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The aim of our study is to evaluate objective and subjective vocal outcomes in patients undergoing vagus nerve stimulation (VNS) therapy for drug-resistant epilepsy and to assess the vocal outcome in the known laryngeal dysmotility patterns induced by VNS. We enrolled 16 adult patients without cognitive impairment who had undergone VNS implant for drug-resistant epilepsy at least 1 year prior. They were evaluated by flexible fibreoptic laryngeal examination and Voice Handicap Index questionnaire administration; acoustic and perceptual voice analysis was performed both at rest and during VNS activation. All recruited patients were admitted to the study. The VNS implant systematically determined laryngeal motility alterations, which were in turn mirrored by perceptual, subjective, and/or acoustic analysis voice alterations in all patients. Patients with intact vocal fold function at rest performed worse during acoustic voice analysis in terms of jitter during VNS activation and shimmer at rest when compared to other laryngeal patterns (P= 0.027 and P = 0.034, respectively, Kruskal-Wallis test). Furthermore, VNS activation determined an overall worsening of the perceptual and acoustically analysed voice quality: the grade of hoarseness, instability and breathiness parameters of the GRBASI (grade, roughness, breathiness, asthenia, strain, instability) scale and the jitter, shimmer and noise-to-harmonic ratio of the acoustic analysis worsened significantly during VNS activation (P = 0.001, P = 0.021, P = 0.012, P.001, P = 00.002, P = 0.039, respectively, Wilcoxon test). According to our results, the VNS implant determines a significantly impaired vocal outcome that has a surprisingly mild impact on Voice Handicap Index scores. Such impairment is significantly greater in patients with intact vocal fold function at rest.

Objectives Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression. Materials and methods Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS. Results VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS. Conclusions The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.

BACKGROUND Transcutaneous auricular vagus nerve stimulation (taVNS) may modulate cardiac autonomic function. However, the response rate of the traditional tonic paradigm is low, and the results remain inconsistent. A recent pilot study presented a novel burst paradigm to activate the cardiac parasympathetic system, which might offer a new approach to treat cardiac autonomic function. The present study reassessed the effect of burst taVNS on modulating heart rate variability and explored the difference between burst and traditional tonic paradigms. MATERIALS AND METHODS Forty-two young adults were recruited for this study. Each participant underwent three types of taVNS with sham (30 sec of stimulation), tonic (25 Hz, 500 μsec), and burst (five pulses at 500 Hz every 200 msec) paradigms, respectively, with simultaneous electrocardiogram recording. One-way analysis of variance, multivariate analysis of variance, and linear regression were used for analysis. Multiple testing was performed using Bonferroni correction. RESULTS Both burst and tonic paradigms induced a significant decrease in heart rate, which continued until poststimulation, and increased cardiac parasympathetic activity. Moreover, two parasympathetic system indicators showed significant increase only in burst taVNS. The response rates during burst (35.7%) and tonic (38.1%) stimulations were both higher than that during sham stimulation (11.9%). The response to taVNS showed parameter specificity with few nonresponders to the tonic paradigm responding to the burst paradigm. The overall response rate increased from 38.1% in tonic taVNS to 54.8% in taVNS using both burst and tonic paradigms. For both burst and tonic responders, baseline cardiac parasympathetic activity was found to be significantly negatively correlated with changes during stimulation. CONCLUSION The burst parameter could be used as an alternative strategy for regulating cardiac parasympathetic function by taVNS, which has the potential to be used as a complementary paradigm to traditional tonic taVNS for promoting clinical treatment efficacy.

OBJECTIVE: Variations in respiration patterns are a characteristic response to distress due to underlying neurorespiratory couplings. Yet, no work to date has quantified respiration pattern variability (RPV) in the context of traumatic stress and studied its functional neural correlates – this analysis aims to address this gap. METHODS: Fifty human subjects with prior traumatic experiences (24 with posttraumatic stress disorder (PTSD)) completed a ~3-hr protocol involving personalized traumatic scripts and active/sham (double-blind) transcutaneous cervical vagus nerve stimulation (tcVNS). High-resolution positron emission tomography functional neuroimages, electrocardiogram (ECG), and respiratory effort (RSP) data were collected during the protocol. Supplementing the RSP signal with ECG-derived respiration for quality assessment and timing extraction, RPV metrics were quantified and analyzed. Specifically, correlation analyses were performed using neuroactivity in selected limbic regions, and responses to active and sham tcVNS were compared. RESULTS: The single-lag unscaled autocorrelation of respiration rate correlated negatively with left amygdala activity and positively with right rostromedial prefrontal cortex (rmPFC) activity for non-PTSD; it also correlated negatively with left and right insulae activity and positively with right rmPFC activity for PTSD. The single-lag unscaled autocorrelation of expiration time was greater following active stimulation for non-PTSD. CONCLUSION: Quantifying RPV is of demonstrable importance to assessing trauma-induced changes in neural function and tcVNS effects on respiratory physiology. SIGNIFICANCE: This is the first demonstration of RPV’s pertinence to traumatic stress- and tcVNS-induced neurorespiratory responses. The open-source processing pipeline elucidated herein uniquely includes both RSP and ECG-derived respiration signals for quality assessment, timing estimation, and RPV extraction.

Objective Transcutaneous auricular vagus nerve stimulation (taVNS) can relieve the symptoms of functional dyspepsia (FD) and improve the quality of life of patients, however, the mechanism underlying this effect remains unclear. Therefore, this study aimed to investigate the effects of taVNS on the expression of intestinal mucosal ligandins. Methods This study was conducted on 24 specific Spathogen-free Sprague–Dawley rats (12 males and 12 females). The rat model of FD was established by tail-clip stimulation. After FD was established successfully, all rats were randomized to either the normal group (n = 6), model group (n = 6), taVNS group (n = 6), or sham-taVNS group (n = 6). After two weeks of the respective intervention, the score of their general conditions, 3 h food intake, gastric emptying rate, and the histology of gastric antrum tissues were observed to evaluate modeling success, and then the effect of taVNS was evaluated. Western blotting was used to assess the expression of the tight junction ligandins —ZO-1 and occludin—and the adhesion ligandin—β-catenin—in the duodenum. The effect of taVNs on the expression of intestinal mucosal barrier ligandins—ZO-1, occludin, and β-catenin—in FD rats was preliminarily investigated. Results When the model-induced period was finished, the manifestations of FD in the model group rats were mental exhaustion, reduced activities, decreased score of the general conditions, and decreased 3 h food intake, compared to the normal group rats. In addition, minimal eosinophil infiltration, without any mucosal erosion or ulcer, was observed in the gastric antrum mucosa. At the end of the study, the mental state of the FD rats improved, and their activities and gastric emptying rate increased in the taVNS group rats. Compared to the normal rats, the duodenal mucosa had less expression of the tight junction ligandins ZO-1 and occludin, but β-catenin expression remained unchangedin the model rats. The expression of the tight junction ligandins ZO-1 and occludin were increased in the duodenal mucosa of model rats after the taVNS intervention. Conclusion TaVNS can improve the gastric motility and mental state of rats with FD. It may play a therapeutic role by improving the expression of the tight junction ligandin ZO-1 and occludin in the duodenal mucosa, while also repairing the duodenal mucosal barrier.

