{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:50:20Z","timestamp":1780473020156,"version":"3.54.1"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PP00P3_176984"],"award-info":[{"award-number":["PP00P3_176984"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007148","name":"Bundesministerium f\u00fcr Wissenschaft und Forschung","doi-asserted-by":"publisher","award":["KKNMS German competence network for multiple sclerosis"],"award-info":[{"award-number":["KKNMS German competence network for multiple sclerosis"]}],"id":[{"id":"10.13039\/501100007148","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging\u2014and almost exclusively performed at 7\u00a0T field strength\u2014depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (1) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3\u00a0T MRI system; and (2) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3\u00a0T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete\/complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable.<\/jats:p>","DOI":"10.1038\/s41598-021-94891-1","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T06:03:26Z","timestamp":1627538606000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Imaging multiple sclerosis pathology at 160\u00a0\u03bcm isotropic resolution by human whole-brain ex vivo magnetic resonance imaging at 3\u00a0T"],"prefix":"10.1038","volume":"11","author":[{"given":"Matthias","family":"Weigel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dechent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Galbusera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Bahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Govind","family":"Nair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Jui","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwig","family":"Kappos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Br\u00fcck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Stadelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Granziera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"94891_CR1","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1016\/j.neuroimage.2003.11.024","volume":"21","author":"A Pfefferbaum","year":"2004","unstructured":"Pfefferbaum, A., Sullivan, E. V., Adalsteinsson, E., Garrick, T. & Harper, C. Postmortem MR imaging of formalin-fixed human brain. Neuroimage 21, 1585\u20131595 (2004).","journal-title":"Neuroimage"},{"key":"94891_CR2","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.neuroimage.2011.03.070","volume":"57","author":"KL Miller","year":"2011","unstructured":"Miller, K. L. et al. Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner. Neuroimage 57, 167\u2013181 (2011).","journal-title":"Neuroimage"},{"key":"94891_CR3","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1097\/NEN.0000000000000096","volume":"73","author":"M Absinta","year":"2014","unstructured":"Absinta, M. et al. Postmortem magnetic resonance imaging to guide the pathologic cut: Individualized, 3-dimensionally printed cutting boxes for fixed brains. J. Neuropathol. Exp. Neurol. 73, 780\u2013788 (2014).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"94891_CR4","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/s41597-019-0254-8","volume":"6","author":"BL Edlow","year":"2019","unstructured":"Edlow, B. L. et al. 7 Tesla MRI of the ex vivo human brain at 100 micron resolution. Sci. Data 6, 244 (2019).","journal-title":"Sci. Data"},{"key":"94891_CR5","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3389\/fnana.2020.00009","volume":"14","author":"TM Shepherd","year":"2020","unstructured":"Shepherd, T. M. et al. Inner SPACE: 400-micron isotropic resolution MRI of the human brain. Front. Neuroanat. 14, 9 (2020).","journal-title":"Front. Neuroanat."},{"key":"94891_CR6","doi-asserted-by":"publisher","first-page":"117285","DOI":"10.1016\/j.neuroimage.2020.117285","volume":"223","author":"G Nair","year":"2020","unstructured":"Nair, G., Dodd, S., Ha, S.-K., Koretsky, A. P. & Reich, D. S. Ex vivo MR microscopy of a human brain with multiple sclerosis: Visualizing individual cells in tissue using intrinsic iron. Neuroimage 223, 117285 (2020).","journal-title":"Neuroimage"},{"issue":"33","key":"94891_CR7","first-page":"400","volume":"1987","author":"M Tovi","year":"1992","unstructured":"Tovi, M. & Ericsson, A. Measurements of T1 and T2 over time in formalin-fixed human whole-brain specimens. Acta Radiol. Stockh. Swed. 1987(33), 400\u2013404 (1992).","journal-title":"Acta Radiol. Stockh. Swed."},{"key":"94891_CR8","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1002\/mrm.20578","volume":"54","author":"CJ Yong-Hing","year":"2005","unstructured":"Yong-Hing, C. J., Obenaus, A., Stryker, R., Tong, K. & Sarty, G. E. Magnetic resonance imaging and mathematical modeling of progressive formalin fixation of the human brain. Magn. Reson. Med. 54, 324\u2013332 (2005).","journal-title":"Magn. Reson. Med."},{"key":"94891_CR9","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.neuroimage.2006.12.028","volume":"35","author":"HE D\u2019Arceuil","year":"2007","unstructured":"D\u2019Arceuil, H. E., Westmoreland, S. & de Crespigny, A. J. An approach to high resolution diffusion tensor imaging in fixed primate brain. Neuroimage 35, 553\u2013565 (2007).","journal-title":"Neuroimage"},{"key":"94891_CR10","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1097\/NEN.0b013e3182588293","volume":"71","author":"BL Edlow","year":"2012","unstructured":"Edlow, B. L. et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J. Neuropathol. Exp. Neurol. 71, 531\u2013546 (2012).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"94891_CR11","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.neuroimage.2012.11.042","volume":"68","author":"E Takahashi","year":"2013","unstructured":"Takahashi, E., Song, J. W., Folkerth, R. D., Grant, P. E. & Schmahmann, J. D. Detection of postmortem human cerebellar cortex and white matter pathways using high angular resolution diffusion tractography: A feasibility study. Neuroimage 68, 105\u2013111 (2013).","journal-title":"Neuroimage"},{"key":"94891_CR12","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1002\/ana.20426","volume":"57","author":"JC Augustinack","year":"2005","unstructured":"Augustinack, J. C. et al. Detection of entorhinal layer II using 7\u00a0Tesla [corrected] magnetic resonance imaging. Ann. Neurol. 57, 489\u2013494 (2005).","journal-title":"Ann. Neurol."},{"key":"94891_CR13","doi-asserted-by":"publisher","DOI":"10.1101\/2020.05.07.082479","author":"C Wang","year":"2020","unstructured":"Wang, C. et al. Methods for quantitative susceptibility and R2* mapping in whole post-mortem brains at 7T. bioRxiv https:\/\/doi.org\/10.1101\/2020.05.07.082479 (2020).","journal-title":"bioRxiv"},{"key":"94891_CR14","doi-asserted-by":"publisher","DOI":"10.3791\/54780","author":"NJ Luciano","year":"2016","unstructured":"Luciano, N. J. et al. Utilizing 3D printing technology to merge MRI with histology: A protocol for brain sectioning. J. Vis. Exp. https:\/\/doi.org\/10.3791\/54780 (2016).","journal-title":"J. Vis. Exp."},{"key":"94891_CR15","doi-asserted-by":"publisher","first-page":"3550","DOI":"10.1093\/brain\/awz290","volume":"142","author":"AD Griffin","year":"2019","unstructured":"Griffin, A. D. et al. Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury. Brain J. Neurol. 142, 3550\u20133564 (2019).","journal-title":"Brain J. Neurol."},{"key":"94891_CR16","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1006\/dbio.1998.8891","volume":"198","author":"GY Huang","year":"1998","unstructured":"Huang, G. Y. et al. Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development. Dev. Biol. 198, 32\u201344 (1998).","journal-title":"Dev. Biol."},{"key":"94891_CR17","first-page":"258","volume":"67","author":"A Haase","year":"1985","unstructured":"Haase, A., Frahm, J., Matthaei, D., H\u00e4nicke, W. & Merboldt, K. D. FLASH imaging: Rapid NMR imaging using low flip-angle pulses. J. Magn. Reson. 67, 258\u2013266 (1985).","journal-title":"J. Magn. Reson."},{"key":"94891_CR18","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.neuroimage.2006.01.015","volume":"31","author":"PA Yushkevich","year":"2006","unstructured":"Yushkevich, P. A. et al. User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability. Neuroimage 31, 1116\u20131128 (2006).","journal-title":"Neuroimage"},{"key":"94891_CR19","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1111\/jon.12669","volume":"30","author":"P Spincemaille","year":"2020","unstructured":"Spincemaille, P. et al. Quantitative susceptibility mapping: MRI at 7T versus 3T. J. Neuroimaging 30, 65\u201375 (2020).","journal-title":"J. Neuroimaging"},{"key":"94891_CR20","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1002\/nbm.3477","volume":"29","author":"C Birkl","year":"2016","unstructured":"Birkl, C. et al. Effects of formalin fixation and temperature on MR relaxation times in the human brain. NMR Biomed. 29, 458\u2013465 (2016).","journal-title":"NMR Biomed."},{"key":"94891_CR21","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1002\/jmri.23638","volume":"35","author":"M Markl","year":"2012","unstructured":"Markl, M. & Leupold, J. Gradient echo imaging. J. Magn. Reson. Imaging 35, 1274\u20131289 (2012).","journal-title":"J. Magn. Reson. Imaging"},{"key":"94891_CR22","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1002\/jmri.23742","volume":"36","author":"B Hargreaves","year":"2012","unstructured":"Hargreaves, B. Rapid gradient-echo imaging. J. Magn. Reson. Imaging 36, 1300\u20131313 (2012).","journal-title":"J. Magn. Reson. Imaging"},{"key":"94891_CR23","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1063\/1.1719961","volume":"37","author":"RR Ernst","year":"1966","unstructured":"Ernst, R. R. Application of Fourier transform spectroscopy to magnetic resonance. Rev. Sci. Instrum. 37, 93 (1966).","journal-title":"Rev. Sci. Instrum."},{"key":"94891_CR24","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1002\/jmri.24542","volume":"39","author":"JP Mugler","year":"2014","unstructured":"Mugler, J. P. Optimized three-dimensional fast-spin-echo MRI. J. Magn. Reson. Imaging 39, 745\u2013767 (2014).","journal-title":"J. Magn. Reson. Imaging"},{"key":"94891_CR25","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1002\/mrm.20816","volume":"55","author":"M Weigel","year":"2006","unstructured":"Weigel, M. & Hennig, J. Contrast behavior and relaxation effects of conventional and hyperecho-turbo spin echo sequences at 1.5 and 3T. Magn. Reson. Med. 55, 826\u2013835 (2006).","journal-title":"Magn. Reson. Med."