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Harmonization of lateral fluid-percussion injury model production and post-injury monitoring in a preclinical multicenter biomarker discovery study on post-traumatic epileptogenesis.

ABSTRACT: Multi-center preclinical studies can facilitate the discovery of biomarkers of antiepileptogenesis and thus facilitate the diagnosis and treatment development of patients at risk of developing post-traumatic epilepsy. However, these studies are often limited by the difficulty in harmonizing experimental protocols between laboratories. Here, we assess whether the production of traumatic brain injury (TBI) using the lateral fluid-percussion injury (FPI) in adult male Sprague-Dawley rats (12 weeks at the time of injury) was harmonized between three laboratories - located in the University of Eastern Finland (UEF), Monash University in Melbourne, Australia (Melbourne) and The University of California, Los Angeles, USA (UCLA). These laboratories are part of the international multicenter-based project, the Epilepsy Bioinformatics Study for Antiepileptogenesis Therapy (EpiBioS4Rx). Lateral FPI was induced in adult male Sprague-Dawley rats. The success of methodological harmonization was assessed by performing inter-site comparison of injury parameters including duration of anesthesia during surgery, impact pressure, post-impact transient apnea, post-impact seizure-like behavior, acute mortality (<72?h post-injury), time to self-right after the impact, and severity of the injury (assessed with the neuroscore). The data was collected using Common Data Elements and Case Report Forms. The acute mortality was 15% (UEF), 50% (Melbourne) and 57% (UCLA) (p??Melbourne?>?UCLA (p?

SUBMITTER: Ndode-Ekane XE

PROVIDER: S-EPMC6812686 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Harmonization of lateral fluid-percussion injury model production and post-injury monitoring in a preclinical multicenter biomarker discovery study on post-traumatic epileptogenesis.

Ndode-Ekane Xavier Ekolle XE Santana-Gomez Cesar C Casillas-Espinosa Pablo M PM Ali Idrish I Brady Rhys D RD Smith Gregory G Andrade Pedro P Immonen Riikka R Puhakka Noora N Hudson Matthew R MR Braine Emma L EL Shultz Sandy R SR Staba Richard J RJ O'Brien Terence J TJ Pitkänen Asla A

Epilepsy research 20190118

Multi-center preclinical studies can facilitate the discovery of biomarkers of antiepileptogenesis and thus facilitate the diagnosis and treatment development of patients at risk of developing post-traumatic epilepsy. However, these studies are often limited by the difficulty in harmonizing experimental protocols between laboratories. Here, we assess whether the production of traumatic brain injury (TBI) using the lateral fluid-percussion injury (FPI) in adult male Sprague-Dawley rats (12 weeks ...[more]

PMID: 30711714

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Project description:The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a National Institutes for Neurological Diseases and Stoke funded Centers-Without-Walls international multidisciplinary study aimed at preventing epileptogenesis. The preclinical biomarker discovery in EpiBios4Rx applies a multicenter study design to allow the number of animals that are required for adequate statistical power for the analysis to be studied in an efficient manner. Further, the use of multiple centers mimics the clinical trial situation, and therefore potentially the chance of successful clinical translation of the outcomes of the study. Its successful implementation requires harmonization of procedures and data analyses between the three contributing centers in Finland, Australia, and USA. The objective of the present analysis was to develop metrics for analysis of the success of harmonization of procedures to guide further data analyses and plan the future multicenter preclinical studies. The interim analysis of data is based on the analysis of data from 212 rats with lateral fluid-percussion injury or sham-operation included in the biomarker discovery by April 30, 2018. The details of protocols, including production of injury, post-injury follow-up, blood sampling, electroencephalogram recording, and magnetic resonance imaging have been presented in the accompanying manuscripts in this Supplement. Implementation of protocols in EpiBios4Rx project participant centers was visualized in 2D using t-distributed stochastic neighborhood embedding (t-SNE). The protocols applied to each rat were presented as feature vectors of procedure related variables (e.g., impact pressure, anesthesia time). The total number of protocol features linked to each rat was 112. The missing data was accounted in visualization by utilizing imputation and adding the number of missing values as a third dimension to 2D t-SNE plot, resulting in a 3D overview of protocol data. Intraclass correlation coefficient (ICC) using Euclidean distances and area under receiver operating characteristic curve (AUC) of k-nearest neighbor classifier (KNN) were utilized to quantify the degree of clustering by center. Both subsets of data with incomplete protocol vectors omitted and missing protocol data imputed were assessed. Our data show that a visible clustering by center was observed in all t-SNE plots, except for day 7 neuroscores. Both ICC and AUC indicated clustering by center in all protocol variable subsets, excluding unimputed day 7 neuroscores (ICC 0.04 and AUC 0.6). ICC for imputed set of all protocol related variables was 0.1 and KNN AUC 0.92. In conclusion, both ICC and AUC indicated differences in protocol between EpiBios4Rx participating centers, which needs to be taken into account in data analysis. Importantly, the majority of observed differences are recoverable as they relate to insufficient updates in record keeping. While AUC score of KNN is a more sensitive measure for protocol harmonization than ICC for data that displays complex splintered clustering, ICC and AUC provide complementary measures to assess the degree of procedural harmonization. This experience should be helpful for other groups planning such multicenter post-traumatic epileptogenesis studies in the future.

Project description:ObjectiveThis study was undertaken to identify prognostic biomarkers for posttraumatic epileptogenesis derived from parameters related to the hippocampal position and orientation.MethodsData were derived from two preclinical magnetic resonance imaging (MRI) follow-up studies: EPITARGET (156 rats) and Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx; University of Eastern Finland cohort, 43 rats). Epileptogenesis was induced with lateral fluid percussion-induced traumatic brain injury (TBI) in adult male Sprague Dawley rats. In the EPITARGET cohort, T2∗ -weighted MRI was performed at 2, 7, and 21 days and in the EpiBioS4Rx cohort at 2, 9, and 30 days and 5 months post-TBI. Both hippocampi were segmented using convolutional neural networks. The extracted segmentation mask was used for a geometric construction, extracting 39 parameters that described the position and orientation of the left and right hippocampus. In each cohort, we assessed the parameters as prognostic biomarkers for posttraumatic epilepsy (PTE) both individually, using repeated measures analysis of variance, and in combination, using random forest classifiers.ResultsThe extracted parameters were highly effective in discriminating between sham-operated and TBI rats in both the EPITARGET and EpiBioS4Rx cohorts at all timepoints (t; balanced accuracy > .9). The most discriminating parameter was the inclination of the hippocampus ipsilateral to the lesion at t = 2 days and the volumes at t ≥ 7 days after TBI. Furthermore, in the EpiBioS4Rx cohort, we could effectively discriminate epileptogenic from nonepileptogenic animals with a longer MRI follow-up, at t = 150 days (area under the curve = .78, balanced accuracy = .80, p = .0050), based on the orientation of both hippocampi. We found that the ipsilateral hippocampus rotated outward on the horizontal plane, whereas the contralateral hippocampus rotated away from the vertical direction.SignificanceWe demonstrate that assessment of TBI-induced hippocampal deformation by clinically translatable MRI methodologies detects subjects with prior TBI as well as those at high risk of PTE, paving the way toward subject stratification for antiepileptogenesis studies.

Project description:BackgroundEpilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1β interacting with its receptors, and transforming growth factor-β signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.ConclusionSeveral inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.

Dataset Information

Harmonization of lateral fluid-percussion injury model production and post-injury monitoring in a preclinical multicenter biomarker discovery study on post-traumatic epileptogenesis.

Publications

Harmonization of lateral fluid-percussion injury model production and post-injury monitoring in a preclinical multicenter biomarker discovery study on post-traumatic epileptogenesis.

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