Difficulty perceiving phonological contrasts in a second language (L2) can impede initial L2 lexical learning. Such is the case for English speakers learning tonal languages, like Mandarin Chinese. Given the hypothesized role of reduced neuroplasticity in adulthood limiting L2 phonological perception, the current study examined whether transcutaneous auricular vagus nerve stimulation (taVNS), a relatively new neuromodulatory technique, can facilitate L2 lexical learning for English speakers learning Mandarin Chinese over 2 days. Using a double-blind design, one group of participants received 10 min of continuous priming taVNS before lexical training and testing each day, a second group received 500 msec of peristimulus (peristim) taVNS preceding each to-be-learned item in the same tasks, and a third group received passive sham stimulation. Results of the lexical recognition test administered at the end of each day revealed evidence of learning for all groups, but a higher likelihood of accuracy across days for the peristim group and a greater improvement in response time between days for the priming group. Analyses of N400 ERP components elicited during the same tasks indicate behavioral advantages for both taVNS groups coincided with stronger lexico-semantic encoding for target words. Comparison of these findings to pupillometry results for the same study reported in Pandža, N. B., Phillips, I., Karuzis, V. P., O'Rourke, P., and Kuchinsky, S. E. (Neurostimulation and pupillometry: New directions for learning and research in applied linguistics. Annual Review of Applied Linguistics, 40, 56–77, 2020) suggest that positive effects of priming taVNS (but not peristim taVNS) on lexico-semantic encoding are related to sustained attentional effort.

Three neuromodulation therapies have been appropriately tested and approved in refractory focal epilepsies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS), and closed-loop responsive neurostimulation of the epileptogenic zone or zones. These therapies are primarily palliative. Only a few individuals have achieved complete freedom from seizures for more than 12 months with these therapies, whereas more than half have benefited from long-term reduction in seizure frequency of more than 50%. Implantation-related adverse events primarily include infection and pain at the implant site. Intracranial haemorrhage is a frequent adverse event for ANT-DBS and responsive neurostimulation. Other stimulation-specific side-effects are observed with VNS and ANT-DBS. Biomarkers to predict response to neuromodulation therapies are not available, and high-level evidence to aid decision making about when and for whom these therapies should be preferred over other antiepileptic treatments is scant. Future studies are thus needed to address these shortfalls in knowledge, approve other forms of neuromodulation, and develop personalised closed-loop therapies with embedded machine learning. Until then, neuromodulation could be considered for individuals with intractable seizures, ideally after the possibility of curative surgical treatment has been carefully assessed and ruled out or judged less appropriate.

Vagus nerve stimulation (VNS) could potentially facilitate arm function recovery after stroke. The aim of this review was to evaluate the effect of VNS paired with rehabilitation on upper limb function recovery after stroke. We considered randomized controlled trials (RCTs) that used VNS paired with rehabilitation for the improvement of upper limb function after stroke and were published in English. Eligible RCTs were identified by searching electronic databases, including MEDLINE, Web of Science, Embase, CENTRAL and PEDro, from their inception until June 2021. Quality of included studies was assessed using PEDro score and Cochrane's risk of bias assessment. A meta-analysis was performed on the collected data. Five studies with a total of 178 participants met the inclusion criteria. Overall, the present meta-analysis revealed a significant effect of VNS on Fugl-Meyer Assessment for Upper Extremity (FMA-UE, MD = 3.59; 95% CI, 2.55-4.63; P < 0.01) when compared with the control group. However, no significant difference was observed in adverse events associated with device implantation between the invasive VNS and control groups (RR = 1.10; 95% CI, 0.92-1.32; P = 0.29). No adverse events associated with device use were reported in invasive VNS, and one was reported in transcutaneous VNS. This study revealed that VNS paired with rehabilitation can facilitate the recovery of upper limb function in patients with stroke on the basis of FMA-UE scores, but the long-term effects remain to be demonstrated.

Epilepsy surgery continues to be profoundly underutilized despite its safety and effectiveness. We sought to investigate factors that may contribute to this phenomenon, with a particular focus on the antecedent underutilization of appropriate preoperative studies. We reviewed patient data from a pediatric epilepsy clinic over an 18-month period. Patients with drug-resistant epilepsy (DRE) were categorized according to brain magnetic resonance imaging (MRI) findings (lesional, MRI-negative, or multifocal abnormalities) and type of epilepsy diagnosis based on semiology and electroencephalography (EEG) (focal or generalized). We then analyzed the rates of diagnostic test utilization, surgical referral, and subsequent epilepsy surgery as well as vagus nerve stimulation (VNS). Of the 249 patients with a diagnosis of epilepsy, 138 (55.4%) were found to have DRE. Excluding the 10 patients with DRE who did not undergo MRI, 76 patients (59.4%) were found to be MRI-negative (non-lesional epilepsy), 37 patients (28.9%) were found to have multifocal abnormalities, and 15 patients (11.7%) were found to have a single epileptogenic lesion on MRI (lesional epilepsy). Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) were each completed in nine patients (7.0%) and magnetoencephalography (MEG) in four patients (3.1%). Despite the low utilization rate of adjunctive studies, over half (56.3%) ultimately underwent VNS alone, and 8.6% ultimately underwent definitive intracranial resection or disconnection surgery. The underutilization of appropriate non-invasive, presurgical testing in patients with focal DRE may in part explain the continued underutilization of definitive, resective/disconnective surgery. For patients without access to a high-volume, multidisciplinary surgical epilepsy center, adjunctive presurgical studies [e.g., PET, SPECT, MEG, electrical source imaging (ESI), EEG-functional magnetic resonance imaging (fMRI)], even when available, are rarely ordered, and this may contribute to excessive rates of VNS in lieu of definitive intracranial surgery.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and unclear etiology. Vagus nerve stimulation (VNS) is an FDA-approved therapy for refractory epilepsy that has been shown to decrease the frequency and severity of seizures. There is a growing interest in alternate non-pharmaceutical therapies for managing super-refractory status epilepticus (SRSE). We present a 29-month-old case, diagnosed with FIRES, whose seizures were successfully controlled by utilization of VNS after ineffective response to intensive pharmacotherapy and ketogenic diet treatment. The VNS was planted after 14 days of refractory seizure activity with a following rapid parameter titration for 42 days without evident side effect, which finally controlled the seizure in the acute phase. VNS may be a potential candidate for the treatment of SRSE in FIRES.

BACKGROUND Vagus nerve stimulation (VNS) therapy was first approved in the mid-1990s in the USA, Europe and Australia, with demonstrable efficacy in paediatric populations. Benefit in seizure frequency reduction can be observed up to 2 years post-intervention; however, few studies assess outcomes beyond this period. Furthermore, paediatric cohort sizes are small, limiting generalisability of outcome assessments. We evaluate VNS insertion outcomes and complications or side-effects in a large paediatric cohort, over a 20-year period from Queensland's first VNS insertion. METHODS A retrospective review was conducted of all paediatric VNS insertions at the Queensland Children's Hospital (QCH) and the Mater Children's Hospital/Mater Children's Private Hospital (MCH/MCPH) Brisbane. A minimum of 1-year follow-up from 1999 to 2020 was required for inclusion. Patients were assessed on demographics, epilepsy details, seizure outcomes and complications or side-effects. RESULTS In this extended follow-up cohort (76 patients, 7.2 ± 5.3 years), 51.3% of patients had ≥ 50% seizure frequency reduction, while 73.7% experienced an Engel III outcome (worthwhile benefit) or better. Eleven patients (14.9%) were seizure-free at follow-up, and 81.6% retained long-term therapy. Stimulation-related side-effects are common (17.1%) but rarely result in stimulation cessation (3.9%). Cessation occurred in 14 patients (18.4%) and most commonly related to minimal benefit (13.2%). Demographics, aetiology, seizure nature and surgical factors did not influence outcomes. CONCLUSION Over extended treatment periods, a large proportion of patients will benefit significantly from VNS therapy. Approximately 4 of 5 patients will retain VNS therapy, and in cases of cessation, this is most commonly related to minimal benefit. Underlying demographics, aetiology or seizure nature do not influence outcomes. This 20-year Queensland assessment of VNS therapy outcomes informs long-term expectation of VNS therapy.

Background/Aims Beginning in April 2019, non-invasive vagus nerve stimulation was included in the NHS Innovation and Technology Payment programme. The programme guaranteed reimbursement of at least a 3-month course of treatment using gammaCore, through a prescription refill card, authorised by a headache specialist for patients with cluster headache who reported a clinically meaningful benefit. This study evaluated prescribing and refill trends to assess the use of gammaCore in England since the beginning of this programme. Methods Data regarding gammaCore prescriptions and refills from 1 April 2019 to 31 December 2020 were collected and tabulated. Patients were categorised into three groups: those who initiated gammaCore therapy under the programme (new starters), those who were prescribed ≥1 refill, and those who were prescribed ≥2 refills. One refill corresponds to 3 months of gammaCore therapy. Results In total, 52 NHS sites submitted 2092 prescriptions for gammaCore devices, including 655 for new starters. Among new starters, 46.3% received ≥1 refill and 30.9% received ≥2 refills. Those who started using gammaCore after its inclusion in the Innovation and Technology Payment programme received up to seven refills during the data collection period, representing 21 months of therapy. Conclusions This is one of the largest clinical audits of patients with cluster headache. Patients' continued use of gammaCore treatment through multiple 3-month refills in this audit suggests that non-invasive vagus nerve stimulation is efficacious, tolerable and practical for patients with cluster headache.

We present a case study article demonstrating successful implementation of ultrasound guided extra cardiac vagus nerve stimulation during cardioneuroablation. To our knowledge it is first published description of this technique, as most ECVS are done in the internal jugular vein bulb area. This method allows for reduction of fluoroscopy time, and most importantly reproducible vagus nerve capture especially after full bi-nodal (sinus and atrioventricular) cardioneuroablation when stimulation of vagus nerve may not give any effect in the heart. This article includes a case study with “dual component” atrioventricular block, where functional component is cured with cardioneuroablation, but structural (PR elongation) remains after procedure.

OBJECTIVE A systematic review and meta-analysis was performed to determine the efficacy of non-invasive neuromodulation modalities for the treatment of acute migraine. BACKGROUND Although pharmacological treatments are the gold standard for the management of acute migraine, some patients may require non-pharmacological treatment options. Non-invasive neuromodulation may provide an alternative, and techniques include transcranial magnetic stimulation (TMS), non-invasive vagal nerve stimulation (nVNS), non-painful remote electrical stimulation (NRES), and external trigeminal nerve stimulation (e-TNS). METHODS This systematic review and meta-analysis was performed following PRISMA guidelines. We searched PUBMED, EMBASE, ClinicalTrials.gov, Cochrane Center Register of Controlled Trials, and LILACS databases. We included randomized controlled clinical trials studying patients with migraine treated with any form of non-invasive neuromodulation. Primary outcome was pain freedom within 2 h post-treatment. Secondary outcomes were pain relief within 2-h post-treatment and sustained pain freedom and sustained pain relief 48 h post-treatment. RESULTS Pooled analysis demonstrated a significant effect of non-invasive neuromodulation on pain-free rates within 2 h (RR, 1.66; 95% CI, 1.35 to 2.05; P

Purpose Surgery initiates pro-inflammatory mediator cascades leading to a variably pronounced sterile inflammation (SIRS). SIRS is associated with intestinal paralysis and breakdown of intestinal barrier and might result in abdominal sepsis. Technological progress led to the development of a neurostimulator for transcutaneous auricular vagal nerve stimulation (taVNS), which is associated with a decline in inflammatory parameters and peristalsis improvement in rodents and healthy subjects via activation of the cholinergic anti-inflammatory pathway. Therefore, taVNS might be a strategy for SIRS prophylaxis. Methods The NeuroSIRS-Study is a prospective, randomized two-armed, sham-controlled, double-blind clinical trial. The study is registered at DRKS00016892 (09.07.2020). A controlled endotoxemia is used as a SIRS-mimicking model. 2 ng/kg bodyweight lipopolysaccharide (LPS) will be administered after taVNS or sham stimulation. The primary objective is a reduction of clinical symptoms of SIRS after taVNS compared to sham stimulation. Effects of taVNS on release of inflammatory cytokines, intestinal function, and vital parameters will be analyzed. Discussion TaVNS is well-tolerated, with little to no side effects. Despite not fully mimicking postoperative inflammation, LPS challenge is the most used experimental tool to imitate SIRS and offers standardization and reproducibility. The restriction to healthy male volunteers exerts a certain bias limiting generalizability to the surgical population. Still, this pilot study aims to give first insights into taVNS as a prophylactic treatment in postoperative inflammation to pave the way for further clinical trials in patients at risk for SIRS. This would have major implications for future therapeutic approaches.

Neural desynchronization was shown as a key mechanism of vagus nerve stimulation (VNS) action in epilepsy, and EEG synchronization measures are explored as possible response biomarkers. Since brain functional organization in sleep shows different synchrony and network properties compared to wakefulness, we aimed to explore the effects of acute VNS on EEG-derived measures in the two different states of vigilance. EEG epochs were retrospectively analyzed from twenty-four VNS-treated epileptic patients (11 responders, 13 non-responders) in calm wakefulness and stage N2 sleep. Weighted Phase Lag Index (wPLI) was computed as connectivity measure of synchronization, for VNS OFF and VNS ON conditions. Global efficiency (GE) was computed as a network measure of integration. Ratios OFF/ON were obtained as desynchronization/de-integration index. Values were compared between responders and non-responders, and between EEG states. ROC curve and area-under-the-curve (AUC) analysis was performed for response classification. In responders, stronger VNS-induced theta desynchronization (p < 0.05) and decreased GE (p < 0.05) were found in sleep, but not in wakefulness. Theta sleep wPLI Ratio OFF/ON yielded an AUC of 0.825, and 79% accuracy as a response biomarker if a cut-off value is set at 1.05. Considering all patients, the VNS-induced GE decrease was significantly more important in sleep compared to awake EEG state (p < 0.01). In conclusion, stronger sleep EEG desynchronization in theta band distinguishes responders to VNS therapy from non-responders. VNS-induced reduction of network integration occurs significantly more in sleep than in wakefulness., SCOPUS: ar.j, info:eu-repo/semantics/published

Vagal nerve stimulation (VNS) has a strong pathophysiological rationale as a potentially beneficial treatment for heart failure with reduced ejection fraction. Despite several promising preclinical studies and pilot clinical studies, the two large, controlled trials-NECTAR-HF and INOVATE-HF-failed to demonstrate the expected benefit. It is likely that clinical application of VNS in phase III studies was performed before a sufficient degree of understanding of the complex pathophysiology of autonomic electrical modulation had been achieved, therefore leading to an underestimation of its potential benefit. More knowledge on the complex dose-response issue of VNS (i.e., pulse amplitude, frequency, duration and duty cycle) has been gathered since these trials and a new randomized study is currently underway with an adaptive design and a refined approach in an attempt to deliver the proper dose to a more selected group of patients.Für die Vagusnervstimulation (VNS) als einer sinnvollen Therapie bei Herzinsuffizienz bestehen starke pathophysiologische Argumente. Trotz mehrerer vielversprechender präklinischer und Pilotstudien konnten die beiden großen kontrollierten Studien NECTAR-HF und INOVATE-HF den erwarteten klinischen Nutzen jedoch nicht zeigen. Vermutlich wurde hierbei die klinische Anwendung dieser Therapie durchgeführt, bevor die komplexe Pathophysiologie der autonomen elektrischen Modulation ausreichend verstanden worden war, sodass diese Studien nicht in der Lage waren, das Potenzial der VNS zu demonstrieren. Seit diesen Studien wurde mehr Wissen über die klinische Anwendung der VNS erlangt, insbesondere zur Patientenselektion und zur Art der Stimulation („Dosis“, d. h. Amplitude, Impulsfrequenz [Hz], Dauer der Anwendung und Arbeitszyklus der VNS). Eine neue randomisierte Studie mit einem adaptiven Design wird aktuell durchgeführt, um die Fragen nach der optimalen Dosis der VNS zu beantworten.

