ABSTRACT
Here, we introduce the Tabulae Paralytica-a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei, and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord1. The Tabulae Paralytica uncovered new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to upregulate circuit-reorganizing programs after injury; an inverse relationship between neuronal stress responses and the activation of circuit reorganization programs; the necessity of re-establishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI and a failure to form this barrier in old mice. We leveraged the Tabulae Paralytica to develop a rejuvenative gene therapy that re-established this tripartite barrier, and restored the natural recovery of walking after paralysis in old mice. The Tabulae Paralytica provides a window into the pathobiology of SCI, while establishing a framework for integrating multimodal, genome-scale measurements in four dimensions to study biology and medicine.
Subject(s)
Cell Nucleus , Epigenomics , Multiomics , Neurons , Single-Cell Analysis , Spinal Cord Injuries , Transcriptome , Animals , Female , Male , Mice , Atlases as Topic , Cell Nucleus/metabolism , Neurons/pathology , Neurons/metabolism , Paralysis/genetics , Paralysis/pathology , Paralysis/rehabilitation , Paralysis/therapy , Recovery of Function , Spinal Cord/pathology , Spinal Cord Injuries/genetics , Spinal Cord Injuries/pathology , Spinal Cord Injuries/rehabilitation , Spinal Cord Injuries/therapy , Walking , Anatomy, Artistic , Neural Pathways , Genetic TherapyABSTRACT
Spinal cord injuries alter motor function by disconnecting neural circuits above and below the lesion, rendering sensory inputs a primary source of direct external drive to neuronal networks caudal to the injury. Here, we studied mice lacking functional muscle spindle feedback to determine the role of this sensory channel in gait control and locomotor recovery after spinal cord injury. High-resolution kinematic analysis of intact mutant mice revealed proficient execution in basic locomotor tasks but poor performance in a precision task. After injury, wild-type mice spontaneously recovered basic locomotor function, whereas mice with deficient muscle spindle feedback failed to regain control over the hindlimb on the lesioned side. Virus-mediated tracing demonstrated that mutant mice exhibit defective rearrangements of descending circuits projecting to deprived spinal segments during recovery. Our findings reveal an essential role for muscle spindle feedback in directing basic locomotor recovery and facilitating circuit reorganization after spinal cord injury.
Subject(s)
Muscle Spindles/physiology , Animals , Early Growth Response Protein 3/genetics , Early Growth Response Protein 3/metabolism , Feedback, Physiological , Locomotion , Mice , Neurons/physiology , Spinal Cord Injuries/metabolism , Spinal Cord RegenerationABSTRACT
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.
Subject(s)
Brain-Computer Interfaces , Brain , Electric Stimulation Therapy , Neurological Rehabilitation , Spinal Cord Injuries , Spinal Cord , Walking , Humans , Brain/physiology , Electric Stimulation Therapy/instrumentation , Electric Stimulation Therapy/methods , Quadriplegia/etiology , Quadriplegia/rehabilitation , Quadriplegia/therapy , Reproducibility of Results , Spinal Cord/physiology , Spinal Cord Injuries/complications , Spinal Cord Injuries/rehabilitation , Spinal Cord Injuries/therapy , Walking/physiology , Leg/physiology , Neurological Rehabilitation/instrumentation , Neurological Rehabilitation/methods , MaleABSTRACT
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.
Subject(s)
Neurons , Paralysis , Spinal Cord Injuries , Spinal Cord , Walking , Animals , Humans , Mice , Neurons/physiology , Paralysis/genetics , Paralysis/physiopathology , Paralysis/therapy , Spinal Cord/cytology , Spinal Cord/physiology , Spinal Cord/physiopathology , Spinal Cord Injuries/genetics , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/therapy , Walking/physiology , Electric Stimulation , Lumbosacral Region/innervation , Neurological Rehabilitation , Sequence Analysis, RNA , Gene Expression ProfilingABSTRACT
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.
Subject(s)
Baroreflex , Biomimetics , Hemodynamics , Prostheses and Implants , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/therapy , Animals , Disease Models, Animal , Female , Humans , Male , Neural Pathways , Primates , Rats , Rats, Inbred Lew , Sympathetic Nervous System/cytology , Sympathetic Nervous System/physiologyABSTRACT
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.).
