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Peer-reviewedCC BYBiology of sex differences

Sex differences in symptom-specific brain abnormalities across disease stages in depression.

  • Xiaoqin Wang1
  • Yi Xia1
  • Junchen Bao1
  • Ciqing Bao2
  • Rui Yan1
  • Zhijian Yao3,4,5
  • Qing Lu6,7
7 affiliations
  1. 1Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China.
  2. 2Wenzhou Seventh People's Hospital, Wenzhou, 325006, China.
  3. 3Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China. [email protected].
  4. 4Nanjing Brain Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Nanjing, 210029, China. [email protected].
  5. 5School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, 210096, China. [email protected].
  6. 6School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, 210096, China. [email protected].
  7. 7Child Development and Learning Science, Key Laboratory of Ministry of Education, Nanjing, China. [email protected].
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Abstract

Background

The incidence and clinical manifestations of major depressive disorder (MDD) differ between sexes. This implies distinct neuropathological mechanisms. This study aimed to investigate sex-specific brain patterns in MDD by stratifying patients according to both sex and disease course.Methods

We recruited 1170 participants (811 MDD patients and 359 healthy controls) who underwent T1-weighted and resting-state functional magnetic resonance imaging. We explored duration-stage-related, sex-specific differences in gray matter (GM), amplitude of low-frequency fluctuation (ALFF), and structural-functional coupling. We also used the structural covariance network (SCN) to assess morphological connectivity reorganization. Finally, we explored the relationship between key brain measures derived from the preceding multimodal analyses and clinical features.Results

GM abnormalities in both sexes were observed first appeared in areas supporting sensorimotor and interoceptive functions, and later extended to areas involved in cognitive and emotional processing. Critically, we found distinct sex-specific epicentres of pathology. In male patients, the right postcentral gyrus (PoCG) exhibited early GM atrophy and decreased betweenness centrality within the SCN. In female patients, the left inferior temporal gyrus (ITG) showed early GM atrophy, increased degree centrality within the SCN, reduced ALFF values, and a two-stage evolution of structural-functional coupling with a transition lasting 3 years. Clinically, GM volumes of the right PoCG in male patients were negatively associated with insomnia-early, genital symptoms, and weight loss, while in female patients, GM volumes of the left ITG were negatively associated with depressed mood, work and interest, and psychic anxiety.Conclusions

This study shows a sex-specific neuropathological origin in MDD, with the left ITG serving as the core pathological area in females and the right PoCG in males. These conclusions not only advance our insight into the sex-dependent mechanisms underlying MDD but also provide a stage-informed framework for individualized interventions, suggesting that the early years of the disease may be a critical period for structure-targeted therapies.

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Cite

BibTeXRIS
BibTeX
@article{wang2026differences,
  title = {{Sex differences in symptom-specific brain abnormalities across disease stages in depression.}},
  author = {Xiaoqin Wang and Yi Xia and Junchen Bao and Ciqing Bao and Rui Yan and Zhijian Yao and Qing Lu},
  journal = {Biology of sex differences},
  year = {2026},
  month = aug,
  doi = {10.1186/s13293-026-00964-z},
  url = {https://europepmc.org/article/MED/42968183},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Sex differences in symptom-specific brain abnormalities across disease stages in depression.
AU  - Xiaoqin Wang
AU  - Yi Xia
AU  - Junchen Bao
AU  - Ciqing Bao
AU  - Rui Yan
AU  - Zhijian Yao
AU  - Qing Lu
PY  - 2026
DA  - 2026/08/04
JO  - Biology of sex differences
DO  - 10.1186/s13293-026-00964-z
UR  - https://europepmc.org/article/MED/42968183
AB  - Background  The incidence and clinical manifestations of major depressive disorder (MDD) differ between sexes. This implies distinct neuropathological mechanisms. This study aimed to investigate sex-specific brain patterns in MDD by stratifying patients according to both sex and disease course.Methods  We recruited 1170 participants (811 MDD patients and 359 healthy controls) who underwent T1-weighted and resting-state functional magnetic resonance imaging. We explored duration-stage-related, sex-specific differences in gray matter (GM), amplitude of low-frequency fluctuation (ALFF), and structural-functional coupling. We also used the structural covariance network (SCN) to assess morphological connectivity reorganization. Finally, we explored the relationship between key brain measures derived from the preceding multimodal analyses and clinical features.Results  GM abnormalities in both sexes were observed first appeared in areas supporting sensorimotor and interoceptive functions, and later extended to areas involved in cognitive and emotional processing. Critically, we found distinct sex-specific epicentres of pathology. In male patients, the right postcentral gyrus (PoCG) exhibited early GM atrophy and decreased betweenness centrality within the SCN. In female patients, the left inferior temporal gyrus (ITG) showed early GM atrophy, increased degree centrality within the SCN, reduced ALFF values, and a two-stage evolution of structural-functional coupling with a transition lasting 3 years. Clinically, GM volumes of the right PoCG in male patients were negatively associated with insomnia-early, genital symptoms, and weight loss, while in female patients, GM volumes of the left ITG were negatively associated with depressed mood, work and interest, and psychic anxiety.Conclusions  This study shows a sex-specific neuropathological origin in MDD, with the left ITG serving as the core pathological area in females and the right PoCG in males. These conclusions not only advance our insight into the sex-dependent mechanisms underlying MDD but also provide a stage-informed framework for individualized interventions, suggesting that the early years of the disease may be a critical period for structure-targeted therapies.
SN  - 2042-6410
ER  -