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This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury.<\/jats:p><jats:p>We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood\u2013brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury.<\/jats:p><jats:p>Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood\u2013brain barrier dysfunction, transforming growth factor \u03b2 (TGF\u03b2) signalling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood\u2013brain barrier dysfunction. Treatment with a selective TGF\u03b2 receptor inhibitor prevented blood\u2013brain barrier opening and reduced injury complications. Consistent with the rodent model, blood\u2013brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury.<\/jats:p><jats:p>We provide evidence that cortical spreading depolarization, blood\u2013brain barrier dysfunction, and pro-inflammatory TGF\u03b2 signalling are associated with severe, potentially life-threatening outcomes following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of TGF\u03b2 signalling may be a novel strategy in treating mild traumatic brain injury.<\/jats:p>","DOI":"10.1093\/brain\/awab450","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T12:08:53Z","timestamp":1639656533000},"page":"2049-2063","source":"Crossref","is-referenced-by-count":28,"title":["Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6072-8197","authenticated-orcid":false,"given":"Ellen","family":"Parker","sequence":"first","affiliation":[{"name":"Department of Medical Neuroscience, Dalhousie University, Faculty of Medicine , Halifax, NS , Canada"},{"name":"Faculty of Medicine, Dalhousie University , Halifax, NS , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Refat","family":"Aboghazleh","sequence":"additional","affiliation":[{"name":"Department of 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