Vagus nerve stimulation and heart rate variability: A scoping review of a somatic oscillatory signal.

The goal of this review is to synthesize the literature on vagus nerve stimulator (VNS)-related changes in heart rate variability (HRV) in patients with drug-resistant epilepsy (DRE) and assess the role of these changes in seizure relief. A scoping literature review was performed with the following inclusion criteria: primary articles written in English, involved implantable VNS in humans, and had HRV as a primary outcome. Twenty-nine studies were retrieved, however with considerable heterogeneity in study methods. The overall depression in HRV seen in DRE patients compared to healthy controls persisted even after VNS implant, indicating that achieving "healthy" HRV is not necessary for VNS therapeutic success. Within DRE patients, changes in frequency domain parameters six months after VNS implant returned to baseline after a year. The mechanism of how VNS reduces seizure burden does not appear to be significantly related to alterations in baseline HRV. However, the subtlety of sympathetic/parasympathetic signaling likely requires a more structured approach to experimental and analytic techniques than currently found in the literature.

Continuing trial responsibilities for implantable neural devices.

Participants of neural implant studies have research-related posttrial care needs (e.g., hardware replacements). Gaps in plans for posttrial care are currently common, which can have major consequences for patients. Professionals and organizations involved should address important unmet posttrial needs.

Rehabilitation of People With Chronic Spinal Cord Injury Using a Laparoscopically Implanted Neurostimulator: Impact on Mobility and Urinary, Anorectal, and Sexual Functions.

OBJECTIVES: This study aimed to assess the impact of the laparoscopic implantation of neuromodulation electrodes (Possover-LION procedure) on mobility and on sexual, urinary, and anorectal functions of people with chronic spinal cord injury (SCI). MATERIAL AND METHODS: Longitudinal analysis of 30 patients with chronic SCI (21 ASIA impairment scale (AIS) A, eight AIS B, and one AIS C) submitted to the Possover-LION procedure for bilateral neuromodulation of femoral, sciatic, and pudendal nerves. Assessments were performed before the surgical procedure and at 3, 6, and 12 months postoperatively. The primary outcome was evolution in walking, measured by the Walking Index for Spinal Cord Injury score, preoperatively and at 12 months. Secondary outcomes were changes in overall mobility (Mobility Assessment Tool for Evaluation of Rehabilitation score), urinary function and quality of life (Qualiveen questionnaire), and bowel (time for bowel emptying proceedings and Wexner's Fecal Incontinence Severity Index [FISI]) and sexual functions (International Index of Erectile Function for men and Female Sexual Function Index for women). Surgical time, intraoperative bleeding, and perioperative complications were also recorded. RESULTS: Qualitatively, 18 of 25 (72%) patients with thoracic injury and 3 of 5 (60%) patients with cervical injury managed to establish a walker-assisted gait at one-year follow-up (p < 0.0001). A total of 11 (47.8%) have improved in their urinary incontinence (p < 0.0001), and seven (30.4%) improved their enuresis (p = 0.0156). The FISI improved from a median of 9 points preoperatively to 5.5 at 12 months (p = 0.0056). Of note, 20 of 28 (71.4%) patients reported an improvement on genital sensitivity at 12 months postoperatively (p < 0.0001), but this was not reflected in sexual quality-of-life questionnaires. CONCLUSIONS: Patients experienced improved mobility and genital sensitivity and a reduction in the number of urinary and fecal incontinence episodes. By demonstrating reproducible outcomes and safety, this study helps establish the Possover-LION procedure as an addition to the therapeutic armamentarium for the rehabilitation of patients with chronic SCI. CLINICAL TRIAL REGISTRATION: This study was registered at the WHO Clinical Trials Database through the Brazilian Registry of Clinical Trials-REBEC (Universal Tracking Number: U1111-1261-4428).

Subcutaneous Stimulation as Add-on Therapy to Spinal Cord Stimulation in Patients With Persistent Spinal Pain Syndrome Significantly Increases the Total Electrical Charge per Second: Aspects on Stimulation Parameters and Energy Requirements of the Implanted Neurostimulators.

