Disrupted intrinsic functional brain topology in patients with major depressive disorder

doi:10.1038/s41380-021-01247-2

Multicenter Study

. 2021 Dec;26(12):7363-7371.

doi: 10.1038/s41380-021-01247-2. Epub 2021 Aug 12.

Disrupted intrinsic functional brain topology in patients with major depressive disorder

Hong Yang^#¹, Xiao Chen^#^{2

3

4}, Zuo-Bing Chen^#⁵, Le Li⁶, Xue-Ying Li^{2

7

8}, Francisco Xavier Castellanos^{9

10}, Tong-Jian Bai¹¹, Qi-Jing Bo¹², Jun Cao¹³, Zhi-Kai Chang^{2

3}, Guan-Mao Chen¹⁴, Ning-Xuan Chen^{2

3}, Wei Chen¹⁵, Chang Cheng¹⁶, Yu-Qi Cheng¹⁷, Xi-Long Cui¹⁶, Jia Duan¹⁸, Yiru Fang¹⁹, Qi-Yong Gong^{20

21}, Wen-Bin Guo¹⁶, Zheng-Hua Hou²², Lan Hu¹³, Li Kuang¹³, Feng Li¹², Hui-Xian Li^{2

3}, Kai-Ming Li²⁰, Tao Li^{23

24}, Yan-Song Liu²⁵, Zhe-Ning Liu²⁶, Yi-Cheng Long²⁶, Bin Lu^{2

3}, Qing-Hua Luo¹³, Hua-Qing Meng¹³, Daihui Peng¹⁹, Hai-Tang Qiu¹³, Jiang Qiu²⁷, Yue-Di Shen²⁸, Yu-Shu Shi¹, Tian-Mei Si²⁹, Yan-Qing Tang¹⁸, Chuan-Yue Wang¹², Fei Wang¹⁸, Kai Wang¹¹, Li Wang²⁹, Xiang Wang¹⁶, Ying Wang¹⁴, Yu-Wei Wang^{2

3}, Xiao-Ping Wu³⁰, Xin-Ran Wu²⁷, Chun-Ming Xie³¹, Guang-Rong Xie¹⁶, Hai-Yan Xie³², Peng Xie^{33

34

35}, Xiu-Feng Xu¹⁷, Jian Yang³⁴, Jia-Shu Yao¹⁵, Shu-Qiao Yao¹⁶, Ying-Ying Yin²², Yong-Gui Yuan²², Yu-Feng Zang^{36

37}, Ai-Xia Zhang³⁸, Hong Zhang³⁰, Ke-Rang Zhang³⁸, Lei Zhang³⁹, Zhi-Jun Zhang³¹, Jing-Ping Zhao²⁶, Rubai Zhou¹⁹, Yi-Ting Zhou²⁴, Jun-Juan Zhu⁴⁰, Zhi-Chen Zhu^{2

