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上对容易上当的人玩的诡计。 实践者和强大而神秘的治愈力量。随着对人类的直接测量的出现 大脑功能，现代科学已经表明，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 代表着一个机会，因为它们为了解影响健康的内部大脑过程提供了一个窗口 这是一个挑战，因为许多临床试验现在由于大量和持久的安慰剂反应而失败。 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 导致一些人比其他人反应更强烈的神经因素--对服用安慰剂至关重要 效果，消除或控制临床试验中的安慰剂反应，并了解心理和 大脑因素使一个人易于成功的治疗和“自发”的改善。安慰剂止痛 是研究最深入的安慰剂效应类型，有关于其大脑的发展良好的范例和初步数据 机械装置。这一背景为更大规模、权威性的研究奠定了基础。 在这个项目中，我们提出了第一个关于安慰剂止痛的大脑机制的大规模研究，结合 神经成像、行为和遗传方法。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止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名患者中安慰剂效应的神经基础 从科罗拉多州双胞胎样本中招募的双胞胎，并预测两个人在安慰剂效应方面的个体差异 各种形式的痛苦。在目标1中，我们将开发模型来预测个体在疼痛中的安慰剂效应的大小 和疼痛神经生理学，基于a)功能磁共振活动，b)大脑结构，和个性的组合， 可用于临床的行为和认知测量。在目标2中，我们进行了第一次分析 安慰剂效应和它们的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 他们与安慰剂效应的关系源于遗传。在目标3中，我们利用50,000人 通过荟萃分析(Enigma)联盟增强神经成像遗传学以确定全基因组 与安慰剂相关的脑功能特征的相关性，并开发安慰剂效应的多基因风险评分。这个 这一努力的研究产品将包括对表征和筛选有用的数据和模型 参与临床试验，评估安慰剂反应和其他治疗之间的相互作用，以及 评估各种疾病的安慰剂效果。

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.