PurposeThis review aimed to provide a complete overview of the current stance and recent developments in antiarrhythmic neuromodulatory interventions, focusing on lifethreatening vetricular arrhythmias.MethodsBoth preclinical studies and clinical studies were assessed to highlight the gaps in knowledge that remain to be answered and the necessary steps required to properly translate these strategies to the clinical setting.ResultsCardiac autonomic imbalance, characterized by chronic sympathoexcitation and parasympathetic withdrawal, destabilizes cardiac electrophysiology and promotes ventricular arrhythmogenesis. Therefore, neuromodulatory interventions that target the sympatho-vagal imbalance have emerged as promising antiarrhythmic strategies. These strategies are aimed at different parts of the cardiac neuraxis and directly or indirectly restore cardiac autonomic tone. These interventions include pharmacological blockade of sympathetic neurotransmitters and neuropeptides, cardiac sympathetic denervation, thoracic epidural anesthesia, and spinal cord and vagal nerve stimulation.ConclusionNeuromodulatory strategies have repeatedly been demonstrated to be highly effective and very promising anti-arrhythmic therapies. Nevertheless, there is still much room to gain in our understanding of neurocardiac physiology, refining the current neuromodulatory strategic options and elucidating the chronic effects of many of these strategic options.

We aimed to describe the experience of a large single-center cohort for the clinical, radiological, and genetic characteristics, as well as to determine the efficacy of different anti-epileptic strategies in children and adults with tuberous sclerosis complex (TSC). We carried out a historical cohort study on 91 TSC patients treated in a single center between 2008 and 2018. Our cohort comprised 46 males and 45 females, with a median age of 15.6 years at the last follow-up. Mean follow-up time was 2.5 ± 0.75–5.5 years (range 0–9.5 years). Of those tested, a disease-causing mutation was identified in 90% of patients, 53% in TSC2, and 37% in TSC1. Epilepsy prevalence was similar among TSC1 and TSC2 mutated patients. The most common radiological finding were cortical tubers in 95% of patients, while subependymal giant cell astrocytoma (SEGA) were detected in 36% of patients. Notably, infantile spasms (IS) were diagnosed in 29%, with SEGA representing the only finding significantly different in prevalence between those with and without IS (62% vs. 28%, respectively, p = 0.009). Lastly, we did not find any difference in efficacy between three anti-epileptic treatments: Vagus nerve stimulation (VNS), CBD-based products, and the ketogenic diet, all showing approximately 30%–40% response rates. Altogether, we provide a comprehensive description of our experience in treating TSC, which could serve to expand current knowledge of the disease and its treatments.

By enhancing vagal activity, auricle transcutaneous electric nerve stimulation (TENS) is developed as a non-invasive therapy for heart failure. Nevertheless, though shoulder TENS used for treating adhesive capsulitis could affect vagal tone, its potential impact on heart functions remains unclear. In this study, electrocardiogram (ECG) and heart rate (HR) of subjects in response to sham, right-sided, or left-sided shoulder TENS (TENS-S, TENS-R, and TENS-L, respectively; 5 min) were recorded and analyzed. During the stimulation period, TENS-R constantly and TENS-L transiently decreased the HR of subjects; both TENS-R and TENS-L increased powers of the low- and high-frequency spectra. While TENS-R exhibiting no effect, TENS-L increased the ratio of low/high-frequency power spectrum indicating TENS-R decreased the HR through potentiating cardiac vagal tone. Collectively, these results suggest TENS could be an early and non-invasive therapy for heart failure patients before considering implant devices or devices are not feasible; moreover, therapists/physicians need to carefully monitor the potential adverse events during treatment for patient safety.Trial registration: The study protocol was registered in ClinicalTrials.gov (NCT03982472; 11/06/2019).

Purpose Autonomic regulation therapy (ART) for heart failure (HF) is delivered using vagus nerve stimulation (VNS), and has been associated with improvement in cardiac function and HF symptoms. VNS is delivered using an implantable pulse generator (IPG) and a lead placed around the cervical vagus nerve. Because HF patients may receive concomitant cardiac defibrillation therapy, testing was conducted to determine the effect of defibrillation (DF) on VNS system performance. Methods Normal swine (n = 4) with VNS system implants on the right cervical vagus nerve received sequential defibrillation shocks with three defibrillation systems: an implantable cardioverter defibrillator (ICD), a subcutaneous ICD (S-ICD), and an external cardioverter defibrillator (ECD). Each system delivered a series of bipolar high-energy shocks and reverse-polarity high-energy shocks. Results The specified cardiac defibrillation shocks were delivered successfully from each of the three defibrillation systems to all animals. After each shock series, interrogation of the IPG confirmed that software and data were unchanged from pre-programmed values. After all of the defibrillation shocks were delivered, the IPGs underwent and passed comprehensive electrical testing demonstrating proper system function. No shifts in IPG parameters or ART system failures were observed, and histologic evaluation of the vagus nerve revealed no anatomic changes. Conclusions Implantable VNS systems were tested in vivo for immunity to defibrillation via ICD, S-ICD, and ECD, and were found to be unaffected by a series of high-energy defibrillation shocks. These results confirm that ART systems are capable of continuing to function after defibrillation and the cervical vagus nerve is anatomically unaffected.

Epilepsy as a common neurological disease is mostly managed effectively with antiepileptic medications. One-third of patients do not respond to medical treatments requiring alternative therapies. Vagus nerve stimulation (VNS) has been used in the last decades for the treatment of medically resistant epilepsy. Despite the extensive use of VNS in these patients, factors associated with clinical outcomes of VNS remain to be elucidated. In this study, we evaluated factors affecting VNS outcomes in epileptic patients to have a better understanding of patients who are better candidates for VNS therapy. Several databases including PubMed, Scopus, and Google Scholar were searched through June 2020 for relevant articles. The following factors were assessed in this review: previous surgical history, age at implantation and gender, types of epilepsy, duration of epilepsy, age at epilepsy onset, frequency of attacks, antiepileptic drugs, VNS parameters, EEG findings, MRI findings, and biomarkers. Literature data show that nonresponder rates range between 25% and 65%. Given the complexity and diversity of factors associated with response to VNS, more clinical studies are needed to establish better paradigm for selection of patients for VNS therapy.

Neuromodulation alters neuronal activity with electrical impulses delivered to the targeted neurologic sites. The various neuromodulation options available today for epilepsy management have proven efficacy primarily in adult trials. These include open-loop stimulation with invasive vagus nerve stimulation and deep brain stimulation, as well as closed-loop responsive neurostimulation. The use of neurostimulation therapy to treat intractable epilepsy in children is growing. This article reviews the literature, historical background, and current principles in pediatric patients.

According to the Centers for Disease Control and Prevention (CDC), traumatic brain injury (TBI) is the leading cause of loss of consciousness, long-term disability, and death in children and young adults (age 1 to 44). Currently, there are no United States Food and Drug Administration (FDA) approved pharmacological treatments for post-TBI regeneration and recovery, particularly related to permanent disability and level of consciousness. In some cases, long-term disorders of consciousness (DoC) exist, including the vegetative state/unresponsive wakefulness syndrome (VS/UWS) characterized by the exhibition of reflexive behaviors only or a minimally conscious state (MCS) with few purposeful movements and reflexive behaviors. Electroceuticals, including non-invasive brain stimulation (NIBS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS) have proved efficacious in some patients with TBI and DoC. In this review, we examine how electroceuticals have improved our understanding of the neuroanatomy of consciousness. However, the level of improvements in general arousal or basic bodily and visual pursuit that constitute clinically meaningful recovery on the Coma Recovery Scale-Revised (CRS-R) remain undefined. Nevertheless, these advancements demonstrate the importance of the vagal nerve, thalamus, reticular activating system, and cortico-striatal-thalamic-cortical loop in the process of consciousness recovery.

