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.

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.

Objective . We recently developed soft neural interfaces enabling the delivery of electrical and chemical stimulation to the spinal cord. These stimulations restored locomotion in animal models of paralysis. Soft interfaces can be placed either below or above the dura mater. Theoretically, the subdural location combines many advantages, including increased selectivity of electrical stimulation, lower stimulation thresholds, and targeted chemical stimulation through local drug delivery. However, these advantages have not been documented, nor have their functional impact been studied in silico or in a relevant animal model of neurological disorders using a multimodal neural interface. Approach . We characterized the recruitment properties of subdural interfaces using a realistic computational model of the rat spinal cord that included explicit representation of the spinal roots. We then validated and complemented computer simulations with electrophysiological experiments in rats. We additionally performed behavioral experiments in rats that received a lateral spinal cord hemisection and were implanted with a soft interface. Main results. In silico and in vivo experiments showed that the subdural location decreased stimulation thresholds compared to the epidural location while retaining high specificity. This feature reduces power consumption and risks of long-term damage in the tissues, thus increasing the clinical safety profile of this approach. The hemisection induced a transient paralysis of the leg ipsilateral to the injury. During this period, the delivery of electrical stimulation restricted to the injured side combined with local chemical modulation enabled coordinated locomotor movements of the paralyzed leg without affecting the non-impaired leg in all tested rats. Electrode properties remained stable over time, while anatomical examinations revealed excellent bio-integration properties. Significance . Soft neural interfaces inserted subdurally provide the opportunity to deliver electrical and chemical neuromodulation therapies using a single, bio-compatible and mechanically compliant device that effectively alleviates locomotor deficits after spinal cord injury.