Spinal cord injury (SCI) is the second leading cause of paralysis, which induces abrupt impairments with devastating consequences for the quality of life of patients. Despite significant progress in SCI treatment through neurorehabilitation training and spinal cord stimulation (SCS) techniques, there is still no cure for SCI and the mechanisms of recovery are poorly understood. My thesis represents a series of studies which investigate the neural mechanisms underlying locomotor recovery after SCI and leverage these findings for the development of brain-controlled neuroprosthetic therapies to enhance the potential of neurorehabilitation therapies.

The first study focused on investigating neural mechanisms underlying locomotor recovery after clinically relevant contusion SCI. During this study, we assessed changes in over a hundred kinematic parameters using gait pattern extraction and principal component analysis. Our results show that the animals learned to step even in the absence of electrochemical enabling factors. Remarkably, we observed a carryover effect of locomotor recovery to the previously unpracticed swimming task. Afterwards, we dissected the neural mechanisms underlying the observed behavioral effect using viral tracing techniques and a double-virus construct allowing targeted pathway inactivation. As a result, we were able to reversibly abolish stepping capacity of rehabilitated rats, suggesting the critical importance of the reticulospinal tract for the recovery from contusion SCI.

These findings gave us the rationale for the second study in which we developed a novel rehabilitation paradigm of brain-controlled stimulation of the mesencephalic locomotor region (MLR). The MLR sends excitatory descending input to reticulospinal neurons in the brainstem, which relay the descending locomotor command through the tissue bridge spared after contusion SCI. Thus, we hypothesized that MLR stimulation may lead to improved locomotion in rats after SCI when combined with neurorehabilitation training and electrochemical SCS. We found that brain-controlled MLR stimulation was able to improve kinematic output in rehabilitated animals and to significantly reduce side effects of non brain-controlled MLR stimulation. Thus, this novel neuroprosthetic paradigm is capable of enhancing existing rehabilitation techniques. However, the long-term effectiveness of this intervention during SCI rehabilitation needs to be further investigated to evaluate its full therapeutic benefit.

Finally, after evaluating the possible beneficial and adverse effects of MLR stimulation in a translational context, we proposed another type of brain-controlled stimulation that directly bypasses the lesion site through an electronic bridge between the brain and the spinal cord. For this, we created a neuroprosthetic system allowing for direct cortical control of spinal cord neuromodulation during gait rehabilitation. This refinement of SCS delivery significantly improved both immediate locomotor output and the long-term recovery of rats after SCI.

In conclusion, this thesis uncovers mechanisms of recovery from SCI and demonstrates the therapeutic potential of brain-controlled neuroprosthetic therapies. Furthermore, it raises important questions and identifies challenges in translating these therapies from the bench to the bedside. Hence, this work constitutes a valuable input for both basic science and the development of clinically relevant interventions.