Transient electronic devices that dissolve after use without causing inflammatory reactions could open avenues to alternative medical applications. This article describes the development of an innovative device designed for two-month electrophysiological monitoring followed by biodegradation. The bioresorbable electrode array is composed of poly(lactic-co-glycolic acid) (PLGA), molybdenum (Mo), and an innovative poly(3,4-ethylenedioxythiophene) (PEDOT):hyaluronan (HA) conducting polymer. First, we characterized in vitro the device's biocompatibility and lifetime, monitoring the mass loss and the evolution of the electrode's electrochemical properties. Second, the devices were implanted cortically in rats and used to record electrochemical impedance and visual evoked potentials over a period of 205 days. In vitro and in vivo characterizations demonstrated the benefits of using bioresorbable conductive polymer ink for medium-term monitoring of biological signals since the device with ink coating showed a decrease in impedance compared to the electrode without ink coating. The lifetime of the conductive polymer was estimated at 28 days and 45 days, respectively, in vitro and in vivo. According to post-mortem neuroinflammation assessment in cortical tissues, we can claim that the devices remained biocompatible for their implantation lifetime. No measurable traces of Mo were found in either the brain or the liver, even using advanced characterization methods. We can assume that the conductive polymer safely degraded in vivo in less than two months. Such devices could be used in the future either for neural recording to guide the resection of epileptic foci or for electrical stimulation to improve wound healing mechanisms.

Sleep disorders substantially impact quality of life, especially in patients with neurodegenerative diseases like Parkinson's disease. Recent advances in deep brain stimulation highlight the potential of closed-loop adaptive stimulation that utilizes neural feedback signals recorded directly from the stimulation electrodes. The subthalamic nucleus, a distinct structure located deep in the brain, plays a major role in processing cortical information and could be used to classify sleep stages. We recorded local field potentials in the subthalamic nucleus of two freely moving nonhuman primates across three nights. Our study examined subthalamic neuronal activity across different vigilance stages using spectral activity, multiscale entropy analysis, and an automatic classification. Results revealed distinct spectral patterns in subthalamic activity corresponding to sleep stages, with a high synchronization between subthalamic nucleus and EEG signals during deeper sleep stages. These deeper stages were associated also with reduced entropy, suggesting decreased neural activity complexity. An automated machine learning classifier based on subthalamic nucleus spectral activity distinguished wakefulness from sleep with high accuracy (94% for both animals). While the classifier performed well for deeper sleep stages, its accuracy was lower for lighter sleep stages. Our findings suggest that subthalamic nucleus activity can mirror cortical dynamics during sleep, supporting its potential use in developing closed-loop stimulation therapies for sleep disorders. This work provides a foundation for further studies in Parkinson's disease models to evaluate the translational relevance of subthalamic nucleus activity in clinical applications.

