PEDIATRIC BRAIN INJURY RECOVERY VIA USE-DRIVEN FUNCTIONAL NETWORK REORGANIZATION

 描述(申请人提供)：脑损伤是儿童长期残疾的主要原因，也是所有儿科疾病中最大的疾病负担。患有脑损伤的儿童往往补偿得非常好，能够发展出通常由现在受损的大脑结构支持的能力。人们认为，这种恢复很大程度上是由使用驱动的大脑复杂功能网络结构的重组造成的。更好地了解活动、网络组织和功能恢复之间的联系，对于开发急需的新的神经康复治疗方法和改进现有的治疗方法至关重要。因此，我们的长期目标是揭示脑损伤儿童使用驱动的功能网络可塑性的系统水平基础。强迫诱导运动疗法(CIMT)是一种治疗偏瘫的方法，它为研究使用驱动的脑重组提供了一个很好的研究模型。接受CIMT治疗的患者在与患侧练习困难任务的同时，他们更强壮的上肢在石膏中被限制了三周。CIMT从根本上改变了上肢的使用，从而持久地改善了治疗侧的功能。目前这项提案的目的是了解强制诱导运动疗法(CIMT)如何改善慢性脑损伤儿童的运动功能。其具体目的是1)确定对改善上肢使用最重要的功能网络变化，2)建立预测治疗反应的神经心理测量标记物，3)调查治疗剂量对结果的影响。这项研究将检验我们的假设，即CIMT的大部分好处来自大脑的注意力和运动网络之间的功能联系向治疗侧的重新加权，并且这些变化受到注意障碍和治疗剂量的调节。为了实现这些目标，我们将使用多模式MRI(功能、功能连接)和可穿戴的加速度计生物传感器，反复评估接受CIMT的儿童的功能网络和运动行为。受试者内的设计和新颖的单一受试者网络分析将首次使我们能够排除病变的不均质性，并提取患者之间由治疗驱动的变化的共性。这项研究将通过确定与脑刺激和神经反馈有关的有益联系来强烈影响健康相关研究，并可能揭示对治疗成功至关重要的可修改的患者(注意力障碍)和治疗因素(剂量)。候选人：Nico Dosenbach博士，候选人，是一位系统神经学家和儿科神经学家，他之前使用功能磁共振成像(FMRI)和功能连接磁共振成像(FcMRI)的研究对理解注意控制网络和功能网络发育做出了重要贡献。在推进儿科脑损伤康复治疗的临床兴趣的推动下，多森巴赫医生正在寻求在运动学、发展神经心理学、生物统计学和临床儿科神经康复方面进行更多培训。多森巴赫博士的职业目标是提高对儿童脑损伤功能网络重组的科学理解，以开发新的神经康复治疗方法，以及优化现有的治疗方法。他的职业发展计划包括与朗博士进行运动科学培训，与巴奇博士进行发展神经心理学培训，与香农博士进行生物统计学培训，并与诺泽尔博士进行临床儿科神经康复培训。多森巴赫博士的主要导师布拉德利·施拉格博士是一名儿科神经学家和发展认知神经学家，他还将提供运动科学和发展神经心理学方面的培训，并传达一名成功、独立的内科科学家的品质和策略。多森巴赫博士将完成运动科学、神经心理学、生物统计学和研究伦理学的课程。环境：华盛顿大学(Wu)的神经影像研究社区是最大和最受尊敬的社区之一，以开放和大力支持年轻研究人员而闻名。许多研究人类功能网络的领先神经学家，如马库斯·雷切尔博士、史蒂文·彼得森博士、莫里齐奥·科贝塔博士和布拉德利·施拉格博士，都在吴教授工作。大卫·范·埃森博士和迪安娜·巴奇博士领导的人类连接组项目(HCP)为吴带来了更多的神经成像资源和专业知识。此外，吴在儿科神经病学(第五名)、职业治疗(第二名)和物理治疗(第三名)方面在全国排名很高(美国新闻和世界报道)。总体而言，对于多森巴赫博士的研究事业发展和拟议项目的成功，吴是可以想象到的最好的机构。

 DESCRIPTION (provided by applicant): Brain injury is the main cause auf long-term disability in children and carries the greatest disease burden out of any pediatric condition. Children with brain injury often compensate remarkably well and can develop abilities typically supported by brain structures now damaged. It is thought that much of this recovery results from the use-driven reorganization of the brain's complex functional network architecture. A better understanding of the links between activity, network organization and functional recovery is paramount to developing much needed novel neurorehabilitative treatments and improving existing ones. Therefore, it is our long-term objective to uncover the systems-level fundamentals of use-driven functional network plasticity in children with brain injury. Constraint-induced movement therapy (CIMT), a treatment for hemiparesis, provides an excellent research model for studying use-driven brain reorganization. Patients treated with CIMT have their stronger upper extremity restrained in a cast for three weeks while practicing difficult tasks with the affected side. CIMT radically alters upper extremity use, thus lastingly improving function on the treated side. The objective of the current proposal is to learn how constraint-induced movement therapy (CIMT) improves motor function in children with chronic brain injury. The specific aims are to 1) identify those functional network changes most important for improved upper extremity use, 2) establish neuropsychometric markers that predict treatment response, and 3) investigate the effect of therapy dose on outcomes. This study will test our hypothesis