Unraveling the neural underpinnings of major depressive disorder and pain: A mendelian randomization study and mediation analysis.

Major depressive disorder (MDD) frequently co-occurs with chronic pain, yet the underlying biological mechanisms remain unclear. This study employed a two-sample bidirectional mendelian randomization (MR) design to investigate the causal relationship between MDD and nine prevalent pain phenotypes, focusing on the mediating role of macro- and micro-structural brain changes. We selected 57 brain regions as potential mediators based on prior literature and performed a two-step MR mediation analysis, using multiple methods (IVW, MR-Egger, weighted median, MR-RAPS) to ensure robustness. Results showed MDD had a causal effect on all pain phenotypes (all pFDR < 0.05) with no reverse causality. MDD specifically reduced gray matter volume (GMV) in the right insular cortex (pFDR = 0.02), with no significant effects in other regions. This GMV in the right insular cortex reduction mediated approximately 13.89% of MDD's total effect on temporomandibular disorder (TMD)-related pain, although the direct association between right insular GMV and TMD-related pain did not survive multiple-testing correction (pFDR = 0.07). These findings provide evidence for a unidirectional causal link from MDD to pain and suggest right insular cortex GMV may be a partial mediator for TMD-related pain, highlighting a potential therapeutic target for MDD-related pain conditions.