scholarly journals Augmentation of Tonic GABAAInhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAAReceptors

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Adam C. Errington ◽  
David W. Cope ◽  
Vincenzo Crunelli
Keyword(s):  
Epileptic Seizures ◽  
Absence Epilepsy ◽  
Vital Role ◽  
Gaba Uptake ◽  
Absence Seizure ◽  
Pharmacological Agents ◽  
Absence Seizures ◽  
Inverse Agonists ◽  
Potential Therapeutic Role ◽  
Necessary And Sufficient

It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABAAreceptors (eGABAAR) and augmented “tonic” GABAAinhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABAAR gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABAARs in absence epilepsy.

scholarly journals Absence Seizure Detection Algorithm for Portable EEG Devices

2021 ◽  
Vol 12 ◽  
Author(s):  
Pawel Glaba ◽  
Miroslaw Latka ◽  
Małgorzata J. Krause ◽  
Sławomir Kroczka ◽  
Marta Kuryło ◽  
...  
Keyword(s):  
Detection Rate ◽  
Low Cost ◽  
Clinical Manifestations ◽  
Epileptic Seizures ◽  
Seizure Detection ◽  
Detection Algorithm ◽  
Absence Epilepsy ◽  
Absence Seizure ◽  
Epileptiform Discharges ◽  
Morlet Continuous Wavelet Transform

Absence seizures are generalized nonmotor epileptic seizures with abrupt onset and termination. Transient impairment of consciousness and spike-slow wave discharges (SWDs) in EEG are their characteristic manifestations. This type of seizure is severe in two common pediatric syndromes: childhood (CAE) and juvenile (JAE) absence epilepsy. The appearance of low-cost, portable EEG devices has paved the way for long-term, remote monitoring of CAE and JAE patients. The potential benefits of this kind of monitoring include facilitating diagnosis, personalized drug titration, and determining the duration of pharmacotherapy. Herein, we present a novel absence detection algorithm based on the properties of the complex Morlet continuous wavelet transform of SWDs. We used a dataset containing EEGs from 64 patients (37 h of recordings with almost 400 seizures) and 30 age and sex-matched controls (9 h of recordings) for development and testing. For seizures lasting longer than 2 s, the detector, which analyzed two bipolar EEG channels (Fp1-T3 and Fp2-T4), achieved a sensitivity of 97.6% with 0.7/h detection rate. In the patients, all false detections were associated with epileptiform discharges, which did not yield clinical manifestations. When the duration threshold was raised to 3 s, the false detection rate fell to 0.5/h. The overlap of automatically detected seizures with the actual seizures was equal to ~96%. For EEG recordings sampled at 250 Hz, the one-channel processing speed for midrange smartphones running Android 10 (about 0.2 s per 1 min of EEG) was high enough for real-time seizure detection.

scholarly journals Cortical Tonic Inhibition Regulates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy

2017 ◽  
Author(s):  
Kile P. Mangan ◽  
Aaron B. Nelson ◽  
Steven Petrou ◽  
Chiara Cirelli ◽  
Mathew V. Jones
Keyword(s):  
Absence Epilepsy ◽  
Tonic Inhibition ◽  
Absence Seizure ◽  
Optimum Level ◽  
Normal Functioning ◽  
Absence Seizures ◽  
Pharmacological Blockade ◽  
Eeg Recordings ◽  
Wave Discharge ◽  
Video Eeg

ABSTRACTSynchronous and bilateral spike-and-wave discharges accompany nonconvulsive behavioral and cognitive arrest during seizures associated with absence epilepsy. Previous investigation of multiple absence animal models suggests that the underlying cause of absence seizures is an increase in thalamic inhibitory tonic currents. In contrast, in this study we provide evidence that the level of cortical tonic inhibition also regulates absence seizure expression. Using continuous video-EEG recordings to monitor absence seizures and spike-and-wave discharge expression we show that pharmacological blockade of cortical tonic inhibition provokes absence seizures in wild-type mice. Furthermore, we show that pharmacological rescue of cortical tonic inhibition in an absence mouse (γ2R43Q) model, which lacks tonic inhibition, suppresses absence seizure and spike-and-wave discharge expression. Collectively, these results suggest an optimum level of tonic inhibition in the thalamocortical circuit is required for normal functioning and that a deviation from this optimum results in aberrant thalamocortical function, SWDs and absence seizures.

scholarly journals Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

2021 ◽  
Vol 15 ◽  
Author(s):  
Sandesh Panthi ◽  
Beulah Leitch
Keyword(s):  
Absence Epilepsy ◽  
Designer Drug ◽  
Absence Seizure ◽  
Absence Seizures ◽  
Feed Forward ◽  
Video Recordings ◽  
Intraperitoneal Dose ◽  
Spike Wave Discharges ◽  
The Impact

Parvalbumin-expressing (PV+) interneurons are a subset of GABAergic inhibitory interneurons that mediate feed-forward inhibition (FFI) within the cortico-thalamocortical (CTC) network of the brain. The CTC network is a reciprocal loop with connections between cortex and thalamus. FFI PV+ interneurons control the firing of principal excitatory neurons within the CTC network and prevent runaway excitation. Studies have shown that generalized spike-wave discharges (SWDs), the hallmark of absence seizures on electroencephalogram (EEG), originate within the CTC network. In the stargazer mouse model of absence epilepsy, reduced FFI is believed to contribute to absence seizure genesis as there is a specific loss of excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at synaptic inputs to PV+ interneurons within the CTC network. However, the degree to which this deficit is directly related to seizure generation has not yet been established. Using chemogenetics and in vivo EEG recording, we recently demonstrated that functional silencing of PV+ interneurons in either the somatosensory cortex (SScortex) or the reticular thalamic nucleus (RTN) is sufficient to generate absence-SWDs. Here, we used the same approach to assess whether activating PV+ FFI interneurons within the CTC network during absence seizures would prevent or reduce seizures. To target these interneurons, mice expressing Cre recombinase in PV+ interneurons (PV-Cre) were bred with mice expressing excitatory Gq-DREADD (hM3Dq-flox) receptors. An intraperitoneal dose of pro-epileptic chemical pentylenetetrazol (PTZ) was used to induce absence seizure. The impact of activation of FFI PV+ interneurons during seizures was tested by focal injection of the “designer drug” clozapine N-oxide (CNO) into either the SScortex or the RTN thalamus. Seizures were assessed in PVCre/Gq-DREADD animals using EEG/video recordings. Overall, DREADD-mediated activation of PV+ interneurons provided anti-epileptic effects against PTZ-induced seizures. CNO activation of FFI either prevented PTZ-induced absence seizures or suppressed their severity. Furthermore, PTZ-induced tonic-clonic seizures were also reduced in severity by activation of FFI PV+ interneurons. In contrast, administration of CNO to non-DREADD wild-type control animals did not afford any protection against PTZ-induced seizures. These data demonstrate that FFI PV+ interneurons within CTC microcircuits could be a potential therapeutic target for anti-absence seizure treatment in some patients.

scholarly journals Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Kathryn A Salvati ◽  
George MPR Souza ◽  
Adam C Lu ◽  
Matthew L Ritger ◽  
Patrice Guyenet ◽  
...  
Keyword(s):  
Respiratory Alkalosis ◽  
Absence Epilepsy ◽  
Ph Sensitive ◽  
Absence Seizure ◽  
Patient Response ◽  
Absence Seizures ◽  
Intralaminar Nuclei ◽  
Highly Sensitive ◽  
Intralaminar Thalamus ◽  
Spike Wave Discharges

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics in the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

scholarly journals Tonic Inhibition is Abolished in GABAA Receptor γ2R43Q Knock-in Mice with Absence Epilepsy and Febrile Seizures

2017 ◽  
Author(s):  
Kile P. Mangan ◽  
Wyatt B. Potter ◽  
Aaron B. Nelson ◽  
Steve Petrou ◽  
Stephen M. Johnson ◽  
...  
Keyword(s):  
Brain Slices ◽  
Febrile Seizures ◽  
Absence Epilepsy ◽  
Protein Quantification ◽  
Tonic Inhibition ◽  
Optimum Level ◽  
Absence Seizures ◽  
Ventrobasal Thalamus ◽  
Patch Clamp Electrophysiology ◽  
Necessary And Sufficient

ABSTRACTThe γ2R43Q GABAA receptor mutation confers absence epilepsy in humans, and γ2R43Q knock-in mice (RQ) display absence seizures and generalized spike-and-wave discharges reminiscent of their human counterparts. Previous work on several rodent models led to the conclusion that elevated tonic inhibition in thalamic neurons is necessary and sufficient to produce typical absence epilepsy. In contrast, here we used patch-clamp electrophysiology in brain slices to show that RQ mice entirely lack tonic inhibition in principal cells of layer II/III somatosensory cortex and ventrobasal thalamus. Additionally, protein quantification and multielectrode electrophysiology show that the mutation interferes with trafficking of GABAA receptor subunits involved in generating tonic currents, leading to increased cortical firing and decreased thalamic bursting rates. Together with previous work, our results suggest that an optimum level of tonic inhibition is required for normal thalamocortical function, such that deviations in either direction away from this optimum enhance susceptibility to absence seizures.

scholarly journals Pretreatment seizure semiology in childhood absence epilepsy

Neurology ◽  
2017 ◽  
Vol 89 (7) ◽  
pp. 673-679 ◽  
Author(s):  
Sudha Kilaru Kessler ◽  
Shlomo Shinnar ◽  
Avital Cnaan ◽  
Dennis Dlugos ◽  
Joan Conry ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Absence Epilepsy ◽  
Absence Seizure ◽  
Seizure Freedom ◽  
Childhood Absence Epilepsy ◽  
Short Term ◽  
Short Term Treatment ◽  
Absence Seizures ◽  
Seizure Semiology ◽  
Eye Involvement

Objective:To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes.Methods:For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit.Results:Video of 1,932 electrographic absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%–84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern.Conclusions:Almost all absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.

scholarly journals Respiratory Alkalosis Provokes Spike-Wave Discharges in Seizure- Prone Rats

2021 ◽  
Author(s):  
Kathryn Salvati ◽  
George M.P.R. Souza ◽  
Adam C Lu ◽  
Matthew L Ritger ◽  
Patrice Guyenet ◽  
...  
Keyword(s):  
Respiratory Alkalosis ◽  
Absence Epilepsy ◽  
Ph Sensitive ◽  
Absence Seizure ◽  
Patient Response ◽  
Absence Seizures ◽  
Intralaminar Nuclei ◽  
Highly Sensitive ◽  
Intralaminar Thalamus ◽  
Spike Wave Discharges

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. Using the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

scholarly journals Maladaptive myelination promotes epileptogenesis in absence epilepsy

2020 ◽  
Author(s):  
Juliet K. Knowles ◽  
Caroline Soane ◽  
Eleanor Frost ◽  
Lydia T. Tam ◽  
Danielle Fraga ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Neuronal Activity ◽  
Absence Epilepsy ◽  
Absence Seizure ◽  
Seizure Onset ◽  
Absence Seizures ◽  
Adaptive Process ◽  
Seizure Disorders ◽  
Activity Dependent ◽  
Over Time

SummaryNeuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a+/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a+/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.

scholarly journals Atypical EEG pattern in children with absence seizures

1995 ◽  
Vol 53 (2) ◽  
pp. 258-261 ◽  
Author(s):  
Délrio F. Silva ◽  
Márcia Marques Lima ◽  
Renato Anghinah ◽  
Edmar Zanoteli ◽  
José Geraldo Camargo Lima
Keyword(s):  
Absence Seizure ◽  
Complete Control ◽  
Absence Seizures ◽  
Normal Finding ◽  
Delta Activity ◽  
Eeg Changes ◽  
Eeg Pattern

We studied four children with diagnosis of absence seizures (generalized primary epilepsy), and with a generalized delta activity on the EEG during clinical attacks provoked by hyperventilation. The lack of ictal generalized spike-and-wave discharges with a frequency of 3 Hz in our patients, makes this an atypical pattern. All children had complete control of their seizures and disappearance of the EEG changes with valproate. We concluded that generalized delta activity observed on EEG during the hyperventilation in children should not always be considered as a normal finding for age, since it could be an ictal event of an absence seizure.

scholarly journals Positive Allosteric Modulator of mGluR4 PHCCC Exhibits Proconvulsant Action in Three Models of Epileptic Seizures in Immature Rats

2012 ◽  
pp. 619-628 ◽  
Author(s):  
E. SZCZUROWSKA ◽  
P. MAREŠ
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Rhythmic Activity ◽  
Epileptic Seizures ◽  
Allosteric Modulator ◽  
Anticonvulsant Effect ◽  
Positive Allosteric Modulator ◽  
Adult Rats ◽  
Absence Seizures ◽  
Implanted Electrodes ◽  
Immature Rats

The activation of metabotropic glutamate receptors subtype 4 (mGluR4) potentiates models of absence seizures in adult rats. These seizures are age-dependent, but data concerning the role of mGluR4 in immature brain is insufficient. N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1acarboxamide (PHCCC), which is a positive allosteric modulator of these receptors, was used in three different models of seizures in immature rats: 1) convulsions induced by high doses of pentetrazol (PTZ; a model of generalised tonic-clonic seizures); 2) rhythmic electro-encephalographic (EEG) activity induced by low doses of PTZ (a model of absence seizures); and 3) electrically elicited cortical afterdischarges (ADs, a model of myoclonic seizures). We administered four doses of PHCCC (1, 3, 10 and 20 mg/kg) in PTZ-induced convulsions and two doses (3 and 10 mg/kg) in the two electrophysiological models of freely moving rats with implanted electrodes. Every dose and age group consisted from 8 to 10 rats. PTZ-elicited convulsions were not significantly influenced by PHCCC. In contrast, PHCCC potentiated the effect of a subconvulsant dose (60 mg/kg) of PTZ. The 10-mg/kg dose of PHCCC significantly prolonged the duration of PTZ-induced rhythmic activity episodes and shortened the intervals between individual episodes in 25-day-old rats (P25). In contrast, this potentiation was not seen in P18 rats. Cortical ADs were significantly prolonged with repeated stimulations by both doses of PHCCC in P12 and P18 animals. P25 rats exhibited only slightly longer AD durations. In conclusion, we did not find any anticonvulsant effect of PHCCC. On the contrary, proconvulsant action was demonstrated in all three models in immature rats.

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