Optimizing Dosing of Vagus Nerve Stimulation for Stroke Recovery.

Vagus nerve stimulation (VNS) paired with rehabilitative training enhances recovery of function in models of stroke and is currently under investigation for use in chronic stroke patients. Dosing is critical in translation of pharmacological therapies, but electrical stimulation therapies often fail to comprehensively explore dosing parameters in preclinical studies. Varying VNS parameters has non-monotonic effects on plasticity in the central nervous system, which may directly impact efficacy for stroke. We sought to optimize stimulation intensity to maximize recovery of motor function in a model of ischemic stroke. The study design was preregistered prior to beginning data collection (DOI: https://doi.org/10.17605/OSF.IO/BMJEK ). After training on an automated assessment of forelimb function and receiving an ischemic lesion in motor cortex, rats were separated into groups that received rehabilitative training paired with VNS at distinct stimulation intensities (sham, 0.4 mA, 0.8 mA, or 1.6 mA). Moderate-intensity VNS at 0.8 mA enhanced recovery of function compared with all other groups. Neither 0.4 mA nor 1.6 mA VNS was sufficient to improve functional recovery compared with equivalent rehabilitation without VNS. These results demonstrate that moderate-intensity VNS delivered during rehabilitation improves recovery and defines an optimized intensity paradigm for clinical implementation of VNS therapy.

Is Noninvasive Vagus Nerve Stimulation a Safe and Effective Alternative to Medication for Acute Migraine Control?

BACKGROUND: Noninvasive neuromodulation devices have been used for a variety of headache disorders, including cluster and migraine, since recently being cleared by the Federal Drug Administration. Although these devices have been touted as low-risk options for improved headache control, the data behind actual efficacy endpoints remain unclear. OBJECTIVE: To critically assess current evidence regarding the efficacy of the noninvasive vagus nerve stimulator (nVNS) device for acute migraine management. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions.Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of headache. RESULTS: A randomized, double-blind, sham-controlled clinical trial was selected for critical appraisal. In this trial, the primary endpoint (pain freedom at 120 min after use of nVNS for first acute migraine attack) was not met when compared with sham device (30.4% for nVNS vs. 19.7% for sham; P=0.067). However, there were statistically significant differences found for various secondary endpoints favoring nVNS, such as pain freedom rates at 30 and 60 minutes, pain relief at 120 minutes, and mean percentage pain score reduction rates at 60 and 120 minutes. CONCLUSIONS: When comparing nVNS with sham, no statistically significant differences were found with regards to the primary endpoint of pain freedom at 120 minutes, although differences were found with various secondary endpoints and post hoc analysis. nVNS is likely a safe alternative to medications.

A proposed guideline for vagus nerve stimulator handling in palliative care and after death.

Vagus nerve stimulation (VNS) is often used for patients with drug-resistant epilepsy. Although this intervention may improve seizure control and mood, a number of factors must be considered when patients with VNS near end of life. We reviewed relevant literature to create a proposed guideline for management of patients with VNS in palliative care and after death. VNS has multiple possible side effects, including cough and swallowing difficulties. For patients with neurologic disease in palliative care, such adverse effects can severely affect quality of life and increase the risk for complications such as aspiration pneumonia. Patients with VNS should be screened regularly for such side effects, and VNS parameters should be adjusted if they are identified. If a patient requires urgent cardiac resuscitation involving external defibrillation, the VNS should be interrogated immediately afterwards to evaluate its function. During defibrillation, paddles should be placed perpendicular to the VNS, and as far as possible away from it. The VNS can be acutely turned off by taping the magnet to the patient's chest, thereby preventing any possible interference with restoration of a normal heart rhythm. After death, any staff involved with handling the body should be notified that a VNS is in place. The device must be removed prior to cremation, as it can explode with high heat. If the cause of death is unclear, a full postmortem examination should be undertaken, per sudden unexpected death in epilepsy guidelines. If there is concern about device malfunction, the device should be returned to the manufacturer for evaluation.

Design and validation of a closed-loop, motor-activated auricular vagus nerve stimulation (MAAVNS) system for neurorehabilitation.

BACKGROUND: Studies have found that pairing vagus nerve stimulation (VNS) with motor activity accelerates cortical reorganization. This synchronous pairing may enhance motor recovery. OBJECTIVE: To develop and validate a motor-activated auricular vagus nerve stimulation (MAAVNS) system as a potential neurorehabilitation tool. METHODS: We created MAAVNS and validated its function as part of an ongoing clinical trial investigating whether taVNS-paired rehabilitation enhances oromotor learning. We compared 3 different MAAVNS EMG electrode configurations in 3 neonates. The active lead was placed over the buccinator muscle. Reference lead placements were orbital, temporal or frontal. RESULTS: The frontal reference lead produced the highest sensitivity (0.87 ± 0.07 (n = 8)) and specificity (0.64 ± 0.13 (n = 8)). Oral sucking reliably triggers MAAVNS stimulation with high confidence. CONCLUSION: EMG electrodes placed on target orofacial muscles can effectively trigger taVNS stimuli in infants in a closed loop fashion.