Subject(s)
Electric Stimulation Therapy , Hypotension, Orthostatic , Multiple System Atrophy , Accelerometry , Atrophy , Blood Pressure/physiology , Electric Stimulation Therapy/methods , Electrodes, Implanted , Epidural Space , Humans , Hypotension, Orthostatic/diagnosis , Hypotension, Orthostatic/etiology , Hypotension, Orthostatic/therapy , Multiple System Atrophy/therapy , Posture/physiology , Thoracic VertebraeABSTRACT
BACKGROUND: Cerebral Palsy (CP) is a major cause of motor and cognitive disability in children due to injury to the developing brain. Early intensive sensorimotor rehabilitation has been shown to change brain structure and reduce CP symptoms severity. We combined environmental enrichment (EE) and treadmill training (TT) to observe the effects of a one-week program of sensorimotor stimulation (EETT) in animals exposed to a CP model and explored possible mechanisms involved in the functional recovery. METHODS: Pregnant Wistar rats were injected with Lipopolysaccharide (LPS - 200 µg/kg) intraperitoneally at embryonic days 18 and 19. At P0, pups of both sexes were exposed to 20' anoxia at 37 °C. From P2 to P21, hindlimbs were restricted for 16 h/day during the dark cycle. EETT lasted from P21 to P27. TT - 15 min/day at 7 cm/s. EE - 7 days in enriched cages with sensorimotor stimulus. Functional 3D kinematic gait analysis and locomotion were analyzed. At P28, brains were collected for ex-vivo MRI and histological assessment. Neurotrophins and key proteins involved in CNS function were assessed by western blotting. RESULTS: CP model caused gross and skilled locomotor disruption and altered CNS neurochemistry. EETT reversed locomotor dysfunction with minor effects over gait kinematics. EETT also decreased brain inflammation and glial activation, preserved myelination, upregulated BDNF signaling and modulated the expression of proteins involved in excitatory synaptic function in the brain and spinal cord. CONCLUSIONS: Using this translational approach based on intensive sensorimotor rehabilitation, we highlight pathways engaged in the early developmental processes improving neurological recovery observed in CP.
Subject(s)
Cerebral Palsy , Disease Models, Animal , Locomotion , Neuronal Plasticity , Rats, Wistar , Animals , Cerebral Palsy/rehabilitation , Cerebral Palsy/physiopathology , Neuronal Plasticity/physiology , Rats , Female , Locomotion/physiology , Male , Brain/metabolism , Brain/physiopathology , Pregnancy , Recovery of Function/physiology , Encephalitis/metabolism , Encephalitis/physiopathology , Encephalitis/rehabilitation , Gait/physiology , Physical Conditioning, Animal/physiology , Physical Conditioning, Animal/methods , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/physiopathologyABSTRACT
Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may spread in the brain from cell to cell in a 'prion-like' manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including globose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathological progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease.
Subject(s)
Neurodegenerative Diseases , Supranuclear Palsy, Progressive , Tauopathies , Animals , Male , Supranuclear Palsy, Progressive/pathology , tau Proteins/metabolism , Neurodegenerative Diseases/pathology , Macaca mulatta/metabolism , Pilot Projects , Tauopathies/pathology , Brain/pathologyABSTRACT
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury1-3, but efficient reversal of this regrowth failure remains elusive4. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity2,5-9, (ii) growth-supportive substrate10,11 and (iii) chemoattraction12,13-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor16,17 delivered via spatially and temporally controlled release from biomaterial depots18,19, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
Subject(s)
Axons/physiology , Nerve Regeneration/physiology , Spinal Cord Injuries/pathology , Spinal Cord Injuries/therapy , Animals , Astrocytes/pathology , Cicatrix/pathology , Electrophysiology , Epidermal Growth Factor/metabolism , Female , Fibroblast Growth Factors/metabolism , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Hydrogels , Laminin/metabolism , Male , Mice , Mice, Inbred C57BL , Neuroglia/metabolism , Proteoglycans/metabolism , Rats , Rats, Inbred Lew , Recovery of Function , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/rehabilitation , Spinal Cord Regeneration , Stromal Cells/pathologyABSTRACT
Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
Subject(s)
Biomedical Technology , Electric Stimulation Therapy , Paralysis/rehabilitation , Spinal Cord Injuries/rehabilitation , Walking/physiology , Activities of Daily Living , Computer Simulation , Electromyography , Epidural Space , Humans , Leg/innervation , Leg/physiology , Leg/physiopathology , Locomotion/physiology , Male , Motor Neurons/physiology , Muscle, Skeletal/innervation , Muscle, Skeletal/physiology , Muscle, Skeletal/physiopathology , Paralysis/physiopathology , Paralysis/surgery , Spinal Cord/cytology , Spinal Cord/physiology , Spinal Cord/physiopathology , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/surgeryABSTRACT
