Final Report Summary - PLACEBO (The placebo effect – a window into the relationship between mind and body)
Many health professionals consider a positive response to placebo a psychological trait related to neurosis and imagination. However, a decade of data suggests the placebo effect to be a powerful demonstration of how mental activity that is shaped by expectation, context and experience can measurably influence physiological functions. The current strategy, in particular in the design of clinical trials, is to minimize potential placebo effects and thus ignoring the positive effects of the placebo response. In the current project we have directly addressed this point and are able to show that the mechanisms underlying placebo analgesia (i.e. expectation and experience) can also be used to augment real treatments. In one study we can show that expectation can boost real treatment effects. Furthermore, we have shown that negative expectations (nocebo manipulation) can increase pain perception and that this effect is already indicated by an increased neuronal response at the first processing stages at the spinal cord. Interestingly, the observed effect is exactly opposite to the effect that we observed previously in a placebo analgesia study. Furthermore, we have investigated the mechanisms and circumstances that promote these effects. In one such study, we could show that a placebo that is labelled as “more expensive” has actually a stronger effect as compared to a “cheap” placebo. This is a clear indication that subjective valuation processes play an important role in the efficacy of placebo/nocebo effects. These studies have only been made possible by methodological advances in which we have established novel MR imaging protocols that allow the assessment of brain activation and spinal cord activation in a single acquisition.
In addition the findings of all these studies have prompted us to propose a unified framework underlying placebo/nocebo effects. Whereas, we initially hypothesized that simple reinforcement learning mechanisms are sufficient to explain placebo effects, we are now convinced that a more general model is better suited to capture the effects observed in placebo analgesia. In particular, we suggest that the ascending and the descending pain pathways resemble a recurrent system that allows for the implementation of predictive coding - meaning that the brain is not passively waiting for nociceptive stimuli to impinge on it, but is actively making inferences based on prior experience and expectations. The Bayesian aspect within the predictive coding framework can directly account for differences in the magnitude, but also the precision of expectations which are known to influence the strength of placebo hypoalgesia. Implicit in this model is also the assumption that modulatory neurotransmitters such as opioids might be related to the characterization of expectations with an emphasis on the precision of these expectations.
In addition the findings of all these studies have prompted us to propose a unified framework underlying placebo/nocebo effects. Whereas, we initially hypothesized that simple reinforcement learning mechanisms are sufficient to explain placebo effects, we are now convinced that a more general model is better suited to capture the effects observed in placebo analgesia. In particular, we suggest that the ascending and the descending pain pathways resemble a recurrent system that allows for the implementation of predictive coding - meaning that the brain is not passively waiting for nociceptive stimuli to impinge on it, but is actively making inferences based on prior experience and expectations. The Bayesian aspect within the predictive coding framework can directly account for differences in the magnitude, but also the precision of expectations which are known to influence the strength of placebo hypoalgesia. Implicit in this model is also the assumption that modulatory neurotransmitters such as opioids might be related to the characterization of expectations with an emphasis on the precision of these expectations.