Experimental placebo analgesia changes resting-state alpha oscillations

Nathan T M Huneke, Christopher A Brown, Edward Burford, Alison Watson, Nelson J Trujillo-Barreto, Wael El-Deredy, Anthony K P Jones, Nathan T M Huneke, Christopher A Brown, Edward Burford, Alison Watson, Nelson J Trujillo-Barreto, Wael El-Deredy, Anthony K P Jones

Abstract

The lack of clear understanding of the pathophysiology of chronic pain could explain why we currently have only a few effective treatments. Understanding how pain relief is realised during placebo analgesia could help develop improved treatments for chronic pain. Here, we tested whether experimental placebo analgesia was associated with altered resting-state cortical activity in the alpha frequency band of the electroencephalogram (EEG). Alpha oscillations have been shown to be influenced by top-down processes, which are thought to underpin the placebo response. Seventy-three healthy volunteers, split into placebo or control groups, took part in a well-established experimental placebo procedure involving treatment with a sham analgesic cream. We recorded ongoing (resting) EEG activity before, during, and after the sham treatment. We show that resting alpha activity is modified by placebo analgesia. Post-treatment, alpha activity increased significantly in the placebo group only (p < 0.001). Source analysis suggested that this alpha activity might have been generated in medial components of the pain network, including dorsal anterior cingulate cortex, medial prefrontal cortex, and left insula. These changes are consistent with a cognitive state of pain expectancy, a key driver of the placebo analgesic response. The manipulation of alpha activity may therefore present an exciting avenue for the development of treatments that directly alter endogenous processes to better control pain.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Experimental design, behavioral and event-related…
Figure 1. Experimental design, behavioral and event-related potential results.
(a) Summary of the experimental placebo procedure used in the present study. Three blocks of repetitive laser stimulation (pre-conditioning, conditioning, and post-conditioning) were administered to the right forearm. During the pre-conditioning block, the laser stimulation was moderately painful. Prior to the conditioning block, a placebo analgesic cream was applied to the right forearm, over the area of laser stimulation. During the conditioning block, the laser energy was surreptitiously reduced to non-painful levels in the placebo group, to condition participants to believe the cream possessed analgesic properties. Participants in the control group were informed that the laser energy was reduced. Moderately painful laser stimulation was resumed during the post-conditioning block. Four resting EEG recordings were also taken during the procedure (blue) to monitor changes in alpha activity. (b) Topographical map of the scalp. To aid statistical analysis, we averaged the power data across electrodes in nine scalp regions. This gave us one value for alpha power in each region during each recording. Abbreviations: LA, left anterior; LM, left middle; LP, left posterior; CA, central anterior; CM, central middle; CP, central posterior; RA, right anterior; RM, right middle; RP, right posterior. (c) Mask for region of interest analysis. The regions in this mask encompass the bilateral dorsolateral prefrontal cortex (DLPFC) (brodmann areas 9, 10 and 46) and bilateral insulae. (d) Pain reduction from the pre-conditioning block to the post-conditioning block in each group. The plot shows the mean with standard deviation bars of pain reduction in each group. The placebo treatment group demonstrated significantly increased pain reduction compared with the control treatment group (p < 0.001). Points lying outside of the whiskers represent outliers. (e) The changes in alpha power over the course of the procedure. Each value represents alpha power averaged across all electrodes. This has been compared with the average alpha power in recording 1 for each group. In this way, we can see how alpha power has changed from the first recording. The placebo treatment group (blue) demonstrated increased alpha power following conditioning (from recording 3 to recording 4), while alpha power decreased in the control treatment group (green) over the same period. The change in alpha power following conditioning between the placebo and control group differed significantly. (f) Topographic maps of alpha power in recording 4 (R4). Maps are shown of alpha power in each group, and the difference between the groups. Alpha power is in units of 10*log10(µV2/Hz).
Figure 2. Significant sources of alpha activity.
Figure 2. Significant sources of alpha activity.
(a) Contrasts shown are R3-R2 (top) and R4-R3 (bottom) in the healthy placebo (left) and healthy control groups (right). Both groups demonstrated significantly increased activity in the dACC/SMA from R2 to R3. From R3 to R4, alpha activity increased in the bilateral mPFC and left insula in the placebo group, but decreased in the mPFC in the control group. The false discovery rate was q ≤ 0.005. (b) The change in alpha activity in the dACC/SMA from R2 to R3 significantly correlated with expectation of pain relief in the placebo group (r = 0.357, p = 0.022). (c) Correlation between change in alpha power in the left DLPFC from R2 to R3 and the change in alpha in dACC/SMA. (d) Correlation between change in alpha power in the right DLPFC from R2 to R3 and the change in alpha in dACC/SMA. There were a significant positive correlations between change in alpha in the dACC/SMA and in the left and right DLPFC from R2 to R3 (p < 0.001). Abbreviations: R2, recording 2; R3, recording 3; R4, recording 4; DLPFC, dorsolateral prefrontal cortex; dACC, dorsal anterior cingulate cortex; SMA, supplementary motor area; mPFC, medial prefrontal cortex; STG, superior temporal gyrus.

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