title: Concussive injury before or after controlled cortical impact exacerbates histopathology and functional outcome in a mixed traumatic brain injury model in mice.
abstract: Traumatic brain injury (TBI) may involve diverse injury mechanisms (e.g., focal impact vs. diffuse impact loading). Putative therapies developed in TBI models featuring a single injury mechanism may fail in clinical trials if the model does not fully replicate multiple injury subtypes, which may occur concomitantly in a given patient. We report development and characterization of a mixed contusion/concussion TBI model in mice using controlled cortical impact (CCI; 0.6 mm depth, 6 m/sec) and a closed head injury (CHI) model at one of two levels of injury (53 vs. 83 g weight drop from 66 in). Compared with CCI or CHI alone, sequential CCI-CHI produced additive effects on loss of consciousness (p<0.001), acute cell death (p<0.05), and 12-day lesion size (p<0.05) but not brain edema or 48-h contusion volume. Additive effects of CHI and CCI on post-injury motor (p<0.05) and cognitive (p<0.005) impairment were observed with sequential CCI-CHI (83 g). The data suggest that concussive forces, which in isolation do not induce histopathological damage, exacerbate histopathology and functional outcome after cerebral contusion. Sequential CHI-CCI may model complex injury mechanisms that occur in some patients with TBI and may prove useful for testing putative therapies.
authors.affiliation: Neuroscience Center , Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Heda R
authors.initials: HR
authors.lastname: Dapul
authors.forename: Juyeon
authors.initials: J
authors.lastname: Park
authors.forename: Jimmy
authors.initials: J
authors.lastname: Zhang
authors.forename: Christopher
authors.initials: C
authors.lastname: Lee
authors.forename: Ali
authors.initials: A
authors.lastname: DanEshmand
authors.forename: Josephine
authors.initials: J
authors.lastname: Lok
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.forename: Tory
authors.initials: T
authors.lastname: Gray
authors.forename: Allison
authors.initials: A
authors.lastname: Scalzo
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qiu
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Whalen
mesh_terms: D000818:Animals; D001924:Brain Concussion / Q000150:complications / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D020127:Recovery of Function