Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke

Abstract

The brain exhibits limited capacity for spontaneous restoration of lost motor functions after stroke. Rehabilitation is the prevailing clinical approach to augment functional recovery, but the scientific basis is poorly understood. Here, we show nearly full recovery of skilled forelimb functions in rats with large strokes when a growth-promoting immunotherapy against a neurite growth-inhibitory protein was applied to boost the sprouting of new fibers, before stabilizing the newly formed circuits by intensive training. In contrast, early high-intensity training during the growth phase destroyed the effect and led to aberrant fiber patterns. Pharmacogenetic experiments identified a subset of corticospinal fibers originating in the intact half of the forebrain, side-switching in the spinal cord to newly innervate the impaired limb and restore skilled motor function.

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…Stroke triggers new connections to form in motor, somatosensory, and premotor cortex adjacent to the stroke site, and in projections from cortex contralateral to the stroke site into distant connections in the striatum, midbrain, and spinal cord 11, 12, 13, 27, 28, 29, 30, 31, 32. In both the cortex contralateral to the stroke, and ipsilateral or peri‐infarct cortex, animal models indicate that axonal sprouting establishes new patterns of connections that are causally linked to recovery.…”

“…In peri‐infarct cortex, when new connections are stimulated from motor to premotor cortex motor recovery is enhanced, and when these same connections are blocked from forming motor recovery is reduced 13, 33. In contralateral cortex, when new connections form in the cervical spinal cord, reaching into the portion of the cervical spinal cord that has lost its original projection from the stroke site, this process mediates part of the motor recovery in a rat stroke model 29. It appears that axonal sprouting is a widespread process after stroke, and that axonal sprouting in different functional areas can control recovery in distinct neuronal systems, such as corticospinal or premotor connections.…”

“…Human studies image large white matter tracts and, through the diffusion of water, their myelination state and their directional organization 35, 37. Rodent studies image truly small axonal collaterals and fine synaptic terminations within the cervical spinal cord 27, 28, 29, 30, 31. One set of studies is looking at the cross‐country electrical power transmission lines and the other is looking at the electrical wiring of the end‐user's house.…”

“…It is quite possible that a rehabilitation therapy may affect white matter structure and myelination, and not affect axonal terminal fields; or that axonal terminal fields may be affected and not gross structure of the myelin tract; or that both are affected by the same behavioral therapy after stroke. Because both myelinated fiber tracts and axonal terminal fields are sensitive to behavioral modulation,29, 36, 38 both are likely altered to some degree after stroke and through neurorehabilitative therapies. But at present, the role of behavioral activity in modulating white matter structure after stroke has not been determined in animal models and only larger white matter tracts can be studied in humans 39…”

“…Axonal connections are confined by the expression of glial growth inhibitory molecules, such as NogoA, EphrinA5, and chondroitin sulfate proteoglycans 11, 12, 27, 28, 29, 30, 31, 32, 33. Opposed to these glial growth inhibitors, sprouting neurons activate a unique regenerative molecular program 11, 12, 13.…”