Abstracts

Rationale: Despite significant advancements in epilepsy research and treatment, the prevalence of seizure disorders continues to rise, contributing a substantial disease burden worldwide. Post-traumatic epilepsy (PTE) is a significant long-term complication of moderate-to-severe traumatic brain injuries (TBI), and comprises as much as 20% of all structural epilepsies. However, there are currently no effective early biomarkers or therapies to prevent epilepsy after TBI in individuals at high risk of PTE, in part because the changes in the post-TBI brain which lead to PTE are unknown. The rodent lateral Fluid Percussion Injury (FPI) model is a gold-standard for studying PTE and testing potential therapies. However, the pathological changes during the early and late ictal and interictal periods in this model remain not completely understood.

Methods: In an effort to uncover mechanisms underlying epileptogenesis in rodent FPI models and to enhance translatability to human epilepsy studies, we interrogated bilateral local field potentials (LFP) of neocortical and hippocampal networks at 1, 4 and 12 weeks after lateral FPI in rats under anesthesia using both high-channel-count skull surface EEG grids and linear silicon probes. Simultaneous recordings were obtained from a 32-channel skull surface EEG grid and bilateral 128-channel linear silicon probes placed along the neocortical-hippocampal axis. This high density, multimodal electrographic approach may help more effectively translate findings in rodent FPI models to scalp and intracranial EEG studies in human epilepsy patients, as traditional EEG studies in rodent FPI models rely on smaller numbers of invasive surface recording sites and single or bipolar depth electrodes.

Results: The relationship between neocortical and temporal activity in FPI models of PTE has not been fully characterized. We show that in acute recordings under anesthesia at 1, 4 and 12 weeks post-FPI there is significant disruption in this relationship compared to naive rats. We found increased synchrony of neocortical and temporal LFP events at progressive timepoints post-FPI, and observed that these changes were unique across the injured and contralateral hemispheres. At 1 week post-FPI, activity in the injured hemisphere was attenuated, while hyperactivity was observed in the contralateral hemisphere. This dysfunction evolved over progressive timepoints, leading to uniquely pathological networks across each hemisphere up to 12 weeks after FPI.

Conclusions: High-channel-count electrographic approaches to characterizing the pathogenesis of post-traumatic epilepsy in animal models may yield valuable novel insights into the mechanisms underlying epileptogenesis. Our findings suggest unique contributions of the injured and contralateral hemispheres to the breakdown over time of the organization between the neocortical and temporal networks in the lateral Fluid Percussion Injury model of post-traumatic epilepsy.

Funding: US Department of Veterans Affairs, US Department of Defense CDMRP ERP, Virginia Commonwealth University