Recovery of walking after paralysis by regenerating characterized neurons to their natural target region.

Axon regeneration can be induced across anatomically complete spinal cord injury (SCI), but robust functional restoration has been elusive. Whether restoring neurological functions requires directed regeneration of axons from specific neuronal subpopulations to their natural target regions remains unclear. To address this question, we applied projection-specific and comparative single-nucleus RNA sequencing to identify neuronal subpopulations that restore walking after incomplete SCI. We show that chemoattracting and guiding the transected axons of these neurons to their natural target region led to substantial recovery of walking after complete SCI in mice, whereas regeneration of axons simply across the lesion had no effect. Thus, reestablishing the natural projections of characterized neurons forms an essential part of axon regeneration strategies aimed at restoring lost neurological functions.

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.

Therapies for obsessive-compulsive disorder: Current state of the art and perspectives for approaching treatment-resistant patients.

Even though obsessive compulsive disorder (OCD) is one of the ten most disabling diseases according to the WHO, only 30-40% of patients suffering from OCD seek specialized treatment. The currently available psychotherapeutic and pharmacological approaches, when properly applied, prove ineffective in about 10% of cases. The use of neuromodulation techniques, especially Deep Brain Stimulation, is highly promising for these clinical pictures and knowledge in this domain is constantly evolving. The aim of this paper is to provide a summary of the current knowledge about OCD treatment, while also discussing the more recent proposals for defining resistance.

Low-Intensity Focused Ultrasound Neuromodulation for Stroke Recovery: A Novel Deep Brain Stimulation Approach for Neurorehabilitation?

Stroke as the leading cause of adult long-term disability and has a significant impact on patients, society and socio-economics. Non-invasive brain stimulation (NIBS) approaches such as transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tES) are considered as potential therapeutic options to enhance functional reorganization and augment the effects of neurorehabilitation. However, non-invasive electrical and magnetic stimulation paradigms are limited by their depth focality trade-off function that does not allow to target deep key brain structures critically important for recovery processes. Transcranial ultrasound stimulation (TUS) is an emerging approach for non-invasive deep brain neuromodulation. Using non-ionizing, ultrasonic waves with millimeter-accuracy spatial resolution, excellent steering capacity and long penetration depth, TUS has the potential to serve as a novel non-invasive deep brain stimulation method to establish unprecedented neuromodulation and novel neurorehabilitation protocols. The purpose of the present review is to provide an overview on the current knowledge about the neuromodulatory effects of TUS while discussing the potential of TUS in the field of stroke recovery, with respect to existing NIBS methods. We will address and discuss critically crucial open questions and remaining challenges that need to be addressed before establishing TUS as a new clinical neurorehabilitation approach for motor stroke recovery.

Targeted dorsal root entry zone stimulation alleviates pain due to meralgia paresthetica.

Objective.Meralgia paresthetica (MP) is a mononeuropathy of the exclusively sensory lateral femoral cutaneous nerve (LFCN) that is difficult to treat with conservative treatments. Afferents from the LFCN enter the spinal cord through the dorsal root entry zones (DREZs) innervating L2 and L3 spinal segments. We previously showed that epidural electrical stimulation of the spinal cord can be configured to steer electrical currents laterally in order to target afferents within individual DREZs. Therefore, we hypothesized that this neuromodulation strategy is suitable to target the L2 and L3 DREZs that convey afferents from the painful territory, and thus alleviates MP related pain.Approach.A patient in her mid-30s presented with a four year history of dysesthesia and burning pain in the anterolateral aspect of the left thigh due to MP that was refractory to medical treatments. We combined neuroimaging and intraoperative neuromonitoring to guide the surgical placement of a paddle lead over the left DREZs innervating L2 and L3 spinal segments.Main results.Optimized electrode configurations targeting the left L2 and L3 DREZs mediated immediate and sustained alleviation of pain. The patient ceased all other medical management, reported improved quality of life, and resumed recreational physical activities.Significance.We introduced a new treatment option to alleviate pain due to MP, and demonstrated how neuromodulation strategies targeting specific DREZs is effective to reduce pain confined to specific regions of the body while avoiding disconfort.

Natural and targeted circuit reorganization after spinal cord injury.

A spinal cord injury disrupts communication between the brain and the circuits in the spinal cord that regulate neurological functions. The consequences are permanent paralysis, loss of sensation and debilitating dysautonomia. However, the majority of circuits located above and below the injury remain anatomically intact, and these circuits can reorganize naturally to improve function. In addition, various neuromodulation therapies have tapped into these processes to further augment recovery. Emerging research is illuminating the requirements to reconstitute damaged circuits. Here, we summarize these natural and targeted reorganizations of circuits after a spinal cord injury. We also advocate for new concepts of reorganizing circuits informed by multi-omic single-cell atlases of recovery from injury. These atlases will uncover the molecular logic that governs the selection of 'recovery-organizing' neuronal subpopulations, and are poised to herald a new era in spinal cord medicine.

