Nonclinical evaluation of chronic cardiac contractility modulation on 3D human engineered cardiac tissues.

INTRODUCTION: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2-day) in vitro CCM assay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). METHODS: Cryopreserved human induced pluripotent stem cell-derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin-based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. RESULTS: Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB) and excitation-contraction coupling (i.e., sodium-calcium exchanger, SLC8). CONCLUSION: These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT-based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues.

Closed-Loop Wearable Device Network of Intrinsically-Controlled, Bilateral Coordinated Functional Electrical Stimulation for Stroke.

Innovative functional electrical stimulation has demonstrated effectiveness in enhancing daily walking and rehabilitating stroke patients with foot drop. However, its lack of precision in stimulating timing, individual adaptivity, and bilateral symmetry, resulted in diminished clinical efficacy. Therefore, a closed-loop wearable device network of intrinsically controlled functional electrical stimulation (CI-FES) system is proposed, which utilizes the personal surface myoelectricity, derived from the intrinsic neuro signal, as the switch to activate/deactivate the stimulation on the affected side. Simultaneously, it decodes the myoelectricity signal of the patient's healthy side to adjust the stimulation intensity, forming an intrinsically controlled loop with the inertial measurement units. With CI-FES assistance, patients' walking ability significantly improved, evidenced by the shift in ankle joint angle mean and variance from 105.53° and 28.84 to 102.81° and 17.71, and the oxyhemoglobin concentration tested by the functional near-infrared spectroscopy. In long-term CI-FES-assisted clinical testing, the discriminability in machine learning classification between patients and healthy individuals gradually decreased from 100% to 92.5%, suggesting a remarkable recovery tendency, further substantiated by performance on the functional movement scales. The developed CI-FES system is crucial for contralateral-hemiplegic stroke recovery, paving the way for future closed-loop stimulation systems in stroke rehabilitation is anticipated.

Treatment with synchronized radiofrequency and facial muscle stimulation: Histologic analysis of human skin for changes in collagen and elastin fibers.

BACKGROUND: Skin's exposure to intrinsic and extrinsic factors causes age-related changes, leading to a lower amount of dermal collagen and elastin. AIM: This study investigated the effects of a novel facial muscle stimulation technology combined with radiofrequency (RF) heating on dermal collagen and elastin content for the treatment of facial wrinkles and skin laxity. METHODS: The active group subjects (N = 6) received four 20-min facial treatments with simultaneous RF and facial muscle stimulation, once weekly. The control subject (N = 1) was untreated. Skin biopsies obtained at baseline, 1-month and 3-month follow-up were evaluated histologically to determine collagen and elastin fibers content. A group of independent aestheticians evaluated facial skin appearance and wrinkle severity. Patient safety was followed. RESULTS: In the active group, collagen-occupied area reached 11.91 ± 1.80 × 106 µm2 (+25.32%, p < 0.05) and 12.35 ± 1.44 × 105 µm2 (+30.00%, p < 0.05) at 1-month and 3-month follow-up visits. Elastin-occupied area at 1-month and 3-month follow-up was 1.64 ± 0.14 × 105 µm2 (+67.23%, p < 0.05), and 1.99 ± 0.21 × 105 µm2 (+102.80%, p < 0.05). In the control group, there was no significant difference (p > 0.05) in collagen and elastin fibers. Active group wrinkle scores decreased from 5 (moderate, class II) to 3 (mild, class I). All subjects, except the control, improved in appearance posttreatment. No adverse events or side effects occurred. CONCLUSION: Decreased dermal collagen and elastin levels contributes to a gradual decline in skin elasticity, leading to facial wrinkles and unfirm skin. Study results showed noticeable improvement in facial appearance and increased dermal collagen and elastin content subsequent to simultaneous, noninvasive RF, and facial muscle stimulation treatments.

Remote programming in stage I sacral neuromodulation: a multicentre prospective feasibility study.

