{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:45:07Z","timestamp":1792644307155,"version":"4.5.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T00:00:00Z","timestamp":1543536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Neuromyelitis optica spectrum disorders (herein called NMO) is an autoimmune disease of the CNS characterized by astrocyte injury, inflammation, and demyelination. In seropositive NMO, immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG) cause primary astrocyte injury. A passive transfer model of NMO was developed in which spatially targeted access of AQP4-IgG into the CNS of seropositive rats was accomplished by pulsed focused ultrasound through intact skin. Following intravenous administration of microbubbles, pulsed ultrasound at 0.5\u2009MPa peak acoustic pressure was applied using a 1\u2009MHz transducer with 6-cm focal length. In brain, the transient opening of the blood-brain barrier (BBB) in an approximately prolate ellipsoidal volume of diameter \u223c3.5\u2009mm and length \u223c44\u2009mm allowed entry of IgG-size molecules for up to 3\u20136 hours. The ultrasound treatment did not cause erythrocyte extravasation or inflammation. Ultrasound treatment in AQP4-IgG seropositive rats produced localized NMO pathology in brain, with characteristic astrocyte injury, inflammation, and demyelination after 5 days. Pathology was not seen when complement was inhibited, when non-NMO human IgG was administered instead of AQP4-IgG, or in AQP4-IgG seropositive AQP4 knockout rats. NMO pathology was similarly created in cervical spinal cord in seropositive rats. These results establish a noninvasive, spatially targeted model of NMO in rats, and demonstrate that BBB permeabilization, without underlying injury or inflammation, is sufficient to create NMO pathology in AQP4-IgG seropositive rats.<\/jats:p>","DOI":"10.1093\/jnen\/nly107","type":"journal-article","created":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T10:55:52Z","timestamp":1543575352000},"page":"47-56","source":"Crossref","is-referenced-by-count":13,"title":["Noninvasive, Targeted Creation of Neuromyelitis Optica Pathology in AQP4-IgG Seropositive Rats by Pulsed Focused Ultrasound"],"prefix":"10.1093","volume":"78","author":[{"given":"Xiaoming","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Medicine and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Medicine and Physiology"},{"name":"Thermal Therapy Research Group, Department of Radiation Oncology, University of California, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D","family":"Jones","sequence":"additional","affiliation":[{"name":"Thermal Therapy Research Group, Department of Radiation Oncology, University of California, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J","family":"Diederich","sequence":"additional","affiliation":[{"name":"Thermal Therapy Research Group, Department of Radiation Oncology, University of California, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan S","family":"Verkman","sequence":"additional","affiliation":[{"name":"Department of Medicine and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,11,30]]},"reference":[{"key":"2019072508100941600_nly107-B1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1084\/jem.20050304","article-title":"IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel","volume":"202","author":"Lennon","year":"2005","journal-title":"J Exp Med"},{"key":"2019072508100941600_nly107-B2","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nrneurol.2010.72","article-title":"AQP4 antibodies in neuromyelitis optica diagnostic and pathogenetic relevance","volume":"6","author":"Jarius","year":"2010","journal-title":"Nat Rev Neurol"},{"key":"2019072508100941600_nly107-B3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jns.2011.02.018","article-title":"Neuromyelitis optica and astrocytic damage in its pathogenesis","volume":"306","author":"Fujihara","year":"2011","journal-title":"J Neurol Sci"},{"key":"2019072508100941600_nly107-B4","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1474-4422(12)70133-3","article-title":"Aquaporin 4 and neuromyelitis optica","volume":"11","author":"Papadopoulos","year":"2012","journal-title":"Lancet Neurol"},{"key":"2019072508100941600_nly107-B5","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.neuropharm.2018.02.002","article-title":"Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in\u00a0vitro and rat models of neuromyelitis optica","volume":"133","author":"Tradtrantip","year":"2018","journal-title":"Neuropharmacology"},{"key":"2019072508100941600_nly107-B6","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s00401-015-1501-5","article-title":"Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS","volume":"130","author":"Zeka","year":"2015","journal-title":"Acta