This study investigates the pathological toe and heel gaits seen in human locomotion using neuromusculoskeletal modelling and simulation. In particular, it aims to investigate potential cause-effect relationships between biomechanical or neural impairments and pathological gaits. Toe and heel gaits are commonly present in spinal cord injury, stroke and cerebral palsy. Toe walking is mainly attributed to spasticity and contracture at plantar flexor muscles, whereas heel walking can be attributed to muscle weakness of biomechanical or neural origin. To investigate the effect of these impairments on gait, this study focuses on the soleus and gastrocnemius muscles as they contribute to ankle plantarflexion. We built a reflex circuit model based on previous work by Geyer and Herr with additional pathways affecting the plantar flexor muscles. The SCONE software, which provides optimisation tools for 2D neuromechanical simulation of human locomotion, is used to optimise the corresponding reflex parameters and simulate healthy gait. We then modelled various bilateral plantar flexor biomechanical and neural impairments, and individually introduced them in the healthy model. We characterised the resulting simulated gaits as pathological or not by comparing ankle kinematics and ankle moment with the healthy optimised gait based on metrics used in clinical studies. Our simulations suggest that toe walking can be generated by hyperreflexia, whereas muscle and neural weaknesses partially induce heel gait. Thus, this 'what if' approach is deemed of great interest as it allows investigation of the effect of various impairments on gait and suggests an important contribution of active reflex mechanisms to pathological toe gait. KEY POINTS: Pathological toe and heel gaits are commonly present in various conditions such as spinal cord injury, stroke and cerebral palsy. These conditions present various neural and biomechanical impairments, but the cause-effect relationships between these impairments and pathological gaits are difficult to establish clinically. Based on neuromechanical simulation, this study focuses on the plantar flexor muscles and builds a new reflex circuit controller to model and evaluate the potential effect of both neural and biomechanical impairments on gait. Our results suggest an important contribution of active reflex mechanisms to pathological toe gait. This 'what if' based on neuromechanical modelling is thus deemed of great interest to target potential causes of pathological gait.
Subject(s)
Gait , Models, Biological , Biomechanical Phenomena , Cerebral Palsy , Gait/physiology , Heel , Humans , Muscle, Skeletal/physiology , Spinal Cord Injuries , Stroke , Toes , Walking/physiologyABSTRACT
Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.
Subject(s)
Brain-Computer Interfaces , Electric Stimulation Therapy/instrumentation , Gait Disorders, Neurologic/complications , Gait Disorders, Neurologic/therapy , Gait/physiology , Neural Prostheses , Spinal Cord Injuries/complications , Spinal Cord Injuries/therapy , Animals , Disease Models, Animal , Electric Stimulation , Gait Disorders, Neurologic/physiopathology , Leg/physiology , Locomotion/physiology , Lumbosacral Region , Macaca mulatta , Male , Microelectrodes , Motor Cortex/physiopathology , Paralysis/complications , Paralysis/physiopathology , Paralysis/therapy , Reproducibility of Results , Spinal Cord/physiopathology , Spinal Cord Injuries/physiopathology , Wireless Technology/instrumentationABSTRACT
Spinal cord injury (SCI) is a devastating condition characterized by loss of function, secondary to damaged spinal neurons, disrupted axonal connections, and myelin loss. Spontaneous recovery is limited, and there are no approved pharmaceutical treatments to reduce ongoing damage or promote repair. Repulsive guidance molecule A (RGMa) is upregulated following injury to the central nervous system (CNS), where it is believed to induce neuronal apoptosis and inhibit axonal growth and remyelination. We evaluated elezanumab, a human anti-RGMa monoclonal antibody, in a novel, newly characterized non-human primate (NHP) hemicompression model of thoracic SCI. Systemic intravenous (IV) administration of elezanumab over 6â¯months was well tolerated and associated with significant improvements in locomotor function. Treatment of animals for 16â¯weeks with a continuous intrathecal infusion of elezanumab below the lesion was not efficacious. IV elezanumab improved microstructural integrity of extralesional tissue as reflected by higher fractional anisotropy and magnetization transfer ratios in treated vs. untreated animals. IV elezanumab also reduced SCI-induced increases in soluble RGMa in cerebrospinal fluid, and membrane bound RGMa rostral and caudal to the lesion. Anterograde tracing of the corticospinal tract (CST) from the contralesional motor cortex following 20â¯weeks of IV elezanumab revealed a significant increase in the density of CST fibers emerging from the ipsilesional CST into the medial/ventral gray matter. There was a significant sprouting of serotonergic (5-HT) fibers rostral to the injury and in the ventral horn of lower thoracic regions. These data demonstrate that 6â¯months of intermittent IV administration of elezanumab, beginning within 24â¯h after a thoracic SCI, promotes neuroprotection and neuroplasticity of key descending pathways involved in locomotion. These findings emphasize the mechanisms leading to improved recovery of neuromotor functions with elezanumab in acute SCI in NHPs.