OBJECTIVE: Sacral neuromodulation (SNM) has emerged as an effective therapy for refractory lower urinary tract dysfunction (LUTD). Remote programming holds promise in addressing the time and economic burdens associated with outpatient programming, especially for patients in the observation period following Stage I implant surgery (where the lead is implanted first without the pulse generator). The study aimed to explore the effectiveness and patient satisfaction of remote programming for Stage I SNM patients, and analyze the benefits patients gain from remote programming. METHODS: This prospective study was conducted at multiple high-level clinical SNM centres in China. Patients requiring SNM implantation were enroled and divided into two groups based on patient preference: remote programming (RP) group and outpatient control (OC) group. Patient attitudes toward RP were assessed through questionnaires, and the degree of symptom improvement was compared between the two groups to explore the usability of RP. RESULTS: A total of 63 participants from 6 centres were included in the study, with 32 belonging to the RP group. The remote programming system presents a high level of usability (98%) and willingness (satisfaction rate: 96.83%) in result of questionnaire. RP showed a significant advantage in improving patients' score of ICSI/ICPI (medianΔICSI/ICPI RP vs. OC= -13.50 vs -2, P =0.015). And slightly ameliorate urinary symptoms such as pain (medianΔVAS RP vs. OC= -1 vs 0, P = 0.164) and urgency (medianΔOBASS -2.5 vs. -1, P = 0.,229), but the difference was not statistically significant. RP did not significantly impact the quality of life of patients ( P =0.113), so do the rate of phase-two conversion ( P = 0.926) or programming parameters. CONCLUSION: To the best of our knowledge, the presented study is the first multicenter research focusing on the remote programming of Stage I SNM patients. Through the clinical implementation and patient feedback, we demonstrate that remote programming is not inferior to in-person programming in terms of success rate, effectiveness, safety, and patient satisfaction.

Physical mechanisms of emerging neuromodulation modalities.

One of the ultimate goals of neurostimulation field is to design materials, devices and systems that can simultaneously achieve safe, effective and tether-free operation. For that, understanding the working mechanisms and potential applicability of neurostimulation techniques is important to develop noninvasive, enhanced, and multi-modal control of neural activity. Here, we review direct and transduction-based neurostimulation techniques by discussing their interaction mechanisms with neurons via electrical, mechanical, and thermal means. We show how each technique targets modulation of specific ion channels (e.g. voltage-gated, mechanosensitive, heat-sensitive) by exploiting fundamental wave properties (e.g. interference) or engineering nanomaterial-based systems for efficient energy transduction. Overall, our review provides a detailed mechanistic understanding of neurostimulation techniques together with their applications toin vitro, in vivo, and translational studies to guide the researchers toward developing more advanced systems in terms of noninvasiveness, spatiotemporal resolution, and clinical applicability.

Walking naturally after spinal cord injury using a brain-spine interface.

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain-spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.

Evaluation the results of electromagnetic compatibility of a prototype device for ear stimulation in patients with tinnitus.

<b><br>Aim:</b> The aim of the study was to evaluate the results of electromagnetic compatibility of a prototype device for ear stimulation in patients with tinnitus.</br> <b><br>Material and methods:</b> The electromagnetic compatibility tests of the prototype device for electro- and magnetostimulation of the hearing organ were carried out at the Center for Attestation and Certification Tests OBAC Sp. z o. o. in Gliwice in 2020. The following product standards were used: PN-EN 60601-1-2:2015-11 - medical electrical equipment (general requirements for basic safety and essential functioning; PN-EN 55011:2012 - industrial, scientific and medical equipment [characteristics of radio frequency disturbances] ) PN-EN 61000-3-2:2014-10 - electromagnetic compatibility (EMC), permissible levels of harmonic current emissions (phase load current ≤ 16 A).</br> <b><br>Results:</b> The level of expanded uncertainty in the measurement of conducted disturbances in the range of 0.150-30MHz does not exceed the level specified in the PN-EN-55016-4-2:2011 standard. In the study of the emission of radiated disturbances up to 1GHz in the frequency range of 30-1000MHz (PN-EN 55011:2012 standard), it was found that the setting of the EUT during the tests was in accordance with the requirements of the standard. The level of expanded uncertainty in the measurement of radiated disturbances in the 30-1000MHz range does not exceed the level specified in the PN-EN 55016-4-2:2011 standard. The measured current harmonic levels (phase power supply current ≤16A) with a frequency range of 50Hz-2kHz do not exceed the permissible levels specified in the PN-EN 61000-3-2:2014-10 standard. The test of resistance to the magnetic field at the frequency of the power grid (PN-EN 61000-4-8: 2010 standard also showed that the setting of the EUT during the tests was in accordance with the requirements of the standard and the result was positive.</br> <b><br>Conclusions:</b> Testing of immunity to radiated radio frequency electromagnetic field (PN-EN 61000-4-3:2007 +A1:2008+A2:2011 standard) and testing of resistance to magnetic field at power frequency (PN-EN 61000-4-8 standard :2010) did not exceed the level specified in the standard and showed a positive result. The measured harmonic levels of the network current (phase supply current ≤16A) with the frequency range 50Hz-2kHz do not exceed the permissible levels specified in the PN-EN 61000- 3-2:2014-10 standard for a class A device.</br>.

