The structural underpinnings of disinhibition in dystonia

项目摘要/摘要 肌张力障碍是一种基于大脑的疾病，会导致受影响的肌肉扭曲和痉挛，使患者扭曲。 变成痛苦和残废的体位。每1000人中就有1人患有肌张力障碍(第三大常见运动 无序)。它可以单独发生，也可以是许多其他神经系统疾病(如中风、脑部疾病)的症状 瘫痪、帕金森氏症)。慢性疼痛、残疾和退学或退学很常见，在 严重的情况下，肌张力障碍可致命。一种共同的电生理异常与多种类型的肌张力障碍有关： 局部和远程解除抑制。这导致了一种假设，即削弱了抑制，以及一个相关的发现， 不良的感觉反馈，导致激动者和拮抗者肌肉的异常协同收缩， 产生肌张力障碍的扭曲动作。然而，抑制能力受损只是机械性思维的一个步骤。 导致肌张力障碍的级联--产生去抑制的潜在结构异常尚不清楚。 神经性疾病的结构异常为改进治疗指明了方向。这项提案将使用 磁共振成像研究大脑区域，这些区域是抑制受损的潜在解剖基础，具有更大的 确定治疗和预防肌张力障碍的新靶点的目标。我们将解决当前存在的两个主要差距 肌张力障碍知识：1)大脑半球间投射在调节皮质运动活动中的作用(远程 去抑制)；2)纹状体隔间、纹状体小体和基质在抑制不必要的运动中的作用。 这项研究将在两个肌张力障碍患者队列中使用新的结构、扩散和功能磁共振技术： 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， 四肢肌张力障碍。这些临床上不同的人群将有助于确定哪些异常是共同的 (机制可推广到其他肌张力障碍)，并针对某些类型的肌张力障碍。 这个辅导式职业发展奖的使命是寻求关于 大脑对运动的抑制控制，并利用这一知识来减轻肌张力障碍的负担。这个目标 与国家神经疾病和中风研究所的研究类似：对神经的研究 感觉和运动回路的机制，可以被疾病破坏。这项建议是为我量身定做的 教育和培训需求，确保我将准备好成为一名成功的独立调查员 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)生物统计学和 网络评估工具，如主成分分析、图论分析和因果关系 2)功能磁共振成像(FMRI)的实验设计与实现，包括两者 基于任务和静息状态的方法；3)纹状体、苍白球、 还有丘脑。我将受益于一个充满神经成像、运动障碍和 神经发育专业知识，在那里我可以为成功的独立人士奠定坚实的基础 致力于改进可用于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.