Transcriptional Correlates of Structure-Function Coupling Plasticity in Trigeminal Neuralgia: Unveiling the Synaptic and Metabolic Mechanisms of Recovery

Transcriptional Correlates of Structure-Function Coupling Plasticity in Trigeminal Neuralgia: Unveiling the Synaptic and Metabolic Mechanisms of Recovery | 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 Transcriptional Correlates of Structure-Function Coupling Plasticity in Trigeminal Neuralgia: Unveiling the Synaptic and Metabolic Mechanisms of Recovery Jian Zhang, Xujing Nie, Shuyue Fu, Yinping Lu, Tiantian Liu, Zhilin Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8527336/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Trigeminal neuralgia (TN) is a neurological disorder characterised by severe facial pain and is a common cause of orofacial headache. While vascular compression is a known peripheral trigger, the condition involves a transition to central sensitization. However, the core central pathophysiological mechanisms—particularly how the brain structurally and functionally reorganises itself to maintain pain or recover after treatment—remain to be fully elucidated. Methods We employed a longitudinal multi-scale design using a graph harmonic model to quantify structure-function (S-F) coupling, a metric reflecting brain network integrity. We analysed multimodal magnetic resonance imaging data from 87 patients with TN and 42 healthy controls (HC). Post-treatment follow-up data were acquired for 46 patients, of whom 39 had complete longitudinal paired data. We further utilised partial least squares (PLS) regression to bridge macroscopic imaging changes with microscopic transcriptomic data from the Allen Human Brain Atlas. Results Compared with HC, patients exhibited significantly reduced global S-F coupling, particularly in the somatomotor and dorsal attention networks. Notably, this decoupling was negatively correlated with disease duration, suggesting a progressive central impact. Following treatment, S-F coupling returned towards normal levels. However, this recovery was not driven by direct repair of the originally damaged nodes but by a complex neural reorganisation process dominated by compensation in the visual and default mode networks. At the molecular level, disease-related decoupling was spatially associated with the expression of genes linked to neuronal energy metabolism and sodium ion channels. In contrast, treatment-induced plasticity was strongly related to the expression of genes involved in cholesterol metabolism, synaptic organisation, and the endogenous opioid system. Conclusions Our findings indicate that the pathophysiology of TN is closely linked to ion channel-mediated neuronal metabolism and progressive network decoupling. Effective treatment restores homeostatic brain network coupling primarily by initiating adaptive, synaptic plasticity-based compensatory mechanisms rather than through direct repair of pathological regions. This work offers a new perspective on the neural circuits underlying pain maintenance and provides potential imaging and molecular biomarkers for developing brain network-targeted therapeutic strategies. Structural-functional coupling (S-F) Graph harmonic model Brain network Multimodal MRI Trigeminal neuralgia (TN) Compensatory mechanism Full Text Additional Declarations No competing interests reported. Tables are available in the Supplementary Files section. Supplementary Files Table1.docx SupplementaryInformation.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 12 Feb, 2026 Reviews received at journal 12 Feb, 2026 Reviews received at journal 09 Feb, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 07 Jan, 2026 Reviewers invited by journal 06 Jan, 2026 Editor assigned by journal 06 Jan, 2026 Submission checks completed at journal 06 Jan, 2026 First submitted to journal 06 Jan, 2026 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. 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-8527336","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":570741284,"identity":"f28e6a06-91be-4cf8-9a6b-be957d9f2322","order_by":0,"name":"Jian Zhang","email":"","orcid":"","institution":"Beijing Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Zhang","suffix":""},{"id":570741285,"identity":"ca596b05-6ac1-436c-ad94-c2009aa33ea9","order_by":1,"name":"Xujing Nie","email":"","orcid":"","institution":"Beijing Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Xujing","middleName":"","lastName":"Nie","suffix":""},{"id":570741286,"identity":"0590cea4-b636-4ac0-aa0b-3b97d398c71f","order_by":2,"name":"Shuyue Fu","email":"","orcid":"","institution":"Beijing Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Shuyue","middleName":"","lastName":"Fu","suffix":""},{"id":570741288,"identity":"fd37107a-1ab0-463a-9e1d-6bba72cb5b24","order_by":3,"name":"Yinping Lu","email":"","orcid":"","institution":"Shenzhen Institutes of Advanced