DYT1 Genotype- and Phenotype-Specific Brain Circuits in Dystonia

项目摘要/摘要 DYT1肌张力障碍是一种破坏性的运动障碍，其特征是肌肉不受控制的收缩 以不正常的、非自愿的姿势。大约30%的DYT1携带者存在肌张力障碍的表型，但它 不知道为什么70%的携带者没有表现出这种疾病。揭示大脑的基因基础 肌张力障碍的网络功能障碍是充分了解这种疾病的关键。有新的证据表明 小脑-纹状体-皮质环路功能障碍在肌张力障碍患者运动皮质输出调节中的作用。 但之前的神经成像研究在分辨率上受到限制。我们有一个前所未有的机会来完成 这一差距通过确定与基因相关的功能脑网络，独立于迷惑的 研究无症状、基因阳性携带者与DYT1症状携带者的临床症状 承运人。我们的中心假设是，认知和运动网络中存在不适应的交互作用， 包括正常运动同步所需的功能性小脑-纹状体-皮质网络 DYT1携带者与对照组相比(即，连接功能障碍是基因特有的)，但不同 与临床表型(即DYT1显性携带者伴肌张力障碍症状与DYT1非显性携带者相比) 这将有助于揭示与表型相关的大脑状态。虽然现有的神经成像研究已经 为肌张力障碍背后的全球神经回路提供了重要的见解，大脑区域组织 个体差异很大，标准的群体分析可能会模糊重要的生物学信号。我们建议 一种新的成像范式可靠地测量受试者特定的、任务诱发的功能激活(目标1)为 以及在这种疾病中首次出现的受试者特定的静息状态功能连接(目标2)。揭示 基因-脑-行为联系在肌张力障碍中，我们将研究一组独特的患者及其 家庭，使用高分辨率功能磁共振成像和先进的大脑计算分析 连接性，以确定基因和临床状态对大脑回路的总体贡献。 R21提案的结果将是对与以下相关的脑网络功能障碍有一个清晰的了解 DYT1基因，以解释为什么一些人会出现肌张力障碍表型(显性)，而另一些人不会。 这些调查结果将为今后的工作提供关键的基础。我们将处于有利地位，能够测试 作为潜在信号的脑基生物标志物，携带DYT1基因的人(携带者)将为其发育 肌张力障碍(显性)或解释新治疗方法的生理效应，以及2)发展 神经调节方案，以解决特定的神经功能障碍作为治疗肌张力障碍，鉴于其能力 修改大脑连接。最后，3)先进的神经成像方法确保提高分辨率 了解复杂的网络异常，可能适用于其他类型的肌张力障碍。

Project Summary/ Abstract DYT1 dystonia is a devastating movement disorder characterized by uncontrolled muscle contractions that result in abnormal, involuntary postures. The phenotype of dystonia is present in about 30% of DYT1 carriers, but it is unknown why 70% of carriers do not manifest the disorder. Unveiling the genetic underpinnings of the brain network dysfunction in dystonia is critical to fully understand the disorder. There is emerging evidence implicating cerebellar-striatal-cortical circuit dysfunction in the regulation of motor cortical output in dystonia. But previous neuroimaging studies were limited in resolution. We have an unprecedented opportunity to close this gap by determining the genotype-associated functional brain network, independent of the confound of clinical symptoms by studying the non-manifesting, gene-positive carriers compared with the DYT1 symptomatic carriers. Our central hypothesis is that there are maladaptive interactions in cognitive and motor networks, including the functional cerebellar-striatal-cortical network required for proper synchronization of movement in carriers with DYT1 compared to controls (i.e., the connectivity dysfunction is gene-specific), but varies according to clinical phenotype (i.e., DYT1 manifesting carriers with dystonia symptoms vs DYT1 non-manifesting carriers) which will help reveal the brain state associated with phenotype. While existing neuroimaging studies have provided important insights into the global neural circuitry underlying dystonia, brain region organization is variable across individuals, and standard group analyses may obscure biologically important signals. We propose a novel imaging paradigm to reliably measure the subject-specific, task-evoked functional activation (Aim 1) as well as subject-specific resting-state functional connectivity (Aim 2) for the first time in this disease. To reveal the gene-brain-behavior links in dystonia, we will study a unique group of patients and their families, using high resolution fMRI and advanced computational analyses of brain connectivity to determine the overall contribution of gene and clinical status to brain circuity. The outcome of this R21 proposal will be a clear understanding of the brain network dysfunction associated with the DYT1 gene, to elucidate why some people develop the dystonia phenotype (manifesting) and others do not. These findings will provide critical underpinnings for future work. We will be well-positioned to 1) test the resultant brain-based biomarker as a potential signal for which people with the DYT1 gene (carriers) will develop dystonia (manifest) or to explicate the physiologic effects of new treatments as they develop, and 2) develop neuromodulation protocols to address specific neural dysfunction as a treatment in dystonia, given its ability to modify brain connectivity. Finally, 3) the advanced neuroimaging methodology assures enhanced resolution in understanding the complex network abnormality that may be applicable in other types of dystonia.