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.

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

“…30,32,47 Recent findings have confirmed that changes in tau, amyloid, and cognition can result from neurotrauma. 9,34,51 The mechanisms underlying how these changes develop is currently unknown.…”

Neuroprotective efficacy of decompressive craniectomy after controlled cortical impact injury in rats: An MRI study

“…To the best of our knowledge, this is the first report of combined in vivo MRI and 1 H-MRS characterization and therapeutic effect analysis of DC induced by CCI. Moreover, this CCI device could also be used to establish focalþdiffuse or diffuse closed brain injury models (Dapul et al, 2013); thus, the CCI technique could also be used to evaluate the potential neuroprotective effect of craniectomy in models of focalþdiffuse or diffuse brain injury in the future.…”

Automated quantification of three-dimensional organization of fiber-like structures in biological tissues

“…Controlled cortical impact (CCI) of the cell seeded constructs is performed at the two week time point by modifications to a custom built set up at Massachusetts General Hospital [30]. The injury is done using a 3 mm flat tip pneumatic piston that hits each construct at a velocity of 6 m/sec.…”