Chronic Sleep Deprivation as a Neuroinflammatory Trigger: Clinical Evidence and Theoretical Framework for the Peripheral-Central Amplification Loop

Chronic Sleep Deprivation as a Neuroinflammatory Trigger: Clinical Evidence and Theoretical Framework for the Peripheral-Central Amplification Loop | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Chronic Sleep Deprivation as a Neuroinflammatory Trigger: Clinical Evidence and Theoretical Framework for the Peripheral-Central Amplification Loop qun liang, han liu, xin cai, Rui Fan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8070202/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Background: Over 2.5 billion people worldwide are affected by chronic sleep deprivation, but there is no integrated theoretical framework explaining how it induces neuroinflammation. Current research is limited to single pathway analyses and does not explain the nature of sleep deprivation as a trigger for multi-system dysregulation. Methods: Systematic retrieval of adult clinical studies from 2015 to 2025, including participants with ≥24 hours of sleep deprivation, ≥2 inflammatory biomarkers, and cognitive assessment; data pooled on a logarithmic scale and converted to odds ratios, reporting 95% confidence intervals and τ²-based prediction intervals. Results: A total of 42 studies (n = 3,847) were included in the analysis. The cumulative sample size across these studies reached 53,847 participants.Chronic deprivation (defined as a minimum of three nights and less than five hours of sleep per night) was found to be significantly correlated with increased levels of IL-6 (2.42-fold increase, 95% CI 2.11–2.73, PI 1.35–4.10), TNF-α (1.89-fold increase, 1.67–2.11, PI 1.20–2.95), and CRP (1.76-fold increase, 1.59–1.93, PI 1.20–2.55). The peak of inflammation occurred on days 3–5, after which it transitioned to a self-sustaining state. The systemic immune-inflammatory index demonstrated a negative correlation with cognition (r = −0.61, P < 0.001). Furthermore, Hartung-Knapp adjustments and sensitivity analyses supported the robustness of the findings. Conclusions : Sleep deprivation establishes a self-sustaining loop via peripheral activation-blood-brain barrier disruption-glial response, consistent with PCAL. Three falsifiable predictions and a 72-hour intervention window are proposed, pointing towards combined circadian-sleep trials with ‘peripheral-central inflammatory phase convergence’ as primary endpoint. Biological sciences/Neuroscience/Circadian rhythms and sleep/Sleep deprivation Biological sciences/Immunology/Innate immunity Biological sciences/Neuroscience/Circadian rhythms and sleep/Sleep Health sciences/Neurology Chronic sleep deprivation Neuroinflammation PCAL Blood–brain barrier Microglia NLRP3 IL-6 TNF-α Cognition Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8070202","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":543215388,"identity":"b7f74ced-3c1d-42ee-8418-e8db11fb7367","order_by":0,"name":"qun liang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACPmYog429geEAUVrYYFr4eA4QqwXGkJNIINJhbOzMzx5+KTucxyb5/OHhghoGeX4xApaxMbOZG8ucO1zMJp1jcHjGMQbDmbMJWAf0i5m0ZNvhxDbpHIbDPGwMCQa3CWph/wbRInn8wWGef0Rp4TGT/AjSIsFgcJi3jTgtZdIM59IT23iAfuHtkyDsF37+49skf5RZJ85vP/74M883G3l+aQJaQICZBx47DBKElYMA4w82wopGwSgYBaNgBAMAdY46mVl8nPUAAAAASUVORK5CYII=","orcid":"","institution":"First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China","correspondingAuthor":true,"prefix":"","firstName":"qun","middleName":"","lastName":"liang","suffix":""},{"id":543215389,"identity":"f63392a4-88ed-4377-b014-3c41abd7121f","order_by":1,"name":"han liu","email":"","orcid":"","institution":"university college london","correspondingAuthor":false,"prefix":"","firstName":"han","middleName":"","lastName":"liu","suffix":""},{"id":543215390,"identity":"838f1831-2aa6-4d59-9c25-ea1ae42b59f6","order_by":2,"name":"xin cai","email":"","orcid":"","institution":"First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China","correspondingAuthor":false,"prefix":"","firstName":"xin","middleName":"","lastName":"cai","suffix":""},{"id":543215391,"identity":"177fc6f2-9c38-4ac6-acdb-1bd293171566","order_by":3,"name":"Rui Fan","email":"","orcid":"","institution":"First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Fan","suffix":""}],"badges":[],"createdAt":"2025-11-09 16:00:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8070202/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8070202/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102295164,"identity":"0b58bc12-7b20-4c9b-83b1-fd0a6ca266fc","added_by":"auto","created_at":"2026-02-10 10:09:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":859549,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscripttitle.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8070202/v1_covered_358d167e-5e74-42b2-b29f-10be28c10baa.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Chronic Sleep Deprivation as a Neuroinflammatory Trigger: Clinical Evidence and Theoretical Framework for the Peripheral-Central Amplification Loop","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Chronic sleep deprivation, Neuroinflammation, PCAL, Blood–brain barrier, Microglia, NLRP3, IL-6, TNF-α, Cognition","lastPublishedDoi":"10.21203/rs.3.rs-8070202/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8070202/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Over 2.5 billion people worldwide are affected by chronic sleep deprivation, but there is no integrated theoretical framework explaining how it induces neuroinflammation. Current research is limited to single pathway analyses and does not explain the nature of sleep deprivation as a trigger for multi-system dysregulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Systematic retrieval of adult clinical studies from 2015 to 2025, including participants with ≥24 hours of sleep deprivation, ≥2 inflammatory biomarkers, and cognitive assessment; data pooled on a logarithmic scale and converted to odds ratios, reporting 95% confidence intervals and τ²-based prediction intervals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 42 studies (n = 3,847) were included in the analysis. The cumulative sample size across these studies reached 53,847 participants.Chronic deprivation (defined as a minimum of three nights and less than five hours of sleep per night) was found to be significantly correlated with increased levels of IL-6 (2.42-fold increase, 95% CI 2.11–2.73, PI 1.35–4.10), TNF-α (1.89-fold increase, 1.67–2.11, PI 1.20–2.95), and CRP (1.76-fold increase, 1.59–1.93, PI 1.20–2.55). The peak of inflammation occurred on days 3–5, after which it transitioned to a self-sustaining state. The systemic immune-inflammatory index demonstrated a negative correlation with cognition (r = −0.61, P \u0026lt; 0.001). Furthermore, Hartung-Knapp adjustments and sensitivity analyses supported the robustness of the findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Sleep deprivation establishes a self-sustaining loop via peripheral activation-blood-brain barrier disruption-glial response, consistent with PCAL. Three falsifiable predictions and a 72-hour intervention window are proposed, pointing towards combined circadian-sleep trials with ‘peripheral-central inflammatory phase convergence’ as primary endpoint.\u003c/p\u003e","manuscriptTitle":"Chronic Sleep Deprivation as a Neuroinflammatory Trigger: Clinical Evidence and Theoretical Framework for the Peripheral-Central Amplification Loop","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-05 16:06:40","doi":"10.21203/rs.3.rs-8070202/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fb2f1eff-bfab-4829-b662-fd1194285126","owner":[],"postedDate":"February 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":57788644,"name":"Biological sciences/Neuroscience/Circadian rhythms and sleep/Sleep deprivation"},{"id":57788645,"name":"Biological sciences/Immunology/Innate immunity"},{"id":57788646,"name":"Biological sciences/Neuroscience/Circadian rhythms and sleep/Sleep"},{"id":57788647,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2026-02-05T16:06:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-05 16:06:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8070202","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8070202","identity":"rs-8070202","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}