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

Xavier Ekolle Ndode-Ekane, Cesar Santana-Gomez, Pablo M. Casillas-Espinosa, Idrish Ali, Rhys D. Brady, Gregory Smith, Pedro Andrade, Riikka Immonen, Noora Puhakka, Matthew R. Hudson, Emma L. Braine, Sandy R. Shultz, Richard J. Staba, Terence J. O'Brien, Asla Pitkänen

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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 < 0.001). The sites differed in the duration of anesthesia, the shortest being at UEF < Melbourne < UCLA (p < 0.001). The impact pressure used also differed between the sites, the highest being in UEF > Melbourne > UCLA (p < 0.001). The impact pressure associated with the severity of the functional deficits (low neuroscore) (P < 0.05) only at UEF, but not at any of the other sites. Additionally, the sites differed in the duration of post-impact transient apnea (p < 0.001) and time to self-right (P < 0.001), the highest values in both parameters was registered in Melbourne. Post-impact seizure-like behavior was observed in 51% (UEF), 25% (Melbourne) and 2% (UCLA) of rats (p < 0.001). Despite the differences in means when all sites were compared there was significant overlap in injury parameters between the sites. The data reflects the technical difficulties in the production of lateral FPI across multiple sites. On the other hand, the data can be used to model the heterogeneity in human cohorts with closed-head injury. Our animal cohort will provide a good starting point to investigate the factors associated with epileptogenesis after lateral FPI.

Original languageEnglish
Pages (from-to)7-16
Number of pages10
JournalEpilepsy Research
Volume151
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Biomarkers
  • Multicenter study
  • Post-traumatic epilepsy
  • Post-traumatic epileptogenesis
  • Traumatic brain injury

Cite this

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title = "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 < 0.001). The sites differed in the duration of anesthesia, the shortest being at UEF < Melbourne < UCLA (p < 0.001). The impact pressure used also differed between the sites, the highest being in UEF > Melbourne > UCLA (p < 0.001). The impact pressure associated with the severity of the functional deficits (low neuroscore) (P < 0.05) only at UEF, but not at any of the other sites. Additionally, the sites differed in the duration of post-impact transient apnea (p < 0.001) and time to self-right (P < 0.001), the highest values in both parameters was registered in Melbourne. Post-impact seizure-like behavior was observed in 51{\%} (UEF), 25{\%} (Melbourne) and 2{\%} (UCLA) of rats (p < 0.001). Despite the differences in means when all sites were compared there was significant overlap in injury parameters between the sites. The data reflects the technical difficulties in the production of lateral FPI across multiple sites. On the other hand, the data can be used to model the heterogeneity in human cohorts with closed-head injury. Our animal cohort will provide a good starting point to investigate the factors associated with epileptogenesis after lateral FPI.",
keywords = "Biomarkers, Multicenter study, Post-traumatic epilepsy, Post-traumatic epileptogenesis, Traumatic brain injury",
author = "Ndode-Ekane, {Xavier Ekolle} and Cesar Santana-Gomez and Casillas-Espinosa, {Pablo M.} and Idrish Ali and Brady, {Rhys D.} and Gregory Smith and Pedro Andrade and Riikka Immonen and Noora Puhakka and Hudson, {Matthew R.} and Braine, {Emma L.} and Shultz, {Sandy R.} and Staba, {Richard J.} and O'Brien, {Terence J.} and Asla Pitk{\"a}nen",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/j.eplepsyres.2019.01.006",
language = "English",
volume = "151",
pages = "7--16",
journal = "Epilepsy Research",
issn = "0920-1211",
publisher = "Elsevier",

}

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; Santana-Gomez, Cesar; Casillas-Espinosa, Pablo M.; Ali, Idrish; Brady, Rhys D.; Smith, Gregory; Andrade, Pedro; Immonen, Riikka; Puhakka, Noora; Hudson, Matthew R.; Braine, Emma L.; Shultz, Sandy R.; Staba, Richard J.; O'Brien, Terence J.; Pitkänen, Asla.

In: Epilepsy Research, Vol. 151, 01.03.2019, p. 7-16.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Santana-Gomez, Cesar

AU - Casillas-Espinosa, Pablo M.

AU - Ali, Idrish

AU - Brady, Rhys D.

AU - Smith, Gregory

AU - Andrade, Pedro

AU - Immonen, Riikka

AU - Puhakka, Noora

AU - Hudson, Matthew R.

AU - Braine, Emma L.

AU - Shultz, Sandy R.

AU - Staba, Richard J.

AU - O'Brien, Terence J.

AU - Pitkänen, Asla

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KW - Multicenter study

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