{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:26:10Z","timestamp":1787199970218,"version":"build-2736575974"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Medical education traditionally presents physiological regulation through homeostatic feedback loops\u2014reactive mechanisms that correct deviations from set points. More recently, allostatic models have emphasized the brain\u2019s anticipatory role in regulation. However, presenting these frameworks as competing paradigms creates conceptual confusion for learners. This paper proposes a unified, three-tiered model of physiological regulation that positions reflexive, homeostatic, and predictive mechanisms as complementary systems operating across different timescales. Tier 1 encompasses local reflexive responses providing millisecond-to-second protection. Tier 2 comprises systemic homeostatic feedback maintaining core variables over minutes to hours. Tier 3 involves brain-centered predictive regulation integrating cognition, emotion, and context to anticipate demands. Critically, these tiers interact hierarchically: reflexive mechanisms provide immediate protective boundaries, homeostatic systems coordinate whole-body stability, and predictive processes adjust regulatory set points in anticipation of future needs. In turn, reflexive and homeostatic mechanisms constrain predictive regulation within biological limits. This hierarchical framework provides medical educators with coherent scaffolding for teaching regulation and prepares students to understand how psychological and contextual factors influence health outcomes.<\/jats:p>","DOI":"10.3389\/fphys.2026.1817927","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:16:29Z","timestamp":1787199389000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating reflex, feedback, and prediction: a tiered model of physiological regulation for contemporary medical education"],"prefix":"10.3389","volume":"17","author":[{"given":"Changiz","family":"Mohiyeddini","sequence":"first","affiliation":[{"name":"Michael Garron Hospital, Toronto East Health Network","place":["Toronto, ON, Canada"]},{"name":"Department of Family and Community Medicine, Temerty Faculty of Medicine, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzan","family":"Kamel-ElSayed","sequence":"additional","affiliation":[{"name":"Department of Foundational Medical Studies, Oakland University William Beaumont School of Medicine","place":["Rochester, MI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1146\/annurev.neuro.28.061604.135709","article-title":"An integrative theory of locus coeruleus\u2013norepinephrine function: Adaptive gain and optimal performance","volume":"28","author":"Aston-Jones","year":"2005","journal-title":"Annu. Rev. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"307","DOI":"10.2165\/00007256-200434050-00003","article-title":"Effects of exercise, diet and weight loss on high blood pressure","volume":"34","author":"Bacon","year":"2004","journal-title":"Sports Med."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.611550","article-title":"Network physiology of exercise: vision and perspectives","volume":"11","author":"Balagu\u00e9","year":"2020","journal-title":"Front. Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"139","DOI":"10.3109\/09540261.2014.911149","article-title":"Circadian misalignment and health","volume":"26","author":"Baron","year":"2014","journal-title":"Int. Rev. Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrn3950","article-title":"Interoceptive predictions in the brain","volume":"16","author":"Barrett","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/j.neuron.2014.10.023","article-title":"Placebo effects: From the neurobiological paradigm to translational implications","volume":"84","author":"Benedetti","year":"2014","journal-title":"Neuron"},{"key":"B7","doi-asserted-by":"publisher","first-page":"S186","DOI":"10.1016\/j.psyneuen.2009.05.021","article-title":"The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders","volume":"34","author":"Binder","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/nyas.12998","article-title":"Mindfulness meditation and the immune system: A systematic review of randomized controlled trials","volume":"1373","author":"Black","year":"2016","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1370\/afm.245","article-title":"The biopsychosocial model 25 years later: Principles, practice, and scientific inquiry","volume":"2","author":"Borrell-Carri\u00f3","year":"2004","journal-title":"Ann. Family Med."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph15030464","article-title":"Generalized unsafety theory of stress: Unsafe environments and conditions, and the default stress response","volume":"15","author":"Brosschot","year":"2018","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B11","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1152\/physrev.1929.9.3.399","article-title":"Organization for physiological homeostasis","volume":"9","author":"Cannon","year":"1929","journal-title":"Physiol. Rev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1152\/advan.00012.2004","article-title":"Homeostasis: A plea for a unified approach","volume":"28","author":"Carpenter","year":"2004","journal-title":"Adv. Physiol. Educ."