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Objectives : Absence seizures impair psychosocial function, yet their detailed neuronal basis remains unknown. Recent work in a rat model suggests that cortical arousal state changes prior to seizures and that single neurons show diverse firing patterns during seizures. Our aim was to extend these investigations to a mouse model with studies of neuronal activity and arousal state to facilitate future fundamental investigations of absence epilepsy. Methods : We performed in vivo extracellular single unit recordings on awake head-fixed C3H/HeJ mice. Mice were implanted with tripolar electrodes for cortical electroencephalography (EEG). Extracellular single unit recordings were obtained with glass micropipettes in the somatosensory barrel cortex, while animals ambulated freely on a running wheel. Signals were digitized and analyzed during seizures and at baseline. Results : Neuronal activity was recorded from 36 cortical neurons in 19 mice while EEG showed characteristic 7–8 Hz spike-wave discharges. Different single neurons showed distinct firing patterns during seizures, but the overall mean population neuronal firing rate during seizures was no different from pre-seizure baseline. However, the rhythmicity of neuronal firing during seizures was significantly increased (p < 0.001). In addition, beginning 10s prior to seizure initiation, we observed a progressive decrease in cortical high frequency (>40 Hz) EEG and an increase in lower frequency (1–39 Hz) activity suggesting decreased arousal state. Significance : We found that the awake head-fixed C3H/HeJ mouse model demonstrated rhythmic neuronal firing during seizures, and a decreased cortical arousal state prior to seizure onset. Unlike the rat model we did not observe an overall decrease in neuronal firing during seizures. Similarities and differences across species strengthen the ability to investigate fundamental key mechanisms. Future work in the mouse model will identify the molecular basis of neurons with different firing patterns, their role in seizure initiation and behavioral deficits, with ultimate translation to human absence epilepsy. • C3H/HeJ mice show variations in single cortical neuronal firing patterns during absence seizures. • Overall there was no change in average neuronal firing rate during seizures. • Unlike the GAERS model there was no sustained decrease in neuronal firing during absence seizures. • There was an increase in rhythmicity of neuronal firing during seizures, resembling previous absence models. • Cortical arousal state decreased 10s before seizure onset, with high frequency EEG decreases and low frequency increases. [ABSTRACT FROM AUTHOR]

• Options for the treatment of typical absence seizures are limited. • CBD is approved and effective for several types of seizures, but not typical absence seizures. • The spike-wave burden measured on EEG worsened in 9 and improved in 5. Clinical trials for typical absence seizures are notoriously difficult, because those seizures are clinically subtle and brief, so that seizure counts by caregivers are inaccurate. As a result, treatment options are limited. Currently, there are no published studies on the use of CBD in typical absence seizures. This pilot study aims to evaluate the efficacy of pharmaceutical grade CBD in typical absence seizures. We prospectively enrolled 14 patients aged 6 years and older, diagnosed with typical absence seizures. A baseline 24-hour ambulatory EEG was conducted, followed by a second 24-hour EEG after 90 days of treatment. The outcome was an objective measure of spike-wave complexes (SWC) burden change from pre- to post- treatment. After taking CBD for 90 days, 9 (64.3%) patients had an increase in SWC (ranging from 8% to 2876.5%) and 5 (35.7%) had a decrease in SWC (ranging from 62.3% to 98.9%). Of the 5 patients who had a decrease, 3 (60%) were on concomitant ethosuximide (with or without other ASMs). All 3 patients on CBD and ethosuximide improved. Although based on a small subset of patients, our results suggest that CBD may not be effective for typical absence seizures. However, patients on concomitant ethosuximide or on CBD monotherapy were more likely to improve. [ABSTRACT FROM AUTHOR]

Defects of the glycosylphosphatidylinositol (GPI) biosynthesis pathway constitute an emerging subgroup of congenital disorders of glycosylation with heterogeneous phenotypes. A mutation in the promoter of PIGM , resulting in a syndrome with portal vein thrombosis and persistent absence seizures, was previously described in three patients. We now report four additional patients in two unrelated families, with further clinical, biochemical and molecular delineation of this unique entity. We also describe the first prenatal diagnosis of PIGM deficiency, allowing characterization of the natural history of the disease from birth. The patients described herein expand the phenotypic spectrum of PIGM deficiency to include macrocephaly and infantile-onset cerebrovascular thrombotic events. Finally, we offer insights regarding targeted treatment of this rare disorder with sodium phenylbutyrate. [ABSTRACT FROM AUTHOR]

