Vagus Nerve Stimulation Therapy Research Articles

Patient Characteristics Associated with Seizure Freedom after Vagus Nerve Stimulation in Pediatric Intractable Epilepsy: An Analysis of “Super-Responders”

AbstractClinical responses to vagus nerve stimulation (VNS) therapy for intractable epilepsy can be unpredictable, and factors that predict response to therapy are elusive. Minority of children undergoing VNS achieve seizure freedom. The current study aimed to characterize this exceptional patient population, defined as “super-responders” (SRs). Retrospective data were collected from 150 children who underwent VNS at a single pediatric institution. The patients' mean age at VNS device implantation was 12.0 years (range, 3.09–17.9 years). Ten SRs (6.7%) were identified who achieved and maintained seizure freedom for longer than 1 year following implantation. The interval between epilepsy onset and VNS device implantation was significantly shorter in SRs than in the other children (mean epilepsy duration 5.72 vs. 8.44 years, respectively; p = 0.032). SRs also had a significantly shorter proportion of life with epilepsy compared with the other children (mean ratio of epilepsy duration to age at implantation 0.52 vs. 0.71, respectively; p = 0.023). SRs reported their seizure freedom relatively early (six patients within 6 months and all patients within 12 months after implantation) at relatively low device settings (mean output current 0.81 mA at their last follow-up). Compared with conventional models, responsive VNS models with autostimulation features did not increase the ratio of SRs. No other clinical or imaging characteristic difference between SRs and the other children was found in this cohort. The current study showed a significant association between shorter epilepsy duration and shorter proportion of life with epilepsy and seizure freedom after VNS.

Vagus nerve stimulation: a 20-year Australian experience.

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 2years 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. 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. In this extended follow-up cohort (76 patients, 7.2 ± 5.3years), 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. 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.

Local activation of \u03b12 adrenergic receptors is required for vagus nerve stimulation induced motor cortical plasticity

Vagus nerve stimulation (VNS) paired with rehabilitation training is emerging as a potential treatment for improving recovery of motor function following stroke. In rats, VNS paired with skilled forelimb training results in significant reorganization of the somatotopic cortical motor map; however, the mechanisms underlying this form of VNS-dependent plasticity remain unclear. Recent studies have shown that VNS-driven cortical plasticity is dependent on noradrenergic innervation of the neocortex. In the central nervous system, noradrenergic α2 receptors (α2-ARs) are widely expressed in the motor cortex and have been critically implicated in synaptic communication and plasticity. In current study, we examined whether activation of cortical α2-ARs is necessary for VNS-driven motor cortical reorganization to occur. Consistent with previous studies, we found that VNS paired with motor training enlarges the map representation of task-relevant musculature in the motor cortex. Infusion of α2-AR antagonists into M1 blocked VNS-driven motor map reorganization from occurring. Our results suggest that local α2-AR activation is required for VNS-induced cortical reorganization to occur, providing insight into the mechanisms that may underlie the neuroplastic effects of VNS therapy.

Vagus nerve stimulation in patients receiving maintenance therapy with electroconvulsive therapy: a series of 10 cases

OBJECTIVES Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management of difficult-to-treat depression. However, frequent acute courses of ECT or prolonged maintenance ECT treatment may increase adverse-effect burden and/or reduce patient acceptability. Therefore, we investigated the effectiveness of adjunctive vagus nerve stimulation (VNS) therapy as an alternative strategy for long-term maintenance treatment in ECT-responsive patients. METHODS This retrospective chart review identified maintenance ECT patients with unipolar (n = 5) and bipolar depression (n = 5) from 2 large hospital systems who had a history of ECT response, but the patients had significant residual incapacitating symptoms or increasing concerns regarding the burden associated with ECT and opted to receive adjunctive VNS therapy. The patients were followed for 2 years after VNS implantation. Response and remission were defined as Clinical Global Impression-Severity scale scores of ≤2 and 1, respectively, obtained at 1- and 2-year postimplantation compared with just before VNS implantation. RESULTS One-year postimplantation, 6 of 10 had responded of which 5 met remission criteria. All 10 patients benefited from adjunctive VNS therapy with either fewer hospitalizations and/or ECT sessions. Seven of 10 stopped maintenance ECT by the end of year 1; an additional patient stopped maintenance ECT by year 2. No patients required an acute course of ECT during the 2-year follow-up. There was a statistically significant reduction (P < 0.0001) in mean (SD) Clinical Global Impression-Severity scale scores between baseline (5.4 [0.51]) and the 1-year postimplantation (2.1 [1.37]) time points, and between baseline and the 2-year postimplantation (2.3 [1.16]) time points, whereas no difference existed between the 1- and 2-year postimplantation time points. CONCLUSIONS Vagus nerve stimulation therapy may be a useful maintenance strategy in patients with difficult-to-treat depression receiving maintenance ECT.

