Epilepsy surgery in developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) present significant treatment challenges due to frequent, drug-resistant seizures and comorbidities that impact quality of life. DEEs include both developmental encephalopathy from underlying pathology and epileptic encephalopathy where seizures exacerbate cognitive and behavioral impairments. Classification by syndrome and etiology is essential for therapy and prognosis, with common syndromes like infantile epileptic spasms syndrome and Dravet syndrome having specific first-line treatments. Etiologies are predominantly genetic, structural, or combined, with targeted therapies increasingly available. Surgery aims to improve seizure control but also may improve development, if the epileptic encephalopathy can be ameliorated. Timely intervention can reduce seizures and epileptiform discharges, maximizing developmental potential and allowing reduction in antiseizure medication. In cases requiring extensive resections, new deficits may be offset by developmental gains. Studies indicate that parents are generally willing to accept some deficits for significant seizure reduction.

Towards spatially selective efferent neuromodulation: anatomical and functional organization of cardiac fibres in the porcine cervical vagus nerve.

Spatially selective vagus nerve stimulation (sVNS) offers a promising approach for addressing heart disease with enhanced precision. Despite its therapeutic potential, VNS is limited by off-target effects and the need for time-consuming titration. Our research aimed to determine the spatial organization of cardiac afferent and efferent fibres within the vagus nerve of pigs to achieve targeted neuromodulation. Using trial-and-error sVNS in vivo and ex vivo micro-computed tomography fascicle tracing, we found significant spatial separation between cardiac afferent and cardiac efferent fibres at the mid-cervical level and they were localized on average on opposite sides of the nerve cross-section. This was consistent between both in vivo and ex vivo methods. Specifically, cardiac afferent fibres were located near pulmonary fibres, consistent with findings of cardiopulmonary convergent circuits and, notably, cardiac efferent fascicles were exclusive. These cardiac efferent regions were located in close proximity to the recurrent laryngeal regions. This is consistent with the roughly equitable spread across the nerve of the afferent and efferent fibres. Our study demonstrated that targeted neuromodulation via sVNS could achieve scalable heart rate decreases without eliciting cardiac afferent-related reflexes; this is desirable for reducing sympathetic overactivation associated with heart disease. These findings indicate that understanding the spatial organization of cardiac-related fibres within the vagus nerve can lead to more precise and effective VNS therapy, minimizing off-target effects and potentially mitigating the need for titration. KEY POINTS: Spatially selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibres in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects such as scalable heart rate decrease without stimulating cardiac afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and potentially eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.

Evaluating the Efficacy of Vagus Nerve Stimulation across 'Minor' and 'Major' Seizure Types: A Retrospective Analysis of Clinical Outcomes in Pharmacoresistant Epilepsy.

Background: Evaluating the differential impact of vagus nerve stimulation (VNS) therapy across various seizure types, our study explores its efficacy specifically in patients with categorized minor and major seizures. Methods: We conducted a retrospective cohort study involving 76 patients with pharmacoresistant epilepsy treated at the University Emergency Hospital of Bucharest between 2021 and 2024. Seizures were classified as 'minor' (including focal-aware and non-motor/absence seizures) and 'major' (including focal to bilateral tonic-clonic and generalized motor seizures), based on modified International League Against Epilepsy (ILAE) criteria. This classification allowed us to assess the response to VNS therapy, defined by a 50% or greater reduction in seizure frequency at the 12-month follow-up. Results: Our findings reveal that major seizures respond more favorably to VNS therapy, significantly reducing both frequency and intensity. In contrast, minor seizures showed a less pronounced response in frequency reduction but noted improvements in neurocognitive functions, suggesting a nuanced benefit of VNS in these cases. Conclusion: The study underscores the importance of seizure type in determining the efficacy of VNS therapy, advocating for personalized treatment approaches based on seizure classification. This approach could potentially enhance clinical outcomes by tailoring VNS settings to specific seizure types, improving overall management strategies in pharmacoresistant epilepsy.

Retention rate of vagus nerve stimulation for the treatment of drug-resistant epilepsy: A single-centre, retrospective study.

