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Conventional approaches beyond compensatory adjustments to disability may be augmented by applying some of the myriad experimental results about mechanisms of intrinsic biological changes after injury and the effects of extrinsic manipulations on spared neuronal assemblies. The organization and inherent adaptability of the anatomical nodes within distributed pathways of the central nervous system offer a flexible substrate for treatment strategies that drive activity\u2010dependent plasticity. Opportunities for a new generation of approaches are manifested by rodent and non\u2010human primate studies that reveal morphologic and physiologic adaptations induced by injury, by learning\u2010associated practice, by the effects of pharmacologic neuromodulators, by the behavioral and molecular bases for enhancing activity\u2010dependent synaptic plasticity, and by cell replacement, gene therapy, and regenerative biologic strategies. Techniques such as functional magnetic resonance imaging and transcranial magnetic stimulation will help determine the most optimal physiologic effects of interventions in patients as the cortical representations for skilled movements and cognitive processes are modified by the combination of conventional and biologic therapies. As clinicians digest the finer details of the neurobiology of rehabilitation, they will translate laboratory data into controlled clinical trials. 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