The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: a 5-year prospective registry

Abstract Background: To compare illness characteristics, treatment history, response and durability, and suicidality scores over a 5-year period in patients with treatment-resistant bipolar depression participating in a prospective, multicenter, open-label registry and receiving Vagus Nerve Stimulation Therapy (VNS Therapy) plus treatment-as-usual (VNS + TAU) or TAU alone. Methods: Response was defined as ≥ 50% decrease from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Response was retained while MADRS score remained ≥ 40% lower than baseline. Time-to-events was estimated using Kaplan-Meier (KM) analysis. Suicidality was assessed using the MADRS Item 10 score. Results: At baseline the VNS + TAU group (N = 97) had more episodes of depression, psychiatric hospitalizations, lifetime suicide attempts and higher suicidality score, more severe symptoms (based on MADRS and other scales), and higher rate of prior electroconvulsive therapy than TAU group (N = 59). Lifetime use of medications was similar between the groups (a mean of 9). Over 5 years, 63% (61/97) in VNS + TAU had an initial response compared with 39% (23/59) in TAU. The time-to-initial response was significantly quicker for VNS + TAU than for TAU (p < 0.03). The mean reduction in suicidality score across the study visits was significantly greater in the VNS + TAU than in the TAU group (p < 0.001). Conclusions: The patients who received VNS + TAU included in this analysis had severe bipolar depression that had proved extremely difficult to treat. The TAU comparator group were similar though had slightly less severe illnesses on some measures and had less history of suicide attempts. Treatment with VNS + TAU was associated with a higher likelihood of attaining a response compared to TAU alone. VNS + TAU was also associated with a significantly greater mean reduction in suicidality. Keywords: Bipolar disorder, Depression, Vagus Nerve Stimulation Therapy, VNS TRD Registry

A prospective, multi-center randomized, controlled, blinded trial of vagus nerve stimulation for difficult to treat depression: A novel design for a novel treatment

Abstract Few treatment options exist for patients with difficult-to-treat depression (DTD). One potentially efficacious treatment is vagus nerve stimulation (VNS): chronic stimulation of the vagus nerve using an implanted stimulator. Given a series of recent VNS clinical studies, including a large, five-year naturalistic investigation, the Center for Medicare and Medicaid Services (CMS) reconsidered the previous non coverage determination and announced coverage for patients participating in a “coverage with evidence” trial. This study, entitled, A PRospective, Multi-cEnter, Randomized Controlled Blinded Trial DemOnstrating the Safety and Effectiveness of VNS Therapy® System as AdjunctivE Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER), includes DTD patients with at least four unsuccessful antidepressant treatments in the current episode and will randomize both unipolar and bipolar DTD participants, each up to 500 evaluable enrollees. Predetermined interim analyses will define the necessary sample size. All participants will be implanted with VNS devices: half receive active stimulation during year one, and half receive delayed stimulation after year one. Participants will be followed for 5 years. This RCT is unique for DTD studies: 1) large sample size and long study duration (one year of controlled comparison); 2) use of a percent time in response as the primary outcome measure, given the chronic illness and its fluctuating course (vis-a-vis meeting a response criteria at a single time point); 3) inclusion of diverse measures of VNS impact on function, including quality of life, degree of disability, health status, and suicidality.

Pre-implant Heart Activity Differs in Responders and Non-responders to Vagal Nerve Stimulation Therapy in Epileptic Patients.

Vagal Nerve Stimulation (VNS) is used to treat patients with pharmacoresistant epilepsy. However, generally accepted tools to predict VNS response do not exist. Here we examined two heart activity measures - mean RR and pNN50 and their complex behavior during activation in pre-implant measurements. The ECG recordings of 73 patients (38 responders, 36 non-responders) were examined in a 30-sec floating window before (120 sec), during (2x120 sec), and after (120 sec) the hyperventilation by nose and mouth. The VNS response differentiation by pNN50 was significant (min p=0.01) in the hyperventilation by a nose with a noticeable descendant trend in nominal values. The mean RR was significant (p=0.01) in the rest after the hyperventilation by mouth but after an approximately 40-sec delay.Clinical Relevance- Our study shows that pNN50 and mean RR can be used to distinguish between VNS responders and non-responders. However, details of dynamic behavior showed how this ability varies in tested measurement segments.