Abstract Generalized spike–wave discharges (SWDs) are the hallmark of generalized epilepsy on the electroencephalogram (EEG). In clinically obvious cases, generalized SWDs produce myoclonic, atonic/tonic, or absence seizures with brief episodes of staring and behavioral unresponsiveness. However, some generalized SWDs have no obvious behavioral effects. A serious challenge arises when patients with no clinical seizures request driving privileges and licensure, yet their EEG shows generalized SWD. Specialized behavioral testing has demonstrated prolonged reaction times or missed responses during SWD, which may present a driving hazard even when patients or family members do not notice any deficits. On the other hand, some SWDs are truly asymptomatic in which case driving privileges should not be restricted. Clinicians often decide on driving privileges based on SWD duration or other EEG features. However, there are currently no empirically-validated guidelines for distinguishing generalized SWDs that are "safe" versus "unsafe" for driving. Here, we review the clinical presentation of generalized SWD and recent work investigating mechanisms of behavioral impairment during SWD with implications for driving safety. As a future approach, computational analysis of large sets of EEG data during simulated driving utilizing machine learning could lead to powerful methods to classify generalized SWD as safe vs. unsafe. This may ultimately provide more objective EEG criteria to guide decisions on driving safety in people with epilepsy. Highlights • Generalized SWDs are associated with varied levels of behavioral impairments. • Discernible EEG features of generalized SWD may predict behavior impairment. • Simulated driving can reveal behavioral impairment in subclinical SWD. [ABSTRACT FROM AUTHOR]

Typical absence seizures (ASs) are brief periods of lack of consciousness, associated with 2.5–4 Hz spike-wave discharges (SWDs) in the EEG, which are highly prevalent in children and teenagers. The majority of probands in these young epileptic cohorts show neuropsychological comorbidities, including cognitive, memory and mood impairments, even after the seizures are pharmacologically controlled. Similar cognition and memory deficits have been reported in different, but not all, genetic animal models of ASs. However, since these impairments are subtle and highly task-specific their presence may be confounded by an anxiety-like phenotype and no study has tested anxiety and memory in the same animals. Moreover, the majority of studies used non-epileptic inbred animals as the only control strain and this may have contributed to a misinterpretation of these behavioural results. To overcome these issues, here we used a battery of behavioural tests to compare anxiety and memory in the same animals from the well-established inbred model of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), their inbred strain of Non-Epileptic Control (NEC) strain (that lack ASs) and normal outbred Wistar rats. We found that GAERS do not exhibit increased anxiety-like behavior and neophobia compared to both NEC and Wistar rats. In contrast, GAERS show decreased spontaneous alternation, spatial working memory and cross-modal object recognition compared to both NEC and Wistar rats. Furthermore, GAERS preferentially used egocentric strategies to perform spatial memory tasks. In summary, these results provide solid evidence of memory deficits in GAERS rats that do not depend on an anxiety or neophobic phenotype. Moreover, the presence of differences between NEC and Wistar rats stresses the need of using both outbred and inbred control rats in behavioural studies involving genetic models of ASs. • GAERS rats do not exhibit anxiety-like behavior and neophobia compared to both NEC and Wistar rats • GAERS rats show decreased spontaneous alternation, attention, spatial working memory and cross-modal object recognition • GAERS rats do not use hippocampal-dependent strategies to perform memory tasks that involve spatial cues. • The memory deficits of the GAERS rats do not depend on an anxiety or neophobic phenotype • This work validates GAERS rats for neurobiological studies of the cognitive comorbidities of absence seizures. [ABSTRACT FROM AUTHOR]

The establishment of a recent theoretical model of a coupled cortical thalamic network is an important step in the spatiotemporal dynamics of the brain. However, choosing the coupling distances and parameters for deep brain stimulation remains a very challenging task. This study aimed to establish a coupled cortical thalamic model with uncertain coupling distances. Utilizing different pathways formed by the pyramidal neuronal population, thalamic reticular nucleus, and thalamic relay nucleus, we reduced epileptic seizures with spike-wave discharges (SWDs) at 2–4 Hz. In modelling terms, numerical simulations demonstrated that a combination (1/3, 1/9) of the left and right ventricles is the optimal coupling distance of the proposed model by analyzing the percentage of SWDs. In simulation terms, on the one hand, the number of SWDs is inversely proportional to the amplitude; on the other hand, the number of SWDs shows a U-shaped trend with the change in frequency. The present study provides an important theoretical basis and direction for the future treatment of absence epilepsy. In brief, our simulation results will hopefully provide some help to patients. [ABSTRACT FROM AUTHOR]

