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AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Purpose: Simulator Adaptation Syndrome arises from a perceptual discordance between expected and actual motion, giving rise to symptoms such as nausea and disorientation. This research focused on determining the benefit of Transcutaneous Vagal Nerve Stimulation (tVNS) and Galvanic Cutaneous Stimulation (GCS), where both were applied in conjunction, as compared to their administration in isolation, to decrease Simulator Adaptation Syndrome (SAS). Method: A driving simulation study was proposed where SAS, body balance, and driving performance were measured. These measurements were taken during seven different stimulation scenarios with a baseline condition without stimulation compared against tVNS and GCS conditions. Results: The main result showed that the combination of tVNS and GCS reduced SAS and improved body balance and driving performance more successfully than their administration in isolation. Conclusion: Similar neuromodulation in the temporoparietal junction is proposed to mitigate SAS for GCS and tVNS (although additional explanations are discussed). Applying both techniques simultaneously is encouraged to decrease SAS in future interventions. [ABSTRACT FROM AUTHOR]

The editorial titled "How does brain stimulation work? Neuroversion and other putative mechanisms of action" explores the evolving field of brain stimulation techniques in psychiatry and neurology. It discusses various methods such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS) that trigger neurochemical and electrophysiological changes in the brain to produce therapeutic effects. The research topic includes 10 articles authored by 76 individuals covering a range of brain stimulation techniques and their applications in neuropsychiatric disorders, aiming to enhance understanding and influence further research and clinical practice. The findings presented in the editorial highlight the diverse applications of brain stimulation techniques and their potential benefits, contributing to the advancement of clinical practice and stimulating further investigation into the mechanisms underlying these therapies. [Extracted from the article]

Anxiety is an increasingly prevalent mental disorder, causing widespread hardship and interfering with society's economic progression. Standard treatments include various talk therapies with poor prognoses or drug interventions with complex side effects, both introducing unnecessary burdens to patients. To remedy this, non-invasive ultrasound stimulation to the vagus nerve is a novel, low-cost treatment that is showing promise. Although vagus nerve stimulation is already approved for epilepsy and other conditions, it requires regular maintenance. In contrast, studies using non-invasive ultrasound stimulation have shown preliminary positive results in affecting vagal activity with minimal drawbacks. This review covers a variety of studies investigating the effects of ultrasound stimulation on the vagus nerve. With rising levels of anxiety with each generation, there is a pressing need for more innovative and diverse treatments with fewer costs and more benefits. [ABSTRACT FROM AUTHOR]

Introduction: Vagal nerve stimulation (VNS) is used as an alternative treatment in drug-resistant epilepsy patients. Effects of VNS on the cardiac autonomic system are controversial. In this study, we aimed to investigate the relationship between VNS parameters and heart rate variability (HRV) in epilepsy patients who underwent VNS treatment. Methods: Our study included 31 patients who underwent VNS for drug-resistant epilepsy. Patients were divided into groups according to response to VNS and VNS parameters. All patients underwent 24-h Holter ECG. Results: The mean age of 31 VNS-treated epilepsy patients included in the study was 33.87 ± 7.6 years. When patients were grouped according to VNS response, 25 patients were in the VNS responder group and six patients were in the VNS-nonresponder group. When comparing Holter parameters in the VNS responder and non-responder groups, the median HF was significantly lower in the VNS responder group. VNS duration and signal frequency had a positive effect on LF/HF, while output and off time had a negative effect on LF/HF. When ROC analysis was performed to determine the cut-off values of the parameters for the VNS-responsive state, the AUC value of the HF parameter was 0.780, which was statistically significant. The cut-off value to distinguish response to VNS was 156.9. Conclusion: In conclusion, the effects of VNS parameters on HRV parameters are quite complex. However, the conclusion is that VNS is a neuromodulation method that affects the autonomic system in a complex way. Different levels of VNS parameters may also contribute to this effect. Furthermore, HRV parameters can be used as biomarkers to predict the patient population that may benefit from VNS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The autonomic regulation of the pulmonary vasculature has been under‐appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Social cognitive deficits and social behavior impairments are common in major depressive disorder (MDD) and affect the quality of life and recovery of patients. This review summarizes the impact of standard and novel treatments on social functioning in MDD and highlights the potential of combining different approaches to enhance their effectiveness. Standard treatments, such as antidepressants, psychotherapies, and brain stimulation, have shown mixed results in improving social functioning, with some limitations and side effects. Newer treatments, such as intranasal oxytocin, mindfulness-based cognitive therapy, and psychedelic-assisted psychotherapy, have demonstrated positive effects on social cognition and behavior by modulating self-referential processing, empathy, and emotion regulation and through enhancement of neuroplasticity. Animal models have provided insights into the neurobiological mechanisms underlying these treatments, such as the role of neuroplasticity. Future research should explore the synergistic effects of combining different treatments and investigate the long-term outcomes and individual differences in response to these promising interventions. [ABSTRACT FROM AUTHOR]

Targeted plasticity therapy (TPT) utilizes vagus nerve stimulation (VNS) to promote improvements in function following neurological injury and disease. During TPT, a brief burst of VNS induces neuromodulator release, which when paired with relevant behavioral events can influence functionally relevant neuroplasticity. Functional improvements following TPT are therefore in part mediated by neuromodulator signaling. Unfortunately, comorbidities associated with neurological disease often result in altered cognitive states that can influence neuromodulator signaling, potentially impeding neuroplasticity induced by TPT. Aside from altered cognitive states, cardiorespiratory rhythms also affect neuromodulator signaling, due to the vagus nerve’s role in relaying visceral sensory information from the cardiovascular and respiratory systems. Moreover, precise VNS delivery during specific periods of the cardiorespiratory rhythms may further improve TPT. Ultimately, understanding the impact of patient-specific states on neuromodulator signaling may likely facilitate optimized VNS delivery, paving the way for personalized neuromodulation during TPT. Overall, this review explores challenges and considerations for developing advanced TPT paradigms, focusing on altered cognitive states and cardiorespiratory rhythms. We specifically discuss the possible impact of these cognitive states and autonomic rhythms on neuromodulator signaling and subsequent neuroplasticity. Altered cognitive states (arousal deficits or pain) could affect VNS intensity, while cardiorespiratory rhythmsmay further inform optimized timing of VNS. We propose that understanding these interactions will lead to the development of personalized state dependent VNS paradigms for TPT. [ABSTRACT FROM AUTHOR]

Objective: This systematic review aims to comprehensively analyze the efficacy and underlying mechanisms of vagus nerve stimulation (VNS) in enhancing cognitive functions and its therapeutic potential for various cognitive impairments. The review focuses on the impact of VNS on emotional processing, executive functions, learning, memory, and its clinical applications in conditions such as epilepsy, depression, Alzheimer's disease, and other neurological disorders. Methods: A systematic search of electronic databases (PubMed, Scopus, Web of Science) was conducted using the keywords "vagus nerve stimulation," "cognitive enhancement," "emotional processing," "executive function," "learning and memory," "epilepsy," "depression," "Alzheimer's disease," "neurological disorders," "attention-deficit/hyperactivity disorder," "sleep disorders," and "long COVID." The inclusion criteria encompassed controlled trials, longitudinal studies, and meta-analyses published in English between 2000 and July 2024. Results: A comprehensive review of 100 articles highlighted the cognitive effects of Vagus Nerve Stimulation (VNS). Studies show that VNS, especially through transcutaneous auricular VNS (taVNS), enhances emotional recognition, particularly for facial expressions, and improves selective attention under high cognitive demands. Additionally, VNS enhances learning and memory, including associative memory and spatial working memory tasks. In clinical applications, VNS exhibits promising benefits for improving cognitive functions in treatment-resistant epilepsy, depression, and Alzheimer's disease. Conclusion: VNS represents a promising therapeutic approach for enhancing cognitive function across diverse patient populations. The reviewed evidence highlights its efficacy in modulating cognitive domains in healthy individuals and improving cognition in neurological conditions. However, the comparative effectiveness of different VNS modalities and the differential effects of online versus offline VNS on cognitive psychology require further investigation. Future research should focus on optimizing VNS protocols and elucidating specific cognitive domains that benefit most from VNS interventions. This ongoing exploration is essential for maximizing the therapeutic potential of VNS in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Long-term post-stroke cognitive impairment (PSCI) exhibits an accelerated rate of long-term cognitive decline, which can impair communication, limit social engagement, and increase rate of institutional dependence. The aim of this case report is to provide evidence for the potential of home-based transcutaneous auricular vagus nerve stimulation (taVNS) for home-bound patients with severe, long-term PSCI. Methods: A 71-year-old male suffered a stroke two and a half years ago, which imaging reported foci of cerebral infarction visible in the left temporal and parietal lobes. The patient was performed taVNS twice a day for 30 min, 5 times a week for 8 weeks. The patient was evaluated the changes of cognitive function and brain white matter at 4 time points: baseline (t0), 4 weeks without taVNS after baseline (t1), 4 weeks of intervention (t2), and 8 weeks of intervention (t3). The effect of taVNS on white matter changes was visualized by DTI. Results: After 8 weeks of taVNS treatment, the scores of Montreal cognitive assessment improved and the time to complete the shape trails test decreased. The DTI results showed that white matter in bilateral dorsal lateral prefrontal cortex remodeled after taVNS. Conclusion: Eight-week home-based taVNS may be beneficial to long-term PSCI. Further studies of home-based taVNS treating patients with long-term PSCI are needed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Migraine is a prevalent neurological disorder, particularly among individuals aged 20–50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Vagus nerve stimulation (VNS) is an established therapy for drug‐resistant epilepsy. However, there is a lack of reliable predictors of VNS response in clinical use. The identification of factors predictive of VNS response is important for patient selection and stratification as well as tailored stimulation programming. We conducted a narrative review of the existing literature on prognostic markers for VNS response using clinical, demographic, biochemical, and modality‐specific information such as from electroencephalography (EEG), magnetoencephalography, and magnetic resonance imaging (MRI). No individual marker demonstrated sufficient predictive power for individual patients, although several have been suggested, with some promising initial findings. Combining markers from underresearched modalities such as T1‐weighted MRI morphometrics and EEG may provide better strategies for treatment optimization. [ABSTRACT FROM AUTHOR]

