Independent replication of motor cortex and cervical spinal cord electrical stimulation to promote forelimb motor function after spinal cord injury in rats
Activity-Dependent Plasticity, Translational Research
Most patients suffering from the spinal cord injury are injured at cervical level, and majority of them have residual corticospinal tract connections left. We could strengthen these spared connections after incomplete cervical spinal cord injury to improve arm and hand function. The goal of this project is to validate independently in our laboratory the rehabilitation effect of paired cortex and spinal cord stimulation protocol developed in Martin Laboratory in rats, as the first step to translate it to human patients use.
Paralysis from spinal cord injury (SCI) is often the result of damage to the corticospinal tract (CST), the pathway that directly connects motor cortex to the spinal cord. Even in fully paralyzed individuals, however, a portion of the CST is often spared, providing an anatomical substrate for therapeutic interventions. Electrical stimulation of the brain or spinal cord has shown efficacy in improving CST function after SCI, either by amplifying the brain control signals or by increasing the sensitivity of the spinal cord. Whereas paired stimulation of the CST and its spinal targets have the potential to amplify the effects of either alone. The parameters for effective paired stimulation, and the site of their interaction, are not known. Our proposed experiments in rat models of CST damage will define the best location and stimulation parameters for pairing brain and spinal cord stimulation, as a means to improve motor function.
Recovery of forearm movement remains a largely unmet need for cervical spinal cord injury patients. We recently demonstrated that the drug 4-Aminopyridine (4-AP) is capable of raising significant levels of neural excitabilty from circuits that are spared after injury. Our main goal is to optimally combine 4-AP and motor training to produce lasting motor recovery in arm and hand function.
The motor circuits or tracts that mediate spontaneous recovery in motor function could be strengthened by electrical stimulation to improve functional recover. However, the mechanism underlying spontaneous recovery after spinal cord injury has not been understood. The goals of this project are to identify motor tracts and circuits responsible spontaneous recovery after spinal cord injury and improve functional recovery by strengthening them with electrical stimulation.
Residual connections left between the cortex and spinal cord after injury are too weak to result in significant functional recovery. Our lab has shown that paired motor cortex and cervical epidural stimulation convergent in the spinal cord produces long-lasting augmentation in motor evoked potentials that is stronger than using either of them alone. But little is known whether this paired stimulation could further strengthen the weak connections left after injury for hand functional recovery.
The young brain is more plastic in its connections than older animals. As a result, animals with nervous system injury early in life often recovery significant function. The overall goal of our experiments is to understand how in neonatal animals brain plasticity allows connections between the brain and spinal cord to become strong after injury. We will also try to improve on this natural recovery by electrically stimulating the brain-spinal cord connections that are spared by injury.
Subcortical motor system strokes, such as those that affect the internal capsule and brain stem, are distinct from cortical strokes in that they leave motor cortex and spinal cord intact but destroy axonal connections between them. In order to develop effective therapies for this common condition, it is critical to have a reproducible animal model.
Previous research combining motor training and axon sprouting therapies in rats shows that a time gap between the two leads to significant improvement in function. Our laboratory has shown that electrical stimulation applied to the uninjured corticospinal tract after partial injury improves functional recovery and promotes axonal outgrowth in a delayed fashion. However, there is a gap in our understanding as to how and when to combine electrical stimulation and motor training to enhance functional outcomes
Long-lasting, softening spinal cord stimulators