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Investigations in Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats that are susceptible to genetic absence epilepsy have demonstrated that environmental modifications affect absence seizures. Previously, we showed that neonatal tactile stimulations produce disease-modifying effect on genetically determined absence epilepsy and associated depression in Wag/Rij rats. The study presented here examined the effect of TS during late ontogenesis (adolescence and young adulthood) on epilepsy and depression outcomes in this genetically epileptic rat strain. On postnatal day (PND) 38, male WAG/Rij rats randomly were assigned to either the tactile stimulation (TS), handled or control group (unhandled) with 8 animals in each group. Following a 7-day adaptation period to their new surroundings, the animals were submitted to tactile stimulation from PND 45 to PND 90, five days per week, for 5  min daily. The tactile-stimulated rat was removed from its cage, placed on the experimenter’s lap, and had its neck and back gently stroked by the researcher. The handled rats were taken to another cage and left alone for 5  min daily from PND 45 to PND 90. The control rats were left undisturbed in their home cage, except for regular cage cleaning. After PND 90, all rats were left undisturbed until behavioral testing and EEG recording. When the animals were 7  months old, they were subjected to the sucrose consumption test (SCT) and the forced swimming test (FST). Electroencephalogram (EEG) recordings were made at 8  months of age in order to measure electroencephalographic seizure activity, thus, the spike– wave discharges (SWDs). Tactile-stimulated rats showed increased sucrose consumption and number of approaches to the sucrose solution in the SCT when compared with the handled and control rats. In the FST, rats in TS group showed lower immobility time and greater immobility latency, active swimming time and diving frequency than the handled and control rats. The duration and the number of seizures were not different amongst the groups. The data obtained suggest that TS in young rats is able to prevent depression in WAG/ Rij rats. [ABSTRACT FROM AUTHOR]

Childhood absence epilepsy (CAE) has a typical electroencephalography (EEG) pattern of generalized 3 Hz spike and wave discharges (SWD). Focal interictal discharges were also documented in a small number of documents. The aim was to investigate the amplitudes of interictal 3 Hz SWD within the 1st second in drug-naïve CAE patients. In this way, areas with maximal electronegativity at the beginning of clinically generalized discharges will be documented. The EEG records of children with drug-naïve CAE were evaluated retrospectively by two child neurologists first for 3 Hz SWD. Then, a machine-learning model evaluated the amplitudes of 3 Hz in the 1st second of SWD. Maximum electronegativity areas were documented and classified as focal, bilateral, and generalized. One hundred and twelve 3 Hz SWD were evaluated in 11 patients. Among discharges within the 1st second, maximum electronegativity areas were documented as focal for 44 (39.2%), bilateral for 8 (7.1%), generalized for 60 (53.5%). Among focal electronegativity areas, mostly right central, left occipital and midline parietal areas were documented in 12 (10.7%), 7 (6.2%), and 6 (5.3%), respectively. Eight (7.1%) of the maximum electronegativity areas were detected bilaterally, of which 7 (6.2%) originated from the frontopolar areas. Focal maximal electronegativity areas were frequently observed in drug-naïve CAE patients, comprising approximately half of non-generalized discharges. Focal discharges might be misleading in diagnosis. Focal areas within the brain may be responsible for and contribute to absence seizures that appear bilaterally symmetrical and generalized clinically. Although its clinical implication is unknown, this warrants further study. [ABSTRACT FROM AUTHOR]

This study was aimed to find out what effect the maternal methyl-enriched diet (MED) in the perinatal period exerts on cognitive functions in adult offspring of WAG/Rij rats, a genetic model of absence epilepsy with comorbid depression. The cognitive functions (learning and memory) were evaluated in the novel object recognition (NOR) and fear conditioning (for fear memory) tests. The experiments were carried out on 6-month-old male WAG/Rij rats. The mothers of the experimental group fed a MED, while the mothers of the control group fed a control diet. The NOR test was used to assess episodic memory. This test is based on innate exploratory (novelty preference) motivation, which is usually reduced in depression. The conditioning of fear memory is the classical Pavlovian defensive conditioned reflex, manifested as freezing in response to negative reinforcement (electric footshock). In the NOR test, in rats of the experimental group, the novel object recognition index (a measure of episodic memory) and the number of entries to the center of the arena (a measure of exploratory motivation) were significantly higher compared to the corresponding measures in the control group. However, no intergroup differences were revealed in the manifestation of conditioned fear memory (% of freezing responses) to a context and a sound cue. The results indicate that the maternal MED improves episodic memory in the NOR test but does not affect the conditioned fear memory associated with a context and sound cue in the adult offspring of WAG/Rij rats. [ABSTRACT FROM AUTHOR]

WAG/Rij rats are a valid model of absence epilepsy and comorbid depression. We have previously shown that WAG/Rij rats have disturbances in the sleep–wake cycle and changes in the characteristics of sleep spindles. A negative correlation was also found between the number of spike-wave discharges (SWD) and the duration of rapid eye movement (REM) sleep. Clinical evidence suggests that the traditional antidepressants imipramine and fluoxetine are effective in suppressing symptoms of depression, but may have a negative impact on the sleep–wake cycle and comorbid epilepsy in patients. Our previous studies in WAG/Rij rats showed that imipramine, when administered chronically, increases the number of SWDs, while fluoxetine at the same dose reduces their number, although both antidepressants have a pronounced antidepressant effect. Comparison of the effects of the antidepressants imipramine and fluoxetine on the sleep–wake cycle and sleep spindles in WAG/Rij rats remains unstudied. The purpose of this work is to find out: (1) what effects do imipramine and fluoxetine have on the sleep–wake cycle and the characteristics of sleep spindles in WAG/Rij rats and (2) whether there are differences in their effects. To achieve this goal, the characteristics of the sleep–wake cycle and sleep spindles were compared in WAG/Rij rats after chronic administration of antidepressants and saline and in non-epileptic Wistar rats. Administration of imipramine led to a significant decrease in the duration of REM sleep. The administration of imipramine, compared with fluoxetine, also increased the latency of the transition to sleep and the transition to REM sleep. Sleep spindle amplitude was significantly increased by both antidepressants. However, the spectral power density of "slow" and "medium" spindles, which predominate in WAG/Rij rats compared to Wistar rats, was significantly higher after administration of imipramine than fluoxetine. The results suggest that imipramine causes greater negative changes in the sleep–wake cycle and sleep spindles than fluoxetine. Studies in the WAG/Rij rat model indicate that fluoxetine is more preferable antidepressant for the treatment of depressive disorders comorbid with absence epilepsy, since it does not cause a significant deterioration in sleep quality. These results are consistent with clinical data. [ABSTRACT FROM AUTHOR]

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.