Objectives: Non-invasive vagus nerve stimulation (nVNS) is an emerging neuromodulation technique in recent years, which plays a role in nervous system diseases, psychiatric diseases, and autoimmune diseases. However, there is currently no comprehensive analysis of all the literature published in this field. Therefore, in this article, a bibliometric analysis will be conducted on all the literature published in the field of nVNS in the past 20 years. Methods: All articles and reviews published in this field from 2004 to 2023 were extracted from the WOS core database. VOSviewer 1.6.18.0, Scimago Graphica, CiteSpace 6.2.R2, and Excel 2021 were used to analyze the number of publications, participating countries, institutions, authors, references, and research hotspots in this field. Results: A total of 843 articles were included in the bibliometric analysis of nVNS. Over the past 20 years, the number of publications in this field has gradually increased, reaching a peak in 2023. The United States and China ranked top two in terms of publication volume, and institutions from these two countries also ranked high in terms of publication volume, citation count, and collaboration intensity. Rong Peijing is the author with the most publications, while Bashar W Badran is the most cited author. Articles in the field of nVNS were most frequently published in Frontiers in Neuroscience, while Brain Stimulation had the most citations. Currently, research hotspots in nVNS mainly focus on its application in diseases and related mechanisms. Conclusion: We conducted a comprehensive analysis of the field of nVNS, clarifying the previous research directions, which is helpful to expand its indications and promote clinical application. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors' clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is characterized by high mortality, disability rates, and a high risk of recurrence. Motor dysfunction, such as limb hemiparesis, dysphagia, auditory disorders, and speech disorders, usually persists after stroke, which imposes a heavy burden on society and the health care system. Traditional rehabilitation therapies may be ineffective in promoting functional recovery after stroke, and alternative strategies are urgently needed. The Food and Drug Administration (FDA) has approved invasive vagus nerve stimulation (iVNS) for the improvement of refractory epilepsy, treatment-resistant depression, obesity, and moderate to severe upper limb motor impairment following chronic ischemic stroke. Additionally, the FDA has approved transcutaneous vagus nerve stimulation (tVNS) for the improvement of cluster headaches and acute migraines. Recent studies have demonstrated that vagus nerve stimulation (VNS) has neuroprotective effects in both transient and permanent cerebral ischemia animal models, significantly improving upper limb motor impairments, auditory deficits, and swallowing difficulties. Firstly, this article reviews two potential neuronal death pathways following IS, including autophagy and inflammatory responses. Then delves into the current status of preclinical and clinical research on the functional recovery following IS with VNS, as well as the potential mechanisms mediating its neuroprotective effects. Finally, the optimal parameters and timing of VNS application are summarized, and the future challenges and directions of VNS in the treatment of IS are discussed. The application of VNS in stroke rehabilitation research has reached a critical stage, and determining how to safely and effectively translate this technology into clinical practice is of utmost importance. Further preclinical and clinical studies are needed to elucidate the therapeutic mechanisms of VNS. [ABSTRACT FROM AUTHOR]

Objective: Vagus nerve stimulation (VNS) Therapy is routinely indicated for people with drug‐resistant epilepsy (DRE). We analyzed the baseline characteristics of individuals receiving the recently released VNS models and identified factors associated with early or late implantation. Methods: The Comprehensive Outcomes Registry of subjects with Epilepsy (CORE‐VNS), a prospective observational study evaluating the clinical and psychosocial outcomes of VNS Therapy®, is following participants for up to 60 months after VNS implantation. In this analysis, we used Cox proportional hazards model to identify baseline characteristics associated with the time from diagnosis to first implantation. Results: Of the 819 enrolled, 792 (96.7%) participants implanted with a VNS device were evaluated. 529 (64.6%) underwent the first implantation and 263 (32.1%) a re‐implantation. Participants' median age at first implant was 24 years; 492 (62.1%) were ≥18 years old and 166 (20.3%) were < 12 years old. The average number of failed ASMs prior to VNS implantation was 7.1, and 145 (17.7%) had undergone previous epilepsy‐related surgery. Epilepsy was classified as focal in 47.7% of participants, generalized in 16.1% and combined focal and generalized in 34.2%. Many of the participants (40.9%) had epilepsy of unknown etiology. The median time from diagnosis to first implantation was 10.33 years and was significantly shorter in participants with combined focal and generalized epilepsy compared to those with focal epilepsy alone, and in participants with genetic and immune epilepsy compared to those with unknown etiologies. Significance: In people with DRE, VNS Therapy is provided after multiple failures of ASMs and after failure of epilepsy surgery in one in six individuals. Time from diagnosis to first implantation is associated with epilepsy type and etiology, likely reflecting variable treatment pathways. Clearer guidelines on when and how non‐drug therapies should be deployed in people with DRE related to different epilepsy factors are needed. Plain Language Summary: Neuromodulation can be a very helpful treatment in people who have seizures that do not respond to medications. The most widely utilized neuromodulation therapy is vagus nerve stimulation (VNS). We present data from a large, global study to show that people use an average of seven anti‐seizure medications before attempting VNS Therapy and that it takes about 10 years for people to get their first VNS implant. We advocate for clearer treatment guidelines on how and when to consider VNS Therapy in people with seizures that are resistant to medication. [ABSTRACT FROM AUTHOR]