},{"key":"B13","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1152\/advan.00169.2016","article-title":"An overview of the core concepts in physiology","volume":"41","author":"Carroll","year":"2017","journal-title":"Adv. Physiol. Educ."},{"key":"B14","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.neubiorev.2009.12.011","article-title":"The cortisol awakening response: More than a measure of HPA axis function","volume":"35","author":"Clow","year":"2010","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B15","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.brat.2014.04.006","article-title":"Maximizing exposure therapy: an inhibitory learning approach","volume":"58","author":"Craske","year":"2014","journal-title":"Behav. Res. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.neuron.2013.02.008","article-title":"Visceral influences on brain and behavior","volume":"77","author":"Critchley","year":"2013","journal-title":"Neuron"},{"key":"B17","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1152\/advan.00027.2016","article-title":"Central neural control of the cardiovascular system: Current perspectives","volume":"40","author":"Dampney","year":"2016","journal-title":"Adv. Physiol. Educ."},{"key":"B18","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1146\/annurev-physiol-021909-135821","article-title":"The mammalian circadian timing system: Organization and coordination of central and peripheral clocks","volume":"72","author":"Dibner","year":"2010","journal-title":"Annu. Rev. Physiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1037\/0033-2909.130.3.355","article-title":"Acute stressors and cortisol responses: A theoretical integration and synthesis of laboratory research","volume":"130","author":"Dickerson","year":"2004","journal-title":"Psychol. Bull."},{"key":"B20","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.neubiorev.2016.10.011","article-title":"Mental stress and human cardiovascular disease","volume":"74","author":"Esler","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B21","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nri3843","article-title":"Fever and the thermal regulation of immunity: The immune system feels the heat","volume":"15","author":"Evans","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1017\/S0033291705006616","article-title":"The heritability of perceived stress","volume":"36","author":"Federenko","year":"2006","journal-title":"Psychol. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1097\/ACM.0b013e3181c88b09","article-title":"Flexner revisited: The role and value of the basic sciences in medical education","volume":"85","author":"Finnerty","year":"2010","journal-title":"Acad. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/nrn2787","article-title":"The free-energy principle: A unified brain theory","volume":"11","author":"Friston","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.biopsycho.2014.11.004","article-title":"Knowing your own heart: Distinguishing interoceptive accuracy from interoceptive awareness","volume":"104","author":"Garfinkel","year":"2015","journal-title":"Biol. Psychol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1016\/S0006-3223(02)01665-7","article-title":"Startle reactivity and anxiety disorders: Aversive conditioning, context, and neurobiology","volume":"52","author":"Grillon","year":"2002","journal-title":"Biol. Psychiatry"},{"key":"B27","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1146\/annurev.psych.58.110405.085605","article-title":"The neurobiology of stress and development","volume":"58","author":"Gunnar","year":"2007","journal-title":"Annu. Rev. Psychol."},{"key":"B28","volume-title":"Guyton and Hall Textbook of Medical Physiology","author":"Guyton","year":"2021"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1016\/j.pnpbp.2005.08.006","article-title":"Limbic system mechanisms of stress regulation: Hypothalamo-pituitary-adrenocortical axis","volume":"29","author":"Herman","year":"2005","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fnetp.2021.711778","article-title":"The new field of network physiology: building the human physiolome","volume":"1","author":"Ivanov","year":"2021","journal-title":"Front. Netw. Physiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.bpsc.2017.12.004","article-title":"Interoception and mental health: A roadmap","volume":"3","author":"Khalsa","year":"2018","journal-title":"Biol. Psychiatry: Cogn. Neurosci. Neuroimaging"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1097\/ACM.0b013e3182a45def","article-title":"Cognition before curriculum: Rethinking the integration of basic science and clinical learning","volume":"88","author":"Kulasegaram","year":"2013","journal-title":"Acad. Med."