Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback.

OBJECTIVE: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS: To this aim, we performed a 6-month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS: All subjects, notwithstanding their important clinical differences, reported stimulation-induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137-154.

Selective neural electrical stimulation restores hand and forearm movements in individuals with complete tetraplegia.

BACKGROUND: We hypothesized that a selective neural electrical stimulation of radial and median nerves enables the activation of functional movements in the paralyzed hand of individuals with tetraplegia. Compared to previous approaches for which up to 12 muscles were targeted through individual muscular stimulations, we focused on minimizing the number of implanted electrodes however providing almost all the needed and useful hand movements for subjects with complete tetraplegia. METHODS: We performed acute experiments during scheduled surgeries of the upper limb with eligible subjects. We scanned a set of multicontact neural stimulation cuff electrode configurations, pre-computed through modeling simulations. We reported the obtained isolated and functional movements that were considered useful for the subject (different grasping movements). RESULTS: In eight subjects, we demonstrated that selective stimulation based on multicontact cuff electrodes and optimized current spreading over the active contacts provided isolated, compound, functional and strong movements; most importantly 3 out of 4 had isolated fingers or thumb flexion, one patient performed a Key Grip, another one the Power and Hook Grips, and the 2 last all the 3 Grips. Several configurations were needed to target different areas within the nerve to obtain all the envisioned movements. We further confirmed that the upper limb nerves have muscle specific fascicles, which makes it possible to activate isolated movements. CONCLUSIONS: The future goal is to provide patients with functional restoration of object grasping and releasing with a minimally invasive solution: only two cuff electrodes above the elbow. Ethics Committee / ANSM clearance prior to the beginning of the study (inclusion period 2016-2018): CPP Sud Méditerranée, #ID-RCB:2014-A01752-45, first acceptance 10th of February 2015, amended 12th of January 2016. TRIAL REGISTRATION: (www.clinicaltrials.gov): #NCT03721861, Retrospectively registered on 26th of October 2018.

Chronic abdominal vagus stimulation increased brain metabolic connectivity, reduced striatal dopamine transporter and increased mid-brain serotonin transporter in obese miniature pigs.

BACKGROUND/OBJECTIVE: Changes in brain metabolism has been investigated thoroughly during unilateral cervical chronic vagal stimulation in epileptic or depressive patients. Bilateral stimulation of the abdominal vagus (aVNS) has received less attention despite the reduction in body weight and an altered feeding behavior in obese animals that could be clinically relevant in obese individuals. Our study aims to examine the changes in brain glucose metabolism (CMRglu) induced by aVNS in obese adult miniature pigs. Dopamine (DAT) and serotonin transporters (SERT) were also quantified to further understand the molecular origins of the alterations in brain metabolism. SUBJECTS/METHODS: Pairs of stimulating electrodes were implanted during laparoscopy on both abdominal vagal trunks in 20 obese adult's miniature pigs. Half of the animals were permanently stimulated while the remaining were sham stimulated. Two months after the onset of stimulation, dynamic 18FDG PET and 123I-ioflupane SPECT were performed. Food intake, resting energy expenditure and fat deposition were also assessed longitudinally. RESULTS: Food intake was halved and resting energy expenditure was increased by 60% in aVNS group compared to sham. The gain in body weight was also 38% less in aVNS group compared to sham. Brain metabolic connectivity increased between numerous structures including striatum, mid-brain, amygdala and hippocampus. On the contrary, increased CMRglu were restricted to the thalamus, the periaqueducal grey and the amygdala. DAT binding potential was decreased by about one third in the striatum while SERT was about doubled in the midbrain. CONCLUSIONS: Our findings demonstrated that aVNS reduced weight gain as a consequence of diminished daily food intake and increased resting energy expenditure. These changes were associated with enhanced connectivity between several brain areas. A lower striatal DAT together with a doubled mid-brain SERT were likely causative for these changes.

Stability of flexible thin-film metallization stimulation electrodes: analysis of explants after first-in-human study and improvement of in vivo performance.

