Abstracts

Rationale: Traumatic brain injury is a complex and heterogeneous injury that often involves both focal and diffuse pathologies. While TBI is a major cause of epilepsy in both military and civilian populations, the mechanisms underlying the development of post-traumatic epilepsy remain unclear. Methods: We therefore developed a unique porcine model of controlled cortical impact (CCI) injury, which recapitulates both focal and diffuse pathologies observed in human TBI. Male Yucatan miniature pigs were injured at 6 months of age and assessed for any neurological deficits. We implemented a Large Animal Custom Enclosure System (LACES), a 64-channel wireless recording system designed for use with a 32-channel hippocampal probe, a 24-channel cortical probe, and 4 bilaterally placed ECoG screws. This system allows for 24/7 video monitoring of awake behaving pigs, with alternate days of monitoring of the electrophysiological signals. Results: Changes in neurophysiological signals were monitored for epileptogenesis and disturbances in sleep-wake states starting at 5 days post CCI injury. We found that CCI-injured (n=5) but not sham (n=4) animals presented with a functional deficit that recovered at 72 hours post injury. Using electrophysiological recordings (sham=2, injured=2), we demonstrated that the brain is abnormally excitable for up to 8 months post CCI injury. At 1 month (n=2), the animals developed epileptiform activity in the cortex in the form of spikes, bursts, and slow wave discharges. At 4 months, electrographic seizures were observed in both hippocampus and cortex during sleep and awake states, and they became synchronized at 8-month post injury (n=1). Moreover, injured animals showed marked alterations in sleep patterns, with significantly more time spent in non-REM vs. REM sleep. While the CCI injury model leads to substantial cortical and axonal pathology at acute time points, it also has the potential for inducing electrographic seizure activity over time. Conclusions: Exploring the circuit level changes in parallel with neuropathology may provide a powerful translational approach to understand the relationship between TBI and epileptogenesis. Funding: DoD ERP CDMRP W81XWH-16- 1-0675 and CURE-TA PTE.