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2014.00756","article-title":"Heart rate variability biofeedback: How and why does it work","volume":"5","author":"Lehrer","year":"2014","journal-title":"Front. Psychol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.bbi.2017.01.011","article-title":"The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis","volume":"64","author":"Marsland","year":"2017","journal-title":"Brain Behavior Immun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1056\/NEJM199801153380307","article-title":"Protective and damaging effects of stress mediators","volume":"338","author":"McEwen","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.ejphar.2007.11.071","article-title":"Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators","volume":"583","author":"McEwen","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1001\/archinte.1993.00410180039004","article-title":"Stress and the individual: Mechanisms leading to disease","volume":"153","author":"McEwen","year":"1993","journal-title":"Arch. Internal Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1152\/advan.00057.2006","article-title":"What makes physiology hard for students to learn? Results of a faculty survey","volume":"31","author":"Michael","year":"2007","journal-title":"Adv. Physiol. Educ."},{"key":"B39","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1152\/advan.00184.2016","article-title":"The \"core concepts\" of physiology: What should students understand","volume":"41","author":"Michael","year":"2017","journal-title":"Adv. Physiol. Educ."},{"key":"B40","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1038\/mp.2009.36","article-title":"Neural substrates of pleiotropic action of genetic variation in COMT: A meta-analysis","volume":"15","author":"Mier","year":"2010","journal-title":"Mol. Psychiatry"},{"key":"B41","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1152\/advan.00107.2015","article-title":"A physiologist's view of homeostasis","volume":"39","author":"Modell","year":"2015","journal-title":"Adv. Physiol. Educ."},{"key":"B42","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1146\/annurev-physiol-020518-114546","article-title":"Central mechanisms for thermoregulation","volume":"81","author":"Morrison","year":"2019","journal-title":"Annu. Rev. Physiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.neubiorev.2018.04.017","article-title":"Interoceptive inference: From computational neuroscience to clinic","volume":"90","author":"Owens","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B44","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/nrendo.2014.22","article-title":"Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids","volume":"10","author":"Picard","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"B45","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9781139026727","volume-title":"The Circuitry of the Human Spinal Cord: Spinal and Corticospinal Mechanisms of Movement","author":"Pierrot-Deseilligny","year":"2012"},{"key":"B46","volume-title":"Neuroscience","author":"Purves","year":"2018"},{"key":"B47","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.tins.2020.09.008","article-title":"Functions of interoception: From energy regulation to experience of the self","volume":"44","author":"Quigley","year":"2021","journal-title":"Trends Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1037\/a0035942","article-title":"Clarifying the roles of homeostasis and allostasis in physiological regulation","volume":"121","author":"Ramsay","year":"2014","journal-title":"Psychol. Rev."},{"key":"B49","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.yhbeh.2019.02.018","article-title":"The physiological significance of the circadian dynamics of the HPA axis: Interplay between circadian rhythms, allostasis and stress resilience","volume":"110","author":"Rao","year":"2019","journal-title":"Horm. Behav."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.6","article-title":"Pancreatic regulation of glucose homeostasis","volume":"48","author":"R\u00f6der","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"B51","first-page":"3","article-title":"The thermoregulation system and how it works","volume-title":"Handbook of Clinical Neurology","author":"Romanovsky","year":"2018"},{"key":"B52","doi-asserted-by":"publisher","first-page":"4453","DOI":"10.1073\/pnas.0808180106","article-title":"Adverse metabolic and cardiovascular consequences of circadian misalignment","volume":"106","author":"Scheer","year":"2009","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/s41577-018-0008-4","article-title":"Clocking in to immunity","volume":"18","author":"Scheiermann","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/j.tins.2019.07.010","article-title":"Allostasis: A brain-centered, predictive mode of physiological regulation","volume":"42","author":"Schulkin","year":"2019","journal-title":"Trends Neurosci."