The purpose of this study is to develop a classifier capable of detecting typical absence seizures in real-time using electroencephalogram (EEG) data and a Support Vector Machine (SVM) model. Methods. Sections of the EEG, previously identified by a specialist as containing typical absences, were used to train the SVM model. Key features for classification include the number of zero crossings, cross-correlation between two consecutive windows, spectral power across various frequency bands, and the standard deviation of instantaneous signal power. Results. Training and testing datasets were established, consisting of EEG windows with various types of artifacts. The SVM model was successfully trained and tested, achieving high performance metrics. The developed algorithm can be integrated into a mobile application and used in conjunction with a wearable EEG device with dry electrodes for real-time detection of typical absences. Conclusion. The study results affirm the potential for using machine learning techniques for the automatic detection and logging of epileptic activity. However, additional testing on a larger dataset is needed for more conclusive results, including data acquired through a wireless EEG device using dry electrodes. Future work will involve selecting a suitable EEG device and developing a mobile application for real-time data collection and analysis.

• VNS reduced absence seizures by 66% in DRAE patients. • 80% of patients responded positively to VNS therapy. • Seizure improvement was independent of age at onset or latency to VNS implant. • VNS may be a promising therapy in pediatric patients with DRAE. Around 11% of patients with absence epilepsy develop drug-resistant absence epilepsy (DRAE), and are at increased risk for developing psychiatric and neurologic comorbidities. Current therapeutic options for DRAE are limited. The purpose of this study was to assess the efficacy of vagus nerve stimulation (VNS) in treating DRAE. Our institution maintains a database of patients who received VNS between 2010 and 2022. We identified DRAE patients who were <18 years of age at seizure onset, were electro-clinically diagnosed with an absence epilepsy syndrome (childhood absence, juvenile absence, or Jeavons Syndrome) by an epileptologist, and had normal brain imaging. The primary outcome measure was post-VNS absence seizure frequency. Twenty-six patients (M/F:14/12) were identified. Median age at seizure onset was 7 years (IQR 4–10) and patients experienced seizures for 6 years (IQR 4.3–7.6) before VNS. After VNS, the median absence seizure frequency reduced to 1.5 days (IQR 0.1–3.5) per week from 7 days (IQR 7–7), a 66% reduction seizure frequency. VNS responder rate was 80%, and seven patients achieved seizure freedom. There was no significant effect on VNS efficacy between the time from DRAE diagnosis to VNS placement (p = 0.067) nor the time from first seizure onset to VNS implant (p = 0.80). The median follow-up duration was 4.1 years (IQR 2.4–6.7), without any significant association between follow-up duration and VNS efficacy (r2=0.023) VNS is effective in managing DRAE. The responder rate was 80%; seizure improvement was independent of age at both seizure onset and latency to VNS after meeting DRAE criteria. [ABSTRACT FROM AUTHOR]

Introduction: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent a model of genetic generalized epilepsy. The present longitudinal study in GAERS and age-matched non-epileptic controls (NEC) aimed to characterize the epileptic brain network using two functional measures, resting statefunctional magnetic resonance imaging (rs-fMRI) and manganese-enhanced MRI (MEMRI) combined with morphometry, and to investigate potential brain network alterations, following long-term seizure activity. Methods: Repeated rs-fMRI measurements at 9.4 T between 3 and 8 months of age were combined with MEMRI at the final time point of the study. We used graph theory analysis to infer community structure and global and local network parameters from rs-fMRI data and compared them to brain regionwise manganese accumulation patterns and deformation-based morphometry (DBM). Results: Functional connectivity (FC) was generally higher in GAERS when compared to NEC. Global network parameters and community structure were similar in NEC and GAERS, suggesting efficiently functioning networks in both strains. No progressive FC changes were observed in epileptic animals. Network-based statistics (NBS) revealed stronger FC within the cortical community, including regions of association and sensorimotor cortex, and with basal ganglia and limbic regions in GAERS, irrespective of age. Higher manganese accumulation in GAERS than in NEC was observed at 8 months of age, consistent with higher overall rs-FC, particularly in sensorimotor cortex and association cortex regions. Functional measures showed less similarity in subcortical regions. Whole brain volumes of 8 months-old GAERS were higher when compared to age-matched NEC, and DBM revealed increased volumes of several association and sensorimotor cortex regions and of the thalamus. Discussion: rs-fMRI, MEMRI, and volumetric data collectively suggest the significance of cortical networks in GAERS, which correlates with an increased fronto-central connectivity in childhood absence epilepsy (CAE). Our findings also verify involvement of basal ganglia and limbic regions. Epilepsy-related network alterations are already present in juvenile animals. Consequently, this early condition seems to play a greater role in dynamic brain function than chronic absence seizures. [ABSTRACT FROM AUTHOR]

In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide–gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors. [ABSTRACT FROM AUTHOR]

