Accelerated brain aging in migraine: a multilevel MRI-based brain age modeling study

Abstract Migraine is increasingly recognized as more than just an episodic headache disorder—it often carries a profound burden marked by emotional and cognitive disturbances. Recent insights point toward a possible link between migraine and accelerated brain aging, yet the specific brain regions affected and the clinical implications remain poorly understood. We investigated gray matter-based brain age using voxel-based morphometry in 110 preventive treatment-naïve patients with migraine and 70 healthy controls, based on T1-weighted MRI and a validated brain-age prediction framework trained on data from 1,318 healthy individuals. Compared with controls, patients with migraine exhibited a significantly higher global brain age gap (mean difference = 4.24 years, CI [0.12, 8.36], p = 0.039, ηₚ² = 0.024). Regionally, 66 out of 442 brain parcels—primarily within the prefrontal, frontal, cingulate, parietal, temporal cortices, and amygdala—showed elevated aging patterns. Permutation-based canonical correlation analysis revealed a stable multivariate association between regional brain age deviations and a combination of migraine-related clinical factors (headache frequency, painkiller usage, and depressive symptoms), although individual factor contributions were variable. Functional annotation of the affected regions highlighted their roles in cognitive, emotional, and perceptual processing. Together, these findings reveal that migraine is linked to widespread, regionally patterned brain aging, mirroring the clinical and neurobiological complexity of the disease. This work not only deepens our understanding of migraine’s impact on the brain, but also opens new avenues for exploring how timely intervention might protect brain health in this population.