that much of CIMTs benefit derives from a reweighting of functional connections between the brain's attention and motor networks towards the treated side and that these changes are modulated by attentional dysfunction and therapy dose. To achieve these aims we will repeatedly assess functional networks and motor behavior with multi-modal MRI (functional, functional connectivity) and wearable accelerometer biosensors, in children undergoing CIMT. A within-subject design and novel single-subject network analytics will for the first time allow us to factor out lesion inhomogeneity and extract commonalities of therapy-driven changes across patients. This study will strongly impact health-related research by identifying beneficial connections that should be targeted with brain stimulation and neurofeedback and potentially revealing modifiable patient (attentional dysfunction) and therapy factors (dose) critical to therapy success. Candidate: Dr. Nico Dosenbach, the candidate, is a systems neuroscientist and pediatric neurologist whose prior research using functional MRI (fMRI) and functional connectivity MRI (fcMRI) has contributed significantly to the understanding of attentional control networks and functional network development. Driven by his clinical interest in advancing rehabilitative treatments for pediatric brain injury, Dr. Dosenbach is seeking additional training in movement science, developmental neuropsychology, biostatistics and clinical pediatric neurorehabilitation. Dr. Dosenbach's career goal is to improve the scientific understanding of functional network reorganization in pediatric brain injury in order to develop novel neurorehabilitative treatments, as well as to optimize current treatments. His career development plan includes training in movement science with Dr. Lang, developmental neuropsychology with Dr. Barch, biostatistics with Dr. Shannon and in clinical pediatric neurorehabilitation with Dr. Noetzel. Dr. Dosenbach's principal mentor, Dr. Bradley Schlaggar, a pediatric neurologist and developmental cognitive neuroscientist, will also provide training in movement science and developmental neuropsychology and convey the qualities and strategies of a successful, independent physician-scientist. Dr. Dosenbach will complete classes in movement science, neuropsychology, biostatistics and Research Ethics. Environment: Washington University's (WU) neuroimaging research community is one of the largest and most highly regarded and has a reputation for openness and strongly supporting young investigators. Many of the leading neuroscientists studying human functional networks, such as Drs. Marcus Raichle, Steven Petersen, Maurizio Corbetta and Bradley Schlaggar, work at WU. The Human Connectome Project (HCP) led by Dr. David Van Essen and Dr. Deanna Barch has brought even greater neuroimaging resources and expertise to WU. In addition, WU is nationally highly ranked (US News and World Report) in pediatric neurology (# 5), occupational therapy (#2) and physical therapy (#3). Overall, WU is the single best institution imaginable for Dr. Dosenbach's research career development and the success of the proposed project.