Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain.

Gene expression networks associated with placebo effects are understudied; in this study, we identified transcriptomic profiles associated with placebo responsivity. Participants suffering from chronic pain underwent a verbal suggestion and conditioning paradigm with individually tailored thermal painful stimulations to elicit conditioned placebo effects. Participants reported pain intensity on a visual analog scale (VAS) anchored from zero = no pain to 100 = maximum imaginable pain. RNA was extracted from venous blood and RNA sequencing and validation tests were performed to identify differentially expressed genes (DEGs) associated with placebo effects, controlling for sex and level of pain. Unbiased enrichment analyses were performed to identify biological processes associated with placebo effects. Of the 10,700 protein-coding genes that passed quality control filters, 667 were found to be associated with placebo effects (FDR <0.05). Most genes (97%) upregulated were associated with larger placebo effects. The 17 top transcriptome-wide significant genes were further validated via RT-qPCR in an independent cohort of chronic pain participants. Six of them (CCDC85B, FBXL15, HAGH, PI3, SELENOM, and TNFRSF4) showed positive and significant (P < 0.05) correlation with placebo effects in the cohort. The overall DEGs were highly enriched in regulation of expression of SLITs and ROBOs (R-HSA-9010553, FDR = 1.26e-33), metabolism of RNA (R-HSA-8953854, FDR = 1.34e-30), Huntington's disease (hsa05016, FDR = 9.84e-31), and ribosome biogenesis (GO:0042254, FDR = 2.67e-15); alternations in these pathways might jeopardize the proneness to elicit placebo effects. Future studies are needed to replicate this finding and better understand the unique molecular dynamics of people who are more or less affected by pain and placebo.

Neuropsychological mechanisms of observational learning in human placebo effects.

Scientific evidence indicates that placebo effects are psychoneurobiological events involving the contribution of distinct central nervous systems and peripheral physiological mechanisms that influence pain perception and other symptoms. Placebo effects can occur without formal conditioning and direct prior experience because crucial information can be acquired through observational learning. Observation of benefits in another person results in placebo effects of a magnitude like those induced by directly experiencing an analgesic benefit. Understanding the psychological mechanisms of observationally induced placebo effects is a complex and multifaceted endeavor. While previous reviews have highlighted various frameworks and models to understand these phenomena, the underlying biological mechanisms have been overlooked. We summarize critically current understanding of its behavioral and neural mechanisms. Understanding the neural mechanisms of hypoalgesia driven by observation can serve as a foundation for future development of novel theoretical and methodological approaches and ultimately, applications.