Pediatric Hemiplegia: Synergistic Treatment using rTMS and CIT

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DESCRIPTION (provided by applicant): Our application addresses broad Challenge Area (04): Clinical Research and specific Challenge Topic, 04- HD-102: Development of Pediatric Medical Devices. The severity of hemiplegia due to damage in the brain in both the pediatric and adult populations stems not only from the loss of neurons killed by the vascular insult but also from the loss of function in viable but dormant neurons in the affected hemisphere. The latter problem may be avoidable and, to a certain extent, correctable. The down-regulated excitability in these neurons results from compensatory overuse of cortical motor neurons in the non-stroke hemisphere, which 1) suppresses motor neurons in the stroke hemisphere through inhibitory transcallosal projections, and 2) competes with and suppresses the functional maturation of corticospinal projections from the stroke hemisphere through its ipsilateral projections to the paretic hand. The strategy in rehabilitating pediatric hemiplegia is to overcome this "developmental disuse". Therefore, in pediatrics, where there may be greater potential for neuroplasticity, the challenge is to restore excitability and voluntary control of these down- regulated neurons. Disruption of the excitability in the non-stroke hemisphere, with resultant increased excitability (disinhibition) in the stroke hemisphere, can be achieved with low-frequency repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating targeted areas of the brain. Furthermore, the disruptive effects of low-frequency rTMS can be increased and prolonged by preceding it with 6-Hz priming stimulation. We have recently demonstrated the safety of this priming/low-frequency rTMS in adults with stroke and we are currently engaged in an NIH-funded study exploring the effectiveness, mechanism and safety of serial treatments of rTMS combined with motor learning training. Very little research, however, has been attempted on interventions to promote brain reorganization and recovery in hemiplegia in children. Thus, this study will determine the effectiveness, mechanism, and safety of 5 treatments of 6-Hz primed low- frequency rTMS applied to the non-stroke hemisphere and combined with constraint induced therapy (CIT) to promote recovery of the paretic hand. Fifteen children with pediatric hemiplegia, age 8 -16 years, at each of two pediatric medical facilities (total N = 30), will be randomly assigned to one of two treatment groups that will receive treatment for 2 weeks. The rTMSreal/CIT group will receive alternating days of the real rTMS and CIT for 5 treatments of each. The rTMSsham/CIT group will receive alternating days of sham rTMS with real CIT for 5 treatments of each. Subjects will be tested at pretest and posttest. The hypotheses are: 1) the rTMS treatment will show no serious side effects, 2) both groups will show improvement in hand function but the rTMSsham/CIT group will show significantly greater improvement, 3) the rTMSreal/CIT group will also show significantly greater improvements in brain reorganization measured by paired-pulse TMS testing, cortical silent period testing, and fMRI. The proposed research is important because very little research on rehabilitation-induced brain reorganization has been done in pediatric hemiplegia. It is innovative because it applies a technique never used before, i.e. 6-Hz primed low-frequency rTMS combined with CIT. The potential impact of this research is a radical change to pediatric rehabilitation that accomplishes a higher functional recovery. This project has the potential to discover a new method of promoting brain reorganization and recovery of hand function in children with hemiplegia. Very little research has been done on children with hemiplegia that addresses brain reorganization. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation, when combined with Constraint Induced Therapy, may show a potent synergism that produces unprecedented rehabilitation gains. Pursuing this knowledge will help to promote higher quality of life in thousands of children each year.