Remote Ischemic Conditioning to Enhance Motor Learning and Corticospinal Excitability in Children with Unilateral Cerebral Palsy

项目总结/摘要 单侧脑性瘫痪（UCP）是儿童残疾的主要原因。早期脑损伤损害 上肢功能，双手协调，影响孩子的独立性。的有效性 现有的改善麻痹手臂功能的康复方法由于较高的训练剂量而受到限制， 适度的效果大小，以及对训练效果的不良保留。因此，迫切需要找到一种有效的启动方法， 代理，当与运动（双手）技能训练配对时，将促进神经生物学过程，以增强 训练效果的大小和提高UCP患儿的功能能力。这项建议旨在 确定一种新的预激剂，远程缺血调节（RIC），当与双手 通过技能训练提高UCP儿童双手技能学习和技能依赖性可塑性。 缺血性条件反射（Ischemic conditioning，IC）是一种通过直接作用于靶器官而保护靶器官免受缺血损伤的现象 使其暴露于短暂的亚致死性缺血。RIC是一种临床可行的IC方法， 局部缺血和再灌注的发作通过血压袖带的循环充气和放气来传递， 手臂或腿。临床前和初步临床试验显示RIC具有神经保护作用。我们 先前的工作已经表明，当与运动训练配对时，RIC增强健康个体的运动学习。 基于RIC的这些多样化的益处，我们的中心假设是RIC的多因素机制 可以作为一种启动剂，以提高运动学习和增强神经可塑性的儿童， UCP。我们的具体目标是：1）确定RIC +训练对双手技能表现的影响，以及2） 确定RIC +训练对皮质脊髓功能的影响， 随机对照试验，30例UCP儿童将首先 上 调节 兴奋性 经历双手速度堆栈性能，功能 肢体和经颅磁刺激评估。然后，儿童将接受RIC/Sham 再加上训练 患有UCP的儿童。在这个三盲实验中， 我们将通过压力的循环充气和放气提供RIC/假调节 使用标准协议将袖带套在麻痹手臂上。训练将包括5天（15次试验/天）的双手速度 堆栈训练医师将在干预后进行相同的基线评估。我们假设 与假条件反射+训练相比，RIC +训练将显著提高：1）双手技能表现 （减少完成双手速度叠加任务的移动时间（秒）），2）双手功能（增加双手速度叠加任务的移动时间（秒））， 辅助手评估评分），3）同侧初级运动皮层（M1）的皮层兴奋性（较大 运动诱发电位的幅度和较低的静息或活动运动阈值），以及4）减少运动皮层 抑制（同病灶M1中短间期皮质内抑制减少和皮质内易化增加）。 我们的长期目标是制定有效的干预措施，以改善儿童的功能与UCP。成果 该项目将为设计确定RIC效果的第二阶段试验提供关键要素 结合强化行为干预，以改善UCP儿童的功能结果。

PROJECT SUMMARY/ABSTRACT Unilateral cerebral palsy (UCP) is a leading cause of childhood disability. An early brain injury impairs the upper extremity function, bimanual coordination, and impacts the child's independence. The effectiveness of existing rehabilitation approaches to improve the paretic arm function is limited due to higher training doses, modest effect sizes, and poor retention of training effects. Thus, there is a critical need to find an effective priming agent that, when paired with motor (bimanual) skill training, will facilitate neurobiological processes to enhance the magnitude of training effects and improve functional capabilities of children with UCP. This proposal aims to determine the effects of a novel priming agent, remote ischemic conditioning (RIC), when paired with bimanual skill training to enhance bimanual skill learning and to augment skill dependent plasticity in children with UCP. Ischemic conditioning (IC) is a phenomenon of protecting the target organ from ischemia by directly exposing it to brief episodes of sublethal ischemia. RIC is a clinically feasible way of performing IC where episodes of ischemia and reperfusion are delivered with cyclic inflation and deflation of a blood pressure cuff on the arm or leg. Pre-clinical and preliminary clinical trials in humans show neuroprotective effects of RIC. Our prior work has shown that when paired with motor training, RIC enhances motor learning in healthy individuals. Based on these diversified benefits of RIC, our central hypothesis is that the multifactorial mechanisms of RIC can be harnessed as a priming agent to enhance motor learning and augment neuroplasticity in children with UCP. Our Specific Aims are: 1) to determine the effects of RIC + training on bimanual skill performance, and 2) to determine the effects of RIC + training on corticospinal randomized controlled trial, 30 children with UCP will first upper conditioning excitability undergo bimanual speed stack performance, functional extremity, and Transcranial Magnetic Stimulation assessments. Children will then undergo RIC/Sham plus training. in children with UCP. In this triple blind, We will deliver RIC/sham conditioning via cyclic inflation and deflation of a pressure cuff on the paretic arm using a standard protocol. Training will involve 5 days (15 trials/day) of bimanual speed stack training. Thechildren will perform the same baseline assessmentspost-intervention. We hypothesize that compared to sham conditioning + training, RIC + training will significantly enhance: 1) bimanual skill performance (decrease in movement time (sec) to complete bimanual speed stack task), 2) bimanual function (increase in the Assisting Hand Assessment scores), 3) cortical excitability in the ipsilesional primary motor cortex (M1) (larger amplitude of motor evoked potentials and lower resting or active motor thresholds), and 4) reduce motor cortex inhibition (reduced short-interval intracortical inhibition and increase in intracortical facilitation in ipsilesional M1). Our long-term goal is to develop effective interventions to improve function of children with UCP. Outcomes of this project will provide critical ingredients for designing Phase II trials that will determine the effects of RIC combined with intensive behavioral interventions to improve functional outcomes in children with UCP.