3}, Chao-Jie Zou¹⁷, Xi-Nian Zuo⁴¹, Chao-Gan Yan^{42

43

44

45}

Affiliations

¹ Department of Radiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
² CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
³ Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
⁴ International Big-Data Center for Depression Research, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
⁵ Department of Rehabilitation Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁶ Center for Cognitive Science of Language, Beijing Language and Culture University, Beijing, China.
⁷ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
⁸ Sino-Danish Center for Education and Research, Beijing, China.
⁹ Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York, NY, USA.
¹⁰ Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
¹¹ Anhui Medical University, Hefei, Anhui, China.
¹² Beijing Anding Hospital, Capital Medical University, Beijing, China.
¹³ Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
¹⁴ The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
¹⁵ Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
¹⁶ The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
¹⁷ First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
¹⁸ Department of Psychiatry, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
¹⁹ Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²⁰ Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
²¹ Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China.
²² Department of Psychosomatics and Psychiatry, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
²³ Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
²⁴ Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
²⁵ Department of Clinical Psychology, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China.
²⁶ The Institute of Mental Health, Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
²⁷ Faculty of Psychology, Southwest University, Chongqing, China.
²⁸ Department of Diagnostics, Affiliated Hospital, Hangzhou Normal University Medical School, Hangzhou, Zhejiang, China.
²⁹ National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
³⁰ Xi'an Central Hospital, Xi'an, Shaanxi, China.
³¹ Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, Jiangsu, China.
³² Department of Psychiatry, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu, Zhejiang, China.
³³ Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
³⁴ Chongqing Key Laboratory of Neurobiology, Chongqing, China.
³⁵ Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³⁶ Center for Cognition and Brain Disorders, Institutes of Psychological Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China.
³⁷ Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, Zhejiang, China.
³⁸ First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
³⁹ Laboratory of Psychological Health and Imaging, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴⁰ Department of Psychiatry, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴¹ State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.
⁴² CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.
⁴³ Department of Psychology, University of Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.
⁴⁴ International Big-Data Center for Depression Research, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.
⁴⁵ Magnetic Resonance Imaging Research Center, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.

^# Contributed equally.

PMID: 34385597
PMCID: PMC8873016
DOI: 10.1038/s41380-021-01247-2

Multicenter Study

Disrupted intrinsic functional brain topology in patients with major depressive disorder

Hong Yang et al. Mol Psychiatry. 2021 Dec.

. 2021 Dec;26(12):7363-7371.

doi: 10.1038/s41380-021-01247-2. Epub 2021 Aug 12.

Authors

Affiliations

¹ Department of Radiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
² CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
³ Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
⁴ International Big-Data Center for Depression Research, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
⁵ Department of Rehabilitation Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁶ Center for Cognitive Science of Language, Beijing Language and Culture University, Beijing, China.
⁷ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
⁸ Sino-Danish Center for Education and Research, Beijing, China.
⁹ Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York, NY, USA.
¹⁰ Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
¹¹ Anhui Medical University, Hefei, Anhui, China.
¹² Beijing Anding Hospital, Capital Medical University, Beijing, China.
¹³ Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
¹⁴ The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
¹⁵ Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
¹⁶ The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
¹⁷ First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
¹⁸ Department of Psychiatry, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
¹⁹ Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²⁰ Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
²¹ Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China.
²² Department of Psychosomatics and Psychiatry, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
²³ Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
²⁴ Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
²⁵ Department of Clinical Psychology, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China.
²⁶ The Institute of Mental Health, Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
²⁷ Faculty of Psychology, Southwest University, Chongqing, China.
²⁸ Department of Diagnostics, Affiliated Hospital, Hangzhou Normal University Medical School, Hangzhou, Zhejiang, China.
²⁹ National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
³⁰ Xi'an Central Hospital, Xi'an, Shaanxi, China.
³¹ Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, Jiangsu, China.
³² Department of Psychiatry, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu, Zhejiang, China.
³³ Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
³⁴ Chongqing Key Laboratory of Neurobiology, Chongqing, China.
³⁵ Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³⁶ Center for Cognition and Brain Disorders, Institutes of Psychological Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China.
³⁷ Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, Zhejiang, China.
³⁸ First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
³⁹ Laboratory of Psychological Health and Imaging, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴⁰ Department of Psychiatry, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴¹ State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.
⁴² CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.
⁴³ Department of Psychology, University of Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.
⁴⁴ International Big-Data Center for Depression Research, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.
⁴⁵ Magnetic Resonance Imaging Research Center, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. ycg.yan@gmail.com.

^# Contributed equally.

PMID: 34385597
PMCID: PMC8873016
DOI: 10.1038/s41380-021-01247-2

Abstract

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Group differences in network topological properties between major depressive disorder (MDD) patients and normal controls (NCs).**
a Violin plots illustrating the area under the curve (AUC) parameters of the global efficiency (E_glob) and local efficiency (E_loc) for MDD patients and NCs. Means and standard deviations are depicted. b E_glob and E_loc across a density range between 10% and 34%. Each point and error bar denote the mean and standard deviation at each density level, respectively. Asterisks indicate a significant difference at this density threshold. c Group differences in efficiency, degree and betweenness at the nodal level. Insignificant nodes are shown as green spheres, whereas blue (MDD < NC) and red (MDD > NC) spheres denote significant differences after FDR correction. The size of the significant nodes reflects the effect sizes of group differences. **: p < 0.01.