The involvement of the prefrontal cortical dopaminergic system in the psychopathology of epilepsies and comorbid conditions such as autism spectrum disorder (ASD) still needs to be explored. We used autoradiography to study the D1-like (D1DR) and D2-like (D2DR) receptor binding density in the prefrontal cortex of normal Wistar rats and Wistar-derived strains with generalized convulsive and/or non-convulsive epilepsy. WAG/Rij rats served as a model for non-convulsive absence epilepsy, WAG/Rij-AGS as a model of mixed convulsive/non-convulsive form, and KM strain was a model for convulsive epilepsy comorbid with an ASD-like behavioral phenotype. The prefrontal cortex of rats with any epileptic pathology studied demonstrated profound decreases in binding densities to both D1DR and D2DR; the effects were localized in the primary and secondary anterior cingulate cortices, and adjacent regions. The local decreased D1DR and D2DR binding densities were independent of (not correlated with) each other. The particular group of epileptic rats with an ASD-like phenotype (KM strain) displayed changes in the lateral prefrontal cortex: D1DR were lowered, whereas D2DR were elevated, in the dysgranular insular cortex and adjacent regions. Thus, epilepsy-related changes in the dopaminergic system of the rat archeocortex were localized in the medial prefrontal regions, whereas ASD-related changes were seen in the lateral prefrontal aspects. The findings point to putative local dopaminergic dysfunctions, associated with generalized epilepsies and/or ASD. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to investigate the long-term prognosis of childhood absence epilepsy (CAE), and identify factors associated with treatment outcomes. Methods: Patients with a definitive diagnosis of CAE according to the International League Against Epilepsy 2021 criteria and with a minimum of 3-year follow-up duration were included. The children were divided according to the time of seizure control. Early seizure remission was defined as seizure freedom within 6 months after the treatment onset. Results: Twenty-four patients with a mean age of 13.7 (9.4-22.0) were included in this study. At the final follow-up, all patients were seizure-free except for one case. Seizure freedom was achieved after initial treatment in a mean of 0.78 years. The treatment was ceased in 19 children (79.2%) after a mean of 3.2 years. Patients having absence seizures without motor components had a higher rate of early seizure remission (p=0.026). In 81.3% of the patients; all of whose repetitive post-treatment EEGs were devoid of any generalized spike-wave discharges and absence seizures; remission was established within 6 months or less (p=0.026). Conclusions: CAE has a favorable prognosis with seizure control obtained in the majority of the cases and more than half of them were obtained within 6 months following the initiation of treatment. Moreover, having an absence seizure without motor components and repetitively normal post-treatment EEGs appear to be associated with a higher rate of early seizure remission. [ABSTRACT FROM AUTHOR]

The transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) regulatory proteins (TARPs), γ2 (stargazin), γ3, γ4, γ5, γ7, and γ8, are a family of proteins that regulate AMPAR trafficking, expression, and biophysical properties that could have a role in the development of absence seizures. Here, we evaluated the expression of TARPs and AMPARs across the development of epilepsy in the genetic absence epilepsy rats from Strasbourg (GAERS) model of idiopathic generalized epilepsy (IGE) with absence seizures. Pre‐epileptic (7‐day‐old), early epileptic (6‐week‐old), and chronically epileptic (16‐week‐old) GAERS, and age‐matched male nonepileptic control rats (NEC) were used. Electroencephalographic (EEG) recordings were acquired from the 6‐ and 16‐week‐old animals to quantify seizure expression. Somatosensory cortex (SCx) and whole thalamus were collected from all the animals to evaluate TARP and AMPAR mRNA expression. Analysis of the EEG demonstrated a gradual increase in the number and duration of seizures across GAERS development. mRNA expression of the TARPs γ2, γ3, γ4, γ5, and γ8 in the SCx, and γ4 and γ5 in the thalamus, increased as the seizures started and progressed in the GAERS compared to NEC. There was a temporal association between increased TARP expression and seizures in GAERS, highlighting TARPs as potential targets for developing novel treatments for IGE with absence seizures. [ABSTRACT FROM AUTHOR]

Investigations in Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats that are susceptible to genetic absence epilepsy have demonstrated that environmental modifications affect absence seizures. Previously, we showed that neonatal tactile stimulations produce disease-modifying effect on genetically determined absence epilepsy and associated depression in Wag/Rij rats. The study presented here examined the effect of TS during late ontogenesis (adolescence and young adulthood) on epilepsy and depression outcomes in this genetically epileptic rat strain. On postnatal day (PND) 38, male WAG/Rij rats randomly were assigned to either the tactile stimulation (TS), handled or control group (unhandled) with 8 animals in each group. Following a 7-day adaptation period to their new surroundings, the animals were submitted to tactile stimulation from PND 45 to PND 90, five days per week, for 5 min daily. The tactile-stimulated rat was removed from its cage, placed on the experimenter’s lap, and had its neck and back gently stroked by the researcher. The handled rats were taken to another cage and left alone for 5 min daily from PND 45 to PND 90. The control rats were left undisturbed in their home cage, except for regular cage cleaning. After PND 90, all rats were left undisturbed until behavioral testing and EEG recording. When the animals were 7 months old, they were subjected to the sucrose consumption test (SCT) and the forced swimming test (FST). Electroencephalogram (EEG) recordings were made at 8 months of age in order to measure electroencephalographic seizure activity, thus, the spike–wave discharges (SWDs). Tactile-stimulated rats showed increased sucrose consumption and number of approaches to the sucrose solution in the SCT when compared with the handled and control rats. In the FST, rats in TS group showed lower immobility time and greater immobility latency, active swimming time and diving frequency than the handled and control rats. The duration and the number of seizures were not different amongst the groups. The data obtained suggest that TS in young rats is able to prevent depression in WAG/Rij rats.

Objective: Absence seizures result from aberrant thalamocortical processing that confers synchronous, bilateral spike-and-wave discharges (SWDs) and behavioral arrest. Previous work has demonstrated that SWDs can result from enhanced thalamic tonic inhibition, consistent with the mechanism of first-line antiabsence drugs that target thalamic low-voltage-activated calcium channels. However, nearly half of patients with absence epilepsy are unresponsive to first-line medications. In this study we evaluated the role of cortical tonic inhibition and its manipulation on absence seizure expression. Methods: We used video-electroencephalogram (EEG) monitoring to show that mice with a γ-aminobutyric acid type A (GABAA) receptor mutation (γ2R43Q) display absence seizures. Voltage-clamp recordings in brain slices from wild type and γ2R43Q mice were used to evaluate the amount of tonic inhibition and its selective pharmacological modulation. Finally, we determined whether modulating tonic inhibition controls seizure expression. Results: γ2R43Q mice completely lack tonic inhibition in principal neurons of both layer 2/3 cortex and ventrobasal thalamus. Blocking cortical tonic inhibition in wild type mice is sufficient to elicit SWDs. Tonic inhibition in slices from γ2R43Q mice could be rescued in a dose-dependent fashion by the synthetic neurosteroid ganaxolone. Low-dose ganaxolone suppressed seizures in γ2R43Q mice. Conclusions: Our data suggest that reduced cortical tonic inhibition promotes absence seizures and that normal function can be restored via selective pharmacological rescue. These results, together with previous findings, suggest that deviations of tonic inhibition either above or below an optimal set point can contribute to absence epilepsy. Returning the thalamocortical system to this set point may provide a novel treatment for refractory absence epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Orexin is a neuropeptide neurotransmitter that regulates the sleep/ wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the involvement of orexin system in epilepsy. Limited data is available about the possible role of orexins in the pathophysiology of absence seizures. This study aims to understand the role of orexinergic signaling through the orexin-type 2 receptor (OX2R) in the pathophysiology of absence epilepsy. The pharmacological effect of a selective OX2R agonist, YNT-185 on spike-andwave-discharges (SWDs) and the OX2R receptor protein levels in the cortex and thalamus in adult GAERS were investigated. Methods: The effect of intracerebroventricular (ICV) (100, 300, and 600  nmol/10  μL), intrathalamic (30 and 40  nmol/500  nL), and intracortical (40  nmol/500  nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. The percentage of slowwave sleep (SWS) and spectral characteristics of background EEG were analyzed after the ICV application of 600  nmol YNT-185. The level of OX2R expression in the somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats. Results: We showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline-administered control group (p  <  0.05). However, intrathalamic and intracortical microinjections of YNT-185 did not show a significant effect on SWDs. ICV microinjections of YNT-185 affect sleep states by increasing the percentage of SWS and showed a significant treatment effect on the 1–4 Hz delta frequency band power during the 1–2  h post-injection period where YNT-185 significantly decreased the SWDs. OXR2 protein levels were significantly reduced in the cortex and thalamus of GAERS when compared to Wistar rats. Conclusion: This study investigated the efficacy of YNT-185 for the first time on absence epilepsy in GAERS and revealed a suppressive effect of OX2R agonist on SWDs as evidenced by the significantly reduced expression of OX2R in the cortex and thalamus. YNT-185 effect on SWDs could be attributed to its regulation of wake/sleep states. The results constitute a step toward understanding the effectiveness of orexin neuropeptides on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy. [ABSTRACT FROM AUTHOR]