Subject(s)
Antibodies, Monoclonal/administration & dosage , GPI-Linked Proteins/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Neuronal Plasticity/drug effects , Neuroprotection/drug effects , Recovery of Function/drug effects , Spinal Cord Injuries/drug therapy , Amino Acid Sequence , Animals , Antibodies, Monoclonal/genetics , Chlorocebus aethiops , Exercise Test/methods , Humans , Injections, Spinal , Male , Neuronal Plasticity/physiology , Neuroprotection/physiology , Primates , Recovery of Function/physiology , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathology , Thoracic Vertebrae/injuriesABSTRACT
Gait analysis has traditionally been carried out in a laboratory environment using expensive equipment, but, recently, reliable, affordable, and wearable sensors have enabled integration into clinical applications as well as use during activities of daily living. Real-time gait analysis is key to the development of gait rehabilitation techniques and assistive devices such as neuroprostheses. This article presents a systematic review of wearable sensors and techniques used in real-time gait analysis, and their application to pathological gait. From four major scientific databases, we identified 1262 articles of which 113 were analyzed in full-text. We found that heel strike and toe off are the most sought-after gait events. Inertial measurement units (IMU) are the most widely used wearable sensors and the shank and foot are the preferred placements. Insole pressure sensors are the most common sensors for ground-truth validation for IMU-based gait detection. Rule-based techniques relying on threshold or peak detection are the most widely used gait detection method. The heterogeneity of evaluation criteria prevented quantitative performance comparison of all methods. Although most studies predicted that the proposed methods would work on pathological gait, less than one third were validated on such data. Clinical applications of gait detection algorithms were considered, and we recommend a combination of IMU and rule-based methods as an optimal solution.
Subject(s)
Activities of Daily Living , Wearable Electronic Devices , Biomechanical Phenomena , Gait , Gait Analysis , HumansABSTRACT
Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa-induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa-induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/drug therapy , Levodopa/adverse effects , Parkinsonian Disorders/drug therapy , Xenon/therapeutic use , Administration, Inhalation , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Dyskinesia, Drug-Induced/etiology , Gait Disorders, Neurologic/drug therapy , Gait Disorders, Neurologic/etiology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , MPTP Poisoning/drug therapy , Mice , Mice, Transgenic , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/complications , Rats , Sensation Disorders/drug therapy , Sensation Disorders/etiology , Sympatholytics/toxicity , Time FactorsABSTRACT
Contrary to cats and primates, cortical contribution to hindlimb locomotor movements is not critical in rats. However, the importance of the motor cortex to regain locomotion after neurological disorders in rats suggests that cortical engagement in hindlimb motor control may depend on the behavioral context. To investigate this possibility, we recorded whole-body kinematics, muscle synergies, and hindlimb motor cortex modulation in freely moving rats performing a range of natural locomotor procedures. We found that the activation of hindlimb motor cortex preceded gait initiation. During overground locomotion, the motor cortex exhibited consistent neuronal population responses that were synchronized with the spatiotemporal activation of hindlimb motoneurons. Behaviors requiring enhanced muscle activity or skilled paw placement correlated with substantial adjustment in neuronal population responses. In contrast, all rats exhibited a reduction of cortical activity during more automated behavior, such as stepping on a treadmill. Despite the facultative role of the motor cortex in the production of locomotion in rats, these results show that the encoding of hindlimb features in motor cortex dynamics is comparable in rats and cats. However, the extent of motor cortex modulations appears linked to the degree of volitional engagement and complexity of the task, reemphasizing the importance of goal-directed behaviors for motor control studies, rehabilitation, and neuroprosthetics. SIGNIFICANCE STATEMENT: We mapped the neuronal population responses in the hindlimb motor cortex to hindlimb kinematics and hindlimb muscle synergies across a spectrum of natural locomotion behaviors. Robust task-specific neuronal population responses revealed that the rat motor cortex displays similar modulation as other mammals during locomotion. However, the reduced motor cortex activity during more automated behaviors suggests a relationship between the degree of engagement and task complexity. This relationship emphasizes the importance of the behavioral procedure to engage the motor cortex during motor control studies, gait rehabilitation, and locomotor neuroprosthetic developments in rats.
