Explore the vast range of titles available.

Epidural electrical stimulation (EES) of the spinal cord restores locomotion in animal models of spinal cord injury but is less effective in humans. Here we hypothesized that this interspecies discrepancy is due to interference between EES and proprioceptive information in humans. Computational simulations and preclinical and clinical experiments reveal that EES blocks a significant amount of proprioceptive input in humans, but not in rats. This transient deafferentation prevents modulation of reciprocal inhibitory networks involved in locomotion and reduces or abolishes the conscious perception of leg position. Consequently, continuous EES can only facilitate locomotion within a narrow range of stimulation parameters and is unable to provide meaningful locomotor improvements in humans without rehabilitation. Simulations showed that burst stimulation and spatiotemporal stimulation profiles mitigate the cancellation of proprioceptive information, enabling robust control over motor neuron activity. This demonstrates the importance of stimulation protocols that preserve proprioceptive information to facilitate walking with EES.

Optoelectronic systems can exert precise control over targeted neurons and pathways throughout the brain in untethered animals, but similar technologies for the spinal cord are not well established. In the present study, we describe a system for ultrafast, wireless, closed-loop manipulation of targeted neurons and pathways across the entire dorsoventral spinal cord in untethered mice. We developed a soft stretchable carrier, integrating microscale light-emitting diodes (micro-LEDs), that conforms to the dura mater of the spinal cord. A coating of silicone–phosphor matrix over the micro-LEDs provides mechanical protection and light conversion for compatibility with a large library of opsins. A lightweight, head-mounted, wireless platform powers the micro-LEDs and performs low-latency, on-chip processing of sensed physiological signals to control photostimulation in a closed loop. We use the device to reveal the role of various neuronal subtypes, sensory pathways and supraspinal projections in the control of locomotion in healthy and spinal-cord injured mice. Optogenetics is applied to the entire mouse spinal cord.

A growing number of complex neurostimulation strategies promise symptom relief and functional recovery for several neurological, psychiatric, and even multi-organ disorders. Although pharmacological interventions are currently the mainstay of treatment, neurostimulation offers a potentially effective and safe alternative, capable of providing rapid adjustment to short-term variation and long-term decline of physiological functions. However, rapid advances made by clinical studies have often preceded the fundamental understanding of mechanisms underlying the interactions between stimulation and the nervous system. In turn, therapy design and verification are largely driven by clinical-empirical evidence. Even with titanic efforts and budgets, it is infeasible to comprehensively explore the multi-dimensional optimization space of neurostimulation through empirical research alone, especially since anatomical structures and thus outcomes vary dramatically between patients. Instead, we believe that the future of neurostimulation strongly depends on personalizable computational tools, i.e. Digital Neuro Twins (DNTs) to efficiently identify effective and safe stimulation parameters. DNTs have the potential to accelerate scientific discovery and hypothesis-driven engineering, and aid as a critical regulatory and clinical decision support tool. We outline here how DNTs will pave the way towards effective, cost-, time-, and risk-limited electronic drugs with a broad application bandwidth.

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. Spatially selective and temporally controlled stimulation of the spinal cord, together with rehabilitation, results in substantial restoration of locomotor function in humans with spinal cord injury.

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 cord 1 – 3 applied during neurorehabilitation 4 , 5 (EES REHAB ) 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 EES REHAB in mice. We applied single-nucleus RNA sequencing 6 – 9 and spatial transcriptomics 10 , 11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type 12 , 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 EES REHAB , 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. Transcriptomic analysis following epidural electrical stimulation of the lumbar spinal cord during neurorehabilitation in mice identifies a population of neurons that orchestrates the restoration of walking following paralysis.