Neuropathol"},{"key":"2019072508100941600_nly107-B7","doi-asserted-by":"crossref","first-page":"14781","DOI":"10.1073\/pnas.1617859114","article-title":"Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4","volume":"113","author":"Sagan","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"2019072508100941600_nly107-B8","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s00401-013-1172-z","article-title":"Involvement of antibody-dependent cell-mediated cytotoxicity in inflammatory demyelination in a mouse model of neuromyelitis optica","volume":"126","author":"Ratelade","year":"2013","journal-title":"Acta Neuropathol"},{"key":"2019072508100941600_nly107-B9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00401-011-0824-0","article-title":"Pathogenic T cell responses against aquaporin 4","volume":"122","author":"Pohl","year":"2011","journal-title":"Acta Neuropathol"},{"key":"2019072508100941600_nly107-B10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00401-017-1734-6","article-title":"Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica","volume":"134","author":"Tradtrantip","year":"2017","journal-title":"Acta Neuropathol"},{"key":"2019072508100941600_nly107-B11","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrneurol.2014.141","article-title":"Treatment of neuromyelitis optica: State-of-the-art and emerging therapies","volume":"10","author":"Papadopoulos","year":"2014","journal-title":"Nat Rev Neurol"},{"key":"2019072508100941600_nly107-B12","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/bpa.12098","article-title":"Experimental models of neuromyelitis optica","volume":"24","author":"Bradl","year":"2014","journal-title":"Brain Pathol"},{"key":"2019072508100941600_nly107-B13","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s12264-015-1552-6","article-title":"Experimental models of neuromyelitis optica: Current status, challenges and future directions","volume":"31","author":"Li","year":"2015","journal-title":"Neurosci Bull"},{"key":"2019072508100941600_nly107-B14","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.msard.2012.06.003","article-title":"Review of animal models of neuromyelitis optica","volume":"1","author":"Jones","year":"2012","journal-title":"Mult Scler Relat Disord"},{"key":"2019072508100941600_nly107-B15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1177\/0300985817712794","article-title":"Experimental models of autoimmune demyelinating diseases in nonhuman primates","volume":"55","author":"Stimmer","year":"2018","journal-title":"Vet Pathol"},{"key":"2019072508100941600_nly107-B16","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1093\/brain\/awl371","article-title":"Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis","volume":"130","author":"Roemer","year":"2007","journal-title":"Brain"},{"key":"2019072508100941600_nly107-B17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/cei.12271","article-title":"Neuromyelitis optica: Clinical features, immunopathogenesis and treatment","volume":"176","author":"Jarius","year":"2014","journal-title":"Clin Exp Immunol"},{"key":"2019072508100941600_nly107-B18","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/brain\/awp309","article-title":"Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice","volume":"133","author":"Saadoun","year":"2010","journal-title":"Brain"},{"key":"2019072508100941600_nly107-B19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12974-016-0577-8","article-title":"Neuromyelitis optica study model based on chronic infusion of autoantibodies in rat cerebrospinal fluid","volume":"13","author":"Marignier","year":"2016","journal-title":"J Neuroinflamm"},{"key":"2019072508100941600_nly107-B20","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00401-013-1204-8","article-title":"Unique neuromyelitis optica pathology produced in naive rats by intracerebral administration of NMO-IgG","volume":"127","author":"Asavapanumas","year":"2014","journal-title":"Acta Neuropathol"},{"key":"2019072508100941600_nly107-B21","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1172\/JCI67554","article-title":"Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica","volume":"123","author":"Zhang","year":"2013","journal-title":"J Clin Invest"},{"key":"2019072508100941600_nly107-B22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jaut.2014.02.011","article-title":"Longitudinally extensive NMO spinal cord pathology produced by passive transfer of NMO-IgG in mice lacking complement inhibitor CD59","volume":"53","author":"Zhang","year":"2014","journal-title":"J Autoimmun"},{"key":"2019072508100941600_nly107-B23","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s00401-013-1220-8","article-title":"Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions","volume":"127","author":"Wrzos","year":"2014","journal-title":"Acta Neuropathol"},{"key":"2019072508100941600_nly107-B24","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.expneurol.2014.12.015","article-title":"The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model","volume":"265","author":"Geis","year":"2015","journal-title":"Exp