Natural and targeted recovery of arm and hand function after cervical spinal cord injury

Cervical spinal cord injury (SCI) disconnects the brain from the regions of the spinal cord controlling the arm and hand, resulting in paralysis that profoundly impairs independence and quality of life. While spontaneous recovery can emerge from spared pathways, it remains partial and poorly understood. Recent therapeutic developments have focused on restoring locomotor function, yet equivalent progress for upper-limbs has been hindered by the complexity of these movements and the limited understanding of the principles underlying spontaneous recovery. This thesis aims to overcome this limitation by identifying the neuronal architecture that supports recovery after cervical SCI in rodent models, and by establishing how neuromodulation of the spinal cord can engage this architecture to further improve recovery. To investigate recovery of upper-limb movements after SCI, we designed a neurorobotic platform capable of delivering precise, quantitative assessment of these movements. This approach provided the controlled environment required to evaluate neurorehabilitative interventions and validate therapeutic concepts under standardized conditions. We then leveraged this model to expose the neuronal architecture responsible for spontaneous and therapeutically-enhanced restoration of arm and hand function after a cervical hemisection. Whole-brain imaging, transcriptional profiling, and intersectional viral tracing revealed that spontaneous recovery of upper-limb movements arises from the progressive reorganization of a distributed neuronal architecture composed of three recovery-organizing nodes: neurons of the contralesional parvicellular reticular nucleus (PARN) that extend new midline-crossing projections below the SCI, and two Vsx2-expressing (Vsx2ON) neuronal subpopulations located above and below the SCI. Genetically-guided experiments revealed that perturbing any of these nodes abolished recovery. We postulated that neuromodulation of the cervical cord during rehabilitation enhances this natural recovery by engaging and remodeling the identified architecture. To test this hypothesis, we developed a preclinical model reproducing the key features and outcomes of ARCEX Therapy, the first clinically approved therapy based on rehabilitation augmented by non-invasive spinal cord stimulation to promote the recovery of arm and hand function after tetraplegia. Genetically-guided anatomical interrogation of the exposed neuronal architecture revealed that ARCEX engages this architecture through the direct recruitment of proprioceptive parvalbumin-positive afferents that converge onto Vsx2ON neurons, thereby accessing the spinal components of the natural recovery-organizing network. Ablation of these neurons abolished both the immediate and sustained functional effects of ARCEX Therapy, confirming their essential role as the spinal gateway through which neuromodulation restores upper-limb function. Together, these studies reveal the principles through which the reorganization of a distributed neuronal architecture promotes spontaneous recovery of upper-limb movements after cervical SCI, and how neuromodulation during rehabilitation augments this reorganization to enhance recovery. By delineating key molecular and cellular features of this architecture, this thesis uncovers the fundamental logic of repair after injury and provides a foundation for the rational design of targeted therapies to restore dexterous arm and hand movements after SCI.