Neurodevelopmental Perspective on Inflammation, Loss, and Neurocognition

炎症、损失和神经认知的神经发育视角

• 批准号: 9147481
• 负责人: Amy Peters
• 金额: $ 4.06万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-16 至 2018-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147481
• 关键词: Address; Adolescence; Adolescent; Adult; Affective; Age; Anti-Inflammatory Agents; Anti-inflammatory; Area; Behavior; Biochemical; Biological; Biological Markers; Bipolar Disorder; Child; Childhood; Chronic; Clinical; Cognition; Cognitive; Comorbidity; Complement; Complex; Control Groups; Cyclothymic Disorder; Data; Data Analyses; Detection; Development; Diagnosis; Diagnostic and Statistical Manual of Mental Disorders; Dimensions; Dysthymic Disorder; Economics; Ethics; Exhibits; Family; Fellowship; Fostering; Functional disorder; Goals; Heterogeneity; Immune; Immune response; Immune system; Immunology; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-10; Interleukin-13; Interleukin-6; Intervention; Knowledge; Life Stress; Link; Measures; Medical; Mental Depression; Mental Health; Mentors; Mentorship; Methodology; Methods; Modeling; Mood Disorders; Moods; Negative Valence; Neuraxis; Neurobiology; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurons; Neurosecretory Systems; Patient Self-Report; Performance; Peripheral; Prevention; Process; Psyche structure; Psychopathology; Public Health; Recording of previous events; Recurrence; Reporting; Research; Research Domain Criteria; Research Personnel; Risk; Risk Factors; Risk Marker; Sampling; Severities; Source; Specific qualifier value; Specificity; Statistical Methods; Stimulus; Stress; Structure; Symptoms; System; TNF gene; Testing; Time; Training; Translational Research; Translations; Trauma; Update; Work; Youth; allostatic load; biological adaptation to stress; career; clinical practice; cognitive control; cognitive system; common symptom; cost; critical period; cytokine; deprivation; disability; disturbance in affect; effective therapy; experience; feeding; immune function; inflammatory marker; meetings; mortality; negative mood; neurobiological mechanism; neurotransmitter metabolism; new therapeutic target; novel marker; psychosocial; public health relevance; response; response biomarker; screening; skills; stressor

 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.

 描述（由申请人提供）：拟议培训计划的目标是进一步发展申请人在情绪失调，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，申请人培训的基石将是与 拟议的研究炎症过程潜在的负面情绪障碍和认知功能障碍的青年。此外，该项目与结构化培训和指导经验密切相关，以促进申请人的最终职业目标，即作为独立研究者对整个发展过程中情感失调和认知功能障碍的神经生物学风险因素进行高质量的转化研究，从而预防疾病进展和干预措施的时机。该培训计划包括课程作业、纵向方法和数据分析经验、定期申办者会议、临床实践和专业发展活动。拟议的研究将通过提供生物化学和神经认知方法，临床样本招募和筛选以及数据分析和解释的应用经验来补充这一培训计划。选择这个特定的研究课题不仅是因为它符合申请人的职业目标和先前的经验，而且还因为抑郁症在青年中非常普遍，是一个巨大的公共卫生问题，是青年残疾，死亡和损伤的主要原因。此外，该项目与研究领域标准（RDoC）倡议相一致，以应用维度方法来研究负效价维度内的特定子域损失，以及认知系统维度内的认知控制，这些子域代表抑郁症的核心功能障碍。拟议的项目具有潜在的影响，为发现新的治疗靶点提供信息， 将这一信息转化为针对青年沿着一系列严重程度高风险的慢性和复发性疾病的有效治疗。 由压力引发的免疫系统反应被认为与多个系统（例如神经递质代谢，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，这种反应的标志物可能代表了理解情绪障碍中压力，损失和认知控制生物标志物的关键进展，因为很少有研究将外周标志物与情绪和认知维度联系起来。此外，这些标志物的研究是惊人的罕见的儿童和青少年，尽管重大的方法障碍，从成年人到青年的普遍发现。因此，所提出的研究的目的1是证明患有任何情绪障碍（AMD谱）的青年与健康对照之间在损失方面的差异，并评估外周炎症标志物与损失子域之间的关联。目的2是证明AMD谱系和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子域之间的关联。目的3是测试生活压力对炎症标记物与损失和认知控制的关联的影响。将从30名患有一系列负面情绪障碍（AMD谱，包括阈下和未指明的状况）的个体和30名年龄在10 - 17岁的健康对照者中收集数据。该项目的导师将由发育期间情绪失调（Amy West博士）、神经认知（Scott Langenecker博士）、神经免疫功能（Pandey和Goldstein博士）和数据分析（亨利博士）领域的专家提供。这项研究将是第一个利用维度建模的角度来理解炎症，损失，认知控制和青年压力之间的关联，以及第一个将免疫系统反应与神经认知功能的测量相关联的研究。因此，拟议的奖学金将有助于推动申请人的职业生涯，并承诺产生的结果，帮助指定是否存在情绪和神经认知功能障碍的神经生物学标志物的关键时期。如果假设得到支持，则表明在治疗中靶向生物应激反应系统可能会破坏炎症反应，情绪失调和神经认知功能障碍之间的前馈循环。