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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - HOW2WALKAGAIN (Mechanisms of recovery after severe spinal cord injury)

Teaser

Summary

Worldwide, an estimated 3 million people live with a chronic spinal cord injury (SCI), and more than half do not recover the ability to stand or walk with current standards of care. We recently introduced a treatment paradigm combining electrical spinal cord stimulation and intense rehabilitation training that restored voluntary control of leg movements in humans with SCI. The objective of HOW2WALKAGAIN is to leverage the most advanced neurotechnologies in rodent models of SCI to identify the neural mechanisms that enable leg motor control during electrical spinal cord stimulation, and the recovery of voluntary leg movements when this paradigm is combined with intense rehabilitative training. This fundamental knowledge is essential to improve current interventions. For example, we found that electrical spinal cord stimulation modulates the spinal cord circuitry through the modulation of afferent fibers innervating sensory receptors embedded into muscles, called proprioceptors. This understanding allowed us to develop more advanced stimulation protocols that exploit the anatomical organization of the proprioceptive system to mediate a more robust facilitation of leg movements. Clinical application of these protocols in humans with SCI enabled the recovery of walking in ecological settings. We also showed that the delivery of these protocols restored voluntary control over the activity of previously paralyzed muscles without stimulation, which had never been observed with conventional stimulation protocols. Consequently, the discoveries emerging from HOW2WALKAGAIN are already impacting the development of clinical treatments to improve recovery from SCI.

Work performed

We have developed and optimized a series of innovative neurotechnologies to record, manipulate and disrupt neural activity over short timescales or extensive periods of time in chronic rodent models of SCI. These methods are allowing us to dissect the function of brain and spinal circuits involved in controlling leg movements in response to electrical spinal cord stimulation, and how these circuits are reorganizing during the course of rehabilitation.
We also implemented an advanced pipeline to characterize the anatomical and functional organization of projection circuits across the entire brain. This pipeline combines virus-mediated tract tracing, whole brain-spinal cord tissue clearing, activity-dependent labeling of neurons, 3D light-sheet microscopy, cell registration in Allen Institute anatomical atlas, and functional connectome analysis. This unbiased analysis is uncovering specific networks of circuits involved in the recovery of leg movements after SCI, thus opening the possibility to target these circuits to further enhance functional recovery.
Moreover, we are conducting single-nucleus sequencing analysis to identify transcriptomic changes of neurons and supporting cells in the spinal cord that underlie improvement of function in response to rehabilitation. This analysis is identifying neurons with unique molecular profiles that are involved in the production of locomotion after rehabilitation and could become new targets to further improve recovery. These results also informed the design of regeneration therapies that allowed us to promote the regrowth of nerve fibers across and beyond a complete SCI.
These combined methodologies and studies are thus yielding scientific results that are modifying our understanding of the recovery mechanisms after SCI, and how electrical spinal cord stimulation and intensive rehabilitation training are improving functional recovery. Many results have been disseminated in high profile journals and in clinical trials.

Final results

Understanding the anatomical and functional logic of the motor-circuit communication system that produces locomotion, and how it can be controlled and remodeled after injury, remains one of the most prominent scientific and medical questions in the fields of motor control and movement disorders. HOW2WALKAGAIN already provided important insights into these questions. For example, we showed that electrical spinal cord stimulation facilitates leg movement after SCI through the recruitment of proprioceptive fibers. However, we also showed that the longer length of proprioceptive afferent fibers in humans compared to rats led to a cancellation of proprioception, and thus, a poor efficacy of this paradigm in patients with SCI. We found strategies to remedy these limitations, which led to a recent clinical breakthrough. Three patients with chronic paralysis were able to regain the ability to walk overground during stimulation. After training, they regained voluntary control over previously paralyzed muscles without stimulation. Experiments in rodent models performed within HOW2WALKAGAIN have described the circuit-level mechanisms that enable the brain to regain such control. Our experiments are also contributing to identifying new targeted strategies to further enhance neurological recovery from SCI. We also achieved the first regrowth of nerve fibers across a complete SCI.