Abstracts

Rationale: Posttraumatic epilepsy (PTE) refers to the development of recurrent spontaneous seizures after a brain injury. The pathophysiology of PTE is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. Current models of PTE have focused on using pentylenetetrazole (PTZ) for testing seizure susceptibility. For example, injured animals subsequently injected with PTZ were more susceptible to generalized seizures and displayed a decrease in latency to the first spike of an epileptiform discharge as compared to control animals. Diffusion MRIs have also shown associations between hippocampal damage and increased seizure susceptibility in post-TBI animals; however, a correlation between cortical damage and seizure susceptibility was not observed. Here, we aim to develop and characterize a new model of PTE in which we will define and correlate EEG biomarkers with optical biomarkers to understand the development of epileptogenesis after a brain injury. Methods: Adult CD1 male mice were used in our experiments and EEG and optical analysis were assessed at various time points after injury. At day 0, animals were subjected to optical imaging using optical coherence tomography (OCT) and a severe TBI (sTBI) using a controlled cortical impact (CCI) injury device. Sham animals received craniotomy only. One week prior to the final time point, animals underwent the final OCT imaging and were implanted with indwelling bipolar electrodes in the dorsal hippocampus. At the final time point, animals were subjected to in vivo intrahippocampal stimulation for the quantitative assessment of electrographic seizure threshold (EST) and electrographic seizure duration (ESD). Each stimulation consisted of a 60-Hz, 1-s train of 1-ms biphasic rectangular pulses and stimulation intensity was increased incrementally by 20 A every 2 min starting at 20 A. EST was recorded when a hippocampal afterdischarge (seizure) of at least 5 s was observed. Stimulation intensity was increased incrementally to 300 A and absence or presence of seizure, EST, and ESD was noted for each animal. Changes in optical attenuation coefficient () were analyzed from OCT data. Additionally, Doppler OCT (DOCT) data were measured and quantified to determine the integrity of the blood-brain barrier (BBB). Results: Preliminary data for EST at 90 d after TBI was 73 7 A with an ESD of 18 6 s (n=3), 60 d after TBI was 70 10 A with an ESD of 52 10 s (n=2). EST at 90 d for sham control was 70 10 A with an ESD of 10 1 s (n=2). Additionally 2 sham animals and 1 TBI animal did not reach EST when stimulated up to 300 A. Mortality rate for injured animals was 10% (1/10 animals) and 0% for sham animals (0/6 animals). OCT data revealed a significant reduction in attenuation coefficient (p < 0.05) between sham animals (n=6) and injured animals (n=9). Dramatic changes in the cerebrovascular network were also qualitatively observed in DOCT data after injury. Conclusions: We found no significant changes in EST between injured animals and sham animals; however, ESD was increased 60 d after injury as compared to 90 d TBI animals and 90 d sham animals (although not statistically significant, p>0.05) suggesting a possible network enhancement towards excitability 60 d after injury. Additionally, a reduction in OCT-derived brain tissue attenuation coefficient could potentially be related to edema due to compromised BBB integrity after TBI. Our data suggest that EEG and optical parameters can be evaluated in our model and correlated with injury-induced epileptogenesis. Future studies will include additional time points and blinded video-EEG monitoring of spontaneous seizures. Funding: N/A