Dispositif OptuneMC pour le traitement des patients adultes atteints d'un glioblastome nouvellement diagnostiqué / Optune™ for the treatment of adult patients with newly diagnosed glioblastoma

MANDAT: L'Institut national d'excellence en santé et en services sociaux (INESSS) a reçu le mandat du Bureau de l'innovation d'estimer la valeur de la technologie OptuneMC et la pertinence de sa couverture par le régime public en tant que dispositif de traitement des patients adultes souffrant d'un glioblastome nouvellement diagnostiqué avec et après la chimiothérapie d'entretien standard au témozolomide. DESCRIPTION: Pour l'indication demandée, le dispositif requiert la pose de matrices de transducteurs fixées sur le crâne rasé des patients afin de délivrer un champ électrique alternatif antitumoral via le générateur de champ OptuneMC. Les champs antitumoraux visent à stopper la progression des tumeurs en ciblant les étapes de la mitose des cellules cancéreuses et ils doivent agir en continu. Le dispositif OptuneMC est donc proposé avec des accessoires permettant un traitement ambulatoire et constant des patients. DÉMARCHE D'ÉVALUATION: Une revue des donn

MANDATE: L'Institut national d'excellence en santé et en services sociaux (INESSS) was mandated by the Bureau de l'innovation to assess the value of OptuneTM technology and the relevance of its coverage by the public plan as a treatment device for adult patients with newly diagnosed glioblastoma with and after standard temozolomide maintenance chemotherapy. DESCRIPTION: For the requested indication, the device requires the placement of transducer arrays to patients' shaved scalp to deliver to deliver a tumour-treating field through the OptuneTM field generator. Tumour treating fields aim to halt tumour progression by targeting the mitosis stages of cancer cells and must act continuously. The OptuneTM device is therefore provided with accessories for constant ambulatory treatment of patients. EVALUATION PROCESS: A review of data from the literature and those provided by the manufacturer was carried out to assess the scientific evidence regarding the application of tumour treating fields provided by Novocure's OptuneTM device for the treatment of newly diagnosed glioblastoma. Contextual and experiential stakeholder data were also collected through an expert advisory committee and one-on-one interviews with caregivers and patients who have used the OptuneTM device. SOCIO-CULTURAL DIMENSION: Despite the media visibility of the OptuneTM device and the enthusiasm for new therapeutic options, the acceptability of the device by Quebec patients is difficult to predict, as several factors need to be taken into consideration - e.g., aesthetic considerations, portability of the device and usage requirements. According to advisory committee members, the maximum acceptability rate could be as high as 50% of eligible patients offered the treatment. Some health technology assessment agencies have assessed OptuneTM and issued divergent recommendations, some favourable from the Haute Autorité de Santé (HAS, France), other unfavourable from the National Institute for Health and Care Excellence (NICE, UK). For their part, publications by listed oncology learned societies have chosen to recommend the OptuneTM device as a complementary treatment option to temozolomide in patients under 70 years of age. POPULATION DIMENSION: Glioblastoma is a heterogeneous cancer, with some subtypes more aggressive than others, affecting an estimated 150 new patient/year in Quebec. Median survival is around 8 months, with a 1-year survival rate of 25%. The disease is both cognitively and physically disabling, and family caregivers play an important role in its management. Current management is mainly based on diagnosis with magnetic resonance imaging (MRI), followed by tumour resection, when possible, combined radiotherapy with temozolomide, and maintenance chemotherapy with temozolomide (Stupp protocol). Despite treatment, 90% of patients will experience a recurrence of their cancer within 7 months. At this stage, there is no recognized standard of care. Glioblastoma is therefore an incurable pathology with limited treatment options, and with high unmet medical needs related to the development of new treatment options to prolong life and reduce the risk of recurrence. CLINICAL DIMENSION: The efficacy of the OptuneTM device is supported by the EF-14 study, an open-label, multicenter, randomized Phase 3 clinical trial conducted in 14 countries, including Canada. This study compared the efficacy of the OptuneTM device / temozolomide combination versus temozolomide alone in adult patients with supratentorial glioblastoma. The EF-14 study is judged to be of