Absence seizures are transient episodes of impaired consciousness accompanied by 3–4 Hz spike–wave discharge on electroencephalography (EEG). Human functional magnetic resonance imaging (fMRI) studies have demonstrated widespread cortical decreases in the blood oxygen-level dependent (BOLD) signal that may play an important role in the pathophysiology of these seizures. Animal models could provide an opportunity to investigate the fundamental mechanisms of these changes, however they have so far failed to consistently replicate the cortical fMRI decreases observed in human patients. This may be due to important differences between human seizures and animal models, including a lack of cortical development in rodents or differences in the frequencies of rodent (7–8 Hz) and human (3–4 Hz) spike–wave discharges. To examine the possible contributions of these differences, we developed a ferret model that exhibits 3–4 Hz spike–wave seizures in the presence of a sulcated cortex. Measurements of BOLD fMRI and simultaneous EEG demonstrated cortical fMRI increases during and following spike–wave seizures in ferrets. However unlike human patients, significant fMRI decreases were not observed. The lack of fMRI decreases was consistent across seizures of different durations, discharge frequencies, and anesthetic regimes, and using fMRI analysis models similar to human patients. In contrast, generalized tonic–clonic seizures under the same conditions elicited sustained postictal fMRI decreases, verifying that the lack of fMRI decreases with spike–wave was not due to technical factors. These findings demonstrate that 3–4 Hz spike–wave discharge in a sulcated animal model does not necessarily produce fMRI decreases, leaving the mechanism for this phenomenon open for further investigation. [ABSTRACT FROM AUTHOR]

Abstract: In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8a V929F). Here, we confirmed the prior suggestion that Scn8a V929F exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when Scn8a V929F is fully placed onto the C57BL/6J strain compared with C3H. Examination of sequence differences in NaV subunits between these two inbred strains suggested NaV1.2V752F as a potential source of this modifier effect. Recognising that the spatial co-localisation of the NaV channels at the axon initial segment (AIS) provides a plausible mechanism for functional interaction, we tested this idea by undertaking biophysical characterisation of the variant NaV channels and by computer modelling. NaV1.2V752F functional analysis revealed an overall gain-of-function and for NaV1.6V929F revealed an overall loss-of-function. A biophysically realistic computer model was used to test the idea that interaction between these variant channels at the AIS contributes to the strain background effect. Surprisingly this modelling showed that neuronal excitability is dominated by the properties of NaV1.2V752F due to “functional silencing” of NaV1.6V929F suggesting that these variants do not directly interact. Consequent genetic mapping of the major strain modifier to Chr 7, and not Chr 2 where Scn2a maps, supported this biophysical prediction. While a NaV1.6V929F loss of function clearly underlies absence seizures in this mouse model, the strain background effect is apparently not due to an otherwise tempting Scn2a variant, highlighting the value of combining physiology and genetics to inform and direct each other when interrogating genetic complex traits such as absence epilepsy. [Copyright &y& Elsevier]

Abstract: Spike–wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. Genetic absence epilepsy rats of Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence, but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies using the Sprague–Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2- to 3-month-old naive female Sprague–Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest, which continued for months. Males exhibited SWDs only after 3months of age, consistent with previous reports (Buzsáki et al., 1990). Housing in atypical lighting during early life appeared to facilitate the incidence of SWDs. Spike–wave discharges were often accompanied by behaviors similar to stage 1–2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to that of hippocampal theta rhythm during exploration for a given animal, typically 7–8Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (>250Hz) during SWDs, suggesting that neuronal activity in the hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague–Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal, and cortical neurons do not prevent SWDs, at least in this animal model. The results suggest that it is possible that SWDs occur in rodent models of TLE and that investigators mistakenly assume that they are stage 1–2 limbic seizures. We discuss the implications of the results and ways to avoid the potential problems associated with SWDs in animal models of TLE. [Copyright &y& Elsevier]

Abstract: The neural bases of altered consciousness in patients with epilepsy during seizures and at rest have raised significant interest in the last decade. This exponential growth has been supported by the parallel development of techniques and methods to investigate brain function noninvasively with unprecedented spatial and temporal resolution. In this article, we review the contribution of magnetoencephalography to deconvolve the bioelectrical changes associated with impaired consciousness during seizures. We use data collected from a patient with refractory absence seizures to discuss how spike–wave discharges are associated with perturbations in optimal connectivity within and between brain regions and discuss indirect evidence to suggest that this phenomenon might explain the cognitive deficits experienced during prolonged 3/s spike–wave discharges. This article is part of a Special Issue entitled Epilepsy and Consciousness. [Copyright &y& Elsevier]

