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Associations among bipolar II depression white matter subgroups, inflammation, symptoms and childhood maltreatment

Nature Mental Health volume 3, pages 724–734 (2025)Cite this article

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Abstract

Childhood maltreatment has long-term effects on brain structure, inflammation and psychiatric symptoms, yet its impact on white matter (WM) integrity in bipolar disorder type II depression (BDII-D) remains understudied. Here, we investigate WM alterations in BDII-D and their associations with childhood maltreatment, inflammation and psychiatric symptoms. Using TractSeg, we analyzed WM integrity in 146 patients with BDII-D and 151 healthy controls, identifying significantly lower fractional anisotropy (FA) in the corpus callosum, left inferior longitudinal fasciculus and right striato-fronto-orbital tract, alongside higher FA in sensory-motor regions. WM alterations were correlated with inflammatory markers and psychiatric symptoms. Non-negative matrix factorization and clustering analysis revealed two BDII-D subgroups, with one subgroup showing lower corpus callosum FA, higher inflammatory markers, greater childhood emotional maltreatment and psychiatric symptoms. These findings suggest deficits in WM integrity in thalamo-subcortical-cortical and somatosensory areas in BDII-D. Childhood emotional maltreatment may contribute to long-term effects on inflammation and psychiatric symptoms in adulthood BDII-D.

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Fig. 1: The five steps of the study are described.
Fig. 2: TractSeg indicates the difference in FA values between BDII-D and HCs and partial correlations between FA values and inflammatory cytokines, inflammatory indicators and psychiatric symptoms in BDII-D.
Fig. 3: Partial correlation analysis between altered FA values and peripheral inflammatory cytokines and psychiatric symptoms in BDII-D (nBDII-D = 146).
Fig. 4: Childhood maltreatment, inflammatory cytokine and psychiatric symptom differences between subgroups of BDII-D (nsubgroup I = 74, nsubgroup II = 72).

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Data availability

Due to ethical concerns, patient confidentiality and our institutional restrictions, we are unable to publicly share the clinical and image data. However, we confirm that the data will be made available upon reasonable request to the corresponding authors, subject to appropriate ethical and institutional approvals.

Code availability

The code for white matter analysis used in this study was from TractSeg: https://github.com/MIC-DKFZ/TractSeg.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant nos. 82471953 and 82271947 to Z.Y.J.), the 1·3·5 Project for Disciplines of Excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (grant no. 2020HXFH005 to Z.Y.J. and grant no. 2022HXFH029 to C.J.Q.), STI2030-Major Projects (grant no. 2021ZD0200600 to C.J.Q.), the Interdisciplinary Center of Clinical Research of the Medical Faculty Jena (L.C.) and the DZPG (German Center for Mental Health) (FKZ: grant no. 01EE2103 to M.W. and L.C.). We thank all participants for their kind contributions. P.L. was supported by a career development award from the National Institute of Mental Health (K23MH122701). The MRI machine in Supplementary Fig. 1 was drawn using FigDraw. We thank H. Xie, J. Mu and H. Sun for their help with the MRI scan; Y. Li, S. Liu and Y. Ma for their help in recruiting the BDII-D individuals; and S. Guo for laboratory testing of blood samples.

Author information

Author notes

  1. These authors contributed equally: Yuan Cao, Paulo Lizano.

  2. These authors jointly supervised this work: Qiyong Gong, Zhiyun Jia.

Authors and Affiliations

  1. Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, China

    Yuan Cao & Zhiyun Jia

  2. Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany

    Yuan Cao, Meng Li, Lejla Colic, Tara Chand, Nooshin Javaheripour & Martin Walter

  3. Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China

    Yuan Cao, Qiyong Gong & Zhiyun Jia

  4. Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Halle-Jena-Magdeburg, Germany

    Yuan Cao, Meng Li & Martin Walter

  5. Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany

    Yuan Cao, Meng Li & Martin Walter

  6. Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Paulo Lizano

  7. Division of Translational Neuroscience, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Paulo Lizano

  8. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Paulo Lizano

  9. German Center for Mental Health (DZPG) partner site Halle-Jena-Magdeburg, Halle-Jena-Magdeburg, Germany

    Meng Li, Lejla Colic & Martin Walter

  10. Department of Clinical Psychology, Friedrich Schiller University Jena, Jena, Germany

    Tara Chand

  11. Jindal Institute of Behavioural Sciences, O. P. Jindal Global University (Sonipat), Sonipat, India

    Tara Chand

  12. Department of Psychiatry, West China Second University Hospital, Sichuan University, Chengdu, China

    Huan Sun

  13. Mental Health Center, West China Hospital of Sichuan University, Chengdu, China

    Gaoju Deng & Changjian Qiu

  14. Department of Clinical Research Management, West China Hospital of Sichuan University, Chengdu, China

    Xiaoqin Zhou

  15. Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Xipeng Long

  16. Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, China

    Qiyong Gong

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Contributions

Y.C. wrote the first draft of the paper; P.L., M.W. and L.C. edited the paper; Y.C., P. L. and M.W. designed the research; Y.C., M.L., N.J., X.Q.Z. and T.C. analyzed data; Y.C., H.S. and G.J.D. were involved in clinical data collection; Y.C. and X.P.L. participated in MRI scans; P.L., M.W., C.J.Q., Q.Y.G. and Z.Y.J. supervised the study. All authors edited the approved final version of the manuscript.

Corresponding authors

Correspondence to Changjian Qiu, Martin Walter or Zhiyun Jia.

Ethics declarations

Competing interests

M.W. is a member of the advisory boards and gave presentations for the following companies: Boehringer Ingelheim, Germany; Bayer AG, Germany; and Biologische Heilmittel Heel GmbH, Germany. M.W. has further conducted studies with institutional research support from HEEL and from Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with major depression unrelated to this investigation. M.W. has not received any financial compensation from the above-mentioned companies. The other authors declare no competing interests.

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Nature Mental Health thanks Tania Silva and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary methods, results, Tables 1–6 and Figs. 1–4.

Reporting Summary

Supplementary Table 1

Partial correlation analysis between FA values that showed significant differences compared with HCs and inflammatory cytokines in BDII-D.

Supplementary Table 2

Partial correlation analysis between FA values that showed significant differences compared with HCs and indirect inflammatory indicators in BDII-D.

Supplementary Table 3

Partial correlation analysis between FA values that showed significant differences compared with HCs and psychiatric symptoms in BDII-D.

Supplementary Table 4

Partial correlation analysis between significant FA values that showed significant differences compared with HCs and clinical profiles in BDII-D.

Supplementary Table 5

Partial correlation analysis between FA values that showed significant differences compared with HCs and childhood maltreatment in BDII-D.

Supplementary Table 6

Partial correlation analysis between FA values that showed significant differences compared with HCs and childhood maltreatment in HCs.

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Cao, Y., Lizano, P., Li, M. et al. Associations among bipolar II depression white matter subgroups, inflammation, symptoms and childhood maltreatment. Nat. Mental Health 3, 724–734 (2025). https://doi.org/10.1038/s44220-025-00432-4

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