Parkinson s disease (PD) is a progressive neurodegenerative disorder and current treatment options only tackle symptoms. We aimed to evaluate the effect of intracranial photobiomodulation (iPBM) on dopaminergic neurons and its consequences on motor symptoms in de novo PD patients. This randomised open label study included 6 de novo PD patients, 3 served as control and 3 were treated by chronic iPBM during 2 years. They were included from december 2020 to april 2022. Researcher analysing the PET data was unaware of patients iPBM status but clinical examinator was aware of it. Data analysis was performed on June 2024. De novo PD patients were recruited and randomized (1:1) to receive iPBM or medical treatment alone for 4 years. PD diagnosis was < 2 years, and no medication was allowed at inclusion. PET scan was performed at baseline and at 1 year This randomized clinical trial was performed in France, at Clinatec-CEA research center and University Hospital, Grenoble and in CERMEP, Lyon, France. Primary outcome was safety. The secondary outcome measure was the evolution at 2 years of motor scales using the MDS-UPDRS part III and the evolution of PET scan (using the [11C]-PE2I ligand) at 1 year. Six patients (1f, 5m) were recruited with a mean age (SD) of 55.3 years (7.6). We showed that iPBM was feasible and safe on the first 3 operated patients. The first novelty of the study was that iPBM improved motor scores in average at 2 years whereas the control group followed the natural clinical decline. Mean (SD) clinical outcome with iPBM was -6.2% (32.9%) improvement on the MDS-UPDRS (part III) compared to baseline versus +130% (143%) for control group. The second novelty was that in the iPBM group, [11C]-PE2I PET scans showed an unusual mean increase in tracer binding within the caudate +21.3%(15.9), nucleus accumbens +22.2%(23.7%), pallidum +89.7% (94.8%) and putamen +26.1%(34%). in the control group, as expected, tracer binding was decreased (SD) on average in the caudate -16.9%(-16.3%), nucleus accumbens -27.5%(-28.4%), and putamen -19.5%(-11.4%), but slightly increased in the pallidum +10.7%(+39.6%). Because of the small number of patients, no statistical test was performed at this stage. Conclusions: iPBM was feasible and safe in this small group of patients. It showed an unusual improvement of motor scores at 2 years that was associated with striking increase of dopamine transporter in the basal ganglia observed on the [11C]-PE2I PET. These preliminary data suggest a possible modifying disease effect related to iBPM. A larger number of patients with longer follow up is mandatory to validate our preliminary results. ### Competing Interest Statement SC is consultant for Medtronic and Boston Scientific ST has received consultant fees from Abbvie, Boston Scientific, Medtronic and payements for lectures from MERZ, Movement Disorders Society, NHC, Aguettant ### Clinical Trial NCT04261569 ### Funding Statement This study was funded by Boston Scientific and the Edmond J Safra Foundation ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The details of the Institutional Review Board (IRB) or oversight body that approved or provided exemption for the research described in this manuscript are outlined below: All analyses conducted as part of the present study were approved by the Comite de Protection des Personnes Phones Alpes Auvergne (2019-A02097-50) April 2020 and received additional authorization from the French National Agency for the Safety of Medicines and Health Products (ANSM) in January 2020. The treatment and handling of data adhered to all applicable ethical regulations. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study will be available upon reasonable request to the authors, after completion of the study

Deep brain stimulation is a well-established treatment for improving motor symptoms in Parkinson’s disease. However, persistent non-motor symptoms, such as excessive daytime sleepiness, remain a significant challenge and necessitate further investigation. In this study, we conducted repeated measurements of daytime sleepiness using a modified multiple sleep latency test in a healthy monkey (macaca fascicularis), which was later rendered parkinsonian through MPTP administration. Deep brain stimulation targeting the lateral hypothalamic area revealed frequency-dependent modulation of both sleepiness level and core body temperature. High-frequency stimulation (80 Hz) increased sleepiness in the healthy state, while low-frequency stimulation (20 Hz) promoted wakefulness in the parkinsonian state. These findings suggest a promising therapeutic approach for addressing sleep/wake disturbances, not only in Parkinson’s disease but also in other severe sleep disorders.

OBJECTIVE:Focal cooling is emerging as a relevant therapy for drug-resistant epilepsy (DRE). However, we lack data on its effectiveness in controlling seizures that originate in deep-seated areas like the hippocampus. We present a thermoelectric solution for focal brain cooling that specifically targets these brain structures. METHODS:A prototype implantable device was developed, including temperature sensors and a cannula for penicillin injection to create an epileptogenic zone (EZ) near the cooling tip in a non-human primate model of epilepsy. The mesial temporal lobe was targeted with repeated penicillin injections into the hippocampus. Signals were recorded from an sEEG (Stereoelectroencephalography) lead placed 2 mm from the EZ. Once the number of seizures had stabilized, focal cooling was applied, and temperature and electroclinical events were monitored using a customized detection algorithm. Tests were performed on two Macaca fascicularis monkeys at three temperatures. RESULTS:Hippocampal seizures were observed 40-120 min post-injection, their duration and frequency stabilized at around 120 min. Compared to the control condition, a reduction in the number of hippocampal seizures was observed with cooling to 21°C (Control: 4.34 seizures, SD 1.704 per 20 min vs Cooling to 21°C: 1.38 seizures, SD 1.004 per 20 min). The effect was more pronounced with cooling to 17°C, resulting in an almost 80% reduction in seizure frequency. Seizure duration and number of interictal discharges were unchanged following focal cooling. After several months of repeated penicillin injections, hippocampal sclerosis was observed, similar to that recorded in humans. In addition, seizures were identified by detecting temperature variations of 0.3°C in the EZ correlated with the start of the seizures. SIGNIFICANCE:In epilepsy therapy, the ultimate aim is total seizure control with minimal side effects. Focal cooling of the EZ could offer an alternative to surgery and to existing neuromodulation devices.

