Transplantation of Human Neural Precursor Cells Reverses Syrinx Growth in a Rat Model of Post-Traumatic Syringomyelia
Posttraumatic syringomyelia (PTS) is a serious condition of progressive expansion of spinal cord cysts, affecting patients with spinal cord injury years after injury. To evaluate neural cell therapy to prevent cyst expansion and potentially replace lost neurons, we developed a rat model of PTS. We c...
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| Veröffentlicht in: | Neurotherapeutics 2021-04, Vol.18 (2), p.1257-1272 |
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| creator | Xu, Ning Xu, Tingting Mirasol, Raymond Holmberg, Lena Vincent, Per Henrik Li, Xiaofei Falk, Anna Benedikz, Eirikur Rotstein, Emilia Seiger, Åke Åkesson, Elisabet Falci, Scott Sundström, Erik |
| description | Posttraumatic syringomyelia (PTS) is a serious condition of progressive expansion of spinal cord cysts, affecting patients with spinal cord injury years after injury. To evaluate neural cell therapy to prevent cyst expansion and potentially replace lost neurons, we developed a rat model of PTS. We combined contusive trauma with subarachnoid injections of blood, causing tethering of the spinal cord to the surrounding vertebrae, resulting in chronically expanding cysts. The cysts were usually located rostral to the injury, extracanalicular, lined by astrocytes. T2*-weighted magnetic resonance imaging (MRI) showed hyperintense fluid-filled cysts but also hypointense signals from debris and iron-laden macrophages/microglia. Two types of human neural stem/progenitor cells—fetal neural precursor cells (hNPCs) and neuroepithelial-like stem cells (hNESCs) derived from induced pluripotent stem cells—were transplanted to PTS cysts. Cells transplanted into cysts 10 weeks after injury survived at least 10 weeks, migrated into the surrounding parenchyma, but did not differentiate during this period. The cysts were partially obliterated by the cells, and cyst walls often merged with thin layers of cells in between. Cyst volume measurements with MRI showed that the volumes continued to expand in sham-transplanted rats by 102%, while the cyst expansion was effectively prevented by hNPCs and hNESCs transplantation, reducing the cyst volumes by 18.8% and 46.8%, respectively. The volume reductions far exceeded the volume of the added human cells. Thus, in an animal model closely mimicking the clinical situation, we provide proof-of-principle that transplantation of human neural stem/progenitor cells can be used as treatment for PTS. |
| doi_str_mv | 10.1007/s13311-020-00987-3 |
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| fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_465005</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2479422386</sourcerecordid><originalsourceid>FETCH-LOGICAL-c512t-8e6523d3adde0b3d3d6a833dabb65d3e6c5428e68385da28d67190952d4ab17a3</originalsourceid><addsrcrecordid>eNp9UsFu1DAQtRAVLQs_wAFZ4sLFYHvixLkgoRW0SKWtSjlbTjzbpiT21k5a9u_xkqW0HDh55HnzPH7vEfJK8HeC8-p9EgBCMC4547zWFYMn5EDoSrOqqOqnua4BWCUF7JPnKV1zrgBq_YzsAxRlrWV9QKaLaH1a99aPduyCp2FFj6bBenqCU7Q9PYvYTjGFSJfY94me4y3GhIl-28TO_6SHMdyNV7Tz1NJzO9KvwWG_ZTkLaWSZPZONXTvDL8Owwb6zL8jeyvYJX-7OBfn--dPF8ogdnx5-WX48Zq0ScmQaSyXBgXUOeZMLV1oN4GzTlMoBlq0qZAZp0MpZqV1ZiZrXSrrCNqKysCBs5k13uJ4as47dYOPGBNuZ3dWPXKEpSrVVZ0E-zPjcGdC16MeswaOxxx3fXZnLcGt0IaEGnQne7ghiuJkwjWboUpuFsx7DlIzMxhRSgi4z9M0_0OswRZ_lMFJld1Q1byRnVBtDShFX98sIbrYpMHMKTE6B-Z0CA3no9cNv3I_8sT0DYKfLeusKxr9v_4f2FwKuv_E</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2569857005</pqid></control><display><type>article</type><title>Transplantation of Human Neural Precursor Cells Reverses Syrinx Growth in a Rat Model of Post-Traumatic