![]() Nine individuals were enroled in the first-in-human clinical trial ‘Stimulation Movement Overground’ (STIMO) (: NCT02936453 Supplementary Information), which aimed to establish the safety and feasibility of EES REHAB to improve the recovery of walking in people with chronic SCI. We first tested whether EES REHAB can restore walking across a large population of individuals with SCI, and whether this recovery involves remodelling of the lumbar spinal cord. Here, we hypothesized that EES REHAB must engage and remodel essential yet unidentified neurons in the spinal cord that become necessary for walking after paralysis. The biological principles through which EES REHAB engages and remodels the lumbar spinal cord to restore walking remain unknown. Isolated case studies have reported that EES can immediately reactivate nonfunctional neurons in the lumbar spinal cord 17, 18, enabling people with paralysis to walk 1, 18, 19, 20. Application of EES during neurorehabilitation (EES REHAB) further improved recovery of walking, even when the stimulation was turned off 1, 21. Whereas the neurons located in the lumbar spinal cord are not directly damaged by the injury, the depletion of essential supraspinal commands renders them nonfunctional 4. A severe spinal cord injury (SCI) scatters this exquisitely organized communication system 15. To walk, the brain broadcasts commands through descending pathways that cascade from the brainstem to activate these neurons 15, 16. The neurons that orchestrate walking reside in the lumbar spinal cord 14. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours. ![]() ![]() ![]() We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EES REHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. 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. A single population of excitatory interneurons nested within intermediate laminae emerged. We then employed cell type 12, 13 and spatial prioritization to identify the neurons involved in the recovery of walking. We applied single-nucleus RNA sequencing 6, 7, 8, 9 and spatial transcriptomics 10, 11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. To identify these putative neurons, we modelled the technological and therapeutic features underlying EES REHAB in mice. 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. ![]() This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord 1, 2, 3 applied during neurorehabilitation 4, 5 (EES REHAB) restored walking in nine individuals with chronic spinal cord injury. Nature volume 611, pages 540–547 ( 2022) Cite this articleĪ spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. The neurons that restore walking after paralysis ![]()
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