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

疼痛是世界范围内的一个主要医疗保健问题。它影响着数百万人的福祉，它给我们的社会带来了相当大的财政负担。据估计，欧洲每年因慢性疼痛而付出的代价为2000亿欧元。因此，迫切需要提高预防和治疗慢性疼痛的能力，以减少其对社会经济和个人的影响。疼痛不是对传入的感官信息的简单反映，而是受到个人对疼痛的期望和信念以及他们应对疼痛的能力的重大影响。这一点最令人印象深刻的表现在安慰剂止痛药中，一种被认为是有效止痛药的惰性物质可以缓解疼痛。然而，更重要的是，预期已被证明影响疼痛治疗的结果，包括作为最常见的疼痛治疗形式的药物干预。在最近对健康志愿者进行的一项神经成像研究中，我们证明，与参与者对治疗效果没有预期的情况相比，疼痛减轻的期望是阿片类药物的止痛效果的两倍(Bingel等人，2011年发表在《科学转化医学》上)。此外，这种药物可能会加剧疼痛的预期完全消除了止痛效果。关键的是，这种预期的调制影响不仅反映在对疼痛的主观体验上，还反映在涉及疼痛和止痛的大脑区域的激活水平上。这些发现突显了与疼痛相关的预期有可能放大药物效果--如果预期破坏了药理作用，则可能产生有害影响。尽管存在明显的临床相关性，但令人惊讶的是，人们对预期在大脑中实施的机制、它们如何影响疼痛感知以及它们是如何修正的知之甚少。然而，对“思想”和“物质”之间的界面的洞察可以为疼痛的预防和治疗开辟新的途径，也可以为更广泛的慢性健康状况开辟新的途径，疼痛可以被视为疼痛的原型。在对健康志愿者进行的一系列四项脑成像实验中，我将研究预期对疼痛感知和疼痛变化产生影响的基本大脑机制。特别是，我将探索大脑中的过程：(I)通过预期来解释疼痛的调制(研究1)，(Ii)触发对疼痛的预期(研究2)，(Iii)允许我们修改预期，以防它们不真实地反映现实，以及那些尽管不正确但有助于坚持预期的过程(研究3)。最后，我将在一项翻译研究中调查维持和修订与止痛相关的期望的过程(研究4)。所有四项研究都将要求参与者在记录大脑反应的同时，反复就他们对实验诱导的疼痛的个人感知做出决定。反映这些决定的测量方法，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。关于与疼痛处理相关的大脑区域的参与以及与预期的形成、维持和修订有关的信息，将得到关于大脑的个人解剖数据以及大脑区域之间相互干扰的数据的补充。几个世纪以来，我们的信仰和期望强烈地影响着我们的感知，这一观察结果已经为人所知。然而，到目前为止，我们还没有能够利用这一强大的机制，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，能够将信念和期望作为一种低成本但高效的干预措施进行治疗性使用。

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.