Neurol"},{"key":"2019072508100941600_nly107-B25","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/2051-5960-2-48","article-title":"Neuromyelitis optica pathology in rats following intraperitoneal injection of NMO-IgG and intracerebral needle injury","volume":"2","author":"Asavapanumas","year":"2014","journal-title":"Acta Neuropathol Commun"},{"key":"2019072508100941600_nly107-B26","doi-asserted-by":"crossref","first-page":"e27412","DOI":"10.1371\/journal.pone.0027412","article-title":"Intravenous neuromyelitis optica autoantibody in mice targets aquaporin-4 in peripheral organs and area postrema","volume":"6","author":"Ratelade","year":"2011","journal-title":"PLoS One"},{"key":"2019072508100941600_nly107-B27","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1212\/WNL.0b013e3181a82621","article-title":"A case of NMO seropositive for aquaporin-4 antibody more than 10 years before onset","volume":"72","author":"Nishiyama","year":"2009","journal-title":"Neurology"},{"key":"2019072508100941600_nly107-B28","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/ana.21802","article-title":"Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica","volume":"66","author":"Bennett","year":"2009","journal-title":"Ann Neurol"},{"key":"2019072508100941600_nly107-B29","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/2051-5960-1-5","article-title":"Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats","volume":"1","author":"Kitic","year":"2013","journal-title":"Acta Neuropathol Commun"},{"key":"2019072508100941600_nly107-B30","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/ana.21837","article-title":"Neuromyelitis optica: Pathogenicity of patient immunoglobulin in\u00a0vivo","volume":"66","author":"Bradl","year":"2009","journal-title":"Ann Neurol"},{"key":"2019072508100941600_nly107-B31","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1158\/0008-5472.CAN-12-0128","article-title":"Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: Safety and efficacy evaluation in rhesus macaques","volume":"72","author":"McDannold","year":"2012","journal-title":"Cancer Res"},{"key":"2019072508100941600_nly107-B32","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1109\/TUFFC.2013.6644731","article-title":"Dependence of the reversibility of focused-ultrasound-induced blood-brain barrier opening on pressure and pulse length in\u00a0vivo","volume":"60","author":"Samiotaki","year":"2013","journal-title":"IEEE Trans Ultrason Ferroelectr Freq Control"},{"key":"2019072508100941600_nly107-B33","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.ultrasmedbio.2011.01.008","article-title":"Focused-ultrasound disruption of the blood-brain barrier using closely-timed short pulses: Influence of sonication parameters and injection rate","volume":"37","author":"O\u2019Reilly","year":"2011","journal-title":"Ultrasound Med Biol"},{"key":"2019072508100941600_nly107-B34","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1038\/jcbfm.2012.100","article-title":"Dynamic study of blood-brain barrier closure after its disruption using ultrasound: A quantitative analysis","volume":"32","author":"Marty","year":"2012","journal-title":"J Cereb Blood Flow Metab"},{"key":"2019072508100941600_nly107-B35","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.ultrasmedbio.2015.10.009","article-title":"Safety validation of repeated blood-brain barrier disruption using focused ultrasound","volume":"42","author":"Kobus","year":"2016","journal-title":"Ultrasound Med Biol"},{"key":"2019072508100941600_nly107-B36","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/gt.2015.25","article-title":"Gene delivery to the spinal cord using MRI-guided focused ultrasound","volume":"22","author":"Weber-Adrian","year":"2015","journal-title":"Gene Ther"},{"key":"2019072508100941600_nly107-B37","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.4103\/1673-5374.221162","article-title":"Magnetic resonance imaging-guided focused ultrasound to increase localized blood-spinal cord barrier permeability","volume":"12","author":"Payne","year":"2017","journal-title":"Neural Regen Res"},{"key":"2019072508100941600_nly107-B38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40478-017-0417-9","article-title":"Marked central nervous system pathology in CD59 knockout rats following passive transfer of neuromyelitis optica immunoglobulin G","volume":"5","author":"Yao","year":"2017","journal-title":"Acta Neuropathol Commun"},{"key":"2019072508100941600_nly107-B39","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1016\/j.ultrasmedbio.2011.08.001","article-title":"Ultrasound insertion loss of rat parietal bone appears to be proportional to animal mass at submegahertz frequencies","volume":"37","author":"O\u2019Reilly","year":"2011","journal-title":"Ultrasound Med