Harmonization of pipeline for detection of HFOs in a rat model of post-traumatic epilepsy in preclinical multicenter study on post-traumatic epileptogenesis☆
Introduction
Studies involving presurgical patients with epilepsy and rodent models of chronic epilepsy induced by status epilepticus show pathological high-frequency oscillations (HFOs; 80–500 Hz) are associated with epileptogenic tissue, and could play a role in generating seizures (for review see Jacobs et al., 2012; Jiruska et al., 2017). Results from studies that recorded EEG immediately after experimental status epilepticus (SE) suggest HFOs could also play a role in the development of epilepsy (Bragin et al., 2004, 2000; Lévesque et al., 2011). The work by Bragin et al. (2004) found little evidence of HFOs after status in rats that did not develop epilepsy, but prominent HFOs were detected in rats that later developed recurrent spontaneous seizures. Moreover, the sooner HFOs were detected, the sooner the first spontaneous seizure occurred (Bragin et al., 2004). These latter data support a hypothesis that pathological HFOs reflect progressive neuronal disturbances after an epileptogenic brain injury and could be a biomarker of epileptgoenesis.
Post-traumatic epilepsy (PTE) is a serious neurological sequela of traumatic brain injury (TBI) and develops in about 16% of cases of severe TBI (Annegers et al., 1998). Currently there are no biomarkers to predict who will develop PTE, which might not manifest until months or years after a TBI. The lack of biomarkers has hindered the development of new treatments that might modify or prevent PTE. However, recent work in a fluid-percussion injury (FPI) rat model of TBI detected pathological HFOs in the perilesional cortex of some, but not all, TBI rats (Bragin et al., 2007). No pathological HFOs were recorded in control rats. In rats that had long-term EEG recordings, rats that had pathological HFOs within two weeks of TBI later developed spontaneous seizures, and none of the rats without these events developed later seizures. Pathological HFOs, similar to those during epileptogenesis in status epilepticus models, might also reflect epileptogenesis in the FPI model.
The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a NINDS-funded, international multi-center project designed to identify biomarkers of epileptogenesis and treatments that could modify the development of PTE. One of the goals of this project will be to determine whether HFOs are a biomarker of epileptogenesis in the rat FPI model. A significant aspect of this work involves the standardization of protocols for the FPI model, the electrodes, and the electrode placements; assessing EEG recording capabilities and algorithms for HFO detection and verification; and identifying issues and generating solutions to solve them, which is described in the current report.
Section snippets
Materials and methods
Three sites from the international NIH-funded Centre without Walls consortium, the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) (http:// http://epibios.loni.usc.edu/) were involved in the harmonization for EEG recording and HFO analysis in the FPI model. These sites were The University of Eastern Finland (UEF), Monash University in Melbourne (Melbourne) and The University of California, Los Angeles (UCLA).
Surgery for impact and electrode implantation
Review of the surgical reports showed that at UEF 45 rats were randomized to TBI or sham-injury (37 TBI and 8 shams) with a 16% (6/37) post-impact mortality rate. The mean impact pressure was (2.79 ± 0.14 atm). At Melbourne randomization produced 32 TBI and 7 shams rats with a post-impact mortality rate of 59% (19/32). The mean impact pressure at Melbourne was 2.41 ± 0.21 atm. At UCLA randomization produced 32 TBI and 7 shams rats with a post-impact mortality of 59% (19/32). The mean impact
Discussion
This first report from the EpiBioS4Rx Consortium demonstrates the standardized placements of epidural and intracerebral electrodes used to record EEG in TBI and sham-injured rats. Twenty-eight days after electrode implantation, EEG files from 2 of the 3 centers contained bursts of HFOs similar to those found in status-epilepticus models of chronic epilepsy. Different computer-automated detection algorithms and small changes in detection parameters produced different results, and common review
Conclusions
Harmonizing the recording and detection of HFOs is crucial in the EpiBioS4Rx multi-center studies in order to establish robust, clinically translatable electrophysiological biomarkers of PTE. Our interim analysis found variability in the detection and review of HFOs that can be attributed to (1) the EEG signal quality, (2) the choice of algorithm and parameters used to detect HFOs, and (3) the manual review criteria for verifying HFOs. Reducing the variability between sites will involve
Acknowledgement
This research was supported by the National Institute of Neurological Disorders and Stroke (NINDS) Center without Walls of the National Institutes of Health (NIH) under Award Number U54NS100064 (EpiBioS4Rx).
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Cited by (16)
Preface - Practical and theoretical considerations for performing a multi-center preclinical biomarker discovery study of post-traumatic epileptogenesis: lessons learned from the EpiBioS4Rx consortium
2019, Epilepsy ResearchCitation Excerpt :To move the field forward, we not only harmonized preclinical procedures for biomarker discovery in the three EpiBioS4Rx centers, but also performed a rigorous interim analysis of the success of procedural harmonization, which is reported in this virtual special issue. The analysis included success of harmonization of the production of animal model (Ekolle Ndode-Ekane et al., 2019), blood sampling (Kamnaksh et al., 2018), EEG analyses (seizures, high-frequency oscillations) (Casillas-Espinosa et al., 2019; Santana-Gomez et al., 2019), and MRI analysis (Immonen et al., 2019). We also present an informatics approach that developed parameters and applied visualization tools to assess the overall success of harmonization (Ciszek et al., 2018).
Harmonization of lateral fluid-percussion injury model production and post-injury monitoring in a preclinical multicenter biomarker discovery study on post-traumatic epileptogenesis
2019, Epilepsy ResearchCitation Excerpt :The EEG follow-up cohort received cortical and intracranial electrodes (EEG-group). Details of electrode implantation and EEG follow-up have been described in the papers, “Harmonization of pipeline for automated seizure detection for phenotyping of post-traumatic epilepsy in a preclinical multicenter study on post-traumatic epileptogenesis” (Casillas-Espinosa et al., 2019) and “Harmonization of pipeline for detection of HFOs in a rat model of post-traumatic epilepsy in preclinical multicenter study on post-traumatic epileptogenesis” (Santana Gomez et al., 2019). At UEF, 98 rats were used in the MRI-group.
Informatics tools to assess the success of procedural harmonization in preclinical multicenter biomarker discovery study on post-traumatic epileptogenesis
2019, Epilepsy ResearchCitation Excerpt :In particular, when considering the pre—project activities needed to train the personnel to achieve sufficient procedural harmonization and for collection of preliminary data to predict inter-center procedural variability to be included in power calculations. The detailed methodologies have been presented in accompanying articles by Ekolle Ndode-Ekane et al., (2019) for injury production and post-impact follow-up by Kamnaksh et al. (2018) for blood sampling, Casillas-Espinosa et al. (2019) for EEG analysis, and Santana Gomez et al. (2019) for HFO analysis. The outline of the study design in terms of variables included in this harmonization assessment is presented in Fig. 1.
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This article is part of a special issue ‘Discovery of diagnostic biomarkers for post-traumatic epileptogenesis – an interim analysis of procedures in preclinical multicenter trial EpiBios4Rx’.
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Contributed equally to this manuscript.