Brain and Genetic Predictors of Individual Differences in Pain and Placebo Analgesia

项目摘要 纵观历史，安慰剂效应一直被认为是医学界对轻信者所开的玩笑。 医生和强大但神秘的治疗力量。随着人类直接测量的出现， 现代科学表明，安慰剂效应两者都不是。相反，它们反映了 心理和大脑过程对大脑和身体疾病的原则性影响。安慰剂效应 代表了一个机会，因为它们提供了一个窗口，了解影响健康的内部大脑过程， 这是一个挑战，因为许多临床试验现在都失败了，因为安慰剂反应大而持久， 医疗保健提供者和消费者的成本。 对与安慰剂反应有关的大脑通路的连续性研究--以及遗传、环境和 导致某些个体比其他个体反应更强烈的神经因素对利用安慰剂至关重要 影响，消除或控制临床试验中的安慰剂反应，并了解心理和 大脑因素使一个人倾向于成功的治疗和“自发”的改善。安慰剂镇痛 是安慰剂效应中研究得最好的一种，有着完善的范例和关于其大脑的初步数据 机制等这一背景为更大规模的确定性研究提供了基础。 在这个项目中，我们提出了第一个这样的大规模研究安慰剂镇痛的大脑机制，结合 神经影像、行为和遗传学方法。它建立在PI Wager实验室15年的经验基础上 关于功能磁共振成像和安慰剂镇痛和行为遗传学研究所（IBG）40年的遗传学研究， 位于博尔德的科罗拉多大学。我们将使用功能磁共振成像来描述600例安慰剂效应的神经基础。 从科罗拉多双胞胎样本中招募的双胞胎，并预测两个样本之间安慰剂效应的个体差异。 疼痛的形式。在目标1中，我们将开发模型，预测个体在疼痛中的安慰剂效应的大小 以及疼痛神经生理学，基于a）功能磁共振成像活动，B）大脑结构，以及个性， 行为和认知的测量，这些测量可以在临床上使用。在目标2中，我们进行了第一次分析， 安慰剂效应的遗传性及其神经预测因子，以及可以识别大脑特征的遗传相关性 其与安慰剂效应的关系源于遗传。在目标3中，我们利用超过5万人的 通过荟萃分析（ENIGMA）联盟增强神经成像遗传学，以识别全基因组 与安慰剂相关的大脑特征的关联，并为安慰剂效应制定多基因风险评分。的 这项奋进的研究成果将包括用于表征和筛选的数据和模型 临床试验参与者，评估安慰剂反应与其他治疗之间的相互作用，以及 评估安慰剂对疾病的影响。

Project Summary Throughout history, placebo effects have been variously considered as tricks played upon the gullible by medical practitioners and powerful but mysterious healing forces. With the advent of direct measurements of human brain function, modern science has shown that placebo effects are neither of these. Rather, they reflect the principled impact of psychological and brain processes on diseases of the brain and body. Placebo effects represent an opportunity because they provide a window into internal brain processes that influence health, and a challenge because many clinical trials have now failed due to large and durable placebo responses, at great cost to health care providers and consumers. Definitive studies of the brain pathways involved in placebo responses—and the genetic, environmental, and neural factors that lead some individuals to respond more strongly than others—are critical to harnessing placebo effects, eliminating or controlling placebo responses in clinical trials, and understanding the psychological and brain factors that predispose one to successful treatment and “spontaneous” improvement. Placebo analgesia is the best-studied type of placebo effect, with well-developed paradigms and preliminary data on its brain mechanisms. This background provides a foundation for larger-scale, definitive studies. In this project, we propose the first such large-scale study of brain mechanisms of placebo analgesia, combining neuroimaging, behavioral, and genetic approaches. It builds on 15 years’ experience in PI Wager’s laboratory on fMRI and placebo analgesia and 40 years of genetics research at the Institute for Behavior Genetics (IBG) at the University of Colorado, Boulder. We will use fMRI to characterize the neural bases of placebo effects in 600 twins recruited from the Colorado Twin Sample and predict individual differences in placebo effects across two forms of pain. In Aim 1, we will develop models that predict the magnitude of individuals’ placebo effects in pain and pain neurophysiology based on a) fMRI activity, b) brain structure, and a combination of personality, behavioral, and cognitive measures that can be deployed clinically. In Aim 2, we conduct the first analyses of heritability of placebo effects and their neural predictors, and genetic correlations that can identify brain features whose relationships with placebo effects are genetic in origin. In Aim 3, we leverage the >50,000 person Enhancing Neuro-Imaging Genetics through Meta-analysis (ENIGMA) consortium to identify genome-wide associations with placebo-linked brain features and develop polygenic risk scores for placebo effects. The research products from this endeavor will include data and models useful for characterizing and screening participants in clinical trials, assessing interactions between placebo responses and other treatments, and assessing placebo effects across disorders.