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

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 (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.