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因血管损伤而死亡的神经元的丧失，还源于受影响半球中活性和休眠神经元的功能丧失。后一个问题是可以避免的，而且在一定程度上是可以纠正的。这些神经元的兴奋性下调是由于非卒中半球皮质运动神经元的代偿性过度使用，这1)通过抑制性经胼胝体投射抑制卒中半球的运动神经元，2)与卒中半球皮质脊髓投射通过其同侧到麻痹手的投射竞争并抑制其功能成熟。小儿偏瘫康复的策略是克服这种“发育废用”。因此，在可能具有更大神经可塑性潜力的儿科，挑战在于恢复这些下调神经元的兴奋性和自主控制。低频重复经颅磁刺激（rTMS）是一种刺激大脑目标区域的非侵入性方法，可以破坏非卒中半球的兴奋性，从而增加卒中半球的兴奋性（去抑制）。此外，低频rTMS的破坏性效应可以通过6hz启动刺激来增强和延长。我们最近已经证明了这种启动/低频rTMS对成人中风患者的安全性，我们目前正在进行一项美国国立卫生研究院资助的研究，探索rTMS结合运动学习训练的系列治疗的有效性、机制和安全性。然而，很少有研究已经尝试干预，以促进大脑重组和恢复偏瘫儿童。因此，本研究将确定5种治疗方法的有效性、机制和安全性，即6 hz启动低频rTMS应用于非卒中半球，并结合约束诱导治疗（CIT）来促进麻痹手的恢复。在两家儿科医疗机构（总N = 30）中，15名8 -16岁的小儿偏瘫儿童将被随机分配到两个治疗组中的一个，接受2周的治疗。rTMSreal/CIT组将接受真实rTMS和CIT交替进行5次治疗。rTMSsham/CIT组将接受假rTMS与真实CIT交替进行的治疗，每种治疗5次。受试者将在测试前和测试后进行测试。假设是：1)rTMS治疗不会出现严重的副作用；2)两组手功能均有改善，但rTMSsham/CIT组改善明显更大；3)rTMSreal/CIT组通过配对脉冲TMS测试、皮质沉默期测试和fMRI测量的大脑重组也有显著更大的改善。这项研究很重要，因为在儿童偏瘫中，康复诱导的大脑重组的研究很少。它的创新之处在于，它采用了一种以前从未使用过的技术，即6赫兹启动低频rTMS与CIT相结合。这项研究的潜在影响是彻底改变儿科康复，实现更高的功能恢复。该项目有可能发现一种促进偏瘫儿童大脑重组和手部功能恢复的新方法。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无创脑刺激，当与约束诱导治疗相结合时，可能显示出强有力的协同作用，产生前所未有的康复效果。追求这方面的知识将有助于提高每年成千上万儿童的生活质量。

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.