How expectations become reality: The neurobiology underlying the influence of expectations on pain

疼痛是世界范围内的主要卫生保健问题。它影响到千百万人的福祉，给我们各国社会造成巨大的财政负担。据估计，欧洲每年的慢性疼痛成本为2000亿欧元。因此，迫切需要提高预防和治疗慢性疼痛的能力，以减少其社会经济和个人影响。疼痛并不是一个简单的感觉信息的反映，而是受到个体对疼痛的期望和信念以及他们科普疼痛的能力的影响，这一点在安慰剂镇痛中得到了最深刻的证明，在安慰剂镇痛中，一种被认为是强效止痛剂的惰性物质可以缓解疼痛。然而，更重要的是，预期已被证明会影响疼痛治疗的结果，包括药物干预作为最常见的疼痛治疗形式。在最近对健康志愿者的神经成像研究中，我们证明，与参与者对治疗效果没有期望的情况相比，对疼痛减轻的期望使阿片类药物的镇痛效果加倍（Bingel et al.，2011年，《科学转化医学》（Science Translational Medicine）此外，药物可能加剧疼痛的预期完全消除了镇痛作用。重要的是，这种预期的调节作用不仅反映在疼痛的主观体验中，而且还反映在与疼痛和镇痛有关的大脑区域的激活水平上。这些发现强调了与疼痛相关的期望放大药物作用的潜力-如果期望破坏药理作用，则会产生有害影响。尽管有明显的临床相关性，但令人惊讶的是，人们对大脑中实现预期的机制知之甚少，它们如何影响疼痛的感知以及如何修正。然而，对“心灵”和“物质”之间界面的洞察可以为预防和治疗疼痛开辟新的途径，也可以为更广泛的慢性健康状况开辟新的途径，疼痛可以被视为原型。在一系列的四个实验研究中，使用健康志愿者的大脑成像，我将调查基本的大脑机制的影响，预期对疼痛的感知和疼痛的变化。特别是，我将探索大脑中的过程，（i）通过期望来调节疼痛（研究1），（ii）触发疼痛的期望（研究2），（iii）允许我们修改我们的期望，以防它们不真实地反映现实，以及那些有助于坚持期望的过程，尽管它们是不正确的（研究3）。最后，我将在一个翻译研究中调查镇痛相关期望的维持和修正过程（研究4）。所有四项研究都要求参与者在记录大脑反应的同时，反复对他们对实验诱导疼痛的个人感知做出决定。反映这些决定的测量结果，如反应时间，将用于分析大脑激活数据，使用一种新的计算方法与尖端的神经成像相结合。与疼痛处理相关的大脑区域参与的信息，以及期望的形成，维持和修改，将由大脑的个体解剖数据以及大脑区域之间的串扰数据来补充。我们的信念和期望强烈地影响我们的感知，这一观察已经有几个世纪了。然而，到目前为止，我们还没有能够利用这种强大的机制，因为缺乏对这种影响背后的神经机制的更基本的见解。我的项目是第一个弥合这一差距的项目，使信念和期望作为一种低成本但高效的干预措施得到治疗性使用。

Pain is a major health care problem worldwide. It affects the well-being of millions of individuals, and its financial burden upon our societies is considerable. Per annum, it is estimated that the cost of chronic pain to Europe is 200 billion euros. Improvements in the ability to prevent and treat chronic pain are therefore urgently needed to reduce its socioeconomic and personal impact. Pain is not a simple reflection of incoming sensory information but is substantially influenced by expectations and beliefs individuals hold about pain and their ability to cope with it. This has most impressively been shown in placebo analgesia in which an inert substance that is believed to be a powerful painkiller induces pain relief. However, more importantly, expectations have been shown to influence the outcome of pain treatment, including pharmacological interventions as the most common form of pain treatment. In a recent neuroimaging study in healthy volunteers we demonstrated that the expectation of pain reduction doubled the analgesic effect of an opioid in comparison to a condition where participants had no expectations regarding the treatment effect (Bingel et al., 2011 in Science Translational Medicine). Furthermore, the expectation that the drug might exacerbate pain completely abolished the analgesic effect. Critically, this modulatory influence of expectations was not only reflected in the subjective experience of pain but also in the activation level of brain regions involved in pain and analgesia. These findings highlight the potential of pain-related expectations to amplify drug effects - and their detrimental effect if expectations undermine the pharmacological action. Despite the obvious clinical relevance, surprisingly little is known about the mechanisms by which expectations are implemented in the brain, how they impact the perception of pain and how they are revised. Insights into the interface between 'mind' and 'matter' could, however, open up new avenues for the prevention and treatment of pain, but also for a wider range of chronic health conditions, for which pain can be seen as a prototype. In a series of four experimental studies using brain imaging in healthy volunteers, I will investigate basic brain mechanisms underlying the influence of expectations on the perception of pain and changes in pain. In particular, I will explore processes in the brain that (i) account for the modulation of pain through expectations (Study 1), (ii) trigger the expectation of pain (Study 2), (iii) allow us to revise our expectations in case they do not truthfully reflect reality and those processes that aid in adhering to expectations although they are incorrect (Study 3). Finally, I will investigate in a translational study the processes involved in the maintenance and revision of expectations related to analgesia (Study 4). All four studies will require the participants to repeatedly make decisions about their individual perception of experimentally induced pain while their brain responses are recorded. Measurements that reflect these decisions such as response times will be used in the analysis of the brain activation data using a novel computational approach in combination with cutting-edge neuroimaging. Information about the engagement of brain regions related to pain processing but also to the formation, maintenance and revision of expectations will be complemented by data on the individual anatomy of the brain as well as data on the crosstalk between brain regions. The observation that our beliefs and expectations strongly impact our perception has been known for centuries. However, so far we have not been able to capitalize on this powerful mechanism as more fundamental insights into the neural mechanisms underlying this influence are lacking. My project is the first to bridge this gap to enable the therapeutic use of beliefs and expectations as a low-cost but highly effective intervention.