Comparison of DSSP and tSSS algorithms for removing artifacts from vagus nerve stimulators in magnetoencephalography data.

OBJECTIVE: Large-amplitude artifacts from vagus nerve stimulator (VNS) implants for refractory epilepsy affect magnetoencephalography (MEG) recordings and are difficult to reject, resulting in unusable data from this important population of patients who are frequently evaluated for surgical treatment of epilepsy. Here we compare the performance of two artifact removal algorithms for MEG data: dual signal subspace projection (DSSP) and temporally extended signal space separation (tSSS). APPROACH: Each algorithm's performance was first evaluated in simulations. We then tested the performance of each algorithm on resting-state MEG data from patients with VNS implants. We also examined how each algorithm improved source localization of somatosensory evoked fields in patients with VNS implants. MAIN RESULTS: DSSP and tSSS algorithms have a similar ability to reject interference in both simulated and real MEG data if the origin location for tSSS is appropriately set. If the origin set for tSSS is inappropriate, the signal after tSSS can be distorted due to a mismatch between the internal region and the actual source space. Both DSSP and tSSS are able to remove large-amplitude artifacts from outside the brain. DSSP might be a better choice than tSSS when the choice of origin location for tSSS is difficult. SIGNIFICANCE: Both DSSP and tSSS algorithms can recover distorted MEG recordings from people with intractable epilepsy and VNS implants, improving epileptic spike identification and source localization of both functional activity and epileptiform activity.

Effect of vagus nerve stimulation on blood glucose concentration in epilepsy patients - Importance of stimulation parameters.

In previous animal experiments, we demonstrated that cervical vagus nerve stimulation (VNS) inhibits pancreatic insulin secretion, thereby raises blood glucose levels, and impairs glucose tolerance through afferent signaling. However, there are no reports suggesting that similar effects occur in patients treated with chronic cervical VNS for epilepsy. In contrast to clinical VNS used for epilepsy, where the stimulation is intermittent with cycles of on and off periods, stimulation was continuous in our previous animal experiments. Thus, we hypothesized that the timing of the stimulation on/off cycles is critical to prevent impaired glucose tolerance in epilepsy patients chronically treated with cervical VNS. We conducted a retrospective analysis of medical records from patients with epilepsy. Blood glucose levels did not differ between patients treated with pharmacotherapy only (98 ± 4 mg/dL, n = 16) and patients treated with VNS plus pharmacotherapy (99 ± 3 mg/dL, n = 24, duration of VNS 4.5 ± 0.5 years). However, a multiple linear correlation analysis of patients with VNS demonstrated that during the follow-up period of 7.9 ± 0.7 years, blood glucose levels increased in patients with long on and short off periods, whereas blood glucose did not change or even decreased in patients that were stimulated with short on and long off periods. We conclude that chronic cervical VNS in patients with epilepsy is unlikely to induce glucose intolerance or hyperglycemia with commonly used stimulation parameters. However, stimulation on times of longer than 25 sec may bear a risk for hyperglycemia, especially if the stimulation off time is shorter than 200 sec.

ReStore: A wireless peripheral nerve stimulation system.

BACKGROUND: The growing use of neuromodulation techniques to treat neurological disorders has motivated efforts to improve on the safety and reliability of implantable nerve stimulators. NEW METHOD: The present study describes the ReStore system, a miniature, implantable wireless nerve stimulator system that has no battery or leads and is constructed using commercial components and processes. The implant can be programmed wirelessly to deliver charge-balanced, biphasic current pulses of varying amplitudes, pulse widths, frequencies, and train durations. Here, we describe bench and in vivo testing to evaluate the operational performance and efficacy of nerve recruitment. Additionally, we also provide results from a large-animal chronic active stimulation study assessing the long-term biocompatibility of the device. RESULTS: The results show that the system can reliably deliver accurate stimulation pulses through a range of different loads. Tests of nerve recruitment demonstrate that the implant can effectively activate peripheral nerves, even after accelerated aging and post-chronic implantation. Biocompatibility and hermeticity tests provide an initial indication that the implant will be safe for use in humans. COMPARISON WITH EXISTING METHOD(S): Most commercially available nerve stimulators include a battery and wire leads which often require subsequent surgeries to address failures in these components. Though miniaturized battery-less stimulators have been prototyped in academic labs, they are often constructed using custom components and processes that hinder clinical translation. CONCLUSIONS: The results from testing the performance and safety of the ReStore system establish its potential to advance the field of peripheral neuromodulation.