Background: Many COVID-19 survivors still experience long-term effects of an acute infection, most often characterised by neurological, cognitive and psychiatric sequelae. The treatment of this condition is challenging, and many hypotheses have been proposed. Non-invasive vagus nerve stimulation using slow-paced breathing (SPB) could stimulate both central nervous system areas and parasympathetic autonomic pathways, leading to neuromodulation and a reduction in inflammation. The aim of the present study was to evaluate physical, cognitive, emotional symptoms, executive functions and autonomic cardiac modulation after one month of at-home slow breathing intervention. Methods: 6655 healthcare workers (HCWs) were contacted via a company email in November 2022, of which N = 58 HCWs were enrolled as long COVID (cases) and N = 53 HCWs as controls. A baseline comparison of the two groups was performed. Subsequently each case was instructed on how to perform a resonant SPB using visual heart rate variability (HRV) biofeedback. They were then given a mobile video tutorial breathing protocol and asked to perform it three times a day (morning, early afternoon and before sleep). N = 33 cases completed the FU. At T0 and T1, each subject underwent COVID-related, psychosomatic and dysfunctional breathing questionnaires coupled with heart rate variability and manual dexterity assessments. Results: After one month of home intervention, an overall improvement in long-COVID symptoms was observed: confusion/cognitive impairment, chest pain, asthenia, headache and dizziness decreased significantly, while only a small increase in manual dexterity was found, and no relevant changes in cardiac parasympathetic modulation were observed. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Introduction: Chronic stress is a condition characterized by prolonged stimulation, leading to mental and physical weakness. It can have detrimental effects on individuals' mental health and cognitive function, potentially causing various health issues. This article explores the potential of non-invasive neuromodulation techniques, specifically transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS), in managing chronic stress and improving sleep quality. Methods: The study conducted a randomized, double-blinded, controlled trial with participants experiencing chronic stress. In total, 100 participants were randomly assigned to one of four conditions: the anodal tDCS group (n = 50), the sham tDCS group (n = 50), the taVNS group (n = 50), or the sham taVNS group (n = 50). Within each condition, participants received five sessions of either active treatment or sham treatment, with 20 min of tDCS over the dorsolateral prefrontal cortex (2 mA) for the tDCS groups, or taVNS on the left ear (20 Hz) for the taVNS groups. At baseline, post-intervention, and 4 weeks thereafter, we evaluated stress using the Lipp's Inventory of Stress Symptoms for Adults (LSSI), perceived stress through the Perceived Stress Scale (PSS-10), and sleep quality via the Pittsburgh Sleep Quality Index (PSQI). Results: The tDCS and taVNS interventions resulted in reduced stress levels, improved sleep quality, and enhanced perception of stress. Discussion: These findings suggest that tDCS and taVNS hold promise as effective treatments for chronic stress, offering a safe and accessible approach to improving individuals' wellbeing and overall quality of life. [ABSTRACT FROM AUTHOR]

The identification of acute cardioprotective strategies against myocardial ischemia/reperfusion (I/R) injury that can be applied in the catheterization room is currently an unmet clinical need and several interventions evaluated in the past at the pre-clinical level have failed in translation. Autonomic imbalance, sustained by an abnormal afferent signalling, is a key component of I/R injury. Accordingly, there is a strong rationale for neuromodulation strategies, aimed at reducing sympathetic activity and/or increasing vagal tone, in this setting. In this review we focus on cervical vagal nerve stimulation (cVNS) and on transcutaneous auricular vagus nerve stimulation (taVNS); the latest has the potential to overcome several of the issues of invasive cVNS, including the possibility of being used in an acute setting, while retaining its beneficial effects. First, we discuss the pathophysiology of I/R injury, that is mostly a consequence of the overproduction of reactive oxygen species. Second, we describe the functional anatomy of the parasympathetic branch of the autonomic nervous system and the most relevant principles of bioelectronic medicine applied to electrical vagal modulation, with a particular focus on taVNS. Then, we provide a detailed and comprehensive summary of the most relevant pre-clinical studies of invasive and non-invasive VNS that support its strong cardioprotective effect whenever there is an acute or chronic cardiac injury and specifically in the setting of myocardial I/R injury. The potential benefit in the emerging field of post cardiac arrest syndrome (PCAS) is also mentioned. Indeed, electrical cVNS has a strong anti-adrenergic, anti-inflammatory, antioxidants, anti-apoptotic and pro-angiogenic effect; most of the involved molecular pathways were already directly confirmed to take place at the cardiac level for taVNS. Pre-clinical data clearly show that the sooner VNS is applied, the better the outcome, with the possibility of a marked infarct size reduction and almost complete left ventricular reverse remodelling when VNS is applied immediately before and during reperfusion. Finally, we describe in detail the limited but very promising clinical experience of taVNS in I/R injury available so far. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nearly all geriatric surgical complications are studied in the context of a single organ system, e.g., cardiac complications and the heart; delirium and the brain; infections and the immune system. Yet, we know that advanced age, physiological stress, and infection all increase sympathetic and decrease parasympathetic nervous system function. Parasympathetic function is mediated through the vagus nerve, which connects the heart, brain, and immune system to form, what we have termed, the brain–heart-immune axis. We hypothesize that this brain–heart-immune axis plays a critical role in surgical recovery among older adults. In particular, we hypothesize that the brain–heart-immune axis plays a critical role in the most common surgical complication among older adults: postoperative delirium. Further, we present heart rate variability as a measure that may eventually become a multi-system vital sign evaluating brain–heart-immune axis function. Finally, we suggest the brain–heart-immune axis as a potential interventional target for bio-electronic neuro-immune modulation to enhance resilient surgical recovery among older adults. [ABSTRACT FROM AUTHOR]