OBJECTIVE: In our previous multicenter randomized controlled trial, we demonstrated the clinical effectiveness of peripheral nerve field stimulation (PNFS) as add-on therapy to spinal cord stimulation (SCS) for the treatment of chronic back pain in patients with persistent spinal pain syndrome (PSPS) or failed back surgery syndrome (FBSS). To our knowledge, no previous study has investigated the effect of PNFS as an add-on to SCS on the energy consumption of the implanted neurostimulators. Therefore, in this study, we compared the specific stimulation parameters and energy requirements of a previously unreported group of patients with only SCS with those of a group of patients with SCS and add-on PNFS. We also investigated differences that might explain the need for PNFS in the treatment of chronic low back pain. MATERIALS AND METHODS: We analyzed 75 patients with complete sets of stimulation parameters, with 21 patients in the SCS-only group and 54 patients in the SCS + PNFS group. Outcome measures were average visual analog scale score, SCS parameters (voltage, frequency, and pulse width), SCS charge per second, and total charge per second. We analyzed baseline characteristics and differences between and within groups over time. RESULTS: Both groups had comparable patient characteristics at baseline and showed a significant decrease in back and leg pain. SCS charge per second did not significantly differ between the groups at baseline or at 12 months. The total charge per second was significantly higher in the active SCS + PNFS group than in the SCS-only group at baseline; in the SCS + PNFS group, this persisted for up to 12 months, and the SCS charge per second and total charge per second increased significantly over time. CONCLUSIONS: Our results show that add-on PNFS increases the total charge per second compared with SCS alone, as expected. However, further research is needed because our results do not directly explain why some patients require add-on PNFS to treat low back pain.

Computed tomography scanning of implanted hypoglossal nerve stimulators and approach to device malfunction: case series.

OBJECTIVE: Serious device-related complications for hypoglossal nerve stimulators are rare, but surgeons should implement a prompt and systematic approach to quickly troubleshoot a non-functioning device. METHOD: Records were queried at a single academic tertiary referral centre between January 2019 and June 2021. RESULTS: The authors present four cases of non-functioning hypoglossal nerve stimulator devices: one case in which migration of the stimulation lead required a revision implantation, one in which the implantable pulse generator was found to be non-functional intra-operatively, one case of an intramuscular sensory lead tract causing pain and one case of implantable pulse generator failure that was probably triggered by implantable cardiac device discharge. In this study, computed tomography imaging was critical to the diagnosis for the first and third cases. CONCLUSION: Given the limited complication reporting available for hypoglossal nerve stimulators, these cases highlight management and unique imaging findings. The authors present an algorithm to work-up non-functioning hypoglossal nerve stimulator devices.

Soft strain-insensitive bioelectronics featuring brittle materials.

Advancing electronics to interact with tissue necessitates meeting material constraints in electrochemical, electrical, and mechanical domains simultaneously. Clinical bioelectrodes with established electrochemical functionalities are rigid and mechanically mismatched with tissue. Whereas conductive materials with tissue-like softness and stretchability are demonstrated, when applied to electrochemically probe tissue, their performance is distorted by strain and corrosion. We devise a layered architectural composite design that couples strain-induced cracked films with a strain-isolated out-of-plane conductive pathway and in-plane nanowire networks to eliminate strain effects on device electrochemical performance. Accordingly, we developed a library of stretchable, highly conductive, and strain-insensitive bioelectrodes featuring clinically established brittle interfacial materials (iridium-oxide, gold, platinum, and carbon). We paired these bioelectrodes with different electrochemical probing methods (amperometry, voltammetry, and potentiometry) and demonstrated strain-insensitive sensing of multiple biomarkers and in vivo neuromodulation.

Cognitive benefits of using non-invasive compared to implantable neural feedback.

