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

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, R 2 = 0.15). Voxel‐wise analyses indicated seven clusters with significant activation during noxious heat stimulation at baseline ( p FDR < 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 ( p FDR < 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.