},{"key":"94891_CR26","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.zemedi.2008.01.008","volume":"18","author":"M Weigel","year":"2008","unstructured":"Weigel, M. & Hennig, J. Development and optimization of T2 weighted methods with reduced RF power deposition (Hyperecho-TSE) for magnetic resonance imaging. Z. Med. Phys. 18, 151\u2013161 (2008).","journal-title":"Z. Med. Phys."},{"key":"94891_CR27","doi-asserted-by":"publisher","first-page":"2705","DOI":"10.1093\/brain\/awh641","volume":"128","author":"A Kutzelnigg","year":"2005","unstructured":"Kutzelnigg, A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705\u20132712 (2005).","journal-title":"Brain"},{"key":"94891_CR28","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1111\/bpa.12813","volume":"30","author":"A Junker","year":"2020","unstructured":"Junker, A. et al. Extensive subpial cortical demyelination is specific to multiple sclerosis. Brain Pathol. 30, 641\u2013652 (2020).","journal-title":"Brain Pathol."},{"key":"94891_CR29","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1002\/ana.1123","volume":"50","author":"JW Peterson","year":"2001","unstructured":"Peterson, J. W., B\u00f6, L., M\u00f6rk, S., Chang, A. & Trapp, B. D. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389\u2013400 (2001).","journal-title":"Ann. Neurol."},{"key":"94891_CR30","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/nrneurol.2010.93","volume":"6","author":"M Calabrese","year":"2010","unstructured":"Calabrese, M., Filippi, M. & Gallo, P. Cortical lesions in multiple sclerosis. Nat. Rev. Neurol. 6, 438\u2013444 (2010).","journal-title":"Nat. Rev. Neurol."},{"key":"94891_CR31","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/nrneurol.2016.59","volume":"12","author":"M Absinta","year":"2016","unstructured":"Absinta, M., Sati, P. & Reich, D. S. Advanced MRI and staging of multiple sclerosis lesions. Nat. Rev. Neurol. 12, 358\u2013368 (2016).","journal-title":"Nat. Rev. Neurol."},{"key":"94891_CR32","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1212\/WNL.0b013e3181b64bf7","volume":"73","author":"C Mainero","year":"2009","unstructured":"Mainero, C. et al. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI. Neurology 73, 941\u2013948 (2009).","journal-title":"Neurology"},{"key":"94891_CR33","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1001\/jamaneurol.2019.2399","volume":"76","author":"M Absinta","year":"2019","unstructured":"Absinta, M. et al. Association of chronic active multiple sclerosis lesions with disability in vivo. JAMA Neurol. 76, 1474\u20131483 (2019).","journal-title":"JAMA Neurol."},{"key":"94891_CR34","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s00401-016-1636-z","volume":"133","author":"A Dal-Bianco","year":"2017","unstructured":"Dal-Bianco, A. et al. Slow expansion of multiple sclerosis iron rim lesions: Pathology and 7 T magnetic resonance imaging. Acta Neuropathol. (Berl.) 133, 25\u201342 (2017).","journal-title":"Acta Neuropathol. (Berl.)"},{"key":"94891_CR35","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1097\/WCO.0000000000000818","volume":"33","author":"M Absinta","year":"2020","unstructured":"Absinta, M., Lassmann, H. & Trapp, B. D. Mechanisms underlying progression in multiple sclerosis. Curr. Opin. Neurol. 33, 277\u2013285 (2020).","journal-title":"Curr. Opin. Neurol."},{"key":"94891_CR36","doi-asserted-by":"publisher","first-page":"2188","DOI":"10.1056\/NEJMoa1100648","volume":"365","author":"CF Lucchinetti","year":"2011","unstructured":"Lucchinetti, C. F. et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365, 2188\u20132197 (2011).","journal-title":"N. Engl. J. Med."},{"key":"94891_CR37","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1093\/brain\/awv398","volume":"139","author":"L Haider","year":"2016","unstructured":"Haider, L. et al. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain. Brain 139, 807\u2013815 (2016).","journal-title":"Brain"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94891-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94891-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94891-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T06:46:25Z","timestamp":1670049985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-94891-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,29]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["94891"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-94891-1","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.01.03.425097","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,29]]},"assertion":[{"value":"7 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Matthias Weigel is funded by the Swiss National Science Fund (SNSF) Grant PP00P3_176984 for multiple sclerosis MRI research and by Biogen Inc. for spinal cord MRI research, he has no conflicts of interest to declare for this work. Po-Jui Lu and Cristina Granziera are funded by the Swiss National Science Fund (SNSF) Grant PP00P3_176984 for multiple sclerosis MRI research, they have no conflicts of interest to declare for this work. Peter Dechent, Riccardo Galbusera, Erik Bahn, Govind Nair, Ludwig Kappos, Wolfgang Br\u00fcck, and Christine Stadelmann have no conflicts of interest to declare for this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15491"}}