DYT1 Genotype- and Phenotype-Specific Brain Circuits in Dystonia

肌张力障碍中 DYT1 基因型和表型特异性脑回路

• 批准号: 10303426
• 负责人: Teresa Jacobson Kimberley
• 金额: $ 46.5万
• 依托单位: MGH INSTITUTE OF HEALTH PROFESSIONS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10303426
• 关键词: 12 year old; Activities of Daily Living; Address; Affect; Base of the Brain; Biological; Biological Markers; Body Regions; Body part; Brain; Brain Diseases; Brain imaging; Brain region; Clinical; Cognitive; Complex; Computer Analysis; Corpus striatum structure; DNA Sequence Alteration; DYT1 gene; Data; Development; Disease; Dystonia; Dystonia Musculorum Deformans; Early Diagnosis; Family; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Mutation; General Hospitals; Genes; Genetic; Genotype; Goals; Hand; Image; Imaging technology; Impairment; Individual; Intervention; Life; Link; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Massachusetts; Measures; Methodology; Motor; Movement; Movement Disorders; Muscle Contraction; Mutation; Neuronal Dysfunction; Noise; Outcome; Output; Pain; Pathway interactions; Patients; Persons; Phenotype; Physiological; Population; Positioning Attribute; Posture; Protocols documentation; Regulation; Resolution; Rest; Signal Transduction; Symptoms; Task Performances; Testing; Time; Tongue; Treatment Efficacy; United States National Institutes of Health; Ursidae Family; Work; base; brain behavior; brain pathway; candidate marker; clinical phenotype; disability; efficacy evaluation; hand dysfunction; insight; mutation carrier; network dysfunction; neural circuit; neuroimaging; neuroregulation; novel; novel diagnostics; predictive marker; prospective; recruit; relating to nervous system; therapy development

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.

项目概要/摘要 DYT1 肌张力障碍是一种破坏性运动障碍，其特征是肌肉收缩失控，导致 处于不正常的、不自觉的姿势。约 30% 的 DYT1 携带者存在肌张力障碍表型，但 未知为什么 70% 的携带者没有表现出这种疾病。揭示大脑的遗传基础 肌张力障碍的网络功能障碍对于充分了解该疾病至关重要。有新的证据 暗示小脑-纹状体-皮质回路功能障碍参与肌张力障碍运动皮质输出的调节。 但之前的神经影像学研究分辨率有限。我们有一个前所未有的机会来关闭 通过确定与基因型相关的功能性大脑网络来消除这一差距，独立于混杂因素 通过研究非表现性基因阳性携带者与 DYT1 有症状的携带者的临床症状 载体。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， 包括运动正确同步所需的功能性小脑-纹状体-皮质网络 与对照组相比，DYT1 携带者存在差异（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 DYT1 携带者与 DYT1 非携带者） 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已经 提供了对肌张力障碍背后的全局神经回路的重要见解，大脑区域组织是 个体之间存在差异，标准的群体分析可能会掩盖生物学上重要的信号。我们建议 一种新颖的成像范例，可以可靠地测量受试者特定的、任务诱发的功能激活（目标 1）： 以及首次在这种疾病中研究受试者特定的静息态功能连接（目标 2）。揭晓 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 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疾病相关的大脑网络功能障碍有一个清晰的认识： DYT1 基因，以阐明为什么有些人会出现肌张力障碍表型（表现出来），而另一些人则不会。 这些发现将为未来的工作提供重要基础。我们将处于有利位置 1) 测试 由此产生的基于大脑的生物标志物作为具有 DYT1 基因（携带者）的人将发展的潜在信号 肌张力障碍（明显）或解释新疗法开发时的生理效应，以及 2) 开发 神经调节方案可解决特定的神经功能障碍，作为肌张力障碍的治疗方法，因为它能够 修改大脑连接。最后，3）先进的神经影像方法确保了增强的分辨率 了解可能适用于其他类型肌张力障碍的复杂网络异常。