Microstructural–functional coupling as a multimodal biomarker of emotional state transitions in bipolar disorder

Bipolar disorder (BD) is characterized by dynamic transitions between depressive and manic states, yet the neural mechanisms underlying these state shifts remain unclear. Here, we developed an integrative framework to quantify the microstructural–functional coupling (MFC) of the brain, which captures the distributional similarity between voxel-wise diffusion and functional features within each cortical region. Using multimodal MRI data from 72 BD patients and 65 matched healthy controls, we observed a global increase of MFC of BD, which indicates a de-similarity of brain microstructure and function. Partial least squares correlation (PLSC) analysis revealed that the principal latent component linking MFC to behavioral scores explained 67.2% of the variance, with the strongest contributions from the control and somatosensory networks. Mediation analysis demonstrated that regional MFC influenced anxiety indirectly through depressive symptoms, supporting a sequential affective transition from depression to anxiety. Moreover, macroscale gradient analysis showed that the principal MFC gradient was significantly correlated with neurotransmitter receptor distributions, including α4β2, 5-HT1B, and H3. Together, these findings highlight MFC as a multimodal biomarker sensitive to emotional state transitions in BD and suggest its potential as a bridge between microstructural alterations, functional dynamics, and neurotransmitter systems.