A glial-mitochondrial axis in bipolar disorder: in vivo MRI signatures and lithium-associated attenuation

Bipolar disorder (BD) is associated with widespread white matter microstructural alterations, yet their cellular and metabolic underpinnings remain poorly understood. Here, we asked whether in vivo magnetic resonance imaging (MRI) signatures of BD spatially align with the distribution of glial and mitochondrial cell populations, whether these patterns are specific to BD across the affective-psychotic spectrum, and whether lithium attenuates them. In individuals with BD (n = 104), major depressive disorder (MDD; n = 135), and psychotic disorders (PY; n = 87) from the UK Biobank, each matched to healthy controls, we mapped multimodal MRI alterations (radial diffusivity [RD], fractional anisotropy [FA], voxel-based morphometry [VBM]) onto reference maps of five glial cell types and six mitochondrial markers. BD showed a reproducible spatial alignment between elevated radial diffusivity and glial-rich regions (astrocytes, microglia, endothelial cells, oligodendrocyte precursors), together with a separable alignment between regional gray-matter loss and mitochondrial respiratory capacity. Across diagnostic groups, psychotic disorders partially shared the glial signature but lacked the mitochondrial one, while MDD diverged on both, supporting a degree of BD specificity for the combined glial-mitochondrial pattern. Within BD, lithium-treated patients showed an attenuation of glial alignment most prominently for astrocytes and oligodendrocyte precursors, consistent with a glial mechanism of lithium action. While effect magnitudes were modest, as is typical for cross-modal spatial alignment studies, they were consistent across markers and modalities. The findings identify glial-mitochondrial coupling as a tractable cellular axis in BD pathophysiology and point to glial pathways as a candidate substrate for lithium's therapeutic effect.