Pediatric Hemiplegia: Synergistic Treatment using rTMS and CIT

描述（由申请人提供）：我们的申请涉及广泛的挑战领域（04）：临床研究和特定的挑战主题，04- HD-102：儿科医疗器械的开发。在儿童和成人人群中，由于脑损伤而导致的偏瘫的严重程度不仅源于血管损伤所杀死的神经元的丧失，而且还源于受影响半球中存活但休眠的神经元的功能丧失。后一个问题可能是可以避免的，在某种程度上是可以纠正的。这些神经元中下调的兴奋性是由于非中风半球中皮质运动神经元的补偿性过度使用，其1）通过抑制性经胼胝体投射抑制中风半球中的运动神经元，以及2）通过中风半球的同侧投射到麻痹手，与来自中风半球的皮质脊髓投射的功能成熟竞争并抑制其功能成熟。儿童偏瘫的康复策略是克服这种“发育性废用”。因此，在儿科，那里可能有更大的潜力，神经可塑性，挑战是恢复兴奋性和自愿控制这些下调的神经元。低频重复性经颅磁刺激（rTMS）是一种刺激大脑目标区域的非侵入性方法，可以破坏非中风半球的兴奋性，从而增加中风半球的兴奋性（去抑制）。此外，低频rTMS的破坏性作用可以增加和延长，它与6-Hz的启动刺激。我们最近已经证明了这种启动/低频rTMS在中风成人中的安全性，我们目前正在进行一项NIH资助的研究，探索rTMS与运动学习训练相结合的系列治疗的有效性，机制和安全性。然而，很少有研究试图干预，以促进脑重组和偏瘫儿童的恢复。因此，本研究将确定应用于非卒中半球的6-Hz预激低频rTMS的5种治疗方法的有效性、机制和安全性，并结合约束诱导治疗（CIT）以促进麻痹手的恢复。将在两家儿科医疗机构（共N = 30）中的每一家，将15名8 - 16岁的小儿偏瘫儿童随机分配至两个治疗组之一，接受2周治疗。rTMS真实的/CIT组将交替接受真实的rTMS和CIT各5次治疗。rTMS假手术/CIT组将交替接受假手术rTMS和真实的CIT，每组5次。受试者将在测试前和测试后接受测试。假设是：1）rTMS治疗不会显示出严重的副作用，2）两组都显示出手功能的改善，但rTMS sham/CIT组将显示出显著更大的改善，3）rTMS real/CIT组也将显示出通过成对脉冲TMS测试、皮质静默期测试和fMRI测量的大脑重组的显著更大的改善。这项研究是重要的，因为很少有研究康复诱导的脑重组已经做了小儿偏瘫。它是创新的，因为它应用了一种以前从未使用过的技术，即6-Hz预激低频rTMS与CIT相结合。这项研究的潜在影响是对儿科康复的根本改变，实现更高的功能恢复。本项目有可能发现一种促进偏瘫儿童脑重组和手功能恢复的新方法。关于偏瘫儿童大脑重组的研究很少。使用重复经颅磁刺激的非侵入性脑刺激，当与约束诱导疗法结合时，可能会显示出产生前所未有的康复收益的有效协同作用。追求这一知识将有助于促进每年成千上万的儿童更高的生活质量。

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.