Syringomyelia</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>SWEPUB Freely available online</source><creator>Xu, Ning ; Xu, Tingting ; Mirasol, Raymond ; Holmberg, Lena ; Vincent, Per Henrik ; Li, Xiaofei ; Falk, Anna ; Benedikz, Eirikur ; Rotstein, Emilia ; Seiger, Åke ; Åkesson, Elisabet ; Falci, Scott ; Sundström, Erik</creator><creatorcontrib>Xu, Ning ; Xu, Tingting ; Mirasol, Raymond ; Holmberg, Lena ; Vincent, Per Henrik ; Li, Xiaofei ; Falk, Anna ; Benedikz, Eirikur ; Rotstein, Emilia ; Seiger, Åke ; Åkesson, Elisabet ; Falci, Scott ; Sundström, Erik</creatorcontrib><description>Posttraumatic syringomyelia (PTS) is a serious condition of progressive expansion of spinal cord cysts, affecting patients with spinal cord injury years after injury. To evaluate neural cell therapy to prevent cyst expansion and potentially replace lost neurons, we developed a rat model of PTS. We combined contusive trauma with subarachnoid injections of blood, causing tethering of the spinal cord to the surrounding vertebrae, resulting in chronically expanding cysts. The cysts were usually located rostral to the injury, extracanalicular, lined by astrocytes. T2*-weighted magnetic resonance imaging (MRI) showed hyperintense fluid-filled cysts but also hypointense signals from debris and iron-laden macrophages/microglia. Two types of human neural stem/progenitor cells—fetal neural precursor cells (hNPCs) and neuroepithelial-like stem cells (hNESCs) derived from induced pluripotent stem cells—were transplanted to PTS cysts. Cells transplanted into cysts 10 weeks after injury survived at least 10 weeks, migrated into the surrounding parenchyma, but did not differentiate during this period. The cysts were partially obliterated by the cells, and cyst walls often merged with thin layers of cells in between. Cyst volume measurements with MRI showed that the volumes continued to expand in sham-transplanted rats by 102%, while the cyst expansion was effectively prevented by hNPCs and hNESCs transplantation, reducing the cyst volumes by 18.8% and 46.8%, respectively. The volume reductions far exceeded the volume of the added human cells. Thus, in an animal model closely mimicking the clinical situation, we provide proof-of-principle that transplantation of human neural stem/progenitor cells can be used as treatment for PTS.</description><identifier>ISSN: 1933-7213</identifier><identifier>ISSN: 1878-7479</identifier><identifier>EISSN: 1878-7479</identifier><identifier>DOI: 10.1007/s13311-020-00987-3</identifier><identifier>PMID: 33469829</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Animal models ; Animals ; Astrocytes ; Biomedical and Life Sciences ; Biomedicine ; Cell therapy ; Cells, Cultured ; Cysts ; Disease Models, Animal ; Embryonic Stem Cells - transplantation ; Female ; Fetuses ; Humans ; Induced Pluripotent Stem Cells - transplantation ; Macrophages ; Magnetic resonance imaging ; Microglia ; Mimicry ; Neural stem cells ; Neurobiology ; Neurology ; Neurosciences ; Neurosurgery ; Original ; Original Article ; Parenchyma ; Pluripotency ; Progenitor cells ; Rats ; Rats, Sprague-Dawley ; Spinal cord ; Spinal cord injuries ; Spinal Cord Injuries - complications ; Spinal Cord Injuries - pathology ; Spinal Cord Injuries - therapy ; Spine ; Stem cell transplantation ; Stem Cell Transplantation - methods ; Stem cells ; Syringomyelia - etiology ; Syringomyelia - pathology ; Syringomyelia - therapy ; Thoracic Vertebrae - injuries ; Trauma ; Vertebrae</subject><ispartof>Neurotherapeutics, 2021-04, Vol.18 (2), p.1257-1272</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c512t-8e6523d3adde0b3d3d6a833dabb65d3e6c5428e68385da28d67190952d4ab17a3</citedby><cites>FETCH-LOGICAL-c512t-8e6523d3adde0b3d3d6a833dabb65d3e6c5428e68385da28d67190952d4ab17a3</cites><orcidid>0000-0003-2931-8015</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423938/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423938/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33469829$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:145713026$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Ning</creatorcontrib><creatorcontrib>Xu, Tingting</creatorcontrib><creatorcontrib>Mirasol, Raymond</creatorcontrib><creatorcontrib>Holmberg, Lena</creatorcontrib><creatorcontrib>Vincent, Per Henrik</creatorcontrib><creatorcontrib>Li, Xiaofei</creatorcontrib><creatorcontrib>Falk, Anna</creatorcontrib><creatorcontrib>Benedikz, Eirikur</creatorcontrib><creatorcontrib>Rotstein, Emilia</creatorcontrib><creatorcontrib>Seiger, Åke</creatorcontrib><creatorcontrib>Åkesson, Elisabet</creatorcontrib><creatorcontrib>Falci, Scott</creatorcontrib><creatorcontrib>Sundström, Erik</creatorcontrib><title>Transplantation of Human Neural Precursor Cells Reverses Syrinx Growth in a Rat Model of Post-Traumatic Syringomyelia</title><title>Neurotherapeutics</title><addtitle>Neurotherapeutics</addtitle><addtitle>Neurotherapeutics</addtitle><description>Posttraumatic syringomyelia (PTS) is a serious condition of progressive expansion of spinal cord cysts, affecting patients with spinal cord injury years after injury. To evaluate neural cell therapy to prevent cyst expansion and potentially replace lost neurons, we developed a rat model of PTS. We combined contusive trauma with subarachnoid injections of blood, causing tethering of the spinal cord to the surrounding vertebrae, resulting in chronically expanding cysts. The cysts were usually located rostral to the injury, extracanalicular, lined by astrocytes. T2*-weighted magnetic resonance imaging (MRI) showed hyperintense fluid-filled cysts but also hypointense signals from debris and iron-laden macrophages/microglia. Two types of human neural stem/progenitor cells—fetal neural precursor cells (hNPCs) and neuroepithelial-like stem cells (hNESCs) derived from induced pluripotent stem cells—were transplanted to PTS cysts. Cells transplanted into cysts 10 weeks after injury survived at least 10 weeks, migrated into the surrounding parenchyma, but did not differentiate during this period. The cysts were partially obliterated by the cells, and cyst walls often merged with thin layers of cells in between. Cyst volume measurements with MRI showed that the volumes continued to expand in sham-transplanted rats by 102%, while the cyst expansion was effectively prevented by hNPCs and hNESCs transplantation, reducing the cyst volumes by 18.8% and 46.8%, respectively. The volume reductions far exceeded the volume of the added human cells. Thus, in an animal model closely mimicking the clinical situation, we provide proof-of-principle that transplantation of human neural stem/progenitor cells can be used as treatment for PTS.</description><subject>Animal models</subject><subject>Animals</subject><subject>Astrocytes</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell therapy</subject><subject>Cells, Cultured</subject><subject>Cysts</subject><subject>Disease Models, Animal</subject><subject>Embryonic Stem Cells - transplantation</subject><subject>Female</subject><subject>Fetuses</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - transplantation</subject><subject>Macrophages</subject><subject>Magnetic resonance imaging</subject><subject>Microglia</subject><subject>Mimicry</subject><subject>Neural stem cells</subject><subject>Neurobiology</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Neurosurgery</subject><subject>Original</subject><subject>Original