DYT1 Genotype- and Phenotype-Specific Brain Circuits in Dystonia

项目概要/摘要 DYT 1肌张力障碍是一种破坏性的运动障碍，其特征在于不受控制的肌肉收缩， 不正常的，不自觉的姿势肌张力障碍的表型存在于约30%的DYT 1携带者中，但它是一种非特异性表型。 不知道为什么70%的携带者没有表现出这种疾病。揭开大脑的遗传基础 肌张力障碍中的网络功能障碍对于充分理解这种疾病至关重要。有新的证据 暗示小脑-纹状体-皮质回路功能障碍在肌张力障碍的运动皮质输出的调节中。 但是以前的神经影像学研究在分辨率上是有限的。我们有一个前所未有的机会 通过确定基因型相关的功能性大脑网络，独立于 通过研究无症状基因阳性携带者与DYT 1症状性 载波我们的中心假设是，认知和运动网络中存在适应不良的相互作用， 包括小脑-纹状体-皮质网络的功能，这些网络是运动正确同步所必需的， 携带DYT 1的携带者与对照相比（即，连接功能障碍是基因特异性的），但根据 临床表型（即，具有肌张力障碍症状的DYT 1表现携带者vs DYT 1非表现携带者） 这将有助于揭示与表型相关的大脑状态。虽然现有的神经影像学研究 提供了重要的见解，全球神经回路的肌张力障碍，脑区组织是 个体之间的差异，标准的组分析可能会掩盖生物学上重要的信号。我们提出 一种新的成像范例，以可靠地测量受试者特异性任务诱发的功能激活（Aim 1）， 以及受试者特异性静息状态功能连接（目标2）首次在这种疾病中。揭示 肌张力障碍的基因-大脑-行为联系，我们将研究一组独特的患者及其 使用高分辨率功能磁共振成像和先进的大脑计算分析， 连接性来确定基因和临床状态对脑回路的总体贡献。 这项R21提案的结果将是对与以下疾病相关的大脑网络功能障碍的清晰理解： DYT 1基因，以阐明为什么有些人发展肌张力障碍表型（表现）和其他人没有。 这些研究结果将为今后的工作提供重要依据。我们将处于有利地位，1）测试 由此产生的基于大脑的生物标志物作为携带DYT 1基因的人（携带者）将发展的潜在信号 肌张力障碍（明显）或解释新治疗的生理效应，因为他们发展，和2）发展 神经调节方案，以解决特定的神经功能障碍作为肌张力障碍的治疗，鉴于其能力， 改变大脑的连通性最后，3）先进的神经成像方法保证了增强的分辨率， 理解复杂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.