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Russell J. Ferland - One of the best experts on this subject based on the ideXlab platform.
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Eight Flurothyl-Induced Generalized Seizures Lead to the Rapid Evolution of Spontaneous Seizures in Mice: A Model of Epileptogenesis with Seizure Remission.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Bruce J. Herron, Joshua Q. Yannix, Julia W. Nalwalk, Barbara S. Beyer, Russell J. FerlandAbstract:The occurrence of recurrent, unprovoked Seizures is the hallmark of human epilepsy. Currently, only two-thirds of this patient population has adequate Seizure control. New epilepsy models provide the potential for not only understanding the development of spontaneous Seizures, but also for testing new strategies to treat this disorder. Here, we characterize a primary Generalized Seizure model of epilepsy following repeated exposure to the GABA A receptor antagonist, flurothyl, in which mice develop spontaneous Seizures that remit within 1 month. In this model, we expose C57BL/6J mice to flurothyl until they experience a Generalized Seizure. Each of these Generalized Seizures typically lasts SIGNIFICANCE STATEMENT Epilepsy is a chronic disorder characterized by the occurrence of recurrent, unprovoked Seizures in which the individual Seizure–ictal events are self-limiting. Remission of recurrent, unprovoked Seizures can be achieved in two-thirds of cases by treatment with anticonvulsant medication, surgical resection, and/or nerve/brain electrode stimulation. However, there are examples in humans of epilepsy with recurrent, unprovoked Seizures remitting without any intervention. While elucidating how recurrent, unprovoked Seizures develop is critical for understanding epileptogenesis, an understanding of how and why recurrent, unprovoked Seizures remit may further our understanding and treatment of epilepsy. Here, we describe a new model of recurrent, unprovoked spontaneous Seizures in which the occurrence of spontaneous Seizures naturally remits over time without any therapeutic intervention.
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Segregation of Seizure Traits in C57 Black Mouse Substrains Using the Repeated-Flurothyl Model
PloS one, 2014Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Bruce J. Herron, Russell J. FerlandAbstract:Identifying the genetic basis of epilepsy in humans is difficult due to its complexity, thereby underlying the need for preclinical models with specific aspects of Seizure susceptibility that are tractable to genetic analyses. In the repeated-flurothyl model, mice are given 8 flurothyl-induced Seizures, once per day (the induction phase), followed by a 28-day rest period (incubation phase) and final flurothyl challenge. This paradigm allows for the tracking of multiple phenotypes including: initial Generalized Seizure threshold, decreases in Generalized Seizure threshold with repeated flurothyl exposures, and changes in the complexity of Seizures over time. Given the responses we previously reported in C57BL/6J mice, we analyzed substrains of the C57BL lineage to determine if any of these phenotypes segregated in these substrains. We found that the Generalized Seizure thresholds of C57BL/10SNJ and C57BL/10J mice were similar to C57BL/6J mice, whereas C57BL/6NJ and C57BLKS/J mice showed lower Generalized Seizure thresholds. In addition, C57BL/6J mice had the largest decreases in Generalized Seizure thresholds over the induction phase, while the other substrains were less pronounced. Notably, we observed only clonic Seizures during the induction phase in all substrains, but when rechallenged with flurothyl after a 28-day incubation phase, ∼80% of C57BL/6J and 25% of C57BL/10SNJ and C57BL/10J mice expressed more complex Seizures with tonic manifestations with none of the C57BL/6NJ and C57BLKS/J mice having complex Seizures with tonic manifestations. These data indicate that while closely related, the C57BL lineage has significant diversity in aspects of epilepsy that are genetically controlled. Such differences further highlight the importance of genetic background in assessing the effects of targeted deletions of genes in preclinical epilepsy models.
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C57BL substrain differences in Generalized Seizure thresholds.