The neurons that restore walking after paralysis.

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord1-3 applied during neurorehabilitation4,5 (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing6-9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.

Principles of gait encoding in the subthalamic nucleus of people with Parkinson's disease.

Disruption of subthalamic nucleus dynamics in Parkinson's disease leads to impairments during walking. Here, we aimed to uncover the principles through which the subthalamic nucleus encodes functional and dysfunctional walking in people with Parkinson's disease. We conceived a neurorobotic platform embedding an isokinetic dynamometric chair that allowed us to deconstruct key components of walking under well-controlled conditions. We exploited this platform in 18 patients with Parkinson's disease to demonstrate that the subthalamic nucleus encodes the initiation, termination, and amplitude of leg muscle activation. We found that the same fundamental principles determine the encoding of leg muscle synergies during standing and walking. We translated this understanding into a machine learning framework that decoded muscle activation, walking states, locomotor vigor, and freezing of gait. These results expose key principles through which subthalamic nucleus dynamics encode walking, opening the possibility to operate neuroprosthetic systems with these signals to improve walking in people with Parkinson's disease.

Epidural electrical stimulation of the cervical dorsal roots restores voluntary upper limb control in paralyzed monkeys.

Regaining arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control has limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury, using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts targeting specific spinal segments produced sustained arm movements, enabling monkeys with arm paralysis to perform an unconstrained reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that residual descending inputs were necessary to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.

Implanted System for Orthostatic Hypotension in Multiple-System Atrophy.

Orthostatic hypotension is a cardinal feature of multiple-system atrophy. The upright posture provokes syncopal episodes that prevent patients from standing and walking for more than brief periods. We implanted a system to restore regulation of blood pressure and enable a patient with multiple-system atrophy to stand and walk after having lost these abilities because of orthostatic hypotension. This system involved epidural electrical stimulation delivered over the thoracic spinal cord with accelerometers that detected changes in body position. (Funded by the Defitech Foundation.).

Intrafascicular peripheral nerve stimulation produces fine functional hand movements in primates.

Restoring dexterous hand control is critical for people with paralysis. Approaches based on surface or intramuscular stimulation provide limited finger control, generate insufficient force to recover functional movements, and require numerous electrodes. Here, we show that intrafascicular peripheral electrodes could produce functional grasps and sustained forces in three monkeys. We designed an intrafascicular implantable electrode targeting the motor fibers of the median and radial nerves. Our interface selectively and reliably activated extrinsic and intrinsic hand muscles, generating multiple functional grips, hand opening, and sustained contraction forces for up to 2 months. We extended those results to a behaving monkey with transient hand paralysis and used intracortical signals to control simple stimulation protocols that enabled this animal to perform a functional grasping task. Our findings show that just two intrafascicular electrodes can generate a rich portfolio of dexterous and functional hand movements with important implications for clinical applicability.

[Assessing occipital nerve stimulation efficacy for chronic refractory headaches]. / Efficacité de la stimulation du nerf occipital pour les céphalées chroniques réfractaires - Une étude prospective lausannoise.

We prospectively followed a cohort of 26 subjects for an average period of 41 months who benefited from occipital nerve stimulation (ONS) in the context of chronic refractory headaches. In 17 patients treated, the frequency of headache decreased, and quality of life scores improved significantly. Among these patients, the "very good" response rate was 34 %. In this cohort, treatment-related adverse events are relatively common (42 %) but not severe. While it is difficult to anticipate the risk factors for non-response to treatment, we estimate that the risk of failure may not be related to the duration of the disease, but rather to the number of different preventives attempted prior to ONS.

Nous avons suivi prospectivement durant une période d'en moyenne 41 mois une cohorte de 26 patients romands qui ont bénéficié d'une stimulation du nerf occipital (ONS) dans le cadre de céphalées chroniques réfractaires. Chez 17 patients non explantés, la fréquence des céphalées a diminué et les scores de qualité de vie se sont améliorés de façon significative. Parmi ces patients, le taux de « très bonne ¼ réponse est de 34 %. On constate dans cette cohorte que les effets indésirables liés au traitement sont relativement courants (42 %) mais non sévères. Même s'il est difficile d'anticiper les facteurs de risque de non-réponse au traitement, nous estimons que la probabilité d'échec ne serait pas corrélée à la durée de la maladie mais plutôt au nombre de traitements préventifs tentés avant l'ONS.

Towards adaptive deep brain stimulation: clinical and technical notes on a novel commercial device for chronic brain sensing.