good methodological quality, despite the presence of a selection bias favouring the inclusion of individuals with a better prognosis. Moreover, the study population is also younger, has a higher performance index and contains a higher proportion of individuals with MGMT (6-O-Methylguanine-DNA methyltransferase) promoter methylation than the Quebec glioblastoma patient population. The main results of the study showed clinically significant gains in progression-free survival of 2.7 months and overall survival of 4.9 months. A dose-response effect was also observed according to patients' level of adherence to treatment, with a minimum use threshold of 50% to obtain a benefit, i.e., 12 hours per day. Secondary analyses failed to identify a sub-population that might benefit more from treatment and showed that all subgroups treated with the OptuneTM device benefited. The main adverse events attributable to this device were skin reactions and irritations. The results of the quality-of-life assessment indicate that the device is well tolerated by patients, as illustrated by the fact that the 75% adherence threshold was reached by 75% of the cohort. Skin irritation was the main cause of reduced quality of life in the cohort studied. Other results are subject to uncertainty due to the open design of the study, the low response of patients to the quality-of-life questionnaires, and the design of the device used, which was heavier, bulkier, and noisier than the model currently available. ORGANIZATIONAL DIMENSION: The OptuneTM device does not replace current care, but it is added to the standard maintenance treatment. GBM patients' diagnosis MRI images are transmitted to the manufacturer for array creation. Once the healthcare professional has assessed the patient's eligibility and transmitted the prescription to the manufacturer, the latter charges a monthly fee for unlimited array replacement, equipment delivery, patient service (technical assistance and training), and healthcare professional service, which includes training and reporting on patient compliance. This rental model is not common in Quebec, and the real involvement of healthcare network professionals and resources in monitoring patient use of the device is also uncertain, for example regarding skin effects, array repositioning and technical problems. However, Quebec centres participated in the EF-14 study and therefore have some experience with the device and the manufacturer. The OptuneTM device requires the help of a third party to place the electrode arrays, which may represent an issue for patients who have no family caregiver and/or for whom resources from the healthcare network could be solicited. Members of the advisory committee consulted are therefore of the opinion that, without access to such a resource, patients may be unable to use the device. In addition, there is uncertainty as to the optimal discontinuation criteria for patients treated with the OptuneTM device. Indeed, according to the members of the advisory committee consulted, there is no clinical advantage to continuing treatment after a first recurrence. Because of the organizational issues, several uncertainties remain as to whether the results of the clinical study can be reproduced in a real healthcare setting. ECONOMIC DIMENSION: The use of the OptuneTM device to treat patients with newly diagnosed glioblastoma concomitantly with temozolomide versus temozolomide alone is not cost-effective. Public coverage could generate additional costs of $ XX million over 5 years for the treatment of 308 patients. The real costs of adding the OptuneTM device, particularly those associated with its implementation in the health and social services network and with the involvement of healthcare personnel in patient follow-up, are uncertain. Market share for the OptuneTM device is also uncertain, since it depends on the quality of the manufacturer's service offering in Quebec, the organizational capacity of the Quebec healthcare network, and real patient acceptability. INESSS'S RECOMMENDATION: Based on the information available to date, and given the importance of the uncertainties raised, INESSS considers that it would not be fair and equitable to provide public coverage for the OptuneTM device for the treatment of adult patients with newly diagnosed supratentorial glioblastoma following maximal reduction surgery and completion of radiotherapy with and after standard maintenance chemotherapy. INESSS may reassess the OptuneTM device, at the request of the ministère de la Santé et des Services sociaux (MSSS), when more information becomes available, including data in reallife settings that will better reduce uncertainties and mitigate associated risks.