Article</subject><subject>Parenchyma</subject><subject>Pluripotency</subject><subject>Progenitor cells</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Spinal cord</subject><subject>Spinal cord injuries</subject><subject>Spinal Cord Injuries - complications</subject><subject>Spinal Cord Injuries - pathology</subject><subject>Spinal Cord Injuries - therapy</subject><subject>Spine</subject><subject>Stem cell transplantation</subject><subject>Stem Cell Transplantation - methods</subject><subject>Stem cells</subject><subject>Syringomyelia - etiology</subject><subject>Syringomyelia - pathology</subject><subject>Syringomyelia - therapy</subject><subject>Thoracic Vertebrae - injuries</subject><subject>Trauma</subject><subject>Vertebrae</subject><issn>1933-7213</issn><issn>1878-7479</issn><issn>1878-7479</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>D8T</sourceid><recordid>eNp9UsFu1DAQtRAVLQs_wAFZ4sLFYHvixLkgoRW0SKWtSjlbTjzbpiT21k5a9u_xkqW0HDh55HnzPH7vEfJK8HeC8-p9EgBCMC4547zWFYMn5EDoSrOqqOqnua4BWCUF7JPnKV1zrgBq_YzsAxRlrWV9QKaLaH1a99aPduyCp2FFj6bBenqCU7Q9PYvYTjGFSJfY94me4y3GhIl-28TO_6SHMdyNV7Tz1NJzO9KvwWG_ZTkLaWSZPZONXTvDL8Owwb6zL8jeyvYJX-7OBfn--dPF8ogdnx5-WX48Zq0ScmQaSyXBgXUOeZMLV1oN4GzTlMoBlq0qZAZp0MpZqV1ZiZrXSrrCNqKysCBs5k13uJ4as47dYOPGBNuZ3dWPXKEpSrVVZ0E-zPjcGdC16MeswaOxxx3fXZnLcGt0IaEGnQne7ghiuJkwjWboUpuFsx7DlIzMxhRSgi4z9M0_0OswRZ_lMFJld1Q1byRnVBtDShFX98sIbrYpMHMKTE6B-Z0CA3no9cNv3I_8sT0DYKfLeusKxr9v_4f2FwKuv_E</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Xu, Ning</creator><creator>Xu, Tingting</creator><creator>Mirasol, Raymond</creator><creator>Holmberg, Lena</creator><creator>Vincent, Per Henrik</creator><creator>Li, Xiaofei</creator><creator>Falk, Anna</creator><creator>Benedikz, Eirikur</creator><creator>Rotstein, Emilia</creator><creator>Seiger, Åke</creator><creator>Åkesson, Elisabet</creator><creator>Falci, Scott</creator><creator>Sundström, Erik</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0003-2931-8015</orcidid></search><sort><creationdate>20210401</creationdate><title>Transplantation of Human Neural Precursor Cells Reverses Syrinx Growth in a Rat Model of Post-Traumatic Syringomyelia</title><author>Xu, Ning ; Xu, Tingting ; Mirasol, Raymond ; Holmberg, Lena ; Vincent, Per Henrik ; Li, Xiaofei ; Falk, Anna ; Benedikz, Eirikur ; Rotstein, Emilia ; Seiger, Åke ; Åkesson, Elisabet ; Falci, Scott ; Sundström, Erik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c512t-8e6523d3adde0b3d3d6a833dabb65d3e6c5428e68385da28d67190952d4ab17a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Astrocytes</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cell therapy</topic><topic>Cells, Cultured</topic><topic>Cysts</topic><topic>Disease Models, Animal</topic><topic>Embryonic Stem Cells - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Neurotherapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Ning</au><au>Xu, Tingting</au><au>Mirasol, Raymond</au><au>Holmberg, Lena</au><au>Vincent, Per Henrik</au><au>Li, Xiaofei</au><au>Falk, Anna</au><au>Benedikz, Eirikur</au><au>Rotstein, Emilia</au><au>Seiger, Åke</au><au>Åkesson, Elisabet</au><au>Falci, Scott</au><au>Sundström, Erik</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transplantation of Human Neural Precursor Cells Reverses Syrinx Growth in a Rat Model of Post-Traumatic Syringomyelia</atitle><jtitle>Neurotherapeutics</jtitle><stitle>Neurotherapeutics</stitle><addtitle>Neurotherapeutics</addtitle><date>2021-04-01</date><risdate>2021</risdate><volume>18</volume><issue>2</issue><spage>1257</spage><epage>1272</epage><pages>1257-1272</pages><issn>1933-7213</issn><issn>1878-7479</issn><eissn>1878-7479</eissn><abstract>Posttraumatic