discussion: Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH., Trial Registration: Clinical Trials Registered, NCT04557618. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: ALH and ECL hold equity in the company Aurenar, LLC. The COI as it relates to this trial has been managed by Washington University., (Copyright: © 2024 Huguenard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized, moderate intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention., (© 2024. The Author(s).)

Learning new skills requires neuroplasticity. Vagus nerve stimulation (VNS) during sensory and motor events can increase neuroplasticity in networks related to these events and might therefore serve to facilitate learning on sensory and motor tasks. We tested if VNS could broadly improve learning on a wide variety of tasks across different skill domains in healthy, female adult rats. VNS was paired with presentation of stimuli or on successful trials during training, strategies known to facilitate plasticity and improve recovery in models of neurological disorders. VNS failed to improve either rate of learning or performance for any of the tested tasks, which included skilled forelimb motor control, speech sound discrimination, and paired-associates learning. These results contrast recent findings from multiple labs which found VNS pairing during training produced learning enhancements across motor, auditory, and cognitive domains. We speculate that these contrasting results may be explained by key differences in task designs, training timelines and animal handling approaches, and that while VNS may be able to facilitate rapid and early learning processes in healthy subjects, it does not broadly enhance learning for difficult tasks., (© 2024. The Author(s).)

Vagus nerve stimulation devices are conditionally approved for MR imaging with stimulation turned off, and the requirement to modify the stimulation settings may be a barrier to scanning in some radiology practices. There is increasing interest in studying the effects of stimulation during MR imaging/fMRI. This study evaluated the safety of standard and investigational microburst vagus nerve stimulation therapies during MR imaging/fMRI. A prospective, multicenter study was conducted in patients with an investigational vagus nerve stimulation device that delivered either standard or investigational microburst vagus nerve stimulation. Thirty participants underwent sequential MR imaging and fMRI scans, encompassing 188 total hours of scan time (62.7 hours with standard vagus nerve stimulation and 125.3 hours with investigational microburst vagus nerve stimulation). No adverse events were reported with active stimulation during MR imaging or during 12 months of follow-up. Our results support the safety of standard and investigational microburst vagus nerve stimulation therapy during MR imaging and fMRI scans., (© 2024 by American Journal of Neuroradiology.)

Purpose: Memory plays an essential role in daily life and is one of the first functions to deteriorate in cognitive impairment and dementia. Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic method; however, its ability to enhance memory is underexplored, especially considering long-term stimulation. We aimed to investigate the effect of a 2-week course of auricular tVNS (taVNS) on memory in a non-clinical population., Methods: This single-blind randomized placebo-wait-list controlled trial recruited 76 participants (30 men; mean age 48.32 years) and randomized them into four groups: early active/sham taVNS and late active/sham taVNS. Participation in the study lasted 4 weeks; early groups underwent 2 weeks intervention immediately following the first study site visit (days 0-13) and late groups 2 weeks after the first study site visit (days 14-27). Active and sham taVNS included 2 weeks of daily 4-h neurostimulation at the tragus or earlobe, respectively. To assess memory, we used the Rey Auditory Verbal Learning Test., Results: Two weeks of active taVNS, but not sham taVNS, improved immediate recall and short-term memory score both in early and late groups. Furthermore, the improvements persisted over subsequent follow-up in early active taVNS. Importantly, the effect of active taVNS was superior to sham for immediate recall in both early and late groups. There were no statistical differences in delayed recall., Conclusion: Our findings suggest that taVNS has potential to improve memory, particularly immediate recall, and may be an effective method in preventing memory loss and mitigating cognitive aging., (© 2024. Springer-Verlag GmbH Germany.)

