Neurodevelopmental Perspective on Inflammation, Loss, and Neurocognition

 描述(由申请者提供)：拟议培训计划的目标是进一步发展申请者在情绪失调、神经认知、神经免疫学、高级统计方法和伦理学领域的知识和研究技能。根据这些目标，申请人培训的基础将是与以下各项相关的日常活动 建议对青少年负性情绪障碍和认知功能障碍潜在的炎症过程进行研究。此外，该项目与有组织的培训和指导经验相结合，以促进申请者的最终职业目标，即作为一名独立调查员，对情感调节失调和认知障碍在整个发育过程中的神经生物学风险因素进行高质量的转化研究，这些因素有助于预防疾病进展和干预的时机。该培训计划包括课程工作、纵向方法和数据分析经验、定期赞助商会议、临床实践和专业发展活动。拟议的研究将通过提供生化和神经认知方法、临床样本招募和筛选以及数据分析和解释方面的应用经验来补充这一培训计划。之所以选择这一特定的研究课题，不仅是因为它与申请者的职业目标和先前的经验很好地契合，还因为抑郁症在年轻人中非常普遍，是一个巨大的公共卫生问题，被列为年轻人残疾、死亡和残疾的主要原因。此外，本项目与研究领域标准(RDoC)倡议相一致，应用维度方法来研究负价维度中的损失和认知系统维度中的认知控制的特定子域，这些领域代表了抑郁症的核心功能障碍。拟议的项目对发现新的治疗靶点和 将这一信息转化为针对不同严重程度的青少年的有效治疗，这些青少年的慢性病和复发性疾病的风险较高。应激引发的免疫系统反应被认为与多种系统(如神经递质代谢、神经内分泌功能)相互作用，从而易患抑郁症和神经认知功能障碍。因此，这种反应的标记物可能代表着在理解情绪障碍中压力、丧失和认知控制的生物标记物方面的关键进展，因为很少有研究将外围标记物与情绪和认知的维度联系起来。此外，对这些标志物的研究在儿童和青少年中非常罕见，尽管将研究结果从成年人推广到青少年存在重大的方法学障碍。因此，该研究的目的1是为了证明患有任何情绪障碍的青少年(AMD谱系)和健康对照组之间在缺失方面的差异，并评估外周炎症标志物和缺失亚域之间的关联。目的二是验证AMD和HC在认知控制方面的差异，并评估外周炎症标志物与认知控制亚域之间的关系。目标3是测试生活压力对炎症标志物与损失和认知控制的关联的影响。数据将从30名患有一系列负面情绪障碍(AMD谱系，包括亚阈值和未指明的情况)的个人和30名年龄在10-17岁的健康对照组收集。这个项目的导师将由以下领域的专家提供：发育过程中的情绪失调(艾米·韦斯特博士)、神经认知(斯科特·朗格内克博士)、神经免疫功能(潘迪和戈尔茨坦博士)和数据分析(亨利博士)。这项研究将第一次利用维度建模的观点来了解青少年中炎症、丧失、认知控制和压力的关联，以及第一个将免疫系统反应与神经认知功能测量联系起来的研究之一。因此，拟议的奖学金将有助于推动申请者的职业生涯，并承诺产生有助于明确情绪和神经认知障碍的神经生物学标记物是否存在关键时期的结果。如果假设得到支持，这将表明在治疗中靶向生物应激反应系统可能会扰乱炎症反应、情绪失调和神经认知功能障碍之间的前馈循环。

 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.