{ "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. Author summary: Subthreshold depression (StD) is a common early stage of depression, marked by low mood and anxiety that fall short of a full diagnosis. People with StD are at higher risk of developing major depression, yet we lack simple biological signs to identify this early stage and guide prevention. In this study, we combined brain imaging with blood-based markers to investigate how brain function and inflammation relate to StD symptoms. We studied 126 young adults with StD and 104 healthy volunteers. Using resting-state brain scans, we measured communication between brain regions in the cingulate cortex, an area important for mood and thinking. We also measured four immune signaling molecules (pro-inflammatory cytokines) in the blood. Compared with healthy volunteers, the StD group showed stronger connections between the cingulate cortex and three brain regions involved in emotion and self-control, together with higher blood levels of three cytokines. Notably, the combined effect of two key cytokines (IL-1beta and IL-17) and altered brain connectivity predicted anxiety and repetitive negative thinking (rumination) in StD. These results link immune changes to early brain alterations in depression and point to a neuroimmune signature that could help identify people at risk and support early, digital-health-based prevention.", "abstract_shown": true, "affiliations": [ "Medical Imaging Center, First Affiliated Hospital of Jinan University, Guangzhou, China", "Institute of Molecular and Functional Imaging, Jinan University, Guangzhou, China", "Department of Public Health and Preventive Medicine, School of Basic Medicine, Jinan University, Guangzhou, China", "Division of Medical Psychology and Behavior Science, School of Basic Medicine, Jinan University, Guangzhou, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 10, "authors": [ { "affs": [ 0 ], "name": "Zhangzhang Qi" }, { "affs": [ 1 ], "name": "Pan Chen" }, { "affs": [ 2 ], "name": "Guanmao Chen" }, { "affs": [ 3 ], "name": "Zhenye Luo" }, { "name": "Shu Zhang" }, { "name": "Lijun Jiang" }, { "name": "Guixian Tang" }, { "name": "Li Huang" }, { "name": "Qian Tao" }, { "name": "Ying Wang" } ], "bibtex": "https://research.draconitic.com/paper/avr4ygk9a1pzs.bib", "cited_by": 0, "doi": "10.1371/journal.pdig.0001665", "fulltext_url": "https://journals.plos.org/digitalhealth/article?id=10.1371/journal.pdig.0001665", "id": "avr4ygk9a1pzs", "issns": [ "2767-3170" ], "landing_url": "https://journals.plos.org/digitalhealth/article?id=10.1371/journal.pdig.0001665", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2805|Functional Brain Connectivity Studies" ], [ "plos", "/Biology and life sciences/Anatomy/Brain/Cingulate cortex" ], [ "plos", "/Biology and life sciences/Developmental biology/Molecular development/Cytokines" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Biology and life sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Biology and life sciences/Neuroscience/Cognitive science/Cognition" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Cytokines" ], [ "plos", "/Biology and life sciences/Psychology" ], [ "plos", "/Biology and life sciences/Psychology/Emotions" ], [ "plos", "/Biology and life sciences/Psychology/Emotions/Anxiety" ], [ "plos", "/Medicine and health sciences/Anatomy/Brain/Cingulate cortex" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Medicine and health sciences/Mental health and psychiatry/Mood disorders/Depression" ], [ "plos", "/Social sciences/Psychology" ], [ "plos", "/Social sciences/Psychology/Emotions" ], [ "plos", "/Social sciences/Psychology/Emotions/Anxiety" ] ], "openalex": "W7213473002", "pdf_url": "https://journals.plos.org/digitalhealth/article/file?id=10.1371/journal.pdig.0001665&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-17", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/avr4ygk9a1pzs.ris", "sources": [ { "first_seen": "2026-10-30T12:17:49Z", "native_id": "10.1371/journal.pdig.0001665", "source": "plos", "url": "https://journals.plos.org/digitalhealth/article?id=10.1371/journal.pdig.0001665" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Inflammation is associated with altered functional connectivity of the cingulate cortex in individuals with subthreshold depression", "title_text": "Inflammation is associated with altered functional connectivity of the cingulate cortex in individuals with subthreshold depression", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:49Z", "url": "https://research.draconitic.com/paper/avr4ygk9a1pzs", "venue": "PLOS Digital Health", "versions": [] }