{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:29:36Z","timestamp":1787840976728,"version":"build-2784847793"},"reference-count":54,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Traumatic brain injury (TBI) significantly reduces the quality of life for millions of survivors worldwide, causing persistent brain tissue damage and cognitive impairments, with no established therapeutic interventions currently available. Slow\u2010wave activity, a hallmark of deep sleep, has been implicated in recovery after TBI, but pharmacological approaches to enhance it lack specificity and scalability, complicating efforts to identify slow\u2010wave activity as a direct mechanistic contributor and severely limiting clinical translation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To overcome these limitations, we developed a preclinical closed\u2010loop auditory stimulation (CLAS) paradigm that targets sleep's slow waves, enabling highly specific and temporally precise enhancement of slow\u2010wave activity. Therefore, we delivered 30\u2010ms sound triggers targeting the up\u2010phase of real\u2010time detected slow\u2010waves (upCLAS: TBI n\u2009=\u20098), or no sound stimulation (mockCLAS: non\u2010TBI n\u2009=\u20098, TBI n\u2009=\u20097) during sleep to healthy controls (non\u2010TBI) or brain injured (TBI) rats. Concomitantly, we assessed the ability of upCLAS\u2010enhanced sleep to counteract brain tissue damage (primary outcome) and symptomatic sequelae (secondary outcome) of TBI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Bayesian analysis revealed that sound\u2010mediated slow\u2010wave activity enhancement: (1) reduces diffuse axonal injury, with TBI mockCLAS posterior estimates falling outside the 95% confidence intervals of both other groups, whereas the posterior distributions of TBI upCLAS and non\u2010TBI groups largely overlapped (~13% posterior differences &gt;0), consistent with a negligible effect size between groups; (2) decreases demyelination, with approximately 97% posterior differences &gt;0 between TBI mockCLAS and TBI upCLAS groups, compared to approximately 60% between non\u2010TBI and TBI upCLAS groups; and (3) preserves cognitive ability, with recognition indexes in the novel object recognition test significantly above chance level in non\u2010TBI (*\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.031) and TBI upCLAS (*\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.026) groups, in contrast to mockCLAS\u2010treated TBI rats (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.156), presenting pronounced cognitive deficit. Furthermore, microglial response to brain injury was increased by deep sleep enhancement, with reduced ionized calcium\u2010binding adaptor molecule 1+ area coverage in TBI upCLAS rats (*\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0445) compared to non\u2010TBI ones.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>These results unambiguously demonstrate slow\u2010wave activity enhancement confers robust disease modification following TBI while overcoming major limitations of other preclinical approaches. Our findings constitute proof\u2010of\u2010concept that boosted sleep intensity mitigates histopathological and cognitive sequelae of brain trauma, suggesting that a clinically relevant, nonobtrusive, sleep\u2010based therapy may represent a novel therapeutic intervention for TBI survivors. ANN NEUROL 2026;100:242\u2013254<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78234","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:35:37Z","timestamp":1778477737000},"page":"242-254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Auditory Stimulation of Slow\u2010Wave Sleep Promotes Recovery after Brain Injury in an Animal Model"],"prefix":"10.1002","volume":"100","author":[{"given":"Carlos","family":"G. Moreira","sequence":"first","affiliation":[{"name":"Department of Neurology University Hospital Zurich, University of Zurich  Zurich Switzerland"},{"name":"Department of Health Sciences and Technology, D\u2010HEST ETH Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8915-8327","authenticated-orcid":false,"given":"Adrian","family":"M\u00fcllner","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Zurich, University of Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8652-0554","authenticated-orcid":false,"given":"Meltem","family":"G\u00f6nel","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Zurich, University of Zurich  Zurich Switzerland"},{"name":"Department of Neurosurgery University Hospital Zurich, University of Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Zurich, University of Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipe","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa C.","family":"Paolicelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Dias","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Zurich, University of Zurich  Zurich Switzerland"},{"name":"Department of Health Sciences and Technology, D\u2010HEST ETH Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4501-7052","authenticated-orcid":false,"given":"Sergio I.","family":"Nemirovsky","sequence":"additional","affiliation":[{"name":"Institute of Biological Chemistry, School of Exact and Natural Sciences (IQUIBICEN). CONICET \u2013 University of Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3417-1978","authenticated-orcid":false,"given":"Christian R.","family":"Baumann","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Zurich, University of Zurich  Zurich Switzerland"},{"name":"University Center of Competence Sleep and Health Zurich (CRPP), University of Zurich  Zurich Switzerland"},{"name":"Neuroscience Center Zurich (ZNZ)  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5482-7933","authenticated-orcid":false,"given":"Daniela","family":"Noain","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Zurich, University of Zurich  Zurich Switzerland"},{"name":"University Center of Competence Sleep and Health Zurich (CRPP), University of Zurich  Zurich Switzerland"},{"name":"Neuroscience Center Zurich (ZNZ)  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002697"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2016.4618"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3171\/2017.10.JNS17352"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105210"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122600"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.08.018"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034406"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2021.108815"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1241224"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1180962"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1592-13.2013"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe7099"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13179"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00208"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01549-4"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102232"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2024.07.007"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2012.09.037"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2013.30"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3020-14.2014"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3274-15.2016"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.5.2S.S27"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3127-12.2013"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2025.115544"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.68043"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856-022-00096-6"},{"key":"e_1_2_9_28_1","article-title":"Auditory enhancement of sleep slow waves in people with Parkinson's disease: a proof\u2010of\u2010concept study","author":"Schreiner SJ","year":"2025","journal-title":"medRxiv"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2015.4001"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(93)90398-5"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00217"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm216"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11458-9"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2008.0461"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0184811"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsz036"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.796"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2869.2012.01039.x"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15405"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2017.5067"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy348"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2021.01.044"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2019.10.020"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1904709116"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.03882.x"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01548-5"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.03.017"},{"key":"e_1_2_9_48_1","article-title":"Bone marrow mesenchymal stromal cells drive protective M2 microglia polarization after brain trauma","volume":"31","author":"Zanier ER","year":"2014","journal-title":"J Neurotrauma"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2022.09.016"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12917"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2024.11.009"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws322"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104713"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.013"},{"key":"e_1_2_9_55_1","article-title":"EEG slow waves in traumatic brain injury: convergent findings in mouse and man","volume":"1","author":"Modarres M","year":"2016","journal-title":"Neurobiol Sleep Circadian Rhythms"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78234","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.78234","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78234","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:33:36Z","timestamp":1787837616000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.78234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,10]]},"references-count":54,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/ana.78234"],"URL":"https:\/\/doi.org\/10.1002\/ana.78234","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,10]]},"assertion":[{"value":"2025-12-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}