Structure-Function Relationships in Dystonia: A Network Approach

肌张力障碍的结构-功能关系：网络方法

• 批准号: 8448201
• 负责人: DAVID EIDELBERG
• 金额: $ 59.06万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448201
• 关键词: Accounting; Adolescence; Autopsy; Basal Ganglia; Biological Markers; Brain; Cerebrovascular Circulation; Childhood; Chronic; Clinical; Clinical Treatment; Data; Deep Brain Stimulation; Defect; Descriptor; Development; Diffusion Magnetic Resonance Imaging; Disease; Distal; Dystonia; Exhibits; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Globus Pallidus; Hereditary Dystonia; Image; Individual; Inherited; Intervention; Lesion; Magnetic Resonance; Measurement; Measures; Mediating; Methods; Modeling; Motor; Motor Cortex; Motor Pathways; Movement; Movement Disorders; Multicenter Studies; Muscle Contraction; Mutation; Neurologic; Operative Surgical Procedures; Output; Participant; Pathway interactions; Patients; Pattern; Penetrance; Positron-Emission Tomography; Postoperative Period; Primary Dystonias; Resolution; Rest; Scanning; Series; Severities; Signal Transduction; Sleep; Sporadic Dystonias; Structure; Structure-Activity Relationship; Symptoms; Task Performances; Testing; Time; Work; base; disability; disabling disease; imaging modality; improved; innovation; mutation carrier; neuropathology; novel; public health relevance; relating to nervous system; research study; response; transmission process; treatment response

DESCRIPTION (provided by applicant): Primary dystonia, which often begins in late childhood or adolescence, has traditionally been attributed to basal ganglia dysfunction, but no specific histopathological lesions of these structures are evident on postmortem examination. In fact, the challenge of primary dystonia is reflected in its clinical definition: the presence of involuntary, sustained muscle contractions in the absence of identifiable brain lesions. This lack of clear neuropathology has this illness difficult to understand and treat. Our recent work supports a new paradigm for understanding dystonia as a neurodevelopmental circuit disorder. Taking advantage of the partial penetrance of inherited dystonia and the fact that dystonic movements disappear during sleep, we employed new magnetic resonance diffusion tensor imaging (DTI) methods in manifesting and non- manifesting mutation carriers to examine motor circuit activity. We made the surprising discovery that both manifesting and non-manifesting mutation carriers exhibit disruptions of the cerebello-thalamo-cortical tract, and that non-manifesting individuals show additional, distal disruptions in the thalamo-cortical projection pathways. This distal defect is clinically "protective": it blocks transmission of the aberrant cerebellar output to the motor cortex. Our work has given rise to a new model for the motor circuitry dysfunction underlying dystonia, which we will test in this proposal as we seek to identify the changes in fiber tract integrity (microstructure) and neural activation responses (function) that regulate clinical penetrance, account for phenotypic differences, and modulate treatment response in primary dystonia. In Specific Aim 1 we will characterize motor circuit abnormalities in hereditary primary dystonia by examining structure-function relationships in manifesting and non-manifesting carriers of the DYT1 and DYT6 mutations. We will assess pathway microstructure (using DTI) and circuit function using H215O PET to measure cerebral blood flow during task performance and in the rest state and fMRI to localize task-related neural activation responses. In Specific Aim 2 we will identify circuit abnormalities in sporadic dystonia, conducting DTI/tractography studies and brain activation experiments and comparing the results to those obtained in patients with hereditary forms of the disease. Finally, in Specific Aim 3, we seek to understand how deep brain stimulation (DBS) works in dystonia when it does work, and identify predictors of patient response. DBS can be effective in treating severe primary dystonia, but not all patients benefit equally, and symptoms can re-emerge after an initial period of abatement. Subjects will undergo preoperative imaging and then participate in a series of studies at multiple postoperative time points following the start of chronic stimulation. The resulting scan data will be used to: (a) measure serial changes in network activity as the treatment response develops; (b) identify patterns of microstructural change at baseline that correlate with clinical treatment response; and (c) develop quantitative preoperative imaging descriptors to predict treatment response in individual subjects.

描述（由申请人提供）：原发性肌张力障碍通常在儿童晚期或青春期开始，传统上被归因于基底神经节功能障碍，但在尸检中没有发现这些结构的特定组织病理学损伤。事实上，原发性肌张力障碍的挑战反映在其临床定义中：在没有可识别的脑部病变的情况下，存在不自主的持续肌肉收缩。由于缺乏明确的神经病理学，这种疾病难以理解和治疗。我们最近的工作支持将肌张力障碍理解为神经发育回路障碍的新范例。利用遗传性肌张力障碍的部分外显率以及肌张力障碍运动在睡眠期间消失的事实，我们采用新的磁共振扩散张量成像（DTI）方法在显性和非显性突变携带者中检查运动回路活动。我们令人惊讶地发现，显性和非显性突变携带者均表现出小脑-丘脑-皮质束的破坏，并且非显性个体在丘脑-皮质投射通路中表现出额外的远端破坏。这种远端缺陷在临床上具有“保护性”：它阻止异常小脑输出传输到运动皮层。我们的工作提出了肌张力障碍背后的运动回路功能障碍的新模型，我们将在本提案中测试该模型，因为我们试图确定调节临床外显率的纤维束完整性（微观结构）和神经激活反应（功能）的变化，解释表型差异，并调节原发性肌张力障碍的治疗反应。在具体目标 1 中，我们将通过检查 DYT1 和 DYT6 突变的显性和非显性携带者的结构-功能关系来表征遗传性原发性肌张力障碍的运动回路异常。我们将使用 H215O PET 来评估通路微观结构（使用 DTI）和回路功能，以测量任务执行期间和休息状态下的脑血流量，并使用 fMRI 来定位与任务相关的神经激活反应。在具体目标 2 中，我们将识别散发性肌张力障碍的脑回路异常，进行 DTI/纤维束成像研究和大脑激活实验，并将结果与​​遗传性肌张力障碍患者的结果进行比较。最后，在具体目标 3 中，我们试图了解深部脑刺激 (DBS) 在肌张力障碍中发挥作用时的作用，并确定患者反应的预测因素。 DBS 可有效治疗严重的原发性肌张力障碍，但并非所有患者都能平等受益，并且症状可能会在最初的缓解期后重新出现。受试者将接受术前成像，然后在慢性刺激开始后的多个术后时间点参与一系列研究。由此产生的扫描数据将用于： (a) 随着治疗反应的发展，测量网络活动的连续变化； (b) 确定与临床治疗反应相关的基线微观结构变化模式； (c) 开发定量的术前成像描述符来预测个体受试者的治疗反应。