Neurodevelopmental profiles related to transdiagnostic and disorder-specific symptoms of anxiety and depression

项目摘要 近40%的青少年患有焦虑症或严重的抑郁症。这些障碍通常首先 在青春期出现，其不良后果往往持续到成年期。因此， 青春期是理解与此相关的生物途径的关键发育期 精神错乱。焦虑和抑郁障碍的评分者间信度和区分性差一直是一个主要原因 NIMH RDoC框架中的因素强调需要研究大脑过程的配对测量 用次元方法研究精神症状学。根据这一框架，这一目标 K99/R00独立之路奖是为申请者提供必要的培训，以识别 不同的发育神经特征与焦虑和抑郁的共同症状相关 (痛苦)，以及与焦虑(焦虑)的特定障碍症状相关的神经特征 焦虑)和抑郁(低积极情绪)。此外，申请人还需要接受遗传学培训，以 成功实现量化遗传影响与独特环境的相对贡献的目标 对焦虑、抑郁症状相关神经功能的影响。为了实现这样的目标 目标，申请者将得到无与伦比的精神病理学、遗传学和 高级神经成像方法(D.Bch，N.Dosenbach，A.Agrawal，J.Constantino，J.Luby，C. Sylvester和D.Greene)，并将在以下地址访问一流的临床、成像和招聘资源 华盛顿大学。拟议的培训计划将使申请者能够实现几个短期目标 促进他成为一名研究机构独立研究员的长期目标所需的目标-I 大学，包括精神病理学和遗传学的新培训(双胞胎设计)。这些培训目标将是 在拟议的研究中取得进展。首先，临床数据和功能连接(FC)MRI数据 将使用青少年大脑和认知发展(ABCD)大样本(n=11,875)来识别和 复制与焦虑的跨诊断和特定障碍症状相关的神经特征(生物类型) 和抑郁(目标1)。此数据集的子集(孪生数据集；n=800对孪生数据集)将用于 评估这些生物型/症状关系的遗传力(目标2.1)。利用FC的最新进展 MRI数据采集能够可靠地量化个体水平的FC(精密功能映射)， 申请者将量化遗传和独特环境对生物型/症状关系的影响， 指出潜在独特的因果途径和独特的干预途径(目标2.2)。值得注意的是， 建议的方法可以扩展到其他发育性神经精神障碍，为 早期个体化治疗干预。具有采用多个融合的研究计划 询问与焦虑和抑郁有关的症状的生物标记物的技术和分析方法 申请者将在他的独立职业生涯中继续研究与NIMH相关的问题。

PROJECT ABSTRACT Nearly 40% of adolescents suffer from an anxiety disorder or major depression. These disorders usually first emerge during adolescence, and the adverse consequences of them often persist into adulthood. As such, adolescence is a critical developmental period for understanding the biological pathways related to these disorders. Poor inter-rater reliability and discriminability of anxiety and depressive disorders has been a major factor in the NIMH RDoC framework emphasizing the need for studies pairing measures of brain processes with dimensional approaches to psychiatric symptomatology. In line with this framework, the goal of this K99/R00 Pathway to Independence Award is to provide the applicant with the training necessary to identify distinct developmental neural features that are related to shared symptoms across anxiety and depression (distress), as well as neural features that are related to disorder-specific symptoms of anxiety (anxious apprehension) and depression (low positive affect). Furthermore, the applicant will require genetics training to succeed in the goal of quantifying the relative contribution of genetic influence vs. unique environmental influence on the neural features related to anxiety and depression symptomatology. In order to achieve such goals, the applicant will receive unparalleled mentorship by experts in psychopathology, genetics, and advanced neuroimaging methodologies (Drs. D. Barch, N. Dosenbach, A. Agrawal, J. Constantino, J. Luby, C. Sylvester, and D. Greene) and will have access to superb clinical, imaging, and recruitment resources at Washington University. The proposed training plan will enable the applicant to achieve several short-term goals necessary to facilitate his long-term goal of becoming an independent investigator at a Research-I University, including new training in psychopathology and genetics (twin designs). These training goals will be advanced through the proposed research. First, clinical data and functional connectivity (FC) MRI data within the large Adolescent Brain and Cognitive Development (ABCD) sample (n=11,875) will be used to identify and replicate the neural signatures (biotypes) related to transdiagnostic and disorder-specific symptoms of anxiety and depression (Aim 1). A subset of this dataset (ABCD twin dataset; n=800 twin pairs) will be leveraged to assess the heritability of these biotype/symptom relationships (Aim 2.1). Capitalizing on recent advances in FC MRI data acquisition enabling reliable quantification of individual-level FC (precision functional mapping), the applicant will quantify the genetic vs. unique environmental influence on biotype/symptom relationships, pointing towards potential unique causal pathways and unique intervention pathways (Aim 2.2). Notably, the proposed methods can be extended to other developmental neuropsychiatric disorders, setting the stage for early individualized treatment intervention. With a research program that employs multiple converging techniques and analysis methods to interrogate biomarkers of symptoms related to anxiety and depression, the applicant will continue to address research questions relevant to the NIMH throughout his independent career.