OBJECTIVE Posttraumatic stress disorder (PTSD) is a disabling condition affecting a large segment of the population; however, current treatment options have limitations. New interventions that target the neurobiological alterations underlying symptoms of PTSD could be highly beneficial. Transcutaneous cervical (neck) vagal nerve stimulation (tcVNS) has the potential to represent such an intervention. The goal of this study was to determine the effects of tcVNS on neural responses to reminders of traumatic stress in PTSD. METHODS Twenty-two participants were randomized to receive either sham (n = 11) or active (n = 11) tcVNS stimulation in conjunction with exposure to neutral and personalized traumatic stress scripts with high-resolution positron emission tomography scanning with radiolabeled water for brain blood flow measurements. RESULTS Compared with sham, tcVNS increased brain activations during trauma scripts (p < .005) within the bilateral frontal and temporal lobes, left hippocampus, posterior cingulate, and anterior cingulate (dorsal and pregenual), and right postcentral gyrus. Greater deactivations (p < .005) with tcVNS were observed within the bilateral frontal and parietal lobes and left thalamus. Compared with tcVNS, sham elicited greater activations (p < .005) in the bilateral frontal lobe, left precentral gyrus, precuneus, and thalamus, and right temporal and parietal lobes, hippocampus, insula, and posterior cingulate. Greater (p < .005) deactivations were observed with sham in the right temporal lobe, posterior cingulate, hippocampus, left anterior cingulate, and bilateral cerebellum. CONCLUSIONS tcVNS increased anterior cingulate and hippocampus activation during trauma scripts, potentially indicating a reversal of neurobiological changes with PTSD consistent with improved autonomic control.Trial Registration: No. NCT02992899.

Summary Objectives/hypothesis This study investigated behavioral management of dysphonia and laryngeal dyspnea secondary to use of vagal nerve stimulation (VNS) in an individual with medically refractory epilepsy. Study design Retrospective chart review. Methods Medical records from a single patient were reviewed. The patient received treatment with the speech-language pathologist (SLP) and laryngologist to observe patterns of laryngeal hyperfunction using biofeedback, and treatment with the SLP to learn to perform rescue breathing techniques, relaxation techniques, and awareness of muscle tension to aid the control of symptoms during activation. Data collected included neurology and laryngology notes. Neurology notes were used to track VNS settings, tolerance, and incidence of seizures. Laryngology notes included documentation of diagnosis, treatment, and measures of patient perception of severity (ie, Voice Handicap Index, Dyspnea Index, Cough Severity Index). Results Prior to treatment, the patient was unable to receive benefits from VNS due to severe laryngeal adverse effects, such that the device remained off for eight months postimplantation. Following treatment, the patient effectively managed laryngeal side effects and was able to tolerate increases in VNS output current, signal frequency, and duration. Conclusions Voice therapy was effective in managing changes in vocal fold mobility and laryngeal tension. As the number of individuals receiving VNS for epilepsy and inflammatory conditions increases, the SLP and laryngologist may play a key role in interdisciplinary management of laryngeal side effects secondary to vagal nerve stimulation.

Objective To observe the influence of transcutaneous auricular vagus nerve stimulation (taVNS) on fasting plasma glucose (FPG) and serum insulin (INS) in Zucker diabetes fatty (ZDF) rats and explore the regulatory effect of taVNS on blood glucose in ZDF rats. Methods A total of 20 male ZDF rats were randomized into a model group and a taVNS group, 10 rats in each one. Besides, the other 10 Zucker Lean (ZL) rats were selected to be a control group. The rats in the control group were fed with common forage and those in the model group and the taVNS group were fed with high-sugar and high-fat forage. The intervention of electric stimulation was applied in the rats of taVNS group, with 2/15 Hz in frequency, disperse-dense wave and 2 mA in intensity. Each intervention lasted 30 min, once a day, consecutively for 12 weeks. No any intervention was given in the control group and the model group. The body mass and FPG level were recorded once every 2 weeks in the rats. After the experiment, the rats were sacrificed and blood sample was collected. Enzyme linked immunosorbent assay (ELISA) was adopted to determine the level of serum INS in the rats. Results After the modeling, compared with the control group, the body mass and FPG level were all higher (P Conclusion taVNS apparently improves in hyperglycemia in ZDF rats and increases serum insulin concentration in the rats.

Drug resistant epilepsy (DRE) is defined as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily dose. Despite the increasing number of available ASD, about a third of patients with epilepsy still suffer from drug resistance. Several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy, including epilepsy onset in the infancy, intellectual disability, symptomatic epilepsy and abnormal neurological exam. Pharmacological management often consists in ASD polytherapy. However, because quality of life is driven by several factors in patients with DRE, including the tolerability of the treatment, ASD management should try to optimize efficacy while anticipating the risks of drug-related adverse events. All patients with DRE should be evaluated at least once in a tertiary epilepsy center, especially to discuss eligibility for non-pharmacological therapies. This is of paramount importance in patients with drug resistant focal epilepsy in whom epilepsy surgery can result in long-term seizure freedom. Vagus nerve stimulation, deep brain stimulation or cortical stimulation can also improve seizure control. Lastly, considering the effect of DRE on psychologic status and social integration, comprehensive care adaptations are always needed in order to improve patients’ quality of life.

The aim of this study was to evaluate the effects of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) on systemic inflammatory responses in patients with drug-resistant epilepsy (DRE). Twenty-two Finnish patients with ANT-DBS implantation were enrolled in this pilot study. Changes in plasma interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were examined using generalized estimating equation models at seven time points (before DBS surgery and 1, 2, 3, 6, 9 and 12 months after implantation). In the whole group, the IL-6/IL-10 ratio decreased significantly over time following ANT-DBS, while the decrease in IL-6 levels and increase in IL-10 levels were not significant. In the responder and nonresponder groups, IL-6 levels remained unchanged during the follow-up. Responders had significantly lower pre-DBS IL-10 levels before the ANT-DBS treatment than nonresponders, but the levels significantly increased over time after the treatment. In addition, responders had a higher pre-DBS IL-6/IL-10 ratio than nonresponders, and the ratio decreased for both groups after treatment, but the decrease did not reach the level of statistical significance. The rate of decrease in the ratio per month tended to be higher in responders than in nonresponders. These results may highlight the anti-inflammatory properties of ANT-DBS treatment associated with its therapeutic effectiveness in patients with DRE. Additional studies are essential to evaluate the potential of the proinflammatory cytokine IL-6, the anti-inflammatory cytokine IL-10, and their ratio as biomarkers to evaluate the therapeutic response to DBS treatment, which could facilitate treatment optimization.

Objective Vagus nerve stimulator (VNS) implantation is an established therapy for pharmacoresistant epilepsy that is not amenable to curative epilepsy surgery. Historically, VNS implantation has been performed by neurosurgeons, but otolaryngologist involvement is increasingly common. In this retrospective study, we aimed to evaluate the efficacy and safety of VNS implantation in children and adolescents from the otolaryngologists’ perspective. Methods This study included children and adolescents who had undergone VNS implantation at the study center between 2014 and 2018. Patient files were analyzed with regards to the durations of device implantation and hospitalization, postoperative complications, and clinical outcome, including seizure frequency, clinical global impression of improvement (CGI-I) score, and quality of life (QoL). Results A total of 73 children underwent VNS surgery. The median age at implantation was 9.3 ± 4.6 years, and median epilepsy duration before VNS surgery was 6 ± 4 years. Lennox–Gastaut syndrome was the most common syndrome diagnosis (62.3%), and structural abnormalities (49.3%) the most frequent etiology. Operation times ranged from 30 to 200 min, and median postoperative hospitalization length was 2 ± 0.9 days. No complications occurred, except for four revisions and two explantations due to local infections (2.7%). Among our patients, 76.7% were responders (≥ 50% reduction in seizure frequency), 72.1% showed improved CGI-I scores, and 18.6–60.5% exhibited considerable improvements in the QoL categories energy, emotional health, and cognitive functions. Conclusion Our results indicate that VNS implantation is a highly effective and safe treatment option for children and adolescents with AED-refractory epilepsies who are not candidates for curative epilepsy surgery.

