Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional study
Abstract Background Bipolar disorder (BD) is a heterogeneous psychiatric condition characterized by distinct episodes: manic (BipM), depressive (BipD), mixed (mBD), and remission (rBD). Current evidence indicates alterations in brain functional connectivity in BD, yet a comprehensive understanding a...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-025-04277-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849333496157306880 |
|---|---|
| author | Xiaobo Liu Bin Wan Xi-Han Zhang Ruifang Cui Siyu Long Ruiyang Ge Lang Liu Jinming Xiao Zhen-Qi Liu Jiadong Yan Ke Xie Meng Yao Xin Wen Sanwang Wang Yujun Gao |
| author_facet | Xiaobo Liu Bin Wan Xi-Han Zhang Ruifang Cui Siyu Long Ruiyang Ge Lang Liu Jinming Xiao Zhen-Qi Liu Jiadong Yan Ke Xie Meng Yao Xin Wen Sanwang Wang Yujun Gao |
| author_sort | Xiaobo Liu |
| collection | DOAJ |
| description | Abstract Background Bipolar disorder (BD) is a heterogeneous psychiatric condition characterized by distinct episodes: manic (BipM), depressive (BipD), mixed (mBD), and remission (rBD). Current evidence indicates alterations in brain functional connectivity in BD, yet a comprehensive understanding across all episodes remains incomplete. Methods Here, to investigate how different BD episodes alter brain functional organization, we calculated the sensory-association axis using diffusion map embedding on the functional connectome matrix and compared this axis between the four BD groups and neurotypical controls. Then, we employed regression dynamic causal modeling to investigate the directional information flow along the reorganized sensory-association axis across different BD episodes. Furthermore, we applied Nested Spectral Partitioning to decode functional integration and segregation along the same axis. Finally, we compared the reorganization patterns with normative maps of clinical symptomatology, cellular composition, and receptor distribution to elucidate symptom-related and molecular-level associations. Results Compared to healthy controls, we observed sensory region expansion and association region compression in BipM, BipD, and rBD. The mBD showed expanded visual and prefrontal regions but compressed motor and precuneus regions. Analyzing neural information flow revealed reduced connectivity in association regions for BipM and BipD, indicating association dominance in functional reorganization. Conversely, mBD exhibited heightened bidirectional signal flow between sensory and association regions, emphasizing increased integrative processing. Network analyses further revealed increased integration and decreased segregation across unipolar episodes, with the highest integration in mBD. Clinical correlations highlighted that emotional fluctuations primarily related to association region reorganization, suggesting potential biomarkers for mood episode detection. Moreover, these functional reorganizations spatially correlated with serotonin transporter, gamma-aminobutyric acid type A receptor, alpha-4-beta-4 nicotinic acetylcholine receptor, and specific cortical neuron layers (layer 4 and layer 5 excitatory neurons). Conclusions Our findings propose functional reorganization as both a biomarker and a simplified neural phenotype framework for systematically quantifying BD-related neural abnormalities. |
| format | Article |
| id | doaj-art-842c1e12db5340c6bd2172d9cf0ab8a9 |
| institution | Kabale University |
| issn | 1741-7015 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj-art-842c1e12db5340c6bd2172d9cf0ab8a92025-08-20T03:45:49ZengBMCBMC Medicine1741-70152025-08-0123111810.1186/s12916-025-04277-7Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional studyXiaobo Liu0Bin Wan1Xi-Han Zhang2Ruifang Cui3Siyu Long4Ruiyang Ge5Lang Liu6Jinming Xiao7Zhen-Qi Liu8Jiadong Yan9Ke Xie10Meng Yao11Xin Wen12Sanwang Wang13Yujun Gao14Department of Psychiatry, Wuhan Wuchang Hospital, Wuhan University of Science and TechnologyMax Planck Institute for Human Cognitive and Brain SciencesDepartment of Psychology, Yale UniversitySchool of Life Science and Technology, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaMcConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityDepartment of Psychiatry, University of British ColumbiaDepartment of Human Genetics, McGill UniversityDepartment of Psychology, Yale UniversityMcConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityMcConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityMcConnell Brain Imaging Centre, Montreal Neurological Institute, McGill UniversityDepartment of Psychology, Yale UniversitySchool of Software, Taiyuan University of TechnologyDepartment of Psychiatry, Renmin Hospital of Wuhan UniversityDepartment of Psychiatry, Wuhan Wuchang Hospital, Wuhan University of Science and TechnologyAbstract Background Bipolar