Functional Reorganization across Three Episodes in Bipolar Disorder

Bipolar disorder (BD) is characterized by a dynamic process encompassing various episode states, including manic episodes (BipM), depressive episodes (BipD), and periods of remission (rBD). Various cognitive and behavioral alterations induced by extreme emotions are implicated across different episodes. However, how exactly brain function is reorganized during these episodes remains largely unstudied. Here, we used low-dimensional representations of brain functions to study the functional organization in individuals with BipM, BipD, rBD, and healthy controls (HC). We found that similar sensory-association reorganization principle across all three episodes, compared to healthy controls. In particular, expansion in sensory regions and compression in association regions were the key principles for reorganization of low-dimensional representation of brain function in BD. Furthermore, such large-scale hierarchical functional reorganization was associated with clinical symptoms at different episodes. Next, this study also implemented regional outward and inward activity propagation to study the information flow in the altered regions. It revealed that all the three episodes had less frequent flows in association regions, clarifying association may be dominant in functional reorganization. By applying a network integration-segregation model, we also observed an increase in functional integration alongside a decrease in functional segregation. Finally, various receptors that were spatially correlated with the episode t-maps including serotonin transporter, gamma-aminobutyric acid type A receptor, Alpha-4-Beta-4 nicotinic acetylcholine receptor, and cell profiles including Layer 4 and Layer 5 thick-tufted cells. This study demonstrates that association-dominated binary functional hierarchical anchors could systematically elucidate abnormal neural phenotypes across various BD states.