Focused Ultrasound Blood-Brain Barrier Opening Elicits a Metabolic Response in Contralateral Striatum of Non-Human Primates

Focused Ultrasound Blood-Brain Barrier Opening Elicits a Metabolic Response in Contralateral Striatum of Non-Human Primates | 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 Focused Ultrasound Blood-Brain Barrier Opening Elicits a Metabolic Response in Contralateral Striatum of Non-Human Primates Soroosh Sanatkhani, Dong Liu, Fabian Munoz, Jack Grinband, Elisa E. Konofagou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7217157/v3 This work is licensed under a CC BY 4.0 License Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Abstract Introduction: Low-Intensity Focused Ultrasound (LIFU) is a promising, non-invasive technique for transiently opening the blood-brain barrier (BBB), enabling targeted drug delivery to deep brain structures. While the local effects of LIFU-mediated BBB opening (LIFU-BBBO) have been studied, the broader physiological and metabolic consequences, particularly in remote brain regions, remain unclear. Objective: This study aims to investigate the local and remote metabolic responses, measured by oxygen extraction fraction (OEF), following focal LIFU-BBBO in non-human primates, with a focus on both the targeted and homologous contralateral regions. Methods: LIFU-BBBO was performed in the striatum of four male macaques using a 500 kHz transducer and intravenously administered microbubbles. MRI-guided treatment planning and post-sonication imaging confirmed precise BBB opening. Quantitative BOLD (qBOLD) MRI was used to map OEF in both the treated and contralateral regions. Results: Focal LIFU-BBBO did not induce significant metabolic changes at the sonicated site. However, a robust and spatially specific increase in OEF was observed in the homologous contralateral striatum, particularly in the putamen. This contralateral effect was confirmed by both linear mixed-effects modeling and hierarchical Bayesian analysis, while no significant changes were found in other brain regions or when averaging across hemispheres. Conclusion: Focal LIFU-BBBO in the striatum elicits a paradoxical increase in metabolic demand in the untreated, homologous contralateral hemisphere, as indicated by elevated OEF. These findings highlight the importance of considering remote, network-level effects when evaluating the safety and efficacy of LIFU-based therapies, and underscore the need for comprehensive assessment of both local and distant physiological responses in future clinical applications. Biomedical Engineering Cognitive Neuroscience Low Intensity Focused Ultrasound Oxygen Extraction Fraction Quantitative BOLD Magnetic Resonance Imaging Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 3 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-7217157","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":499562386,"identity":"1b2f54a0-9323-4c54-a00d-c2658f82a243","order_by":0,"name":"Soroosh Sanatkhani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYFAC5gMGHwxsGBjYgUwGA5BIAiEtbAmFMwrSQOqJ1sKj8Jnnw2GoFgYitMj3n2HcOMPgvDw/M4/p5oICOwZ+9hwDvFoMbuQeBvrltuHMZh6z2zMMkhkke94Q0CLBl2Y4w+B2gsFhoBYeA6B3bhCwBegw8988BudgWuoZ7AlpYTiQY2DMY3AApuUw0F6CfklLADosGegXtjKgX47zSJx5VkDAYYeBUfnHTp6fvXnb7YI/1XL87ckb8DsMHfCQpnwUjIJRMApGAVYAAJmiRADzB0eOAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4745-0669","institution":"Zuckerman Mind Brain Behavior Institute, Columbia University, USA","correspondingAuthor":true,"prefix":"","firstName":"Soroosh","middleName":"","lastName":"Sanatkhani","suffix":""},{"id":499562387,"identity":"b48f35eb-a708-41cd-a107-ace5806c0b77","order_by":1,"name":"Dong Liu","email":"","orcid":"https://orcid.org/0000-0002-0960-2935","institution":"Zuckerman Mind Brain Behavior Institute, Columbia University, USA","correspondingAuthor":false,"prefix":"","firstName":"Dong","middleName":"","lastName":"Liu","suffix":""},{"id":499562388,"identity":"99f9af9a-e85b-4601-9392-6640fc115ee9","order_by":2,"name":"Fabian Munoz","email":"","orcid":"","institution":"Zuckerman Mind Brain Behavior Institute, Columbia University, USA","correspondingAuthor":false,"prefix":"","firstName":"Fabian","middleName":"","lastName":"Munoz","suffix":""},{"id":506476180,"identity":"65cd0559-3a0e-40b5-9814-72d780ce1439","order_by":3,"name":"Jack Grinband","email":"","orcid":"https://orcid.org/0000-0001-7658-6755","institution":"Departments of Psychiatry, Columbia University, USA","correspondingAuthor":false,"prefix":"","firstName":"Jack","middleName":"","lastName":"Grinband","suffix":""},{"id":499562389,"identity":"bf289891-4760-4adb-bd3b-a9c4975818ee","order_by":4,"name":"Elisa E. Konofagou","email":"","orcid":"https://orcid.org/0000-0002-9636-7936","institution":"Department of Biomedical Engineering, Columbia University, USA","correspondingAuthor":false,"prefix":"","firstName":"Elisa","middleName":"E.","lastName":"Konofagou","suffix":""},{"id":499562390,"identity":"fc43200d-9029-4dad-a305-0a2dbcf38262","order_by":5,"name":"Vincent