**Fig. 2. Subgroup differences in network topological properties (efficiency, E_glob, and local efficiency, E_loc).**
Distributions of areas under the curve (AUCs) are depicted. a First episode drug naïve (FEDN) patients with major depressive disorder (MDD) vs. normal controls (NCs). b Patients with recurrent MDD vs. NCs. c recurrent patients with MDD vs. FEDN patients. **: p < 0.01, ***: p < 0.001.

**Fig. 3. Subgroup differences in efficiency, degree and betweenness at the nodal level.**
Nonsignificant nodes are shown as green spheres. Blue (a: FEDN < NC; b: recurrent MDD < NC; c: recurrent MDD < FEDN) and red (a: FEDN > NC; b: recurrent MDD > NC; c: recurrent MDD > FEDN) spheres denote significant differences after FDR correction. The sizes of the significant nodes reflect the effect sizes of group differences. NC normal control, FEDN first-episode drug naïve.

**Fig. 4. L_p and C_p differences between major depressive disorder (MDD) patients and normal controls (NCs) as well as subgroup contrasts.**
Distributions of areas under the curve (AUCs) are depicted. a MDD vs. NCs. b First-episode drug naïve (FEDN) patients with major depressive disorder (MDD) vs. normal controls (NCs). c Patients with recurrent MDD vs. NCs. d patients with recurrent MDD vs. FEDN patients. *: p < 0.05, **: p < 0.01, ***: p < 0.001.

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References

1. Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:11. - PMC - PubMed
1. Sharp LK, Lipsky MS. Screening for depression across the lifespan: a review of measures for use in primary care settings. Am Fam Phys. 2002;66:1001–8. - PubMed
1. Battle DE. Diagnostic and statistical manual of mental disorders (DSM) Codas. 2013;25:191–2. - PubMed
1. Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry. 2015;72:603–11. - PMC - PubMed
1. Mulders PC, van Eijndhoven PF, Schene AH, Beckmann CF, Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review. Neurosci Biobehav Rev. 2015;56:330–44. - PubMed

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[1] Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:11. - PMC - PubMed

[2] Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:11. - PMC - PubMed

[3] Sharp LK, Lipsky MS. Screening for depression across the lifespan: a review of measures for use in primary care settings. Am Fam Phys. 2002;66:1001–8. - PubMed

[4] Sharp LK, Lipsky MS. Screening for depression across the lifespan: a review of measures for use in primary care settings. Am Fam Phys. 2002;66:1001–8. - PubMed

[5] Battle DE. Diagnostic and statistical manual of mental disorders (DSM) Codas. 2013;25:191–2. - PubMed

[6] Battle DE. Diagnostic and statistical manual of mental disorders (DSM) Codas. 2013;25:191–2. - PubMed

[7] Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry. 2015;72:603–11. - PMC - PubMed

[8] Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry. 2015;72:603–11. - PMC - PubMed

[9] Mulders PC, van Eijndhoven PF, Schene AH, Beckmann CF, Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review. Neurosci Biobehav Rev. 2015;56:330–44. - PubMed

[10] Mulders PC, van Eijndhoven PF, Schene AH, Beckmann CF, Tendolkar I. Resting-state functional connectivity in major depressive disorder: a review. Neurosci Biobehav Rev. 2015;56:330–44. - PubMed

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Disrupted intrinsic functional brain topology in patients with major depressive disorder

Affiliations

Disrupted intrinsic functional brain topology in patients with major depressive disorder

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