Functional Reorganization across Three Episodes in Bipolar Disorder

Bipolar disorder (BD) is a heterogeneous psychiatric condition encompassing various episode states, including manic (BipM), depressive (BipD), mixed (mBD), and remission (rBD). Cumulative evidence has revealed that few BD episodes exhibit brain functional connectome changes; however, these findings remain fragmentary, and a systematic understanding of these functional alterations among all episodes is still lacking. Here, we firstly aimed to investigate how these episodes are differentially represented along the sensory-association axis, which constitutes the primary functional organization spectrum of the human cortex. We found expansion in sensory regions with compression in association regions in BipM, BipD and rBD as well as expansion in visual regions and prefrontal regions, compression motor regions, and precuneus regions for mBD compared to healthy controls. By examining outward and inward activity propagation in association regions, we observed less frequent flows in BipM and BipD, clarifying that association may be dominant in functional reorganization. mBD showed more frequent inward flows than other episodes in both sensory and associations, emphasizing information exchange between these two anchors. By evaluating the network integration and segregation, we observed an increase in functional integration alongside a decrease in functional segregation for unipolar episodes and the greatest functional integration for mBD. Furthermore, clinical relevance analysis suggests that emotional changes were mainly related to association functional reorganization, which may be used as specific and sensitive biomarkers to detect mood changes in different episodes. Finally, the episode representations were spatially correlated with distribution of serotonin transporter, gamma-aminobutyric acid type A receptor, Alpha-4-Beta-4 nicotinic acetylcholine receptor, layer 4 and layer 5 excitatory neurons. This study demonstrates functional reorganization as a biomarker as well as a uniform and simplified framework of neural phenotype to quantify mental abnormality of different BD episodes systematically.