Reduced Cortical Surface Area in the Frontal Operculum as a Causal Risk Predictor for Chronic Pain

Chronic pain is a prevalent and debilitating condition that imposes substantial personal and societal burdens. Despite its significance, the neural mechanisms underlying individual susceptibility to chronic pain remain inadequately understood. In this study, we examined the prospective associations between 1325 brain structural imaging phenotypes and the future risk of developing chronic pain in a UK Biobank cohort of 5754-5756 participants. These phenotypes encompassed regional and tissue volume, cortical surface area and thickness. General linear models (GLMs) were employed to identify brain structural variations associated with the risk of developing chronic pain, and then Mendelian randomization (MR) was employed to explore potential causal relationships between brain structure and chronic pain development. GLMs identified three significant associations between imaging phenotypes and the future development of chronic pain. All three imaging phenotypes pertained to the cortical surface area of the frontal operculum, albeit derived from three different brain atlases. Specifically, reduced cortical surface area in the frontal operculum was significantly associated with an increased risk of developing chronic pain: BA atlas area 44 (T=-4.10, p=4.24 × 10^-5), Desikan atlas pars opercularis (T=-4.21, p=2.55 × 10^-5), and DKT atlas pars opercularis (T=-3.96, p=7.47 × 10^-5). Subsequent MR analysis further demonstrated a causally protective effect of larger cortical area in the prefrontal operculum against the risk of developing chronic pain (OR = 0.91, p=1.91 × 10^-2). These results indicate a critical role of the surface area of frontal operculum in individual chronic pain susceptibility and provide a potential risk predictor for chronic pain development.