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Clinical Trial
. 2023 Sep;27(8):1023-1035.
doi: 10.1002/ejp.2145. Epub 2023 Jun 21.

Task-dependent functional connectivity of pain is associated with the magnitude of placebo analgesia in pain-free individuals

Nicholas J Bush  1   2 , Jeff Boissoneault  1   2 , Janelle Letzen  2   3 , Roland Staud  2   4 , Michael E Robinson  1   2
Affiliations
Clinical Trial

Task-dependent functional connectivity of pain is associated with the magnitude of placebo analgesia in pain-free individuals

Nicholas J Bush et al. Eur J Pain. 2023 Sep.

Abstract

Background: Task-based functional connectivity (FC) of pain-related regions resulting from expectancy-based placebo induction has yet to be examined, limiting our understanding of regions and networks associated with placebo analgesia.

Methods: Fifty-five healthy pain-free adults over 18 (M = 22.8 years, SD = 7.75) were recruited (65.5% women; 63.6% non-Hispanic/Latino/a/x; 58.2% White). Participants completed a baseline followed by a placebo session involving the topical application of an inactive cream in the context of an expectancy-enhancing instruction set. Noxious heat stimuli were applied to the thenar eminence of the right palm using an fMRI-safe thermode. Stimulus intensity was individually calibrated to produce pain ratings of approximately 40 on a 100-point visual analogue scale.

Results: A total of 67.3% of the participants showed a reduction in pain intensity in the placebo condition with an average reduction in pain across the whole sample of 12.7%. Expected pain intensity was associated with reported pain intensity in the placebo session (b = 0.32, p = 0.004, R2 = 0.15). Voxel-wise analyses indicated seven clusters with significant activation during noxious heat stimulation at baseline (pFDR < 0.05). Generalized psychophysiological interaction analysis suggested that placebo-related FC changes between middle frontal gyrus-superior parietal lobule during noxious stimulation were significantly associated with the magnitude of pain reduction (pFDR < 0.05).

Conclusions: Results suggest that stronger expectancy-based placebo responses might be underpinned by greater FC among attentional and somatosensory regions.

Significance: This article provides support and insight for task-dependent functional connectivity differences related to the magnitude of placebo analgesia. Our findings provide key support that the magnitude of expectation-based placebo response depends on the coupling of regions associated with somatosensory and attentional processing.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to report. This article was prepared while JEL was employed at Johns Hopkins University. She is now employed through the National Institutes of Health. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Figures

Figure 1.
Figure 1.
One sample t-test results where painful stimulation > warm stimulation during the baseline condition
Figure 2.
Figure 2.
One sample t-test results where painful stimulation > warm stimulation during the placebo condition
Figure 3.
Figure 3.
Paired samples t-test results where placebo > baseline for painful stimulation > warm stimulation
Figure 4.
Figure 4.
Left middle frontal gyrus (green; −30, −6, 52) and a significant cluster associated with the left superior parietal lobule (−24, −50, 60) where greater functional connectivity during the placebo condition compared to the baseline was associated with greater percent pain reduction
Figure 5.
Figure 5.
Scatterplot demonstrating the significant gPPI association between change in functional connectivity (placebo – baseline) and percent pain reduction between the left middle frontal gyrus and a cluster predominately located in the left superior parietal lobule.
See this image and copyright information in PMC

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