A non-optimal prosthesis integration into an amputee's body schema suggests some important functional and health consequences after lower limb amputation. These include low perception of a prosthesis as a part of the body, experiencing it as heavier than the natural limb, and cognitively exhausting use for users. Invasive approaches, exploiting the surgical implantation of electrodes in residual nerves, improved prosthesis integration by restoring natural and somatotopic sensory feedback in transfemoral amputees. A non-invasive alternative that avoids surgery would reduce costs and shorten certification time, significantly increasing the adoption of such systems. To explore this possibility, we compared results from a non-invasive, electro-cutaneous stimulation system to outcomes observed with the use of implants in above the knee amputees. This non-invasive solution was tested in transfemoral amputees through evaluation of their ability to perceive and recognize touch intensity and locations, or movements of a prosthesis, and its cognitive integration (through dual task performance and perceived prosthesis weight). While this managed to evoke the perception of different locations on the artificial foot, and closures of the leg, it was less performant than invasive solutions. Non-invasive stimulation induced similar improvements in dual motor and cognitive tasks compared to neural feedback. On the other hand, results demonstrate that remapped, evoked sensations are less informative and intuitive than the neural evoked somatotopic sensations. The device therefore fails to improve prosthesis embodiment together with its associated weight perception. This preliminary evaluation meaningfully highlights the drawbacks of non-invasive systems, but also demonstrates benefits when performing multiple tasks at once. Importantly, the improved dual task performance is consistent with invasive devices, taking steps towards the expedited development of a certified device for widespread use.

Safety and Management of Implanted Epilepsy Devices for Imaging and Surgery.

Permanently implanted devices that deliver electrical stimulation are increasingly used to treat patients with drug-resistant epilepsy. Primary care physicians, neurologists, and epilepsy clinicians may encounter patients with a variety of implanted neuromodulation devices in the course of clinical care. Due to the rapidly changing landscape of available epilepsy-related neurostimulators, there may be uncertainty related to how these devices should be handled during imaging procedures and perioperative care. We review the safety and management of epilepsy-related implanted neurostimulators that may be encountered during imaging and surgery. We provide a summary of approved device labeling and recommendations for the practical management of these devices to help guide clinicians as they care for patients treated with bioelectronic medicine.

Estimulación de la médula espinal: más allá del manejo del dolor / Spinal cord stimulation: Beyond pain management

Introducción: La descripción de la teoría de la compuerta del dolor fue el punto de partida para el desarrollo de la estimulación de la médula espinal (EME). El presente artículo describe las indicaciones para el tratamiento del dolor y otros usos no relacionados con este. Desarrollo: En la actualidad existen diversos paradigmas de EME: tónica, de alta frecuencia en ráfaga o simplemente de alta frecuencia. Estas se distinguen por la presencia de parestesias. La EME ha mostrado beneficio sobre todo en dolor de tipo neuropático. El síndrome de cirugía espinal fallida muestra las mejores tasas de respuesta, aunque en casos de síndrome doloroso regional complejo y neuropatía diabética, así como de radiculopatía y lumbago sin cirugía espinal previa, también se logra una reducción importante del dolor. Aunque su aplicación en el dolor de tipo fantasma y en el asociado a enfermedad vascular periférica o cardiovascular parece útil, no existe una evidencia sólida para generalizar su empleo. Por otra parte, la EME también reduce el dolor neuropático secundario a tumor, a pesar de que esta línea ha sido poco explorada. Otras indicaciones no relacionadas con el dolor son trastornos de movimiento, espasticidad y secuelas de trauma medular. Sin embargo, el uso de la EME se ve limitado por dos factores principales: las complicaciones mecánicas y el costo de la terapia. Conclusión: Durante los 50 años de aplicación, la EME ha mostrado grandes avances. Asimismo, a medida que se perfeccione el hardware y el software relacionados con esta, se podrá mejorar la efectividad y reducir el rango de complicaciones. La indicación para la EME se podría extender a otras enfermedades y su uso se expandiría si, además, se lograra diseñar una tecnología asequible. (AU)

