Characterization of post-traumatic epileptiform features and behavioral disturbances in a clinically-relevant rodent model of hemorrhagic closed-head injury

Abstract

Background: Currently, there are no clinically available treatments to prevent traumatic brain injury (TBI)-related epilepsy, and the associated cognitive disturbances. Post-traumatic epilepsy (PTE) represents 20percent of symptomatic epilepsies, and its incidence is reported to be as high as 53percent after severe head injury. The pediatric population is particularly at risk given the developmental consequences of TBI, even after non-penetrating closed-head injuries that account for 75percent of all TBI cases. Investigating new drugs has been hindered by the low rate of seizure emergence in available rodent models (as low as 3percent in open head injuries). Hemorrhage, among others, constitutes an important risk factor for PTE. Therefore, we hypothesize that producing a traumatic lesion with a substantial hemorrhagic component will lead to higher rates of PTE emergence in a rodent TBI model. In this study, we used a modified controlled cortical impact (CCI) TBI model where bleeding is promoted with a pre-impact single heparin injection. The partial sacrifice of construct validity with the use of heparin aims at improving the face validity of increasing PTE rates; a common scenario in most rat seizure models that rely on the administration of chemicals. Following closed-head hemorrhagic TBI, we investigated PTE and cognitive deficits, two of the most clinically-relevant outcomes of TBI. Methods: Closed-TBI was induced in postnatal day 35 (P35) male Sprague-Dawley rats using the modified CCI model, targeting the skull overlying the right parieto-temporal area. Prior to injury induction, each rat received an intraperitoneal heparin injection (600 IU-Kg) in the CTBIHP group (closed-TBI with heparin, n=11) or a volume matched injection of normal saline in the CTBINS group (closed-TBI with normal saline, n=14). Weight-matched control littermates were sham manipulated and received either heparin in the HP group (control with heparin, n=8) or normal saline in the NS group (control with normal saline, n=10). Continuous epidural EEG recordings