Noradrenergic modulation of hemiplegia: facilitation and maintenance of recovery.

This review presents data from laboratory studies and clinical trials indicating the efficacy of the "Noradrenergic Strategy" for enhancing recovery after cortical injury. Short-term acute treatment combining Physical Therapy (PT) with drugs increasing noradrenaline (NA) levels enhances recovery of hemiplegia in both laboratory studies and clinical trials which also report improved aphasia recovery. Importantly these effects endure even when treatment is initiated months after stroke onset. The hypothesized mechanisms included modulation of neuronal processes underlying "spontaneous" recovery since drugs reducing NA levels slow spontaneous recovery. The effect of some drugs change with time after sensorimotor cortex (SMCx) injury. Drugs reducing NA levels, including clonidine and prazosin, and GABA receptor agonists at doses having little effect early after injury, when administered to animals or stroke patients after "complete recovery" transiently reinstate the original symptoms. Reinstatement by prazosin remains unchanged after repeated testing for over six months in rat, and the deficits can be as severe as the first days after injury. This suggests "completed" recovery is an inaccurate label for an enduring "fragile" state. This transient reinstatement of symptoms may be useful for distinguishing causal from corollary relationships between symptoms and physiological processes proposed as mechanisms for recovery of function.