{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:59:18Z","timestamp":1790312358843,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 112-2314-B-002-219"],"award-info":[{"award-number":["NSTC 112-2314-B-002-219"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NSTC 112-2314-B-002-219"],"award-info":[{"award-number":["NSTC 112-2314-B-002-219"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU114-MF-49"],"award-info":[{"award-number":["CMU114-MF-49"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CMU114-MF-49"],"award-info":[{"award-number":["CMU114-MF-49"]}],"id":[{"id":"https:\/\/ror.org\/00v408z34","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Taiwan University Hospital Foundation","award":["114-S0206"],"award-info":[{"award-number":["114-S0206"]}],"id":[{"id":"https:\/\/ror.org\/03nteze27","id-type":"ROR","asserted-by":"crossref"}]},{"award":["114-S0206"],"award-info":[{"award-number":["114-S0206"]}],"id":[{"id":"https:\/\/ror.org\/03nteze27","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Ischemic stroke remains a leading cause of long-term disability worldwide, and effective neurorehabilitative strategies to enhance functional recovery are limited. This preclinical study compared noninvasive low-intensity pulsed ultrasound (LIPUS), aerobic exercise (AE) rehabilitation, and their combination in a mouse model of ischemic stroke. Transient focal cerebral ischemia was induced in male C57BL\/6 mice using middle cerebral artery occlusion (MCAO). Male mice assigned to LIPUS-containing groups received LIPUS preconditioning for three consecutive days before MCAO, followed by two days of recovery and 14 days of post-stroke LIPUS, running wheel-based AE, or combined treatment. Functional recovery was assessed using open-field activity, neurological deficit scoring, and rotarod performance. Histological, immunohistochemical, TUNEL, and Western blot analyses were performed. MCAO caused marked motor and neurological impairments and brain tissue injury. LIPUS, AE, and their combination improved functional and histopathological outcomes, with the combined treatment showing greater effects for selected outcomes. All three interventions increased FNDC5 and BDNF and reduced TUNEL positivity. LIPUS and combined treatment, but not AE alone, increased SOD2 and catalase and reduced 8-OHdG immunoreactivity. These findings provide proof-of-concept in male mice to support further investigation of LIPUS combined with exercise rehabilitation for ischemic stroke recovery.<\/jats:p>","DOI":"10.3390\/ijms27198498","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:03:26Z","timestamp":1790172206000},"page":"8498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Transcranial Ultrasound Stimulation with Exercise-Based Rehabilitation for Ischemic Stroke Recovery: A Preclinical Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Chang-Mu","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, College of Medicine and Hospital, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Yu","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin-Hwa","family":"Long","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, College of Medicine and Hospital, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7240-8465","authenticated-orcid":false,"given":"Cheng-Tien","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nutrition, China Medical University, Taichung 406040, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-1197","authenticated-orcid":false,"given":"Shing-Hwa","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"},{"name":"Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 406040, Taiwan"},{"name":"Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1177\/17474930241308142","article-title":"World Stroke Organization: Global Stroke Fact Sheet 2025","volume":"20","author":"Feigin","year":"2025","journal-title":"Int. J. Stroke"},{"key":"ref_2","unstructured":"World Stroke Organization (WSO) (2025). About Stroke: Impact of Stroke [Internet], World Stroke Organization. Available online: https:\/\/www.world-stroke.org\/world-stroke-day-campaign\/about-stroke\/impact-of-stroke."},{"key":"ref_3","unstructured":"GBD 2019 Stroke Collaborators (2021). Global, regional, and national burden of stroke and its risk factors, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol., 20, 795\u2013820."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.4103\/1673-5374.187045","article-title":"Dynamic changes in neuronal autophagy and apoptosis in the ischemic penumbra following permanent ischemic stroke","volume":"11","author":"Deng","year":"2016","journal-title":"Neural Regen. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"577318","DOI":"10.1016\/j.jneuroim.2020.577318","article-title":"Neuroinflammation and fibrosis in stroke: The good, the bad and the ugly","volume":"346","author":"Amruta","year":"2020","journal-title":"J. Neuroimmunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1177\/1545968314562108","article-title":"Effects of physical exercise on neuroinflammation, neuroplasticity, neurodegeneration, and behavior: What we can learn from animal models in clinical settings","volume":"29","author":"Svensson","year":"2015","journal-title":"Neurorehabilit. Neural Repair"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1002\/ana.10722","article-title":"Mechanisms of stroke protection by physical activity","volume":"54","author":"Endres","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/jnr.23890","article-title":"Enhanced apoptosis from early physical exercise rehabilitation following ischemic stroke","volume":"95","author":"Li","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ynstr.2016.09.002","article-title":"Forced treadmill exercise can induce stress and increase neuronal damage in a mouse model of global cerebral ischemia","volume":"5","author":"Svensson","year":"2016","journal-title":"Neurobiol. Stress"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1159\/000347061","article-title":"Train the vessel, gain the brain: Physical activity and vessel function and the impact on stroke prevention and outcome in cerebrovascular disease","volume":"35","author":"Schmidt","year":"2013","journal-title":"Cerebrovasc. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.21037\/tau.2016.02.04","article-title":"Clinical applications of low-intensity pulsed ultrasound and its potential role in urology","volume":"5","author":"Xin","year":"2016","journal-title":"Transl. Androl. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1007\/s10439-014-1013-9","article-title":"Ultrasound effect on neural differentiation of gingival stem\/progenitor cells","volume":"42","author":"Alhadlaq","year":"2014","journal-title":"Ann. Biomed. Eng."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.brs.2011.03.007","article-title":"A review of low-intensity focused ultrasound pulsation","volume":"4","author":"Bystritsky","year":"2011","journal-title":"Brain Stimul."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5568","DOI":"10.1038\/s41598-018-23929-8","article-title":"Preventive effect of low intensity pulsed ultrasound against experimental cerebral ischemia\/reperfusion injury via apoptosis reduction and brain-derived neurotrophic factor induction","volume":"8","author":"Chen","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.nurt.2007.05.012","article-title":"Ultrasound-enhanced thrombolysis in acute ischemic stroke: Potential, failures, and safety","volume":"4","author":"Tsivgoulis","year":"2007","journal-title":"Neurotherapeutics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.neures.2014.06.007","article-title":"Aerobic exercise effects on neuroprotection and brain repair following stroke: A systematic review and perspective","volume":"87","author":"Austin","year":"2014","journal-title":"Neurosci. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1016\/j.apmr.2015.03.005","article-title":"Exercise stress testing after stroke or transient ischemic attack: A scoping review","volume":"96","author":"Gaverth","year":"2015","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhu, M., Chen, W., and Zhang, J. (2025). Aerobic exercise, an effective intervention for cognitive impairment after ischemic stroke. Front. Aging Neurosci., 17.","DOI":"10.3389\/fnagi.2025.1514271"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Waseem, R., Shamsi, A., Mohammad, T., Hassan, M.I., Kazim, S.N., Chaudhary, A.A., Rudayni, H.A., Al-Zharani, M., Ahmad, F., and Islam, A. (2022). FNDC5\/Irisin: Physiology and pathophysiology. Molecules, 27.","DOI":"10.3390\/molecules27031118"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Leal, L.G., Lopes, M.A., and Batista, M.L. (2018). Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.01307"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nature10777","article-title":"A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis","volume":"481","author":"Bostrom","year":"2012","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3233\/BPL-150019","article-title":"FNDC5\/irisin\u2014Their role in the nervous system and as a mediator for beneficial effects of exercise on the brain","volume":"1","author":"Wrann","year":"2015","journal-title":"Brain Plast."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.cmet.2013.09.008","article-title":"Exercise induces hippocampal BDNF through a PGC-1alpha\/FNDC5 pathway","volume":"18","author":"Wrann","year":"2013","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1080\/10641963.2018.1529779","article-title":"Type 2 diabetes with hypertensive patients results in changes to features of adipocytokines: Leptin, Irisin, LGR4, and Sfrp5","volume":"41","author":"Li","year":"2019","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kim, O.Y., and Song, J. (2018). The Role of Irisin in Alzheimer\u2019s Disease. J. Clin. Med., 7.","DOI":"10.3390\/jcm7110407"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s12967-022-03824-7","article-title":"Low-intensity pulsed ultrasound triggers a beneficial neuromodulation in dementia mice with chronic cerebral hypoperfusion via activation of hippocampal Fndc5\/irisin signaling","volume":"21","author":"Song","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_27","first-page":"387","article-title":"Trackless lesions in nervous tissues produced by high intensity focused ultrasound (high-frequency mechanical waves)","volume":"102","author":"Warwick","year":"1968","journal-title":"J. Anat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1118\/1.1513990","article-title":"An image-guided high intensity focused ultrasound device for uterine fibroids treatment","volume":"29","author":"Chan","year":"2002","journal-title":"Med. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.pbiomolbio.2006.07.005","article-title":"Therapeutic applications of ultrasound","volume":"93","year":"2007","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107844","DOI":"10.1016\/j.ultras.2025.107844","article-title":"Safety and efficacy of transcranial ultrasound stimulation for the treatment of Alzheimer\u2019s disease: A randomized, double-blind, placebo-controlled trial","volume":"159","author":"Fuh","year":"2026","journal-title":"Ultrasonics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"115420","DOI":"10.1016\/j.expneurol.2025.115420","article-title":"Low-intensity pulsed ultrasound enhances microglial-mediated Abeta clearance and synaptic preservation in an APP transgenic mouse model of Alzheimer\u2019s disease","volume":"394","author":"Su","year":"2025","journal-title":"Exp. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.neuint.2015.03.001","article-title":"Inhibition of mTOR pathway restrains astrocyte proliferation, migration and production of inflammatory mediators after oxygen-glucose deprivation and reoxygenation","volume":"83\u201384","author":"Li","year":"2015","journal-title":"Neurochem. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4103\/2152-7806.118349","article-title":"Immunology primer for neurosurgeons and neurologists part 2: Innate brain immunity","volume":"4","author":"Blaylock","year":"2013","journal-title":"Surg. Neurol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1097\/NEN.0b013e31821db3aa","article-title":"Differences in origin of reactive microglia in bone marrow chimeric mouse and rat after transient global ischemia","volume":"70","author":"Lambertsen","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Strohm, A.O., and Majewska, A.K. (2024). Physical exercise regulates microglia in health and disease. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1420322"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"113210","DOI":"10.1016\/j.intimp.2024.113210","article-title":"Treadmill exercise improves cerebral ischemia injury by regulating microglia polarization via downregulation of MMP12","volume":"142","author":"Zhang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.neuroscience.2020.05.007","article-title":"Pro-BDNF knockout causes abnormal motor behaviours and early death in mice","volume":"438","author":"Li","year":"2020","journal-title":"Neuroscience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1210\/endrev\/bnab003","article-title":"Progress and challenges in the biology of FNDC5 and irisin","volume":"42","author":"Maak","year":"2021","journal-title":"Endocr. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1161\/01.STR.17.3.472","article-title":"Rat middle cerebral artery occlusion: Evaluation of the model and development of a neurologic examination","volume":"17","author":"Bederson","year":"1986","journal-title":"Stroke"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.2147\/NDT.S121779","article-title":"Treadmill exercise promotes neuroprotection against cerebral ischemia-reperfusion injury via downregulation of pro-inflammatory mediators","volume":"12","author":"Zhang","year":"2016","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wu, C.T., Yang, T.H., Chen, M.C., Chung, Y.P., Guan, S.S., Long, L.H., Liu, S.H., and Chen, C.M. (2019). Low Intensity Pulsed Ultrasound Prevents Recurrent Ischemic Stroke in a Cerebral Ischemia\/Reperfusion Injury Mouse Model via Brain-derived Neurotrophic Factor Induction. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205169"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e71246","DOI":"10.1096\/fj.202502379R","article-title":"Low-intensity pulsed ultrasound attenuates neuroinflammation and preserves synaptic integrity by modulating microglial polarization through the MAPK-NF-kappaB pathway after traumatic brain injury","volume":"39","author":"Hsiau","year":"2025","journal-title":"FASEB J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8498\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:14:42Z","timestamp":1790309682000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198498"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198498","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]}}}