Adolescence is a critical time period for the onset of depression, and many patients do not respond to treatment. Transcutaneous auricular vagus nerve stimulation may be a promising alternative. Here, we present the case of an adolescent girl with treatment-resistant depression who received transcutaneous auricular vagus nerve stimulation over the course of 7.5 months., Competing Interests: Declaration of Competing Interest The work was supported by funds from the German Federal Ministry of Education and Research (BMBF) under grant number 13GW0492D (PI: J.K.). J.K. has collaborative third-party funding with tVNS technologies Erlangen, Germany. He receives no honorarium by the company. The company was not involved in the present case report. J.V. has no conflict of interest of declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis., Methods: Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days., Results: Either left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice., Conclusions: For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [VAP, SSC, and KJT have co-authored patents broadly related to the content of this paper. They have assigned their rights to the Feinstein Institutes for Medical Research. KJT also declares that he is a consultant to SetPoint Medical. RD is a member of the Scientific Advisory Board of GoodCap Pharma, Toronto, Ontario, Canada for work not related to the present study]., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Transcutaneous auricular vagus nerve stimulation (taVNS) targets subcutaneous axons in the auricular branch of the vagus nerve at the outer ear. Its non-invasive nature makes it a potential treatment for various disorders. taVNS induces neuromodulatory effects within the nucleus of the solitary tract (NTS), and due to its widespread connectivity, the NTS acts as a gateway to elicit neuromodulation in both higher-order brain regions and other brainstem nuclei (e.g. spinal trigeminal nucleus; Sp5). Our objective was to examine stimulation parameters on single-neuron electrophysiological responses in α-chloralose-anaesthetized Sprague-Dawley rats within NTS and Sp5. taVNS was also compared to traditional cervical VNS (cVNS) on single neuronal activation. Specifically, electrophysiological extracellular recordings were evaluated for a range of frequency and intensity parameters (20-250 Hz, 0.5-1.0 mA). Neurons were classified as positive, negative or non-responders based on increased activity, decreased activity or no response during stimulation, respectively. Frequency-dependent analysis showed that 20 and 100 Hz generated the highest proportion of positive responders in NTS and Sp5 with 1.0 mA intensities eliciting the greatest magnitude of response. Comparisons between taVNS and cVNS revealed similar parameter-specific activation for caudal NTS neuronal populations; however, individual neurons showed different activation profiles. The latter suggests that cVNS and taVNS send afferent input to NTS via different neuronal pathways. This study demonstrates differential parameter-specific taVNS responses and begins an investigation of the mechanisms responsible for taVNS modulation. Understanding the neuronal pathways responsible for eliciting neuromodulatory effects will enable more tailored taVNS treatments in various clinical disorders. KEY POINTS: Transcutaneous auricular vagus nerve stimulation (taVNS) offers a non-invasive alternative to invasive cervical vagus nerve stimulation (cVNS) by activating vagal afferents in the ear to induce neuromodulation. Our study evaluated taVNS effects on neuronal firing patterns in the nucleus of the solitary tract (NTS) and spinal trigeminal nucleus (Sp5) and found that 20 and 100 Hz notably increased neuronal activity during stimulation in both nuclei. Increasing taVNS intensity not only increased the number of neurons responding in Sp5 but also increased the magnitude of response, suggesting a heightened sensitivity to taVNS compared to NTS. Comparisons between cVNS and taVNS revealed similar overall activation but different responses on individual neurons, indicating distinct neural pathways. These results show parameter-specific and nuclei-specific responses to taVNS and confirm that taVNS can elicit responses comparable to cVNS at the neuronal level, but it does so through different neuronal pathways., (© 2024 The Author(s). The Journal of Physiology © 2024 The Physiological Society.)

Currently, clinical practice and scientific research mostly revolve around a single disease or system, but the single disease-oriented diagnostic and therapeutic paradigm needs to be revised. This review describes how transcutaneous auricular vagus nerve stimulation (taVNS), a novel non-invasive neuromodulation approach, connects the central and peripheral systems of the body. Through stimulation of the widely distributed vagus nerve from the head to the abdominal cavity, this therapy can improve and treat central system disorders, peripheral system disorders, and central-peripheral comorbidities caused by autonomic dysfunction. In the past, research on taVNS has focused on the treatment of central system disorders by modulating this brain nerve. As the vagus nerve innervates the heart, lungs, liver, pancreas, gastrointestinal tract, spleen and other peripheral organs, taVNS could have an overall modulatory effect on the region of the body where the vagus nerve is widespread. Based on this physiological basis, the authors summarize the existing evidence of the taVNS ability to regulate cardiac function, adiposity, glucose levels, gastrointestinal function, and immune function, among others, to treat peripheral system diseases, and complex diseases with central and peripheral comorbidities. This review shows the successful examples and research progress of taVNS using peripheral neuromodulation mechanisms from more perspectives, demonstrating the expanded scope and value of taVNS to provide new ideas and approaches for holistic therapy from both central and peripheral perspectives., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)