2014Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Bruce J. Herron, Russell J. FerlandAbstract:The latency to a Generalized Seizure (Generalized Seizure threshold (GST)) on each Seizure trial was determined for 5 C57BL substrains (n = 12 mice/substrain: 10SNJ, 10J, 6J, 6NJ, and KSJ) by exposure to 10% flurothyl during eight induction trials followed by a 28-day rest period and a single flurothyl retest. The baseline GST of 10SNJ mice and 10J mice were similar to that of 6J mice, whereas 6NJ and KSJ mice have significantly lower initial GST (P
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The slopes of the myoclonic jerk thresholds and Generalized Seizure thresholds across the 8 trial flurothyl induction phase in C57BL substrains.
2014Co-Authors: Sridhar B. Kadiyala, Dominick Papandrea, Bruce J. Herron, Russell J. FerlandAbstract:The slopes of the myoclonic jerk thresholds and Generalized Seizure thresholds across the 8 trial flurothyl induction phase in C57BL substrains.
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The effects of brain-irradiation-induced decreases in hippocampal mitotic activity on flurothyl-induced epileptogenesis in adult C57BL/6J mice.
Experimental neurology, 2003Co-Authors: Russell J. Ferland, Robert A. Gross, Jacqueline P. Williams, Craig D. ApplegateAbstract:Previous studies have demonstrated that Seizures are potent inducers of mitotic activity in the rodent hippocampus. The role of this mitotic activity in epileptogenesis currently remains unknown. In the present study, we investigated the effect of alterations in hippocampal mitotic activity on changes in Seizure threshold and phenotype using flurothyl kindling. In flurothyl kindling, eight repeated flurothyl-induced Generalized forebrain (clonic) Seizures result in a rapid, progressive, and permanent lowering of the Generalized Seizure threshold in mice and in a slowly evolving increase in the percentage of animals expressing forebrain-brain stem (clonic-tonic) Seizures when reexposed to flurothyl following a 2- to 4-week stimulation-free period. Therefore, flurothyl kindling serves as an excellent model for evaluating mechanisms of Generalized Seizure threshold and Seizure propagation. To investigate this relationship between hippocampal mitotic activity and epileptogenesis, mice were given brain irradiation, focused mainly on the hippocampus, bilaterally, and were exposed to the flurothyl kindling model of epileptogenesis. Brain irradiation virtually eliminated all basal and Seizure-induced mitotic activity in the hippocampal dentate gyrus of mice. In addition, animals that underwent irradiation and flurothyl kindling did not differ from control mice on measures of Seizure threshold (threshold induction and maintenance) and Seizure phenotype. Overall, these results suggest that Seizure-induced increases in mitotic activity in the hippocampal dentate gyrus are not directly related to the processes that underlie the shift in behavioral Seizure phenotype or in either the induction or the maintenance of lowered Seizure threshold that is observed in this flurothyl model of epileptogenesis.
Jason S. Haukoos - One of the best experts on this subject based on the ideXlab platform.
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the denver Seizure score anion gap metabolic acidosis predicts Generalized Seizure
American Journal of Emergency Medicine, 2011Co-Authors: Katherine Bakes, Jeff P. Faragher, Vince Markovchick, Kevin Donahoe, Jason S. HaukoosAbstract:Abstract Objectives Anion gap (AG) and serum bicarbonate concentration (BICARB) may help confirm a diagnosis of Seizure in an unwitnessed collapse; however, little data exist to support this practice. Our objective was to assess the association between AG metabolic acidosis and Generalized Seizure and to derive a simple score to predict Seizure. Methods This was a case-control study at an urban teaching hospital. Patients transported to our emergency department with witnessed loss of consciousness and final confirmed diagnoses of Generalized Seizure (cases) or syncope (controls) were eligible for enrollment. Multivariable logistic regression analysis was used to model associations between AG, BICARB, and Seizure. Results In 49 cases and 40 controls, patients in the Seizure group were more likely to have a lower median BICARB (17 [range, 14-34] vs 23 [range, 20-24], P 20), with 21% (95% confidence interval [CI], 5%-51%), 40% (95% CI, 26%-56%), and 96% (95% CI, 82%-100%) being categorized as Seizure, respectively. Conclusions Anion gap metabolic acidosis is associated with Generalized Seizure. A Denver Seizure Score greater than 20 predicts Generalized Seizure in the emergency department and may be useful for differentiating patients with unwitnessed loss of consciousness.
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The Denver Seizure Score: anion gap metabolic acidosis predicts Generalized Seizure ☆ ☆☆
The American journal of emergency medicine, 2010Co-Authors: Katherine Bakes, Jeff P. Faragher, Vince Markovchick, Kevin Donahoe, Jason S. HaukoosAbstract:Abstract Objectives Anion gap (AG) and serum bicarbonate concentration (BICARB) may help confirm a diagnosis of Seizure in an unwitnessed collapse; however, little data exist to support this practice. Our objective was to assess the association between AG metabolic acidosis and Generalized Seizure and to derive a simple score to predict Seizure. Methods This was a case-control study at an urban teaching hospital. Patients transported to our emergency department with witnessed loss of consciousness and final confirmed diagnoses of Generalized Seizure (cases) or syncope (controls) were eligible for enrollment. Multivariable logistic regression analysis was used to model associations between AG, BICARB, and Seizure. Results In 49 cases and 40 controls, patients in the Seizure group were more likely to have a lower median BICARB (17 [range, 14-34] vs 23 [range, 20-24], P 20), with 21% (95% confidence interval [CI], 5%-51%), 40% (95% CI, 26%-56%), and 96% (95% CI, 82%-100%) being categorized as Seizure, respectively. Conclusions Anion gap metabolic acidosis is associated with Generalized Seizure. A Denver Seizure Score greater than 20 predicts Generalized Seizure in the emergency department and may be useful for differentiating patients with unwitnessed loss of consciousness.
Craig D. Applegate - One of the best experts on this subject based on the ideXlab platform.
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the effects of brain irradiation induced decreases in hippocampal mitotic activity on flurothyl induced epileptogenesis in adult c57bl 6j mice
Experimental Neurology, 2003Co-Authors: Russell J. Ferland, Robert A. Gross, Jacqueline P. Williams, Craig D. ApplegateAbstract:Previous studies have demonstrated that Seizures are potent inducers of mitotic activity in the rodent hippocampus. The role of this mitotic activity in epileptogenesis currently remains unknown. In the present study, we investigated the effect of alterations in hippocampal mitotic activity on changes in Seizure threshold and phenotype using flurothyl kindling. In flurothyl kindling, eight repeated flurothyl-induced Generalized forebrain (clonic) Seizures result in a rapid, progressive, and permanent lowering of the Generalized Seizure threshold in mice and in a slowly evolving increase in the percentage of animals expressing forebrain-brain stem (clonic-tonic) Seizures when reexposed to flurothyl following a 2- to 4-week stimulation-free period. Therefore, flurothyl kindling serves as an excellent model for evaluating mechanisms of Generalized Seizure threshold and Seizure propagation. To investigate this relationship between hippocampal mitotic activity and epileptogenesis, mice were given brain irradiation, focused mainly on the hippocampus, bilaterally, and were exposed to the flurothyl kindling model of epileptogenesis. Brain irradiation virtually eliminated all basal and Seizure-induced mitotic activity in the hippocampal dentate gyrus of mice. In addition, animals that underwent irradiation and flurothyl kindling did not differ from control mice on measures of Seizure threshold (threshold induction and maintenance) and Seizure phenotype. Overall, these results suggest that Seizure-induced increases in mitotic activity in the hippocampal dentate gyrus are not directly related to the processes that underlie the shift in behavioral Seizure phenotype or in either the induction or the maintenance of lowered Seizure threshold that is observed in this flurothyl model of epileptogenesis.
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The effects of brain-irradiation-induced decreases in hippocampal mitotic activity on flurothyl-induced epileptogenesis in adult C57BL/6J mice.
Experimental neurology, 2003Co-Authors: Russell J. Ferland, Robert A. Gross, Jacqueline P. Williams, Craig D. ApplegateAbstract:Previous studies have demonstrated that Seizures are potent inducers of mitotic activity in the rodent hippocampus. The role of this mitotic activity in epileptogenesis currently remains unknown. In the present study, we investigated the effect of alterations in hippocampal mitotic activity on changes in Seizure threshold and phenotype using flurothyl kindling. In flurothyl kindling, eight repeated flurothyl-induced Generalized forebrain (clonic) Seizures result in a rapid, progressive, and permanent lowering of the Generalized Seizure threshold in mice and in a slowly evolving increase in the percentage of animals expressing forebrain-brain stem (clonic-tonic) Seizures when reexposed to flurothyl following a 2- to 4-week stimulation-free period. Therefore, flurothyl kindling serves as an excellent model for evaluating mechanisms of Generalized Seizure threshold and Seizure propagation. To investigate this relationship between hippocampal mitotic activity and epileptogenesis, mice were given brain irradiation, focused mainly on the hippocampus, bilaterally, and were exposed to the flurothyl kindling model of epileptogenesis. Brain irradiation virtually eliminated all basal and Seizure-induced mitotic activity in the hippocampal dentate gyrus of mice. In addition, animals that underwent irradiation and flurothyl kindling did not differ from control mice on measures of Seizure threshold (threshold induction and maintenance) and Seizure phenotype. Overall, these results suggest that Seizure-induced increases in mitotic activity in the hippocampal dentate gyrus are not directly related to the processes that underlie the shift in behavioral Seizure phenotype or in either the induction or the maintenance of lowered Seizure threshold that is observed in this flurothyl model of epileptogenesis.
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Regional analysis of the spatial patterns of Fos induction in brain following flurothyl kindling.
Neuroscience, 1998Co-Authors: Gary M. Samoriski, Diane T. Piekut, Craig D. ApplegateAbstract:Abstract We have recently demonstrated that eight, daily flurothyl-induced Generalized clonic Seizures, followed by a four week stimulus-free interval, results in a long-lasting reduction in Generalized Seizure threshold and a change in the type of Seizure expressed in response to flurothyl from clonic to tonic. There is a progressive increase in the probability that a mouse will express a tonic Seizure during the four week interval, suggesting that prior flurothyl Seizures initiate a proepileptogenic process that requires time to develop. In this study, the immunohistochemical detection of the c-fos protein (Fos) was used to evaluate whether Seizure-induced epileptogenesis resulted in regional differences in the degree of neuronal activation. Fos immunoreactivity was examined 1.5 h following either a single Generalized Seizure, the last of eight consecutive daily Seizures or a retest Seizure evoked two weeks after the last of eight Seizures. In each condition, Generalized Seizure behaviours were elicited in C57BL/6 mice using flurothyl and classified as either “forebrain” (face and forelimb clonus) or “brainstem” (running bouncing, treading, tonic extension). The spatial distribution of Fos induction was compared on the basis of the Seizure phenotype and the Seizure history. The predominant differences in Fos distribution were found to be related to the type of Seizure expressed regardless of the Seizure history. Furthermore, the different motor components that make up a “brainstem” Seizure could not be distinguished by the pattern of Fos labelling suggesting that multiple convulsive behaviours are mediated by one anatomical system. Finally, Fos induction in the ventromedial hypothalamic nucleus preceded and predicted the change in Seizure type from “forebrain” to “brainstem”. These data support the concept that separate anatomical systems mediate the expression of the two Generalized Seizure phenotypes. In addition, the ventromedial nucleus of the hypothalamus may be a point of interaction between the systems and may play a role in Seizure-induced neural reorganization.
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Repeated Generalized Seizures Induce Time-Dependent Changes in the Behavioral Seizure Response Independent of Continued Seizure Induction
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997Co-Authors: Gary M. Samoriski, Craig D. ApplegateAbstract:This study examined both the acute and long-lasting changes in Seizure susceptibility that occur in response to the repeated induction of Generalized Seizure activity. Daily flurothyl-induced Generalized clonic Seizures resulted in a progressive decrease in both the Generalized Seizure threshold and the latency to the first myoclonic jerk. The threshold reduction was significant as early as the second trial and was maximal by trial 5. However, a minimum of eight Seizures was necessary for the maximal reduction to be long-lasting. The present study also examined the effects of the number of Seizures and the duration of the stimulation-free interval on the type of Generalized Seizure expressed. During the induction phase of the experiment, only Generalized clonic Seizures (“forebrain Seizures”) were expressed. If, however, the animal was retested after a 1, 2, 3, or 4 week stimulation-free interval, a progressive increase in both the proportion of animals expressing “brainstem Seizure” behaviors and the median Seizure score was observed. The progression of flurothyl-induced Generalized Seizure behaviors was significantly altered if (1) a minimum of eight Generalized clonic Seizures had been expressed, and (2) a minimum of a 2 week stimulation-free interval followed. Fewer Generalized clonic Seizures failed to reliably produce changes in Seizure phenotype, even after extended stimulus-free intervals. These data indicate that specific kindling processes are initiated during the interval of repeated Seizure induction and evolve in the absence of continued Seizure induction. Furthermore, these mechanisms of epileptogenesis were found to be manifest predominantly as a change in the Seizure phenotype expressed and to proceed independent of changes in the Generalized Seizure threshold.
Michael C Antle - One of the best experts on this subject based on the ideXlab platform.
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a single Generalized Seizure alters the amplitude but not phase of the circadian activity rhythm of the hamster
Chronobiology International, 2009Co-Authors: Victoria Smith, Jason Baserman, Kimberly Hagel, Campbell G Teskey, Michael C AntleAbstract:People with epilepsy exhibit high rates of sleep disturbances. In many cases, these sleep disruptions appear to be related to the occurrence of the Seizures themselves. Changes in sleep structure may reflect underlying changes in the circadian clock, as circadian rhythms of locomotor activity, body temperature, and hormone release are disrupted following a Seizure. The present study was designed to determine if a single Generalized Seizure could alter the phase and waveform of the circadian rhythm of wheel‐running behavior in the Syrian hamster. Animals were housed in constant darkness, and were administered either a sham treatment or a maximal electroconvulsive shock at one of three time‐points: 6 h before activity onset, 1 h after activity onset, or 6 h after activity onset. Seizures at all of these phases did not significantly affect the phase of the circadian activity rhythm. The circadian locomotor activity levels were significantly attenuated following Seizures at all three phases. This attenuation ...
Shigeya Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Generalized Seizures induced by an epileptic focus in the mesencephalic reticular formation: impact on the understanding of the generalizing mechanism.
Stereotactic and functional neurosurgery, 2000Co-Authors: Kiyotaka Hashizume, Tatsuya Tanaka, Tsutomu Fujita, Shigeya TanakaAbstract:The mode of Seizure propagation was studied using a Generalized Seizure model induced by microinjection of kainic acid (KA) into a unilateral mesencephalic reticular formation (MRF) in cats and rats. Stereotactic surgery was performed under pentobarbital anesthesia; an injection cannula was placed into a unilateral MRF, and bipolar electrodes were implanted into the MRF and the thalamus. Microinjection of KA induced Generalized Seizures. Focal electrical Seizures were elicited in the injected site of the MRF starting 30 min after the injection. The initial clinical change during each Seizure was behavioral arrest. These Seizures immediately developed to Generalized Seizures, which were characterized by Generalized tonic convulsions with short-term clonic convulsions. On EEG, each Generalized Seizure started at the same time in all the sites of the brain recorded. Autoradiographic study using a rat model demonstrated high glucose utilization in the MRF, bilateral thalamus, forebrain and bilateral cerebral cortices. The results demonstrated an active participation of MRF in the mechanism of Generalized Seizures.