Abstract: Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij rats, non-epileptic inbred ACI rats and outbred Wistar rats. The WAG/Rij strain is a genetic model for absence epilepsy and comorbidity for depression, which originates from the population of Wistar rats and, therefore, shares their genetic background. In a separate experiment, WAG/Rij rats were exposed to FS on three consecutive days. Electroencephalograms (EEGs) were recorded before and after FS, and the number of absence seizures (spike-wave-discharges, SWDs) was quantified. Both WAG/Rij rats and ACI rats exhibited elevated basal levels of corticosterone and a rapid corticosterone increase in response to acute stress. The WAG/Rij rats also displayed the most rapid normalization of corticosterone during the recovery phase compared to that of ACI and Wistar rats. FS had a biphasic effect on SWDs; an initial suppression was followed by an aggravation of the SWDs. By the third day, this aggravation of seizures was present in the hour preceding FS. This increase in SWDs may arise from anticipatory stress about the upcoming FS. Together, these results suggest that the distinct secretion profile of corticosterone found in WAG/Rij rats may contribute to the severity of the epileptic phenotype. Although the acute stressor results in an initial suppression of SWDs followed by an increase in SWDs, stress prior to a predictable negative event aggravates absences. [Copyright &y& Elsevier]

Abstract: Interleukin (IL)-1β plays a crucial role in the mechanisms of limbic seizures in rodent models of temporal lobe epilepsy. We addressed whether activation of the IL-1β signaling occurs in rats with genetic absence epilepsy (GAERS) during the development of spike-and-wave discharges (SWDs). Moreover, we studied whether inhibition of IL-1β biosynthesis in GAERS could affect SWD activity. IL-1β expression and glia activation were studied by immunocytochemistry in the forebrain of GAERS at postnatal days (PN)14, PN20, and PN90 and in age-matched non-epileptic control Wistar rats. In PN14 GAERS, when no SWDs have developed yet, IL-1β immunostaining was undetectable, and astrocytes and microglia showed a resting phenotype similar to control Wistar rats. In 3 out of 9 PN20 GAERS, IL-1β was observed in activated astrocytes of the somatosensory cortex; the cytokine expression was associated with the occurrence of immature-type of SWDs. In all adult PN90 GAERS, when mature SWDs are established, IL-1β was observed in reactive astrocytes of the somatosensory cortex but not in adjacent cortical areas or in extra-cortical regions. An age-dependent c-fos activation was found in the somatosensory cortex of GAERS with maximal levels reached in PN90 rats; c-fos was also induced in some thalamic nuclei in PN20 and PN90 GAERS. Inhibition of IL-1β biosynthesis in PN90 GAERS by 4-day systemic administration of a specific ICE/Caspase-1 blocker, significantly reduced both SWD number and duration. These results show that IL-1β is induced in reactive astrocytes of the somatosensory cortex of GAERS at the onset of SWDs. IL-1β has pro-ictogenic properties in this model, and thus it may play a contributing role in the mechanisms underlying the occurrence of absence seizures. [Copyright &y& Elsevier]

Abstract: Rodent models of absence seizures are used to investigate the network properties and regulatory mechanisms of the seizure''s generalized spike and wave discharge (SWD). As rats age, SWDs occur more frequently, suggesting aging-related changes in the regulation of the corticothalamic mechanisms generating the SWD. We hypothesized that brain resetting mechanisms – how the brain “resets” itself to a more normal functional state following a transient period of abnormal function, e.g., a SWD – are impaired in aged animals and that brain infarction would further affect these resetting mechanisms. The main objective of this study was to determine the effects of aging, infarction, and their potential interaction on the resetting of EEG dynamics assessed by quantitative EEG (qEEG) measures of linear (signal energy measured by amplitude variation; signal frequency measured by mean zero-crossings) and nonlinear (signal complexity measured by the pattern match regularity statistic and the short-term maximum Lyapunov exponent) brain EEG dynamics in 4- and 20-month-old F344 rats with and without brain infarction. The main findings of the study were: 1) dynamic resetting of both linear and nonlinear EEG characteristics occurred following SWDs; 2) animal age significantly affected the degree of dynamic resetting in all four qEEG measures: SWDs in older rats exhibited a lower degree of dynamic resetting; 3) infarction significantly affected the degree of dynamic resetting only in terms of EEG signal complexity: SWDs in infarcted rats exhibited a lower degree of dynamic resetting; and 4) in all four qEEG measures, there was no significant interaction effect between age and infarction on dynamic resetting. We conclude that recovery of the brain to its interictal state following SWDs was better in young adult animals compared with aged animals, and to a lesser degree, in age-matched controls compared with infarction-injured animal groups, suggesting possible effects of brain resetting mechanisms and/or the disruption of the epileptogenic network that triggers SWDs. [Copyright &y& Elsevier]