Technology","correspondingAuthor":false,"prefix":"","firstName":"Yinping","middleName":"","lastName":"Lu","suffix":""},{"id":570741290,"identity":"6ed1424f-c908-45f6-93d9-9eb97c34e588","order_by":4,"name":"Tiantian Liu","email":"","orcid":"","institution":"Beijing Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Tiantian","middleName":"","lastName":"Liu","suffix":""},{"id":570741292,"identity":"dfbfe58f-bc15-445b-9892-dde87c86ed06","order_by":5,"name":"Zhilin Zhang","email":"","orcid":"","institution":"Shenzhen Institutes of Advanced Technology","correspondingAuthor":false,"prefix":"","firstName":"Zhilin","middleName":"","lastName":"Zhang","suffix":""},{"id":570741295,"identity":"74f7d635-5554-482b-acda-c8ff86b3cd64","order_by":6,"name":"Jinglong Wu","email":"","orcid":"","institution":"Beijing Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Jinglong","middleName":"","lastName":"Wu","suffix":""},{"id":570741296,"identity":"8c1b0108-f7c7-4335-a6cc-913ff2bcffc7","order_by":7,"name":"Xuezhi Tong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIie3PMWrDMBTGcQmBvLyg1YYc4gVDgsHEV1EJeMrQqbPAoC7J7lwks4wgk3EOkEV7F5ksHQqt6VLoIGcsVP9RfD8eIiQW+8shE95ILEEIFV7CDyEr557rZdaaRwkh+cp5W6KSYVIlR/u20GW1SUidSrwCEkP9uA9cgaEuTrpmRUMuE7nBhimWnc4Bku7XOGrL0VL9TQplOFvMkSf9CWgZn8gAaOQsyd2oTYqWM5RoHiB9v6btsEO0QJ3EHWRt1wT/krwe8ju8bCu89qR7/9hWQjSdHwNkiqe/HqgK7qeYn1vEYrHYP+8LUjNOJapMDc0AAAAASUVORK5CYII=","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xuezhi","middleName":"","lastName":"Tong","suffix":""},{"id":570741297,"identity":"580c7052-9134-4153-868e-530a4c489f33","order_by":8,"name":"Tanyi Yan","email":"","orcid":"","institution":"Beijing Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Tanyi","middleName":"","lastName":"Yan","suffix":""}],"badges":[],"createdAt":"2026-01-06 06:23:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8527336/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8527336/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99834318,"identity":"f297ac2b-77c4-4cf8-9afd-90d1d2439b72","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"tif","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1121574,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.Flowchartofparticipantselection.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/a9951479116d79c35221bbe3.tif"},{"id":99834319,"identity":"59539d87-b588-432a-a2a5-408f2ac3b0ab","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9071564,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2Overviewofthemultiscaleanalysispipeline.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/736aff11f6fc820c48889658.tif"},{"id":100356976,"identity":"9507e45b-75d8-494f-862b-1f38093bf0ea","added_by":"auto","created_at":"2026-01-16 07:18:10","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":119536,"visible":true,"origin":"","legend":"","description":"","filename":"TranscriptionalCorrelatesofStructureFunctionCouplingPlasticityinTrigeminalNeuralgiaUnveilingtheSynapticandMetabolicMe.docx","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/5e3ee728fdbbfaf5eb7434b7.docx"},{"id":100356580,"identity":"12fed71f-8aa4-4500-b73a-305f77f6e5bc","added_by":"auto","created_at":"2026-01-16 07:15:48","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":23385,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/bd914e03edfd3fbca95dc53b.docx"},{"id":99834364,"identity":"f776b049-cd93-4381-86ef-d3221ee54e7c","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6814538,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3SpatialDistributionandNetworkHierarchicalPatternofCoupling.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/7f548f30c75b1c40838636e3.tif"},{"id":99834320,"identity":"560b721c-fe9e-4862-ae9e-bcae56a0ad15","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"tif","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6487194,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4SFdecouplingworsenswithdiseasedurationandreversesviacompensation.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/2e62a0ebdb882bb1eb281066.tif"},{"id":100357005,"identity":"b8ff5151-3531-4a04-9272-047c6a5207a3","added_by":"auto","created_at":"2026-01-16 07:18:15","extension":"tif","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6026026,"visible":true,"origin":"","legend":"","description":"","filename":"Figure5MolecularBasisoftheDiseaseEffectonSFCoupling.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/9e7a3a819a7bc83506187095.tif"},{"id":99834328,"identity":"42409343-bc3f-420c-8dca-ddb064a6e0b0","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"tif","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6280664,"visible":true,"origin":"","legend":"","description":"","filename":"Figure6MolecularBasisoftheTreatmentEffectonSFCoupling.