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

项目概要/摘要 阿片类药物使用障碍（OUD）是美国的一个公共卫生危机。即使在接受治疗的人中， 坚持服药的程度很低，复发是正常现象。复发的一个核心触发因素是压力的体验， 通常涉及心理社会或人际关系的挑战。OUD的临床前模型表明，压力影响 神经，内分泌和行为功能，增加了一个人发起和维持 成瘾行为在这里，我们的目标是将这些临床前发现转化为人类OUD患者的药物治疗- 辅助治疗（主要药物：海洛因;稳定在相同的药物剂量1-6个月）。我们会委聘 两种用于检查患者心理社会压力的广泛方法，一种利用慢性标记物（即，类特质 行为和成像表型）和一种利用急性标记（即，对实验室的类状态反应 归纳范式，测试压力系统的适应能力）。这些方法充分 互补（正交），因为慢性标志物取决于人与人之间的差异，而急性标志物取决于人与人之间的差异。 标记取决于每个参与者基线的内部波动。慢性心理社会压力 在研究的第1天获得的标记包括：（1）社会认知功能（情绪识别任务）， (2)在涉及暴露于威胁和药物相关图像的决策任务期间， （3）用结构MRI和基于体素的形态测量法评估灰质体积。急性心理社会 将在研究的第2天（第1天后两周）获得压力标记物，在此期间，参与者接受 通过个人化的想象进行实验性的压力诱导。急性应激标志物包括：实验- 诱导的渴求、唾液皮质醇（HPA功能的标志物）和唾液α淀粉酶（标志物） 交感神经激活）。对于这两种方法中的每一种，我们将测试以下两种方法之间的假设差异： OUD参与者和匹配的健康对照（HC），然后在OUD中，我们将测试假设的 压力变量与累积逆境访谈（CAI）分数的相关性，一个经过验证的 衡量终生累积心理压力的指标。最后，OUD参与者将被随访8个月， 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进行前瞻性预测 标记。通过这种设计，我们将解决我们的研究目的，即发现是否有异常， 神经，内分泌和行为相关的压力在OUD与HC;是否这种异常在OUD 累积的逆境加剧;以及压力及其生物学机制是否预测OUD复发 轨迹我们的研究将推进OUD中应激生物学的基础知识，这是一个迄今为止 与其他成瘾相比，被深深地低估了。这些知识可以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，以帮助打击阿片类药物的流行。

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.