Photobiomodulation (PBM)-the irradiation of tissue with low-intensity light-mitigates neuropathology in rodent models of Parkinson's disease (PD) when targeted at the head ('transcranial PBM'). In humans, however, attenuation of light energy by the scalp and skull necessitates a different approach. We have reported that targeting PBM at the body also protects the brain by a mechanism that spreads from the irradiated tissue ('remote PBM'), although the optimal peripheral tissue target for remote PBM is currently unclear. This study compared the neuroprotective efficacy of remote PBM targeting the abdomen or leg with transcranial PBM, in mouse and non-human primate models of PD. In a pilot study, the neurotoxin MPTP was used to induce PD in non-human primates; PBM (670 nm, 50 mW/cm2 , 6 min/day) of the abdomen (n = 1) was associated with fewer clinical signs and more surviving midbrain dopaminergic cells relative to MPTP-injected non-human primates not treated with PBM. Validation studies in MPTP-injected mice (n = 10 per group) revealed a significant rescue of midbrain dopaminergic cells in mice receiving PBM to the abdomen (~80%, p < .0001) or legs (~80%, p < .0001), with comparable rescue of axonal terminals in the striatum. Strikingly, this degree of neuroprotection was at least as, if not more, pronounced than that achieved with transcranial PBM. These findings confirm that remote PBM provides neuroprotection against MPTP-induced destruction of the key circuitry underlying PD, with both the abdomen and legs serving as viable remote targets. This should provide the impetus for a comprehensive investigation of remote PBM-induced neuroprotection in other models of PD and, ultimately, human patients.

Background:Deep brain electromodulation (DBEM), also known as deep brain stimulation in different intracerebral targets, is the most widely used surgical treatment due to its effects in reducing motor symptoms of Parkinson's disease. The intracerebral microelectrode recording has been considered for decades as a necessary tool for the success of Parkinson's surgery. However, some publications give more importance to intracerebral stimulation as a better predictive test. Since 2002, we initiated a technique of brain implant of electrodes without micro recording and based solely on image-guided stereotaxis followed by intraoperative macrostimulation. In this work, we analyze our long-term results, taking into account motor skills and quality of life (QL) before and after surgery, and we also establish the patient's time of clinical improvement.Methods:This is a descriptive clinical study in which the motor state of the patients was evaluated with the unified Parkinson's disease scale (UPDRS) and the QL using the Parkinson's disease QL questionnaire 39 questionnaires before surgery, in the "on" state of the medication; and after surgery, under active stimulation and in the "on" state.Results:Twenty-four patients with ages ranging from 37 to 78 years undergoing surgery DBEM on the subthalamic nucleus were studied. An improvement of 41.4% in motor skills and 41.7% in QL was obtained.Conclusion:When microrecording is not available, the results that can be obtained, based on preoperative imaging and clinical intraoperative findings, are optimal and beneficial for patients.

Epilepsy is synonymous with individuals suffering repeated "fits" or seizures. The seizures are triggered by bursts of abnormal neuronal activity, across either the cerebral cortex and/or the hippocampus. In addition, the seizure sites are characterized by considerable neuronal death. Although the factors that generate this abnormal activity and death are not entirely clear, recent evidence indicates that mitochondrial dysfunction plays a central role. Current treatment options include drug therapy, which aims to suppress the abnormal neuronal activity, or surgical intervention, which involves the removal of the brain region generating the seizure activity. However, ~30% of patients are unresponsive to the drugs, while the surgery option is invasive and has a morbidity risk. Hence, there is a need for the development of an effective non-pharmacological and non-invasive treatment for this disorder, one that has few side effects. In this review, we consider the effectiveness of a potential new treatment for epilepsy, known as photobiomodulation, the use of red to near-infrared light on body tissues. Recent studies in animal models have shown that photobiomodulation reduces seizure-like activity and improves neuronal survival. Further, it has an excellent safety record, with little or no evidence of side effects, and it is non-invasive. Taken all together, this treatment appears to be an ideal treatment option for patients suffering from epilepsy, which is certainly worthy of further consideration.

Patients with Parkinson's disease often complain of excessive daytime sleepiness which negatively impacts their quality of life. The pedunculopontine nucleus, proposed as a target for deep brain stimulation to improve freezing of gait in Parkinson's disease, is also known to play a key role in the arousal system. Thus, the putative control of excessive daytime sleepiness by pedunculopontine nucleus area stimulation merits exploration for treating Parkinson's disease patients. To this end, two adult nonhuman primates (macaca fascicularis) received a deep brain stimulation electrode implanted into the pedunculopontine nucleus area along with a polysomnographic equipment. Stimulation at low frequencies and high frequencies was studied, in healthy and then MPTP-treated nonhuman primates. Here, we observed that MPTP-treated nonhuman primates suffered from excessive daytime sleepiness and that low-frequency stimulation of the pedunculopontine nucleus area was effective in reducing daytime sleepiness. Indeed, low-frequency stimulation of the pedunculopontine nucleus area induced a significant increase in sleep onset latency, longer continuous periods of wakefulness and thus, a partially restored daytime wake architecture. These findings may contribute to the development of new therapeutic strategies in patients suffering from excessive daytime sleepiness.

Parkinsonian patients often experience wake/sleep behavior disturbances, which can appear at an early stage of the disease in a way that is still not fully described. We aimed here at reproducing and characterizing these clinical signs in a progressive non-human primate model of the Parkinson’s disease to better understand the underlying physiopathology and to identify biomarkers of the disease. Three adult non-human primates ( macaca fascicularis ) were equipped with a polysomnographic telemetry system allowing the characterization of the wake/sleep behavior by long-term neurophysiological recordings and a modified multiple sleep latency test. Experiments were first performed in healthy animals and then during the progressive induction of a parkinsonian syndrome by chronic intramuscular injections of low doses of MPTP. We observed a significant early onset of wake/sleep behavior disturbances, before any motor symptoms, resulting in (i) a disorganization of nighttime sleep with more deep sleep and (ii) a disorganization of daytime naps with an excessive daytime sleepiness characterized by longer duration of naps, which occurred faster. These observations persisted and worsened in stable symptomatic state. In that latter state, we observed persistent excessive daytime sleepiness and more disorganized nighttime sleep architecture and continuity. Interpolating to the human condition, the present study suggests that nighttime and daytime sleep disorders may appear in early stage of the disease. They could thus be used as biomarkers of the disease for early stratification of patients who are at risk of developing Parkinson’s disease.

Parkinsonian patients often experience sleep/wake disturbances, which may appear at an early stage of the disease; however, these disturbances have not been fully described. To better understand the evolution of these disturbances with respect to disease progression, we aimed to characterize these clinical signs in a progressive nonhuman primate model of Parkinson's disease. Three adult macaques (Macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of sleep/wake behavior via long-term neurophysiological recordings and underwent a modified multiple sleep latency test. Experiments were first performed in a healthy state and then during the progressive induction of a parkinsonian syndrome by intramuscular injections of low doses of MPTP. We observed an early onset of significant sleep/wake disturbances (i.e., before the appearance of motor symptoms). These disturbances resulted in (i) a disorganization of nighttime sleep with reduced deep sleep quality and (ii) an excessive daytime sleepiness characterized by sleep episodes occurring more rapidly in the morning and spreading through the middle of the day. The present study suggests that nighttime and daytime sleep/wake disturbances may appear early in the disease and should be considered in the development of biomarkers in further studies.