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/a4082a345bbb1ec2282ed9cf.tif"},{"id":100357151,"identity":"f2dcdee9-2cc4-4bc7-a6bc-65fcb97f55a0","added_by":"auto","created_at":"2026-01-16 07:19:02","extension":"json","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11353,"visible":true,"origin":"","legend":"","description":"","filename":"20b2c4773a0447358009e53ed4006b6f.json","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/ebd3b99f60e59be387447108.json"},{"id":100357154,"identity":"9749fbae-407e-449c-9d86-a1e0cd04d405","added_by":"auto","created_at":"2026-01-16 07:19:08","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":153440,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/67f9d74280e33f4f86233453.xlsx"},{"id":99834342,"identity":"1700a1d0-5e04-4245-8c06-5ccea85e8816","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":181774,"visible":true,"origin":"","legend":"","description":"","filename":"20b2c4773a0447358009e53ed4006b6f1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/7aad375841f5ef6bb1a90804.xml"},{"id":100356807,"identity":"c426988c-b9f3-4000-8613-a3ae2ca11bb1","added_by":"auto","created_at":"2026-01-16 07:17:36","extension":"tif","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1121574,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.Flowchartofparticipantselection.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/ed361e0656a8599bb8e0d67d.tif"},{"id":100356968,"identity":"853b0574-025d-443e-84b5-c014655c812d","added_by":"auto","created_at":"2026-01-16 07:18:08","extension":"tif","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9071564,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2Overviewofthemultiscaleanalysispipeline.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/9552aa0f28ca01c5e0353a87.tif"},{"id":100356769,"identity":"97b79282-e20b-4ba0-a351-e9757082a4cf","added_by":"auto","created_at":"2026-01-16 07:17:24","extension":"tif","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6814538,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3SpatialDistributionandNetworkHierarchicalPatternofCoupling.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/948c2988e535d0ea6b9df48c.tif"},{"id":100356715,"identity":"5c042c27-8142-4d13-ae6d-15d2bfb83423","added_by":"auto","created_at":"2026-01-16 07:17:06","extension":"tif","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6487194,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4SFdecouplingworsenswithdiseasedurationandreversesviacompensation.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/f1f116dea3a20209f95d50ef.tif"},{"id":99834345,"identity":"5503e477-ce64-4b7c-8348-c20ffb089c7a","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"tif","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6026026,"visible":true,"origin":"","legend":"","description":"","filename":"Figure5MolecularBasisoftheDiseaseEffectonSFCoupling.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/876b08971dfb75245ae39f16.tif"},{"id":99834380,"identity":"dcab559c-d334-4d33-8063-f9f3798b3140","added_by":"auto","created_at":"2026-01-08 18:27:10","extension":"tif","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6280664,"visible":true,"origin":"","legend":"","description":"","filename":"Figure6MolecularBasisoftheTreatmentEffectonSFCoupling.tif","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/028279b30a69236f52efcd5e.tif"},{"id":100356346,"identity":"661d2fc6-b8ac-46ae-b986-cf2ea1205c0f","added_by":"auto","created_at":"2026-01-16 07:04:05","extension":"wmf","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":764,"visible":true,"origin":"","legend":"","description":"","filename":"image1.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/d09c896ae731a37faac92718.wmf"},{"id":100357134,"identity":"973ac6b9-d306-4ce7-a15b-70f6619279c8","added_by":"auto","created_at":"2026-01-16 07:18:56","extension":"wmf","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":624,"visible":true,"origin":"","legend":"","description":"","filename":"image10.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/dbfeb3d39d8084a521a6c184.wmf"},{"id":99834343,"identity":"58c5a3b0-af94-48c4-ad33-3f891607e332","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"wmf","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":730,"visible":true,"origin":"","legend":"","description":"","filename":"image11.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/a17876f40fea281c31d0ba49.wmf"},{"id":99834382,"identity":"6bc618b2-11f1-41c8-bb08-4aa989ba8c2a","added_by":"auto","created_at":"2026-01-08 18:27:10","extension":"wmf","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":730,"visible":true,"origin":"","legend":"","description":"","filename":"image12.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/7dedd9dbcd05fa537b8cbb60.wmf"},{"id":99834323,"identity":"533e0b43-0775-4496-a11f-af81d029a18c","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"wmf","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":624,"visible":true,"origin":"","legend":"","description":"","filename":"image13.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/233316caedadd995f23f0211.wmf"},{"id":100357296,"identity":"41ebe99f-0fbd-4eb9-ba54-9b94fcfa5258","added_by":"auto","created_at":"2026-01-16 07:19:37","extension":"wmf","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":730,"visible":true,"origin":"","legend":"","description":"","filename":"image14.