Subject(s)
Hindlimb/innervation , Hindlimb/physiology , Locomotion/physiology , Motor Cortex/physiology , Animals , Behavior, Animal/physiology , Biomechanical Phenomena , Electromyography , Female , Gait/physiology , Muscle, Skeletal/innervation , Muscle, Skeletal/physiology , Neural Pathways/physiology , Pyramidal Tracts/cytology , Pyramidal Tracts/physiology , Rats , Rats, Inbred LewABSTRACT
Epidural electrical stimulation (EES) of lumbosacral segments can restore a range of movements after spinal cord injury. However, the mechanisms and neural structures through which EES facilitates movement execution remain unclear. Here, we designed a computational model and performed in vivo experiments to investigate the type of fibers, neurons, and circuits recruited in response to EES. We first developed a realistic finite element computer model of rat lumbosacral segments to identify the currents generated by EES. To evaluate the impact of these currents on sensorimotor circuits, we coupled this model with an anatomically realistic axon-cable model of motoneurons, interneurons, and myelinated afferent fibers for antagonistic ankle muscles. Comparisons between computer simulations and experiments revealed the ability of the model to predict EES-evoked motor responses over multiple intensities and locations. Analysis of the recruited neural structures revealed the lack of direct influence of EES on motoneurons and interneurons. Simulations and pharmacological experiments demonstrated that EES engages spinal circuits trans-synaptically through the recruitment of myelinated afferent fibers. The model also predicted the capacity of spatially distinct EES to modulate side-specific limb movements and, to a lesser extent, extension versus flexion. These predictions were confirmed during standing and walking enabled by EES in spinal rats. These combined results provide a mechanistic framework for the design of spinal neuroprosthetic systems to improve standing and walking after neurological disorders.
Subject(s)
Epidural Space/physiology , Models, Neurological , Motor Neurons/physiology , Sensory Receptor Cells/physiology , Spinal Cord/physiology , Algorithms , Animals , Computer Simulation , Electric Stimulation , Electrodes, Implanted , Electrophysiological Phenomena/physiology , Female , Finite Element Analysis , Interneurons/physiology , Nerve Fibers/physiology , Rats , Rats, Inbred Lew , Recruitment, Neurophysiological/physiology , Spinal Cord/cytology , Walking/physiologyABSTRACT
Severe spinal cord injury in humans leads to a progressive neuronal dysfunction in the chronic stage of the injury. This dysfunction is characterized by premature exhaustion of muscle activity during assisted locomotion, which is associated with the emergence of abnormal reflex responses. Here, we hypothesize that undirected compensatory plasticity within neural systems caudal to a severe spinal cord injury contributes to the development of neuronal dysfunction in the chronic stage of the injury. We evaluated alterations in functional, electrophysiological and neuromorphological properties of lumbosacral circuitries in adult rats with a staggered thoracic hemisection injury. In the chronic stage of the injury, rats exhibited significant neuronal dysfunction, which was characterized by co-activation of antagonistic muscles, exhaustion of locomotor muscle activity, and deterioration of electrochemically-enabled gait patterns. As observed in humans, neuronal dysfunction was associated with the emergence of abnormal, long-latency reflex responses in leg muscles. Analyses of circuit, fibre and synapse density in segments caudal to the spinal cord injury revealed an extensive, lamina-specific remodelling of neuronal networks in response to the interruption of supraspinal input. These plastic changes restored a near-normal level of synaptic input within denervated spinal segments in the chronic stage of injury. Syndromic analysis uncovered significant correlations between the development of neuronal dysfunction, emergence of abnormal reflexes, and anatomical remodelling of lumbosacral circuitries. Together, these results suggest that spinal neurons deprived of supraspinal input strive to re-establish their synaptic environment. However, this undirected compensatory plasticity forms aberrant neuronal circuits, which may engage inappropriate combinations of sensorimotor networks during gait execution.
Subject(s)
Nerve Net/physiopathology , Neuronal Plasticity/physiology , Severity of Illness Index , Spinal Cord Injuries/physiopathology , Spinal Cord/physiopathology , Animals , Disease Models, Animal , Electric Stimulation , Electrodes, Implanted , Exercise Test , Female , Hindlimb/physiopathology , Muscle, Skeletal/physiopathology , Rats , Spinal Cord/cytology , Spinal Cord Injuries/complicationsABSTRACT
Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARCEX Therapy to improve arm and hand functions in people with chronic SCI. ARCEX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARCEX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARCEX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARCEX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472 .