Effects of Vagus Nerve Stimulation following Corpus Callosotomy for Patients with Drug-Resistant Epilepsy.

Objective: The effectiveness of vagus nerve stimulation (VNS) for residual seizures after corpus callosotomy (CC) has not yet been fully investigated. We hypothesized that seizure control would be improved by VNS after CC. The purpose of this study was to compare seizure frequency between patients with implantation of a VNS generator (post-VNS group) or without VNS (non-post-VNS group) following CC. Methods: We retrospectively reviewed patients who underwent CC between January 2009 and May 2019 in our institution. We evaluated proportions of ≥50% reduction in seizure frequency (responders) and seizure reduction rate 1 and 2 years after VNS. To investigate factors related to responders, uni- and multivariate logistic regression analyses were performed regarding age, number of anti-seizure medications (ASMs), addition of novel ASMs (levetiracetam, lacosamide or perampanel), and post-VNS or non-post-VNS status. Results: Thirteen post-VNS patients and 24 non-post-VNS patients were analyzed in this study. Responder rate at 1 year after VNS differed significantly between the post-VNS group (53.9%) and non-post-VNS group (12.5%, p = 0.017). Number of ASMs at the time of CC and post-VNS were significantly associated with responders in univariate analyses (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13–0.88, p = 0.025 and OR 8.2, 95%CI 1.6–41.6, p = 0.011, respectively), whereas age, sex, seizure frequency, and addition of novel ASMs were not. In multivariate analysis, the presence of VNS procedures after CC was the only factor favorably associated with responder status (OR 82.2, 95%CI 1.55–4355.7, p = 0.03). Conclusions: VNS therapy after CC may increase the proportion of responders independent of the addition of novel ASMs.

Severe autonomic nervous system imbalance in Lennox-Gastaut syndrome patients demonstrated by heart rate variability recordings

ObjectivePatients diagnosed with Lennox Gastaut syndrome (LGS), an epileptic encephalopathy characterized by usually drug resistant generalized and focal seizures, are often considered as candidates for vagus nerve stimulation (VNS). Recent research shows that heart rate variability (HRV) differs in epilepsy patients and is related to VNS treatment response. This study investigated pre-ictal HRV in generalized onset seizures of patients with LGS in correlation with their VNS response. MethodsIn drug resistant epilepsy (DRE) patients diagnosed with LGS video-electroencephalography recording was performed during their pre-surgical evaluation. Six HRV parameters (time and-, frequency domain, non-linear parameters) were evaluated for every seizure in epochs of 10 min at baseline (60 to 50 min before seizure onset) and pre-ictally (10 min prior to seizure onset). The results were correlated to VNS response after one year of VNS therapy. ResultsSeven patients and 31 seizures were included, two patients were classified as VNS responders (≥ 50 % seizure reduction). No difference in pre-ictal HRV parameters between VNS responders and VNS non-responders could be found, but high frequency (HF) power, reflecting the parasympathetic tone increased significantly in the pre-ictal epoch in both VNS responders and VNS non-responders (p = 0.017, p = 0.004). SignificanceIn this pilot data pre-ictal HRV did not differ in VNS responders compared to VNS non-responders, but showed a significant increase in HF power – a parasympathetic overdrive - in both VNS responders and VNS non-responders. This sudden autonomic imbalance might have an influence on the cardiovascular system in the ictal period. Generalized tonic-clonic seizures are regarded as the main risk factor for SUDEP and severe seizure-induced autonomic imbalance may play a role in the pathophysiological pathway.

Vagus Nerve Stimulation Elicits Sleep EEG Desynchronization and Network Changes in Responder Patients in Epilepsy.

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 EEGstate (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.

