Mendelian Randomization Analysis Reveal the Role of Circulating Inflammatory Proteins in Mediating Functional Brain Networks and Peripheral Neuropathic Pain Effects.

Objective: The perception of pain is thought to arise from the integration of information between multiple brain regions. Data from observational studies indicates that dysfunction of brain resting-state functional networks is present in a wide range of peripheral neuropathic pain (pNP). The present study thus sought to investigate whether a causal relationship exists and to determine the potential mediating role of circulating inflammatory proteins in this association.

Methods: The resting-state functional magnetic imaging phenotype is defined as a stable feature that quantifies the pattern of functional connectivity (i.e., synchronized activity) between different regions of the brain in the resting state of an individual. We gathered publicly available genome-wide association study (GWAS) summary statistics for brain functional networks, including 191 rsfMRI phenotypes and postherpetic neuralgia (PHN) and trigeminal neuralgia (TN) in the FinnGen biobank. Furthermore, data were collected on genetic variation related to inflammation, including 91 circulating inflammatory proteins. We performed two-sample MR analysis to investigate the causal effects of functional brain networks on PHN and TN. To explore the possible mediation of inflammatory factor changes between rsfMRI phenotypes and PHN and TN.

Results: The forward MR approach identifies five rs-fMRI phenotypes that are causally associated with the risk of developing PHN. For instance, enhanced motor network connectivity was found to be associated with a reduced risk of PHN. Six rsfMRI phenotypes were identified as causally associated with TN risk. These brain network phenotypes mainly involve the default mode network (DMN), the sensory-motor network (SMN), and the motor network, etc. Two-step MR-mediated analysis revealed that the inflammatory protein interleukin 20 receptor alpha (IL-20RA) is a mediator of the pathway from the phenotype Pheno 12 of the brain motor network to PHN.

Conclusion: The findings provide valuable insights into potential targets for disease intervention and treatment at the level of functional brain networks.