{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:10:15Z","timestamp":1779340215267,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"\n Background<\/jats:title>\n Severe traumatic brain injury (sTBI) often results in prolonged coma and significant long-term disability. Evidence-based, widely accessible approaches to accelerate recovery of consciousness remain limited. This study evaluated whether adding a combined regimen of hyperbaric oxygen therapy (HBOT) and systematic auditory stimulation (SAS) to standard neurosurgical care improves recovery of consciousness and short-term outcomes in comatose patients with sTBI.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this prospective randomized controlled trial, 89 comatose patients with sTBI [Glasgow Coma Scale (GCS)\u202f&lt;\u202f8] were randomized to standard neurosurgical care (control,\n n<\/jats:italic>\n \u202f=\u202f44) or standard care in addition to HBOT and SAS (HBOT+SAS,\n n<\/jats:italic>\n \u202f=\u202f45). HBOT was delivered at a pressure of 2.0 atmospheres absolute (ATA) for 60\u202fmin\/session, five sessions per week for 4\u202fweeks. SAS consisted of structured family-delivered storytelling and music sessions three times daily following a predefined schedule. The primary outcome was the change in the Full Outline of UnResponsiveness (FOUR) score from baseline to Day 28. Secondary outcomes included the GCS and Coma Recovery Scale-Revised (CRS-R) scores, the Glasgow Outcome Scale (GOS) score at 3\u202fmonths, and serum biomarkers [such as S100B, neuron-specific enolase (NSE), and brain-derived neurotrophic factor (BDNF)]; care-related satisfaction was analyzed as an exploratory outcome. Secondary endpoints were interpreted using a prespecified Bonferroni-adjusted threshold (\n p<\/jats:italic>\n \u202f&lt;\u202f0.01).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Compared to the control group, the HBOT+SAS group demonstrated greater improvement in measures of consciousness at Day 28 (FOUR: 12.1\u202f\u00b1\u202f2.4 vs. 9.3\u202f\u00b1\u202f2.1; GCS: 11.3\u202f\u00b1\u202f2.2 vs. 9.1\u202f\u00b1\u202f1.9; CRS-R: 11.8\u202f\u00b1\u202f2.3 vs. 8.1\u202f\u00b1\u202f2.0; all\n p<\/jats:italic>\n \u202f&lt;\u202f0.001). At 3\u202fmonths, the functional outcome was higher in the HBOT+SAS group (GOS: 4.3\u202f\u00b1\u202f0.5 vs. 3.6\u202f\u00b1\u202f0.6,\n p<\/jats:italic>\n \u202f&lt;\u202f0.001). Biomarker patterns indicated a reduction in neuronal injury and an enhancement in neurotrophic activity. Specifically, levels of S100B and NSE were lower in the HBOT+SAS group (both\n p<\/jats:italic>\n \u202f&lt;\u202f0.001), and BDNF was higher (\n p<\/jats:italic>\n \u202f=\u202f0.003) in this group. No serious adverse events related to the intervention were reported. Satisfaction outcomes favored HBOT+SAS (88.89% vs. 59.09%,\n p<\/jats:italic>\n \u202f=\u202f0.005) and were interpreted as exploratory due to the unblinded design of the study.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n The addition of HBOT+SAS to standard care was associated with improved recovery of consciousness and better 3-month functional outcomes in comatose patients with sTBI, supported by consistent findings from clinical scales and serum biomarkers. However, since the trial did not include HBOT-only or SAS-only comparator arms, the findings support the effectiveness of the combined regimen compared to standard care but do not determine whether HBOT and SAS have a synergistic effect.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fneur.2026.1775204","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:38:56Z","timestamp":1779338336000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The awakening effect of hyperbaric oxygen therapy combined with systematic auditory stimulation in comatose patients with craniocerebral injury and its influence on serum biomarkers"],"prefix":"10.3389","volume":"17","author":[{"given":"Jie Li","family":"Rong","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi Xiang","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun Yan","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao Jiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gui Lan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su Ya","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hai'an People's Hospital","place":["Nantong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1097\/00001199-200405000-00006","article-title":"Rehabilitative management of patients with disorders of consciousness: grand rounds","volume":"19","author":"Giacino","year":"2004","journal-title":"J Head Trauma Rehabil"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.3390\/jcm13154527","article-title":"Severe