The aim of this single-centre, retrospective, observational study was to evaluate long-term effectiveness of vagus nerve stimulation (VNS) in drug-resistant epilepsy (DRE) by using retention rate as a surrogate measure for seizure reduction. We included all patients with DRE, treated at the adult neurology department of the University Hospitals Leuven and who started VNS therapy from January 1, 1994, until May 1, 2021, with follow-up data cutoff on January 1, 2023. Retention rate of VNS was defined as the percentage of patients who maintain VNS at established time points. We estimated cumulative retention rate and battery replacement rate and correlated these with seizure reduction, using Kaplan-Meier analysis. Statistical analysis of potential predictors of VNS outcome (age, sex and epilepsy duration at implantation) was performed using mono- and multivariate analyses. VNS was started in 110 patients with DRE, with a mean follow-up of 8.7 years (SD 6.5). VNS was discontinued in 55 patients (50%), with ineffectiveness as the main reason for discontinuation (98%). The battery was replaced at least once in 42 patients (38%). Estimated retention rates were 70%, 52%, 45% and 33% after 5, 10, 15 and 20 years, respectively. Estimated first battery replacement rates were 16%, 42% and 47% after 5, 10 and 15 years, respectively. Both estimates showed a statistically significant correlation with seizure reduction. No independent predictors of long-term outcome of VNS were found. This is the first long-term study using retention rate of VNS to assess effectiveness. VNS is a well-tolerated therapy, but retention rates decline with long follow-up.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

Minimally invasive vagus nerve stimulation modulates mast cell degranulation via the microbiota-gut-brain axis to ameliorate blood-brain barrier and intestinal barrier damage following ischemic stroke.

Mast cells (MCs) play a significant role in various diseases, and their activation and degranulation can trigger inflammatory responses and barrier damage. Several studies have indicated that vagus nerve stimulation (VNS) exerts ameliorates neurological injury, and regulates gut MC degranulation. However, there is limited research on the modulatory effect of VNS on MCs in both the gut and brain in brain ischemia-reperfusion (I/R) injury in this process. We aim to develop a minimally invasive, targeted and convenient VNS approach to assess the impact of VNS and to clarify the relationship between VNS and MCs on the prognosis of acute ischemic stroke. We utilized middle cerebral artery occlusion/reperfusion (MCAO/r) to induce brain I/R injury. After the experiment, the motor function and neurofunctional impairments of the rats were detected, and the gastrointestinal function, blood-brain barrier (BBB) and intestinal barrier damage, and systemic and local inflammation were evaluated by Nissl, TTC staining, Evans blue, immunofluorescence staining, transmission electron microscopy, western blot assays, ELISA, and fecal 16S rRNA sequencing methods. Our research confirmed that our minimally invasive VNS method is a novel approach for stimulating the vagus nerve. VNS alleviated motor deficits and gastrointestinal dysfunction while also suppressing intestinal and neuroinflammation. Additionally, VNS ameliorated gut microbiota dysbiosis in rats. Furthermore, our analysis indicated that VNS reduces chymase secretion by modulating MCs degranulation and improves intestinal and BBB damage. Our results showed that VNS treatment can alleviate the damage of BBB and colonic barrier after cerebral I/R by modulating mast cell degranulation, and alleviates systemic inflammatory responses.

Efficacy of vagus nerve stimulation in managing drug-resistant absence epilepsy syndromes.

PURPOSE: Around 11% of patients with absence epilepsy develop drug-resistant absence epilepsy (DRAE), and are at increased risk for developing psychiatric and neurologic comorbidities. Current therapeutic options for DRAE are limited. The purpose of this study was to assess the efficacy of vagus nerve stimulation (VNS) in treating DRAE. METHODS: Our institution maintains a database of patients who received VNS between 2010 and 2022. We identified DRAE patients who were <18 years of age at seizure onset, were electro-clinically diagnosed with an absence epilepsy syndrome (childhood absence, juvenile absence, or Jeavons Syndrome) by an epileptologist, and had normal brain imaging. The primary outcome measure was post-VNS absence seizure frequency. RESULTS: Twenty-six patients (M/F:14/12) were identified. Median age at seizure onset was 7 years (IQR 4-10) and patients experienced seizures for 6 years (IQR 4.3-7.6) before VNS. After VNS, the median absence seizure frequency reduced to 1.5 days (IQR 0.1-3.5) per week from 7 days (IQR 7-7), a 66% reduction seizure frequency. VNS responder rate was 80%, and seven patients achieved seizure freedom. There was no significant effect on VNS efficacy between the time from DRAE diagnosis to VNS placement (p = 0.067) nor the time from first seizure onset to VNS implant (p = 0.80). The median follow-up duration was 4.1 years (IQR 2.4-6.7), without any significant association between follow-up duration and VNS efficacy (r2=0.023) CONCLUSIONS: VNS is effective in managing DRAE. The responder rate was 80%; seizure improvement was independent of age at both seizure onset and latency to VNS after meeting DRAE criteria.