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.

Simultaneous perception of prosthetic and natural vision in AMD patients.

Loss of photoreceptors in atrophic age-related macular degeneration (AMD) results in severe visual impairment. Since the low-resolution peripheral vision is retained in such conditions, restoration of central vision should not jeopardize the surrounding healthy retina and allow for simultaneous use of the natural and prosthetic sight. This interim report, prespecified in the study protocol, presents the first clinical results with a photovoltaic substitute of the photoreceptors providing simultaneous use of the central prosthetic and peripheral natural vision in atrophic AMD. In this open-label single group feasibility trial (NCT03333954, recruitment completed), five patients with geographic atrophy have been implanted with a wireless 2 x 2 mm-wide 30 µm-thick device, having 378 pixels of 100 µm in size. All 5 patients achieved the primary outcome of the study by demonstrating the prosthetic visual perception in the former scotoma. The four patients with a subretinal placement of the chip demonstrated the secondary outcome: Landolt acuity of 1.17 ± 0.13 pixels, corresponding to the Snellen range of 20/460-20/565. With electronic magnification of up to a factor of 8, patients demonstrated prosthetic acuity in the range of 20/63-20/98. Under room lighting conditions, patients could simultaneously use prosthetic central vision and their remaining peripheral vision in the implanted eye and in the fellow eye.

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).

Selective Facial Muscle Activation with Acute and Chronic Multichannel Cuff Electrode Implantation in a Feline Model.

OBJECTIVES: Facial paralysis is a debilitating condition with substantial functional and psychological consequences. This feline-model study evaluates whether facial muscles can be selectively activated in acute and chronic implantation of 16-channel multichannel cuff electrodes (MCE). METHODS: Two cats underwent acute terminal MCE implantation experiments, 2 underwent chronic MCE implantation in uninjured facial nerves (FN) and tested for 6 months, and 2 underwent chronic MCE implantation experiments after FN transection injury and tested for 3 months. The MCE were wrapped around the main trunk of the skeletonized FN, and data collection consisted of EMG thresholds, amplitudes, and selectivity of muscle activation. RESULTS: In acute experimentation, activation of specific channels (ie, channels 1-3 and 6-8) resulted in selective activation of orbicularis oculi, whereas activation of other channels (ie, channels 4, 5, or 8) led to selective activation of levator auris longus with higher EMG amplitudes. MCE implantation yielded stable and selective facial muscle activation EMG thresholds and amplitudes up to a 5-month period. Modest selective muscle activation was furthermore obtained after a complete transection-reapproximating nerve injury after a 3-month recovery period and implantation reoperation. Chronic implantation of MCE did not lead to fibrosis on histology. Field steering was achieved to activate distinct facial muscles by sending simultaneous subthreshold currents to multiple channels, thus theoretically protecting against nerve damage from chronic electrical stimulation. CONCLUSION: Our proof-of-concept results show the ability of an MCE, supplemented with field steering, to provide a degree of selective facial muscle stimulation in a feline model, even following nerve regeneration after FN injury. LEVEL OF EVIDENCE: N/A.

Phrenic nerve stimulation prevents diaphragm atrophy in patients with respiratory failure on mechanical ventilation.

BACKGROUND: Diaphragm atrophy and dysfunction is a major problem among critically ill patients on mechanical ventilation. Ventilator-induced diaphragmatic dysfunction is thought to play a major role, resulting in a failure of weaning. Stimulation of the phrenic nerves and resulting diaphragm contraction could potentially prevent or treat this atrophy. The subject of this study is to determine the effectiveness of diaphragm stimulation in preventing atrophy by measuring changes in its thickness. METHODS: A total of 12 patients in the intervention group and 10 patients in the control group were enrolled. Diaphragm thickness was measured by ultrasound in both groups at the beginning of study enrollment (hour 0), after 24 hours, and at study completion (hour 48). The obtained data were then statistically analyzed and both groups were compared. RESULTS: The results showed that the baseline diaphragm thickness in the interventional group was (1.98 ± 0.52) mm and after 48 hours of phrenic nerve stimulation increased to (2.20 ± 0.45) mm (p=0.001). The baseline diaphragm thickness of (2.00 ± 0.33) mm decreased in the control group after 48 hours of mechanical ventilation to (1.72 ± 0.20) mm (p<0.001). CONCLUSIONS: Our study demonstrates that induced contraction of the diaphragm by pacing the phrenic nerve not only reduces the rate of its atrophy during mechanical ventilation but also leads to an increase in its thickness - the main determinant of the muscle strength required for spontaneous ventilation and successful ventilator weaning. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (18/06/2018, NCT03559933, https://clinicaltrials.gov/ct2/show/NCT03559933 ).