OBJECTIVE: Micro-fabricated neural interfaces based on polyimide (PI) are achieving increasing importance in translational research. The ability to produce well-defined micro-structures with properties that include chemical inertness, mechanical flexibility and low water uptake are key advantages for these devices. APPROACH: This paper reports the development of the transverse intrafascicular multichannel electrode (TIME) used to deliver intraneural sensory feedback to an upper-limb amputee in combination with a sensorized hand prosthesis. A failure mode analysis on the explanted devices was performed after a first-in-human study limited to 30 d. MAIN RESULTS: About 90% of the stimulation contact sites of the TIMEs maintained electrical functionality and stability during the full implant period. However, optical analysis post-explantation revealed that 62.5% of the stimulation contacts showed signs of delamination at the metallization-PI interface. Such damage likely occurred due to handling during explantation and subsequent analysis, since a significant change in impedance was not observed in vivo. Nevertheless, whereas device integrity is mandatory for long-term functionality in chronic implantation, measures to increase the bonding strength of the metallization-PI interface deserve further investigation. We report here that silicon carbide (SiC) is an effective adhesion-promoting layer resisting heavy electrical stimulation conditions within a rodent animal trial. Optical analysis of the new electrodes revealed that the metallization remained unaltered after delivering over 14 million pulses in vivo without signs of delamination at the metallization-PI interface. SIGNIFICANCE: Failure mode analysis guided implant stability optimization. Reliable adhesion of thin-film metallization to substrate has been proven using SiC, improving the potential transfer of micro-fabricated neural electrodes for chronic clinical applications. (Document number of Ethical Committee: P/905/CE/2012; Date of approval: 2012-10-04).

Reliability of parylene-based multi-electrode arrays chronically implanted in adult rat brains, and evidence of electrical stimulation on contact impedance.

OBJECTIVE: The goal of this study was to evaluate the long-term behavior of the surface electrode through electrochemical characterization and follow-up of implanted parylene/platinum microelectrodes. APPROACH: To this aim, we designed and manufactured specific planar electrodes for cortical implantation for a rat model. This work was included in the INTENSE® project, one of the goals of which was to prove the feasibility of selective neural recording or stimulation with cuff electrodes around the vagus nerve. MAIN RESULTS: After a 12-week implantation in a rat model, we can report that these microelectrodes have withstood in vivo use. Regarding the biocompatibility of the electrodes (materials and manufacturing process), no adverse effect was reported. Indeed, after the three-month implantation, we characterized limited tissue reaction beneath the electrodes and showed an increase and a stabilization of their impedance. Interestingly, the follow-up of the electrochemical impedance combined with electrical stimulation highlighted a drop in the impedance up to 60% at 1 kHz after ten minutes of electrical stimulation at 110 Hz. SIGNIFICANCE: This study gives evidence of the biocompatibility of the parylene platinum contact array designed for the project and confirms the effect of stimulation on the contact impedance.

Evaluation of chronically implanted subdural boron doped diamond/CNT recording electrodes in miniature swine brain.

When implantable recording devices for brain or neural electrical activity are designed, the number of available materials for electrodes is quite limited. The material must be biocompatible with respect to ISO10993, its electrochemical properties must remain stable and the response of cells or tissues can be mitigated, especially on the glial scar. This involves electrode characterization pre- implantation and impedance spectroscopy during chronic implantation, in order to evaluate both electrode properties and performance. This study was aimed at a comparison of the long-term behavior of a nanostructured boron-doped diamond (BDD) with a nanostructured Platinum Iridium (PtIr) electrode. Firstly, a batch of cortical grids with bare and modified contacts (2 mm in diameter) was engineered for implantation. Secondly a miniature swine model was developed. This study highlighted the predominant role of electrode surface roughness on the quality of recordings. Rough PtIr contacts and BDD coated ones showed comparable behavior after three-month implantation with a slight increase of the modulus of the impedance and a tissue capsule. Nevertheless, immunohistochemistry analysis did not exhibit either a toxic or irritation reaction. With regard to biocompatibility, promising long term results are shown for both materials.

Pancreatic nerve electrostimulation inhibits recent-onset autoimmune diabetes.

Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in ß-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.

