Abstracts

Rationale: Post-traumatic epilepsy (PTE) is a significant neurological sequela of traumatic brain injury (TBI), developing in about 16% of cases of severe TBI. Currently there are no biomarkers to predict who is likely to develop PTE, which has hindered the development of new treatments that could modify or prevent PTE. However, numerous studies involving patients with epilepsy show that pathological high-frequency oscillations (HFOs; 80-500Hz) are strongly associated with epileptogenic tissue, and limited evidence from status epileptic models of epilepsy suggest pathological HFOs could be an electrophysiological biomarker of epileptogenesis. Our objective is to develop and standardize an approach to detect HFOs after TBI in the rat lateral fluid-percussion injury (FPI) model as part of a multi-center project to determine whether HFOs are a biomarker of post-traumatic epileptogenesis. Methods: Three sites from the international, multicenter-based project, “The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy” (EpiBioS4Rx), were involved in this project: University of Eastern Finland (Site 1), University of Melbourne/Monash University (Site 2) and Regents of the University of California, Los Angeles (Site 3). Across all sites, lateral FPI was induced through a 5 mm craniotomy centered over the left hemisphere (coordinates) of adult, male Sprague Dawley rats using a pendulum fluid-percussion device. The control group consisted of rats that underwent the same surgical procedures as rats in the TBI group, but lateral FPI was not induced. In all rats, either during the same surgery session (Sites 1 & 3) or 24-h after lateral FPI (Site 2), screws and subpial electrodes were positioned over and within the cortex and hippocampus ipsilateral to the injury and in the cortex contralateral to the injury.  EEG activity was recorded 24/7 for the first week after surgery and thereafter for 48-h at the start of each month for 6-mos. EEG was sampled at a minimum of 2 kHz per channel, and band-passed between 0.1 and 500 Hz. Results: Preliminary results indicate that all sites adhered to the standard electrode placements that consisted of screw electrodes over the perilesional cortex anterior and posterior to injury and contralateral homotopic sites, and paired subpial electrodes in the perilesional cortex anterior and posterior to injury, and hippocampus anterior to injury. All sites followed the EEG recording protocol, and to date at least 7 weeks of EEG has been recorded from the following number of rats: 42 rats from Site 1, 14 rats from Site 2, and 19 rats from Site 3. Importantly, a plan was developed to facilitate the HFO analysis between sites, which consists of the following steps: 1) operational HFO definition; 2) manual detection of HFOs in a 10-min sample of non-theta EEG from all sites; 3) inter-center reliability analysis; 4) revise HFO definition and re-test, if needed; 5) computer-automated detection of HFOs followed by manual verification; and 6) sensitivity and specificity analysis with respect to manually detected HFOs. Conclusions: Planning and personnel training are needed to achieve a high degree of harmonization for international, multi-center EEG studies. An objective and quantitative approach to detect HFOs should produce a reliable analysis of HFOs during the development of PTE. Funding: Supported by NINDS Center without Walls, U54 NS100064 (EpiBioS4Rx)