Imaging Neural Substrates of Early Life Stress in Major Depression

早期生活压力(ELS)是严重抑郁障碍(MDD)的已知危险因素。这种风险是如何在特定神经通路的水平上表达的还是个未知数。该项目将测试主要的假设，即大脑系统水平的抑郁症涉及高度整合的边缘-皮质-纹状体回路的选择性功能障碍，该回路负责调节对日常生活事件的适应性动机、情绪和认知反应。这项拟议的研究将检验两个假设：(1)抑郁症特有通路中的特定神经反应会因暴露于ELS而改变；(2)正是这些特定的神经系统变化构成了MDD的易感因素。计划中的影像研究建立并扩展了当前CCNMD资助期的两个主要观察结果：(1)在儿童早期发育的关键时间点，虐待、忽视和失去父母与对各种情绪刺激的敏化自主神经、内分泌和行为反应有关；(2)这种敏化似乎增加了后来发展为各种情绪障碍的风险，大多数 值得注意的是严重抑郁障碍(MDD)。在此背景下，将通过从Project 0007中选择一组具有良好特征的ELs的女性受试者的大脑区域和相关通路来检验ELs作为抑郁风险因素的作用。之前在健康受试者中验证过的情绪、自我参照和显著加工的神经成像探针将被用来调查按MDD和ELS分层的患者亚组中的脆弱性和变异性影响。选择特定的成像探针是基于它们与主要抑郁症主要症状的理论相关性，以及它们在影响在已发表的抑郁症患者群体结构磁共振、死后形态测量、静息状态PET和功能磁共振激活研究中最一致确定的大脑区域变化方面的可靠性。此外，特定的范式和计划的分析策略也被证明对抑郁亚组、疾病状态和特征差异以及治疗效果敏感。CCNMD核心提供的基础设施，再加上在Project 0007中对ELS暴露受试者的人口统计、遗传、内分泌和行为标志物的仔细描述，提供了一个无与伦比的机会，可以系统地测试ELS对已知参与MDD的选择性途径的影响。这些研究将为确定MDD脆弱性的脑生物标记物提供关键数据，这些标记物可能导致对高患病风险个体进行潜在的症状前压力测试。识别一致的神经系统与MDD亚型的相关性将为未来基于大脑的算法的发展奠定基础，以优化个体抑郁症患者的诊断和治疗选择。

Early Life Stress (ELS) is a known risk factor for major depressive disorder (MDD). How this risk is expressed at the level of specific neural pathways is unknown. This Project will test the overarching hypothesis that depression at the brain systems-level involves selective dysfunction of highly integrated limbic-cortical-striatal circuits responsible for mediating adaptive motivational, emotional, and cognitive responses to everyday life events. The proposed studies will test two hypotheses: (1) that specific neural responses in depression-specific pathways are altered by exposure to ELS; and (2) that it is these specific neural system alterations that constitute a vulnerability factor for MDD. The planned imaging studies build and extend two main observations from the current CCNMD funding period: (1) abuse, neglect and parental loss at critical time points in early child development are associated with sensitized autonomic, endocrine and behavioral responses to various emotional stimuli; and (2) such sensitization appears to convey increased risk for the later development of various mood disorders, most notably major depressive disorder (MDD). In this context, the role of ELS as a depression risk factor will be examined by characterizing brain regions and associated pathways in a select subset of female subjects with well-characterized ELS from Project 0007. Neuroimaging probes of mood, self-reference and salience processing previously validated in healthy subjects will be used to investigate vulnerability and variability effects in patient subgroups stratified by MDD and ELS. The specific imaging probes were selected on the basis of their theoretical relevance to primary symptoms of major depression and their reliability in effecting changes in those brain regions most consistently identified across published structural MRI, post-mortem morphometric, resting state PET, and fMRI activation studies of depressed patient populations. In addition, the specific paradigms and planned analytic strategies have also been shown to be sensitive to depression subgroups, illness state and trait differences as well as treatment effects. The infrastructure provided by the CCNMD cores, combined with the careful characterization of demographic, genetic, endocrine and behavioral markers in ELS exposed subjects in Project 0007 provide an unparalleled opportunity to systematically test the impact of ELS on selective pathways of known involvement in MDD. These studies will provide critical data for defining brain-biomarkers of MDD vulnerability that may lead to potential pre-symptomatlc stress tests for individual at high illness risk. Identification of consistent neural systems correlates of MDD subtypes will lay foundation for the future development of brain-based algorithms to optimize diagnosis and treatment selection in individual depressed patients.