Neurobiological mechanisms of perceived stress and their modification through behavioral intervention

项目总结 压力感在急、慢性应激源对长期心理的影响中起中介作用 因此，这是创伤后应激障碍和抑郁症等疾病的一个重要风险因素。建议数 该项目将通过识别感知压力的新的假定大脑机制来填补知识空白，从而允许 为了更好地识别高危个人并制定干预措施的治疗目标 以增强抗压能力。该职业发展奖将为候选人提供以下方面的培训 先进的结构和弥散加权磁共振成像方法和基础教学和辅导培训 临床试验研究。这一新的训练将被用来测试关于海马体的新假设 对感知到的压力的贡献，以及通过正念干预来修改这些机制。在一个 来自社区的300人样本，研究1将调查感知到的压力之间的关系 以及模式分离行为，这是一种海马体依赖的过程，允许细粒度的辨别 安全环境与威胁环境的对比，理论上这与过度泛化恐惧和 负面影响。利用高分辨率结构成像和多图谱的海马区分割，Aim 1将研究模式分离行为、海马子区体积和 对日常生活压力源和急性实验室压力源的看法。在目标2中，先进的扩散加权成像 方法将被用来洞察海马神经纤维(轴突和 树枝状)。这将允许对主观感知的微观结构相关性进行新的研究 应激，假设包括海马区内神经突起密度降低和不太连贯的方向 连接海马体和内侧前额叶皮质的白质束。在研究2中，80名参与者将是 随机分为等待名单对照组或基于正念的压力减轻(MBSR)，这是已知的减少压力的方法 对压力的主观感觉。目标3将测试MBSR参与者是否在模式上表现出改进 分离行为、海马体体积和海马微结构，以及这些海马体 变化与感知压力的预期减少有关。目标1-2将通过新的培训得到促进 在先进的海马体结构成像和先进的扩散加权成像方法中， 在这些领域拥有丰富专业知识的培训团队的支持下，丰富的资源使之成为可能 一个世界级的脑成像中心。目标3将通过授课、体验式和指导性培训来支持 美国国立卫生研究院资助的临床与转化研究所的临床研究基础 (卢旺达问题国际法庭)。总而言之，本项目的研究和培训目标旨在阐明新的神经生物学 感知压力的机制，并提供先进的神经成像方法和临床试验方面的新培训 方法论。该奖项将使候选人能够进行未来的干预研究，旨在预防 通过参与这些神经生物学靶点来发展与压力相关的障碍。

PROJECT SUMMARY Subjective perceptions of stress mediate the effects of acute and chronic stressors on long-term psychological outcomes, and thus represent an important risk factor for disorders such as PTSD and depression. The proposed project will fill a knowledge gap by identifying novel putative brain mechanisms of perceived stress, thus allowing for better identification of at-risk individuals and the development of treatment targets for interventions that seek to enhance stress resilience. This Career Development Award will provide the candidate with training in advanced structural and diffusion-weighted MRI methods and didactic and mentored training in the fundamentals of clinical trials research. This new training will be leveraged to test novel hypotheses regarding hippocampal contributions to perceived stress, and modification of these mechanisms by a mindfulness intervention. In a sample of 300 individuals from the community, Study 1 will investigate relationships between perceived stress and pattern separation behavior, a hippocampal-dependent process that allows for fine-grained discrimination of safe vs. threatening contexts, and which has been theoretically linked to over-generalization of fear and negative affect. Using high-resolution structural imaging and multi-atlas segmentation of the hippocampus, Aim 1 will investigate relationships between pattern separation behavior, hippocampal subfield volumes, and perceptions of daily life stressors and acute laboratory stressors. In Aim 2, advanced diffusion-weighted imaging methods will be used to gain insight into the density and orientation of hippocampal neurites (axons and dendrites). This will allow for a novel investigation of the microstructural correlates of subjectively perceived stress, hypothesized to include reduced neurite density within the hippocampus and less coherent orientation of white matter tracts linking the hippocampus and medial prefrontal cortex. In Study 2, 80 participants will be randomized to a wait-list control group or mindfulness-based stress reduction (MBSR), which is known to reduce subjective perceptions of stress. Aim 3 will test whether MBSR participants demonstrate improvements in pattern separation behavior, hippocampal volume, and hippocampal microstructure, and whether these hippocampal changes are associated with expected reductions in perceived stress. Aims 1-2 will be facilitated by new training in advanced structural imaging of the hippocampus and advanced diffusion-weighted imaging methods, supported by a training team with extensive expertise in these domains and made possible by the rich resources of a world-class brain imaging center. Aim 3 will be supported by didactic, experiential, and mentored training in the fundamentals of clinical research through the NIH-funded Institute for Clinical and Translational Research (ICTR). Collectively, the research and training aims of this project seek to illuminate novel neurobiological mechanisms of perceived stress and provide new training in advanced neuroimaging methods and clinical trials methodology. This award will enable the candidate to conduct future intervention studies aimed at preventing the development of stress-related disorders by engaging these neurobiological targets.