Enhancing functional abilities and cognitive integration of the lower limb prosthesis.

Lower limb amputation (LLA) destroys the sensory communication between the brain and the external world during standing and walking. Current prostheses do not restore sensory feedback to amputees, who, relying on very limited haptic information from the stump-socket interaction, are forced to deal with serious issues: the risk of falls, decreased mobility, prosthesis being perceived as an external object (low embodiment), and increased cognitive burden. Poor mobility is one of the causes of eventual device abandonment. Restoring sensory feedback from the missing leg of above-knee (transfemoral) amputees and integrating the sensory feedback into the sensorimotor loop would markedly improve the life of patients. In this study, we developed a leg neuroprosthesis, which provided real-time tactile and emulated proprioceptive feedback to three transfemoral amputees through nerve stimulation. The feedback was exploited in active tasks, which proved that our approach promoted improved mobility, fall prevention, and agility. We also showed increased embodiment of the lower limb prosthesis (LLP), through phantom leg displacement perception and questionnaires, and ease of the cognitive effort during a dual-task paradigm, through electroencephalographic recordings. Our results demonstrate that induced sensory feedback can be integrated at supraspinal levels to restore functional abilities of the missing leg. This work paves the way for further investigations about how the brain interprets different artificial feedback strategies and for the development of fully implantable sensory-enhanced leg neuroprostheses, which could drastically ameliorate life quality in people with disability.

Phantom somatosensory evoked potentials following selective intraneural electrical stimulation in two amputees.

OBJECTIVE: The aim of the paper is to objectively demonstrate that amputees implanted with intraneural interfaces are truly able to feel a sensation in the phantom hand by recording "phantom" somatosensory evoked potentials from the corresponding brain areas. METHODS: We implanted four transverse intrafascicular multichannel electrodes, available with percutaneous connections to a multichannel electrical stimulator, in the median and ulnar nerves of two left trans-radial amputees. Two channels of the implants that were able to elicit sensations during intraneural nerve stimulation were chosen, in both patients, for recording somatosensory evoked potentials. RESULTS: We recorded reproducible evoked responses by stimulating the median and the ulnar nerves in both cases. Latencies were in accordance with the arrival of somatosensory information to the primary somatosensory cortex. CONCLUSION: Our results provide evidence that sensations generated by intraneural stimulation are truly perceived by amputees and located in the phantom hand. Moreover, our results strongly suggest that sensations perceived in different parts of the phantom hand result in different evoked responses. SIGNIFICANCE: Somatosensory evoked potentials obtained by selective intraneural electrical stimulation in amputee patients are a useful tool to provide an objective demonstration of somatosensory feedback in new generation bidirectional prostheses.

Obesity-Associated Alterations in Glucose Metabolism Are Reversed by Chronic Bilateral Stimulation of the Abdominal Vagus Nerve.

Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole-body and organ-specific insulin sensitivities 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual-channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight (i.e., lean nonstimulated, obese nonstimulated, and obese stimulated). Twelve weeks after surgery, glucose uptake and insulin sensitivity were measured using positron emission tomography during an isoglycemic clamp. Mean whole-body insulin sensitivity was lower by 34% (P < 0.01) and the hepatic glucose uptake rate was lower by 33% (P < 0.01) in obese-nonstimulated mini-pigs but was no different in obese-stimulated compared with lean mini-pigs. An improvement in skeletal glucose uptake rate was also observed in obese-stimulated compared with obese-nonstimulated groups (P < 0.01). Vagal stimulation was associated with increased glucose metabolism in the cingulate and prefrontal brain areas. We conclude that chronic vagal stimulation improves insulin sensitivity substantially in diet-induced obesity by both peripheral and central mechanisms.

Effects of chronic abdominal vagal stimulation of small-diameter neurons on brain metabolism and food intake.

