The Two Sides of Placebo Analgesia: Differential Functional Connectivity Reveals Mechanisms of Placebo Analgesic Response

Nicholas J Bush,1,2 Adriana K Cushnie,2 Jeff Boissoneault,1,2 Sharmagh Aghabeigi,1 Casey Alexander,1 Roland Staud,3 Michael E Robinson1 1Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, USA; 2Department of Anesthesiology, University of Minnesota - Twin Cities, Minneapolis, MN, USA; 3Department of Medicine, University of Florida, Gainesville, FL, USACorrespondence: Nicholas J Bush, Department of Anesthesiology, University of Minnesota, Minneapolis, MN, 55414, USA, Tel +1 612-624-7357, Email [email protected]: Previous research has demonstrated that placebo induction manipulations can reduce an individual’s pain through non-specific mechanisms, such as expectancy manipulations. However, despite robust research characterizing these effects, individual differences in predicting placebo analgesic responses are not well understood.Methods: Fifty-four healthy pain-free adults over 18 (M=22.8, SD=7.82) were recruited (66.7% women). Participants completed a baseline followed by a placebo session involving the application of an inactive cream in the context of an expectancy-enhancing instruction set while undergoing a functional magnetic resonance imaging scan (fMRI). Painful heat stimuli were applied to the thenar eminence of the right palm. Stimulus intensity was individually calibrated to produce pain ratings of approximately 40 on a 100-point visual analog scale. Generalized psychophysiological interaction (gPPI) was used to assess the group differences in functional connectivity during painful stimulation compared to warmth stimulation.Results: About 68.5% showed a reduction in pain in the placebo condition with an average decrease of 30.3%. Non-responders showed an increase in pain in the placebo condition, with an average increase of 18.6%. Repeated measures ANOVA demonstrated a significant within-subjects interaction between expectancy and responder type (F(1,49)=4.27, p=0.04, ηp2=0.08). Expected pain was significantly associated with pain in the placebo session for the responders (b=0.37, R2=0.29, p< 0.001), but not for the non-responders (b=0.11, R2=0.04, p=0.42). gPPI analysis revealed three clusters exhibiting greater increases in FC in areas related to attention and sensory integration in placebo responders compared to non-responders. One cluster was identified where greater increases in functional connectivity were associated with non-responders compared to responders in regions associated with attention and motor processing.Conclusion: Our results provide evidence that responders and non-responders have differential behavioral and functional responses to acute pain during a placebo analgesic task.Keywords: placebo analgesia, placebo, responder, placebo non-responder, pain, functional connectivity