TY  - JOUR
PY  - 2021//
TI  - Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction
JO  - Brain: a journal of neurology
A1  - Parker, Ellen
A1  - Aboghazleh, Refat
A1  - Mumby, Griffin
A1  - Veksler, Ronel
A1  - Ofer, Jonathan
A1  - Newton, Jillian
A1  - Smith, Rylan
A1  - Kamintsky, Lyna
A1  - Jones, Casey M. A.
A1  - O'Keeffe, Eoin
A1  - Kelly, Eoin
A1  - Doelle, Klara
A1  - Roach, Isabelle
A1  - Yang, Lynn T.
A1  - Moradi, Pooyan
A1  - Lin, Jessica M.
A1  - Gleason, Allison J.
A1  - Atkinson, Christina
A1  - Bowen, Chris
A1  - Brewer, Kimberly D.
A1  - Doherty, Colin P.
A1  - Campbell, Matthew
A1  - Clarke, David B.
A1  - van Hameren, Gerben
A1  - Kaufer, Daniela
A1  - Friedman, Alon
SP  - ePub
EP  - ePub
VL  - ePub
IS  - ePub
N2  - The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration, remain poorly understood. 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. 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-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. 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-brain barrier dysfunction, transforming growth factor β signaling, 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-brain barrier dysfunction. Treatment with a selective transforming growth factor β receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory transforming growth factor β signaling are associated with severe, potentially life-threatening outcomes, following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of transforming growth factor β signaling may be a novel strategy in treating mild traumatic brain injury.<p />  <p>Language: en</p>
LA  - en
SN  - 0006-8950
UR  - http://dx.doi.org/10.1093/brain/awab450
ID  - ref1
ER  -