We studied the microselective neurotomy (MSN) and its advantages to alleviate disabling spasticity. The best indication for MSN is focal spasticity. We performed 298 MSN, 87 nerves on the upper limb, 211 nerves on the lower limb) in 68 patients. The initial causes were: stroke, cranial trauma, postoperative complications and multiple sclerosis. MSN procedures were performed on the median nerve (n = 40) for wrist and finger flexion; musculo-cutaneus nerve (n = 38) for elbow flexion; ulnaris nerve (n = 9) for cubital deviation of the hand; gastrocnemius nerve (n = 98) and soleus nerve (n = 49) for equinus foot, tibial posterior nerve (n = 45) for varus foot, and fascicles (or bundles) of the flexor digitorum for “claw” toes (n = 19). The main preoperative test to identify the responsible nerve was a neuromuscular block with local anesthesia (lidocaine or bupivacaine) injected into the site of the nerve connecting the spastic muscle. During surgery, the identified nerve was exposed and its epineurium opened. Nerve bundles were teased apart into individual rootlets and a number of rootlets cut were previously planned, according to the spasticity. Follow-up was performed for up to 10 years, with a mean period of 29 months. Results demonstrated a reduction of limb spasticity of 2 to 3 points: modified Ashworth scale (MAS). Pain and clonus were also diminished in the affected limb. In some cases, voluntary movement was once again possible. MSN is a useful alternative in those cases of focal spasticity where physiotherapy and nerve block with botulinum toxin or phenol no longer produce satisfactory results.

In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson's disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson's disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson's disease, given that the major zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson's disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option.

In Parkinson’s disease (PD), dopaminergic neurons reduce the regulation of glutamatergic (glutamate-Glu) input from the cortex to neostriatum (caudate and putamen nuclei) consequently leading to a hyperactivity of globus pallidus internae (GPi) neurons that release gamma-amino-butyric acid (GABA) into the thalamic ventrolateral (VL) nucleus. The objective of the present experiment was to measure changes in GABA and Glu in the caudate and the thalamus of 2 patients during the application of electrical stimuli following either a pallidotomy or a thalamotomy. Proper insertion of the electrode was tested by applying high frequency electrical pulses (HFEP). During these procedures, we obtained neurochemical information placing cerebral (CMD) microdialysis probes in caudate nucleus and VL nucleus of ipsi- and contra-lateral thalamus. In VL thalamus, extracellular GABA decreased during HFEP, tending to reach previous levels once HFEP was finalized. Following the pallido- or thalamotomy GABA decreased again. Similarly, in the contralateral VL thalamus, extracellular GABA levels showed a similar but less pronounced profile but did not show any decrement after the lesion. Caudate Glu decreases when HFEP is applied to the GPi and recovers to previous levels after HFEP, but did not decrease again after lesion (GPi-tomy), instead it continued to rise. These results suggest that HFEP exerts a similar but reversible biochemical effect as thermopallido- or thermothalamotomy on GABA extracellular concentration in the ipsilateral VL thalamus. We also observe a distant effect of HFEP, but not of thermolesion, on contralateral thalamic GABA and ipsilateral caudate Glu.

Neurosurgery for psychiatric disorders, notably for obsessive-compulsive disorder (OCD), was initiated in Venezuela in the decade of 1970, and consisted since that time in the classic stereotactic anterior cingulotomy.In order to know further about the physiopathology of this disorder, we performed intracerebral microdialysis in 2 patients who were operated on.The aim was to measure changes in extracellular neurotransmitters within the basal ganglia.The microdialysis probes were stereotactically placed in the right caudate nucleus and in the dorsomedial nucleus of the right thalamus.The microdialysis was done before the left cingulotomy, during the pause and after the right cingulotomy.Glutamate and gamma-aminobutyric acid (GABA) changes were similar in the caudate nucleus of both patients, whereas in the dorsomedial nucleus the changes were opposite among the 2 patients.Although this study does not bring enough data to explain such differences yet, the existence of dynamic changes in the neurochemistry of the basal ganglia during cingulotomy shows that intracerebral microdialysis can help in the understanding of the pathophysiology of OCD and eventually in the design of new surgeries with better results.

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. (C) 2019 Elsevier B.V. All rights reserved.

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.