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/9d5239b6002698ed5586ee1e.wmf"},{"id":99834329,"identity":"6c1fb917-7c5c-4e5a-a57f-c6aea558414f","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"wmf","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":736,"visible":true,"origin":"","legend":"","description":"","filename":"image15.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/35a0c36d6feb256b83bc7550.wmf"},{"id":100356647,"identity":"dba09345-deea-4265-be13-a96b413e2c9a","added_by":"auto","created_at":"2026-01-16 07:16:20","extension":"wmf","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":730,"visible":true,"origin":"","legend":"","description":"","filename":"image16.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/5b06b4093ca533a689bb9af3.wmf"},{"id":100356923,"identity":"0aca0644-e203-4f3d-a8f5-1fb31f5f1100","added_by":"auto","created_at":"2026-01-16 07:17:59","extension":"wmf","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":730,"visible":true,"origin":"","legend":"","description":"","filename":"image17.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/a0309fedea4041223ad105cd.wmf"},{"id":99834366,"identity":"eefa36f6-6221-4519-b367-267e146e7a68","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"wmf","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":736,"visible":true,"origin":"","legend":"","description":"","filename":"image18.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/85f34d9827a7522f21cb4d7c.wmf"},{"id":99834337,"identity":"46ae484a-d50e-46a1-8803-f0b496e139c8","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"wmf","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":736,"visible":true,"origin":"","legend":"","description":"","filename":"image19.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/66d00163162211e3fb0493bc.wmf"},{"id":100356780,"identity":"0c31f9ce-3225-4c20-b4da-3a20579ff07b","added_by":"auto","created_at":"2026-01-16 07:17:27","extension":"wmf","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":624,"visible":true,"origin":"","legend":"","description":"","filename":"image2.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/3529bccacf11e215d1e7b81d.wmf"},{"id":99834334,"identity":"fe401090-84ce-43a4-9d82-7652b35c613d","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"wmf","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":736,"visible":true,"origin":"","legend":"","description":"","filename":"image20.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/d53712cbaed4df8d4293668e.wmf"},{"id":99834357,"identity":"2a731b8f-e1af-46bd-aba3-2096bca6ea5a","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"wmf","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":634,"visible":true,"origin":"","legend":"","description":"","filename":"image3.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/551a2c114094702bfe300044.wmf"},{"id":99834338,"identity":"4ac34c27-8e3c-4600-9541-3a17e3040a1b","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"wmf","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1160,"visible":true,"origin":"","legend":"","description":"","filename":"image4.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/df486c083bd7c638040b28d3.wmf"},{"id":100357034,"identity":"396e3d44-7347-4a1f-8ff3-1f7236f3284d","added_by":"auto","created_at":"2026-01-16 07:18:22","extension":"wmf","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":670,"visible":true,"origin":"","legend":"","description":"","filename":"image5.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/be69d301b6965a33994fc0bd.wmf"},{"id":99834379,"identity":"aa1cf098-fc5e-4d0a-ad80-e381190cc7c9","added_by":"auto","created_at":"2026-01-08 18:27:10","extension":"wmf","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":624,"visible":true,"origin":"","legend":"","description":"","filename":"image6.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/5ebd4787b9aadab1c1dbd495.wmf"},{"id":99834365,"identity":"2138f2bd-7e22-4738-8ff9-f15cdab3d413","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"wmf","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":736,"visible":true,"origin":"","legend":"","description":"","filename":"image7.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/c2e923fb9b4be37504e78634.wmf"},{"id":100356735,"identity":"e81c9557-985b-4c8b-a056-e23d3d0e6aa8","added_by":"auto","created_at":"2026-01-16 07:17:16","extension":"wmf","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2164,"visible":true,"origin":"","legend":"","description":"","filename":"image8.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/a5337ad178961b0f6c92f6e8.wmf"},{"id":99834369,"identity":"1be4e264-90c0-4832-89f1-38c7c901b99b","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"wmf","order_by":36,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":730,"visible":true,"origin":"","legend":"","description":"","filename":"image9.wmf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/82714cfe1754cb9711f4127b.wmf"},{"id":99834347,"identity":"d1f0d328-39bd-4e6c-88e5-06de6bd419d4","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"png","order_by":37,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":148518,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1.Flowchartofparticipantselection.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/4b9518edb7e4a861f618eb10.png"},{"id":100356856,"identity":"20949d01-06c5-4b68-9a0e-562ba676d9d0","added_by":"auto","created_at":"2026-01-16 07:17:49","extension":"png","order_by":38,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":709388,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2Overviewofthemultiscaleanalysispipeline.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/c2fdac7d35f7d6460b3b5ae4.png"},{"id":99834336,"identity":"a911c0f3-5dc0-496e-8db6-fd3812983f7b","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"png","order_by":39,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":650796,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure3SpatialDistributionandNetworkHierarchicalPatternofCoupling.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/62c46cffa373e6adb85440e1.png"},{"id":99834352,"identity":"4250546b-1959-453c-b40a-e01ec8976d4f","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":40,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":620930,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure4SFdecouplingworsenswithdiseasedurationandreversesviacompensation.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/2a4e37e760b0767831204eb4.png"},{"id":100357136,"identity":"b79ea034-4d84-4eaa-9eb1-25110a02a090","added_by":"auto","created_at":"2026-01-16 07:18:56","extension":"png","order_by":41,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":642481,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure5MolecularBasisoftheDiseaseEffectonSFCoupling.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/b2d9bdf49d39426d386f4f27.png"},{"id":100357025,"identity":"16e815fd-9d5a-4b6b-81fb-a75d12ff9413","added_by":"auto","created_at":"2026-01-16 07:18:20","extension":"png","order_by":42,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":656389,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure6MolecularBasisoftheTreatmentEffectonSFCoupling.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/e19cf1625b8882aeb24fb743.png"},{"id":99834363,"identity":"1b90266f-1138-49a3-9d2d-e17e855a97e8","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":43,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":455,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/e3ff45574bc493dd0967ed28.png"},{"id":99834375,"identity":"b9a18240-6de2-40ae-af45-444f8d762245","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":44,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":261,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/bb7974d6cf9205b257d9098e.png"},{"id":99834340,"identity":"926c6e57-1abe-4fc8-8a31-795e4dc9a363","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"png","order_by":45,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":337,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/38ae44e10502b8108e6bad2c.png"},{"id":99834356,"identity":"ec692096-e667-4319-8d48-f46c9ad5d644","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":46,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":363,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/aaae9a143c8738e3c262ba28.png"},{"id":99834377,"identity":"0d17758b-cbaa-417f-8c95-e0e7850fcb36","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":47,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":236,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/6c976fd146d1ec06ebece081.png"},{"id":100357326,"identity":"b90cfe2a-1bcd-41b7-ad04-b34ea380cefe","added_by":"auto","created_at":"2026-01-16 07:19:40","extension":"png","order_by":48,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":279,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/1fae1248b944e50e13e98878.png"},{"id":100356425,"identity":"d2ebd9cc-b691-41fe-aa65-e542967a99e9","added_by":"auto","created_at":"2026-01-16 07:09:02","extension":"png","order_by":49,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":293,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage15.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/e6f3cf48b32d00d90eec2f56.png"},{"id":100357001,"identity":"001b4894-405d-4716-b0a0-19110325be3f","added_by":"auto","created_at":"2026-01-16 07:18:15","extension":"png","order_by":50,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":254,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage16.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/3028110ad945ae0ecf361b29.png"},{"id":100356566,"identity":"acbffb0a-3aac-4cfe-82f2-43ebdcaeb9c3","added_by":"auto","created_at":"2026-01-16 07:15:43","extension":"png","order_by":51,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":279,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/e641883ee8ef5c02d72f9295.png"},{"id":99834351,"identity":"a64fdcc6-be09-4fed-95e4-928da1a8a6c8","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":52,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":293,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage15.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/511eaf1c906972363493266f.png"},{"id":100356942,"identity":"54fc1215-7164-4476-baa2-9ce0355a7f28","added_by":"auto","created_at":"2026-01-16 07:18:03","extension":"png","order_by":53,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":316,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage19.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/d61780f335dfc2354c059ad4.png"},{"id":99834350,"identity":"ef541e43-2afa-4ad2-a3ed-90c023d9d54d","added_by":"auto","created_at":"2026-01-08 18:27:08","extension":"png","order_by":54,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":227,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/c4c423c9adcfd9e539f6e29e.png"},{"id":99834383,"identity":"82c74dcf-82c8-4d11-a0da-b3ced51e42e6","added_by":"auto","created_at":"2026-01-08 18:27:10","extension":"png","order_by":55,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":316,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage19.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/7b739fbf0f75bc86d73497d6.png"},{"id":99834370,"identity":"00cb01f8-9695-4021-997f-700b133a5a19","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":56,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":255,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/2f82de0370591ddd82947d5c.png"},{"id":99834354,"identity":"72c928af-2db6-460e-b232-539952fe3f4d","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":57,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":812,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/57a32ea06c208346378e7679.png"},{"id":99834360,"identity":"d006ede5-b032-45ea-950e-3dcf63d88588","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":58,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":545,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/542283683328ddde4e8fea90.png"},{"id":100357026,"identity":"e55c1b5f-2af0-46e1-a186-757158f46113","added_by":"auto","created_at":"2026-01-16 07:18:20","extension":"png","order_by":59,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":170,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/366d3cb03a5464ba48372240.png"},{"id":100357087,"identity":"0f52b289-cc2e-4d62-aa85-c64c2d6896d1","added_by":"auto","created_at":"2026-01-16 07:18:40","extension":"png","order_by":60,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":316,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage19.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/36ecb08dcf210778b7f81f05.png"},{"id":99834372,"identity":"e65e4315-bb0e-4a37-b030-7fe7d30a8ce1","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"png","order_by":61,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1174,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/0caa41eae9fcab6b9da02e6b.png"},{"id":100356793,"identity":"6909d638-0a3d-4679-9c19-4006dd5c1f87","added_by":"auto","created_at":"2026-01-16 07:17:30","extension":"png","order_by":62,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":288,"visible":true,"origin":"","legend":"","description":"","filename":"Onlineimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/021db0dc8af12a06249fe385.png"},{"id":100357000,"identity":"29b33134-8464-4ec7-8418-023fa264a470","added_by":"auto","created_at":"2026-01-16 07:18:15","extension":"xml","order_by":63,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":179061,"visible":true,"origin":"","legend":"","description":"","filename":"20b2c4773a0447358009e53ed4006b6f1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/b177f22315e95bd3756611d9.xml"},{"id":99834374,"identity":"91fd30b8-499d-4242-add9-26250592285b","added_by":"auto","created_at":"2026-01-08 18:27:09","extension":"html","order_by":64,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":197017,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/290a78739f1dabf870576f7e.html"},{"id":100380024,"identity":"f611ce76-289b-47e2-b375-5f7202448078","added_by":"auto","created_at":"2026-01-16 10:09:39","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1685220,"visible":true,"origin":"","legend":"","description":"","filename":"TranscriptionalCorrelatesofStructureFunctionCouplingPlasticityinTrigeminalNeuralgiaUnveilingtheSynapticandMetabolicMe.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1_covered_0fce6975-8521-469a-a79b-e9548f719dc1.pdf"},{"id":99834317,"identity":"f8598d3e-d43d-40aa-978c-46b0c65ccb11","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":23385,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/c193e1f3c9175fceffb01b5c.docx"},{"id":99834322,"identity":"845b9226-3022-4073-9f69-17b57a69f115","added_by":"auto","created_at":"2026-01-08 18:27:07","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":153440,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8527336/v1/3b1f0d63384ddd319dd7d200.xlsx"}],"financialInterests":"\u003cp\u003eNo competing interests reported.\u003c/p\u003e\n\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e","formattedTitle":"Transcriptional Correlates of Structure-Function Coupling Plasticity in Trigeminal Neuralgia: Unveiling the Synaptic and Metabolic Mechanisms of Recovery","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":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Structural-functional coupling (S-F), Graph harmonic model, Brain network, Multimodal MRI, Trigeminal neuralgia (TN), Compensatory mechanism","lastPublishedDoi":"10.21203/rs.3.rs-8527336/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8527336/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTrigeminal neuralgia (TN) is a neurological disorder characterised by severe facial pain and is a common cause of orofacial headache. While vascular compression is a known peripheral trigger, the condition involves a transition to central sensitization. However, the core central pathophysiological mechanisms\u0026mdash;particularly how the brain structurally and functionally reorganises itself to maintain pain or recover after treatment\u0026mdash;remain to be fully elucidated.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe employed a longitudinal multi-scale design using a graph harmonic model to quantify structure-function (S-F) coupling, a metric reflecting brain network integrity. We analysed multimodal magnetic resonance imaging data from 87 patients with TN and 42 healthy controls (HC). Post-treatment follow-up data were acquired for 46 patients, of whom 39 had complete longitudinal paired data. We further utilised partial least squares (PLS) regression to bridge macroscopic imaging changes with microscopic transcriptomic data from the Allen Human Brain Atlas.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCompared with HC, patients exhibited significantly reduced global S-F coupling, particularly in the somatomotor and dorsal attention networks. Notably, this decoupling was negatively correlated with disease duration, suggesting a progressive central impact. Following treatment, S-F coupling returned towards normal levels. However, this recovery was not driven by direct repair of the originally damaged nodes but by a complex neural reorganisation process dominated by compensation in the visual and default mode networks. At the molecular level, disease-related decoupling was spatially associated with the expression of genes linked to neuronal energy metabolism and sodium ion channels. In contrast, treatment-induced plasticity was strongly related to the expression of genes involved in cholesterol metabolism, synaptic organisation, and the endogenous opioid system.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur findings indicate that the pathophysiology of TN is closely linked to ion channel-mediated neuronal metabolism and progressive network decoupling. Effective treatment restores homeostatic brain network coupling primarily by initiating adaptive, synaptic plasticity-based compensatory mechanisms rather than through direct repair of pathological regions. This work offers a new perspective on the neural circuits underlying pain maintenance and provides potential imaging and molecular biomarkers for developing brain network-targeted therapeutic strategies.\u003c/p\u003e","manuscriptTitle":"Transcriptional Correlates of Structure-Function Coupling Plasticity in Trigeminal Neuralgia: Unveiling the Synaptic and Metabolic Mechanisms of Recovery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-08 18:27:02","doi":"10.21203/rs.3.rs-8527336/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-13T01:59:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-12T10:11:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-09T12:29:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"228381874903899649611048554874898857993","date":"2026-01-20T09:46:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85127789688378887059024611423707406412","date":"2026-01-07T10:01:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-06T12:55:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-06T12:37:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-06T12:26:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Journal of Headache and Pain","date":"2026-01-06T06:02:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cd6be462-996e-4d50-8209-44dc7389a759","owner":[],"postedDate":"January 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-16T03:09:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-08 18:27:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8527336","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8527336","identity":"rs-8527336","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}