traumatic brain injury and pulmonary embolism: risks, prevention, diagnosis and management","volume":"13","author":"Vrettou","year":"2024","journal-title":"J Clin Med"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1080\/02699052.2021.1972149","article-title":"Management of severe traumatic brain injury in regions with limited resources","volume":"35","author":"Rubiano","year":"2021","journal-title":"Brain Inj"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/nrneurol.2013.22","article-title":"Changing patterns in the epidemiology of traumatic brain injury","volume":"9","author":"Roozenbeek","year":"2013","journal-title":"Nat Rev Neurol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1089\/neu.2011.2134","article-title":"Chinese head trauma data bank: effect of gender on the outcome of patients with acute traumatic brain injury","volume":"38","year":"2021","journal-title":"J Neurotrauma"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.2105\/ajph.2012.301107","article-title":"Reducing traumatic brain injuries in youth sports: youth sports traumatic brain injury state laws, January 2009\u2013December 2012","volume":"103","author":"Harvey","year":"2013","journal-title":"Am J Public Health"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.seizure.2024.03.004","article-title":"Posttraumatic epilepsy in chronic disorders of consciousness due to severe traumatic brain injury after traffic accidents","volume":"117","author":"Yasuda","year":"2024","journal-title":"Seizure"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"609","DOI":"10.3760\/cma.j.cn121430-20200611-00462","article-title":"Combination of apparent diffusion coefficient and amplitude-integrated electroencephalogram to predict the 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fMRI","volume":"359","author":"Peng","year":"2018","journal-title":"Hear Res"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.3892\/etm.2016.3463","article-title":"Successful treatment with hyperbaric oxygen therapy for severe brain edema characterized by radiological appearance of pseudosubarachnoid hemorrhage in a child","volume":"12","author":"Xin","year":"2016","journal-title":"Exp Ther Med"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"508","DOI":"10.3389\/fnhum.2017.00508","article-title":"Hyperbaric oxygen therapy can induce angiogenesis and regeneration of nerve fibers in traumatic brain injury patients","volume":"11","author":"Tal","year":"2017","journal-title":"Front Hum Neurosci"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4331\/wjbc.v4.i1.1","article-title":"S100B protein in tissue development, repair and regeneration","volume":"4","author":"Sorci","year":"2013","journal-title":"World J Biol Chem"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.3390\/biom11081210","article-title":"The effects of hyperbaric oxygenation on oxidative stress, inflammation and angiogenesis","volume":"11","author":"De Wolde","year":"2021","journal-title":"Biomolecules"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3181\/00379727-121-30690","article-title":"Effects of hyperbaric oxygenation metabolism. 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Oxidative phosphorylation in rat brain, liver and kidney","volume":"121","author":"Sanders","year":"1966","journal-title":"Proc Soc Exp Biol Med"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1002\/jnr.25022","article-title":"Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease","volume":"100","author":"Keifer","year":"2022","journal-title":"J Neurosci Res"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1007\/s13311-022-01339-z","article-title":"BDNF augmentation using riluzole reverses doxorubicin-induced decline in cognitive function and neurogenesis","volume":"20","author":"Usmani","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.mcn.2009.09.002","article-title":"Thyroxin regulates BDNF expression to promote survival of injured neurons","volume":"42","author":"Shulga","year":"2009","journal-title":"Mol Cell Neurosci"},{"key":"ref46","first-page":"713","article-title":"Post-intensive care unit rehabilitation: reducing the long-term effects of muscle weakness","volume":"32","author":"Patsaki","year":"2016","journal-title":"Arch Hellen Med"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1775204\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:39:11Z","timestamp":1779338351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1775204\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":46,"alternative-id":["10.3389\/fneur.2026.1775204"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1775204","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,21]]},"article-number":"1775204"}}