Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging

Abstract

In this study, a well established expectancy manipulation model was combined with a novel placebo intervention, a validated sham acupuncture needle, to investigate the brain network involved in placebo analgesia. Sixteen subjects completed the experiment. We found that after placebo acupuncture treatment, subjective pain rating reduction (pre minus post) on the placebo-treated side was significantly greater than on the control side. When we calculated the contrast that subtracts the functional magnetic resonance imaging (fMRI) signal difference between post-treatment and pretreatment during pain application on placebo side from the same difference on control side [e.g., placebo (post - pre) - control (post - pre)], significant differences were observed in the bilateral rostral anterior cingulate cortex (rACC), lateral prefrontal cortex, right anterior insula, supramarginal gyrus, and left inferior parietal lobule. The simple regression (correlation) analysis between each subject's fMRI signal difference of post-treatment and pretreatment difference on placebo and control side and the corresponding subjective pain rating difference showed that significant negative correlation was observed in the bilateral lateral/orbital prefrontal cortex, rACC, cerebellum, right fusiform, parahippocampus, and pons. These results are different from a previous study that found decreased activity in pain-sensitive regions such as the thalamus, insula, and ACC when comparing the response to noxious stimuli applied to control and placebo cream-treated areas of the skin. Our results suggest that placebo analgesia may be configured through multiple brain pathways and mechanisms.

Figure 1.

Details of experimental procedure. A, In session 2, we used a marker to draw a numbered two-by-three grid on the medial aspect of the right forearm. We placed the thermal probe in one box of the grid for each of the stimulus sequences (e.g., RS and IS). After placebo acupuncture treatment, decreased stimulus temperatures (dIS and dRS), indicated by green color, were applied on the placebo side but not the control side. Thus, after expectancy manipulation, each subject was given an unmistakable experience of analgesia. B, In session 3, subjects were told that session 2 procedures would be repeated during the fMRI scan. However, only the temperatures of the identical sequences were decreased (green) on the treated side after placebo treatment. The four RSs were delivered at the original stimulus temperature without decrease on the same skin areas of the arm as before on both placebo and control sides to test for placebo analgesia. fMRI scans were only collected during each RS. The differences of pretreatment and post-treatment difference in pain rating and fMRI signal change during the four RSs applied on placebo and control sides are the primary outcomes of this study.

Figure 2.

A, fMRI signal changes evoked by all pretreatment high pain minus all pretreatment low pain stimuli applied on both placebo and control side. Brain regions including the bilateral insular/opercular cortices, ACC/MPFC, cerebellum, and brainstem showed activation above threshold (p < 0.005; uncorrected with 20 contiguous voxels). These regions were used as a mask for the following fMRI analysis. B, C, Representative regions revealed by the contrast of the post-treatment and pretreatment difference (post minus pre) on the control side subtracted from the same difference on the placebo side [e.g., placebo (post – pre) – control (post – pre)]. B shows activation in right anterior insula (46, 20, –4), and C shows activation in bilateral rACC (2, 44, 10). The bar graphs show the fMRI contrast estimated β value at peak activation on both sides for both pain levels (mean ± SE). Pre-LOW, Pretreatment low pain; Pre-HIGH, pretreatment high pain; Post-LOW, post-treatment low pain; Post-HIGH, posttreatment high pain; R, right side.