BACKGROUND: Abdominal bilateral vagal stimulation reduces food intake in animals. However, the classical square wave, mA range current generator is poorly effective to evoke action potentials on A∂ and C neurons that represent the majority of vagal neurons at the abdominal level. OBJECTIVE/HYPOTHESIS: METHODS: The current thresholds for pulsons (S2 & S3) and millisecond pulses (S1) required to trigger action potentials were calculated in 5 anaesthetized pigs using single fibre recording. Similar stimulation protocols were compared chronically to sham stimulation in 24 pigs. After two weeks of chronic stimulation, food intake and brain metabolism were investigated. The electrical characteristics and histology of the vagus nerve were also studied. RESULTS: S3 stimulation required a lower amount of charges to trigger an action potential. Chronically applied S2 & S3 activated the dorsal vagal complex and increased the metabolism of its afferent cortical structures. They also reduced energy intake together with a reduced ingestion of high fat and high sugar diets. All these effects were not observed for the S1 group. The vagal histology for the S1, S2 and S3 groups was not different from that of the sham. CONCLUSIONS: These findings demonstrate that pulsons applied bilaterally on the abdominal vagus reduced food intake as a consequence of the activation of the brainstem and higher-order brain areas.

Original electronic design to perform epimysial and neural stimulation in paraplegia.

This paper presents an original electronic architecture to manage epimysial and neural stimulation using the same implantable device. All the muscles needed to achieve lower limb movements such as standing and walking can thus be activated. Mainly for surgical reasons, some muscles need to be stimulated through different inputs: epimysium or motor nerve. We developed an electronic solution, including the design of an application-specific integrated circuit, to meet the requirements of both types of stimulation. Five years after the successful implantation of the system, we were able to evaluate the system's performance. The patient is still using the system at home and no failure occurred during this 5-year period. We conclude that the electronic design not only provides a unique investigative tool for research, but that it can also be used to restore the motor function of the lower limb. This technology has an advantage over external stimulation because the patient can safely use the system at home. However, improvements such as lower power consumption, and thus greater autonomy, are needed. We further conclude that the modelling of the electrical behaviour of the electrodes is reliable and the estimated parameter values are homogeneous and consistent for the same type of electrode. Thus, the three parameters of the first-order model can be identified from an acute animal experiment and provide a means to optimize the design of the output stage of implanted stimulators.

An implantable neuroprosthesis for standing and walking in paraplegia: 5-year patient follow-up.

We present the results of a 5-year patient follow-up after implantation of an original neuroprosthesis. The system is able to stimulate both epimysial and neural electrodes in such a way that the complete flexor-extensor chain of the lower limb can be activated without using the withdrawal reflex. We demonstrate that standing and assisted walking are possible, and the results have remained stable for 5 years. Nevertheless, some problems were noted, particularly regarding the muscle response on the epimysial channels. Analysis of the electrical behaviour and thresholds indicated that the surgical phase is crucial because of the sensitivity of the functional responses to electrode placement. Neural stimulation proved to be more efficient and more stable over time. This mode requires less energy and provides more selective stimulation. This FES system can be improved to enable balanced standing and less fatiguing gait, but this will require feedback on event detection to trigger transitions between stimulation sequences, as well as feedback to the patient about the state of his lower limbs.

Development of a neurotechnological system for relieving phantom limb pain using transverse intrafascicular electrodes (TIME).

Phantom limb pain (PLP) is a chronic condition that develops in the majority of amputees. The underlying mechanisms are not completely understood, and thus, no treatment is fully effective. Based on recent studies, we hypothesize that electrical stimulation of afferent nerves might alleviate PLP by giving sensory input to the patient if nerve fibers can be activated selectively. The critical component in this scheme is the implantable electrode structure. We present a review of a novel electrode concept to distribute highly selective electrode contacts over the complete cross section of a peripheral nerve to create a distributed activation of small nerve fiber ensembles at the fascicular level, the transverse intrafascicular multichannel nerve electrode (TIME). The acute and chronic implantations in a small animal model exhibited a good surface and structural biocompatibility as well as excellent selectivity. Implantation studies on large animal models that are closer to human nerve size and anatomical complexity have also been conducted. They proved implant stability and the ability to selectively activate nerve fascicles in a limited proximity to the implant. These encouraging results have opened the way forward for human clinical trials in amputees to investigate the effect of selective electrical stimulation on PLP.