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

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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.