White and gray matter alterations in bipolar I and bipolar II disorder subtypes compared with healthy controls – exploring associations with disease course and polygenic risk
Katharina Thiel, Hannah Lemke, Alexandra Winter, Kira Flinkenflügel, Lena Waltemate, Linda M. Bonnekoh, Dominik Grotegerd, Katharina Dohm, Tim Hahn, Katharina Förster, Philipp Kanske, Jonathan Repple, Nils Opel, Ronny Redlich, Friederike S. David, Andreas J. Forstner, Frederike Stein, Katharina Brosch, Florian Thomas‐Odenthal, Paula Usemann, Lea Teutenberg, Benjamin Straube, Nina Alexander, Hamidreza Jamalabadi, Andreas Jansen, Stephanie H. Witt, Till F. M. Andlauer, Andrea Pfennig, Michael Bauer, Igor Nenadić, Tilo Kircher, Susanne Meinert, Udo Dannlowski
Abstract
Abstract Patients with bipolar disorder (BD) show alterations in both gray matter volume (GMV) and white matter (WM) integrity compared with healthy controls (HC). However, it remains unclear whether the phenotypically distinct BD subtypes (BD-I and BD-II) also exhibit brain structural differences. This study investigated GMV and WM differences between HC, BD-I, and BD-II, along with clinical and genetic associations. N = 73 BD-I, n = 63 BD-II patients and n = 136 matched HC were included. Using voxel-based morphometry and tract-based spatial statistics, main effects of group in GMV and fractional anisotropy (FA) were analyzed. Associations between clinical and genetic features and GMV or FA were calculated using regression models. For FA but not GMV, we found significant differences between groups. BD-I patients showed lower FA compared with BD-II patients ( p tfce-FWE = 0.006), primarily in the anterior corpus callosum. Compared with HC, BD-I patients exhibited lower FA in widespread clusters ( p tfce-FWE < 0.001), including almost all major projection, association, and commissural fiber tracts. BD-II patients also demonstrated lower FA compared with HC, although less pronounced ( p tfce-FWE = 0.049). The results remained unchanged after controlling for clinical and genetic features, for which no independent associations with FA or GMV emerged. Our findings suggest that, at a neurobiological level, BD subtypes may reflect distinct degrees of disease expression, with increasing WM microstructure disruption from BD-II to BD-I. This differential magnitude of microstructural alterations was not clearly linked to clinical and genetic variables. These findings should be considered when discussing the classification of BD subtypes within the spectrum of affective disorders.