Neurostimulation treatments for epilepsy: Deep brain stimulation, responsive neurostimulation and vagus nerve stimulation.

Epilepsy is a common and debilitating neurological disorder, and approximately one-third of affected individuals have ongoing seizures despite appropriate trials of two anti-seizure medications. This population with drug-resistant epilepsy (DRE) may benefit from neurostimulation approaches, such as vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). In some patient populations, these techniques are FDA-approved for treating DRE. VNS is used as adjuvant therapy for children and adults. Acting via the vagus afferent network, VNS modulates thalamocortical circuits, reducing seizures in approximately 50 â€‹% of patients. RNS uses an adaptive (closed-loop) system that records intracranial EEG patterns to activate the stimulation at the appropriate time, being particularly well-suited to treat seizures arising within eloquent cortex. For DBS, the most promising therapeutic targets are the anterior and centromedian nuclei of the thalamus, with anterior nucleus DBS being used for treating focal and secondarily generalized forms of DRE and centromedian nucleus DBS being applied for treating generalized epilepsies such as Lennox-Gastaut syndrome. Here, we discuss the indications, advantages and limitations of VNS, DBS and RNS in treating DRE and summarize the spatial distribution of neuroimaging observations related to epilepsy and stimulation using NeuroQuery and NeuroSynth.

Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation.

Cardiac disease progression reflects the dynamic interaction between adversely remodeled neurohumoral control systems and an abnormal cardiac substrate. Vagal nerve stimulation (VNS) is an attractive neuromodulatory option to dampen this dynamic interaction; however, it is limited by off-target effects. Spatially-selective VNS (sVNS) offers a promising solution to induce cardioprotection while mitigating off-target effects by specifically targeting pre-ganglionic parasympathetic efferent cardiac fibers. This approach also has the potential to enhance therapeutic outcomes by eliminating time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. By using trial-and-error sVNS in vivo in combination with ex vivo micro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179±55° SD microCT, p<0.05 and 200±137° SD, p<0.05 sVNS - degrees of separation across a cross-section of nerve) at the mid-cervical level. We also show that cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability of sVNS to selectively elicit desired scalable heart rate decrease without stimulating afferent-related reflexes. By elucidating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating cardiac pathology, allowing for improved therapeutic efficacy.

Device therapy for patients with atrial fibrillation and heart failure with preserved ejection fraction.

Device therapy is a nonpharmacological approach that presents a crucial advancement for managing patients with atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF). This review investigated the impact of device-based interventions and emphasized their potential for optimizing treatment for this complex patient demographic. Cardiac resynchronization therapy, augmented by atrioventricular node ablation with His-bundle pacing or left bundle-branch pacing, is effective for enhancing cardiac function and establishing atrioventricular synchrony. Cardiac contractility modulation and vagus nerve stimulation represent novel strategies for increasing myocardial contractility and adjusting the autonomic balance. Left ventricular expanders have demonstrated short-term benefits in HFpEF patients but require more investigation for long-term effectiveness and safety, especially in patients with AF. Research gaps regarding complications arising from left ventricular expander implantation need to be addressed. Device-based therapies for heart valve diseases, such as transcatheter aortic valve replacement and transcatheter edge-to-edge repair, show promise for patients with AF and HFpEF, particularly those with mitral or tricuspid regurgitation. Clinical evaluations show that these device therapies lessen AF occurrence, improve exercise tolerance, and boost left ventricular diastolic function. However, additional studies are required to perfect patient selection criteria and ascertain the long-term effectiveness and safety of these interventions. Our review underscores the significant potential of device therapy for improving the outcomes and quality of life for patients with AF and HFpEF.

Efficacy of transauricular vagus nerve stimulation for the treatment of chemotherapy-induced painful peripheral neuropathy: a randomized controlled exploratory study.