Anterior Nucleus of the Thalamus Deep Brain Stimulation with Concomitant Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

The Food and Drug Administration approved the deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) as an adjunctive therapy for drug-resistant epilepsy (DRE) in the United States in 2018. The DBS Therapy for Epilepsy Post-Approval Study is further evaluating the safety and effectiveness of ANT-DBS among different patients' groups. For this study, devices for vagus nerve stimulation (VNS) must be removed prior to enrolment. To investigate the outcomes of concomitant ANT-DBS and VNS treatment for DRE. A retrospective analysis was performed for 33 patients who underwent ANT-DBS using previous VNS to define distinct subgroups: standard ANT-DBS (9 subjects), ANT-DBS with functional VNS (12 subjects), and ANT-DBS with the VNS implantable pulse generator explanted or turned off at the time of the DBS (12 subjects). Effectiveness and safety data were analyzed across the whole population and among subgroups. A mean decrease in seizure frequency of 55% was observed after a mean follow-up of 25.5 mo. Approximately 67% of patients experienced ≥50% reduction in seizure frequency. Seizure reduction percentage was not significantly different among groups. Approximately 50% of subjects with no appreciable improvement and 75% of those who showed benefit after VNS (including improvement in seizure frequency, seizure severity, and seizure duration or quality of life) achieved a seizure reduction ≥50% after ANT-DBS surgery. There were no complications related to concomitant VNS and ANT-DBS. ANT-DBS for DRE provides excellent results despite previous and ongoing VNS therapy. Removal of VNS does not appear to be necessary before ANT-DBS.

Evolution of the Vagus Nerve Stimulation (VNS) Therapy System Technology for Drug-Resistant Epilepsy

The vagus nerve stimulation (VNS) Therapy® System is the first FDA-approved medical device therapy for the treatment of drug-resistant epilepsy. Over the past two decades, the technology has evolved through multiple iterations resulting in software-related updates and implantable lead and generator hardware improvements. Healthcare providers today commonly encounter a range of single- and dual-pin generators (models 100, 101, 102, 102R, 103, 104, 105, 106, 1000) and related programming systems (models 250, 3000), all of which have their own subtle, but practical differences. It can therefore be a daunting task to go through the manuals of these implant models for comparison, some of which are not readily available. In this review, we highlight the technological evolution of the VNS Therapy System with respect to device approval milestones and provide a comparison of conventional open-loop vs. the latest closed-loop generator models. Battery longevity projections and an in-depth examination of stimulation mode interactions are also presented to further differentiate amongst generator models.

Vagus Nerve Stimulation Therapy for the Treatment of Seizures in Refractory Postencephalitic Epilepsy: A Retrospective Study.

BackgroundVagus nerve stimulation (VNS) has been demonstrated to be safe and effective for patients with refractory epilepsy, but there are few reports on the use of VNS for postencephalitic epilepsy (PEE). This retrospective study aimed to evaluate the efficacy of VNS for refractory PEE.MethodsWe retrospectively studied 20 patients with refractory PEE who underwent VNS between August 2017 and October 2019 in Chinese PLA General Hospital and Beijing Children’s Hospital. VNS efficacy was evaluated based on seizure reduction, effective rate (percentage of cases with seizure reduction ≥ 50%), McHugh classification, modified Early Childhood Epilepsy Severity Scale (E-Chess) score, and Grand Total EEG (GTE) score. The follow-up time points were 3, 6, and 12 months after VNS. Pre- and postoperative data were compared and analyzed.ResultsThe median [interquartile range (IQR)] seizure reduction rates at 3, 6, and 12 months after VNS were 23.72% (0, 55%), 46.61% (0, 79.04%), and 67.99% (0, 93.78%), respectively. The effective rates were 30% at 3 months, 45% at 6 months, and 70% at 12 months. E-chess scores before the operation and at 3, 6, and 12 months after the operation were 10 (10, 10.75), 9 (9, 10), 9 (9, 9.75), and 9 (8.25, 9) (P < 0.05), respectively. GTE scores before surgery and at 12 months after the operation were 11 (9, 13) and 9 (7, 11) (P < 0.05), respectively. The mean intensity of VNS current was 1.76 ± 0.39 (range: 1.0–2.5) mA. No intraoperative complications or severe post-operative adverse effects were reported.ConclusionsOur study shows that VNS can reduce the frequency and severity of seizure in patients with refractory PEE. VNS has a good application prospect in patients with refractory PEE.

Factors Affecting Vagus Nerve Stimulation Outcomes in Epilepsy.

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.

