PREDICTING OUTCOME IN CHILDREN WITH TIC DISORDERS USING NEUROIMAGING DATA

描述(由申请人提供)：多达25%的儿童在某些时候有抽搐(短暂、重复的动作或噪音)，但每个人的预后差异很大。即使在抽动发作后的第一年内，一些儿童的病情改善，没有明显的损害，而另一些儿童则发展为慢性疾病(抽动症：TS)，严重影响他们的生活质量。了解早期出现的脑部特征 调节或预测这些不同结果的TS可能会对预后和治疗产生革命性影响。这个指导研究科学家发展奖(K01)的目的是为申请者提供必要的培训，以过渡到独立的研究计划，专注于TS和相关障碍(例如，注意力缺陷/多动障碍：ADHD，强迫症：OCD)的大脑机制。申请者的长期目标是识别有助于指导预后和治疗的预测性生物标记物。为了实现这些目标，申请者将得到TS和神经成像方法专家(K.Black博士、B.Schlaggar博士、E.Sowell博士、R.Poldrack博士和T.Hershey博士)无与伦比的指导，并将获得华盛顿大学一流的临床和成像资源。拟议的培训计划将使申请者能够实现促进其长期目标所需的几个短期目标，包括结构磁共振方法、高级分析策略和纵向研究设计方面的新培训，以及静息状态功能连通性磁共振以及TS及其并存情况的临床方面的继续培训。这些培训目标将通过拟议的研究加以推进。首先，将使用监督学习方法来识别大脑结构和功能的模式，这些模式可以将单个儿童归类为患有TS或不患有TS，为探索预测性生物标志物提供了一个原则性的起点(目标1)。第二，非监督学习方法将被用来识别基于大脑的TS表型亚组，帮助更好地解释TS的异质性(目标2)。最后，监督学习方法将被用来预测儿童首次出现抽搐时的症状进展，使用儿童抽动后第一年的纵向跟踪(目标3)。因此，拟议的项目是朝着对抽搐儿童进行基于大脑的个性化预测迈出的第一步。值得注意的是，拟议的方法可以扩展到其他儿童神经精神障碍(例如自闭症、ADHD)，为早期治疗以及发现潜在机制奠定了基础。作为该奖项的一部分，收集的纵向数据将为未来针对TS的发展轨迹的R01应用奠定基础。本申请中提出的培训和研究计划将有助于申请人过渡到翻译发展神经科学领域的独特和独立的研究生涯。通过一个采用多种汇聚技术和分析方法来询问TS和相关疾病的生物标记物的研究计划，申请者将在她的独立职业生涯中继续解决与NIMH相关的研究问题。

DESCRIPTION (provided by applicant): As many as 25% of all children have tics (brief, repetitive movements or noises) at some point, yet individuals have greatly varying prognoses. Even within the first year after tic onset, some children improve and experience no significant impairment, while others develop a chronic disorder (Tourette syndrome: TS) that can severely impinge upon their quality of life. Understanding the brain features present early in the course of TS that mediate or predict these different outcomes could revolutionize prognosis and treatment. The purpose of this Mentored Research Scientist Development Award (K01) is to provide the applicant with the training necessary to transition to independence with a research program focused on the brain mechanisms underlying TS and related disorders (e.g., attention-deficit/hyperactivity disorder: ADHD, obsessive-compulsive disorder: OCD). The applicant's long-term goal is to identify predictive biomarkers that can help guide prognosis and treatment. In order to achieve such goals, the applicant will receive unparalleled mentorship by experts in TS and neuroimaging methodologies (Drs. K. Black, B. Schlaggar, E. Sowell, R. Poldrack, and T. Hershey) and will have access to superb clinical and imaging resources at Washington University. The proposed training plan will enable the applicant to achieve several short-term goals necessary to facilitate her long-term goals, including new training in structural MRI methods, advanced analytic strategies, and longitudinal study design, and continued training in resting state functional connectivity MRI and in the clinical aspects of TS and its comorbid conditions. These training goals will be advanced through the proposed research. First, supervised learning methods will be used to identify patterns of brain structure and function that can classify an individual child as having TS or not, providing a principled starting point for exploring predictive biomarkers (Aim 1). Second, unsupervised learning methods will be used to identify brain-based phenotypic subgroups of TS, helping to better account for the heterogeneity of TS (Aim 2). Finally, supervised learning methods will be used to predict symptom progression for children when they first present with tics, using longitudinal follow-up of children during ther first year after tic onset (Aim 3). Thus, the proposed project is a first step toward brain- based individualized predictions for children with tics. Notably, the proposed methods can be extended to other childhood neuropsychiatric disorders (e.g., autism, ADHD), setting the stage for early treatment, as well as discovery of the underlying mechanisms. The longitudinal data collected as part of this award will be foundational for future R01 applications targeting the developmental trajectory of TS. The training and research plan proposed in this application will facilitate the applicant's transition to a unique and independent research career in translational developmental neuroscience. With a research program that employs multiple converging techniques and analysis methods to interrogate biomarkers of TS and related disorders, the applicant will continue to address research questions relevant to the NIMH throughout her independent career.