Concussive injury before or after controlled cortical impact exacerbates histopathology and functional outcome in a mixed traumatic brain injury model in mice.

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.