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

项目概要 纵观历史，安慰剂效应一直被不同程度地认为是医学界对容易上当受骗者的欺骗。 练习者和强大但神秘的治愈力量。随着直接测量人体的出现 现代科学表明，安慰剂效应与大脑功能无关。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了解影响健康的内部大脑过程的窗口，并且 这是一个挑战，因为许多临床试验现在由于大量且持久的安慰剂反应而失败了，在很大程度上 医疗保健提供者和消费者的成本。 对涉及安慰剂反应的大脑通路以及遗传、环境和 导致某些人比其他人反应更强烈的神经因素对于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 有助于成功治疗和“自发”改善的大脑因素。安慰剂镇痛 是研究最充分的安慰剂效应类型，具有完善的范式和关于其大脑的初步数据 机制。这一背景为更大规模、明确的研究奠定了基础。 在这个项目中，我们提出了第一个针对安慰剂镇痛的大脑机制的大规模研究，结合 神经影像、行为和遗传学方法。它建立在 PI Wager 实验室 15 年的经验之上 功能磁共振成像和安慰剂镇痛以及行为遗传学研究所 (IBG) 40 年的遗传学研究 科罗拉多大学博尔德分校。我们将使用功能磁共振成像来描述 600 种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，并预测两个人之间安慰剂效应的个体差异 疼痛的形式。在目标 1 中，我们将开发模型来预测个体安慰剂对疼痛的影响程度 疼痛神经生理学基于 a) 功能磁共振成像活动、b) 大脑结构以及个性的组合， 可在临床上应用的行为和认知测量。在目标 2 中，我们进行了首次分析 安慰剂效应及其神经预测因子的遗传性，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本质上是遗传的。在目标 3 中，我们利用超过 50,000 名员工 通过荟萃分析 (ENIGMA) 联盟增强神经影像遗传学，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 这项工作的研究产品将包括可用于表征和筛选的数据和模型 临床试验的参与者，评估安慰剂反应和其他治疗之间的相互作用，以及 评估安慰剂对各种疾病的影响。

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.