BACKGROUND: Chemotherapy-induced painful peripheral neuropathy (CIPN) is a common adverse event in cancer patients, and there is still a lack of effective treatment. Transauricular vagal nerve stimulation (taVNS) is a minimally invasive treatment, but there are few reports regarding its efficacy for CIPN. OBJECTIVE: To investigate the efficacy and possible mechanism of taVNS in patients with CIPN. METHODS: Twenty-seven patients with CIPN were randomly divided into a taVNS group (n = 14) and a sham stimulation (SS) group (n = 13). A numerical rating scale (NRS) for pain, NCICTCAE 4.0 (neurotoxicity classification), quantitative sensory test (QST), Short-Form-Health Survey-12 (SF-12), and Athens Insomnia Scale (AIS) were administered before the intervention (D-10) and on the day after the intervention (D0), and the inflammatory cytokines in plasma were also measured. The NRS, NCI-CTCAE 4.0, SF-12, and AIS were administered again at D30 and D90. RESULTS: Compared with the SS group, the NRS and AIS in the taVNS group were significantly lower at D0. The impact lasted until D30. There were no statistically significant differences in the NRS and AIS between the 2 groups at D90. On D30, the mental component score of the SF-12 was significantly higher in the taVNS group than in the SS group. No adverse events were found. There was no significant difference in QST and plasma inflammatory cytokines between the 2 groups. CONCLUSION: taVNS can relieve chemotherapy-induced neuropathic pain in the short term, can improve sleep status and quality of life, and is expected to become a novel clinical treatment method for CIPN.

Left Vagus Stimulation Modulates Contralateral Subthalamic ß Power Improving the Gait in Parkinson's Disease.

BACKGROUND: Transcutaneous vagus nerve stimulation (VNS) showed early evidence of efficacy for the gait treatment of Parkinson's disease (PD). OBJECTIVES: Providing data on neurophysiological and clinical effects of transauricular VNS (taVNS). METHODS: Ten patients with recording deep brain stimulation (DBS) have been enrolled in a within participant design pilot study, double-blind crossover sham-controlled trial of taVNS. Subthalamic local field potentials (ß band power), Unified Parkinson's Disease Rating Scales (UPDRS), and a digital timed-up-and-go test (TUG) were measured and compared with real versus sham taVNS during medication-off/DBS-OFF condition. RESULTS: The left taVNS induced a reduction of the total ß power in the contralateral (ie, right) subthalamic nucleus and an improvement of TUG time, speed, and variability. The taVNS-induced ß reduction correlated with the improvement of gait speed. No major clinical changes were observed at UPDRS. CONCLUSIONS: taVNS is a promising strategy for the management of PD gait, deserving prospective trials of chronic neuromodulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Application of vagus nerve stimulation on the rehabilitation of upper limb dysfunction after stroke: a systematic review and meta-analysis.