Cel pracy:Celem pracy była ocena bezpieczeństwa i skuteczności przezskórnej stymulacji nerwu błędnego (taVNS) jako metody dodanej do standardowej farmakoterapii w grupie pacjentów z depresją lekooporną.Materiał i metodyPrezentujemy wyniki badania pilotażowego obejmującego wykorzystanie dostępnych na rynku przezskórnych stymulatorów nerwu błędnego. Dzięki zewnętrznemu, nieinwazyjnemu charakterowi rozwiązania, pacjent unika możliwych powikłań interwencji chirurgicznej. taVNS jest stosunkowo nową, nieinwazyjną metodą VNS, której działanie wynika z tego, że na powierzchni ucha jest umiejscowiona uszna gałąź nerwu błędnego. Grupa pilotażowa składała się z 5 pacjentów cierpiących na depresję lekooporną. U wszystkich pacjentów rozpoznano depresję o nasileniu ciężkim, pomimo co najmniej 2 pełnych kuracji lekiem przeciwdepresyjnym w odpowiedniej dawce nie wystąpiła u nich reakcja na leczenie. Zakładany czas obserwacji wynosił 12 tygodni. Czas trwania stymulacji wynosił 4 godziny dziennie, podzielone na 2 sesje dziennie. Stan psychiczny oceniano podczas badania z wykorzystaniem Skali Oceny Depresji Hamiltona (HAMD-17) i Sali Ogólnego Wrażenia Klinicznego (CGI).WynikiW 2 przypadkach zaobserwowano znaczącą poprawę stanu psychicznego (istotne zmniejszenie punktacji w skalach, poprawę nastroju i napędu, zmniejszenie lęku). W 3 przypadkach pacjenci zrezygnowali z badania z powodu trudności w obsłudze urządzenia.WnioskiStymulacja nerwu błędnego może stanowić istotny postęp w terapii przewlekłych i opornych na leczenie zaburzeń depresyjnych. Przezskórna stymulacja wydaje się bezpieczniejszą alternatywą dla wcześniej stosowanych metod wymagających chirurgicznego wszczepienia stymulatora. Wyniki leczenia można zaobserwować po kilku tygodniach lub nawet kilku miesiącach terapii. Ze względu na możliwe długoterminowe korzyści i działania niepożądane związane ze stymulacją taVNS konieczne są dalsze badania kliniczne w celu oceny skuteczności i bezpieczeństwa tej metody.

Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is characterized by hypothalamus-pituitary-adrenal axis dysfunction. As the neuroendocrinological axis has been shown to react under the regulation of the central nerve system through the corticotropin-releasing factor (CRF) releasing from the hypothalamic paraventricular nucleus. Whether one of the neuromodulation therapies, vagus nerve stimulation, is able to treat this neuroendocrinological disorder remains unknown. In this study, we explored the effects of vagus nerve stimulation (VNS) on CRF-induced serum ACTH level change in normal rats. After the vagus nerve electrode placement, the ACTH and corticosterone levels were measured multiple times before and after the administration of CRF (2 μg/kg) in switched-ON and -OFF groups, respectively, compared to the control group. Our results showed that 2 h continuous stimulation on the vagus nerve inhibited CRF-induced ACTH release up to 1 h compared with the control group, while the corticosterone level was not influenced. The vagus nerve might be a potential therapeutic target in the treatment of ACTH-dependent Cushing's syndrome disorders involving hypothalamus-pituitary-adrenal axis dysfunction.

With the large number of VNS implants performed worldwide, the need for removal or replacement of the device in selected cases is emerging, this removal or replacement of VNS can be challenging.To describe the feasibility and safety of revising vagal nerve stimulation surgery in terms of the indications, surgical techniques, and outcomes.A retrospective study, a series of eight cases with VNS implants that needed revision surgery have been reviewed, four devices were completely removed and four were only revised. The revision surgery was performed after a range of 7 months to 6 years, due to different reasons. Initial surgeries and revisions were performed at the otolaryngology department in a major tertiary center.We concluded that the previously implanted vagal nerve stimulation electrodes can be completely removed without any significant sequelae on the nerve. It may also be re-implanted safely at the previously used segment of the vagus nerve with a similar outcome in seizure control as the initial implantation.

The autonomic nervous system plays an important role in maintaining homeostasis in organisms. Recent studies have shown that it also controls inflammation by directly altering the function of the immune system. The cholinergic anti-inflammatory pathway (CAP) is one of the neural circuits operating through the vagus nerve. Acetylcholine released from the terminal of the vagus nerve, which is a parasympathetic nerve, acts on the α7 nicotinic acetylcholine receptor of macrophages and reduces inflammation in the body. Previous animal studies demonstrated that vagus nerve stimulation reduced renal ischemia–reperfusion injury. Furthermore, restraint stress and pulsed ultrasound had similar protective effects against kidney injury, which were mainly thought to be mediated by the CAP. Using optogenetics, which can stimulate specific nerves, it was also revealed that activation of the CAP by restraint stress was mediated by C1 neurons in the medulla oblongata. Nevertheless, there still remain many unclear points regarding the role of the nervous and immune systems in controlling renal diseases, and further research is needed.

Objective Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments. Methods We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information. Results We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI. Conclusion Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.

Background Transcutaneous auricular Vagus Nerve Stimulation (taVNS) is a non-invasive neuromodulation technique that may constitute an effective treatment for a wide range of neurological, psychiatric, and medical conditions. One key challenge in taVNS research is the high interindividual response variability. To gain an understanding of this variability, reliable biomarkers for taVNS responsiveness would be highly desirable. In this study, we investigated physiological candidate biomarkers while systematically varying stimulation conditions and observing physiological state characteristics. Methods Forty-four healthy young adults received taVNS and sham-stimulation. Subjects were pseudo-randomly assigned to stimulation of the left or right ear. Each subject underwent six blocks of stimulation. Across blocks, respiration-locking (inhalation-locked taVNS vs. exhalation-locked taVNS vs. sham) and the electrode location (tragus vs. cymba conchae) were varied. We analyzed heart rate (HR), various heart rate variability (HRV) scores, and neuro-cardiac coupling (NCC), indexed by the relationship between electroencephalographic delta power and heartbeat length. Results We observed an effect of taVNS on HR and HRV scores during, but not after stimulation. The direction of the effects was consistent with parasympathetic activation. We did not observe any systematic influence of the stimulation conditions that we varied. However, we found baseline NCC scores to be significant predictors for the individual effect of taVNS on HRV scores. Conclusion Cardiac effects of taVNS indicate parasympathetic activation. These effects were short lived, which might explain that some previous studies were unable to detect them. We propose NCC as a novel candidate biomarker for responsiveness to taVNS.

Objective Patients with drug‐resistant epilepsy (DRE) pose considerable management challenges for patients, their families, and providers. Both the vagus nerve stimulator (VNS) and the ketogenic diet (KD) have been shown to be safe and effective in treating DRE. Nevertheless, information is lacking regarding treatment with combination of both modalities. This study reports the efficacy and tolerability of combining VNS and KD in a pediatric cohort with intractable epilepsy. Methods This is a retrospective review of 33 patients (0‐17 years) with DRE treated with VNS and KD at a single pediatric level IV epilepsy center. We compared seizure reduction rates for each patient at baseline and at every clinic visit for 24 months after adding the second nonpharmacological therapy. The frequency of adverse events on the combined therapy was collected to assess safety and tolerability. Results There were a total of 170 visits for all patients while on the combined therapy. At 88% (95% CI: 83%‐93%) of the visits, patients reported some reduction in seizure frequency. The proportion of patients reporting a greater than 50% seizure reduction over all visits was 62% (95% CI: 55%‐69%). The proportion of a patient's visits with at least a greater than 50% reduction in seizure frequency had a median of 71% (IQR 33%‐100%). Continued improvement was seen over time of combined treatment; for every one‐unit time unit change (one month), there was a 6% increase in the odds of having a reduction in seizure frequency of >50% (OR = 1.06, 95% CI: 1.01‐1.11). Significance This study shows that combining the VNS and KD in patients with drug‐resistant epilepsy is well tolerated and reduces seizure frequency more than either one modality used alone and that the benefits in terms of seizure reduction continue to increase with the length of treatment.