Introduction: The gate control theory of pain was the starting point of the development of spinal cord stimulation (SCS). We describe the indications for the treatment in pain management and other uses not related to pain. Development: There are currently several paradigms for SCS: tonic, burst, and high frequency. The main difference lies in the presence of paraesthesias. SCS is most beneficial for treating neuropathic pain. Patients with failed back surgery syndrome show the best response rates, although a considerable reduction in pain is also observed in patients with complex regional pain syndrome, diabetic neuropathy, radiculopathy, and low back pain without previous surgery. Phantom pain or pain related to cardiovascular or peripheral vascular disease may improve, although there is a lack of robust evidence supporting generalisation of its use. SCS also improves cancer-related pain, although research on this issue is scarce. Non-pain-related indications for SCS are movement disorders, spasticity, and sequelae of spinal cord injury. The main limiting factors for the use of SCS are mechanical complications and the cost of the treatment. Conclusion: In its 50-year history, SCS has progressed enormously. The perfection of hardware and software may improve its effectiveness and reduce the rate of complications. Indications for SCS could include other diseases, and its use could be expanded, if the costs of the technology are reduced. (AU)

Wide bandgap semiconductor nanomembranes as a long-term biointerface for flexible, implanted neuromodulator.

Electrical neuron stimulation holds promise for treating chronic neurological disorders, including spinal cord injury, epilepsy, and Parkinson's disease. The implementation of ultrathin, flexible electrodes that can offer noninvasive attachment to soft neural tissues is a breakthrough for timely, continuous, programable, and spatial stimulations. With strict flexibility requirements in neural implanted stimulations, the use of conventional thick and bulky packages is no longer applicable, posing major technical issues such as short device lifetime and long-term stability. We introduce herein a concept of long-lived flexible neural electrodes using silicon carbide (SiC) nanomembranes as a faradic interface and thermal oxide thin films as an electrical barrier layer. The SiC nanomembranes were developed using a chemical vapor deposition (CVD) process at the wafer level, and thermal oxide was grown using a high-quality wet oxidation technique. The proposed material developments are highly scalable and compatible with MEMS technologies, facilitating the mass production of long-lived implanted bioelectrodes. Our experimental results showed excellent stability of the SiC/silicon dioxide (SiO2) bioelectronic system that can potentially last for several decades with well-maintained electronic properties in biofluid environments. We demonstrated the capability of the proposed material system for peripheral nerve stimulation in an animal model, showing muscle contraction responses comparable to those of a standard non-implanted nerve stimulation device. The design concept, scalable fabrication approach, and multimodal functionalities of SiC/SiO2 flexible electronics offer an exciting possibility for fundamental neuroscience studies, as well as for neural stimulation-based therapies.

Neuromodulación eléctrica en el tratamiento del dolor neuropático refractario. Colocación del primer estimulador medular en Cuba / Electric neuromodulation in the treatment of refractory pain. Placement of the first spinal stimulator in Cuba

El dolor es una causa importante de sufrimiento físico y emocional. El tratamiento médico de los pacientes con dolor crónico refractario es un gran reto. Se presenta el caso de una paciente de 19 años con un cuadro radicular compresivo secundario a Hernia discal L5-S1 derecha, que se le aplicó una discectomía L5-S1 por técnica de Caspar. Al mes de evolución regresa con igual sintomatología. A pesar de múltiples terapias farmacológicas y procederes intervencionistas, el dolor neuropático no mejora, después de múltiples estudios y discusiones en colectivo se determina la posibilidad de la colocación de un neuroestimulador medular, proceder que se lleva a cabo con mejoría considerable de su cuadro doloroso(AU)

Pain is a major cause of physical and emotional suffering. The management of patients with refractory chronic pain is a great challenge. The case is presented of a 19-year-old female patient with compressive radicular symptoms secondary to right L5-S1 disc herniation, who underwent L5-S1 discectomy with Caspar technique. After one month of evolution, she returned with the same symptoms. Despite multiple pharmacological therapies and interventional procedures, the neuropathic pain did not improve. After multiple studies and collective discussions, the possibility of placing a spinal neurostimulator was decided. After the procedure, the patient improved considerably with respect to her painful symptoms(AU)

Reducing VNS stimulation parameters: Is it safe?

