Personalized functional topography–based multisite brain age prediction modeling reveals divergent neurodevelopment in major depression

Major depressive disorder (MDD) is associated with widespread alterations in functional brain networks across the lifespan. However, heterogeneity in atypical brain development among patients with MDD remains largely uncharacterized. Using a multisite resting-state functional MRI dataset consisting of 1,105 MDD patients and 1,065 healthy controls, we constructed a harmonized multicenter brain age prediction model based on individualized functional topography and identified two patient subgroups with positive or negative brain age gaps (BAGs). In patients with a positive BAG (BAG+), expansion of the salience network (SAL) into the dorsolateral prefrontal and ventrolateral prefrontal cortices, in addition to contraction of the sensorimotor and dorsal attention networks (DAN), contributes to accelerated brain aging. Conversely, in the negative BAG (BAG-) group, SAL expansion into the orbitofrontal cortex (OFC) and contraction of the visual and sensorimotor networks (SMN) were linked to delayed brain development. These subgroups also exhibited distinct neurodevelopmental trajectories. Clinically, BAG+ patients showed stronger associations between higher-order network topography and mood symptoms, whereas BAG- patients exhibited links between visual/default mode network topography and insomnia. At the molecular level, both groups showed enrichment of genes related to synaptic signaling but displayed distinct expression patterns and divergent expression trajectories in key neurodevelopmental gene sets. Notably, antidepressant treatment modulated the brain in ways that were specific to each subgroup. These findings reveal heterogeneous neurodevelopmental profiles in MDD with distinct biological and clinical signatures, offering insights into personalized precision medicine for this disorder.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-03-11
DOI
https://doi.org/10.1073/pnas.2519586123
Primary Topic
Functional Brain Connectivity Studies
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article
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article

Personalized functional topography–based multisite brain age prediction modeling reveals divergent neurodevelopment in major depression

Yao Cheng, Min Xia, Taolin Chen, BangShan Liu et al.
Proceedings of the National Academy of Sciences
Functional Brain Connectivity Studies
article

Personalized functional topography–based multisite brain age prediction modeling reveals divergent neurodevelopment in major depression

Yao Cheng, Min Xia, Taolin Chen, BangShan Liu, Senhui Qiu, Xin Sun, Jianlong Zhao, Qixiang Lin, Xinyuan Liang, Chenxuan Pang, Xiaowen Lu, Yankun Wu, DIDA-MDD Working Group, Qiangli Dong, Dongtao Wei, Fei Wang, Yong He, Yuan Chen, Chu-Chung Huang, Lianglong Sun, Jiang Qiu, Lingjiang Li, Tianmei Si, Jinrong Sun, Qiyong Gong, Xiufeng Xu, Peng Xie, Yanqing Tang, Liang Zhang, Yanting Zheng, Ching-Po Lin, Jingliang Cheng, Xiaoqin Wang
article en

Abstract

Major depressive disorder (MDD) is associated with widespread alterations in functional brain networks across the lifespan. However, heterogeneity in atypical brain development among patients with MDD remains largely uncharacterized. Using a multisite resting-state functional MRI dataset consisting of 1,105 MDD patients and 1,065 healthy controls, we constructed a harmonized multicenter brain age prediction model based on individualized functional topography and identified two patient subgroups with positive or negative brain age gaps (BAGs). In patients with a positive BAG (BAG+), expansion of the salience network (SAL) into the dorsolateral prefrontal and ventrolateral prefrontal cortices, in addition to contraction of the sensorimotor and dorsal attention networks (DAN), contributes to accelerated brain aging. Conversely, in the negative BAG (BAG-) group, SAL expansion into the orbitofrontal cortex (OFC) and contraction of the visual and sensorimotor networks (SMN) were linked to delayed brain development. These subgroups also exhibited distinct neurodevelopmental trajectories. Clinically, BAG+ patients showed stronger associations between higher-order network topography and mood symptoms, whereas BAG- patients exhibited links between visual/default mode network topography and insomnia. At the molecular level, both groups showed enrichment of genes related to synaptic signaling but displayed distinct expression patterns and divergent expression trajectories in key neurodevelopmental gene sets. Notably, antidepressant treatment modulated the brain in ways that were specific to each subgroup. These findings reveal heterogeneous neurodevelopmental profiles in MDD with distinct biological and clinical signatures, offering insights into personalized precision medicine for this disorder.

Proceedings of the National Academy of SciencesVol. 123(11)
Central South University (CN), Southwest University (CN), McGovern Institute for Brain Research (US), National Yang Ming Chiao Tung University (TW), Xiamen University (CN), Peking University (CN), Sichuan University (CN), Fudan University (CN), Beijing Normal University (CN), Kunming Medical University (CN), First Affiliated Hospital of Xiamen University (CN), West China Hospital of Sichuan University (CN), First Affiliated Hospital of Guangzhou University of Chinese Medicine (CN), Chinese Institute for Brain Research (CN), Taipei City Hospital (TW), First Affiliated Hospital of Kunming Medical University (CN), Lanzhou University Second Hospital (CN), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Hangzhou Seventh Peoples Hospital (CN), Shanghai University of Medicine and Health Sciences (CN), Northern Jiangsu People's Hospital (CN), Second Xiangya Hospital of Central South University (CN), First Affiliated Hospital of Zhengzhou University (CN), National Institute of Mental Health (US), Hunan Institute of Mental Health (CN), Peking University Sixth Hospital (CN), Shanghai Center for Brain Science and Brain-Inspired Technology (CN), Huazhong University of Science and Technology (CN), East China Normal University (CN), Lanzhou University (CN), Yangzhou University (CN), Chongqing Medical University (CN), China Medical University (CN)
Openalex Percentile: Top 29%
Functional Brain Connectivity Studies
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