Every year in the US, about 12 000 new spinal cord injuries occur, nearly half of which are complete injuries. Despite decades of active research, few effective treatment strategies exist to help in functional recovery, aside from aggressive rehabilitation. The mechanism of recovery in fortunate patients is also unclear, making it difficult to know how best to target therapeutic options.
Under certain conditions, the spinal cord has the capacity to maintain locomotion even after a complete transaction (ie, the “stepping cat”). This phenomenon has been attributed to local spinal circuits within the distal spinal cord that can continue to function despite disconnection from cortical input. In 2009, Coutine and Edgerton demonstrated that the threshold to engage this local spinal motor circuitry in locomotion can be lowered with epidural stimulation and serotonergic agonist infiltration.1 Under those conditions, rats with complete spinal cord injury recovered amazing stepping capacity on treadmills after training. However, it also became clear that the regained stepping capacity was completely treadmill dependent. The rats did not gain any voluntary control of locomotion and returned back to complete paraplegia without the treadmill.
Courtine's recent study, published in the June 2012 issue of Science, confirms the importance of overground training in reorganizing supraspinal control and voluntary locomotion recovery after paralyzing spinal cord injury.2 Staggered lateral hemisections, disrupting most of the direct supraspinal control of the lower extremity movement, were performed in rats with no spontaneous recovery of lower limb function even after 2 months. A robotic neuroprosthetic training system was then used to encourage and enforce the active participation of the rats in goal oriented locomotion training, assisted with epidural stimulation and serotonergic agonist infiltration.3 All the rats with this training regimen regained the ability to initiate and sustain voluntary full weight-bearing locomotion toward the target, even stair-climbing and obstacles avoidance after a few weeks of training. In comparison, none of rats that received treadmill restricted training were able to have voluntary control of locomotion, despite the recovery of automatic stepping on the treadmills. Most importantly, the authors further explored the mechanisms to explain the difference in recovery. In the overground training group, significantly more ventral thoracic interneurons were activated around the lesion sites. The activated interneurons seemed to function as the vital relay between the supraspinal input and the lower motor circuitry. Inactivating those interneurons resulted in the loss of the recovered overground locomotion but not the treadmill stepping capacity. Electrophysiologic studies demonstrated a prolonged latency with activation of the lower extremity muscles from brain stimulation in the mice with recovered overground locomotion compared to intact animals, suggesting that the supraspinal control of the recovered locomotion occurs through the addition of the interneuron relay.
These results provide important experimental data in guiding the management of spinal cord injury. It emphasized the importance of engaging patients with spinal cord injury in goal oriented, overground locomotion training instead of or at least in addition to the passive treadmill training to ensure that the neuroplasticity favors the rewiring from the supraspinal control instead of local sensory input from a treadmill. Results also point to the importance of interneurons at the injury site that can function as essential relay stations for the reconnection of the supraspinal information to the lower motor circuitry given proper training. Treatment strategies that increase interneuron survival and/or promote their sprouting and reconnection may have great potentials in promoting significant functional recovery after spinal cord injury. For complete spinal cord injury, stem cells that can be transformed into appropriate interneurons might be the key for treating this historically incurable ailment. With either treatment strategy, it is of vital importance that aggressive goal oriented, overground training regimen be implemented to maximally guide neural plasticity to reconnect the brain control with its lost targets.
1. Courtine G, Gerasimenko Y, van den Brand R, et al.. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat Neurosci. 2009;12(10):1333–1342.
2. van den Brand R, Heutschi J, Barraud Q, et al.. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 2012;336(6085):1182–1185.
3. Dominici N, Keller U, Vallery H, et al.. Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders [published online ahead of print]. Nat Med. 2012. doi: 10.1038/nm. 2845.