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Individuals with spinal cord injury (SCI) can face decades with permanent disabilities. Advances in clinical management have decreased morbidity and improved outcomes, but no randomized clinical trial has demonstrated the efficacy of a repair strategy for improving recovery from SCI. Here, we summarize recent advances in biological and engineering strategies to augment neuroplasticity and/or functional recovery in animal models of SCI that are pushing toward clinical translation.Advances in cellular regeneration and technical approaches to spinal cord repair are on the verge of being translated into clinical trials.

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.

CLP290 restored the functionality of relay circuits by preventing downregulation of KCC2 and thus maintaining the balance between inhibition and excitation (Fig. 1). [...]the researchers showed that CLP290 did not affect the growth of new neuronal projections - recovery was triggered merely by restoring this balance in relay circuits. [...]Chen et al. demonstrated through two experiments that brain commands were being transmitted through the reactivated relays in CLP290-treated mice. [...]neurons between the staggered lesions were more active in response to locomotor activity in treated than in non-treated mice.

Implantable neuroprostheses are engineered systems designed to restore or substitute function for individuals with neurological deficits or disabilities. These systems involve at least one uni- or bidirectional interface between a living neural tissue and a synthetic structure, through which information in the form of electrons, ions or photons flows. Despite a few notable exceptions, the clinical dissemination of implantable neuroprostheses remains limited, because many implants display inconsistent long-term stability and performance, and are ultimately rejected by the body. Intensive research is currently being conducted to untangle the complex interplay of failure mechanisms. In this Review, we emphasize the importance of minimizing the physical and mechanical mismatch between neural tissues and implantable interfaces. We explore possible materials solutions to design and manufacture neurointegrated prostheses, and outline their immense therapeutic potential. Implantable neuroprostheses communicate with the nervous system to provide diagnosis or therapy to the injured body. In this review, we discuss materials-based approaches to overcome the physical and mechanical mismatch at the tissue–implant interface and to design long-term neurointegrated prostheses.

The delivery of brain-controlled neuromodulation therapies during motor rehabilitation may augment recovery from neurological disorders. To test this hypothesis, we conceived a brain-controlled neuromodulation therapy that combines the technical and practical features necessary to be deployed daily during gait rehabilitation. Rats received a severe spinal cord contusion that led to leg paralysis. We engineered a proportional brain–spine interface whereby cortical ensemble activity constantly determines the amplitude of spinal cord stimulation protocols promoting leg flexion during swing. After minimal calibration time and without prior training, this neural bypass enables paralyzed rats to walk overground and adjust foot clearance in order to climb a staircase. Compared to continuous spinal cord stimulation, brain-controlled stimulation accelerates and enhances the long-term recovery of locomotion. These results demonstrate the relevance of brain-controlled neuromodulation therapies to augment recovery from motor disorders, establishing important proofs-of-concept that warrant clinical studies. Brain–spine interfaces have been used to enable leg movement following spinal cord injury, but movement is either involuntary or not adjustable. Here, the authors show in rats that a proportional stimulation interface permits voluntary movement and augments recovery in conjunction with rehabilitation.

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 authors summarize changes in circuits after spinal cord injury and current strategies to target these circuits in order to improve recovery, but also advocate for new concepts of reorganizing circuits informed by multi-omic single-cell atlases.

A spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions. Deep brain stimulation and epidural electrical stimulation of the spinal cord enable locomotion in humans with spinal cord injury (SCI) but the potential synergy between both approaches is unclear. The authors show that a complex technological approach is required to enable volitional walking in rats with SCI.

Advances in single-cell genomics now enable large-scale comparisons of cell states across two or more experimental conditions. Numerous statistical tools are available to identify individual genes, proteins or chromatin regions that differ between conditions, but many experiments require inferences at the level of cell types, as opposed to individual analytes. We developed Augur to prioritize the cell types within a complex tissue that are most responsive to an experimental perturbation. In this protocol, we outline the application of Augur to single-cell RNA-seq data, proceeding from a genes-by-cells count matrix to a list of cell types ranked on the basis of their separability following a perturbation. We provide detailed instructions to enable investigators with limited experience in computational biology to perform cell-type prioritization within their own datasets and visualize the results. Moreover, we demonstrate the application of Augur in several more specialized workflows, including the use of RNA velocity for acute perturbations, experimental designs with multiple conditions, differential prioritization between two comparisons, and single-cell transcriptome imaging data. For a dataset containing on the order of 20,000 genes and 20 cell types, this protocol typically takes 1–4 h to complete. This protocol provides a step-by-step workflow for prioritizing the cell types most responsive to an experimental perturbation in single-cell data and describes various applications of the pipeline in five case studies.

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 injury 1 – 3 , but efficient reversal of this regrowth failure remains elusive 4 . 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 capacity 2 , 5 – 9 , (ii) growth-supportive substrate 10 , 11 and (iii) chemoattraction 12 , 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 SCI 14 , 15 ; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor 16 , 17 delivered via spatially and temporally controlled release from biomaterial depots 18 , 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. Stimulating the intrinsic growth capacity of neurons and providing growth-supportive substrate and chemoattraction can allow axon regrowth across anatomically complete spinal cord injuries in adult rodents.

Biological and engineering strategies for neural repair and recovery from neurotrauma continue to emerge at a rapid pace. Until recently, studies of the impact of neurotrauma and repair strategies on the reorganization of the central nervous system have focused on broadly defined circuits and pathways. Optogenetic modulation and recording methods now enable the interrogation of precisely defined neuronal populations in the brain and spinal cord, allowing unprecedented precision in electrophysiological and behavioral experiments. This mini-review summarizes the spectrum of light-based tools that are currently available to probe the properties and functions of well-defined neuronal subpopulations in the context of neurotrauma. In particular, we highlight the challenges to implement these tools in damaged and reorganizing tissues, and we discuss best practices to overcome these obstacles.