White Matter Microstructure in Individuals With and At Risk for Bipolar Disorder: Evidence for an Endophenotype From a Voxel-Based Meta-analysis

BACKGROUND: Aberrant white matter (WM) microstructure has been proposed as a mechanism underlying bipolar disorder (BD). Given the strong genetic underpinnings of both WM microstructure and BD, such WM aberrations may be not only a disease marker, but also an endophenotype of BD. If so, they should be observable in individuals at risk for BD (AR) (i.e., first-degree relatives). This meta-analysis integrates evidence on perturbed WM microstructure in individuals with or at risk for BD. METHODS: A comprehensive search of literature published through April 2020 identified diffusion tensor imaging studies that used a voxel-based approach to compare fractional anisotropy (FA) and radial diffusivity between individuals with BD and/or AR individuals and healthy volunteers. Effect size comparison and conjunction analysis allowed identification of endophenotypes and disease markers of BD. Effects of age, sex, mood state, and psychotropic medication were explored using meta-regressions. RESULTS: We included 57 studies in individuals with BD (N = 4631) and 10 in AR individuals (N = 753). Both individuals with and at risk for BD were associated with lower FA in the body and splenium of the corpus callosum. In the BD group, decreased FA and increased radial diffusivity comprised the entire corpus callosum, anterior thalamic radiation, fronto-orbito-polar tracts, and superior longitudinal fasciculus, and were influenced by age, sex, and mood state. Studies with higher proportions of individuals taking lithium or antipsychotics reported smaller FA reductions in BD. CONCLUSIONS: Findings suggest that abnormalities in the body and splenium of the corpus callosum may be an endophenotype for BD, and they associate BD with WM tracts relevant for working memory performance, attention, and reward processing.