Motor system plasticity in stroke models: intrinsically use-dependent, unreliably useful.

F unctional impairment is a powerful incentive for behav-ioral change. The natural response to disability in one limb is to learn new ways of using the other limb. Animals, including humans, with upper extremity impairments spontaneously learn to use the less-affected (nonparetic) hand in novel ways to perform daily activities. In intact brains, the acquisition of manual skills depends on practice-dependent synaptic structural and functional reorganization of motor cortex (MC). After stroke, this skill acquisition overlaps with ongoing degenerative and regenerative responses to the injury, many of which are also neural activity dependent 6,7 and sensitive to behavioral manipulations. 8–10 When they converge on the same circuits, ischemia-induced and experience-driven remodeling responses interact. 3 Learning to rely on the non-paretic hand is a particularly prevalent and profound form of poststroke behavioral compensation, but compensatory strategies can be found across different impairment modalities, body sides, and injury loci. Their development is among the most reliable consequences of brain injury survival. The implication is that understanding the brain's typical adaptation to stroke will require understanding its interactions with compensatory behavioral changes. The compensatory reliance on the better functioning limb after stroke has long been thought to contribute to persistent dysfunction in the affected (paretic) limb by encouraging its disuse (ie, learned nonuse). 14 Our recent findings suggest that it can go well beyond this to directly disrupt the neural sub-strates paretic limb functional improvements. Here we overview these findings, as revealed in rodent models of chronic upper extremity impairments using precise control and manipulation of forelimb experiences to understand bilateral and interhemispheric contributions to motor functional outcome. After unilateral ischemic MC damage in rats, a relatively subtle variation in behavioral experience—learning a single new motor skill with the nonparetic limb—reduces spontaneous recovery and limits functional improvements resulting from subsequent rehabilitative training of the paretic limb, but without affecting infarct size or cell loss. 15–17 This is found in rats trained to perform a unimanual reach-to-grasp task, first with the nonparetic limb (nonparetic forelimb training [NPT]) for the first few weeks after the infarcts and subsequently with the paretic limb, as rehabilitative training (Figure). Deleterious NPT effects are found when the reaching skill is novel to either limb at the time of the infarct or was established in the to-be-paretic limb before the infarct. Learning a skill with one hand does not normally result in such notable decrements in the other. For example, …