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is effective in regulating mood and high-level cognition in patients with major depressive disorder (MDD). This study aimed to investigate the efficacy of taVNS treatment in patients with MDD and an altered brain topological organization of functional networks. Methods: Nineteen patients with MDD were enrolled in this study. Patients with MDD underwent 4 weeks of taVNS treatments; resting-state functional magnetic resonance imaging (rs-fMRI) data of the patients were collected before and after taVNS treatment. The graph theory method and network-based statistics (NBS) analysis were used to detect abnormal topological organizations of functional networks in patients with MDD before and after taVNS treatment. A correlation analysis was performed to characterize the relationship between altered network properties and neuropsychological scores. Results: After 4 weeks of taVNS treatment, patients with MDD had increased global efficiency and decreased characteristic path length (Lp). Additionally, patients with MDD exhibited increased nodal efficiency (NE) and degree centrality (DC) in the left angular gyrus. NBS results showed that patients with MDD exhibited reduced connectivity between default mode network (DMN)–frontoparietal network (FPN), DMN–cingulo-opercular network (CON), and FPN–CON. Furthermore, changes in Lp and DC were correlated with changes in Hamilton depression scores. Conclusions: These findings demonstrated that taVNS may be an effective method for reducing the severity of depressive symptoms in patients with MDD, mainly through modulating the brain's topological organization. Our study may offer insights into the underlying neural mechanism of taVNS treatment in patients with MDD. [ABSTRACT FROM AUTHOR]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that modulates the noradrenergic activity of the locus coeruleus (LC). Yet, there is still uncertainty about the most effective stimulation and reliable outcome parameters. In a double blind, sham-controlled study including a sample of healthy young individuals (N = 29), we compared a shorter (3.4 s) and a longer (30 s) stimulation duration and investigated the effects of taVNS (real vs. sham) on saliva samples (alpha amylase and cortisol concentration), pupil (pupillary light reflex and pupil size at rest) and EEG data (alpha and theta activity at rest, ERPs for No-Go signals), and cognitive tasks (Go/No-Go and Stop Signal Tasks). Salivary alpha amylase concentration was significantly increased in the real as compared to sham stimulation for the 30 s stimulation condition. In the 3.4 s stimulation condition, we found prolonged reaction times and increased error rates in the Go/No-Go task and increased maximum acceleration in the pupillary light reflex. For the other outcomes, no significant differences were found. Our results show that prolonged stimulation increases salivary alpha-amylase, which was expected from the functional properties of the LC. The finding of longer response times to short taVNS stimulation was not expected and cannot be explained by an increase in LC activity. We also discuss the difficulties in assessing pupil size as an expression of taVNS-mediated LC functional changes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The bidirectional communication network between the gut and the brain, known as the gut–brain axis, plays a crucial role in health and disease. This review explores the mechanisms underlying gut–brain interaction disorders and highlights translational therapies bridging neurology and gastroenterology. Mechanisms encompass anatomical, endocrine, humoral, metabolic, and immune pathways, with the gut microbiota exerting profound influence. Clinical evidence links gut microbiota fluctuations to mood disorders, GI disruptions, and neurodevelopmental conditions, emphasizing the microbiome's pivotal role in shaping brain–gut interactions. Pharmacological therapies such as amitriptyline and selective serotonin reuptake inhibitors modulate neurotransmitter activity, offering relief in functional gastrointestinal disorders like irritable bowel syndrome (IBS). Non-pharmacological interventions like cognitive–behavioral therapy and hypnotherapy address maladaptive thoughts and induce relaxation, alleviating gastrointestinal symptoms exacerbated by stress. Emerging therapies include gut microbiota modulation, dietary interventions, vagus nerve stimulation, and intestinal barrier modulation, offering novel approaches to manage neurological disorders via the gastrointestinal tract. Understanding and harnessing the gut–brain axis holds promise for personalized therapeutic strategies in neurogastroenterology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Anxiety disorders significantly reduce patients' quality of life. Current pharmacological treatments, primarily benzodiazepines and antidepressants, are associated with numerous side effects. Consequently, there is a continual search for alternative methods to traditional therapies that are less burdensome for patients and broaden their therapeutic options. Our objective was to determine the role of selected alternative methods in the treatment of anxiety disorders. Methods: In this review, we examined recent evidence on alternative treatments for anxiety disorders, including physical activity, mindfulness, virtual reality (VR) technology, biofeedback, herbal remedies, transcranial magnetic stimulation (TMS), cryotherapy, hyperbaric therapy, vagus nerve stimulation (VNS), 3,4-methylenedioxymethamphetamine (MDMA), electroconvulsive therapy (ECT), and eye movement desensitization and reprocessing (EMDR) therapy. For this purpose we reviewed PubMed and after initial search, we excluded works unrelated to our aim, non-orginal data and animal studies. We conducted second search to cover all minor methods. Results: We included 116 studies, which data is presented in Tables. We have investigated which methods can support treatment and which can be used as a stand-alone treatment. We assessed the risks to benefits of using alternative treatments. Conclusion: Alternative treatments significantly expand the options available to patients and clinicians, with many serving as adjuncts to traditional therapies. Among the methods presented, mindfulness has the most significant therapeutic potential. [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract Objective Vagus nerve stimulation (VNS) Therapy is routinely indicated for people with drug‐resistant epilepsy (DRE). We analyzed the baseline characteristics of individuals receiving the recently released VNS models and identified factors associated with early or late implantation. Methods The Comprehensive Outcomes Registry of subjects with Epilepsy (CORE‐VNS), a prospective observational study evaluating the clinical and psychosocial outcomes of VNS Therapy®, is following participants for up to 60 months after VNS implantation. In this analysis, we used Cox proportional hazards model to identify baseline characteristics associated with the time from diagnosis to first implantation. Results Of the 819 enrolled, 792 (96.7%) participants implanted with a VNS device were evaluated. 529 (64.6%) underwent the first implantation and 263 (32.1%) a re‐implantation. Participants' median age at first implant was 24 years; 492 (62.1%) were ≥18 years old and 166 (20.3%) were

