Biological subtypes of cognitive impairment in first-episode medication-naïve MDD linking individualized functional connectome, cognition, and symptom

Wenqi Lü; Yuanyuan Li; Ziwei Wang; Yongbo Hu; Xiqin Liu; Xin Yang; Huifang Xu; Haizhen Xu; Chunting Lin; Xiao Jiang; Shan Rao; Rong Ren; Hesheng Liu; Qiyong Gong; Weihong Kuang

doi:10.1016/j.jad.2026.121557

Biological subtypes of cognitive impairment in first-episode medication-naïve MDD linking individualized functional connectome, cognition, and symptom

J Affect Disord. 2026 Jul 1:404:121557. doi: 10.1016/j.jad.2026.121557. Epub 2026 Mar 3.

Authors

Wenqi Lü¹, Yuanyuan Li², Ziwei Wang³, Yongbo Hu⁴, Xiqin Liu², Xin Yang⁵, Huifang Xu⁶, Haizhen Xu⁷, Chunting Lin⁷, Xiao Jiang⁸, Shan Rao⁹, Rong Ren¹⁰, Hesheng Liu¹¹, Qiyong Gong¹², Weihong Kuang¹³

Affiliations

¹ Mental Health Center, West China Hospital of Sichuan University, Chengdu, China; Sleep Medicine Center, West China Hospital of Sichuan University, Chengdu, China.
² Department of Radiology, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China.
³ Department of Clinical Medicine, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
⁴ Department of Radiology, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China; Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, China.
⁵ Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.
⁶ The Fourth People's Hospital of Chengdu, Chengdu, China.
⁷ Mental Health Center, West China Hospital of Sichuan University, Chengdu, China; Department of Radiology, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China.
⁸ Ziyang Psychosis Hospital, Ziyang, China.
⁹ Chengdu Jinxin Mental Diseases Hospital, Chengdu, China.
¹⁰ Sleep Medicine Center, West China Hospital of Sichuan University, Chengdu, China.
¹¹ Changping Laboratory, Science Park Road, Changping District, Beijing, China; Biomedical Pioneering Innovation Center, Peking University, Beijing, China.
¹² Department of Radiology, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, 610041, China; Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, China. Electronic address: qiyonggong@hmrrc.org.cn.
¹³ Mental Health Center, West China Hospital of Sichuan University, Chengdu, China. Electronic address: kwhhlj@scu.edu.cn.

PMID: 41780209
DOI: 10.1016/j.jad.2026.121557

Abstract

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide and exhibits high heterogeneity, particularly in cognitive impairments. Understanding the biological mechanisms underlying cognitive impairment in MDD is crucial for developing individualized treatment.

Methods: This study included 80 first-episode medication-naïve (FEDN) MDD patients and 40 healthy controls (HC). Sparse multiple canonical correlation analysis (smCCA) and K-means clustering were used to identify MDD subtypes based on individualized functional connectivity (FC), cognitive performance, and clinical symptoms.

Results: Two data-driven MDD subtypes were identified: the global impairment subtype (giMDD), characterized by widespread cognitive deficits across memory, processing speed, and executive function; and the memory-specific impairment subtype (miMDD), showing memory-specific impairments. giMDD exhibited unique hyperconnectivity between the dorsal attention network (DAN) and frontoparietal network (FN), and between the ventral attention network (VAN) and FN.

Conclusions: This study highlights the heterogeneity of cognitive impairment in MDD and identifies two data-driven MDD subtypes associated with distinct brain network connectivity patterns. These findings provide insights into the biological mechanisms underlying MDD heterogeneity and offer a potential framework for personalized treatment strategies. Future studies are needed to evaluate the clinical utility of these subtypes in improving individualized care for MDD.

Keywords: Cognition; Individualized functional connectome; Major depressive disorder; Subtype; fMRI.

MeSH terms

Adult
Brain* / diagnostic imaging
Brain* / physiopathology
Cognition* / physiology
Cognitive Dysfunction* / diagnostic imaging
Cognitive Dysfunction* / physiopathology
Connectome*
Executive Function / physiology
Female
Humans
Magnetic Resonance Imaging
Major Depressive Disorder* / classification
Major Depressive Disorder* / complications
Major Depressive Disorder* / diagnostic imaging
Major Depressive Disorder* / physiopathology
Major Depressive Disorder* / psychology
Male
Nerve Net / diagnostic imaging
Nerve Net / physiopathology
Neuropsychological Tests
Young Adult