Abstract
Neuroimaging has revealed that major depression is underpinned by dysfunctional brain networks, with symptom variability stemming from altered interactions within and between brain regions. While the effect of depression severity is well-studied, the effect of depression duration (chronicity) is relatively neglected, despite its clinical significance. This study examined how severity, chronicity, and their interaction affect brain network connectivity and grey matter volume. Forty-six patients (31 females, mean age 40.5) were assessed using whole-brain network modeling and voxel-based morphometry (VBM). Severity was measured via the Hamilton Depression Rating Scale, and chronicity was defined as an episode lasting over 24 months. The key finding was that chronicity moderated the impact of severity on functional connectivity between the Central Executive Network (CEN) and the precuneus (part of the Default Mode Network, DMN). Chronic versus non-chronic patients showed opposite patterns. Non-chronic patients showed stronger CEN-Default Mode Precuneus connectivity at low severity and weaker at high severity; chronic patients showed the reverse. This study reveals a novel impact of chronicity on CEN-DMN interactions, a neglected moderator of brain-symptom severity correlations in depression.
Data availability
Owing to the ethically sensitive nature of the research, supporting data cannot be made openly available. Anonymized data can be provided upon reasonable request from Dr. Andre Brunoni (e-mail Andre.russowskybrunoni@utsouthwestern.edu) .
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Funding
This study was supported by a FAPESP grant (2012/20911-5) and by the NIHR Oxford Health Biomedical Research Centre (NIHR203316). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. TZ is a recipient of FAPESP grants 2020/03235-2 and 2022/09688-4. PHRS is a recipient of FAPESP grants 22/03266-0 and 23/13893-5. JOS is a Sir Henry Dale Fellow funded by the Royal Society and the Wellcome Trust (215451/Z/19/Z). The Oxford University Centre for Integrative Neuroimaging (OxCIN) was supported by Wellcome Trust funding between 2017 and 2025 [203139/Z/16/Z and 203139/A/16/Z], during which time it was known as WIN (Wellcome Centre for Integrative Neuroimaging). ELECT-TDCS funding: Sao Paulo Research State Foundation (FAPESP) and others. Registration: ClinicalTrials.gov NCT01894815.
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TZ, PS, ARB, JOS: conceptualization, data curation, formal analysis, investigation, methodology, software, validation, visualization, writing—original draft preparation, writing—review and editing. LBR, PHRS: methodology, data acquisition, writing—review and editing.
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Zanao, T., Salvan, P., B. Razza, L. et al. Chronicity moderates the impact of severity on central executive-default mode network functional interactions in depression. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40364-2
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DOI: https://doi.org/10.1038/s41598-026-40364-2