Funding Agency:

National Institutes of Health, National Institute of Child Health and Human Development (Grant No. R01 HD046700)

Total Project Period:

12/10/04 - 11/30/08

Total Project Award:

$1,269,676

Principal Investigator:

Anthony E. Kline, MD (Department of Physical Medicine and Rehabilitation)

Co-Investigators:

C. Edward Dixon, PhD, Robert B. Gibbs (Pharmaceutical Sciences), Amy K. Wagner, MD (Department of Physical Medicine and Rehabilitation), Ross D. Zafonte, MD (Department of Physical Medicine and Rehabilitation)

Project Summary:

Traumatic brain injury (TBI) affects 1.5 to 2 million individuals in the United States each year. Approximately 100,000 severe-TBI survivors endure long-term memory and/or physical impairments that require rigorous and costly rehabilitative therapy. While there are currently no accepted treatments for human TBI, we have data showing that early (15 min after TBI) administration of serotonin1A receptor (5-HT1AR) agonists – a pharmacotherapy novel to TBI, but used routinely to treat anxiety and depression in humans – attenuate experimental TBI-induced behavioral deficits. While the benefits of this early treatment are compelling, the potential efficacy of delayed and chronic 5-HT 1AR agonist treatments after TBI is unknown. This issue is paramount given the secondary sequelae that are prevalent hours to days after TBI and that perturb the recovery process. Empirical investigation of pharmacological interventions that restore and/or enhance neuromodulation when given hours vs. minutes post-TBI is essential for successful rehabilitation. Also warranted is further investigation of environmental enrichment (EE) on recovery. EE enhances outcome after TBI vs. standard environments, is a relevant experimental analogue of the rehabilitation paradigm, and may provide clinical utility alone or as an adjunct to pharmacotherapy. Thus, the goals of this proposal are to further examine the effects of the 5-HT1AR agonist buspirone and EE alone or in conjunction with each other. It is hypothesized that buspirone and EE will facilitate memory and motor recovery after TBI, but the combination of treatments will be more efficacious than either alone. This project represents the first systematic investigation of delayed and chronic 5-HT1AR agonist treatment, EE, and their combination on memory and motor function after TBI, and will provide a framework for further empirical research of potential mechanisms. Our long-term goal is to develop therapies that facilitate functional recovery after human TBI.