Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder
Abstract Major depressive disorder (MDD) is a devastating mental disorder characterized by considerable clinical and biological heterogeneity. While comparable clinical symptoms may represent a common pathological endpoint, it is conceivable that distinct neurophysiological mechanisms underlie their...
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Nature Publishing Group
2025-06-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03413-4 |
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| author | Qi Liu Xinqi Zhou Chunmei Lan Xiaolei Xu Yuanshu Chen Taolin Chen Jinhui Wang Bo Zhou Dezhong Yao Keith M. Kendrick Benjamin Becker Weihua Zhao |
| author_facet | Qi Liu Xinqi Zhou Chunmei Lan Xiaolei Xu Yuanshu Chen Taolin Chen Jinhui Wang Bo Zhou Dezhong Yao Keith M. Kendrick Benjamin Becker Weihua Zhao |
| author_sort | Qi Liu |
| collection | DOAJ |
| description | Abstract Major depressive disorder (MDD) is a devastating mental disorder characterized by considerable clinical and biological heterogeneity. While comparable clinical symptoms may represent a common pathological endpoint, it is conceivable that distinct neurophysiological mechanisms underlie their manifestation. In this study, both static and model-based dynamic functional connectivity were employed as predictive variables in the normative model to map multilevel functional developmental trajectories and determined clusters of distinguishable MDD subgroups in a large multi-site resting fMRI dataset of 2428 participants (healthy controls: N = 1128; MDD: N = 1300). An independent cohort of 72 participants (healthy controls: N = 35; MDD: N = 37) with both resting fMRI and task-based fMRI data was utilized to validate the identified MDD subtypes and explore subtype-specific task-based neural representations. Our findings indicated brain-wide, interpatient heterogeneous multilevel brain functional deviations in MDD. We identified two distinct and reproducible MDD subtypes, exhibiting comparable severity of clinical symptoms but opposing patterns of multilevel functional deviations. Specifically, MDD subtype 1 displayed positive deviations in the frontoparietal and default mode networks, coupled with negative deviations in the occipital and sensorimotor networks. Conversely, MDD subtype 2 exhibited a significantly contrasting deviation pattern. Additionally, we found that these two identified MDD subtypes exhibited different neural representations during empathic processing, while the subtypes did not differ during implicit face processing. These findings underscore the neurobiological complexity of MDD and highlights the need for a multifaceted approach to diagnosis and treatment that can be tailored specifically to individual subtypes, facilitating personalized and more effective interventions for individuals with MDD. |
| format | Article |
| id | doaj-art-e29fd806378f46aa812911b3c06240c3 |
| institution | DOAJ |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-e29fd806378f46aa812911b3c06240c32025-08-20T03:21:02ZengNature Publishing GroupTranslational Psychiatry2158-31882025-06-0115111210.1038/s41398-025-03413-4Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorderQi Liu0Xinqi Zhou1Chunmei Lan2Xiaolei Xu3Yuanshu Chen4Taolin Chen5Jinhui Wang6Bo Zhou7Dezhong Yao8Keith M. Kendrick9Benjamin Becker10Weihua Zhao11The Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaInstitute of Brain and Psychological Sciences, Sichuan Normal UniversitySchool of Sport Training, Chengdu Sport UniversitySchool of Psychology, Shandong Normal UniversityInstitute of Brain and Psychological Sciences, Sichuan Normal UniversityDepartment of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityInstitute for Brain Research and Rehabilitation, South China Normal UniversityThe Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaThe Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for NeuroInformation, School of Life Science and Technology, University of Electronic Science and Technology of ChinaThe Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for NeuroInformation, School of Life Science and Technology, University of Electronic Science and Technology of ChinaThe Department of Psychology, The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong KongThe Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaAbstract Major depressive disorder (MDD) is a devastating mental disorder characterized by considerable clinical and biological heterogeneity. While comparable clinical symptoms may represent a common pathological endpoint, it is conceivable that distinct neurophysiological mechanisms underlie their manifestation. In this study, both static and model-based dynamic functional connectivity were employed as predictive variables in the normative model to map multilevel functional developmental trajectories and determined clusters of distinguishable MDD subgroups in a large multi-site resting fMRI dataset of 2428 participants (healthy controls: N = 1128; MDD: N = 1300). An independent cohort of 72 participants (healthy controls: N = 35; MDD: N = 37) with both resting fMRI and task-based fMRI data was utilized to validate the identified MDD subtypes and explore subtype-specific task-based neural representations. Our findings indicated brain-wide, interpatient heterogeneous multilevel brain functional deviations in MDD. We identified two distinct and reproducible MDD subtypes, exhibiting comparable severity of clinical symptoms but opposing patterns of multilevel functional deviations. Specifically, MDD subtype 1 displayed positive deviations in the frontoparietal and default mode networks, coupled with negative deviations in the occipital and sensorimotor networks. Conversely, MDD subtype 2 exhibited a significantly contrasting deviation pattern. Additionally, we found that these two identified MDD subtypes exhibited different neural representations during empathic processing, while the subtypes did not differ during implicit face processing. These findings underscore the neurobiological complexity of MDD and highlights the need for a multifaceted approach to diagnosis and treatment that can be tailored specifically to individual subtypes, facilitating personalized and more effective interventions for individuals with MDD.https://doi.org/10.1038/s41398-025-03413-4 |
| spellingShingle | Qi Liu Xinqi Zhou Chunmei Lan Xiaolei Xu Yuanshu Chen Taolin Chen Jinhui Wang Bo Zhou Dezhong Yao Keith M. Kendrick Benjamin Becker Weihua Zhao Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder Translational Psychiatry |
| title | Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder |
| title_full | Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder |
| title_fullStr | Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder |
| title_full_unstemmed | Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder |
| title_short | Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder |
| title_sort | multilevel brain functional connectivity and task based representations explaining heterogeneity in major depressive disorder |
| url | https://doi.org/10.1038/s41398-025-03413-4 |
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