Spasticity is a secondary neurological condition associated with brain and spinal cord injury that is often one of the most difficult problems that encumbers the care and lifestyle of individuals following nervous system injury. Although progress has been made in the therapeutic treatment of spasticity, many unknowns remain regarding fundamental mechanisms that underlie the pathophysiology of spasticity, how treatments specifically address fundamental mechanisms, and ultimately, how chronic treatments impact these fundamental processes. The experiments proposed in this application address these issues and have come out of our studies aimed at understanding fundamental neurophysiological processes that underlie normal reflex excitability, how these change following contusion spinal cord injury, and how these changes correlate with the development of spasticity. Use of the experimental midthoracic contusion injury revealed significant neurophysiological, locomotor, neuromuscular, and histological changes that confirm the feasibility of reproducing significant features of human spasticity in a laboratory model. Two particularly sensitive quantitative tools that were developed during these studies (neurophysiological analysis of rate-depression and analysis of velocity-dependent ankle torque) can now be used in conjunction with behavioral and histological study as a multidisciplinary assay to further quantitate changes produced by injury and experimental treatments. Therefore, the objectives of this proposal are to obtain a better understanding of the long term functional disability imposed by spasticity, and the potential for early intervention therapy using locomotor exercise and antispastic medication (intrathecal baclofen) (initiated before spastic patterns are firmly established) to influence long term outcome measures of spasticity and voluntary motor activity. An additional objective is to evaluate the reversibility of plasticity induced by chronic intrathecal baclofen treatment. Approach. These studies will compare neurophysiological and behavioral outcome measures in treated and untreated animals following midthoracic spinal cord contusion injuries. Treatments will consist of self-paced activity wheel running and constant infusion intrathcal baclofen, administered independently and as combined therapies utilizing both acute and subchronic injury-to-treatment intervals to initiate an understanding of safety, feasibility, and therapeutic window for these treatments.
