Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome

Xiaoyi Sun; Jinrong Sun; Xiaowen Lu; Qiangli Dong; Liang Zhang; Wenxu Wang; Jin Liu; Qing Ma; Xiaoqin Wang; Dongtao Wei; Yuan Chen; Bangshan Liu; Chu-Chung Huang; Yanting Zheng; Yankun Wu; Taolin Chen; Yuqi Cheng; Xiufeng Xu; Qiyong Gong; Tianmei Si; Shijun Qiu; Ching-Po Lin; Jingliang Cheng; Yanqing Tang; Fei Wang; Jiang Qiu; Peng Xie; Lingjiang Li; Yong He; DIDA-MDD Working Group; Mingrui Xia

doi:10.1016/j.biopsych.2023.05.021

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome

Biol Psychiatry. 2023 Dec 15;94(12):936-947. doi: 10.1016/j.biopsych.2023.05.021. Epub 2023 Jun 7.

Authors

Xiaoyi Sun¹, Jinrong Sun², Xiaowen Lu³, Qiangli Dong⁴, Liang Zhang⁵, Wenxu Wang⁶, Jin Liu⁷, Qing Ma⁸, Xiaoqin Wang⁹, Dongtao Wei⁹, Yuan Chen¹⁰, Bangshan Liu¹¹, Chu-Chung Huang¹², Yanting Zheng¹³, Yankun Wu¹⁴, Taolin Chen¹⁵, Yuqi Cheng¹⁶, Xiufeng Xu¹⁶, Qiyong Gong¹⁷, Tianmei Si¹⁴, Shijun Qiu¹³, Ching-Po Lin¹⁸, Jingliang Cheng¹⁰, Yanqing Tang¹⁹, Fei Wang¹⁹, Jiang Qiu⁹, Peng Xie²⁰, Lingjiang Li¹¹, Yong He²¹; DIDA-MDD Working Group; Mingrui Xia²²

Collaborators

DIDA-MDD Working Group:
Yong He, Lingjiang Li, Jingliang Cheng, Qiyong Gong, Ching-Po Lin, Jiang Qiu, Shijun Qiu, Tianmei Si, Yanqing Tang, Fei Wang, Peng Xie, Xiufeng Xu, Mingrui Xia

Affiliations

¹ State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China; School of Systems Science, Beijing Normal University, Beijing, China.
² Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Technology Institute of Psychiatry, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China; Affiliated WuTaiShan Hospital of Medical College of Yangzhou University, Yangzhou Mental Health Centre, Yangzhou, China.
³ Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Technology Institute of Psychiatry, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China; Affiliated Wuhan Mental Health Center, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Technology Institute of Psychiatry, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China; Department of Psychiatry, Lanzhou University Second Hospital, Lanzhou, China.
⁵ Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Technology Institute of Psychiatry, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China; Mental Health Education and Counseling Center, Shanghai University of Medicine and Health Sciences, Shanghai, China.
⁶ School of Systems Science, Beijing Normal University, Beijing, China.
⁷ State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.
⁸ State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
⁹ Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China; Department of Psychology, Southwest University, Chongqing, China.
¹⁰ Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹¹ Department of Psychiatry and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Technology Institute of Psychiatry, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China.
¹² Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center, School of Psychology and Cognitive Science, East China Normal University, Shanghai, China.
¹³ Department of Radiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
¹⁴ 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, Beijing, China.
¹⁵ Huaxi Magnetic Resonance Research Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
¹⁶ Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China.
¹⁷ Huaxi Magnetic Resonance Research Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China; Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China.
¹⁸ Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.
¹⁹ Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China.
²⁰ Chongqing Key Laboratory of Neurobiology, Chongqing, China; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
²¹ State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China; Chinese Institute for Brain Research, Beijing, China.
²² State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China. Electronic address: mxia@bnu.edu.cn.

PMID: 37295543
DOI: 10.1016/j.biopsych.2023.05.021

Abstract

Background: Major depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Studies aimed at quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking.

Methods: Leveraging resting-state functional magnetic resonance imaging data from 1148 patients with MDD and 1079 healthy control participants (ages 11-93), we conducted the largest multisite analysis to date for neurophysiological MDD subtyping. First, we characterized typical lifespan trajectories of functional connectivity strength based on the normative model and quantitatively mapped the heterogeneous individual deviations among patients with MDD. Then, we identified neurobiological MDD subtypes using an unsupervised clustering algorithm and evaluated intersite reproducibility. Finally, we validated the subtype differences in baseline clinical variables and longitudinal treatment predictive capacity.

Results: Our findings indicated great intersubject heterogeneity in the spatial distribution and severity of functional connectome deviations among patients with MDD, which inspired the identification of 2 reproducible neurophysiological subtypes. Subtype 1 showed severe deviations, with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and the predictive ability of baseline deviations for antidepressant treatment outcomes.

Conclusions: These findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.

Keywords: Default mode network; Depression; Functional connectivity; Individual differences; Normative model; Resting-state fMRI.

MeSH terms

Adolescent
Adult
Brain / diagnostic imaging
Brain Mapping
Connectome*
Depressive Disorder, Major* / diagnostic imaging
Depressive Disorder, Major* / drug therapy
Humans
Magnetic Resonance Imaging / methods
Reproducibility of Results