Introduction Vagal nerve stimulation (VNS) is an adjuvant therapy used in the treatment of patients with refractory epilepsy who are not candidates for resective surgery or who have limited results after surgical procedures. Currently, there is enough evidence to support its use in patients with various types of epilepsy. Therefore, the present study was conducted to explore the possibility of optimizing therapy by reducing the consumption of the system's battery. Methods The prospective and double-blind analysis consisted in the evaluation of 6 patients submitted to VNS implantation for 3 months, followed by adjustment of the stimulation settings and continuity of follow-up for another month. The standard protocol was replaced by another with a frequency value of 20 Hz instead of 30 Hz to increase battery life. The safety of this procedure was evaluated through the assessment of two main variables: seizures and side effects. Results The stimulation at 20 Hz showed 68% reduction in the incidence of seizures (p»0.054) as well as low incidence of side effects. Conclusion The present study suggests that the reduction of the stimulation frequency from 30 to 20 Hz is a safe procedure, and it does not compromise the effectiveness of therapy.

The Relationship Between Cortical Activation in Response to Anorectal Stimuli and Continence Behavior in Freely Behaving Rats Before and After Application of Sacral Nerve Stimulation.

BACKGROUND: Changes in anorectal sensation have been reported in patients with fecal incontinence, and there is limited evidence that sacral nerve stimulation can restore normal sensation. OBJECTIVE: The aims of the present study were to investigate changes in the transmission of sensory anorectal stimuli in a rodent model of fecal incontinence and to study the effects of sacral nerve stimulation on defecation behavior. DESIGN: An established model of fecal incontinence was utilized for this study. INTERVENTION: Pudendal nerve stretch and compression were used in 16 adult female Wistar rats and were monitored for 3 weeks: 6 rats received sacral nerve stimulation for 1 week by using an implantable neurostimulator and 10 rats had nonfunctioning "dummy" devices inserted. Five additional rats were sham operated. Anorectal cortical evoked potentials were used as a surrogate marker for anorectal sensory function. MAIN OUTCOME MEASURES: The primary outcomes measured were fecal incontinence index, evoked potential amplitude, and latency. RESULTS: Fifty percent of rats showed behavioral signs of fecal incontinence measured by the Fecal Incontinence Index (>0.20), calculated by using the pellet distribution outside the cage's latrine area. Anorectal evoked potential amplitude was reduced in rats with a Fecal Incontinence Index >0.20 (p = 0.019). The amplitude of forepaw evoked potentials recorded as a control was not different between groups. Chronic sacral nerve stimulation using the fully implantable device and custom rodent lead was safe and stable during this chronic prospective study. Incontinent rats (n = 3) that received sacral nerve stimulation showed an improvement of Fecal Incontinence Index and an increase of evoked potential amplitude to anorectal stimulation compared with the dummy implant controls (n = 5). LIMITATIONS: The main limitation is the small number of animals that received sacral nerve stimulation. CONCLUSIONS: Chronic sacral nerve stimulation is feasible in rats when miniature telemetric devices are used. Behavioral signs of fecal incontinence were positively correlated with the latency of anorectal evoked potentials. See Video Abstract at http://links.lww.com/DCR/B712.RELACIÓN ENTRE LA ACTIVACIÓN CORTICAL EN RESPUESTA A LOS ESTÍMULOS ANORRECTALES Y EL COMPORTAMIENTO DE CONTINENCIA EN RATAS QUE SE COMPORTAN LIBREMENTE ANTES Y DESPUÉS DE LA APLICACIÓN DE ESTIMULACIÓN DEL NERVIO SACRO. ANTECEDENTES: Se han informado cambios en la sensación anorrectal en pacientes con incontinencia fecal y hay evidencia limitada de que la estimulación del nervio sacro puede restaurar la sensación normal. OBJETIVO: Los objetivos del presente estudio fueron investigar los cambios en la transmisión de estímulos