The emerging role of gammaCore® in the management of cluster headache: expert panel recommendations.

A panel of 9 experts, including neurologists, other headache specialists, and medical and pharmacy directors, from 4 health plans (1 integrated delivery network and 3 plans with commercial, Medicare, and Medicaid lines of business), convened to discuss cluster headache (CH). Topics covered included the current treatment landscape, treatment challenges, economic impact of disease, and gaps in care for patients with CH. One major challenge in the management of CH is that it is underrecognized and frequently misdiagnosed, leading to delays in and suboptimal treatment for patients who suffer from this painful and disabling condition. The management of CH is challenging due to the lack of a robust evidence base for preventive treatment, the adverse events (AEs) associated with conventional preventive treatments, the variability of response to acute treatments, and the challenging reimbursement landscape for well-accepted treatments (eg, oxygen). The lack of effective prevention for many patients may lead to the excessive use of acute therapies, often multiple times each day, which drives the cost of illness up significantly. The goal of the panel discussion was to discuss the role of gammaCore, the recently released first non-invasive vagus nerve stimulation (nVNS) therapy in the acute treatment of patients with episodic CH (eCH), in the management of CH. The panel reviewed current practices and formulated recommendations on incorporating a newly released therapy into CH management. The panel explored the role of traditional management strategies as well as that of gammaCore in the acute treatment of patients with eCH. Resources that may be useful in the treatment of patients with CH were also discussed.

Neurostimulation Devices for the Treatment of Neurologic Disorders.

Rapid advancements in neurostimulation technologies are providing relief to an unprecedented number of patients affected by debilitating neurologic and psychiatric disorders. Neurostimulation therapies include invasive and noninvasive approaches that involve the application of electrical stimulation to drive neural function within a circuit. This review focuses on established invasive electrical stimulation systems used clinically to induce therapeutic neuromodulation of dysfunctional neural circuitry. These implantable neurostimulation systems target specific deep subcortical, cortical, spinal, cranial, and peripheral nerve structures to modulate neuronal activity, providing therapeutic effects for a myriad of neuropsychiatric disorders. Recent advances in neurotechnologies and neuroimaging, along with an increased understanding of neurocircuitry, are factors contributing to the rapid rise in the use of neurostimulation therapies to treat an increasingly wide range of neurologic and psychiatric disorders. Electrical stimulation technologies are evolving after remaining fairly stagnant for the past 30 years, moving toward potential closed-loop therapeutic control systems with the ability to deliver stimulation with higher spatial resolution to provide continuous customized neuromodulation for optimal clinical outcomes. Even so, there is still much to be learned about disease pathogenesis of these neurodegenerative and psychiatric disorders and the latent mechanisms of neurostimulation that provide therapeutic relief. This review provides an overview of the increasingly common stimulation systems, their clinical indications, and enabling technologies.

Neuromodulation in refractory epilepsy: Brazilian specialists consensus.

Epilepsy is a potentially devastating brain disorder characterized by a predisposition to spontaneous epileptic seizures. In patients with medically refractory epilepsy, new non-pharmacological therapeutic approaches may be considered. In this scenario, palliative surgery such as vagus nerve stimulation (VNS) or deep brain stimulation (DBS) may be indicated in a subset of patients. In this paper we make recommendations for the use of VNS and DBS in patients in Brazil with refractory epilepsy.

Neuromodulation in refractory epilepsy: Brazilian specialists consensus / Neuromodulação em epilepsia refratária: consenso dos especialistas brasileiros

ABSTRACT Epilepsy is a potentially devastating brain disorder characterized by a predisposition to spontaneous epileptic seizures. In patients with medically refractory epilepsy, new non-pharmacological therapeutic approaches may be considered. In this scenario, palliative surgery such as vagus nerve stimulation (VNS) or deep brain stimulation (DBS) may be indicated in a subset of patients. In this paper we make recommendations for the use of VNS and DBS in patients in Brazil with refractory epilepsy.

RESUMO Epilepsia é uma doença cerebral potencialmente devastadora caracterizada por predisposição em gerar crises epilépticas espontâneas. Em pacientes com epilepsia refratária novas abordagens terapêuticas, não farmacológicas, podem ser consideradas. Neste cenário, cirurgias paliativas, como a estimulação do nervo vago (VNS) ou estimulação cerebral profunda (DBS) podem ser indicadas em um subgrupo de pacientes. Neste trabalho sugerimos recomendações sobre as indicações de uso do VNS e do DBS em pacientes com epilepsia refratária no Brasil.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 4. Neurostimulation Treatments.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Neurostimulation Treatments" is the fourth of six sections of the 2016 guidelines. RESULTS: Evidence-informed responses were developed for 31 questions for 6 neurostimulation modalities: 1) transcranial direct current stimulation (tDCS), 2) repetitive transcranial magnetic stimulation (rTMS), 3) electroconvulsive therapy (ECT), 4) magnetic seizure therapy (MST), 5) vagus nerve stimulation (VNS), and 6) deep brain stimulation (DBS). Most of the neurostimulation treatments have been investigated in patients with varying degrees of treatment resistance. CONCLUSIONS: There is increasing evidence for efficacy, tolerability, and safety of neurostimulation treatments. rTMS is now a first-line recommendation for patients with MDD who have failed at least 1 antidepressant. ECT remains a second-line treatment for patients with treatment-resistant depression, although in some situations, it may be considered first line. Third-line recommendations include tDCS and VNS. MST and DBS are still considered investigational treatments.

Decision analysis of intracranial monitoring in non-lesional epilepsy.

PURPOSE: Up to one third of epilepsy patients develop pharmacoresistant seizures and many benefit from resective surgery. However, patients with non-lesional focal epilepsy often require intracranial monitoring to localize the seizure focus. Intracranial monitoring carries operative morbidity risk and does not always succeed in localizing the seizures, making the benefit of this approach less certain. We performed a decision analysis comparing three strategies for patients with non-lesional focal epilepsy: (1) intracranial monitoring, (2) vagal nerve stimulator (VNS) implantation and (3) medical management to determine which strategy maximizes the expected quality-adjusted life years (QALYs) for our base cases. METHOD: We constructed two base cases using parameters reported in the medical literature: (1) a young, otherwise healthy patient and (2) an elderly, otherwise healthy patient. We constructed a decision tree comprising strategies for the treatment of non-lesional epilepsy and two clinical outcomes: seizure freedom and no seizure freedom. Sensitivity analyses of probabilities at each branch were guided by data from the medical literature to define decision thresholds across plausible parameter ranges. RESULTS: Intracranial monitoring maximizes the expected QALYs for both base cases. The sensitivity analyses provide estimates of the values of key variables, such as the surgical risk or the chance of localizing the focus, at which intracranial monitoring is no longer favored. CONCLUSION: Intracranial monitoring is favored over VNS and medical management in young and elderly patients over a wide, clinically-relevant range of pertinent model variables such as the chance of localizing the seizure focus and the surgical morbidity rate.

Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology.

OBJECTIVE: To evaluate the evidence since the 1999 assessment regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients >12 years. METHODS: We reviewed the literature and identified relevant published studies. We classified these studies according to the American Academy of Neurology evidence-based methodology. RESULTS: VNS is associated with a >50% seizure reduction in 55% (95% confidence interval [CI] 50%-59%) of 470 children with partial or generalized epilepsy (13 Class III studies). VNS is associated with a >50% seizure reduction in 55% (95% CI 46%-64%) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies). VNS is associated with an increase in ≥ 50% seizure frequency reduction rates of ≈ 7% from 1 to 5 years postimplantation (2 Class III studies). VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies). Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio 3.4, 95% CI 1.0-11.2). VNS is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy. VNS may have improved efficacy over time. RECOMMENDATIONS: VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after VNS implantation.

Vagus nerve stimulator in patients with epilepsy: indications and recommendations for use.

Epilepsy comprises a set of neurologic and systemic disorders characterized by recurrent spontaneous seizures, and is the most frequent chronic neurologic disorder. In patients with medically refractory epilepsy, therapeutic options are limited to ablative brain surgery, trials of experimental antiepileptic drugs, or palliative surgery. Vagal nerve stimulation is an available palliative procedure of which the mechanism of action is not understood, but with established efficacy for medically refractory epilepsy and low incidence of side-effects. In this paper we discuss the recommendations for VNS use as suggested by the Brazilian League of Epilepsy and the Scientific Department of Epilepsy of the Brazilian Academy of Neurology Committee of Neuromodulation.

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response.

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.

Neurostimulation for primary headache disorders: Part 2, review of central neurostimulators for primary headache, overall therapeutic efficacy, safety, cost, patient selection, and future research in headache neuromodulation.

This article is the second of 2 articles reviewing neurostimulation for primary headaches. In Part 1, we described methods, pathophysiology and anatomy, and history of neuromodulation in the treatment of headache, as well as reviewing the literature on peripheral neuromodulation for primary headaches. Peripheral targets for stimulation include percutaneous nerves, transcranial holocephalic, occipital nerves, auriculotemporal nerves, supraorbital nerves, cervical epidural, and sphenopalatine ganglia. In Part 2, we describe available literature on central neuromodulation in primary headaches. Central stimulation targets include vagus nerve and deep brain structures. Part 2 also analyzes overall therapeutic efficacy, safety, cost, patient selection, and recommendations for further research of neurostimulation modalities based on available data.