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.

项目摘要 /摘要 肌张力障碍是一种基于脑部疾病，导致受影响的肌肉扭曲和痉挛，扭曲了患者 进入痛苦和致残的位置。 疾病）。 麻痹，帕金森病）。 严重的病例，肌张力障碍可能致命。 局部和远程抑制作用。 池状的感觉反馈，导致激动剂和拮抗剂肌肉的异常共同收缩， 然而，产生肌张力障碍的问题。 导致肌张力障碍的级联反应 - 产生抑制作用的潜在结构异常。 神经系统疾病的结构异常指向改善疗法的道路。 MRI调查大脑区域潜在的解剖基质抑制受损，较大的抑制作用 确定肌张力障碍和预防的新目标。 肌张力障碍知识：1）短暂性投影在调节皮质运动活动（远程（远程））中的作用 2）纹状体隔室的作用，静态和矩阵，抑制不必要的运动。 该研究将在两种肌张力障碍患者队列中采用新的结构，扩散和功能性MRI技术： 我们将以成年人，宫颈肌张力障碍和儿童的最常见形式进行成像评估， 肢体肌张力障碍。 （可推广到其他肌张力纳斯的机制），这些机制特定于某些类型的肌张力障碍。 指导职业发展奖的使命是寻求有关您的基金会知识 大脑对运动的抑制控制，对我们而言，减轻了肌张力障碍的负担。 国家神经学疾病和中风研究所的并行：调查神经 疾病破坏的感觉和运动回路的机制是为我的 教育和培训需求，确保我将准备好作为独立研究者的成功 利用系统神经科学的工具。 网络评估工具，例如主要组件分析，图理论分析和因果关系 推理建模 基于任务和静止状态的方法； 3）纹状体的结构和连通性 这受益于丰富神经影像，运动障碍和杜松子酒的富集 神经发育专业知识，我可以为成功的独立建立巨大的基础 研究职业致力于改善可用于治疗肌张力障碍的疗法。

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.

• DOI: 10.3389/fnins.2023.1178473
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Funk, Adrian T.;Hassan, Asim A. O.;Bruggemann, Norbert;Sharma, Nutan;Breiter, Hans C.;Blood, Anne J.;Waugh, Jeff L.
• 通讯作者: Waugh, Jeff L.