title: Increasing recovery time between injuries improves cognitive outcome after repetitive mild concussive brain injuries in mice.
abstract: BACKGROUND
  Although previous evidence suggests that the cognitive effects of concussions are cumulative, the effect of time interval between repeat concussions is largely unknown.
  
  
  OBJECTIVE
  To determine the effect of time interval between repeat concussions on the cognitive function of mice.
  
  
  METHODS
  We used a weight-drop model of concussion to subject anesthetized mice to 1, 3, 5, or 10 concussions, each a day apart. Additional mice were subjected to 5 concussions at varying time intervals: daily, weekly, and monthly. Morris water maze performance was measured 24 hours, 1 month, and 1 year after final injury.
  
  
  RESULTS
  After 1 concussion, injured and sham-injured mice performed similarly in the Morris water maze. As the number of concussions increased, injured mice performed worse than sham-injured mice. Mice sustaining 5 concussions either 1 day or 1 week apart performed worse than sham-injured mice. When 5 concussions were delivered at 1-month time intervals, no difference in Morris water maze performance was observed between injured and sham-injured mice. After a 1-month recovery period, mice that sustained 5 concussions at daily and weekly time intervals continued to perform worse than sham-injured mice. One year after the final injury, mice sustaining 5 concussions at a daily time interval still performed worse than sham-injured mice.
  
  
  CONCLUSIONS
  When delivered within a period of vulnerability, the cognitive effects of multiple concussions are cumulative, persistent, and may be permanent. Increasing the time interval between concussions attenuates the effects on cognition. When multiple concussions are sustained by mice daily, the effects on cognition are long term.
authors: Sports Concussion Clinic, Division of Sports Medicine, Department of Orthopedics and Brain Injury Center, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. concussion.sportsmed@childrens.harvard.edu
authors: William P
authors: WP
authors: Meehan
authors: Jimmy
authors: J
authors: Zhang
authors: Rebekah
authors: R
authors: Mannix
authors: Michael J
authors: MJ
authors: Whalen
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000473:pathology; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001924:Brain Concussion / Q000150:complications*; D001929:Brain Edema / Q000175:diagnosis / Q000209:etiology; D016923:Cell Death / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D018782:Maze Learning; D008569:Memory Disorders / Q000175:diagnosis / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology; D020127:Recovery of Function / Q000502:physiology*; D013028:Space Perception / Q000502:physiology; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor