Cross-Scale Energy Coordination in Brain–Body Systems Supports Cognitive Function Across the Lifespan

Cross-Scale Energy Coordination in Brain–Body Systems Supports Cognitive Function Across the Lifespan | 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 Research Article Cross-Scale Energy Coordination in Brain–Body Systems Supports Cognitive Function Across the Lifespan Diego Lombardo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9279633/v4 This work is licensed under a CC BY 4.0 License Status: Posted Version 4 posted You are reading this latest preprint version Show more versions Abstract Cognitive function is commonly framed as neural information processing and formalized in approaches such as active inference, in which metabolism is typically treated as a constraint on network dynamics rather than as an active component of cognition and physiological regulation. This perspective leaves a conceptual gap, in which whole-body processes—particularly peripheral physiology and energy regulation—are not explicitly incorporated as computational contributors to brain homeostasis and cognitive function. Here, we introduce a unified in silico generative framework that integrates whole-brain network dynamics, autonomic oscillations, and a dynamical energy variable into a single dynamical system, enabling explicit bidirectional coupling between neural activity and metabolic regulation. Within this model, Brain–Body coupling is a system-level metric quantifying the alignment between neural metastability and physiological–metabolic fluctuations, capturing coordination not reflected in standard dynamical measures. Across simulated populations, Brain–Body coupling showed limited direct association with synthetic cognitive outcomes but exerted a consistent indirect influence via energy efficiency. Mediation analyses indicate that energy efficiency partially accounts for the relationship between system-level coordination and a metabolism-dependent cognitive proxy. These effects were absent in null simulations and attenuated for energy-independent control outcomes, supporting the specificity of the observed pathway and identifying energy efficiency as a plausible intermediate variable linking brain–body coordination and cognitive performance in the model. To ensure robustness and reduce circularity, we evaluated multiple independent cognitive formulations, including a prediction-based proxy derived from an external dynamical system that does not incorporate metabolic variables. Results were consistent across formulations. Lifespan simulations further revealed a developmental shift in dominant mechanisms, with predictive dynamics more strongly shaping cognitive structure in early life, and energy-related influences becoming increasingly prominent with age. Collectively, this work provides a unified generative framework linking neural dynamics, physiology, and brain metabolism, and demonstrates that large-scale neural coordination may contribute not only to computation but also to the regulation of metabolic efficiency in coupled brain–body systems. Although based on simulations, the model generates empirically testable hypotheses regarding how energy regulation shapes brain–body coordination and cognitive variability across the lifespan. Computational Neuroscience Brain–body integration Whole-brain modeling Metastability Energy regulation Neurovisceral dynamics Lifespan vulnerability Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SuplementaryMaterialFinal.docx Cite Share Download PDF Status: Posted Version 4 posted You are reading this latest preprint version Show more versions 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9279633","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":630525601,"identity":"9a826bd2-e7d4-49de-b5cb-394b5ab98bd2","order_by":0,"name":"Diego Lombardo","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-1897-0983","institution":"Savoie Mont Blanc University","correspondingAuthor":true,"prefix":"","firstName":"Diego","middleName":"","lastName":"Lombardo","suffix":""}],"badges":[],"createdAt":"2026-03-31 12:12:49","currentVersionCode":4,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9279633/v4","doiUrl":"https://doi.org/10.21203/rs.3.rs-9279633/v4","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109222310,"identity":"d14e5142-3762-469e-88b3-cd54e13eef73","added_by":"auto","created_at":"2026-05-13 21:07:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":665471,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptLombardo2026.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9279633/v4_covered_e4af25a0-e424-4a57-afcf-04c618731dda.pdf"},{"id":109216328,"identity":"31e288de-1ca2-4cbf-98f2-98d3bc8e0c6d","added_by":"auto","created_at":"2026-05-13 18:04:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1467802,"visible":true,"origin":"","legend":"","description":"","filename":"SuplementaryMaterialFinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-9279633/v4/04f25549a4c69be66befd59d.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Cross-Scale Energy Coordination in Brain–Body Systems Supports Cognitive Function Across the Lifespan","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Université Savoie Mont Blanc","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Brain–body integration; Whole-brain modeling; Metastability; Energy regulation; Neurovisceral dynamics; Lifespan vulnerability","lastPublishedDoi":"10.21203/rs.3.rs-9279633/v4","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9279633/v4","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCognitive function is commonly framed as neural information processing and formalized in approaches such as active inference, in which metabolism is typically treated as a constraint on network dynamics rather than as an active component of cognition and physiological regulation. 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