anorrectales sensoriales en un modelo de roedor de incontinencia fecal y estudiar los efectos de la estimulación del nervio sacro en la conducta de defecación. DISEO: Un modelo establecido de incontinencia fecal. INTERVENCIN: Se utilizó estiramiento y compresión del nervio pudendo en 16 ratas Wistar hembras adultas y se les realizó un seguimiento durante 3 semanas: seis ratas recibieron estimulación del nervio sacro durante 1 semana utilizando un neuroestimulador implantable y diez ratas tuvieron insertados dispositivos "ficticios" no funcionantes. Se operaron simuladamente cinco ratas adicionales. Los potenciales evocados corticales anorrectales se utilizaron como marcador subrogado de la función sensorial anorrectal. PRINCIPALES MEDIDAS DE RESULTADO: Índice de incontinencia fecal, amplitud de potenciales evocados y latencia. RESULTADOS: El cincuenta por ciento de las ratas mostró signos de comportamiento de incontinencia fecal medidos por el Índice de incontinencia fecal (> 0.20), calculado utilizando la distribución de heces fuera del área de la letrina de la jaula. La amplitud del potencial evocado anorrectal se redujo en ratas con un índice de incontinencia fecal >0.20 (p = 0.019). La amplitud de los potenciales evocados de la pata delantera registrados como control no fue diferente entre los grupos. La estimulación crónica del nervio sacro utilizando un dispositivo totalmente implantable y un cable de roedor personalizado fue segura y estable durante este estudio prospectivo crónico. Las ratas con incontinencia (N = 3) que recibieron estimulación del nervio sacro mostraron una mejora del índice de incontinencia fecal y un aumento de la amplitud del potencial evocado a la estimulación anorrectal en comparación con los controles de implante ficticio (N = 5). LIMITACIONES: La principal limitación es el pequeño número de animales que recibieron estimulación del nervio sacro. CONCLUSIONES: La estimulación crónica del nervio sacro es factible en ratas cuando se utilizan dispositivos telemétricos en miniatura. Los signos conductuales de incontinencia fecal se correlacionaron positivamente con la latencia de los potenciales evocados anorrectales. Consulte Video Resumen en http://links.lww.com/DCR/B712. (Traducción-Dr. Jorge Silva Velazco).

A review on magnetic and spintronic neurostimulation: challenges and prospects.

In the treatment of neurodegenerative, sensory and cardiovascular diseases, electrical probes and arrays have shown quite a promising success rate. However, despite the outstanding clinical outcomes, their operation is significantly hindered by non-selective control of electric fields. A promising alternative is micromagnetic stimulation (µMS) due to the high permeability of magnetic field through biological tissues. The induced electric field from the time-varying magnetic field generated by magnetic neurostimulators is used to remotely stimulate neighboring neurons. Due to the spatial asymmetry of the induced electric field, high spatial selectivity of neurostimulation has been realized. Herein, some popular choices of magnetic neurostimulators such as microcoils (µcoils) and spintronic nanodevices are reviewed. The neurostimulator features such as power consumption and resolution (aiming at cellular level) are discussed. In addition, the chronic stability and biocompatibility of these implantable neurostimulator are commented in favor of further translation to clinical settings. Furthermore, magnetic nanoparticles (MNPs), as another invaluable neurostimulation material, has emerged in recent years. Thus, in this review we have also included MNPs as a remote neurostimulation solution that overcomes physical limitations of invasive implants. Overall, this review provides peers with the recent development of ultra-low power, cellular-level, spatially selective magnetic neurostimulators of dimensions within micro- to nano-range for treating chronic neurological disorders. At the end of this review, some potential applications of next generation neuro-devices have also been discussed.

High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways.

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation.