Spatiotemporal asymmetries on brain energy landscape uncover system entrapment related to depression severity

Spatiotemporal asymmetries on brain energy landscape uncover system entrapment related to depression severity | 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 Spatiotemporal asymmetries on brain energy landscape uncover system entrapment related to depression severity Ülgen Kilic, Jenna Jubeir, Priti Balchandani, James Murrough, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7312306/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 We investigate the spatiotemporal organization of resting-state brain activity in individuals with and without major depressive disorder (MDD), identifying stable and recurring whole-brain functional co-activation patterns that serve as attractor-like configurations. A particularly prominent brain state, marked by suppressed default mode and frontoparietal networks and heightened salience system engagement, occurring more frequently and with shorter dwell times in MDD and correlating with greater anhedonia severity. Transition dynamics further reveal that MDD participants exhibit reduced transitions between visual-attentional and limbic-default mode systems, which is associated with higher overall depression symptoms, suggestive of affective and cognitive rigidity. By evaluating the dynamic properties in relation to white matter architecture, we find that MDD individuals preferentially transition along energetically costly trajectories, particularly from salience-reactive to introspective states, despite the presence of structurally facilitated alternatives, implicating inefficient structure-function coupling. Finally, characterizing the energetic asymmetries of entry and exit transitions uncovers the landscape on which the brain travels between source- and sink-like attractors, with MDD dynamics disproportionately becoming trapped between a local maximum and a deep basin. These results offer a mechanistic account of how depression may emerge from maladaptive state trajectories within an energetically imbalanced neural landscape. Biological sciences/Neuroscience/Computational neuroscience/Dynamical systems Biological sciences/Neuroscience/Diseases of the nervous system/Depression Biological sciences/Systems biology/Control theory Biological sciences/Neuroscience/Computational neuroscience/Network models Full Text Additional Declarations Yes there is potential Competing Interest. Dr. Murrough has provided paid consultation services for Autobahn Therapeutics, Inc., Biohaven Pharmaceuticals, Inc., Cliniclabs, Inc., Clexio Biosciences, Ltd., Compass Pathfinder, Plc., Dr Jay, Frontier Pharma, LLC, HMP Collective, Janssen Pharmaceuticals, LivaNova, Plc., Merck & Co., Inc., Otsuka Pharmaceutical, Ltd, WCG Clinical, Inc., and Xenon Pharmaceuticals, Inc. Dr. Priti Balchandani is a named inventor on patents relating to magnetic resonance imaging (MRI) and RF pulse design. This intellectual property has been licensed to GE Healthcare, Siemens AG, and Philips international. Dr. Balchandani received one-time royalty payments for this intellectual property. 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. 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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-7312306","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":499320436,"identity":"cd545c9b-5dde-4e94-930a-d6656537e4d0","order_by":0,"name":"Ülgen Kilic","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYDACdhBxwIKBH0QnFBCjhRmsRYJBsgGkxYAULQYHQAxitBgcZr/4uOCMhLzx+dWJHx4YMMjzix0gpIWn2HjGDQnDbTfebpYAOsxw5uwEglrSpHk+SCSY3Ti7AaQlweA2YS3pv0FajGec3fyDSC3sx5h5bgDN5+/dRpwtkod5mKV5zkgYzrjBu80iwUCCsF/4jrc//MxzzEaev//s5ps/KoAMaQJaGBh4oHEhAVYpQUg5CLA/gND8B4hRPQpGwSgYBSMRAAAfUUOtmheagQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4096-8417","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":true,"prefix":"","firstName":"Ülgen","middleName":"","lastName":"Kilic","suffix":""},{"id":499320437,"identity":"1e1c1cd1-43ad-449f-abf0-38443cff7ed8","order_by":1,"name":"Jenna Jubeir","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Jenna","middleName":"","lastName":"Jubeir","suffix":""},{"id":499320438,"identity":"45878c4b-3819-4a61-8599-b476b708f797","order_by":2,"name":"Priti Balchandani","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Priti","middleName":"","lastName":"Balchandani","suffix":""},{"id":499320439,"identity":"4266d5ac-bdc6-4148-9f0e-cd38bf2b7553","order_by":3,"name":"James Murrough","email":"","orcid":"https://orcid.org/0000-0001-6286-1242","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"Murrough","suffix":""},{"id":499320440,"identity":"9d7480ba-da77-4155-b923-6cca2ffed59b","order_by":4,"name":"Laurel Morris","email":"","orcid":"https://orcid.org/0000-0002-5862-6650","institution":"Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Laurel","middleName":"","lastName":"Morris","suffix":""},{"id":499320441,"identity":"93db5e9d-fcca-40b3-a0b3-c6dfd09514c6","order_by":5,"name":"Yael Jacob","email":"","orcid":"https://orcid.org/0000-0003-3278-9264","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Yael","middleName":"","lastName":"Jacob","suffix":""}],"badges":[],"createdAt":"2025-08-06 18:15:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7312306/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7312306/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89371612,"identity":"a06474c8-4ab0-4cdf-8f87-69a4cf574dfb","added_by":"auto","created_at":"2025-08-19 10:14:02","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":19287707,"visible":true,"origin":"","legend":"Article File","description":"","filename":"maincombined.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7312306/v1_covered_1bbb1ae1-e67d-49a0-8b4d-1db6a38aaa86.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nDr. Murrough has provided paid consultation services for Autobahn Therapeutics, Inc., Biohaven Pharmaceuticals, Inc., Cliniclabs, Inc., Clexio Biosciences, Ltd., Compass Pathfinder, Plc., Dr Jay, Frontier Pharma, LLC, HMP Collective, Janssen Pharmaceuticals, LivaNova, Plc., Merck \u0026 Co., Inc., Otsuka Pharmaceutical, Ltd, WCG Clinical, Inc., and Xenon Pharmaceuticals, Inc. 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