The Experts below are selected from a list of 3108 Experts worldwide ranked by ideXlab platform
Pedro Andrade - One of the best experts on this subject based on the ideXlab platform.
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harmonization of pipeline for detection of hfos in a rat model of post Traumatic Epilepsy in preclinical multicenter study on post Traumatic epileptogenesis
Epilepsy Research, 2019Co-Authors: Cesar Emmanuel Santanagomez, Pedro Andrade, Tomi Paananen, Robert Ciszek, Idrish Ali, Brian K Rundle, Xavier Ekolle Ndodeekane, Matthew R Hudson, Gregory Smith, Pablo M CasillasespinosaAbstract:Studies of chronic Epilepsy show pathological high frequency oscillations (HFOs) are associated with brain areas capable of generating epileptic seizures. Only a few of these studies have focused on HFOs during the development of Epilepsy, but results suggest pathological HFOs could be a biomarker of epileptogenesis. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy" (EpiBioS4Rx) is a multi-center project designed to identify biomarkers of epileptogenesis after a Traumatic brain injury (TBI) and evaluate treatments that could modify or prevent the development of post-Traumatic Epilepsy. One goal of the EpiBioS4Rx project is to assess whether HFOs could be a biomarker of post-Traumatic epileptogenesis. The current study describes the work towards this goal, including the development of common surgical procedures and EEG protocols, an interim analysis of the EEG for HFOs, and identifying issues that need to be addressed for a robust biomarker analysis. At three participating sites - University of Eastern Finland (UEF), Monash University in Melbourne (Melbourne) and University of California, Los Angeles (UCLA) - TBI was induced in adult male Sprague-Dawley rats by lateral fluid-percussion injury. After injury and in sham-operated controls, rats were implanted with screw and microwire electrodes positioned in neocortex and hippocampus to record EEG. A separate group of rats had serial magnetic resonance imaging after injury and then implanted with electrodes at 6 months. Recordings 28 days post-injury were available from UEF and UCLA, but not Melbourne due to technical issues with their EEG files. Analysis of recordings from 4 rats - UEF and UCLA each had one TBI and one sham-operated control - showed EEG contained evidence of HFOs. Computer-automated algorithms detected a total of 1,819 putative HFOs and of these only 40 events (2%) were detected by all three sites. Manual review of all events verified 130 events as HFO and the remainder as false positives. Review of the 40 events detected by all three sites was associated with 88% agreement. This initial report from the EpiBioS4Rx Consortium demonstrates the standardization of EEG electrode placements, recording protocol and long-term EEG monitoring, and differences in detection algorithm HFO results between sites. Additional work on detection strategy, detection algorithm performance, and training in HFO review will be performed to establish a robust, preclinical evaluation of HFOs as a biomarker of post-Traumatic epileptogenesis.
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harmonization of the pipeline for seizure detection to phenotype post Traumatic Epilepsy in a preclinical multicenter study on post Traumatic epileptogenesis
Epilepsy Research, 2019Co-Authors: Pablo M Casillasespinosa, Pedro Andrade, Tomi Paananen, Robert Ciszek, Idrish Ali, Cesar Emmanuel Santanagomez, Xavier Ekolle Ndodeekane, Gregory Smith, Rhys D Brady, Jussi TohkaAbstract:Abstract Rationale The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Centre without walls is an NIH funded multicenter consortium. One of EpiBioS4Rx projects is a preclinical post-Traumatic epileptogenesis biomarker study that involves three study sites: The University of Eastern Finland, Monash University (Melbourne) and the University of California Los Angeles. Our objective is to create a platform for evaluating biomarkers and testing new antiepileptogenic treatments for post-Traumatic Epilepsy (PTE) using the lateral fluid percussion injury (FPI) model in rats. As only 30–50% of rats with severe lateral FPI develop PTE by 6 months post-injury, prolonged video-EEG monitoring is crucial to identify animals with PTE. Our objective is to harmonize the surgical and data collection procedures, equipment, and data analysis for chronic EEG recording in order to phenotype PTE in this rat model across the three study sites. Methods Traumatic brain injury (TBI) was induced using lateral FPI in adult male Sprague-Dawley rats aged 11–12 weeks. Animals were divided into two cohorts: a) the long-term video-EEG follow-up cohort (Specific Aim 1), which was implanted with EEG electrodes within 24 h after the injury; and b) the magnetic resonance imaging (MRI) follow-up cohort (Specific Aim 2), at 5 months after lateral FPI. Four cortical epidural screw electrodes (2 ipsilateral, 2 contralateral) and three intracerebral bipolar electrodes were implanted (septal CA1 and the dentate