Neurodevelopmental Perspective on Inflammation, Loss, and Neurocognition

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 DESCRIPTION (provided by applicant): The goal of the proposed training plan is to further develop the applicant's knowledge and research skills in the areas of mood dysregulation, neurocognition, neuro-immunology, advanced statistical methods, and ethics. In line with these goals, the cornerstone of the applicant's training will be the daily activities associated with the proposed study of the inflammatory processes underlying negative mood disturbances and cognitive dysfunction among youth. In addition, this project is carefully aligned with structured training and mentoring experiences to promote the applicant's ultimate career goal to conduct high-quality translational research as an independent investigator on the neurobiological risk factors for affective dysregulation and cognitive dysfunction throughout development that inform the prevention of illness progression and timing of interventions. This training plan includes course work, experience with longitudinal methods and data analyses, regular sponsor meetings, clinical practice, and professional development activities. The proposed research will complement this training plan by providing applied experience with biochemical and neurocognitive methodology, clinical sample recruitment and screening, and data analysis and interpretation. This particular research topic was chosen not only because it fits well with the applicant's career goals and prior experience, but also because depression is highly prevalent among youth and an enormous public health problem, ranking as the leading cause of disability, mortality, and impairment among youth. Further, this project is aligned with the Research Domain Criteria (RDoC) initiative to apply a dimensional approach to study the specific sub- domains of loss within the dimension of negative valence, and cognitive control within the dimension of cognitive systems, that represent core dysfunctions in depression. The proposed project has potential implications for informing the discovery of novel therapeutic targets and the translation of this information into effective treatments specific to youth along a spectrum of severity at elevated risk for a chronic and recurrent course of illness. Immune system response, triggered by stress, is thought to interact with multiple systems (e.g. neurotransmitter metabolism, neuroendocrine function) to predispose towards depression and neurocognitive dysfunction. Therefore, markers of this response may represent a key advance in understanding biomarkers of stress, loss, and cognitive control in mood disorders, as few studies have linked peripheral markers with dimensions of mood and cognition. Further, studies of these markers are strikingly rare among children and adolescents, despite significant methodological obstacles to generalizing findings from adults to youth. Therefore, Aim 1 of the proposed study is to demonstrate differences between youth with any mood disorder (AMD spectrum) and healthy controls in loss and evaluate the association between peripheral inflammatory markers and the loss sub-domain. Aim 2 is to demonstrate differences between AMD spectrum and HC in cognitive control and evaluate the association between peripheral inflammatory markers and the cognitive control sub-domain. Aim 3 is to test the impact of life stress on the association of inflammatory makers with loss and cognitive control. Data will be collected from 30 individuals with a range of negative mood disturbance (AMD spectrum, inclusive of sub-threshold and unspecified conditions) and 30 healthy controls ages 10-17. Mentorship for this project will be provided by experts in the areas of mood dysregulation during development (Dr. Amy West), neurocognition (Dr. Scott Langenecker), neuro-immune function (Drs. Pandey and Goldstein) and data analysis (Dr. Henry). This study will be the first to utilize a dimensional modeling perspective to understanding the associations of inflammation, loss, cognitive control, and stress among youth, as well as one of the first to relate immune system response with measures of neurocognitive function. Thus, the proposed fellowship will be instrumental in propelling the applicant's career and promises to yield results that help specify whether there exist critical periods for neurobiological markers of mood and neurocognitive dysfunction. If the hypotheses are supported it would suggest that targeting biological stress response systems in treatment may disrupt the feed-forward cycle between inflammatory response, mood dysregulation, and neurocognitive dysfunction.