IntroductionGenetic Absence Epilepsy Rats from Strasbourg (GAERS) represent a model of genetic generalized epilepsy. The present longitudinal study in GAERS and age-matched non-epileptic controls (NEC) aimed to characterize the epileptic brain network using two functional measures, resting state-functional magnetic resonance imaging (rs-fMRI) and manganese-enhanced MRI (MEMRI) combined with morphometry, and to investigate potential brain network alterations, following long-term seizure activity.MethodsRepeated rs-fMRI measurements at 9.4 T between 3 and 8 months of age were combined with MEMRI at the final time point of the study. We used graph theory analysis to infer community structure and global and local network parameters from rs-fMRI data and compared them to brain region-wise manganese accumulation patterns and deformation-based morphometry (DBM).ResultsFunctional connectivity (FC) was generally higher in GAERS when compared to NEC. Global network parameters and community structure were similar in NEC and GAERS, suggesting efficiently functioning networks in both strains. No progressive FC changes were observed in epileptic animals. Network-based statistics (NBS) revealed stronger FC within the cortical community, including regions of association and sensorimotor cortex, and with basal ganglia and limbic regions in GAERS, irrespective of age. Higher manganese accumulation in GAERS than in NEC was observed at 8 months of age, consistent with higher overall rs-FC, particularly in sensorimotor cortex and association cortex regions. Functional measures showed less similarity in subcortical regions. Whole brain volumes of 8 months-old GAERS were higher when compared to age-matched NEC, and DBM revealed increased volumes of several association and sensorimotor cortex regions and of the thalamus.Discussionrs-fMRI, MEMRI, and volumetric data collectively suggest the significance of cortical networks in GAERS, which correlates with an increased fronto-central connectivity in childhood absence epilepsy (CAE). Our findings also verify involvement of basal ganglia and limbic regions. Epilepsy-related network alterations are already present in juvenile animals. Consequently, this early condition seems to play a greater role in dynamic brain function than chronic absence seizures.

Abstract Objective Anterior nucleus of thalamus (ANT) has been widely accepted as a potential therapeutic target for drug‐resistant epilepsy. Although increased volume of the ANT was also reported in patients with absence epilepsy, the relationship between the ANT and absence epilepsy has been barely illustrated. Methods Using chemogenetics, we evaluated the effect of ANT parvalbumin (PV) neurons on pentylenetetrazole (PTZ)‐induced absence seizures in mice. Results We found that intraperitoneal injection of PTZ (30 mg/kg) can stably induce absence‐like seizures characterized by bilaterally synchronous spike–wave discharges (SWDs). Selective activation of PV neurons in the ANT by chemogenetics could aggravate the severity of absence seizures, whereas selective inhibition of that cannot reverse this condition and even promote absence seizures as well. Moreover, chemogenetic inhibition of ANT PV neurons without administration of PTZ was also sufficient to generate SWDs. Analysis of background EEG showed that chemogenetic activation or inhibition of ANT PV neurons could both significantly increase the EEG power of delta oscillation in the frontal cortex, which might mediate the pro‐seizure effect of ANT PV neurons. Significance Our findings indicated that either activation or inhibition of ANT PV neurons might disturb the intrinsic delta rhythms in the cortex and worsen absence seizures, which highlighted the importance of maintaining the activity of ANT PV neurons in absence seizure.

IntroductionOrexin is a neuropeptide neurotransmitter that regulates the sleep/wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the involvement of orexin system in epilepsy. Limited data is available about the possible role of orexins in the pathophysiology of absence seizures. This study aims to understand the role of orexinergic signaling through the orexin-type 2 receptor (OX2R) in the pathophysiology of absence epilepsy. The pharmacological effect of a selective OX2R agonist, YNT-185 on spike-and-wave-discharges (SWDs) and the OX2R receptor protein levels in the cortex and thalamus in adult GAERS were investigated.MethodsThe effect of intracerebroventricular (ICV) (100, 300, and 600 nmol/10 μL), intrathalamic (30 and 40 nmol/500 nL), and intracortical (40 nmol/500 nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. The percentage of slow-wave sleep (SWS) and spectral characteristics of background EEG were analyzed after the ICV application of 600 nmol YNT-185. The level of OX2R expression in the somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats.ResultsWe showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline-administered control group (p

While anti-seizure medications are effective for many patients, nearly one-third of individuals have seizures that are refractory to pharmacotherapy. Prior studies using evoked preclinical seizure models have shown that pharmacological activation or excitatory optogenetic stimulation of the deep and intermediate layers of the superior colliculus (DLSC) display multi-potent anti-seizure effects. Here we monitored and modulated DLSC activity to suppress spontaneous seizures in the WAG/Rij genetic model of absence epilepsy. Female and male WAG/Rij adult rats were employed as study subjects. For electrophysiology studies, we recorded single unit activity from microwire arrays placed within the DLSC. For optogenetic experiments, animals were injected with virus coding for channelrhodopsin-2 or a control vector, and we compared the efficacy of continuous neuromodulation to that of closed-loop neuromodulation paradigms. For each, we compared three stimulation frequencies on a within-subject basis (5, 20, 100 Hz). For closed-loop stimulation, we detected seizures in real time based on the EEG power within the characteristic frequency band of spike-and-wave discharges (SWDs). We quantified the number and duration of each SWD during each 2 h-observation period. Following completion of the experiment, virus expression and fibre-optic placement was confirmed. We found that single-unit activity within the DLSC decreased seconds prior to SWD onset and increased during and after seizures. Nearly 40% of neurons displayed suppression of firing in response to the start of SWDs. Continuous optogenetic stimulation of the DLSC (at each of the three frequencies) resulted in a significant reduction of SWDs in males and was without effect in females. In contrast, closed-loop neuromodulation was effective in both females and males at all three frequencies. These data demonstrate that activity within the DLSC is suppressed prior to SWD onset, increases at SWD onset, and that excitatory optogenetic stimulation of the DLSC exerts anti-seizure effects against absence seizures. The striking difference between open- and closed-loop neuromodulation approaches underscores the importance of the stimulation paradigm in determining therapeutic effects. [ABSTRACT FROM AUTHOR]

The solute carrier family 6 member 1 (SLC6A1) gene encodes GAT‐1, a γ‐aminobutyric acid transporter expressed on astrocytes and inhibitory neurons. Mutations in SLC6A1 are associated with epilepsy and developmental disorders, including motor and social impairments, but variant‐specific animal models are needed to elucidate mechanisms. Here, we report electrocorticographic (ECoG) recordings and clinical data from a patient with a variant in SLC6A1 that encodes GAT‐1 with a serine‐to‐leucine substitution at amino acid 295 (S295L), who was diagnosed with childhood absence epilepsy. Next, we show that mice bearing the S295L mutation (GAT‐1S295L/+) have spike‐and‐wave discharges with motor arrest consistent with absence‐type seizures, similar to GAT‐1+/− mice. GAT‐1S295L/+ and GAT‐1+/− mice follow the same pattern of pharmacosensitivity, being bidirectionally modulated by ethosuximide (200 mg/kg ip) and the GAT‐1 antagonist NO‐711 (10 mg/kg ip). By contrast, GAT‐1−/− mice were insensitive to both ethosuximide and NO‐711 at the doses tested. In conclusion, ECoG findings in GAT‐1S295L/+ mice phenocopy GAT‐1 haploinsufficiency and provide a useful preclinical model for drug screening and gene therapy investigations. [ABSTRACT FROM AUTHOR]

Objective: Anterior nucleus of thalamus (ANT) has been widely accepted as a potential therapeutic target for drug‐resistant epilepsy. Although increased volume of the ANT was also reported in patients with absence epilepsy, the relationship between the ANT and absence epilepsy has been barely illustrated. Methods: Using chemogenetics, we evaluated the effect of ANT parvalbumin (PV) neurons on pentylenetetrazole (PTZ)‐induced absence seizures in mice. Results: We found that intraperitoneal injection of PTZ (30 mg/kg) can stably induce absence‐like seizures characterized by bilaterally synchronous spike–wave discharges (SWDs). Selective activation of PV neurons in the ANT by chemogenetics could aggravate the severity of absence seizures, whereas selective inhibition of that cannot reverse this condition and even promote absence seizures as well. Moreover, chemogenetic inhibition of ANT PV neurons without administration of PTZ was also sufficient to generate SWDs. Analysis of background EEG showed that chemogenetic activation or inhibition of ANT PV neurons could both significantly increase the EEG power of delta oscillation in the frontal cortex, which might mediate the pro‐seizure effect of ANT PV neurons. Significance: Our findings indicated that either activation or inhibition of ANT PV neurons might disturb the intrinsic delta rhythms in the cortex and worsen absence seizures, which highlighted the importance of maintaining the activity of ANT PV neurons in absence seizure. [ABSTRACT FROM AUTHOR]

Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosinemetabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells. [ABSTRACT FROM AUTHOR]

• Absence seizures affect visual attention and eye movements variably. • Deficits in visual attention during absences are associated with differences in EEG features and network activation. • Our findings can be employed in clinical practice for tailored risk assessment in patients. Absences affect visual attention and eye movements variably. Here, we explore whether the dissimilarity of these symptoms during absences is reflected in differences in electroencephalographic (EEG) features, functional connectivity, and activation of the frontal eye field. Pediatric patients with absences performed a computerized choice reaction time task, with simultaneous recording of EEG and eye-tracking. We quantified visual attention and eye movements with reaction times, response correctness, and EEG features. Finally, we studied brain networks involved in the generation and propagation of seizures. Ten pediatric patients had absences during the measurement. Five patients had preserved eye movements (preserved group) and five patients showed disrupted eye movements (unpreserved group) during seizures. Source reconstruction showed a stronger involvement of the right frontal eye field during absences in the unpreserved group than in the preserved group (dipole fraction 1.02% and 0.34%, respectively, p < 0.05). Graph analysis revealed different connection fractions of specific channels. The impairment of visual attention varies among patients with absences and is associated with differences in EEG features, network activation, and involvement of the right frontal eye field. Assessing the visual attention of patients with absences can be usefully employed in clinical practice for tailored advice to the individual patient. [ABSTRACT FROM AUTHOR]

Depression is a severe and widespread psychiatric disease that often accompanies epilepsy. Antidepressant treatment of depression comorbid with epilepsy is a major concern due to the risk of seizure aggravation. SAMe, a universal methyl donor for DNA methylation and the synthesis of brain monoamines, is known to have high antidepressant activity. This study aimed to find out whether L-methionine (L-MET), a precursor of SAMe, can have antidepressant and/or anxiolytic effects in the WAG/Rij rat model of depression comorbid with absence epilepsy. The results indicate that L-MET reduces the level of anxiety and depression in WAG/Rij rats and suppresses associated epileptic seizures, in contrast to conventional antidepressant imipramine, which aggravates absence seizures. The antidepressant effect of L-MET was comparable with that of the conventional antidepressants imipramine and fluoxetine. However, the antidepressant profile of L-MET was more similar to imipramine than to fluoxetine. Taken together, our findings suggest that L-MET could serve as a promising new antidepressant drug with anxiolytic properties for the treatment of depression comorbid with absence epilepsy. Increases in the level of monoamines and their metabolites—DA, DOPAC, HVA, NA, and MHPG—in several brain structures, is suggested to be a neurochemical mechanism of the beneficial phenotypic effect of L-MET. [ABSTRACT FROM AUTHOR]

In the present study, the effect of quercetin, a powerful antioxidant flavonoid, on genetic absence epilepsy was studied in WAG/Rij rats. Tripolar electrodes were implanted into WAG/Rij rats. Basal electrocorticography (ECoG) was recorded following a recovery period. After basal ECoG recording, different doses of quercetin (QRC) (25, 50 and 100 mg/kg) were injected intraperitoneally (i.p.) for 30 days. ECoG recording was continued for 31 days, three hours a day. After recording, the rats were anesthetized and euthanized through cervical dislocation and their brains were excised. Biochemically, TNF-alpha, IL-6 and NO were studied in whole rat brains. In WAG/Rij rats, low-dose quercetin (25 mg/kg) reduced the number and duration of spike-wave discharges (SWDs) compared to the control group. However, 50 and 100 mg/kg quercetin doses increased SWDs. Duration of SWDs was prolonged only with 100 mg/kg dose. None of the quercetin doses had any effect on average amplitude of SWDs. In addition, it was observed in biochemical analyses that 25 mg/kg quercetin reduced TNF-alpha, IL-6 and NO levels compared to the control group. While TNF-alpha and IL-6 levels in rat brains were not affected by 50 or 100 mg/kg doses, both doses were found to increase NO levels in rat brains. Based on the results of the present study, 25 mg/kg low-dose quercetin may have reduced absence seizures by reducing proinflammatory cytokines and NO, but high-dose quercetin may have increased absence seizures through increasing the NO level. This contrasting effect of quercetin on absence seizures needs to be investigated by advanced mechanisms. [ABSTRACT FROM AUTHOR]

Rationale: Low-voltage-activated or T-type Ca2+ channels play a key role in the generation of seizures in absence epilepsy. We have described a homozygous, gain of function substitution mutation (R1584P) in the CaV3.2 T-type Ca2+ channel gene (Cacna1h) in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The non-epileptic control (NEC) rats, derived from the same original Wistar strains as GAERS but selectively in-breed not to express seizures, are null for the R1584P mutation. To study the effects of this mutation in rats who otherwise have a GAERS or NEC genetic background, we bred congenic GAERS-Cacna1hNEC (GAERS null for R1584P mutation) and congenic NEC-Cacna1hGAERS (NEC homozygous for R1584P mutation) and evaluated the seizure and behavioral phenotype of these strains in comparison to the original GAERS and NEC strains. Methods: To evaluate seizure expression in the congenic strains, EEG electrodes were implanted in NEC, GAERS, GAERS-Cacna1hNEC without the R1584P mutation, and NEC-Cacna1hGAERS with the R1584P mutation rats. In the first study, continuous EEG recordings were acquired from week 4 (when seizures begin to develop in GAERS) to week 14 of age (when GAERS display hundreds of seizures per day). In the second study, the seizure and behavioral phenotype of GAERS and NEC-Cacna1hGAERS strains were evaluated during young age (6 weeks of age) and adulthood (16 weeks of age) of GAERS, NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The Open field test (OFT) and sucrose preference test (SPT) were performed to evaluate anxiety-like and depressive-like behavior, respectively. This was followed by EEG recordings at 18 weeks of age to quantify the seizures, and spike-wave discharge (SWD) cycle frequency. At the end of the study, the whole thalamus was collected for T-type calcium channel mRNA expression analysis. Results: GAERS had a significantly shorter latency to first seizures and an increased number of seizures per day compared to GAERS-Cacna1hNEC. On the other hand, the presence of the R1584P mutation in the NEC-Cacna1hGAERS was not enough to generate spontaneous seizures in their seizure-resistant background. 6 and 16-week-old GAERS and GAERS-Cacna1hNEC rats showed anxiety-like behavior in the OFT, in contrast to NEC and NEC-Cacna1hGAERS. Results from the SPT showed that the GAERS developed depressive-like in the SPT compared to GAERS-Cacna1hNEC, NEC, and NEC-Cacna1hGAERS. Analysis of the EEG at 18 weeks of age showed that the GAERS had an increased number of seizures per day, increased total seizure duration and a higher cycle frequency of SWD relative to GAERS-Cacna1hNEC. However, the average seizure duration was not significantly different between strains. Quantitative real-time PCR showed that the T-type Ca2+ channel isoform CaV3.2 channel expression was significantly increased in GAERS compared to NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The presence of the R1584P mutation increased the total ratio of CaV3.2 + 25/−25 splice variants in GAERS and NEC-Cacna1hGAERS compared to NEC and GAERS-Cacna1hNEC. Discussion: The data from this study demonstrate that the R1584P mutation in isolation on a seizure-resistant NEC genetic background was insufficient to generate absence seizures, and that a GAERS genetic background can cause seizures even without the mutation. However, the study provides evidence that the R1584P mutation acts as a modulator of seizures development and expression, and depressive-like behavior in the SPT, but not the anxiety phenotype of the GAERS model of absence epilepsy.

The WAG/Rij rats are a genetic model of absence epilepsy with comorbid depression. Pathological phenotype in WAG/Rij rats is associated with reduced dopamine (DA) tone in the mesolimbic DA system. Perinatal maternal methyl-enriched diet (MED) is known to increase DA levels in the mesolimbic DA system and reduce manifestations of absence seizures with comorbid depression in an adult offspring of WAG/Rij rats. The ventral tegmental area (VTA), which contains DAergic neurons and gives rise to the mesocortical and mesolimbic DAergic pathways, is the main source of mesolimbic DA synthesis. The aim of this study was to test the hypothesis that increases in mesolimbic DA tone, induced in offspring by a maternal MED, may be due to an increase in the number of thyrosine hydroxylase (TH)-synthesizing DAergic neurons in the VTA. Immunohistochemical staining for TH was used to assess the number of TH-immunopositive cells in the adult offspring of WAG/Rij rats born to mothers that were fed a control diet (CD) or MED and exposed or not exposed to behavioral testing for two consecutive days in the light–dark choice, open field, elevated plus maze, and forced swim tests. Animals were anesthetized 1 h after the forced swim test. Brains were fixed via transcardial perfusion. The number of DAergic neurons was determined by the number of TH-immunopositive cells in brain slices taken at the VTA level and counted in the left and right hemispheres separately. We found a significant effect of a maternal MED on the number of TH-expressing neurons in the VTA. Adult WAG/Rij offspring born to MED-fed mothers showed an increased number of TH-immunopositive cells compared to the offspring born to CD-fed mothers. Moreover, in the WAG/Rij offspring born to MED-fed mothers, the number of TH-immunopositive cells was greater in animals exposed vs. unexposed to behavioral testing. The effects of a maternal MED and behavioral testing on the number of TH-immunopositive cells in the VTA were equally pronounced in the left and right cerebral hemispheres. Our results suggest that maternal MED can affect the development of the mesolimbic DA system, contributing to the generation and/or preservation of DAergic neurons in the VTA and thus preventing the occurence of genetic absence epilepsy and comorbid depression in the offspring of WAG/Rij rats. [ABSTRACT FROM AUTHOR]

Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. Methods: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague–Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. Results: In Sprague–Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. Conclusions: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors. [ABSTRACT FROM AUTHOR]

Connectivity analysis using modern approaches like Granger causality, partial directed coherence and transfer entropy always demands additional statistical evaluation of the obtained measures for significance. Although for very simple linear autoregressive processes and quasilinear oscillatory activities theoretical estimates are available, the real biological signals are too complex for application of analytical approaches and surrogate data come into use. When pathological activity like epileptic seizures is studied, the question can also rise in a somewhat different way: one asks whether the studied activity is different from the normal one rather than whether connectivity exists. The similar question is also valid if one compares connectivity in different physiological states like sleep and wakefulness. Here, we study two different approaches to statistical evaluation of transfer entropy estimates in application to the study of spike–wave discharges (SWDs), the main encephalographic manifestation of absence epilepsy, registered in local field potentials of WAG/Rij rats (genetic models). The first approach is to compare distributions of the estimators for the baseline and different stages of pathological activity using traditional measures like t-test with additional corrections for multiple testing. The second approach is to make surrogate data and test whether the achieved estimators differ for surrogate series and for real ones. To support our findings and to understand the methods better, the series simulated using simple oscillatory models of epileptic activity are evaluated in the same way as the experimental data. We show that the most pronounced phenomena like bidirectional increase in coupling between frontal and parietal cortical areas during SWDs in comparison to baseline activity are considered to be significant by both approaches. But when the less expressed coupling changes are under consideration, the approach base on surrogate data provides less false positives. These results confirm that the primary outcomes of connectivity analysis for absence epilepsy (and not only it) achieved previously are valid although the statistical evaluation of the connectivity estimators was suboptimal. [ABSTRACT FROM AUTHOR]

In the present report, we evaluated adrenergic mechanisms of generalized spike-wave epileptic discharges (SWDs), which are the encephalographic hallmarks of idiopathic generalized epilepsies. SWDs link to a hyper-synchronization in the thalamocortical neuronal activity. We unclosed some alpha2-adrenergic mechanisms of sedation and provocation of SWDs in rats with spontaneous spike-wave epilepsy (WAG/Rij and Wistar) and in control non-epileptic rats (NEW) of both sexes. Dexmedetomidine (Dex) was a highly selective alpha-2 agonist (0.003–0.049 mg/kg, i.p.). Injections of Dex did not elicit de novo SWDs in non-epileptic rats. Dex can be used to disclose the latent form of spike-wave epilepsy. Subjects with long-lasting SWDs at baseline were at high risk of absence status after activation of alpha2- adrenergic receptors. We create the concept of alpha1- and alpha2-ARs regulation of SWDs via modulation of thalamocortical network activity. Dex induced the specific abnormal state favorable for SWDs—"alpha2 wakefulness". Dex is regularly used in clinical practice. EEG examination in patients using low doses of Dex might help to diagnose the latent forms of absence epilepsy (or pathology of cortico-thalamo-cortical circuitry). [ABSTRACT FROM AUTHOR]

Objective:The aim of the present study was to evaluate the effects of antiepileptic drug lacosamide on spontaneous absence seizures and anxiety in genetic absence-epilepsy WAG/Rij rats.Methods:Tripolar electrodes were placed in the cortex of WAG/Rij rats in each group using a stereotaxic instrument. Saline (4 mL/kg) was administered to the rats in the control group, while 5, 10, 25, and 50 mg/kg lacosamide was administered intraperitoneally to the rats in lacosamide groups. After lacosamide injections, elect roenc ephal ograp hy recording was taken for 180 minutes. Then, the open field test was performed for 5 minutes.Results:The total number and duration of spikes and wave discharges increased significantly in a dose-dependent manner after lacosamide injection in all lacosamide groups compared to the control group (P < .001). In addition, the seizure activity of rats in all groups began to increase 10 minutes after lacosamide injections (P < 0.001). Intermittent loss of clinical righting reflex was observed after absence seizures and convulsions also developed. Epileptic seizure activity with simultaneous sharp spikes was observed in the elect roenc ephal ograp hy recording, and a dose-dependent seizure activity increase was observed (P < .001). All lacosamide groups had significantly lower values for the number of squares crossed, number of rearing, and duration of grooming in the open field test compared to the control group.Conclusion:It was found in the present study that absence seizures in WAG/Rij rats increased in a dose-dependent manner after lacosamide treatment. Anxietylike behaviors were also increased by lacosamide treatment.

Abstract Background Ethosuximide and other anti-epileptic drugs have been reported to cause idiosyncratic reactions such as lupus-like syndromes, with elevated antinuclear antibody (ANA) levels. Herein, we present a case of a girl who developed a very severe Raynaud’s phenomenon reaction and anti-Scl-70 antibodies related to treatment with ethosuximide, due to juvenile absence epilepsy (JAE). Case presentation A 12-year-old girl was diagnosed with JAE and treatment with ethosuximide was initiated. Two and a half months later her fingers, digits II–V bilaterally, began to ache and were discolored, alternatingly white, blue, or normal-colored. Two weeks later, her fingers were bluish-black, aching severely, almost continuously. The family sought medical advice. Ethosuximide was halted and due to the severe symptoms, treatment with both prednisolone and intravenous iloprost was commenced. Laboratory tests revealed high ANA levels with anti-Scl-70 pattern and confirmed anti-Scl-70 antibodies. After a few weeks, she started to improve and the symptoms slowly decreased over five months. Anti-Scl-70 was still detectable four months after onset of symptoms, though she was much improved. After eleven months, repeated ANA analyses were completely negative. Conclusion Although extremely rare, it is important to recognize that severe Raynaud’s phenomenon, threatening peripheral digital circulation, may occur as an idiosyncratic reaction to ethosuximide, raising concern over possible onset of vasculitis.

This review discusses the long-term effects of early-life environment on epileptogenesis, epilepsy, and neuropsychiatric comorbidities with an emphasis on the absence epilepsy. The WAG/Rij rat strain is a well-validated genetic model of absence epilepsy with mild depression-like (dysthymia) comorbidity. Although pathologic phenotype in WAG/Rij rats is genetically determined, convincing evidence presented in this review suggests that the absence epilepsy and depression-like comorbidity in WAG/Rij rats may be governed by early-life events, such as prenatal drug exposure, early-life stress, neonatal maternal separation, neonatal handling, maternal care, environmental enrichment, neonatal sensory impairments, neonatal tactile stimulation, and maternal diet. The data, as presented here, indicate that some early environmental events can promote and accelerate the development of absence seizures and their neuropsychiatric comorbidities, while others may exert anti-epileptogenic and disease-modifying effects. The early environment can lead to phenotypic alterations in offspring due to epigenetic modifications of gene expression, which may have maladaptive consequences or represent a therapeutic value. Targeting DNA methylation with a maternal methyl-enriched diet during the perinatal period appears to be a new preventive epigenetic anti-absence therapy. A number of caveats related to the maternal methyl-enriched diet and prospects for future research are discussed.

The distribution of the D2-like dopamine receptor (D2DR) in the cortex and striatum was compared between rats with absence, audiogenic, or combined genetically determined epilepsy and normal Wistar rats by autoradiography. A significantly lower D2DR binding density was observed in the dorsal and ventrolateral aspects of the nucleus accumbens in epileptic vs. non-epileptic rats. Rats with audiogenic epilepsy additionally showed a higher D2DR density in the dorsal striatum and motor and somatosensory cortex and a lower D2DR density in the ventrolateral part of the nucleus accumbens. The findings indicated that a common neuronal circuit is involved in the pathogenesis of both convulsive and nonconvulsive forms of generalized epilepsy. [ABSTRACT FROM AUTHOR]

The reduced expression of the HCN1 ion channel in the somatosensory cortex (SSC) and mesolimbic dopamine deficiency are thought to be associated with the genesis of spike-wave discharges (SWDs) and comorbid depression in the WAG/Rij rat model of absence epilepsy. This study aimed to investigate whether the maternal methyl-enriched diet (MED), which affects DNA methylation, can alter DNMT1, HCN1, and TH gene expression and modify absence seizures and comorbid depression in WAG/Rij offspring. WAG/Rij mothers were fed MED (choline, betaine, folic acid, vitamin B12, L-methionine, zinc) or a control diet for a week before mating, during pregnancy, and for a week after parturition. MED caused sustained suppression of SWDs and symptoms of comorbid depression in the offspring. Disease-modifying effects of MED were associated with increased expression of the DNMT1 and HCN1 genes in the SSC and hippocampus, as well as DNMT1, HCN1, and TH genes in the nucleus accumbens. No changes in gene expression were detected in the hypothalamus. The results indicate that maternal MED can suppress the genetic absence epilepsy and comorbid depression in offspring. Increased expression of the DNMT1, HCN1, and TH genes is suggested to be a molecular mechanism of this beneficial phenotypic effect. [ABSTRACT FROM AUTHOR]

Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosine-metabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells.

Approximately 1 in 26 people will develop epilepsy in their lifetime, but current treatment options leave as many as half of all epilepsy patients with uncontrolled seizures. In addition to the burden of the seizures themselves, chronic epilepsy can be associated with cognitive deficits, structural changes, and devastating negative outcomes such as sudden unexpected death in epilepsy (SUDEP). Thus, major challenges in epilepsy research surround the need to both develop new therapeutic targets for intervention as well as shed light on the mechanisms by which chronic epilepsy can lead to comorbidities and negative outcomes. Despite not being traditionally associated with epilepsy or seizures, the cerebellum has emerged as not only a brain region that can serve as an important target for seizure control, but one that may also be profoundly impacted by chronic epilepsy. Here, we discuss targeting the cerebellum for potential therapeutic intervention and discuss pathway insights gained from recent optogenetic studies. We then review observations of cerebellar alterations during seizures and in chronic epilepsy, as well as the potential for the cerebellum to be a seizure focus. Cerebellar alterations in epilepsy may be critical to patient outcomes, highlighting the need for a more comprehensive understanding and appreciation of the cerebellum in the epilepsies.

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.

Objective: Absence seizures result from aberrant thalamocortical processing that confers synchronous, bilateral spike-and-wave discharges (SWDs) and behavioral arrest. Previous work has demonstrated that SWDs can result from enhanced thalamic tonic inhibition, consistent with the mechanism of first-line antiabsence drugs that target thalamic low-voltage-activated calcium channels. However, nearly half of patients with absence epilepsy are unresponsive to first-line medications. In this study we evaluated the role of cortical tonic inhibition and its manipulation on absence seizure expression. Methods: We used video-electroencephalogram (EEG) monitoring to show that mice with a γ-aminobutyric acid type A (GABAA) receptor mutation (γ2R43Q) display absence seizures. Voltage-clamp recordings in brain slices from wild type and γ2R43Q mice were used to evaluate the amount of tonic inhibition and its selective pharmacological modulation. Finally, we determined whether modulating tonic inhibition controls seizure expression. Results: γ2R43Q mice completely lack tonic inhibition in principal neurons of both layer 2/3 cortex and ventrobasal thalamus. Blocking cortical tonic inhibition in wild type mice is sufficient to elicit SWDs. Tonic inhibition in slices from γ2R43Q mice could be rescued in a dose-dependent fashion by the synthetic neurosteroid ganaxolone. Low-dose ganaxolone suppressed seizures in γ2R43Q mice. Conclusions: Our data suggest that reduced cortical tonic inhibition promotes absence seizures and that normal function can be restored via selective pharmacological rescue. These results, together with previous findings, suggest that deviations of tonic inhibition either above or below an optimal set point can contribute to absence epilepsy. Returning the thalamocortical system to this set point may provide a novel treatment for refractory absence epilepsy.