Rehabilitative experience following focal ischemic brain injury: Evidence for bihemispheric neural reorganization and the existence of a critical period for enhanced morphological plasticity and functional recovery

For most stroke victims, physical rehabilitation is the only treatment option. Several clinical studies have demonstrated the efficacy of rehabilitative therapy to improve sensorimotor function following stroke (Sunderland et al., 1992; Kopp et al., 1999; Kunkel et al., 1999), although the neural mechanisms underlying recovery are poorly understood.; The initial series of experiments utilized serial nuclear magnetic resonance (NMR) imaging to characterize a novel model of middle cerebral artery (MCA) occlusion in the rat. Application of the vasoconstrictive peptide endothelin-1 (ET-1) adjacent to the proximal MCA caused a moderate, but prolonged reduction in cerebral blood flow (CBF) resulting in tissue infarction that subsequently evolved over 48 hours. Importantly, this model of MCA occlusion was found to closely resemble the dynamics observed in clinical stroke.; Rehabilitative therapy provides modest functional improvement after brain injury that is associated with reorganization of cortical neural circuitry in regions adjacent to the infarction (Nudo et al., 1996a). Utilizing the ET-1 model of focal ischemia, Chapter 3 expands on these findings by demonstrating that intensive enriched-rehabilitation of the impaired forelimb provides long-term (3 months) sensorimotor recovery following extensive ischemic injury to both striatum and the cerebral cortex. Improved function was associated with enhanced dendritic growth within the contralateral, undamaged motor cortex, thereby providing a potential morphological substrate for bihemispheric brain activation patterns observed in recovering stroke patients during movement of the affected limb.; Chapter 4 asked specifically whether the observed neuronal remodeling within the undamaged hemisphere contributes to functional recovery of the (ipsilateral) affected forelimb after ischemic brain injury. Lidocaine anesthesia of the undamaged forelimb motor cortex during forelimb reaching of recovering animals reinstated initial motor deficits and abolished reaching ability. Recruitment of the undamaged motor cortex during reaching with the affected limb following focal ischemic injury was dependent on severity of infarction, since only moderate impairment was observed following lidocaine challenge in animals with small infarcts or control animals. The pattern of functional neuronal reorganization after stroke may be dependent on size and distribution of injury.; Finally, Chapter 5 identifies a critical period during which the post-stroke brain is most responsive to rehabilitative intervention. Rehabilitation initiated at either 5 or 14 days after the stroke provided significant functional gains and a marked elevation in neuronal growth that was not observed when the same treatment was delayed for one month. This finding has important (and immediate) implications for rehabilitative practices following stroke.