Abstract: The oscillatory rhythms underlying many physiological and pathological states, including absence seizures, require both the thalamus and cortices for full expression. A co-culture preparation combining cortical and thalamic explants provides a unique model for investigating how such oscillations initiate and spread. Here we investigated the dynamics of synchronized thalamocortical activity by simultaneous measurement of field-potential recordings and rapid imaging of Ca2+ transients by fluorescence methods. Spontaneous sustained hypersynchronized “seizure-like” oscillations required reciprocal cortico-thalamocortical connections. Isolated cortical explants can independently develop brief discharges, while thalamic explants alone were unable to do so. Rapid imaging of Ca2+ transients demonstrated deep-layer cortical initiation of oscillatory network activity in both connected and isolated explants. Further, cortical explants derived from a rat model of genetic absence epilepsy showed increased bursting duration consistent with an excitable cortex. We propose that thalamocortical oscillatory network activity initiates in deep layers of the cortex with reciprocal thalamic interconnections enabling sustained hyper-synchronization. [ABSTRACT FROM AUTHOR]

Abstract: In patients with idiopathic generalized epilepsies (IGEs), bursts of generalized spike and wave discharges (GSWDs) lasting ≥2seconds are considered absence seizures. The location of the absence seizures generators in IGEs is thought to involve interplay between various components of thalamocortical circuits; we have recently postulated that medication resistance may, in part, be related to the location of the GSWD generators [Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Epilepsy Behav. 2010;17:525–30]. In the present study we hypothesized that patients with medication-refractory IGE (R-IGE) and continued absence seizures may have GSWD generators in locations other than the thalamus, as typically seen in patients with IGE. Hence, the objective of this study was to determine the location of the GSWD generators in patients with R-IGE using EEG/fMRI. Eighty-three patients with IGE received concurrent EEG/fMRI at 4T. Nine of them (aged 15–55) experienced absence seizures during EEG/fMRI and were included; all were diagnosed with R-IGE. Subjects participated in up to three 20-minute EEG/fMRI sessions (400 volumes, TR=3 seconds) performed at 4T. After removal of fMRI and ballistocardiographic artifacts, 36 absence seizures were identified. Statistical parametric maps were generated for each of these sessions correlating seizures to BOLD response. Timing differences between brain regions were tested using statistical parametric maps generated by modeling seizures with onset times shifted relative to the GSWD onsets. Although thalamic BOLD responses peaked approximately 6seconds after the onset of absence seizures, other areas including the prefrontal and dorsolateral cortices showed brief and nonsustained peaks occurring ∼2seconds prior to the maximum of the thalamic peak. Temporal lobe peaks occurred at the same time as the thalamic peak, with a cerebellar peak occurring ∼1second later. Confirmatory analysis averaging cross-correlation between cortical and thalamic regions of interest across seizures corroborated these findings. Finally, Granger causality analysis showed effective connectivity directed from frontal lobe to thalamus, supporting the notion of earlier frontal than thalamic involvement. The results of this study support our original hypothesis and indicate that in the patients with R-IGE studied, absence seizures may be initiated by widespread cortical (frontal and parietal) areas and sustained in subcortical (thalamic) regions, suggesting that the examined patients have cortical onset epilepsy with propagation to thalamus. [Copyright &y& Elsevier]

Abstract: The substantia nigra pars reticulata (SNpr) is involved in controlling a variety of seizure phenomena. Intranigral transplants of GABAergic cells have been shown to decrease the severity of already established epileptic seizures, but the effects observed have been short-lived. This study evaluated the ability of intranigral transplants of GABA-producing cells to reduce spontaneous absence seizures in a genetic animal model for periods up to 3months after transplantation. Intranigral transplants did not induce any behavioral deficits in the animals, and they did not form tumors; however, the transplants failed to decrease absence seizures in the genetic model. The assumed increase in intranigral levels of GABA after the transplants may be insufficient to counteract all the factors involved in generating the absence seizures; in this animal model, it may be necessary to further decrease nigral activity by implanting GABAergic cells in another area. These results bear down on the fact that cell transplants need to be tailored for each type of convulsive disorder in terms of the type of cells delivered and the location of the transplants. [ABSTRACT FROM AUTHOR]

Abstract: N-Acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THIQ-10c) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that has been demonstrated to antagonize generalized tonic–clonic seizures in different animal models of epilepsy. In the study described here, we tested the potential effect of such a compound alone or co-administered with ethosuximide in a genetic animal model of absence epilepsy, the WAG/Rij rat. The intraperitoneal or intracerebroventricular microinjection of THIQ-10c alone was unable to significantly modify the number and duration of spike-and-wave discharges (SWDs). In contrast, intracerebroventricular administration of AMPA induced a dose-dependent increase in the number of SWDs. THIQ-10c dose-dependently antagonized this effect. Furthermore, co-administration of THIQ-1c with ethosuximide (50mg/kg, intraperitoneally) was able to significantly increase the efficacy of the anti-absence drug. In conclusion, although noncompetitive AMPA receptor antagonists alone might not be useful in the treatment of absence epilepsy because of their low therapeutic index, combining them with ethosuximide might be helpful in controlling absence seizures in patients not tolerating this drug or in refractory patients. [Copyright &y& Elsevier]

