The structural underpinnings of disinhibition in dystonia

项目总结/摘要 肌张力障碍是一种以大脑为基础的疾病，导致受影响的肌肉扭曲和痉挛，扭曲患者 变成痛苦和瘫痪的姿势肌张力障碍折磨1千人（第三最常见的运动 障碍）。它可以单独发生，也可以是许多其他神经系统疾病的症状（如中风，脑 麻痹、帕金森病）。慢性疼痛、残疾和从学校或工作中退出是常见的， 严重的情况下，肌张力障碍可能是致命的。一个共同的电生理异常联系着许多类型的肌张力障碍： 局部和远程去抑制。这导致了一个假设，即抑制受损，以及一个相关的发现， 不完善的感觉反馈，导致激动肌和拮抗肌的异常共同收缩， 产生肌张力障碍的扭曲运动。然而，受损的抑制只是一个机制的一步， 导致肌张力障碍的级联反应-产生去抑制的潜在结构异常尚不清楚。 神经系统疾病的结构异常为改进治疗指明了方向。该提案将使用 MRI研究作为抑制受损的潜在解剖学基底的脑区域， 目的是确定肌张力障碍治疗和预防的新靶点。我们将解决当前的两个关键差距 肌张力障碍知识：1）半球间投射在调节皮质运动活动（长程）中的作用 去抑制）; 2）纹状体区室，纹状体和基质，在抑制不必要的运动的作用。 本研究将在两个肌张力障碍患者队列中采用新型结构、弥散和功能MRI技术： 我们将在成人、颈肌张力障碍和儿童中以最常见的形式进行成像评估， 肢体肌张力障碍这些临床上不同的人群将有助于确定哪些异常是共同的 （可推广到其他肌张力障碍的机制）并且其是特定于某些类型的肌张力障碍的。 这个指导职业发展奖的使命是寻求有关的基本知识， 大脑对运动的抑制控制，并利用这些知识来减轻肌张力障碍的负担。这一目标 类似于国家神经疾病和中风研究所的研究：研究神经系统疾病， 感觉和运动回路的机制可能会受到疾病的影响。该提案是根据我的 教育和培训需求，确保我为成为一名成功的独立调查员做好准备 利用系统神经科学的工具。有了这个奖项，我将获得以下方面的基本培训：1）生物统计学， 网络评估工具，如主成分分析、图论分析和因果分析 推理建模; 2）功能磁共振成像（fMRI）的实验设计和实现，包括两者 基于任务和静息状态的方法; 3）纹状体，苍白球， 和丘脑。我将受益于一个环境丰富的神经成像，运动障碍， 神经发育专业知识，在那里我可以建立一个成功的独立的坚实基础， 致力于改善治疗肌张力障碍的疗法的研究生涯。

PROJECT SUMMARY / ABSTRACT Dystonia is a brain-based disorder that leads affected muscles to twist and spasm, contorting the sufferer into painful and disabling positions. Dystonia afflicts 1 in 1000 people (the third-most common movement disorder). It can occur in isolation or be a symptom of many other neurological disorders (eg, stroke, cerebral palsy, Parkinson disease). Chronic pain, disability, and withdrawal from school or work are common, and in severe cases, dystonia can be fatal. A shared electrophysiologic abnormality links many types of dystonia: local and long-range disinhibition. This led to the hypothesis that impaired inhibition, and a related finding, poorly-refined sensory feedback, leads to abnormal co-contraction of agonist and antagonist muscles, producing the contorting movements of dystonia. However, impaired inhibition is only one step in a mechanistic cascade that leads to dystonia – the underlying structural abnormalities that produce disinhibition are unknown. Structural abnormalities in neurological disorders point the way to improved therapies. This proposal will use MRI to investigate brain regions that are potential anatomical substrates for impaired inhibition, with a larger goal of identifying new targets for dystonia treatment and prevention. We will address two key gaps in current dystonia knowledge: 1) the role of interhemispheric projections in regulating cortical motor activity (long-range disinhibition); 2) the role of the striatal compartments, striosome and matrix, in inhibiting unwanted movements. The study will employ novel structural, diffusion, and functional MRI techniques in two dystonia patient cohorts: we will carry out our imaging assessments in the most common forms in adults, cervical dystonia, and children, limb dystonia. These clinically-distinct populations will help determine which abnormalities are shared (mechanisms generalizable to other dystonias) and which are specific to certain types of dystonia. The mission of this Mentored Career Development Award is to seek fundamental knowledge about the brain’s inhibitory control of movement, and to use that knowledge to reduce the burden of dystonia. This goal parallels that of the National Institute of Neurological Disorders and Stroke: to investigate the neural mechanisms of sensory and motor circuits that can be compromised by disease. The proposal is tailored to my educational and training needs, ensuring that I will be prepared to succeed as an independent investigator utilizing the tools of systems neuroscience. With this award, I will gain essential training in: 1) biostatistics and network assessment tools such as principal component analysis, graph theoretical analysis, and causal inference modeling; 2) the experimental design and implementation of functional MRI (fMRI), including both task-based and resting state methods; 3) knowledge of the structure and connectivity of the striatum, pallidum, and thalamus. I will benefit from an environment enriched in neuroimaging, movement disorders, and neurodevelopmental expertise, where I can build a substantial foundation for a successful independent research career devoted to improving the therapies available for treating dystonia.