Background Dementia is a prevalent, progressive, neurodegenerative condition with multifactorial causes. Due to the lack of effective pharmaceutical treatments for dementia, there are growing clinical and research interests in using vagus nerve stimulation (VNS) as a potential non-pharmacological therapy for dementia. However, the extent of the research volume and nature into the effects of VNS on dementia is not well understood. This study aimed to examine the extent and nature of research activities in relation to the use of VNS in dementia and disseminate research findings for the potential utility in dementia care. Methods We performed a scoping review of literature searches in PubMed, HINARI, Google Scholar, and the Cochrane databases from 1980 to November 30th, 2023, including the reference lists of the identified studies. The following search terms were utilized: brain stimulation, dementia, Alzheimer's disease, vagal stimulation, memory loss, Deme*, cognit*, VNS, and Cranial nerve stimulation. The included studies met the following conditions: primary research articles pertaining to both humans and animals for both longitudinal and cross-sectional study designs and published in English from January 1st, 1980, to November 30th, 2023; investigated VNS in either dementia or cognitive impairment; and were not case studies, conference proceedings/abstracts, commentaries, or ordinary review papers. Findings and conclusions We identified 8062 articles, and after screening for eligibility (sequentially by titles, abstracts and full text reading, and duplicate removal), 10 studies were included in the review. All the studies included in this literature review were conducted over the last three decades in high-income geographical regions (i.e., Europe, the United States, the United Kingdom, and China), with the majority of them (7/10) being performed in humans. The main reported outcomes of VNS in the dementia cases were enhanced cognitive functions, an increased functional connectivity of various brain regions involved in learning and memory, microglial structural modifications from neurodestructive to neuroprotective configurations, a reduction of cerebral spinal fluid tau-proteins, and significant evoked brain tissue potentials that could be utilized to diagnose neurodegenerative disorders. The study outcomes highlight the potential for VNS to be used as a non-pharmacological therapy for cognitive impairment in dementia-related diseases such as Alzheimer's disease.

Abstract 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.

Introduction: Current guidelines for pain treatment recommend a personalized, multimodal and interdisciplinary approach as well as the use of a combination of drug and non-drug therapies. Risk factors for chronification should already be reduced in patients with acute pain, e.g., after surgery or trauma. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy in the multimodal treatment of chronic and acute pain. The aim of this systematic review and meta-analysis is to evaluate the clinical efficacy and safety of aVNS in treating chronic and acute pain conditions. Methods: A systematic literature search was performed regarding the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence (Jadad scale), scientific validity and risk of bias (RoB 2 tool) and analyzed regarding indication, method, stimulation parameters, duration of treatment and efficacy and safety. A meta-analysis on (randomized) controlled trials (using different comparators) was performed for chronic and acute pain conditions, respectively, including subgroup analysis for percutaneous (pVNS—needle electrodes) and transcutaneous (tVNS—surface electrodes) aVNS. The visual analog pain scale (VAS) was defined as primary efficacy endpoint. Results: A total of n = 1496 patients were treated with aVNS in 23 identified and analyzed studies in chronic pain, 12 studies in acute postoperative pain and 7 studies in experimental acute pain. Of these, seven studies for chronic pain and six studies for acute postoperative pain were included in the meta-analysis. In chronic pain conditions, including back pain, migraine and abdominal pain, a statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control treatment with an effect size Hedges' g/mean difference of − 1.95 (95% confidence interval [CI]: − 3.94 to 0.04, p = 0.008) could be shown and a more favorable effect in pVNS compared to tVNS (− 5.40 [− 8.94; − 1.85] vs. − 1.00 [− 1.55; − 0.44]; p = 0.015). In acute pain conditions, single studies showed significant improvements with aVNS, e.g., in kidney donor surgery or tonsillectomy but, overall, a non-statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control with − 0.70 [− 2.34; 0.93] (p = 0.15) could be observed in the meta-analysis. In acute pain results vary greatly between studies depending especially on co-medication and timepoints of assessment after surgery. A significant reduction in analgesics or opiate intake was documented in most studies evaluating this effect in chronic and acute pain. In 3 of the 12 randomized controlled trials in patients with chronic pain, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated. Conclusion: This systematic review and meta-analysis indicate that aVNS can be an effective and safe non-drug treatment in patients with specific chronic and acute postoperative pain conditions. Further research is needed to identify the influence of simulation parameters and find optimal and standardized treatment protocols while considering quality-of-life outcome parameters and prolonged follow-up periods. A more standardized approach and harmonization in study designs would improve comparability and robustness of outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Conditioned pain modulation (CPM) is a quantitative estimation of the capacity for endogenous pain modulation. Reduced CPM enables chronic painful event development or exacerbates pre-existing pain symptoms. Emerging reports indicate that patients with trigeminal neuralgia (TN) have dysregulated endogenous pain modulation. Transauricular vagus nerve stimulation (taVNS) is known to alleviate both acute and chronic pain symptoms. Its role in modulation or management of TN remains unknown. Here, we evaluated the taVNS efficacy in modulating CPM among TN patients. Conclusions from this investigation may facilitate establishment of novel non-invasive adjunctive approaches to treating TN patients. Methods: All research work was conducted at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital). In all, we recruited 62 study participants, 31 TN patients and 31 healthy volunteers, for a 2-day experimental test. At the beginning of the experiment (Day 1), all subjects received 30 min of active taVNS. On Day 2, they received sham taVNS with the same duration and intensity. Meanwhile, technicians documented participant pressure pain thresholds (PPT) and CPM values at baseline, and at 15 and 30 min post-active or sham taVNS. Results: A 30-min active taVNS exposure substantially elevated the PPT and CPM effect (P < 0.05) among TN patients, and we also observed a notable rise in the PPT and CPM effect (P < 0.05) among healthy controls. Additionally, there were no serious adverse events from the administered treatment. Conclusion: Exposure to 30 min of active taVNS strongly augmented the CPM effect and elevated the PPT among TN patients and healthy controls. These effects were not observed with sham stimulation. Despite the limitations inherent to survey studies, such as duration and compliance biases, we consider that taVNS is a promising, safe, and cost-effective therapy. In future investigations, we recommend assessment of long-term taVNS application and its effects on CPM and clinical pain. Trial Registration: ChiCTR2300078673 (www.Chictr.org.cn). [ABSTRACT FROM AUTHOR]

