The Neural Bases of Placebo Effects and their Relation to Regulatory Processes

描述（由申请人提供）：纵观历史，安慰剂效应一直被认为是医生和强大但神秘的治疗力量对轻信者的伎俩。随着人类大脑功能的直接测量的出现，现代科学已经表明安慰剂效应既不是这些。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--因为它提供了一个了解影响健康的内部大脑过程的窗口--也是一个挑战，因为几十个临床试验现在都未能证明常用处方药优于安慰剂，这给医疗服务提供者和消费者带来了巨大的成本。这可能不是由于药物的无效，而是似乎与高安慰剂反应率有关。对安慰剂效应背后的大脑机制的研究可以提供有价值的见解，了解大脑如何积极地预测，响应和学习积极的治疗，以及这些过程对疼痛和其他健康方面的影响。在本基金的前一阶段，安慰剂和阿片类药物作用的功能性磁共振成像（fMRI）有助于确定安慰剂治疗影响疼痛的神经生物学，包括对与疼痛体验最密切相关的皮质和皮质下大脑区域的影响。这项研究还提供了一些关于大脑中产生安慰剂效应的相互作用的第一批证据，并证明了前额叶皮质-皮质下-脑干系统和内源性阿片系统的参与。出现的观点是，安慰剂治疗涉及与概念思维（外显信念）和学习过程相关的大脑系统，这些系统改变了分配给治疗线索和疼痛本身的价值。在此更新应用程序中，我们在此基础上解决了许多尚未解决的问题，这些问题需要在理解安慰剂效应之前解决，在治疗中利用，并在临床试验和实践中与药物效应完全分离。这些问题包括：a） 安慰剂调节的“疼痛相关”过程（它们是疼痛特有的，还是一般的情感过程？）和B）产生安慰剂镇痛所需的临界条件。我们的工作假设是，概念和学习过程相互作用，两者都是至关重要的。学习系统从根本上塑造了疼痛的激励价值，并调节皮层下脑干系统的伤害感受，需要概念过程来将感知到的益处归因于安慰剂治疗并参与学习。为了更好地理解这些系统，我们带来了新的计算机器学习工具，可以识别和测试安慰剂对疼痛特定大脑活动模式的影响。我们还测试了几种神经化学系统阿片类药物，多巴胺和催产素的参与，以及它们与安慰剂反应生成过程中特定大脑和心理方面的关系。

DESCRIPTION (provided by applicant): 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 dozens of clinical trials have now failed to show the superiority of commonly prescribed drugs to placebo, at great cost to health care providers and consumers. This may not be due to the ineffectiveness of the medications, but rather seems to be related to high placebo response rates. Studies of the brain mechanisms underlying placebo effects can provide valuable insight into how the brain actively anticipates, responds to, and learns about active treatments, and the effects of these processes on pain and other aspects of health. In the previous period of this grant, functional magnetic resonance imaging (fMRI) of placebo and opiate drug effects was instrumental in establishing that placebo treatments impact the neurobiology of pain, including effects on the cortical and subcortical brain regions most closely associated with pain experience. The research also provided some of the first evidence on the interactions in the brain that give rise to placebo effects, and demonstrated the involvement of prefrontal cortical-subcortical-brainstem systems and the endogenous opioid system. The view that emerged is that placebo treatments engage brain systems related to both conceptual thought (explicit beliefs) and learning processes that change the value assigned to treatment cues and pain itself. In this Renewal application, we build on this foundation to address some of the many unanswered questions that need to be addressed before placebo effects are understood, harnessed in therapy, and separated cleanly from drug effects in clinical trials and practice. These include fundamental questions about a) the nature of the "pain-related" processes regulated by placebos (are they specific to pain, or general affective processes?) and b) the critical conditions required to create placebo analgesia. Our working hypothesis is that conceptual and learning processes interact, and that both are critical. Learning systems fundamentally shape the motivational value of pain and modulate nociception in subcortical-brainstem systems, and conceptual processes are needed to attribute perceived benefits to the placebo treatment and engage learning. To better understand these systems, we bring to bear new computational machine-learning tools that can identify and test placebo effects on patterns of brain activity specific to pain. We also test the involvement of several neurochemical systems-opioids, dopamine, and oxytocin-and their relationships with specific brain and psychological aspects of the placebo response-generation process.