Purpose Vagus nerve stimulation (VNS) is an effective and well-known treatment for drug resistant epilepsy (DRE) patients since 1997, yet prediction of treatment response before implantation is subject of ongoing research. Neuroimaging and neurophysiological studies investigating the vagal afferent network in resting state documented that differences in between epilepsy patients were related to treatment response. This study investigated whether an event-related parameter, pre-ictal heart rate variability (HRV) is associated with response to VNS therapy. Methods DRE patients underwent video-electroencephalography (EEG) recording before VNS implantation. HRV parameters (time, non-linear and frequency domain) were assessed for every seizure during two 10 min timeframes: baseline (60 min before seizure onset) and pre-ictal (10 min before seizure onset). Pre-ictal HRV parameter alterations were correlated with VNS response after one year of VNS therapy and seizure characteristics (temporal/extratemporal, left/right or bilateral). Results 104 seizures from 22 patients were evaluated. Eleven patients were VNS responders with a seizure frequency reduction of ≥ 50 % after one year of VNS. In VNS responders no changes in HRV parameters were found while in VNS non-responders the time domain and non-linear HRV variables decreased significantly (p = 0.024, p = 0.005, p = 0.005) during the pre-ictal time frame. 10/11 VNS non-responders had a seizure lateralization to the left compared to 4/11 VNS responders. Conclusion VNS non-responders were characterized by a significant decrease of pre-ictal HRV (time domain/non-linear variables) suggesting a sudden autonomic imbalance probably due to an impaired central autonomic function that makes it at the same time unlikely to respond to VNS.

Context The parasympathetic-mediated inflammatory reflex inhibits excessive proinflammatory cytokine production. Noninvasive techniques, including occipitoatlantal decompression (OA-D) and transcutaneous auricular vagus nerve stimulation (taVNS), have been demonstrated to increase parasympathetic tone. Objectives To test the hypothesis that OA-D and taVNS increase parasympathetic nervous system activity and inhibit proinflammatory cytokine mobilization and/or production. Methods Healthy adult participants were randomized to receive OA-D (5 min of OA-D followed by 10 min of rest; n=8), taVNS (15 min; n=9), or no intervention (15 min, time control; n=10) on three consecutive days. Before and after these interventions, saliva samples were collected for determination of the cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α). Arterial blood pressure and the electrocardiogram were recorded for a 30-min baseline, throughout the intervention, and during a 30-min recovery period to derive heart rate and blood pressure variability markers as indices of vagal and sympathetic control. Results OA-D and taVNS increased root mean square of successive RR interval differences (RMSSD) and high frequency heart rate variability, which are established markers for parasympathetic modulation of cardiac function. In all three groups, the experimental protocol was associated with a significant increase in salivary cytokine concentrations. However, the increase in IL-1β was significantly less in the taVNS group (+66 ± 13 pg/mL; p2 after OA-D vs. 28 ± 5 mmHg2 before OA-D; p Conclusions Both OA-D and taVNS elicited antiinflammatory responses that were associated with increases in heart rate variability-derived markers for parasympathetic function. These findings suggest that OA-D and taVNS activate the parasympathetic antiinflammatory reflex. Furthermore, an antihypertensive effect was observed with OA-D that may be mediated by reduced sympathetic modulation of vascular tone and/or increased baroreceptor reflex sensitivity.

Lennox-Gastaut syndrome (LGS) is a severe form of childhood onset epilepsy in which patients require multiple medications and may be candidates for palliative surgical intervention. In this meta-analysis, we sought to evaluate the impact of palliative vagus nerve stimulation (VNS), corpus callosotomy (CC), and resective surgery (RS) by analyzing their impact on seizure control, antiepileptic drug (AED) usage, quality of life (QOL), behavior, cognition, prognostic factors, and complications. A systematic search of PubMed MEDLINE, Scopus, and Cochrane Database of Systematic Reviews was performed to find articles that met the following criteria: (1) prospective/retrospective study with original data, (2) at least one LGS surgery patient aged less than 18 years, and (3) information on seizure frequency reduction (measured as percentage, Engel class, or qualitative comment). Seizures were analyzed quantitatively in a meta-analysis of proportions and a random-effects model, whereas other outcomes were analyzed qualitatively. Forty studies with 892 LGS patients met the selection criteria, with 19 reporting on CC, 17 on VNS, four on RS, two on RS + CC, one on CC + VNS, and one on deep brain stimulation. CC seizure reduction rate was 74.1% (95% confidence interval [CI] = 64.5%-83.7%), and VNS was 54.6% (95% CI = 42.9%-66.3%), which was significantly different (p < .001). RS seizure reduction was 88.9% (95% CI = 66.1%-99.7%). Many VNS patients reported alertness improvements, and most had no major complications. VNS was most effective for atonic/tonic seizures; higher stimulation settings correlated with better outcomes. CC patients reported moderate cognitive and QOL improvements; disconnection syndrome, transient weakness, and respiratory complications were noted. Greater callosotomy extent correlated with better outcomes. AED usage most often did not change after surgery. RS showed considerable QOL improvements for patients with localized seizure foci. In the reported literature, CC appeared to be more effective than VNS for seizure reduction. VNS may provide a similar or higher level of QOL improvement with lower aggregate risk of complications. Patient selection, anatomy, and seizure type will inform decision-making.

Context Management of atrial fibrillation includes either rhythm control that aims at establishing a sinus rhythm or rate control that aims at lowering the ventricular rate, usually with atrioventricular nodal blocking agents. Another potential strategy for ventricular rate control is to induce a negative dromotropic effect by augmenting cardiac vagal activity, which might be possible through noninvasive and nonpharmacologic techniques. Thus, the hypothesis of this study was that occipitoatlantal decompression (OA-D) and transcutaneous auricular vagus nerve stimulation (taVNS) not only increase cardiac parasympathetic tone as assessed by heart rate variability (HRV), but also slow atrioventricular conduction, assessed by the PQ-interval of the electrocardiogram (EKG) in generally healthy study participants without atrial fibrillation. Objectives To test whether OA-D and/or transcutaneous taVNS, which have been demonstrated to increase cardiac parasympathetic nervous system activity, would also elicit a negative dromotropic effect and prolong atrioventricular conduction. Methods EKGs were recorded in 28 healthy volunteers on three consecutive days during a 30 min baseline recording, a 15 min intervention, and a 30 min recovery period. Participants were randomly assigned to one of three experimental groups that differed in the 15 min intervention. The first group received OA-D for 5 min, followed by 10 min of rest. The second group received 15 min of taVNS. The intervention in the third group that served as a time control group (CTR) consisted of 15 min of rest. The RR- and PQ-intervals were extracted from the EKGs and then used to assess HRV and AV-conduction, respectively. Results The OA-D group had nine participants (32.1%), the taVNS group had 10 participants (35.7%), and the CTR group had nine participants (32.1%). The root mean square of successive differences between normal heartbeats (RMSSD), an HRV measure of cardiac parasympathetic modulation, tended to be higher during the recovery period than during the baseline recording in the OA-D group (mean ± standard error of the mean [SEM], 54.6 ± 15.5 vs. 49.8 ± 15.8 ms; p Conclusions The lengthening of the PQ-interval in the OA-D and taVNS groups was accompanied by an increase in RMSSD. This implies that the negative dromotropic effects of OA-D and taVNS are mediated through an increase in cardiac parasympathetic tone. Whether these findings suggest their utility in controlling ventricular rates during persistent atrial fibrillation remains to be determined.

