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

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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.