Temporal window of vulnerability to repetitive experimental concussive brain injury.
OBJECTIVE
Repetitive concussive brain injury (CBI) is associated with cognitive alterations and increased risk of neurodegenerative disease.


METHODS
To evaluate the temporal window during which the concussed brain remains vulnerable to a second concussion, anesthetized mice were subjected to either sham injury or single or repetitive CBI (either 3, 5, or 7 days apart) using a clinically relevant model of CBI. Cognitive, vestibular, and sensorimotor function (balance and coordination) were evaluated, and postmortem histological analyses were performed to detect neuronal degeneration, cytoskeletal proteolysis, and axonal injury.


RESULTS
No cognitive deficits were observed in sham-injured animals or those concussed once. Mice subjected to a second concussion within 3 or 5 days exhibited significantly impaired cognitive function compared with either sham-injured animals (P < 0.05) or mice receiving a single concussion (P < 0.01). No cognitive deficits were observed when the interconcussion interval was extended to 7 days, suggestive of a transient vulnerability of the brain during the first 5 days after an initial concussion. Although all concussed mice showed transient motor deficits, vestibulomotor dysfunction was more pronounced in the group that sustained two concussions 3 days apart (P < 0.01 compared with all other groups). Although scattered degenerating neurons, evidence of cytoskeletal damage, and axonal injury were detected in selective brain regions between 72 hours and 1 week after injury in all animals sustaining a single concussion, the occurrence of a second concussion 3 days later resulted in significantly greater traumatic axonal injury (P < 0.05) than that resulting from a single CBI.


CONCLUSIONS
These data suggest that a single concussion is associated with behavioral dysfunction and subcellular alterations that may contribute to a transiently vulnerable state during which a second concussion within 3 to 5 days can lead to exacerbated and more prolonged axonal damage and greater behavioral dysfunction.
Longhi
Luca
L
Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA. lucalonghi@policlinico.mi.it
Saatman
Kathryn E
KE
Fujimoto
Scott
S
Raghupathi
Ramesh
R
Meaney
David F
DF
Davis
Jason
J
McMillan B S
Asenia
A
Conte
Valeria
V
Laurer
Helmut L
HL
Stein
Sherman
S
Stocchetti
Nino
N
McIntosh
Tracy K
TK
D000818:Animals; D001924:Brain Concussion / Q000150:complications* / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology; D051379:Mice; D019957:Motor Skills Disorders / Q000209:etiology; D012008:Recurrence; D013997:Time Factors