Abstract: In this study, we tested whether over-expressing the GABAB receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3–6 Hz slow spike and wave discharges between 2 and 4 months of age. These discharges are blocked by ethosuximide and exacerbated by baclofen confirming their absence nature. The discharges occur coincident with absence-like behaviors such as staring, facial myoclonus, and whisker twitching. However, in contrast to typical absence epilepsy models, these mice move during the ictal event, display spike and wave discharges in both thalamocortical and limbic circuitry, exhibit impaired hippocampal synaptic plasticity, and display significantly impaired learning ability. Collectively, these features are more characteristic of the less common but more debilitating atypical form of absence epilepsy. Thus, these data support a role for the GABABR1a receptor subtype in the etiology of atypical absence epilepsy. [Copyright &y& Elsevier]

Abstract: Neocortical networks play a major role in the genesis of generalized spike-and-wave (SW) discharges associated with absence seizures in humans and in animal models, including genetically predisposed WAG/Rij rats. Here, we tested the hypothesis that alterations in GABAB receptors contribute to neocortical hyperexcitability in these animals. By using Real-Time PCR we found that mRNA levels for most GABAB(1) subunits are diminished in epileptic WAG/Rij neocortex as compared with age-matched non-epileptic controls (NEC), whereas GABAB(2) mRNA is unchanged. Next, we investigated the cellular distribution of GABAB(1) and GABAB(2) subunits by confocal microscopy and discovered that GABAB(1) subunits fail to localize in the distal dendrites of WAG/Rij neocortical pyramidal cells. Intracellular recordings from neocortical cells in an in vitro slice preparation demonstrated reduced paired-pulse depression of pharmacologically isolated excitatory and inhibitory responses in epileptic WAG/Rij rats as compared with NECs; moreover, paired-pulse depression in NEC slices was diminished by a GABAB receptor antagonist to a greater extent than in WAG/Rij rats further suggesting GABAB receptor dysfunction. In conclusion, our data identify changes in GABAB receptor subunit expression and distribution along with decreased paired-pulse depression in epileptic WAG/Rij rat neocortex. We propose that these alterations may contribute to neocortical hyperexcitability and thus to SW generation in absence epilepsy. [Copyright &y& Elsevier]

Abstract: The mechanisms of injured brain that establish poststroke seizures and epilepsy are not well understood, largely because animal modeling of these phenomena has had limited development. We studied the electrobehavioral properties of 2.5-month-old male Long–Evans rats by video-electroencephalogram (EEG) recordings during the 6 months following sham operation or lesioning by transient unilateral middle cerebral artery (MCA) and common carotid artery (CCA) occlusion (MCA/CCAO). The main findings of this study were: (1) control animals demonstrated interictal focal or restricted bilateral 7–8 Hz spike–wave discharges (SWDs) lasting 1–2 s without behavioral change and ictal generalized 7–8 Hz SWDs (absence seizures), which were prolonged, frequent, and associated with motor arrest of the animal; (2) lesioned animals demonstrated cortical infarction associated with interictal SWDs similar to controls, except that focal discharges were more numerous relative to bilateral discharges, and ictal SWDs, which were of shorter duration and less frequent than those of controls; (3) lesioned animals demonstrated decreased hemispheric and regional spectral power at ∼7 and 15 Hz compared with controls, directly related to the reduced occurrence of ictal SWDs; and (4) lesioning did not independently generate either focal or generalized epileptic seizures. These studies demonstrate distinct electrobehavioral properties of Long–Evans rats lesioned by MCA/CCAO as juveniles and monitored by video-EEG recordings during young adulthood but fail to provide evidence of poststroke seizures or epilepsy. [Copyright &y& Elsevier]

Abstract: The interaction between thalamus and cortex appears to be critical to the pathophysiology of idiopathic generalized epilepsies (IGEs). The objective of this study was to investigate thalamic volumes of a group of patients with IGEs using high-resolution MRI. Thalamic segmentation was performed by the same rater, who was unaware of the diagnosis. Thalamic volumes were divided into anterior half and posterior half. One hundred forty-seven patients were scanned (71 with juvenile myoclonic epilepsy, 49 with generalized tonic–clonic seizures only, and 27 with absence epilepsy). Subgroup analyses with corrections for multiple comparisons showed that, when compared with those of controls, anterior thalamic volumes were increased in patients with absence epilepsy and juvenile myoclonic epilepsy with absence seizures, but not in patients with generalized tonic–clonic seizures only and juvenile myoclonic epilepsy without absence seizures. Our results demonstrated that the anterior thalamus is structurally different in patients with IGEs and absence seizures as compared with patients with IGEs without absence seizures. [Copyright &y& Elsevier]