Comparison of efficiency between VNS and ANT-DBS therapy in drug-resistant epilepsy: A one year follow up study

Vagus nerve stimulation (VNS) and anterior thalamic deep brain stimulation (ANT-DBS) have both been used for treatments of drug-resistant epilepsy (DRE). However, there is no comparative study on the effectiveness of two methods from one single center. 17 patients with DRE who underwent VNS therapy and 18 patients who underwent DBS were enrolled. A retrospective study was performed starting from baseline before operation extending to 12 months after operation. The seizure types, duration of epilepsy, age at implantation, failed numbers of antiepileptic drugs (AEDs) before operation, history of craniotomy, stimulation parameters and response rate were described. The analysis of liner regression on the age of onset, duration of epilepsy, numbers of AEDs, and the seizure reduction at 12 months after operation was applied. The mean seizure reduction in patients with DBS at 3, 6, 9 and 12 months after the operation was 57.22%, 61.61%, 63.94% and 65.28%, and that in cases with VNS was 36.06%, 39.94%, 45.24% and 48.35%, respectively. At 1 year after the operation, the patients with older operation age, focal seizures and older age of onset responded better to VNS; and those older operation age, focal generalized seizures, history of craniotomy and longer duration of disease responded better to DBS. The efficiency of ANT-DBS was higher than that of VNS at each follow up time point. Patients can choose the appropriate treatment according to the individual clinical characteristics.

Staging and Combining Brain Stimulation Interventions: Vagus Nerve Stimulation and Electroconvulsive Therapy.

Staging and Combining Brain Stimulation Interventions: Vagus Nerve Stimulation and Electroconvulsive Therapy.

Long-term results of vagus nerve stimulation in children with Dravet syndrome: Time-dependent, delayed antiepileptic effect

ObjectiveThis study aimed to assess the long-term outcomes of vagus nerve stimulation (VNS) in children with pharmaco-resistant Dravet syndrome (DS). MethodsWe enrolled 22 patients with pharmaco-resistant DS who underwent VNS implantation at Severance Children’s Hospital from March 2005 to October 2020. Efficacy and tolerability were assessed at 3, 6, 12, 18, 24, 30, and 36 months after VNS implantation. Efficacy was measured as the percentage reduction in seizure frequency at each follow-up compared with the baseline (pre-implantation) values. ResultsMedian patient age at VNS implantation was 10.0 years (interquartile range 7.7–13.3). The median follow-up period was 4.3 years (interquartile range 3.0–6.5) after VNS implantation. All cases were followed up for ≥2 years after VNS implantation. Three (13.6 %) patients maintained seizure freedom for ≥1 year. Among them, one achieved seizure freedom after 30 months of VNS. More than 50 % reduction in seizure frequency was observed in 36.4 % (8/22), 54.5 % (12/22), and 63.2 % (12/19) of the patients at 12, 24, and 36 months, respectively. The median percent reduction in seizure frequency was 18.8 %, 50.6 %, and 60.0 % at 12, 24, and 36 months, respectively. Compared with the baseline value, the seizure frequency was significantly lower at 24, 30, and 36 months, as well as at the longest follow-up period (p < 0.05, Wilcoxon signed-rank test). The symptom that was mostly associated with adverse events was hoarseness (4/22, 18.2 %); however, they had temporary or minimal effects on activities of daily living. ConclusionsOur findings demonstrate that VNS therapy allows long-term, progressive, and time-dependent improvement in seizure control for pharmaco-resistant DS. Clinicians should be aware of the delayed VNS efficacy over the years and should encourage long-term VNS maintenance by patients.

Vagus nerve stimulation does not alter brainstem nuclei morphology in patients with refractory epilepsy

ObjectiveTo describe morphological characteristics of the brainstem nuclei in response to chronic vagus nerve stimulation (VNS) in patients with refractory epilepsy. BackgroundVNS is a treatment option for individuals with medically refractory epilepsy. While treatment with VNS may achieve up to 50% seizure reduction and is protective against sudden unexpected death in epilepsy (SUDEP), its mechanism of action is not fully understood. Long-term structural and cellular changes in response to VNS have rarely been addressed in humans. MethodsFour autopsy cases with history of chronic epilepsy treated with VNS (VNS+) and 4 age- and sex-matched chronic epilepsy-related death cases without VNS (VNS-) were included. Detailed clinical and postmortem data were obtained. Serial horizontal sections of the brainstem were prepared and stained with hematoxylin, eosin, and luxol fast blue (HE/LFB). Three regions of interest (ROIs) were delineated, including nucleus tractus solitarius (NTS), locus coeruleus (LC), and the rostral pontine group of raphe nuclei (rRN). Immunohistochemistry studies were performed using antibodies to GFAP, NeuN, HLA-DR, and IBA-1. Immunolabeling index was analyzed. ResultsThree of the 4 VNS+ patients and all 4 control (VNS-) patients died of SUDEP. There was no laterality difference in the NeuN, GFAP, HLA-DR and IBA-1 expression in LC and NTS of VNS+ patients. Similarly, there was no difference in the rRN, LC, and NTS between the VNS+ and VNS- groups. ConclusionThis study represents the first histopathological study of the long-term effects of VNS therapy in the human brain. There was no difference observed in the neuronal cell number, degree of astrocytosis, and neuroinflammation in the main brainstem vagal afferent nuclei after prolonged VNS treatment in patients with refractory epilepsy.

Analysing vagus nerve spontaneous activity using finite element modelling

Objective. Finite element modelling has been widely used to understand the effect of stimulation on the nerve fibres. Yet the literature on analysis of spontaneous nerve activity is much scarcer. In this study, we introduce a method based on a finite element model, to analyse spontaneous nerve activity with a typical bipolar electrode recording setup, enabling the identification of spontaneously active fibres. We applied our method to the vagus nerve, which plays a key role in refractory epilepsy. Approach. We developed a 3D model including dynamic action potential (AP) propagation, based on the vagus nerve geometry. The impact of key recording parameters—inter-electrode distance and temperature—and uncontrolled parameters—fibre size and position in the nerve—on the ability to discriminate active fibres were quantified. A specific algorithm was implemented to detect and classify APs from recordings, and tested on six rat in-vivo vagus nerve recordings. Main results. Fibre diameters can be discriminated if they are below 3 μm and 7 μm, respectively for inter-electrode distances of 2 mm and 4 mm. The impact of the position of the fibre inside the nerve on fibre diameter discrimination is limited. The range of active fibres identified by modelling in the vagus nerve of rats is in agreement with ranges found at histology. Significance. The nerve fibre diameter, directly proportional to the AP propagation velocity, is related to a specific physiological function. Estimating the source fibre diameter is thus essential to interpret neural recordings. Among many possible applications, the present method was developed in the context of a project to improve vagus nerve stimulation therapy for epilepsy.

Fascicle localisation within peripheral nerves through evoked activity recordings: A comparison between electrical impedance tomography and multi-electrode arrays

BackgroundThe lack of understanding of fascicular organisation in peripheral nerves limits the potential of vagus nerve stimulation therapy. Two promising methods may be employed to identify the functional anatomy of fascicles within the nerve: fast neural electrical impedance tomography (EIT), and penetrating multi-electrode arrays (MEA). These could provide a means to image the compound action potential within fascicles in the nerve. New methodWe compared the ability to localise fascicle activity between silicon shanks (SS) and carbon fibre (CF) multi-electrode arrays and fast neural EIT, with micro-computed tomography (MicroCT) as an independent reference. Fast neural EIT in peripheral nerves was only recently developed and MEA technology has been used only sparingly in nerves and not for source localisation. Assessment was performed in rat sciatic nerves while evoking neural activity in the tibial and peroneal fascicles. ResultsRecorded compound action potentials were larger with CF compared to SS (∼700 μV vs ∼300 μV); however, background noise was greater (6.3 μV vs 1.7 μV) leading to lower SNR. Maximum spatial discrimination between Centres-of-Mass of fascicular activity was achieved by fast neural EIT (402 ± 30 μm) and CF MEA (414 ± 123 μm), with no statistical difference between MicroCT (625 ± 17 μm) and CF (p > 0.05) and between CF and EIT (p > 0.05). Compared to CF MEAs, SS MEAs had a lower discrimination power (103 ± 51 μm, p < 0.05). Comparison with existing methodsEIT and CF MEAs showed localisation power closest to MicroCT. Silicon MEAs adopted in this study failed to discriminate fascicle location. Re-design of probe geometry may improve results. ConclusionsNerve EIT is an accurate tool for assessment of fascicular position within nerves. Accuracy of EIT and CF MEA is similar to the reference method. We give technical recommendations for performing multi-electrode recordings in nerves.