Electrical Stimulation of Spared Corticospinal Axons Augments Connections with Ipsilateral Spinal Motor Circuits after Injury

Abstract

Activity-dependent competition shapes corticospinal (CS) axon outgrowth in the spinal cord during development. An important question in neural repair is whether activity can be used to promote outgrowth of CS axons in maturity. After injury, spared CS axons sprout and make new connections, but often not enough to restore function. We propose that electrically stimulating spared axons after injury will enhance sprouting and strengthen connections with spinal motor circuits. To study the effects of activity, we electrically stimulated CS tract axons in the medullary pyramid. To study the effects of injury, one pyramid was lesioned. We studied sparse ipsilateral CS projections of the intact pyramid as a model of the sparse connections preserved after CNS injury. We determined the capacity of CS axons to activate ipsilateral spinal motor circuits and traced their spinal projections. To understand the separate and combined contributions of injury and activity, we examined animals receiving stimulation only, injury only, and injury plus stimulation. Both stimulation and injury alone strengthened CS connectivity and increased outgrowth into the ipsilateral gray matter. Stimulation of spared axons after injury promoted outgrowth that reflected the sum of effects attributable to activity and injury alone. CS terminations were densest within the ventral motor territories of the cord, and connections in these animals were significantly stronger than after injury alone, indicating that activity augments injury-induced plasticity. We demonstrate that activity promotes plasticity in the mature CS system and that the interplay between activity and injury preferentially promotes connections with ventral spinal motor circuits.

Functional and Anatomical Reorganization of the Sensory-Motor Cortex after Incomplete Spinal Cord Injury in Adult Rats

“…Unilateral cortical injury or pyramidotomy also deprives the spinal cord unilaterally of direct cortical input. In adult rodents, sprouting of the CST from the intact side across the midline can be induced by suppression of the neurite growth inhibitor Nogo pathway (Thallmair et al, 1998;Wiessner et al, 2003), by local neurotrophic factors (Zhou and Shine, 2003), or by electrical stimulation of the injury-spared CST (Brus-Ramer et al, 2007). The rearranged CST is crucial for the observed recovery of skilled movements (Kartje-Tillotson et al, 1987).…”

Invasive Neurostimulation in Stroke Rehabilitation

“…In the absence of any resources on the paretic side, however, where ipsilesional motor systems are damaged beyond threshold level, harnessing contralesional activity may be partially adaptive through formation of atypical connections [60][61][62].…”

Strengthening Corticospinal Connections with Chronic Electrical Stimulation after Injury

“…One approach to facilitate motor recovery after neurotrauma is to target intact or spared pathways. For example, in a recent study published in The Journal of Neuroscience, spared corticospinal axons were chronically stimulated to strengthen their connections with spinal circuits in adult rats (Brus-Ramer et al, 2007). Results indicated that activity-dependent mechanisms facilitate plasticity of spared ipsilateral corticospinal axons after injury.…”

“…For example, in a recent study published in The Journal of Neuroscience, spared corticospinal axons were chronically stimulated to strengthen their connections with spinal circuits in adult rats (Brus-Ramer et al, 2007). Results indicated that activity-dependent mechanisms facilitate plasticity of spared ipsilateral corticospinal axons after injury.In the study by Brus-Ramer et al (2007), the left pyramidal tract of adult rats was lesioned, abolishing corticospinal projections to the ipsilateral and contralateral spinal cord. In some rats, an electrode was placed over the right pyramidal tract to chronically stimulate spared corticospinal axons after lesion.…”

“…The relative proportions of ipsilateral corticospinal presynaptic terminals contacting different types of postsynaptic partners could be determined and compared between groups. More direct synaptic contacts with motoneurons could indicate that spared ipsilateral corticospinal axons are attempting to form new and more direct spinal motor circuits.To determine whether structural changes correlated with an increased transmission efficacy of spared corticospinal axons, Brus-Ramer et al (2007) stimulated the intact pyramid and recorded the electroneurogram of the deep radial nerves. This allowed them to determine the motor thresholds (that is, the threshold of stimulation required to evoke a response in the nerve) of intact ipsilateral and contralateral corticospinal projections in all groups of rats.…”