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20287-3","article-title":"Human skeletal muscle possesses an epigenetic memory of hypertrophy","volume":"8","author":"Seaborne","year":"2018","journal-title":"Sci. Rep."},{"key":"B56","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1017\/S0140525X12002270","article-title":"Extending predictive processing to the body: Emotion as interoceptive inference","volume":"36","author":"Seth","year":"2012","journal-title":"Behav. Brain Sci."},{"key":"B57","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1136\/medhum-2018-011598","article-title":"Chronic fatigue syndrome and an illness-focused approach to care: Controversy, morality and paradox","volume":"45","author":"Sharpe","year":"2019","journal-title":"Med. Humanities"},{"key":"B58","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1152\/advan.00087.2006","article-title":"Teaching and learning in the interactive classroom","volume":"30","author":"Silverthorn","year":"2006","journal-title":"Adv. Physiol. Educ."},{"key":"B59","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1037\/a0035302","article-title":"From stress to inflammation and major depressive disorder: A social signal transduction theory of depression","volume":"140","author":"Slavich","year":"2014","journal-title":"Psychol. Bull."},{"key":"B60","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.smrv.2016.02.003","article-title":"Circadian mechanisms of 24-hour blood pressure regulation and patterning","volume":"33","author":"Smolensky","year":"2017","journal-title":"Sleep Med. Rev."},{"key":"B61","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/sj.npp.1301422","article-title":"Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders","volume":"33","author":"Stein","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"B62","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.physbeh.2011.06.004","article-title":"Allostasis: A model of predictive regulation","volume":"106","author":"Sterling","year":"2012","journal-title":"Physiol. Behav."},{"key":"B63","doi-asserted-by":"crossref","DOI":"10.7551\/mitpress\/11472.001.0001","volume-title":"What is Health? Allostasis and the Evolution of Human Design","author":"Sterling","year":"2020"},{"key":"B64","first-page":"629","article-title":"Allostasis: A new paradigm to explain arousal pathology","volume-title":"Handbook of Life Stress, Cognition and Health","author":"Sterling","year":"1988"},{"key":"B65","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/j.neubiorev.2011.11.009","article-title":"A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health","volume":"36","author":"Thayer","year":"2012","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B66","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s12160-009-9101-z","article-title":"Heart rate variability, prefrontal neural function, and cognitive performance: The neurovisceral integration perspective on self-regulation, adaptation, and health","volume":"37","author":"Thayer","year":"2009","journal-title":"Ann. Behav. Med."},{"key":"B67","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/S0165-0327(00)00338-4","article-title":"A model of neurovisceral integration in emotion regulation and dysregulation","volume":"61","author":"Thayer","year":"2000","journal-title":"J. Affect. Disord."},{"key":"B68","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nrn2647","article-title":"Neural regulation of endocrine and autonomic stress responses","volume":"10","author":"Ulrich-Lai","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"B69","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/nrn3976","article-title":"The neuroscience of placebo effects: Connecting context, learning and health","volume":"16","author":"Wager","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1126\/science.1093065","article-title":"Placebo-induced changes in fMRI in the anticipation and experience of pain","volume":"303","author":"Wager","year":"2004","journal-title":"Science"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1093\/function\/zqab038","article-title":"Nucleus type-specific DNA methylomics reveals epigenetic \"memory\" of prior adaptation in skeletal muscle","volume":"2","author":"Wen","year":"2021","journal-title":"Function"},{"key":"B72","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1113\/jphysiol.2013.268953","article-title":"Integrative regulation of human brain blood flow","volume":"592","author":"Willie","year":"2014","journal-title":"J. Physiol."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2026.1817927\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:16:31Z","timestamp":1787199391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2026.1817927\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":72,"alternative-id":["10.3389\/fphys.2026.1817927"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2026.1817927","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"article-number":"1817927"}}