Neural, endocrine, and behavioral markers of psychosocial stress predicting drug use outcomes in human opioid addiction

项目摘要/摘要 阿片类药物使用障碍(OUD)是美国的公共健康危机。即使在接受治疗的人中，也是长期的 服药依从性低，复发是常态。复发的一个核心诱因是压力的经历， 通常涉及心理社会或人际关系方面的挑战。OUD的临床前模型显示，压力影响 神经、内分泌和行为功能，增加一个人启动和维持 上瘾的行为。在这里，我们的目标是将这些临床前发现转化为正在接受药物治疗的人类OUD患者- 辅助治疗(主要药物：海洛因；在相同剂量的药物上稳定1-6个月)。我们将聘用 检查患者心理社会压力的两种广泛方法，一种是利用慢性标记物(即，类似特质的 行为和成像表型)和利用急性标志物(即实验室的状态样反应)的一种 测试压力系统适应能力的归纳范式)。这些方法完全是 互补性(正交性)，因为慢性标志物取决于人与人之间的差异，而急性标志物 分数取决于从每个参与者的基线开始的人内波动。慢性心理社会压力 将在研究的第一天获得的标记包括：(1)社会认知功能(情绪识别任务)， (2)在涉及暴露于威胁性和毒品相关图像的决策任务期间的功能磁共振激活， (3)用结构MRI和体素形态计量学方法测量灰质体积。尖锐的心理社会 应激标记物将在研究的第二天(第一天后两周)获得，在此期间，参与者将接受 一种通过个性化想象进行的实验性压力诱导。急性应激标记包括：实验上- 引起渴望、唾液皮质醇(HPA功能的标志)和唾液α淀粉酶(标志)的变化 交感神经激活)。对于这两种方法中的每一种，我们都将测试 OUD参与者和匹配的健康对照组(HC)，然后在OUD内我们将测试假设 压力变量与累积逆境访谈(CAI)成绩的相关性 测量一生累积的心理社会压力。最后，OUD参与者将接受为期8个月的跟踪调查 跟踪复发状态和药物使用，我们假设这将通过我们的多模式压力来前瞻性地预测 记号笔。通过这一设计，我们将解决我们的研究目标，即揭示 神经、内分泌和行为与OUD和HC的应激相关；OUD中是否存在这种异常 因累积的逆境而加剧；以及压力及其生物机制是否预示着OUD复发 轨迹。我们的研究将促进OUD应激生物学的基本知识，这是一个迄今为止已经 与其他上瘾行为相比，人们对此的研究严重不足。这些知识可能会为新的治疗方法提供信息 药物开发和心理社会干预的目标，以帮助抗击阿片类药物流行。

PROJECT SUMMARY/ABSTRACT Opioid use disorder (OUD) is a public health crisis in America. Even among those in treatment, long-term adherence to medication is low, and relapse is the norm. A core trigger for relapse is the experience of stress, often involving psychosocial or interpersonal challenges. Preclinical models of OUD show that stress impacts neural, endocrine, and behavioral functioning, increasing one’s vulnerability for initiating and sustaining the addictive behavior. Here, we aim to translate these preclinical findings to human OUD patients on medication- assisted treatment (primary drug: heroin; stabilized on the same medication dose for 1-6 months). We will employ two broad approaches for examining psychosocial stress in patients, one utilizing chronic markers (i.e., trait-like behavioral and imaging phenotypes) and one utilizing acute markers (i.e., state-like reactivity to a laboratory induction paradigm which tests the adaptive capacity of the stress system). These approaches are fully complementary (orthogonal), in that the chronic markers depend on between-person differences while the acute markers depend on within-person fluctuations from each participant’s baseline. The chronic psychosocial stress markers, to be acquired on Day 1 of the study, include: (1) social-cognitive functioning (emotion recognition task), (2) fMRI activation during a decision-making task that involves exposure to threatening and drug-related images, and (3) gray matter volume assessed with structural MRI and voxel-based morphometry. The acute psychosocial stress markers will be acquired on Day 2 of the study (two weeks after Day 1), during which participants undergo an experimental stress induction via personalized imagery. The acute stress markers include: experimentally- induced changes in craving, salivary cortisol (marker of HPA functioning), and salivary alpha amylase (marker of sympathetic activation). For each of these two approaches, we will test for hypothesized differences between OUD participants and matched healthy controls (HC), and then within OUD we will test for hypothesized correlations of the stress variables with scores from the Cumulative Adversity Interview (CAI), a well-validated measure of lifetime cumulative psychosocial stress. Finally, OUD participants will be followed for 8 months to track relapse status and drug use, which we hypothesize will be prospectively predicted by our multimodal stress markers. With this design, we will address our study aims of uncovering whether there are abnormalities in the neural, endocrine, and behavioral correlates of stress in OUD versus HC; whether such abnormalities in OUD are exacerbated by cumulative adversity; and whether stress and its biological mechanisms predict OUD relapse trajectories. Our study will advance basic knowledge of stress biology in OUD, a research area that to date has been profoundly understudied compared with other addictions. Such knowledge may inform new therapeutic targets for medication development and psychosocial intervention to help combat the opioid epidemic.