Pathophysiological mechanisms of impaired limb use and repair strategies for motor systems after unilateral injury of the developing brain

Abstract

The corticospinal tract (CST) is important for limb control. In humans, it begins developing prenatally but CST connections do not have a mature pattern until about 6 months of age and its capacity to evoke muscle contraction does not mature until mid-adolescence. An initially bilateral projection is subsequently refined, so that most ipsilateral CST connections are eliminated. Unilateral brain damage during refinement leads to bilateral developmental impairments. The damaged side develops sparse and weak contralateral spinal connections and the non-involved hemisphere maintains its ipsilateral projection to develop an aberrant bilateral spinal projection. In a kitten model of unilateral spastic cerebral palsy, we replicate key features of the CST circuit changes: robust bilateral CST projections from the non-involved hemisphere, sparse contralateral connections from the affected hemisphere, and motor impairments. We discuss the role of activity-dependent synaptic competition in development of bilateral CSTs and consider several experimental strategies for restoring a more normal pattern of CST connections from the damaged and non-involved sides. We highlight recent results stressing the importance of combined repair of CST axons, restoration of a more normal motor cortex motor representation, and key involvement of spinal cholinergic interneurons in restoring skilled motor function.