disorder (BD) is a heterogeneous psychiatric condition characterized by distinct episodes: manic (BipM), depressive (BipD), mixed (mBD), and remission (rBD). Current evidence indicates alterations in brain functional connectivity in BD, yet a comprehensive understanding across all episodes remains incomplete. Methods Here, to investigate how different BD episodes alter brain functional organization, we calculated the sensory-association axis using diffusion map embedding on the functional connectome matrix and compared this axis between the four BD groups and neurotypical controls. Then, we employed regression dynamic causal modeling to investigate the directional information flow along the reorganized sensory-association axis across different BD episodes. Furthermore, we applied Nested Spectral Partitioning to decode functional integration and segregation along the same axis. Finally, we compared the reorganization patterns with normative maps of clinical symptomatology, cellular composition, and receptor distribution to elucidate symptom-related and molecular-level associations. Results Compared to healthy controls, we observed sensory region expansion and association region compression in BipM, BipD, and rBD. The mBD showed expanded visual and prefrontal regions but compressed motor and precuneus regions. Analyzing neural information flow revealed reduced connectivity in association regions for BipM and BipD, indicating association dominance in functional reorganization. Conversely, mBD exhibited heightened bidirectional signal flow between sensory and association regions, emphasizing increased integrative processing. Network analyses further revealed increased integration and decreased segregation across unipolar episodes, with the highest integration in mBD. Clinical correlations highlighted that emotional fluctuations primarily related to association region reorganization, suggesting potential biomarkers for mood episode detection. Moreover, these functional reorganizations spatially correlated with serotonin transporter, gamma-aminobutyric acid type A receptor, alpha-4-beta-4 nicotinic acetylcholine receptor, and specific cortical neuron layers (layer 4 and layer 5 excitatory neurons). Conclusions Our findings propose functional reorganization as both a biomarker and a simplified neural phenotype framework for systematically quantifying BD-related neural abnormalities.https://doi.org/10.1186/s12916-025-04277-7Bipolar disorderEpisode statesFunctional gradientsFunctional integration and segregationSignal flowReceptor and cellular maps |
| spellingShingle | Xiaobo Liu Bin Wan Xi-Han Zhang Ruifang Cui Siyu Long Ruiyang Ge Lang Liu Jinming Xiao Zhen-Qi Liu Jiadong Yan Ke Xie Meng Yao Xin Wen Sanwang Wang Yujun Gao Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional study BMC Medicine Bipolar disorder Episode states Functional gradients Functional integration and segregation Signal flow Receptor and cellular maps |
| title | Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional study |
| title_full | Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional study |
| title_fullStr | Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional study |
| title_full_unstemmed | Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional study |
| title_short | Episode-specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder: a cross-sectional study |
| title_sort | episode specific cortical functional connectome reorganization and neurobiological correlates in bipolar disorder a cross sectional study |
| topic | Bipolar disorder Episode states Functional gradients Functional integration and segregation Signal flow Receptor and cellular maps |
| url | https://doi.org/10.1186/s12916-025-04277-7 |
| work_keys_str_mv | AT xiaoboliu episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT binwan episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT xihanzhang episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT ruifangcui episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT siyulong episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT ruiyangge episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT langliu episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT jinmingxiao episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT zhenqiliu episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT jiadongyan episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT kexie episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT mengyao episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT xinwen episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT sanwangwang episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy AT yujungao episodespecificcorticalfunctionalconnectomereorganizationandneurobiologicalcorrelatesinbipolardisorderacrosssectionalstudy |