Impact of Body Mass Index and Discomfort on Upper Airway Stimulation: ADHERE Registry 2020 Update.

OBJECTIVES/HYPOTHESIS: To provide the ADHERE registry Upper Airway Stimulation (UAS) outcomes update, including analyses grouped by body mass index (BMI) and therapy discomfort. STUDY DESIGN: Prospective observational study. METHODS: ADHERE captures UAS outcomes including apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), therapy usage, patient satisfaction, clinician assessment, and safety over a 1-year period. BMI ≤32 kg/m2 (BMI32 ) and 32 < BMI ≤35 kg/m2 (BMI35 ) group outcomes were examined. RESULTS: One thousand eight hundred forty-nine patients enrolled in ADHERE, 1,019 reached final visit, 843 completed the visit. Significant changes in AHI (-20.9, P < .0001) and ESS (- 4.4, P < .0001) were demonstrated. Mean therapy usage was 5.6 ± 2.2 hr/day. Significant therapy use difference was present in patients with reported discomfort versus no discomfort (4.9 ± 2.5 vs. 5.7 ± 2.1 hr/day, P = .01). Patients with discomfort had higher final visit mean AHI versus without discomfort (18.9 ± 18.5 vs. 13.5 ± 13.7 events/hr, P = .01). Changes in AHI and ESS were not significantly different. Serious adverse events reported in 2.3% of patients. Device revision rate was 1.9%. Surgical success was less likely in BMI35 versus BMI32 patients (59.8% vs. 72.2%, P = .02). There was a significant therapy use difference: 5.8 ± 2.0 hr/day in BMI32 versus 5.2 ± 2.2 hr/day in BMI35 (P = .028). CONCLUSIONS: Data from ADHERE demonstrate high efficacy rates for UAS. Although surgical response rate differs between BMI32 and BMI35 patient groups, the AHI and ESS reduction is similar. Discomfort affects therapy adherence and efficacy. Thus, proper therapy settings adjustment to ensure comfort is imperative to improve outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2616-2624, 2021.

Application of fMRI and Simultaneous fMRI-EEG Neurofeedback in Post-Stroke Motor Rehabilitation.

This article discusses the contribution of fMRI- and fMRI-EEG-neurofeedback into recovery of motor function in two subacute stroke patients during the early post-stroke period. Premotor and supplementary motor zones of the cortex were chosen as the targets of voluntary control. Patient 1 received 6 sessions of motor imagery-based fMRI neurofeedback of secondary motor areas activity and Patient 2 received a similar course with the addition of µ- and ß-EEG activity suppression. Both reduced the motor deficit severity, improved on the quality of life, and increased the C3/C4 coherence to other central leads within EEG µ-band. Patient 1 reliably increased the fMRI signal in target areas and improved on the strength and speed of hand movements. Patient 2 (fMRI-EEG) mastered the EEG activity regulation to a greater degree. The authors conclude that pure fMRI neurofeedback and bi-modal fMRI-EEG neurofeedback produce different clinical effects in motor rehabilitation, which confirms the prospect of the closed-loop stroke treatment.

A self-powered implantable and bioresorbable electrostimulation device for biofeedback bone fracture healing.

