The neurons that restore walking after paralysis

Abstract

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.

Electrical stimulation for the treatment of spinal cord injuries: A review of the cellular and molecular mechanisms that drive functional improvements

“…In support of this, Kathe et al (2022) observed that EES combined with rehabilitation decreased metabolic activity within the lumbar segments in nine participants with various severities of Gate control theory of pain following electrical stimulation. Stimulating large-diameter afferents (blue) via electrical stimulation excites inhibitory interneurons (black) in the substantial gelatinosa.…”

Neuroprosthetics: from sensorimotor to cognitive disorders

“…Spatiotemporal SCS led to an immediate facilitation of walking and a long-term recovery of motor function within 6 months of training in three subjects with chronic incomplete SCI 13 . This approach was recently expanded to a total of nine participants 49 , including three patients with motor-complete SCI implanted with a new electrode array tailored for both leg and trunk motor functions 14 . Overall, these results have created a surge of interest to now integrate SCS into rehabilitation protocols after SCI.…”

Editorial: Smart nanomaterials for biosensing and therapy applications

“…At present, medical science is facing many challenges in early diagnosis and effective treatment of diseases. How to carry out effective diagnosis and treatment of diseases is very important for the improvement of people’s health level ( Cao et al, 2022 ; Diaz et al, 2022 ; Kathe et al, 2022 ; Vistain et al, 2022 ; Xue et al, 2022 ). Smart nanomaterials have received extensive attention in the field of bioengineering and biotechnology due to their unique structural and functional properties.…”