The structural underpinnings of disinhibition in dystonia

肌张力障碍去抑制的结构基础

• 批准号: 10686944
• 负责人: Jeffrey L. Waugh
• 金额: $ 19.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686944
• 关键词: Absenteeism at work; Adolescent; Adult; Affect; Agonist; Anatomy; Animals; Assessment tool; Award; Behavior; Biometry; Brain; Brain Injuries; Brain region; Cerebral Palsy; Cervical; Cervical Dystonia; Child; Clinical; Contralateral; Corpus Callosum; Corpus striatum structure; Deep Brain Stimulation; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disinhibition; Dystonia; Electrophysiology (science); Ensure; Experimental Designs; Failure; Foundations; Functional Magnetic Resonance Imaging; Globus Pallidus; Goals; Graph; Human; Image; Impairment; Individual; Inherited; Intervention; Ipsilateral; K-Series Research Career Programs; Knowledge; Limb Dystonia; Limb structure; Link; MRI Scans; Magnetic Resonance Imaging; Mentors; Methods; Mission; Modeling; Motor; Motor Activity; Motor Cortex; Motor output; Movement; Movement Disorders; Muscle; National Institute of Neurological Disorders and Stroke; Neuroanatomy; Neurosciences; Operative Surgical Procedures; Pain; Parkinson Disease; Pathway Analysis; Patient Selection; Patients; Pattern; Persons; Pharmaceutical Preparations; Population; Positioning Attribute; Posture; Prevention; Principal Component Analysis; Regimen; Research; Research Personnel; Rest; Role; Schools; Side; Signal Transduction; Site; Source; Spasm; Stroke; Structural defect; Structure; Symptoms; Syndrome; System; Techniques; Thalamic structure; Tissues; Training; Training and Education; Withdrawal; Work; antagonist; base; brain abnormalities; brain based; brain magnetic resonance imaging; career; chronic pain; cohort; disability; environmental enrichment for laboratory animals; improved; motor control; nervous system disorder; neuroimaging; neuromechanism; neuropathology; novel; novel therapeutics; segregation; sensory cortex; sensory feedback; sensory mechanism; skills; source localization; striosome; tool; tractography

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.

项目概要/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 千分之一的人患有肌张力障碍（第三常见的运动）。 它可以单独发生，也可以是许多其他神经系统疾病（例如中风、脑卒中）的症状。 麻痹、帕金森病），慢性疼痛、残疾和辍学或工作是很常见的。 严重的情况下，肌张力障碍可能是致命的。一种共同的电生理异常与多种类型的肌张力障碍有关： 这导致了抑制受损的假设以及相关的发现， 感觉反馈不完善，导致主动肌和拮抗肌共同收缩异常， 然而，抑制受损只是机制中的一个步骤。 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。 MRI 研究大脑区域，这些区域是抑制受损的潜在解剖基质，具有更大的 确定肌张力障碍治疗和预防新目标的目标是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 2) 纹状体区室、纹状体和基质在抑制不必要的运动中的作用。 该研究将在两个肌张力障碍患者队列中采用新颖的结构、扩散和功能 MRI 技术： 我们将以成人、颈肌张力障碍和儿童最常见的形式进行影像学评估， 这些临床上不同的人群将有助于确定哪些异常是共有的。 （可推广到其他肌张力障碍的机制）以及特定于某些类型肌张力障碍的机制。 该指导性职业发展奖的使命是寻求有关以下领域的基础知识： 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。 与国家神经疾病和中风研究所相似：研究神经系统 该提案是为我量身定制的。 教育和培训需求，确保我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，我将获得以下方面的基本培训：1）生物统计学和 主成分分析、图论分析、因果分析等网络评估工具 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）了解纹状体、苍白球的结构和连接性， 我将受益于富含神经影像、运动障碍和 神经发育专业知识，我可以为成功的独立学习奠定坚实的基础 研究生涯致力于改善肌张力障碍的治疗方法。

项目成果

In humans, striato-pallido-thalamic projections are largely segregated by their origin in either the striosome-like or matrix-like compartments.

在人类中，纹状体-苍白球-丘脑投射很大程度上根据其起源于纹状体样或基质样区室而被分离。

• 发表时间: 2023
• 作者: Funk, Adrian T;Hassan, Asim A O;Brüggemann, Norbert;Sharma, Nutan;Breiter, Hans C;Blood, Anne J;Waugh, Jeff L
• 通讯作者: Waugh, Jeff L