Biol"},{"key":"2019072508100941600_nly107-B40","volume-title":"The Rat Brain in Stereotaxic Coordinates","author":"Paxinos","year":"2007","edition":"6th ed"},{"key":"2019072508100941600_nly107-B41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s40478-017-0462-4","article-title":"Complement regulator CD59 prevents peripheral organ injury in rats made seropositive for neuromyelitis optica immunoglobulin G","volume":"5","author":"Yao","year":"2017","journal-title":"Acta Neuropathol Commun"},{"key":"2019072508100941600_nly107-B42","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/1471-2377-13-104","article-title":"Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis","volume":"13","author":"Saini","year":"2013","journal-title":"BMC Neurol"},{"key":"2019072508100941600_nly107-B43","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/2051-5960-1-85","article-title":"T cell-activation in neuromyelitis optica lesions plays a role in their formation","volume":"1","author":"Pohl","year":"2013","journal-title":"Acta Neuropathol Commun"},{"key":"2019072508100941600_nly107-B44","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ddtec.2016.07.007","article-title":"Ultrasound-mediated drug delivery to the brain: Principles, progress and prospects","volume":"20","author":"Dasgupta","year":"2016","journal-title":"Drug Discov Today Technol"},{"key":"2019072508100941600_nly107-B45","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.neuropharm.2016.02.014","article-title":"Noninvasive and targeted delivery of therapeutics to the brain using focused ultrasound","volume":"120","author":"Poon","year":"2017","journal-title":"Neuropharmacology"},{"key":"2019072508100941600_nly107-B46","doi-asserted-by":"crossref","first-page":"e27877","DOI":"10.1371\/journal.pone.0027877","article-title":"Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier","volume":"6","author":"Burgess","year":"2011","journal-title":"PLoS One"},{"key":"2019072508100941600_nly107-B47","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jconrel.2016.10.011","article-title":"Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption","volume":"250","author":"Park","year":"2017","journal-title":"J Control Release"},{"key":"2019072508100941600_nly107-B48","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.brainres.2017.10.015","article-title":"Investigating the efficacy of a combination Abeta-targeted treatment in a mouse model of Alzheimer\u2019s disease","volume":"1678","author":"Liu","year":"2018","journal-title":"Brain Res"},{"key":"2019072508100941600_nly107-B49","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.7150\/thno.5576","article-title":"Optimization of the ultrasound-induced blood-brain barrier opening","volume":"2","author":"Konofagou","year":"2012","journal-title":"Theranostics"},{"key":"2019072508100941600_nly107-B50","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.jconrel.2017.07.004","article-title":"Ultrasound targeted CNS gene delivery for Parkinson\u2019s disease treatment","volume":"261","author":"Fan","year":"2017","journal-title":"J Control Release"},{"key":"2019072508100941600_nly107-B51","doi-asserted-by":"crossref","first-page":"3989","DOI":"10.7150\/thno.21630","article-title":"Acute inflammatory response following increased blood-brain barrier permeability induced by focused ultrasound is dependent on microbubble dose","volume":"7","author":"McMahon","year":"2017","journal-title":"Theranostics"},{"key":"2019072508100941600_nly107-B52","doi-asserted-by":"crossref","first-page":"e45783","DOI":"10.1371\/journal.pone.0045783","article-title":"Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring","volume":"7","author":"Arvanitis","year":"2012","journal-title":"PLoS One"},{"key":"2019072508100941600_nly107-B53","doi-asserted-by":"crossref","first-page":"33264","DOI":"10.1038\/srep33264","article-title":"Focused ultrasound-induced blood-brain barrier opening: Association with mechanical index and cavitation index analyzed by Dynamic contrast-enhanced magnetic-resonance imaging","volume":"6","author":"Chu","year":"2016","journal-title":"Sci Rep"}],"container-title":["Journal of Neuropathology &amp; Experimental Neurology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jnen\/article-pdf\/78\/1\/47\/28999252\/nly107.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T23:38:19Z","timestamp":1569281899000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jnen\/article\/78\/1\/47\/5222659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,30]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,11,30]]},"published-print":{"date-parts":[[2019,1,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jnen\/nly107","relation":{},"ISSN":["0022-3069","1554-6578"],"issn-type":[{"value":"0022-3069","type":"print"},{"value":"1554-6578","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,1]]},"published":{"date-parts":[[2018,11,30]]}}}