Clinical pain increased with older brain age, yet placebo effects were preserved

Chronic pain is linked to accelerated brain aging, often measured through the brain-age gap (BAG), the difference between chronological age and neuroimaging-derived brain age. Whether endogenous pain modulation declines with brain aging remains unknown. We tested this in participants with temporomandibular disorder (TMD) in a cross-sectional study with 84 TMD participants and 84 age- and sex-matched healthy controls (HCs) from the Cambridge Centre for Ageing and Neuroscience database. Temporomandibular disorder participants completed the Graded Chronic Pain Scale and a placebo procedure combining verbal suggestion and classical conditioning. We estimated brain age using machine-learning and deep-learning approaches: a previously published Gaussian process regression (GPR) model trained on cortical thickness features, and a convolutional neural network (CNN) trained end-to-end on T1-weighted volumes. The brain-age gap was calculated as the difference between the estimated brain age and chronological age. Using both GPR and CNN models, we found that TMD participants exhibited an older estimated brain age compared with HCs. Higher estimated brain age was associated with greater pain severity and statistically mediated the link between chronological age and pain severity. In addition, the CNN model suggested that older brain age was associated with greater pain interference and a higher likelihood of experiencing high-impact pain, controlling for sex and race. However, neither estimated brain age nor BAG influenced the magnitude of placebo effects. These findings suggest that while older brain age is associated with greater chronic pain severity and interference, placebo effects remain robust despite age-related changes in the brain, highlighting the therapeutic potential of placebo effects for older adults living with chronic pain.