AbstractBackgroundBipolar disorder (BD) is a highly heritable psychiatric disorder characterized by episodes of manic and depressed mood states, and associated with cortical brain abnormalities. Although the course of BD is often progressive, longitudinal brain imaging studies are scarce. It remains unknown whether brain abnormalities are static traits of BD, or result from pathological changes over time. Moreover, the genetic effect on implicated brain regions remains unknown. MethodsBD patients and healthy controls (HC) underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC) and after six years (90 patients, 61 HC). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between BD and HC across the whole brain. We related our findings to genetic risk for BD, and tested for effects of demographic and clinical variables. ResultsPatients showed abnormal cortical thinning of temporal cortices, and thickness increases in visual/somatosensory brain areas. Thickness increases were related to genetic risk and lithium use. Patients, who experienced (hypo)manic episodes between timepoints revealed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between the diagnostic subtypes I and II. ConclusionsIn the largest longitudinal BD study to date, we detected abnormal cortical changes with high anatomical resolution. We delineated regional effects of clinical symptoms, genetic factors and medication that may explain progressive brain changes in BD. Our study yields important insights into disease mechanisms and suggests that neuroprogression plays a role in BD.