Inflammation is associated with altered functional connectivity of the cingulate cortex in individuals with subthreshold depression.

Overview

1. Medical Imaging Center, First Affiliated Hospital of Jinan University, Guangzhou, China
2. Institute of Molecular and Functional Imaging, Jinan University, Guangzhou, China
3. Department of Public Health and Preventive Medicine, School of Basic Medicine, Jinan University, Guangzhou, China
4. Division of Medical Psychology and Behavior Science, School of Basic Medicine, Jinan University, Guangzhou, China

Abstract

Subthreshold depression (StD) represents a critical prodromal phase that often precedes clinical depression. Identifying biological indicators during this stage is essential for the prophylaxis of major depressive disorder. The present study investigated the interplay between serum pro-inflammatory cytokines, functional connectivity (FC) within subregions of the cingulate cortex (CC), and psychometric profiles in an StD cohort. The study included 126 participants with StD and 104 healthy controls. Resting-state functional magnetic resonance imaging data, psychological assessments [Center for Epidemiologic Studies Depression Scale (CES-D), 24-item Hamilton Depression Rating Scale (HAMD-24), Hamilton Anxiety Scale (HAMA), Ruminative Responses Scale (RRS)], and serum pro-inflammatory cytokine levels [tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and IL-17] were collected. The StD group exhibited increased FC in three specific circuits: The left middle CC (MCC) to the bilateral caudate nucleus (CN); the left supracallosal anterior CC (supACC) to the bilateral anterior cerebellar lobe; the right supACC to the right superior frontal gyrus (SFG). Furthermore, serum concentrations of TNF-α, IL-1β, and IL-17 were significantly increased. FC between the left MCC and bilateral CN was associated with CES-D and RRS scores, whereas FC between the right supACC and right SFG was associated with HAMA scores. Interaction between IL-1β and FC in the right supACC-SFG circuit was independently associated with HAMA scores, whereas interaction between IL-17 and FC in the same circuit independently predicted RRS scores. The statistical interaction between IL-1β and IL-17 levels and right supACC-SFG FC is associated with anxiety and rumination symptoms in StD, which may indicate an increased risk of progression to major depression. These findings underscore the significance of neuroimmune associations in subthreshold depression.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:32688009, at figshare; found in “Data Availability”

Data Availability

All de-identified demographic data, cytokine measurement data, and key preprocessed fMRI functional connectivity values supporting the findings of this study are fully available without restriction. De-identified participant-level data (demographics, education years, cytokine concentrations, and key functional connectivity values extracted from significant clusters) have been deposited as Supporting Information S2_File_Clinical_Cytokine_Data accompanying this manuscript. Clinical scale data (CES-D, HAMD, HAMA, RRS) are not included in the public dataset as they contain sensitive psychological information. These data are available upon reasonable request from the IRB of Jinan University (Email: ), subject to IRB review and a signed data use agreement. Whole-brain preprocessed fMRI functional connectivity maps (in NIfTI format, 2,300 files for 10 seeds × 230 participants) are publicly available at Figshare (DOI: [10.6084/m9.figshare.32688009]). Raw DICOM-format fMRI data are not publicly available due to privacy and ethical restrictions concerning neuroimaging data. All data will be retained for a minimum of 10 years following publication.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 4 funders, 63 references.

Cite

This paper

Qi, Z., Chen, P., Chen, G., Luo, Z., Zhang, S., Jiang, L., Tang, G., Huang, L., Tao, Q., & Wang, Y. (2026). Inflammation is associated with altered functional connectivity of the cingulate cortex in individuals with subthreshold depression. PLOS digital health, 5(9), e0001665. https://doi.org/10.1371/journal.pdig.0001665

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