Background Approximately 20% of traumatic cervical spinal cord injuries result in tetraplegia. Neuroprosthetics are being developed to manage this condition and thus improve the lives of patients. We aimed to test the feasibility of a semi-invasive technique that uses brain signals to drive an exoskeleton. Methods We recruited two participants at Clinatec research centre, associated with Grenoble University Hospital, Grenoble, France, into our ongoing clinical trial. Inclusion criteria were age 18-45 years, stability of neurological deficits, a need for additional mobility expressed by the patient, ambulatory or hospitalised monitoring, registration in the French social security system, and signed informed consent. The exclusion criteria were previous brain surgery, anticoagulant treatments, neuropsychological sequelae, depression, substance dependence or misuse, and contraindications to magnetoencephalography (MEG), EEG, or MRI. One participant was excluded because of a technical problem with the implants. The remaining participant was a 28-year-old man, who had tetraplegia following a C4-C5 spinal cord injury. Two bilateral wireless epidural recorders, each with 64 electrodes, were implanted over the upper limb sensorimotor areas of the brain. Epidural electrocorticographic (ECoG) signals were processed online by an adaptive decoding algorithm to send commands to effectors (virtual avatar or exoskeleton). Throughout the 24 months of the study, the patient did various mental tasks to progressively increase the number of degrees of freedom. Findings Between June 12,2017, and July 21,2019, the patient cortically controlled a programme that simulated walking and made bimanual, multi-joint, upper-limb movements with eight degrees of freedom during various reach-andtouch tasks and wrist rotations, using a virtual avatar at home (64.0% [SD 5.1] success) or an exoskeleton in the laboratory (70.9% [11.6] success). Compared with rnicroelectrodes, epidural ECoG is semi-invasive and has similar efficiency. The decoding models were reusable for up to approximately 7 weeks without recalibration. Interpretation These results showed long-term (24-month) activation of a four-limb neuroprosthetic exoskeleton by a complete brain-machine interface system using continuous, online epidural ECoG to decode brain activity in a tetraplegic patient. Up to eight degrees of freedom could be simultaneously controlled using a unique model, which was reusable without recalibration for up to about 7 weeks. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

OBJECTIVEWireless technology is a novel tool for the transmission of cortical signals. Wireless electrocorticography (ECoG) aims to improve the safety and diagnostic gain of procedures requiring invasive localization of seizure foci and also to provide long-term recording of brain activity for brain-computer interfaces (BCIs). However, no wireless devices aimed at these clinical applications are currently available. The authors present the application of a fully implantable and externally rechargeable neural prosthesis providing wireless ECoG recording and direct cortical stimulation (DCS). Prolonged wireless ECoG monitoring was tested in nonhuman primates by using a custom-made device (the ECoG implantable wireless 16-electrode [ECOGIW-16E] device) containing a 16-contact subdural grid. This is a preliminary step toward large-scale, long-term wireless ECoG recording in humans.METHODSThe authors implanted the ECOGIW-16E device over the left sensorimotor cortex of a nonhuman primate (Macaca fascicularis), recording ECoG signals over a time span of 6 months. Daily electrode impedances were measured, aiming to maintain the impedance values below a threshold of 100 KΩ. Brain mapping was obtained through wireless cortical stimulation at fixed intervals (1, 3, and 6 months). After 6 months, the device was removed. The authors analyzed cortical tissues by using conventional histological and immunohistological investigation to assess whether there was evidence of damage after the long-term implantation of the grid.RESULTSThe implant was well tolerated; no neurological or behavioral consequences were reported in the monkey, which resumed his normal activities within a few hours of the procedure. The signal quality of wireless ECoG remained excellent over the 6-month observation period. Impedance values remained well below the threshold value; the average impedance per contact remains approximately 40 KΩ. Wireless cortical stimulation induced movements of the upper and lower limbs, and elicited fine movements of the digits as well. After the monkey was euthanized, the grid was found to be encapsulated by a newly formed dural sheet. The grid removal was performed easily, and no direct adhesions of the grid to the cortex were found. Conventional histological studies showed no cortical damage in the brain region covered by the grid, except for a single microscopic spot of cortical necrosis (not visible to the naked eye) in a region that had undergone repeated procedures of electrical stimulation. Immunohistological studies of the cortex underlying the grid showed a mild inflammatory process.CONCLUSIONSThis preliminary experience in a nonhuman primate shows that a wireless neuroprosthesis, with related long-term ECoG recording (up to 6 months) and multiple DCSs, was tolerated without sequelae. The authors predict that epilepsy surgery could realize great benefit from this novel prosthesis, providing an extended time span for ECoG recording.