The effects of systemic theophylline administration on spike–wave discharge (SWD) frequency in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats are investigated. After an hour of baseline recording, animals were injected intraperitoneally (ip) with 5, 10, and 20mg/kg theophylline and electroencephalograms (EEGs) were recorded for 2h postinjection. Then, the number and total duration of SWDs were analyzed. Spontaneous behaviors of the animals was also observed before and after drug administration. Our results show that systemic administration of theophylline suppresses the occurrence of SWDs in a dose-dependent manner. The greatest suppression was seen in the group administered 20mg/kg theophylline. Theophylline also induced a mild increase in exploratory and automatic behavior. These results indicate that blockage of adenosinergic receptors via the methylxanthine derivative theophylline decreases the occurrence of SWDs, probably by augmenting the efficacy of excitator neurotransmission and increasing vigilance and arousal levels. [Copyright &y& Elsevier]

Mixed forms of epilepsy in patients are often refractory. Therefore, animal models of comorbid convulsive and nonconvulsive seizure are needed for experimental research. Susceptibility to audiogenic convulsions was studied in a large group of young and adult WAG/Rij rats with inherited absence epilepsy. In 30% of adult rats, sound stimulation provoked audiogenic seizures of moderate intensity. The seizures had two excitation periods separated by a remarkably stable “arrest” of paroxysmal movements. Up to 20% of young WAG/Rij rats were also susceptible to audiogenic seizures, with a longer latency, lower intensity, and more simple seizure patterns. No difference in manifestations of spike–wave discharges was observed between the WAG/Rij rats with and without audiogenic seizures. This subpopulation of WAG/Rij rats genetically predisposed to absence and audiogenic seizures is proposed as an animal model suitable for investigation of basal mechanisms and pharmacological profiles of this mixed form of epilepsy. [Copyright &y& Elsevier]

Absence epilepsy (AE) is related to both cognitive and physical impairments. In this narrative review, we critically discuss the pathophysiology of AE and the impairment of attention in children and adolescents with AE. In particular, we contextualize the attentive dysfunctions of AE with the associated risks, such as accidental injuries. An extensive literature search on attention deficits and the rate of accidental injuries in AE was run. The search was conducted on Scopus, Pubmed, and the online libraries of the University of Twente and Maastricht University. Relevant references of the included articles were added. Retrospective and prospective studies, case reports, meta-analysis, and narrative reviews were included. Only studies written in English were considered. Date of last search is February 2020. The keywords used were "absence epilepsy" AND "attention"/"awareness", "absence epilepsy" AND "accidental injuries"/"accident*"/"injuries". Ten retrospective and two prospective studies on cognition and AE were fully screened. Seventeen papers explicitly referring to attention in AE were reviewed. Just one paper was found to specifically focus on accidental injuries and AE, while twelve studies generally referring to epilepsy syndromes – among which AE – and related accidents were included. Absence epilepsy and attention deficits show some patterns of pathophysiological association. This relation may account for dysfunctions in everyday activities in the pediatric population. Particular metrics, such as the risk related to biking in children with AE, should be used in future studies to address the problem in a novel way and to impact clinical indications. • Absence epilepsy and attention deficits show patterns of pathophysiological association • Attentive dysfunctions in absence epilepsy account for dysfunctions in every-day activities • Patients with absence epilepsy may be more likely to incur in casualties • Quantitative measures of the risk of accidents in patients with asbences are relevant to formulate clinical indications [ABSTRACT FROM AUTHOR]

