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Introduction/Background Over the past decade, we have developed spatiotemporal neuromodulation therapies of spinal circuits and gravity-assist training procedures in pre-clinical model of spinal cord injury (SCI) which allowed to restore supraspinal control of locomotion in rats with a SCI leading to complete and permanent paralysis. So far, human studies on epidural electrical stimulation (EES) were mainly limited to continuous neuromodulation, which has demonstrated several limitations to promote the recovery of functional movements such as walking. In this study, we aimed to assess the feasibility and the efficacy of a neuroprosthetic rehabilitation program that combines spatiotemporal EES and gravity-assist training to enhance the recovery of voluntary motor control and functional autonomy. Material and method Individuals with a chronic incomplete SCI were surgically implanted with a spinal cord electrostimulation system with 16 independent electrodes positioned over the lumbar spinal cord. The stimulator was equipped with real-time triggering capacities based on movement feedback. They then underwent 20 weeks of rehabilitation, four sessions per week, with a gravity-assist that provided a tailored, multidirectional assistance of trunk movements during gait training. Multifaceted evaluations of clinical scores, gait analysis, sensorimotor functions, urodynamics, electrophysiology, and imaging were performed before and throughout the rehabilitation program. Results A total of 4 chronic SCI patients have been included to date, with deficits ranging from AIS-B to AIS-D. The participants who completed the study have demonstrated various types of improvements in term of muscle force, gait autonomy and quality as well as daily-life-related activities. These positive results have been observed both immediately when the EES therapy was applied and were reinforced after the long-term training. Electrophysiological and neuro-imaging analysis contributed to explaining the mechanisms underlying the long-term improvements. Conclusion Preliminary data provides encouraging results on the ability of this therapeutic intervention to improve the recovery of motor functions and other important bodily functions after a chronic SCI. [ABSTRACT FROM AUTHOR]