The article discusses the concept of combination treatment in managing migraine, which involves using two or more acute or preventive treatments simultaneously. It emphasizes the importance of clear terminology to enhance communication and implementation of treatment strategies, especially in regions with diverse practices. The text highlights the need for a standardized lexicon among clinicians and researchers to improve patient care and reduce ambiguity in the field. The authors suggest a stepwise approach to combining treatments, starting with identifying a baseline treatment and layering subsequent treatments based on individual patient characteristics and disease burden. [Extracted from the article]

Aim: Polycystic ovary syndrome (PCOS) is an increasingly recognized endocrine disorder. The pathogenesis is not fully known. Polycystic ovary syndrome is still difficult to diagnose correctly, despite simple diagnostic criteria. The aim of the study is to review the current knowledge about PCOS and treatment options for patients with the disease. To explore this topic, publications were reviewed and conclusions drawn from them. The incidence of hyperandrogenism in a patient with PCOS may be as high as 60-80%. Increased androgen levels affect ovulation and menstruation, and also result in hirsutism and acne. Additionally, patients have problems with proper glucose tolerance (insulin resistance), type 2 diabetes, hypertension, cardiovascular diseases and metabolic syndrome. PCOS results in various symptoms in patients. Methods: The latest treatment methods were analysed. A standard review of publications in the field of diagnosis and treatment of PCOS, IR and hyperandrogenism was used. Results: Lifestyle, especially diet, deserves special attention due to its ease of use. Sleep quality, physical activity and stress reduction are also important. Diet should be the treatment of first choice. Only if dietary intervention does not bring results, the doctor considers pharmacotherapy. Recently, acupuncture and herbal medicine, vagus nerve stimulation have been used in the treatment of PCOS and regulation of hormone levels. Patients are given supplementation to improve the quality of functioning, but it must be remembered that inappropriate doses or too long use may result in a toxic effect opposite to the therapeutic one. Conclusion: Appropriate diet, physical activity - lifestyle changes are crucial in the treatment of PCOS. Supplementation and pharmaceuticals support treatment. It is mandatory to examine these environmental and lifestyle factors as they not only contribute to the occurrence of the disease but also influence its progression. [ABSTRACT FROM AUTHOR]

As a crucial component of the cardiac autonomic nervous system, the cardiac vagus nerve plays a significant role in the management of chronic heart failure. In recent years, several studies have found that vagus nerve stimulation protects cardiac function and delays the progression of chronic heart failure by reducing the expression of inflammatory factors and related proteins, apoptosis-related proteins, and improving myocardial function and ventricular remodeling. However, there are limited reports related to the mechanism of inflammation and apoptosis of the vagus nerve in chronic heart failure. Hence, this article reviews the anatomy of the cardiac vagus nerve, potential treatment mechanisms, practical parameters of vagus nerve stimulation, and the recent applications and clinical progress of vagus nerve stimulation in inflammation and apoptosis mechanisms in chronic heart failure, in order to provide a reference for the future related research.