syringomyelia (PTS) is a serious condition of progressive expansion of spinal cord cysts, affecting patients with spinal cord injury years after injury. To evaluate neural cell therapy to prevent cyst expansion and potentially replace lost neurons, we developed a rat model of PTS. We combined contusive trauma with subarachnoid injections of blood, causing tethering of the spinal cord to the surrounding vertebrae, resulting in chronically expanding cysts. The cysts were usually located rostral to the injury, extracanalicular, lined by astrocytes. T2*-weighted magnetic resonance imaging (MRI) showed hyperintense fluid-filled cysts but also hypointense signals from debris and iron-laden macrophages/microglia. Two types of human neural stem/progenitor cells—fetal neural precursor cells (hNPCs) and neuroepithelial-like stem cells (hNESCs) derived from induced pluripotent stem cells—were transplanted to PTS cysts. Cells transplanted into cysts 10 weeks after injury survived at least 10 weeks, migrated into the surrounding parenchyma, but did not differentiate during this period. The cysts were partially obliterated by the cells, and cyst walls often merged with thin layers of cells in between. Cyst volume measurements with MRI showed that the volumes continued to expand in sham-transplanted rats by 102%, while the cyst expansion was effectively prevented by hNPCs and hNESCs transplantation, reducing the cyst volumes by 18.8% and 46.8%, respectively. The volume reductions far exceeded the volume of the added human cells. Thus, in an animal model closely mimicking the clinical situation, we provide proof-of-principle that transplantation of human neural stem/progenitor cells can be used as treatment for PTS.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>33469829</pmid><doi>10.1007/s13311-020-00987-3</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-2931-8015</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Neurotherapeutics, 2021-04, Vol.18 (2), p.1257-1272 |
| issn | 1933-7213 1878-7479 1878-7479 |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; SWEPUB Freely available online |
| subjects | Animal models Animals Astrocytes Biomedical and Life Sciences Biomedicine Cell therapy Cells, Cultured Cysts Disease Models, Animal Embryonic Stem Cells - transplantation Female Fetuses Humans Induced Pluripotent Stem Cells - transplantation Macrophages Magnetic resonance imaging Microglia Mimicry Neural stem cells Neurobiology Neurology Neurosciences Neurosurgery Original Original Article Parenchyma Pluripotency Progenitor cells Rats Rats, Sprague-Dawley Spinal cord Spinal cord injuries Spinal Cord Injuries - complications Spinal Cord Injuries - pathology Spinal Cord Injuries - therapy Spine Stem cell transplantation Stem Cell Transplantation - methods Stem cells Syringomyelia - etiology Syringomyelia - pathology Syringomyelia - therapy Thoracic Vertebrae - injuries Trauma Vertebrae |
| title | Transplantation of Human Neural Precursor Cells Reverses Syrinx Growth in a Rat Model of Post-Traumatic Syringomyelia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T17%3A53%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Transplantation%20of%20Human%20Neural%20Precursor%20Cells%20Reverses%20Syrinx%20Growth%20in%20a%20Rat%20Model%20of%20Post-Traumatic%20Syringomyelia&rft.jtitle=Neurotherapeutics&rft.au=Xu,%20Ning&rft.date=2021-04-01&rft.volume=18&rft.issue=2&rft.spage=1257&rft.epage=1272&rft.pages=1257-1272&rft.issn=1933-7213&rft.eissn=1878-7479&rft_id=info:doi/10.1007/s13311-020-00987-3&rft_dat=%3Cproquest_swepu%3E2479422386%3C/proquest_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2569857005&rft_id=info:pmid/33469829&rfr_iscdi=true |