Multi-system neurorehabilitative strategies to restore motor functions following severe spinal cord injury

Severe spinal cord injury (SCI) permanently abolishes motor functions caudal to the lesion. However, the neuronal machinery sufficient to produce standing and stepping is located below most SCI, and can be reactivated with training. Therefore, why do rats and humans fail to regain significant levels of motor control after a severe SCI? In this review, we argue that the lack of sustainable excitability in locomotor circuitries after SCI prevents the emergence of functional motor states during training, thus limiting the occurrence of activity-dependent plasticity in paralyzed subjects. In turn, we show that spinal rats trained with combinations of epidural electrical stimulation and monoamine agonists, which promote locomotor permissive states during rehabilitation, can regain coordinated stepping with full weight bearing capacities in the total absence of supraspinal influences. This impressive recovery of function relies on the ability of spinal circuitries to utilize multisensory information as a source of control and learning after the loss of brain input. We finally discuss the implication of these findings for the design of multi-system neurorehabilitative interventions capable of restoring some degree of function in humans with severe SCI.

Fig. Transformation of dormant spinal locomotor circuitries into highly functional states after the loss of supraspinal input. Schematic drawings of locomotor circuits are shown after a spinal cord transection at the thoracic level that completely interrupts both glutamatergic (blue) and monoaminergic (red) descending pathways originating from various brainstem areas. Without any intervention the lumbosacral circuitries for stepping are in a quiescent state; no or limited locomotor movements can be generated (left). The com- bination of monoamine receptor agonists and epidural electrical stimulation (EES) at the L2 and S1 levels can transform the physiological state of spinal circuits to a level sufficient for stepping and standing to occur. Tonic EES (blue) replaces the excitatory drive provided by glutamatergic pathways under normal conditions while pharmacological agents (red) mimic the modulatory action of monoaminergic systems (right). The generation of efficient locomotor movements relies on the capacity of spinal circuitries to ensure a continuous match between afferent input and efferent output defining optimal motor states.