Background. In case of ineffective conservative antiepileptic therapy, surgical treatment aimed at removing the epileptogenic focus may be applied. Resection procedures allow to eliminate seizures in most patients, but in 20–30% cases they persist or recur, thereby proposing to use some neuromodulation.Objective: to assess effectiveness of neuromodulation in patients with drug-resistant epilepsy (DRE) after failed resection surgical interventions.Material and methods. A retrospective data analysis was carried out involving 23 DRE patients who had undergone vagus nerve stimulation (VNS) or deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) or hippocampus (HP) after failed surgeries. The VNS system was implanted in 18 (78.3%) patients, the HP-DBS system – in 3 (13.0%), and the ANT-DBS system – in 2 (8.7%). The results after surgical interventions were assessed according to the Engel scale, VNS therapy – by the McHugh (MH) scale, DBS therapy – by the degree of reduced seizure rate as a percentage. The average follow-up was 56.5 months.Results. Patients with implanted VNS system were found to have the outcome presented as MH Ia–IIb in 3 (16.7%) cases, MH IIIa–IIIb in 10 (55.5%) cases, MH IV–V in 5 (27.8%) cases. In HP-DBS group, 2 out of 3 patients showed a decline in seizure rate by more than 50% from the baseline level, and 1 patient experienced an improvement in seizure severity. In the ANT-DBS group, one patient had a 60% reduction in seizure rate and an improvement in seizure severity, another one showed no change in seizure rate.Conclusion. Neuromodulation in DRE patients can significantly lower seizure rate in more than half of patients after failed surgical treatment.

Ridengnaxi E, Yan Wang Department of Rehabilitation Medicine, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, People’s Republic of ChinaCorrespondence: Yan Wang, Department of Rehabilitation Medicine, Inner Mongolia Autonomous Region People’s Hospital, No. 20 of Zhaowuda Road, Saihan District, Hohhot, 010017, People’s Republic of China, Tel/Fax +86 18148253963, Email wangyanyw26@126.comAbstract: Vagus nerve stimulation (VNS) is acknowledged as a highly effective therapy for various neurological conditions, including refractory epilepsy, depression, Alzheimer’s disease (AD), migraine, and stroke. Presently, there is an increasing focus on understanding the impact of VNS on cognitive aspects. Numerous studies suggest that VNS suppresses the body’s inflammatory response, leading to enhanced cognitive function in patients. Vascular cognitive impairment (VCI) is a severe cognitive dysfunction syndrome resulting from prolonged chronic cerebral hypoperfusion (CCH), where the primary pathogenesis is CCH-induced neuroinflammation. In this paper, we present a comprehensive overview of the research advancements in using VNS for treating VCI and discuss that VNS improves cognitive function in VCI patients by suppressing neuroinflammation, offering insights into a potential novel approach for addressing this condition.Keywords: cholinergic anti-inflammatory pathway, chronic cerebral hypoperfusion, cognition, neuroinflammation, vagus nerve stimulation, vascular cognitive impairment

Abstract Background Vagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. Achieving a better understanding of the relationship between VNS parameters and neural and physiological responses is therefore necessary to enable the design of personalized dosing procedures and improve precision and efficacy of VNS therapies. Methods We used biomarkers from recorded evoked fiber activity and short-term physiological responses (throat muscle, cardiac and respiratory activity) to understand the response to a wide range of VNS parameters in anaesthetised pigs. Using signal processing, Gaussian processes (GP) and parametric regression models we analyse the relationship between VNS parameters and neural and physiological responses. Results Firstly, we illustrate how considering multiple stimulation parameters in VNS dosing can improve the efficacy and precision of VNS therapies. Secondly, we describe the relationship between different VNS parameters and the evoked fiber activity and show how spatially selective electrodes can be used to improve fiber recruitment. Thirdly, we provide a detailed exploration of the relationship between the activations of neural fiber types and different physiological effects. Finally, based on these results, we discuss how recordings of evoked fiber activity can help design VNS dosing procedures that optimize short-term physiological effects safely and efficiently. Conclusion Understanding of evoked fiber activity during VNS provide powerful biomarkers that could improve the precision, safety and efficacy of VNS therapies.

Background: Transcutaneous Vagal Nerve Stimulation (tVNS) has been used as a promising noninvasive neuromodulation technique for the treatment of various systems.The aim of this study was to analyze the research hotspots and future directions of tVNS in the 21st century by using bibliometric methods. Methods: The study object was the literature related to tVNS from the Web of Science database from 2000 to May 2024. In order to measure and analyze the number of literature issuance, institutions, authors, countries, keywords, cocitations, and journals of publication, we used VOSviewer, Citespace, Bibliometrix R-package, and Scimago Graphica software. A narrative review of the current research content of tVNS was conducted to gain a better understanding of the current state of the field. Results: A total of 569 papers were included in the study. The results show that from 2000 to 2024, the number of publications shows an increasing trend year by year, involving a total of 326 research institutions. The United States, China, and Germany are the major research centers. The study identified 399 keywords, which roughly formed 11 natural clusters, revealing that the current hotspots of related research are mainly reflected in 3 areas: intervention efficacy on nervous system diseases, mechanism of action of tVNS, and stimulation mode of tVNS. The top 10 most cited references focus on research into the mechanism of action of tVNS. Conclusion: The efficacy and safety of tVNS have been confirmed in previous studies, but a standardized tVNS treatment protocol has not yet been developed, and most clinical studies have small sample sizes and lack multicenter and multidisciplinary collaboration. Currently, tVNS is used in the treatment of neurological diseases, psychiatric diseases, cardiovascular diseases, and some autoimmune diseases. It is expected that future research in this field will continue to focus on the application of tVNS in central nervous system diseases and the exploration of related mechanisms, and at the same time, with the rise of non-invasive neuromodulation technology, the application of tVNS in other diseases also has great potential for development. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]