Epidural electrical stimulation (EES) targeting the dorsal roots of lumbosacral segments restores walking in people with spinal cord injury (SCI). However, EES is delivered with multielectrode paddle leads that were originally designed to target the dorsal column of the spinal cord. Here, we hypothesized that an arrangement of electrodes targeting the ensemble of dorsal roots involved in leg and trunk movements would result in superior efficacy, restoring more diverse motor activities after the most severe SCI. To test this hypothesis, we established a computational framework that informed the optimal arrangement of electrodes on a new paddle lead and guided its neurosurgical positioning. We also developed software supporting the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. We tested these neurotechnologies in three individuals with complete sensorimotor paralysis as part of an ongoing clinical trial ( www.clinicaltrials.gov identifier NCT02936453). Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements. Neurorehabilitation mediated sufficient improvement to restore these activities in community settings, opening a realistic path to support everyday mobility with EES in people with SCI. Implantation of a multielectrode paddle that allows personalized electrical stimulation to all regions of the spinal cord involved in leg and trunk movements rapidly restores motor function in patients with spinal cord injury with complete paralysis.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival 1 – 3 , impairs neurological recovery 4 , 5 , increases the risk of cardiovascular disease 6 , 7 , and reduces quality of life 8 , 9 . Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord 10 , 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 injury 11 , and restored walking after paralysis 12 . 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. An epidural spinal cord stimulation system regulates blood pressure in the acute and chronic phases of spinal cord injury.

The use of kilohertz-frequency (KHF) waveforms has rapidly gained momentum in transcutaneous spinal cord stimulation (tSCS) to restore motor function after paralysis. However, the mechanisms by which these fast-alternating currents depolarize efferent and afferent fibers remain unknown. Our study fills this research gap by providing a hypothesis-and evidence-based investigation using peripheral nerve stimulation, lumbar tSCS, and cervical tSCS in 25 unimpaired participants together with computational modeling. Peripheral nerve stimulation experiments and computational modeling showed that KHF waveforms negatively impact the processes required to elicit action potentials, thereby increasing response thresholds and biasing the recruitment towards efferent fibers. While these results translate to tSCS, we also demonstrate that lumbar tSCS results in the preferential recruitment of afferent fibers, while cervical tSCS favors recruitment of efferent fibers. Given the assumed importance of proprioceptive afferents in motor recovery, our work suggests that the use of KHF waveforms should be reconsidered to maximize neurorehabilitation outcomes, particularly for cervical tSCS. We posit that careful analysis of the mechanisms that mediate responses elicited by novel approaches in tSCS is crucial to understanding their potential to restore motor function after paralysis.

Transcutaneous spinal cord stimulation (tSCS) applied over the cervical or lumbar spinal cord facilitates motor function after paralysis. However, emerging electrophysiological evidence indicates mechanistic differences between cervical and lumbar tSCS and across different cervical tSCS paradigms. To clarify these discrepancies, we developed and validated a multi-scale, whole-body computational model of tSCS-induced volume conduction, axonal recruitment, and synaptic transmission. Across 24 cervical and four lumbar tSCS paradigms, simulations showed that somatosensory afferents consistently exhibit lower stimulation thresholds than motor efferents. In turn, region-specific synaptic transmission differences may explain electrophysiological discrepancies between cervical and lumbar tSCS. Across cervical tSCS paradigms, substantial volume conduction and axonal recruitment differences were observed that explain electrophysiological discrepancies. Specifically, clinically-prevalent paradigms, including those with anodes placed over the clavicles or iliac crests, engaged peripheral nerves in addition to spinal roots. This effect was amplified by multiphasic waveforms, which introduced recruitment sites near the anodes. By integrating simulations with electrophysiological recordings in 14 able-bodied individuals, we investigated previously unexplored cervical tSCS paradigms on their capacity to recruit somatosensory afferents relative to motor threshold.Competing Interest StatementA.R., F.W., K.M., E.N. hold several patents related to spinal cord stimulation. E.N. is minority shareholder and part-time employee of ZMT, which commercializes the Sim4Life platform.Funder Information DeclaredBundesministerium für Forschung, Technologie und Raumfahrt, 01ZZ2016Fondation pour la Recherche Médicale, https://ror.org/04w6kn183Institut pour la Recherche sur la Moelle Epinière et l'Encéphale, https://ror.org/04wsmmg28GPR inhibition programNational Institutes of Health, K01NS127936Personalized Health & Related Technologies