P. Ferrera","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYFACxscPPsDYDxgYEthADB68WpjNDGfA2AlEajGQhitIACMCWgxuNzMY29QcjuZvYH74ILFtWx4f+wHGB2/b8Gi5c5jhcc6xw7kzDrAZGyS23S5m40lgNpyLR4vkjPwDxrkNh3M3MPCwSQC1JLYBvSPNi1dLMoO0JYoW/gfsv/Fp4ZcAamFE0SKRwMaMV4vMYTbDnmPpuTMOA/2ScA7oF4mHzZJzzuHWwibdzPzgR411bn9788MHH8pu58n3Jx/88KYMtxYGCRiDGS7E2IBHPbKWUTAKRsEoGAW4AACMck7ZdqDSYQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-6599-7740","institution":"Zuckerman Mind Brain Behavior Institute, Columbia University, USA","correspondingAuthor":true,"prefix":"","firstName":"Vincent","middleName":"P.","lastName":"Ferrera","suffix":""}],"badges":[],"createdAt":"2025-07-25 20:41:40","currentVersionCode":3,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true},"doi":"10.21203/rs.3.rs-7217157/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-7217157/v3","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90191154,"identity":"51dcb259-9108-4d87-b67c-3f323f24277a","added_by":"auto","created_at":"2025-08-29 15:47:12","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4610604,"visible":true,"origin":"","legend":"\u003cp\u003eOverview pipeline. (A) Acoustic simulations performed in the k-Wave toolbox showing the modeled focused ultrasound transducer and its focus within the brain. (B) LIFU treatment planning in 3D Slicer using the subject's MRI to define stereotaxic coordinates for targeting. (C) Acoustic calibration of the LIFU system using CereVista system calibration module. (D) In-vivo experimental setup showing the transducer coupled to the NHP’s head in a stereotaxic frame (using 3D printed head of the NHP). (E) Timeline and details of the sonication pulse sequence. (F) Post-LIFU MRI acquisition and data processing pipeline.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7217157/v3/722e6263e98555029adb86ed.jpg"},{"id":90191158,"identity":"49a481fd-0ab0-432d-aef2-81551d330c2c","added_by":"auto","created_at":"2025-08-29 15:47:12","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1769427,"visible":true,"origin":"","legend":"\u003cp\u003eAcoustic simulation results for NHP M1. (A) Simulated acoustic pressure map and (B) corresponding temperature map overlaid on the subject's T1-weighted MRI for perpendicular transducer orientation. (C) Graph comparing the maximum pressure at the focus (line plot, right y-axis) with the maximum temperature rise and temperature after 30 s cooling at the focus and skull (bar plots, left y-axis) across four simulated transducer orientations.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7217157/v3/f4b035dfaa7e40d653cc5682.jpg"},{"id":90191736,"identity":"638c2306-ca89-44a6-8a6a-3e6426542315","added_by":"auto","created_at":"2025-08-29 15:55:12","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2213475,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative post-gadolinium T1-weighted MR images from M3 and M4 comparing the T1-MPRAGE (top row) and T1-SPACE (bottom row) sequences for detecting blood-brain barrier opening (BBBO) following LIFU targeting the right/left caudate.\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7217157/v3/a860e79e8bfb0f43793ad156.jpg"},{"id":90191737,"identity":"4c43046a-1d47-44ea-a66a-9fcdb4b4c3ea","added_by":"auto","created_at":"2025-08-29 15:55:12","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":6047934,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative OEF maps and corresponding anatomical images for two NHPs (M3 and M4) after LIFU-BBBO. Each row displays a different experimental session targeting either the right or left caudate nucleus (Cd. Target). The first two columns show OEF maps for control and LIFU-BBBO conditions, respectively. The third column shows post-gadolinium (Gd) T1-weighted images, where dashed lines indicate the LIFU ROI and solid lines delineate the caudate (1) and putamen (2). The final column displays the OEF change map, showing an increase in OEF primarily in the homologous contralateral striatum.\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7217157/v3/d13c0cd6172b9dfd5f84ac37.jpg"},{"id":90191739,"identity":"a66c3bcf-6178-42a2-8ad6-fd0c9edf4e5d","added_by":"auto","created_at":"2025-08-29 15:55:12","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2864301,"visible":true,"origin":"","legend":"\u003cp\u003eQuantitative Analysis of the Contralateral Metabolic Response to LIFU-BBBO. (A-D) Representative anatomical (T1w+Gd) and OEF change (Δz\u003csub\u003eOEF\u003c/sub\u003e) maps from sessions targeting the right (A, B) and left (C, D) caudate nucleus. Note the increase in OEF in the homologous contralateral ROI. (E) Box plots comparing the change in OEF z-score between the LIFU ROI and the entire hemisphere across all sessions (n=8). A significant increase is observed specifically in the contralateral LIFU ROI (p \u0026lt; 0.0001, linear mixed-effects model). (F, G) This contralateral effect is significant when targeting both the (F) caudate (n=8, p \u0026lt; 0.05) and (G) putamen (n=6, p \u0026lt; 0.05). (H) Posterior probability distributions from the primary hierarchical Bayesian model, confirming a credible positive ‘Contralateral Effect’ (solid gray distribution) whose 95% Highest Density Interval (HDI) does not overlap zero, while main effects for sonication and ROI side are centered near zero. (I-K) Session-level analysis showing the mean Δz\u003csub\u003eOEF\u003c/sub\u003e (± 95% CI) for sonications targeting the right (RCN) and left (LCN) caudate nucleus, demonstrating the consistency of the contralateral effect across (I) all ROIs, (J) the caudate, and (K) the putamen. (L) Posterior distributions from the sub-regional Bayesian model, indicating the contralateral effect is credibly driven by changes in the putamen.\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7217157/v3/40b6ddf077e43e0fd1ce4eb5.jpg"},{"id":90192932,"identity":"acca1c57-ff41-49b3-9dd1-f58e61ebcee8","added_by":"auto","created_at":"2025-08-29 16:19:24","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":18499268,"visible":true,"origin":"","legend":"","description":"","filename":"OEFpaperprePrint202508271033.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7217157/v3_covered_d73fa01b-1aec-4e39-a99b-b3bf0c3f6dce.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Focused Ultrasound Blood-Brain Barrier Opening Elicits a Metabolic Response in Contralateral Striatum of Non-Human Primates","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Columbia University","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":"Low Intensity Focused Ultrasound, Oxygen Extraction Fraction, Quantitative BOLD, Magnetic Resonance Imaging","lastPublishedDoi":"10.21203/rs.3.rs-7217157/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7217157/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLow-Intensity Focused Ultrasound (LIFU) is a promising, non-invasive technique for transiently opening the blood-brain barrier (BBB), enabling targeted drug delivery to deep brain structures. While the local effects of LIFU-mediated BBB opening (LIFU-BBBO) have been studied, the broader physiological and metabolic consequences, particularly in remote brain regions, remain unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aims to investigate the local and remote metabolic responses, measured by oxygen extraction fraction (OEF), following focal LIFU-BBBO in non-human primates, with a focus on both the targeted and homologous contralateral regions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLIFU-BBBO was performed in the striatum of four male macaques using a 500 kHz transducer and intravenously administered microbubbles. MRI-guided treatment planning and post-sonication imaging confirmed precise BBB opening. Quantitative BOLD (qBOLD) MRI was used to map OEF in both the treated and contralateral regions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFocal LIFU-BBBO did not induce significant metabolic changes at the sonicated site. However, a robust and spatially specific increase in OEF was observed in the homologous contralateral striatum, particularly in the putamen. This contralateral effect was confirmed by both linear mixed-effects modeling and hierarchical Bayesian analysis, while no significant changes were found in other brain regions or when averaging across hemispheres.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFocal LIFU-BBBO in the striatum elicits a paradoxical increase in metabolic demand in the untreated, homologous contralateral hemisphere, as indicated by elevated OEF. These findings highlight the importance of considering remote, network-level effects when evaluating the safety and efficacy of LIFU-based therapies, and underscore the need for comprehensive assessment of both local and distant physiological responses in future clinical applications.\u003c/p\u003e","manuscriptTitle":"Focused Ultrasound Blood-Brain Barrier Opening Elicits a Metabolic Response in Contralateral Striatum of Non-Human Primates","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2025-08-29 15:47:07","doi":"10.21203/rs.3.rs-7217157/v3","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}},{"code":2,"date":"2025-08-12 18:38:52","doi":"10.21203/rs.3.rs-7217157/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}},{"code":1,"date":"2025-07-30 07:51:18","doi":"10.21203/rs.3.rs-7217157/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}}],"origin":"","ownerIdentity":"ebe1f476-0493-4f69-aa24-685aaae5425d","owner":[],"postedDate":"August 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53795312,"name":"Biomedical Engineering"},{"id":53795313,"name":"Cognitive Neuroscience"}],"tags":[],"updatedAt":"2025-07-30T07:51:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-29 15:47:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v3","identity":"rs-7217157","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7217157","identity":"rs-7217157","version":["v3"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}