gyrus, layers II and VI of the perilesional cortex both anterior and posterior to the injury site). During the 7th post-TBI month, animals underwent 4 weeks of continuous video-EEG recordings to diagnose of PTE. Results All centers harmonized the induction of TBI and surgical procedures for the implantation of EEG recordings, utilizing 4 or more EEG recording channels to cover areas ipsilateral and contralateral to the brain injury, perilesional cortex and the hippocampus and dentate gyrus. Ground and reference screw electrodes were implanted. At all sites the minimum sampling rate was 512 Hz, utilizing a finite impulse response (FIR) and impedance below 10 KΩ through the entire recording. As part of the quality control criteria we avoided electrical noise, and monitoring changes in impedance over time and the appearance of noise on the recordings. To reduce electrical noise, we regularly checked the integrity of the cables, stability of the EEG recording cap and the appropriate connection of the electrodes with the cables. Following the pipeline presented in this article and after applying the quality control criteria to our EEG recordings all of the sites were successful to phenotype seizure in chronic EEG recordings of animals after TBI. Discussion Despite differences in video-EEG acquisition equipment used, the three centers were able to consistently phenotype seizures in the lateral fluid-percussion model applying the pipeline presented here. The harmonization of methodology will help to improve the rigor of preclinical research, improving reproducibility of pre-clinical research in the search of biomarkers and therapies to prevent antiepileptogenesis.
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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
Epilepsy Research, 2019Co-Authors: Xavier Ekolle Ndodeekane, Pedro Andrade, Riikka Immonen, Pablo M Casillasespinosa, Rhys D Brady, Cesar Santanagomez, Gregory T Smith, Noora PuhakkaAbstract: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 ( Melbourne > UCLA (p
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Algorithm for automatic detection of spontaneous seizures in rats with post-Traumatic Epilepsy
Journal of neuroscience methods, 2018Co-Authors: Pedro Andrade, Tomi Paananen, Robert Ciszek, Niina Lapinlampi, Asla PitkanenAbstract:Abstract Background Labor intensive electroencephalogram (EEG) analysis is a major bottleneck to identifying anti-epileptogenic treatments in experimental models of post-Traumatic Epilepsy. We aimed to develop an algorithm for automated seizure detection in experimental post-Traumatic Epilepsy. New method Continuous (24/7) 1-month-long video-EEG monitoring with three epidural screw electrodes was started 154 d after lateral fluid-percussion induced Traumatic brain injury (TBI; n = 97) or sham-injury (n = 29) in adult male Sprague–Dawley rats. First, an experienced researcher screened a total of 90,720 h of digitized recordings on a computer screen to annotate the occurrence of spontaneous seizures. The same files were then analyzed using an algorithm in Spike2 (ver.9), which searching for temporally linked power peaks (14–42 Hz) in all three EEG channels, and then positive events were marked as a probable seizures. Finally, an experienced researcher confirmed all seizure candidates visually on the computer screen. Results Visual analysis identified 197 seizures in 29 rats. Automatic detection identified 4346 seizure candidates in 109 rats, of which 202 in the same 29 rats were true positives, resulting in a false positive rate of 0.046/h or 1.10/d. The algorithm demonstrated 5% specificity and 100% sensitivity. The algorithm analyzed 1-month 3-channel EEG in 7 cohorts in 2 h, whereas analysis by an experienced technician took ∼500 h. Comparison with Existing Methods The algorithm had 100% sensitivity. It performed slightly better and was substantially faster than investigator-performed visual analysis. Conclusions We present a novel seizure detection algorithm for automated detection of seizures in a rat model of post-Traumatic Epilepsy.
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disease modifying effect of atipamezole in a model of post Traumatic Epilepsy
Epilepsy Research, 2017Co-Authors: Jari Nissinen, Pedro Andrade, Teemu Natunen, Mikko Hiltunen, Tarja Malm, Katja M Kanninen, Joana Soares, Olena Shatillo, Jukka SallinenAbstract:Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of Traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α2-adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion-induced TBI. The rats were treated with atipamezole (started at 30min or 7 d after TBI) or SR141716A (2min or 30min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of Epilepsy. SR141716A administered as a single dose at 2min post-TBI or initiated at 30min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α2-adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α2A-noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α2C-adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI.
Asla Pitkanen - One of the best experts on this subject based on the ideXlab platform.
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inflammation at the neurovascular unit in post Traumatic Epilepsy
2021Co-Authors: Xavier Ekolle Ndodeekane, Jenni Kyyriainen, Asla PitkanenAbstract:Post-Traumatic Epilepsy (PTE) is one of the clinical outcomes in about 16% of patients with Traumatic brain injury (TBI). Patients develop PTE after several months to years following the initial brain injury. Over the years, there have been an increasing number of reports suggesting that post-Traumatic inflammation, which is a major component of the pathophysiology of TBI, may be a key player in the development of PTE. The inflammatory process begins within minutes to hours after the primary injury and may proceed for several years after initial insult. Evidence suggest that the neurovascular unit (NVU) play a key role in the post-Traumatic inflammatory cascade. Also, there is growing number of data supporting the hypothesis that anti-inflammatory treatments may improve the post-TBI clinical outcome. In this chapter we will give insights into how the different members of the NVU, including the blood-brain barrier, microglial cells, NG2-glial cells, pericytes, and astrocytes, contribute to the post-Traumatic inflammation and the development of PTE.
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big data sharing and analysis to advance research in post Traumatic Epilepsy
Neurobiology of Disease, 2019Co-Authors: Dominique Duncan, Asla Pitkanen, Paul M Vespa, Niina Lapinlampi, Adebayo Braimah, Arthur W TogaAbstract:We describe the infrastructure and functionality for a centralized preclinical and clinical data repository and analytic platform to support importing heterogeneous multi-modal data, automatically and manually linking data across modalities and sites, and searching content. We have developed and applied innovative image and electrophysiology processing methods to identify candidate biomarkers from MRI, EEG, and multi-modal data. Based on heterogeneous biomarkers, we present novel analytic tools designed to study epileptogenesis in animal model and human with the goal of tracking the probability of developing Epilepsy over time.
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Algorithm for automatic detection of spontaneous seizures in rats with post-Traumatic Epilepsy
Journal of neuroscience methods, 2018Co-Authors: Pedro Andrade, Tomi Paananen, Robert Ciszek, Niina Lapinlampi, Asla PitkanenAbstract:Abstract Background Labor intensive electroencephalogram (EEG) analysis is a major bottleneck to identifying anti-epileptogenic treatments in experimental models of post-Traumatic Epilepsy. We aimed to develop an algorithm for automated seizure detection in experimental post-Traumatic Epilepsy. New method Continuous (24/7) 1-month-long video-EEG monitoring with three epidural screw electrodes was started 154 d after lateral fluid-percussion induced Traumatic brain injury (TBI; n = 97) or sham-injury (n = 29) in adult male Sprague–Dawley rats. First, an experienced researcher screened a total of 90,720 h of digitized recordings on a computer screen to annotate the occurrence of spontaneous seizures. The same files were then analyzed using an algorithm in Spike2 (ver.9), which searching for temporally linked power peaks (14–42 Hz) in all three EEG channels, and then positive events were marked as a probable seizures. Finally, an experienced researcher confirmed all seizure candidates visually on the computer screen. Results Visual analysis identified 197 seizures in 29 rats. Automatic detection identified 4346 seizure candidates in 109 rats, of which 202 in the same 29 rats were true positives, resulting in a false positive rate of 0.046/h or 1.10/d. The algorithm demonstrated 5% specificity and 100% sensitivity. The algorithm analyzed 1-month 3-channel EEG in 7 cohorts in 2 h, whereas analysis by an experienced technician took ∼500 h. Comparison with Existing Methods The algorithm had 100% sensitivity. It performed slightly better and was substantially faster than investigator-performed visual analysis. Conclusions We present a novel seizure detection algorithm for automated detection of seizures in a rat model of post-Traumatic Epilepsy.
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generalized seizures after experimental Traumatic brain injury occur at the transition from slow wave to rapid eye movement sleep
Journal of Neurotrauma, 2017Co-Authors: Pedro Andrade, Jari Nissinen, Asla PitkanenAbstract:Abstract Sleep disturbances commonly occur after Traumatic brain injury (TBI) and may predispose patients to epileptic seizures. We hypothesized that unprovoked seizure occurrence post-TBI depends on the sleep-wake cycle, and that the electrographic characteristics of a given sleep stage provide biomarkers for post-Traumatic Epilepsy (PTE). We show, in a rat lateral fluid percussion model, that 92% of spontaneous generalized seizures occur during the transition from stage III to rapid eye movement sleep. Moreover, a reduction in spindle duration and dominant frequency during the transition stage present as specific and sensitive noninvasive biomarkers for experimentally induced PTE with generalized electrographic seizures.
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Epilepsy Related to Traumatic Brain Injury
Neurotherapeutics, 2014Co-Authors: Asla Pitkanen, Riikka ImmonenAbstract:Post-Traumatic Epilepsy accounts for 10–20 % of symptomatic Epilepsy in the general population and 5 % of all Epilepsy. During the last decade, an increasing number of laboratories have investigated the molecular and cellular mechanisms of post-Traumatic epileptogenesis in experimental models. However, identification of critical molecular, cellular, and network mechanisms that would be specific for post-Traumatic epileptogenesis remains a challenge. Despite of that, 7 of 9 proof-of-concept antiepileptogenesis studies have demonstrated some effect on seizure susceptibility after experimental Traumatic brain injury, even though none of them has progressed to clinic. Moreover, there has been some promise that new clinically translatable imaging approaches can identify biomarkers for post-Traumatic epileptogenesis. Even though the progress in combating post-Traumatic epileptogenesis happens in small steps, recent discoveries kindle hope for identification of treatment strategies to prevent post-Traumatic Epilepsy in at-risk patients.
Pablo M Casillasespinosa - One of the best experts on this subject based on the ideXlab platform.
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harmonization of pipeline for detection of hfos in a rat model of post Traumatic Epilepsy in preclinical multicenter study on post Traumatic epileptogenesis
Epilepsy Research, 2019Co-Authors: Cesar Emmanuel Santanagomez, Pedro Andrade, Tomi Paananen, Robert Ciszek, Idrish Ali, Brian K Rundle, Xavier Ekolle Ndodeekane, Matthew R Hudson, Gregory Smith, Pablo M CasillasespinosaAbstract:Studies of chronic Epilepsy show pathological high frequency oscillations (HFOs) are associated with brain areas capable of generating epileptic seizures. Only a few of these studies have focused on HFOs during the development of Epilepsy, but results suggest pathological HFOs could be a biomarker of epileptogenesis. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy" (EpiBioS4Rx) is a multi-center project designed to identify biomarkers of epileptogenesis after a Traumatic brain injury (TBI) and evaluate treatments that could modify or prevent the development of post-Traumatic Epilepsy. One goal of the EpiBioS4Rx project is to assess whether HFOs could be a biomarker of post-Traumatic epileptogenesis. The current study describes the work towards this goal, including the development of common surgical procedures and EEG protocols, an interim analysis of the EEG for HFOs, and identifying issues that need to be addressed for a robust biomarker analysis. At three participating sites - University of Eastern Finland (UEF), Monash University in Melbourne (Melbourne) and University of California, Los Angeles (UCLA) - TBI was induced in adult male Sprague-Dawley rats by lateral fluid-percussion injury. After injury and in sham-operated controls, rats were implanted with screw and microwire electrodes positioned in neocortex and hippocampus to record EEG. A separate group of rats had serial magnetic resonance imaging after injury and then implanted with electrodes at 6 months. Recordings 28 days post-injury were available from UEF and UCLA, but not Melbourne due to technical issues with their EEG files. Analysis of recordings from 4 rats - UEF and UCLA each had one TBI and one sham-operated control - showed EEG contained evidence of HFOs. Computer-automated algorithms detected a total of 1,819 putative HFOs and of these only 40 events (2%) were detected by all three sites. Manual review of all events verified 130 events as HFO and the remainder as false positives. Review of the 40 events detected by all three sites was associated with 88% agreement. This initial report from the EpiBioS4Rx Consortium demonstrates the standardization of EEG electrode placements, recording protocol and long-term EEG monitoring, and differences in detection algorithm HFO results between sites. Additional work on detection strategy, detection algorithm performance, and training in HFO review will be performed to establish a robust, preclinical evaluation of HFOs as a biomarker of post-Traumatic epileptogenesis.
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harmonization of the pipeline for seizure detection to phenotype post Traumatic Epilepsy in a preclinical multicenter study on post Traumatic epileptogenesis
Epilepsy Research, 2019Co-Authors: Pablo M Casillasespinosa, Pedro Andrade, Tomi Paananen, Robert Ciszek, Idrish Ali, Cesar Emmanuel Santanagomez, Xavier Ekolle Ndodeekane, Gregory Smith, Rhys D Brady, Jussi TohkaAbstract:Abstract Rationale The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Centre without walls is an NIH funded multicenter consortium. One of EpiBioS4Rx projects is a preclinical post-Traumatic epileptogenesis biomarker study that involves three study sites: The University of Eastern Finland, Monash University (Melbourne) and the University of California Los Angeles. Our objective is to create a platform for evaluating biomarkers and testing new antiepileptogenic treatments for post-Traumatic Epilepsy (PTE) using the lateral fluid percussion injury (FPI) model in rats. As only 30–50% of rats with severe lateral FPI develop PTE by 6 months post-injury, prolonged video-EEG monitoring is crucial to identify animals with PTE. Our objective is to harmonize the surgical and data collection procedures, equipment, and data analysis for chronic EEG recording in order to phenotype PTE in this rat model across the three study sites. Methods Traumatic brain injury (TBI) was induced using lateral FPI in adult male Sprague-Dawley rats aged 11–12 weeks. Animals were divided into two cohorts: a) the long-term video-EEG follow-up cohort (Specific Aim 1), which was implanted with EEG electrodes within 24 h after the injury; and b) the magnetic resonance imaging (MRI) follow-up cohort (Specific Aim 2), at 5 months after lateral FPI. Four cortical epidural screw electrodes (2 ipsilateral, 2 contralateral) and three intracerebral bipolar electrodes were implanted (septal CA1 and the dentate gyrus, layers II and VI of the perilesional cortex both anterior and posterior to the injury site). During the 7th post-TBI month, animals underwent 4 weeks of continuous video-EEG recordings to diagnose of PTE. Results All centers harmonized the induction of TBI and surgical procedures for the implantation of EEG recordings, utilizing 4 or more EEG recording channels to cover areas ipsilateral and contralateral to the brain injury, perilesional cortex and the hippocampus and dentate gyrus. Ground and reference screw electrodes were implanted. At all sites the minimum sampling rate was 512 Hz, utilizing a finite impulse response (FIR) and impedance below 10 KΩ through the entire recording. As part of the quality control criteria we avoided electrical noise, and monitoring changes in impedance over time and the appearance of noise on the recordings. To reduce electrical noise, we regularly checked the integrity of the cables, stability of the EEG recording cap and the appropriate connection of the electrodes with the cables. Following the pipeline presented in this article and after applying the quality control criteria to our EEG recordings all of the sites were successful to phenotype seizure in chronic EEG recordings of animals after TBI. Discussion Despite differences in video-EEG acquisition equipment used, the three centers were able to consistently phenotype seizures in the lateral fluid-percussion model applying the pipeline presented here. The harmonization of methodology will help to improve the rigor of preclinical research, improving reproducibility of pre-clinical research in the search of biomarkers and therapies to prevent antiepileptogenesis.
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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
Epilepsy Research, 2019Co-Authors: Xavier Ekolle Ndodeekane, Pedro Andrade, Riikka Immonen, Pablo M Casillasespinosa, Rhys D Brady, Cesar Santanagomez, Gregory T Smith, Noora PuhakkaAbstract: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 ( Melbourne > UCLA (p
Riikka Immonen - One of the best experts on this subject based on the ideXlab platform.
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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
Epilepsy Research, 2019Co-Authors: Xavier Ekolle Ndodeekane, Pedro Andrade, Riikka Immonen, Pablo M Casillasespinosa, Rhys D Brady, Cesar Santanagomez, Gregory T Smith, Noora PuhakkaAbstract: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 ( Melbourne > UCLA (p
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Epilepsy Related to Traumatic Brain Injury
Neurotherapeutics, 2014Co-Authors: Asla Pitkanen, Riikka ImmonenAbstract:Post-Traumatic Epilepsy accounts for 10–20 % of symptomatic Epilepsy in the general population and 5 % of all Epilepsy. During the last decade, an increasing number of laboratories have investigated the molecular and cellular mechanisms of post-Traumatic epileptogenesis in experimental models. However, identification of critical molecular, cellular, and network mechanisms that would be specific for post-Traumatic epileptogenesis remains a challenge. Despite of that, 7 of 9 proof-of-concept antiepileptogenesis studies have demonstrated some effect on seizure susceptibility after experimental Traumatic brain injury, even though none of them has progressed to clinic. Moreover, there has been some promise that new clinically translatable imaging approaches can identify biomarkers for post-Traumatic epileptogenesis. Even though the progress in combating post-Traumatic epileptogenesis happens in small steps, recent discoveries kindle hope for identification of treatment strategies to prevent post-Traumatic Epilepsy in at-risk patients.
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Anti-epileptogenesis in rodent post-Traumatic Epilepsy models
Neuroscience letters, 2011Co-Authors: Asla Pitkanen, Tamuna Bolkvadze, Riikka ImmonenAbstract:Post-Traumatic Epilepsy (PTE) accounts for 10–20% of symptomatic epilepsies. The urgency to understand the process of post-Traumatic epileptogenesis and search for antiepileptogenic treatments is emphasized by a recent increase in Traumatic brain injury (TBI) related to military combat or accidents in the aging population. Recent developments in modeling of PTE in rodents have provided tools for identification of novel drug targets for antiepileptogenesis and biomarkers for predicting the risk of epileptogenesis and treatment efficacy after TBI. Here we review the available data on endophenotypes of humans and rodents with TBI associated with Epilepsy. Also, current understanding of the mechanisms and biomarkers for PTE as well as factors associated with preclinical study designs are discussed. Finally, we summarize the attempts to prevent PTE in experimental models.
Xavier Ekolle Ndodeekane - One of the best experts on this subject based on the ideXlab platform.
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inflammation at the neurovascular unit in post Traumatic Epilepsy
2021Co-Authors: Xavier Ekolle Ndodeekane, Jenni Kyyriainen, Asla PitkanenAbstract:Post-Traumatic Epilepsy (PTE) is one of the clinical outcomes in about 16% of patients with Traumatic brain injury (TBI). Patients develop PTE after several months to years following the initial brain injury. Over the years, there have been an increasing number of reports suggesting that post-Traumatic inflammation, which is a major component of the pathophysiology of TBI, may be a key player in the development of PTE. The inflammatory process begins within minutes to hours after the primary injury and may proceed for several years after initial insult. Evidence suggest that the neurovascular unit (NVU) play a key role in the post-Traumatic inflammatory cascade. Also, there is growing number of data supporting the hypothesis that anti-inflammatory treatments may improve the post-TBI clinical outcome. In this chapter we will give insights into how the different members of the NVU, including the blood-brain barrier, microglial cells, NG2-glial cells, pericytes, and astrocytes, contribute to the post-Traumatic inflammation and the development of PTE.
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harmonization of pipeline for detection of hfos in a rat model of post Traumatic Epilepsy in preclinical multicenter study on post Traumatic epileptogenesis
Epilepsy Research, 2019Co-Authors: Cesar Emmanuel Santanagomez, Pedro Andrade, Tomi Paananen, Robert Ciszek, Idrish Ali, Brian K Rundle, Xavier Ekolle Ndodeekane, Matthew R Hudson, Gregory Smith, Pablo M CasillasespinosaAbstract:Studies of chronic Epilepsy show pathological high frequency oscillations (HFOs) are associated with brain areas capable of generating epileptic seizures. Only a few of these studies have focused on HFOs during the development of Epilepsy, but results suggest pathological HFOs could be a biomarker of epileptogenesis. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy" (EpiBioS4Rx) is a multi-center project designed to identify biomarkers of epileptogenesis after a Traumatic brain injury (TBI) and evaluate treatments that could modify or prevent the development of post-Traumatic Epilepsy. One goal of the EpiBioS4Rx project is to assess whether HFOs could be a biomarker of post-Traumatic epileptogenesis. The current study describes the work towards this goal, including the development of common surgical procedures and EEG protocols, an interim analysis of the EEG for HFOs, and identifying issues that need to be addressed for a robust biomarker analysis. At three participating sites - University of Eastern Finland (UEF), Monash University in Melbourne (Melbourne) and University of California, Los Angeles (UCLA) - TBI was induced in adult male Sprague-Dawley rats by lateral fluid-percussion injury. After injury and in sham-operated controls, rats were implanted with screw and microwire electrodes positioned in neocortex and hippocampus to record EEG. A separate group of rats had serial magnetic resonance imaging after injury and then implanted with electrodes at 6 months. Recordings 28 days post-injury were available from UEF and UCLA, but not Melbourne due to technical issues with their EEG files. Analysis of recordings from 4 rats - UEF and UCLA each had one TBI and one sham-operated control - showed EEG contained evidence of HFOs. Computer-automated algorithms detected a total of 1,819 putative HFOs and of these only 40 events (2%) were detected by all three sites. Manual review of all events verified 130 events as HFO and the remainder as false positives. Review of the 40 events detected by all three sites was associated with 88% agreement. This initial report from the EpiBioS4Rx Consortium demonstrates the standardization of EEG electrode placements, recording protocol and long-term EEG monitoring, and differences in detection algorithm HFO results between sites. Additional work on detection strategy, detection algorithm performance, and training in HFO review will be performed to establish a robust, preclinical evaluation of HFOs as a biomarker of post-Traumatic epileptogenesis.
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harmonization of the pipeline for seizure detection to phenotype post Traumatic Epilepsy in a preclinical multicenter study on post Traumatic epileptogenesis
Epilepsy Research, 2019Co-Authors: Pablo M Casillasespinosa, Pedro Andrade, Tomi Paananen, Robert Ciszek, Idrish Ali, Cesar Emmanuel Santanagomez, Xavier Ekolle Ndodeekane, Gregory Smith, Rhys D Brady, Jussi TohkaAbstract:Abstract Rationale The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Centre without walls is an NIH funded multicenter consortium. One of EpiBioS4Rx projects is a preclinical post-Traumatic epileptogenesis biomarker study that involves three study sites: The University of Eastern Finland, Monash University (Melbourne) and the University of California Los Angeles. Our objective is to create a platform for evaluating biomarkers and testing new antiepileptogenic treatments for post-Traumatic Epilepsy (PTE) using the lateral fluid percussion injury (FPI) model in rats. As only 30–50% of rats with severe lateral FPI develop PTE by 6 months post-injury, prolonged video-EEG monitoring is crucial to identify animals with PTE. Our objective is to harmonize the surgical and data collection procedures, equipment, and data analysis for chronic EEG recording in order to phenotype PTE in this rat model across the three study sites. Methods Traumatic brain injury (TBI) was induced using lateral FPI in adult male Sprague-Dawley rats aged 11–12 weeks. Animals were divided into two cohorts: a) the long-term video-EEG follow-up cohort (Specific Aim 1), which was implanted with EEG electrodes within 24 h after the injury; and b) the magnetic resonance imaging (MRI) follow-up cohort (Specific Aim 2), at 5 months after lateral FPI. Four cortical epidural screw electrodes (2 ipsilateral, 2 contralateral) and three intracerebral bipolar electrodes were implanted (septal CA1 and the dentate gyrus, layers II and VI of the perilesional cortex both anterior and posterior to the injury site). During the 7th post-TBI month, animals underwent 4 weeks of continuous video-EEG recordings to diagnose of PTE. Results All centers harmonized the induction of TBI and surgical procedures for the implantation of EEG recordings, utilizing 4 or more EEG recording channels to cover areas ipsilateral and contralateral to the brain injury, perilesional cortex and the hippocampus and dentate gyrus. Ground and reference screw electrodes were implanted. At all sites the minimum sampling rate was 512 Hz, utilizing a finite impulse response (FIR) and impedance below 10 KΩ through the entire recording. As part of the quality control criteria we avoided electrical noise, and monitoring changes in impedance over time and the appearance of noise on the recordings. To reduce electrical noise, we regularly checked the integrity of the cables, stability of the EEG recording cap and the appropriate connection of the electrodes with the cables. Following the pipeline presented in this article and after applying the quality control criteria to our EEG recordings all of the sites were successful to phenotype seizure in chronic EEG recordings of animals after TBI. Discussion Despite differences in video-EEG acquisition equipment used, the three centers were able to consistently phenotype seizures in the lateral fluid-percussion model applying the pipeline presented here. The harmonization of methodology will help to improve the rigor of preclinical research, improving reproducibility of pre-clinical research in the search of biomarkers and therapies to prevent antiepileptogenesis.
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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
Epilepsy Research, 2019Co-Authors: Xavier Ekolle Ndodeekane, Pedro Andrade, Riikka Immonen, Pablo M Casillasespinosa, Rhys D Brady, Cesar Santanagomez, Gregory T Smith, Noora PuhakkaAbstract: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 ( Melbourne > UCLA (p
