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

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.

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 solely determined by sensory input but is critically influenced by expectations and beliefs individuals hold. The influence of expectations on pain has been shown in the exacerbation of symptoms when patients catastrophize about pain, in placebo analgesia and expectancy-related modulations of pharmacologically induced analgesia (Tracey, 2010).

Here, I will capitalize (i) on the formalization of the influence of expectations as an inferential process ('perception as inference') and (ii) the investigation of this inferential process using a combined approach of recent advances in computational modeling (Friston & Dolan, 2010) and neuroimaging techniques. This allows for the characterization of neural mechanisms underlying the different steps involved in the inferential process and the investigation of aberrant processing.

In four cross-sectional studies using functional neuroimaging in combination with computational modelling in healthy volunteers I will focus on the following questions:

- How can expectations lead to a biased perception of pain? (Study 1)
- What triggers expectations of pain in the brain? (Study 2)
- When does a discrepancy between expectation and sensory input lead to updating of the expectation? (Study 3)
- How do expectations affect the perception of change in pain during pain treatment? (Study 4)



References: 1. Tracey, I. (2010). Nature Medicine, 16(11), 1277-1283; 2. Friston, K.J., Dolan, R.J. (2010). NeuroImage, 52(3), 752-765.

The research proposed in this application is predicted to impact a range of non-academic beneficiaries over the shorter and longer term. Short-term benefits may include increased understanding of the role of expectations on the perception of pain and changes in pain, and increased awareness of the effect of expectations on the perception of pain. These will be achieved over the course of the study. In the long term the project outcome could potentially also be applied in other contexts involving treatment or training (e.g. education or rehabilitation) in which expectations are predicted to have an effect. The results of could therefore potentially also be beneficial for several other groups (e.g. sportsmen/women, teachers and students or criminal offenders). Because novel prevention, treatment and training protocols for pain and other situations would require validation they are, however, likely to take several more years to reach users.

PAIN PATIENTS AND POTENTIALLY OTHER PATIENTS, THEIR FAMILIES AND CARERS

1. Improved patient information through tailoring of information to exploit the beneficial effects of expectation while reducing unwanted negative effects
2. Increased understanding of the role of expectations in prevention treatment and training
3. Availability of improved protocols for prevention, treatment and training
4. Improved performance and quality of life (including for families and carers)
5. Increased understanding of principle of translating basic research into clinical solutions (e.g. 'bench to beside')
6. Potential availability of novel brain-computer interface devices for modifying expectations


UK AND INTERNATIONAL BIOSCIENCE/HUMAN RESOURCES INDUSTRY

1. Potential for development of prevention/treatment protocol and devices
2. Increased success of drug discovery through reduction of unspecific expectancy-related events on drug efficacy (e.g. placebo effects)
3. Potential to develop diagnostic assays to predict course of disease and treatment options
4. Potential to improved training protocols, performance management and teaching aids


UK HEALTHCARE AND EDUCATION

1. Improved training of clinicians regarding role of expectations in treatment
2. Potential validation of biological pathways to stimulate further translational research on expectations
3. Potential development of new therapies, which might reduce the clinical burden of pain and other diseases
4. Availability of diagnostic test to predict course of disease and treatment options. Identification protocols for prevention, treatment and training in disease addiction etc.
5. Improved training protocols for training and education


THE BROADER UK ECONOMY

1. Reduced loss of productive working years
2. Reduced clinical burden of pain and psychiatric disease
3. Reduced cost of benefits for patients