Objective. Technical advances in deep brain stimulation (DBS) are crucial to improve therapeutic efficacy and battery life. We report the potentialities and pitfalls of one of the first commercially available devices capable of recording brain local field potentials (LFPs) from the implanted DBS leads, chronically and during stimulation. The aim was to provide clinicians with well-grounded tips on how to maximize the capabilities of this novel device, both in everyday practice and for research purposes.Approach. We collected clinical and neurophysiological data of the first 20 patients (14 with Parkinson's disease (PD), five with dystonia, one with chronic pain) that received the Percept™ PC in our centres. We also performed tests in a saline bath to validate the recordings quality.Main results. The Percept PC reliably recorded the LFP of the implanted site, wirelessly and in real time. We recorded the most promising clinically useful biomarkers for PD and dystonia (beta and theta oscillations) with and without stimulation. Furthermore, we provide an open-source code to facilitate export and analysis of data. Critical aspects of the system are presently related to contact selection, artefact detection, data loss, and synchronization with other devices.Significance. New technologies will soon allow closed-loop neuromodulation therapies, capable of adapting stimulation based on real-time symptom-specific and task-dependent input signals. However, technical aspects need to be considered to ensure reliable recordings. The critical use by a growing number of DBS experts will alert new users about the currently observed shortcomings and inform on how to overcome them.

MRI-Compatible and Conformal Electrocorticography Grids for Translational Research.

Intraoperative electrocorticography (ECoG) captures neural information from the surface of the cerebral cortex during surgeries such as resections for intractable epilepsy and tumors. Current clinical ECoG grids come in evenly spaced, millimeter-sized electrodes embedded in silicone rubber. Their mechanical rigidity and fixed electrode spatial resolution are common shortcomings reported by the surgical teams. Here, advances in soft neurotechnology are leveraged to manufacture conformable subdural, thin-film ECoG grids, and evaluate their suitability for translational research. Soft grids with 0.2 to 10 mm electrode pitch and diameter are embedded in 150 µm silicone membranes. The soft grids are compatible with surgical handling and can be folded to safely interface hidden cerebral surface such as the Sylvian fold in human cadaveric models. It is found that the thin-film conductor grids do not generate diagnostic-impeding imaging artefacts (<1 mm) nor adverse local heating within a standard 3T clinical magnetic resonance imaging scanner. Next, the ability of the soft grids to record subdural neural activity in minipigs acutely and two weeks postimplantation is validated. Taken together, these results suggest a promising future alternative to current stiff electrodes and may enable the future adoption of soft ECoG grids in translational research and ultimately in clinical settings.

Hyperpolarized 13C-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma.

Glioblastoma (GBM) is the most aggressive brain tumor type in adults. GBM is heterogeneous, with a compact core lesion surrounded by an invasive tumor front. This front is highly relevant for tumor recurrence but is generally non-detectable using standard imaging techniques. Recent studies demonstrated distinct metabolic profiles of the invasive phenotype in GBM. Magnetic resonance (MR) of hyperpolarized 13C-labeled probes is a rapidly advancing field that provides real-time metabolic information. Here, we applied hyperpolarized 13C-glucose MR to mouse GBM models. Compared to controls, the amount of lactate produced from hyperpolarized glucose was higher in the compact GBM model, consistent with the accepted "Warburg effect". However, the opposite response was observed in models reflecting the invasive zone, with less lactate produced than in controls, implying a reduction in aerobic glycolysis. These striking differences could be used to map the metabolic heterogeneity in GBM and to visualize the infiltrative front of GBM.

Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective.

AIM: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families. METHOD: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases. RESULTS: Patients and their families reported that DBS of the globus pallidus can be effective both for motor and behavioral disturbances in LND. However, outcome measures were often not significantly changed owing to substantial variability among individuals, and were overall less positive than in previous reports based on clinician assessments. In addition, there was an unexpectedly high rate of adverse events, tempering overall enthusiasm for the procedure. INTERPRETATION: Although DBS might be an effective treatment for LND, more research is needed to understand the reasons for response variability and the unusually high rates of adverse events before DBS can be recommended for these patients. What this paper adds Individuals with Lesch-Nyhan disease and their families report variable efficacy of deep brain stimulation. Long-term outcomes are associated with a high adverse event rate.

Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.

Recruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord.

Epidural electrical stimulation (EES) of lumbosacral sensorimotor circuits improves leg motor control in animals and humans with spinal cord injury (SCI). Upper-limb motor control involves similar circuits, located in the cervical spinal cord, suggesting that EES could also improve arm and hand movements after quadriplegia. However, the ability of cervical EES to selectively modulate specific upper-limb motor nuclei remains unclear. Here, we combined a computational model of the cervical spinal cord with experiments in macaque monkeys to explore the mechanisms of upper-limb motoneuron recruitment with EES and characterize the selectivity of cervical interfaces. We show that lateral electrodes produce a segmental recruitment of arm motoneurons mediated by the direct activation of sensory afferents, and that muscle responses to EES are modulated during movement. Intraoperative recordings suggested similar properties in humans at rest. These modelling and experimental results can be applied for the development of neurotechnologies designed for the improvement of arm and hand control in humans with quadriplegia.