Objective: This study aimed to elucidate the efficacy, safety, and long-term implications of vagus nerve stimulation (VNS) as a viable therapeutic option for patients with upper limb dysfunction following a stroke. Methods: Data from the following libraries were searched from inception to December 2022: PubMed, Wanfang, Scopus, China Science and Technology Journal Database, Embase, Web of Science, China Biology Medicine Disc, Cochrane Library, and China National Knowledge Infrastructure. Outcomes included indicators of upper limb motor function, indicators of prognosis, and indicators of safety (incidence of adverse events [AEs] and serious AEs [SAEs]). Two of the authors extracted the data independently. A third researcher arbitrated when disputes occurred. The quality of each eligible study was evaluated using the Cochrane Risk of Bias tool. Meta-analysis and bias analysis were performed using Stata (version 16.0) and RevMan (version 5.3). Results: Ten trials (VNS combined with rehabilitation group vs. no or sham VNS combined with rehabilitation group) with 335 patients were included in the meta-analysis. Regarding upper extremity motor function, based on Fugl-Meyer assessment scores, VNS combined with other treatment options had immediate (mean difference [MD] = 2.82, 95% confidence interval [CI] = 1.78-3.91, I2 = 62%, p < 0.00001) and long-term (day-30 MD = 4.20, 95% CI = 2.90-5.50, p < 0.00001; day-90 MD = 3.27, 95% CI = 1.67-4.87, p < 0.00001) beneficial effects compared with that of the control treatment. Subgroup analyses showed that transcutaneous VNS (MD = 2.87, 95% CI = 1.78-3.91, I2 = 62%, p < 0.00001) may be superior to invasive VNS (MD = 3.56, 95% CI = 1.99-5.13, I2 = 77%, p < 0.0001) and that VNS combined with integrated treatment (MD = 2.87, 95% CI = 1.78-3.91, I2 = 62%, p < 0.00001) is superior to VNS combined with upper extremity training alone (MD = 2.24, 95% CI = 0.55-3.93, I2 = 48%, p = 0.009). Moreover, lower frequency VNS (20 Hz) (MD = 3.39, 95% CI = 2.06-4.73, I2 = 65%, p < 0.00001) may be superior to higher frequency VNS (25 Hz or 30 Hz) (MD = 2.29, 95% CI = 0.27-4.32, I2 = 58%, p = 0,03). Regarding prognosis, the VNS group outperformed the control group in the activities of daily living (standardized MD = 1.50, 95% CI = 1.10-1.90, I2 = 0%, p < 0.00001) and depression reduction. In contrast, quality of life did not improve (p = 0.51). Safety was not significantly different between the experimental and control groups (AE p = 0.25; SAE p = 0.26). Conclusion: VNS is an effective and safe treatment for upper extremity motor dysfunction after a stroke. For the functional restoration of the upper extremities, noninvasive integrated therapy and lower-frequency VNS may be more effective. In the future, further high-quality studies with larger study populations, more comprehensive indicators, and thorough data are required to advance the clinical application of VNS. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023399820.

Vagus nerve stimulation using an endovascular electrode array.

Objective. Vagus nerve stimulation (VNS), which involves a surgical procedure to place electrodes directly on the vagus nerve (VN), is approved clinically for the treatment of epilepsy, depression, and to facilitate rehabilitation in stroke. VNS at surgically implanted electrodes is often limited by activation of motor nerve fibers near and within the VN that cause neck muscle contraction. In this study we investigated endovascular VNS that may allow activation of the VN at locations where the motor nerve fibers are not localized.Approach. We used endovascular electrodes within the nearby internal jugular vein (IJV) to electrically stimulate the VN while recording VN compound action potentials (CAPs) and neck muscle motor evoked potentials (MEPs) in an acute intraoperative swine experiment.Main Results. We show that the stimulation electrode position within the IJV is critical for efficient activation of the VN. We also demonstrate use of fluoroscopy (cone beam CT mode) and ultrasound to determine the position of the endovascular stimulation electrode with respect to the VN and IJV. At the most effective endovascular stimulation locations tested, thresholds for VN activation were several times higher than direct stimulation of the nerve using a cuff electrode; however, this work demonstrates the feasibility of VNS with endovascular electrodes and provides tools to optimize endovascular electrode positions for VNS.Significance. This work lays the foundation to develop endovascular VNS strategies to stimulate at VN locations that would be otherwise too invasive and at VN locations where structures such as motor nerve fibers do not exist.

Effects on heart rate from direct current block of the stimulated rat vagus nerve.

Objective.Although electrical vagus nerve stimulation has been shown to augment parasympathetic control of the heart, the effects of electrical conduction block have been less rigorously characterized. Previous experiments have demonstrated that direct current (DC) nerve block can be applied safely and effectively in the autonomic system, but additional information about the system dynamics need to be characterized to successfully deploy DC nerve block to clinical practice.Approach.The dynamics of the heart rate (HR) from DC nerve block of the vagus nerve were measured by stimulating the vagus nerve to lower the HR, and then applying DC block to restore normal rate. DC block achieved rapid, complete block, as well as partial block at lower amplitudes.Main Results. Complete block was also achieved using lower amplitudes, but with a slower induction time. The time for DC to induce complete block was significantly predicted by the amplitude; specifically, the amplitude expressed as a percentage of the current required for a rapid, 60 s induction time. Recovery times after the cessation of DC block could occur both instantly, and after a significant delay. Both blocking duration and injected charge were significant in predicting the delay in recovery to normal conduction.Significance. While these data show that broad features such as induction and recovery can be described well by the DC parameters, more precise features of the HR, such as the exact path of the induction and recoveries, are still undefined. These findings show promise for control of the cardiac autonomic nervous system, with potential to expand to the sympathetic inputs as well.

