Personalized functional topography–based multisite brain age prediction modeling reveals divergent neurodevelopment in major depression
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (32)
Chenxuan Pang
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University
Xiaoyi Sun
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University
Jianlong Zhao
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University
Xinyuan Liang
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University
Lianglong Sun
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University
Qixiang Lin
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University
Jinrong Sun
Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University
Xiaowen Lu
Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University
Qiangli Dong
Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University
Liang Zhang
Xiaoqin Wang
Dongtao Wei
Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education
Yuan Chen
School of Chemical and Biomolecular Engineering
Bangshan Liu
Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University
Chu-Chung Huang
Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center (East China Normal University), School of Psychology and Cognitive Science, East China Normal University
Yanting Zheng
Department of Radiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine
Yankun Wu
Peking University Sixth Hospital, Peking University Institute of Mental Health, National Health Commission Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University
Taolin Chen
Department of Radiology, Huaxi MR Research Center, Institute of Radiology and Medical Imaging, West China Hospital of Sichuan University
Yuqi Cheng
Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine
Yong He
Department of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University
Lingjiang Li
Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University
Jingliang Cheng
Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University
Qiyong Gong
Department of Radiology, Huaxi MR Research Center, Institute of Radiology and Medical Imaging, West China Hospital of Sichuan University
Ching-Po Lin
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University
Jiang Qiu
Department of Psychology, Zhejiang Normal University
Shijun Qiu
Department of Radiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine
Tianmei Si
Peking University Sixth Hospital, Peking University Institute of Mental Health, National Health Commission Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University
Yanqing Tang
Department of Psychiatry, The First Affiliated Hospital of China Medical University
Fei Wang
Peng Xie
Chongqing Key Laboratory of Neurobiology
Xiufeng Xu
Department of Medicine, Huddinge, Karolinska Institutet
Mingrui Xia
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University