When Expectancies Are Violated: A Functional Magnetic Resonance Imaging Study

Abstract

Positive and negative expectancies drive behavioral and neurobiological placebo and nocebo effects, which in turn can have profound effects on patient improvement or worsening. However, expectations of events and outcomes are often not met in daily life and clinical practice. It is currently unknown how this affects placebo and nocebo effects. We have demonstrated that the violation of expectancies, such as when there is a discrepancy between what is expected and what is actually presented, reduces both placebo and nocebo effects while causing an extinction of placebo effects. The reduction of placebo and nocebo effects was paralleled by an activation of the left inferior parietal cortex, a brain region that redirects attention when discrepancies between sensory and cognitive events occur. Our findings highlight the importance of expectancy violation in shaping placebo and nocebo effects and open up new avenues for managing positive and negative expectations in clinical trials and practices.

Trial registration: ClinicalTrials.gov NCT01328561.

Conflict of interest statement

Conflict of Interest

Luana Colloca received lecture honorarium within the US. Oliver Robinson serves a consultant for IESO Digital Health / Peak.com and received honoraria for Lectures within the UK. All other authors declared no competing interests for this work.

© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Figures

Figure 1:. Experimental design.

(A) Anticipatory (red, yellow, and green) and face (fearful, neutral, and happy) cues were presented with three painful stimulations delivered at an average intensity of 47, 44, and 41 °C to provide a perception of high, medium, and low painful sensation, respectively. During the acquisition phase, the red-fearful face cue indicated high pain, the green-happy cue indicated low pain, and the yellow-neutral face indicated the medium (control) level of pain. (B) During the test phase in the fMRI scanner, the anticipatory and face cues were mismatched in 50% of the trials to violate participants’ expectancy (e.g., red: neutral or happy face). Moreover, the level of pain (in °C) was set for all the matched and mismatched trials at the individually-calibrated medium pain. The difference in visual analog scale (VAS) ratings observed in the red and green-associated stimulations represent placebo and nocebo effects, respectively. Any difference in red vs. yellow-associated stimulations and green- vs. yellow-associated pain ratings were operationally defined as nocebo and placebo effects.

Figure 2:. Behavioral and neural results.

(A) Time course of the VAS pain ratings for each trial for the nocebo (red), control (yellow), and placebo (green) condition. The nocebo (red – yellow) and placebo effect (green – yellow), was larger during the matched trials (left) compared to the mismatched trials (right, Nocebo: F1,968=25.9, p=0.001; Placebo: F1,968=32.3, p<0.001). The mismatch alters placebo and nocebo effects with a reduction of the effect size for both placebo and nocebo effects and an extinction of placebo effects. Data are presented as mean ± sem. (B) Individual VAS pain ratings for nocebo, control, and placebo, for matched (left) and mismatched (right). Each dot represents the condition-specific rating for each participant. (C) At the neural level, the placebo and nocebo changes between the mismatched and matched conditions, were paralleled by the activation of the left inferior parietal cortex, including the supramarginal gyrus and angular gyrus (all mismatched contrast – matched contrast: PFWE = 0.03 (whole brain correction), kE =399, T = 4.59 [−32 −52 34]) X,Y,Z represent Montreal Neurological Institute coordinates; L indicates left side, Bar indicates t values.