title: Temporal window of vulnerability to repetitive experimental concussive brain injury.
abstract: 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.
authors.affiliation: Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA. lucalonghi@policlinico.mi.it
authors.forename: Luca
authors.initials: L
authors.lastname: Longhi
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Saatman
authors.forename: Scott
authors.initials: S
authors.lastname: Fujimoto
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.forename: Jason
authors.initials: J
authors.lastname: Davis
authors.forename: Asenia
authors.initials: A
authors.lastname: McMillan B S
authors.forename: Valeria
authors.initials: V
authors.lastname: Conte
authors.forename: Helmut L
authors.initials: HL
authors.lastname: Laurer
authors.forename: Sherman
authors.initials: S
authors.lastname: Stein
authors.forename: Nino
authors.initials: N
authors.lastname: Stocchetti
authors.forename: Tracy K
authors.initials: TK
authors.lastname: McIntosh
mesh_terms: 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