Abstract Background Chronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI (fMRI) has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, fMRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response. Methods Here, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) to investigate whether neurotransmission-enriched functional connectivity (FC) mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. Chronic knee osteoarthritis (OA) pain patients (n=56) underwent pre-treatment brain scans in two clinical trials. Study 1 ( n =17) was a 2-week single-blinded placebo pill trial. Study 2 ( n =39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor. Results Across two independent studies, we found that chronic pain OA patients present FC alterations in the FC related to the serotonin (SERT) and noradrenaline (NET) transporters, when compared to age-matched healthy controls. Placebo responders presented with higher pre-treatment dopamine transporter (DAT)-enriched FC than non-responders. Duloxetine responders presented with higher pre-treatment SERT and NET-enriched FC than non-responders. Pre-treatment SERT and NET-enriched FC achieved predictive positive values of duloxetine response up to 85.71%. Conclusion Neurotransmission-enriched FC mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.

A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain