Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness after TBI

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DESCRIPTION (provided by applicant): One-third of severe traumatic brain injury (TBI) survivors will not recover conscious behavior. Survivors will continue to live in states of seriousy impaired consciousness (SIC) because there are few to no treatments that improve function. Our long-term goal is to develop treatments that safely induce and modulate neural ac- tivity resulting in improved function for persons incurring severe TBI and this R21 addresses this need by tak-ing the first step toward developing a robust and safe treatment. The R21 research objective is to examine the safety and efficacy of repetitive transcranal magnetic stimulation (rTMS) combined with Amantadine (TMS + Amantadine) relative to rTMS Alone and Amantadine Alone for persons in chronic states of SIC. The hypothesis is that provision of rTMS+Amantadine will provide a safe yet synergistic effect that induces or ac- celerates functional recovery. This hypothesis is based on (a) preliminary data indicating partially improved neurobehavioral functioning mechanistically related to rTMS-induced neural activity and connectivity as well as improved integrity of white fiber tracts, (b) relationship between dopamine (DA) and common TBI impairments, (c) role of DA in mediating consciousness, (d) the commonality between and DA and rTMS-targeted pathways, (e) clinical efficacy and safety of Amantadine, (f) mechanisms of action of Amantadine, and (g) the association between rTMS and Amantadine with up-regulating brain derived neurotrophic factor . The rationale is that pairing rTMS with Amantadine will have a complementary and synergistic effect on factors promoting conscious behavior. This R21 research has the potential to provide new treatments for the study population and to advance the field of TBI neurorehabilitation. The specific aims are to: (1) Demonstrate that rTMS+Amantadine is safely tolerated, (2) Determine neurobehavioral effect of rTMS+Amantadine, and (3) Characterize pre-and post-treatment neural changes in neural. Aim 1 is based on our preliminary safety data and safety data regarding Amantadine. To address Aims 2 & 3 we use a repeated measures baseline control design with randomized treatment orders yielding three treatment groups; rTMS + Amantadine, rTMS Alone and Amantadine Alone. Analyses for Aims 2 and 3 involve comparing these treatment groups according to neurobehavioral growth trajectories, mean amount of neural activation and connectivity within and between brain regions, and indices of fiber tract directionality. Findings will advance knowledge about how rTMS + Amantadine safely enable neurobehavioral gains. Findings will be used to select and refine treatments to be examined in a future effectiveness trial. This project is innovative because rTMS alone as a neurotherapeutic for severe TBI is novel and because the combination of a drug with rTMS has never been examined as a po- tential neurotherapeutic. The proposed research is significant because it is expected to expand understanding of how Amantadine adds to the rTMS effect and how this relates to functioning. These contributions will lead to developing treatment options for a complex patient population for whom few to no treatment options exist.