Estimated EEG functional connectivity and aperiodic component induced by vagal nerve stimulation in patients with drug-resistant epilepsy.

Background: Vagal nerve stimulation (VNS) improves seizure frequency and quality of life in patients with drug-resistant epilepsy (DRE), although the exact mechanism is not fully understood. Previous studies have evaluated the effect of VNS on functional connectivity using the phase lag index (PLI), but none has analyzed its effect on EEG aperiodic parameters (offset and exponent), which are highly conserved and related to physiological functions. Objective: This study aimed to evaluate the effect of VNS on PLI and aperiodic parameters and infer whether these changes correlate with clinical responses in subjects with DRE. Materials and methods: PLI, exponent, and offset were derived for each epoch (and each frequency band for PLI), on scalp-derived 64-channel EEG traces of 10 subjects with DRE, recorded before and 1 year after VNS. PLI, exponent, and offset were compared before and after VNS for each patient on a global basis, individual scalp regions, and channels and separately in responders and non-responders. A correlation analysis was performed between global changes in PLI and aperiodic parameters and clinical response. Results: PLI (global and regional) decreased after VNS for gamma and delta bands and increased for an alpha band in responders, but it was not modified in non-responders. Aperiodic parameters after VNS showed an opposite trend in responders vs. non-responders: both were reduced in responders after VNS, but they were increased in non-responders. Changes in aperiodic parameters correlated with the clinical response. Conclusion: This study explored the action of VNS therapy from a new perspective and identified EEG aperiodic parameters as a new and promising method to analyze the efficacy of neuromodulation.

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

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

The Future Is Noninvasive: A Brief Review of the Evolution and Clinical Utility of Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) is a form of neuromodulation that stimulates the vagus nerve. VNS had been suggested as an intervention in the late 1800s and was rediscovered in the late 1980s as a promising treatment for refractory epilepsy. Since then, VNS has been approved by the U.S. Food and Drug Administration (FDA) for treatment of epilepsy, morbid obesity, and treatment-resistant depression. Unfortunately, VNS is underutilized, as it is costly to implant and often only suggested when all other treatment options have been exhausted. Discovery of a noninvasive method of VNS known as transcutaneous auricular VNS (taVNS), which activates the vagus through stimulation of the auricular branch of the vagus nerve, has reignited excitement around VNS. taVNS has immense potential as a safe, at-home, wearable treatment for various neuropsychiatric disorders. Major strides are being made in both invasive and noninvasive VNS that aim to make this technology more accessible to patients who would find benefit, including the ongoing RECOVER trial, a randomized controlled trial in up to 1,000 individuals to further evaluate the efficacy of VNS for treatment-resistant depression. In this brief review, we first discuss the early history of VNS; then its clinical utility in FDA-approved indications; and, finally, noninvasive VNS.

Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity.

Vagus nerve stimulation (VNS) delivered during motor rehabilitation enhances recovery from a wide array of neurological injuries and was recently approved by the U.S. FDA for chronic stroke. The benefits of VNS result from precisely timed engagement of neuromodulatory networks during rehabilitative training, which promotes synaptic plasticity in networks activated by rehabilitation. Previous studies demonstrate that lesions that deplete these neuromodulatory networks block VNS-mediated plasticity and accompanying enhancement of recovery. There is a great deal of interest in determining whether commonly prescribed pharmacological interventions that influence these neuromodulatory networks would similarly impair VNS effects. Here, we sought to directly test the effects of three common pharmaceuticals at clinically relevant doses that target neuromodulatory pathways on VNS-mediated plasticity in rats. To do so, rats were trained on a behavioral task in which jaw movement during chewing was paired with VNS and received daily injections of either oxybutynin, a cholinergic antagonist, prazosin, an adrenergic antagonist, duloxetine, a serotonin-norepinephrine reuptake inhibitor, or saline. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate reorganization of motor cortex representations, with area of cortex eliciting jaw movement as the primary outcome. In animals that received control saline injections, VNS paired with training significantly increased the movement representation of the jaw compared to naïve animals, consistent with previous studies. Similarly, none of the drugs tested blocked this VNS-dependent reorganization of motor cortex. The present results provide direct evidence that these common pharmaceuticals, when used at clinically relevant doses, are unlikely to adversely impact the efficacy of VNS therapy.