Electrostimulation has been recognized as a promising nonpharmacological treatment in orthopedics to promote bone fracture healing. However, clinical applications have been largely limited by the complexity of equipment operation and stimulation implementation. Here, we present a self-powered implantable and bioresorbable bone fracture electrostimulation device, which consists of a triboelectric nanogenerator for electricity generation and a pair of dressing electrodes for applying electrostimulations directly toward the fracture. The device can be attached to irregular tissue surfaces and provide biphasic electric pulses in response to nearby body movements. We demonstrated the operation of this device on rats and achieved effective bone fracture healing in as short as 6 wk versus the controls for more than 10 wk to reach the same healing result. The optimized electrical field could activate relevant growth factors to regulate bone microenvironment for promoting bone formation and bone remodeling to accelerate bone regeneration and maturation, with statistically significant 27% and 83% improvement over the control groups in mineral density and flexural strength, respectively. This work provided an effective implantable fracture therapy device that is self-responsive, battery free, and requires no surgical removal after fulfilling the biomedical intervention.

Twelve-month Durability of a Fully-implanted, Nickel-sized and Shaped Tibial Nerve Stimulator for the Treatment of Overactive Bladder Syndrome with Urgency Urinary Incontinence: A Single-Arm, Prospective Study.

OBJECTIVES: To evaluate the safety and efficacy of the eCoin - a nickel-sized, primary battery-powered, neuromodulation device for the treatment of urgency urinary incontinence which is implanted in the lower leg in a 20-minute procedure under local anesthesia. A feasibility clinical trial was conducted and the results after 1 year of treatment with the eCoin are presented. METHODS: A total of 46 participants with refractory urgency urinary incontinence were included in this prospective, single-arm, open-label study. This study was conducted at 7 sites in the United States and New Zealand. Participants in this study were implanted with the eCoin in the lower leg over the tibial nerve and activated after 4 weeks. Bladder diary data and validated quality-of-life instruments, collected at 3, 6, and 12 months' post-activation, were compared to baseline values. RESULTS: Responders were defined as those who had a ≥50% reduction in reported episodes of urgency urinary incontinence. At 12 months', 65% of participants were considered responders with 26% of participants achieving complete continence. The median number of urgency urinary incontinence episodes per day decreased from 4.2 at baseline to 1.7 at 12 months'. Seventy percent of participants reported feeling "better", "much better", or "very much better" on the Likert 7-point maximum scale. One participant experienced a related serious adverse event. CONCLUSION: The eCoin is a safe and effective treatment for urgency urinary incontinence associated with overactive bladder syndrome, with significant reduction or complete resolution of symptoms and no significant safety concerns.

A compact system for simultaneous stimulation and recording for closed-loop myoelectric control.

BACKGROUND: Despite important advancements in control and mechatronics of myoelectric prostheses, the communication between the user and his/her bionic limb is still unidirectional, as these systems do not provide somatosensory feedback. Electrotactile stimulation is an attractive technology to close the control loop since it allows flexible modulation of multiple parameters and compact interface design via multi-pad electrodes. However, the stimulation interferes with the recording of myoelectric signals and this can be detrimental to control. METHODS: We present a novel compact solution for simultaneous recording and stimulation through dynamic blanking of stimulation artefacts. To test the system, a feedback coding scheme communicating wrist rotation and hand aperture was developed specifically to stress the myoelectric control while still providing meaningful information to the subjects. Ten subjects participated in an experiment, where the quality of closed-loop myoelectric control was assessed by controlling a cursor in a two degrees of freedom target-reaching task. The benchmark performance with visual feedback was compared to that achieved by combining visual feedback and electrotactile stimulation as well as by using electrotactile feedback only. RESULTS: There was no significant difference in performance between visual and combined feedback condition with regards to successfully reached targets, time to reach a target, path efficiency and the number of overshoots. Therefore, the quality of myoelectric control was preserved in spite of the stimulation. As expected, the tactile condition was significantly poorer in completion rate (100/4% and 78/25% for combined and tactile condition, respectively) and time to reach a target (9/2 s and 13/4 s for combined and tactile condition, respectively). However, the performance in the tactile condition was still good, with no significant difference in path efficiency (38/8%) and the number of overshoots (0.5/0.4 overshoots), indicating that the stimulation was meaningful for the subjects and useful for closed-loop control. CONCLUSIONS: Overall, the results demonstrated that the developed system can provide robust closed-loop control using electrotactile stimulation. The system supports different encoding schemes and allows placing the recording and stimulation electrodes next to each other. This is an important step towards an integrated solution where the developed unit will be embedded into a prosthetic socket.