BackgroundMood plays an important role in our life which is illustrated by the disruptive impact of aberrant mood states in depression. Although vagus nerve stimulation (VNS) has been shown to improve symptoms of depression, the exact mechanism is still elusive, and it is an open question whether non-invasive VNS could be used to swiftly and robustly improve mood.MethodsHere, we investigated the effect of left- and right-sided transcutaneous auricular VNS (taVNS)v.a sham control condition on mood after the exertion of physical and cognitive effort in 82 healthy participants (randomized cross-over design) using linear mixed-effects and hierarchical Bayesian analyses of mood ratings.ResultsWe found that 90 min of either left-sided or right-sided taVNS improved positive mood [b= 5.11, 95% credible interval, CI (1.39–9.01), 9.6% improvement relative to the mood intercept, BF10= 7.69,pLME= 0.017], yet only during the post-stimulation phase. Moreover, lower baseline scores of positive mood were associated with greater taVNS-induced improvements in motivation [r= −0.42, 95% CI (−0.58 to −0.21), BF10= 249].ConclusionsWe conclude that taVNS boosts mood after a prolonged period of effort exertion with concurrent stimulation and that acute motivational effects of taVNS are partly dependent on initial mood states. Collectively, our results show that taVNS may help quickly improve affect after a mood challenge, potentially by modulating interoceptive signals contributing to the reappraisal of effortful behavior. This suggests that taVNS could be a useful add-on to current behavioral therapies.

Nicolaides–Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via “Network Therapy of Rare Epilepsies (NETRE)” and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.

Purpose Disturbed autonomic function is implicated in high mortality rates in heart failure patients. High-intensity vagus nerve stimulation therapy was shown to improve intrinsic heart rate recovery and left ventricular ejection fraction over a period of 1 year. Whether these beneficial effects are sustained across multiple years and are related to improved baroreceptor response was unknown. Methods All patients (n = 21) enrolled in the ANTHEM-HF clinical trial (NCT01823887, registered 4/3/2013) with 24 h ambulatory electrocardiograms at all time points and 54 normal subjects (PhysioNet database) were included. Intrinsic heart rate recovery, based on ~ 2000 spontaneous daily activity-induced heart rate acceleration/deceleration events per patient, was analyzed at screening and after 12, 24, and 36 months of chronic vagus nerve stimulation therapy (10 or 5 Hz, 250 μs pulse width, 18% duty cycle, maximum tolerable current amplitude). Results In response to chronic high-intensity vagus nerve stimulation (≥ 2.0 mA), intrinsic heart rate recovery (all time points, p p ≤ 0.02), and left ventricular ejection fraction (all, p ≤ 0.04) were improved over screening at 12, 24, and 36 months. Intrinsic heart rate recovery and heart rate turbulence slope were inversely correlated at both screening (r = 0.67, p r = 0.78, p Conclusion This non-randomized study provides evidence of an association between improvement in intrinsic heart rate recovery and left ventricular ejection fraction during high-intensity vagus nerve stimulation for a period of ≥ 3 years. Correlated favorable effects on heart rate turbulence slope implicate enhanced baroreceptor function in response to chronic, continuously cyclic vagus nerve stimulation as a physiologic mechanism.

Patients with heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF) experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased mortality risk. The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) trial reported improved heart rate variability (HRV) and heart rate turbulence (HRT) and reduced T-wave alternans (TWA) after 12 months of vagus nerve stimulation (VNS). We investigated whether the benefits of chronic VNS persist in the long term.Effects of chronic VNS on heart rate, HRV, HRT, TWA, R-wave and T-wave heterogeneity (RWH, TWH), and nonsustained ventricular tachycardia (NSVT) incidence were evaluated in all ANTHEM-HF patients with ambulatory ECG data at 24 and 36 months (n = 25). Autonomic markers improved significantly at 24 and 36 months compared to baseline [heart rate, square root of the mean squared differences of successive normal-to-normal intervals (rMSSD), standard deviation of the normal-to-normal intervals (SDNN), HF-HRV, HRT slope, P0.05]. Peak TWA levels remained reduced at 24 and 36 months (P0.0001). Reductions in RWH and TWH at 6 and 12 months persisted at 24 and 36 months (P0.01). NSVT decreased at 12, 24, and 36 months (P0.025). No sudden cardiac deaths, ventricular fibrillation, or sustained ventricular tachycardia occurred.In symptomatic patients with HFrEF, chronic VNS appears to confer wide-ranging, persistent improvements in autonomic tone (HRV), baroreceptor sensitivity (HRT), and cardiac electrical stability (TWA, RWH, TWH).

Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient's lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%-68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%-78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat-OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a 'one size fits all' approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.

Purpose Viral encephalitis (VE) or bacterial meningoencephalitis (BME) in early childhood may cause brain injury and neurological sequelae, including epilepsy. Postencephalitic epilepsy (PEE) characterized by epileptic spasms (ES) is a rare but serious condition; there is an urgent need to develop new methods to evaluate the characteristics of these children and select appropriate treatments. Methods We conducted an observational study of 20 patients (11 males, 9 females) who experienced ES after VE or BME at the Chinese PLA General Hospital. Patients were followed up for over 12 months, and outcomes were analyzed. Results The median ages at the onset of encephalitis and ES were 5.5 and 11.5 months, respectively. The median age at follow-up was 35.5 months. Sixteen (80 %) patients developed drug-resistant epilepsy (DRE), including all 12 patients with VE and 4 of 8 patients with BME. Epileptiform discharges were detected on electroencephalography, including 15 patients with hypsarrhythmia and 5 without. Fifteen of the patients were treated with a 14-day intravenous infusion of adrenocorticotropic hormone (ACTH) at a dose 2.5 U/kg (≤25 U); 12 showed a short-term response but 10 experienced recurrence. Three patients received vigabatrin, and none of these patients responded to treatment. Six patients started a ketogenic diet (KD); five failed to respond and the outcome was not known in one. Four patients were treated by vagus nerve stimulation (VNS), and all showed a partial response. Conclusion Children with PEE characterized by ES are more likely to develop DRE. The prognosis was worse for patients with VE compared to those with BME. Clarifying the efficacies of treatments involving ACTH (low-dose), KD, vigabatrin, and VNS will require further investigation.

Sensory and sympathetic nerves have been shown to promote the progression of endometriosis through the release of neuromediators and the lesional activation of respective receptors. The role of vagus nerves (VN) in lesional progression, however, is completely unclear, despite the signs suggestive of increased sympathetic tone in women with endometriosis. This study was undertaken to investigate whether VN plays any role in the progression of endometriosis. We recruited 45 patients with endometriosis and 42 healthy women, who were given electrocardiogram test and their heart rate variability was evaluated. In addition, three prospective, and randomized mouse experiments were conducted that evaluated, respectively, the effect of vagotomy, the effect of VN stimulation (VNS), and the therapeutic potential of VNS after the endometriosis was well established. All lesions were excised, weighed, and processed for immunohistochemistry and histochemistry analysis of select markers for lesional progression and fibrosis. We found that endometriosis patients exhibited reduced vagal activity as compared with controls, indicative of disrupted autonomic balance. Vagotomy increased while VNS decreased the lesion weight as compared with control mice, concomitant with more progressive and retarded lesion development and fibrogenesis, respectively. In addition, VNS demonstrated promising therapeutic effect, as evidenced by significantly reduced lesion weight, more attenuated lesional progression concomitant with improved hyperalgesia. Taken together, our data indicate that VN activity may play a dampening role in the progression of endometriosis. Consequently, boosting the VN activity may have therapeutic potentials for patients with endometriosis.