Hyperventilation (HV) in children can lead to HV-induced high-amplitude rhythmic slowing (HIHARS) on the EEG (electroencephalogram) which is sometimes associated with altered awareness (AA) and concomitant semiological features. Our aims were to determine the frequency of HIHARS in children, to assess if the associated semiological features were temporally related to HV, and to evaluate if specific semiological features can differentiate HIHARS with AA from absence seizures. Consecutive children with suspected new onset seizure(s) underwent HV and awareness testing during video-EEG acquisition. Hyperventilation-induced high-amplitude rhythmic slowing was defined as 2.5- to 5-Hz generalized rhythmic slowing with amplitude ≥ 100 μv lasting for ≥ 3 s. The associated semiological features were compared between the group of children with HIHARS and AA, an age- and gender-matched control group without HIHARS, and in children who experienced absence seizures during HV. One hundred sixteen children with a mean age of 9.8 years were included. Hyperventilation-induced high-amplitude rhythmic slowing occurred in 39 children (33.6%) with AA documented in 30 (76.9%). The probability of developing AA during HIHARS was significantly and positively correlated with the HIHARS duration. The frequencies of HIHARS were not significantly different between children diagnosed with seizure(s) and those with nonepileptic spells. Hyperventilation cessation and staring did not occur in any child of the control group. Fidgeting and yawning were significantly more common in the group with HIHARS with AA while staring and blinking were significantly more frequent in the group of children with absence seizures. We ascertained that HIHARS with AA is a relatively common occurrence in children and most likely represents an age-related nonepileptic phenomenon. When associated with fidgeting or yawning, it can help differentiate this phenomenon from absence seizures. However, recording the concomitant presence of generalized spike wave discharges on the EEG remains essential to confirm the diagnosis of absence seizures. • Hyperventilation-induced high-amplitude slowing (HIHARS) is a frequent pattern in children. • HIHARS is commonly associated with altered awareness (AA) and may mimic absences. • Fidgeting and yawning may differentiate HIHARS with AA from absence seizures. • Recording generalized spike wave discharges on the EEG remains essential to diagnose absences. [ABSTRACT FROM AUTHOR]

Hyperventilation (HV) in children can lead to HV-induced high-amplitude rhythmic slowing (HIHARS) on the EEG (electroencephalogram) which is sometimes associated with altered awareness (AA) and concomitant semiological features. Our aims were to determine the frequency of HIHARS in children, to assess if the associated semiological features were temporally related to HV, and to evaluate if specific semiological features can differentiate HIHARS with AA from absence seizures. Consecutive children with suspected new onset seizure(s) underwent HV and awareness testing during video-EEG acquisition. Hyperventilation-induced high-amplitude rhythmic slowing was defined as 2.5- to 5-Hz generalized rhythmic slowing with amplitude ≥ 100 μv lasting for ≥ 3 s. The associated semiological features were compared between the group of children with HIHARS and AA, an age- and gender-matched control group without HIHARS, and in children who experienced absence seizures during HV. One hundred sixteen children with a mean age of 9.8 years were included. Hyperventilation-induced high-amplitude rhythmic slowing occurred in 39 children (33.6%) with AA documented in 30 (76.9%). The probability of developing AA during HIHARS was significantly and positively correlated with the HIHARS duration. The frequencies of HIHARS were not significantly different between children diagnosed with seizure(s) and those with nonepileptic spells. Hyperventilation cessation and staring did not occur in any child of the control group. Fidgeting and yawning were significantly more common in the group with HIHARS with AA while staring and blinking were significantly more frequent in the group of children with absence seizures. We ascertained that HIHARS with AA is a relatively common occurrence in children and most likely represents an age-related nonepileptic phenomenon. When associated with fidgeting or yawning, it can help differentiate this phenomenon from absence seizures. However, recording the concomitant presence of generalized spike wave discharges on the EEG remains essential to confirm the diagnosis of absence seizures. • Hyperventilation-induced high-amplitude slowing (HIHARS) is a frequent pattern in children. • HIHARS is commonly associated with altered awareness (AA) and may mimic absences. • Fidgeting and yawning may differentiate HIHARS with AA from absence seizures. • Recording generalized spike wave discharges on the EEG remains essential to diagnose absences. [ABSTRACT FROM AUTHOR]

A single injection of the cannabinoid agonist R(+)WIN55,212-2 (WIN) is known to cause an increase of the mean duration of spontaneously occurring spike-and-wave discharges (SWDs) in rats of the WAG/Rij strain, a genetic model for absence epilepsy. The aim of the present study was to establish whether repeated activation of CB 1 receptors with WIN leads to tolerance in its effect on SWD parameters, spectral density, and behavior over time. Adult male WAG/Rij rats (n = 16) were treated with WIN (6 mg/kg) or vehicle (olive oil). Injections (s.c.) took place 3 times per week during 2 weeks. Electroencephalogram (EEG) recordings, each lasting 24 h, were made 3 times: immediately before the first injection (baseline), immediately after the first injection (acute treatment), and after 2 weeks of treatment (subchronic treatment). The recordings were analyzed regarding incidence, durations of SWDs, and hazard rates of the durations of SWDs, the latter to describe SWD stopping probabilities. Putative changes in the spectral content of the EEG before and after WIN during active and passive behaviors were additionally investigated. Spike-and-wave discharge incidence was not affected by the acute and subchronic treatments. The mean duration of the SWDs was significantly longer than controls in the acute WIN-treated animals [11.9-s standard error of the mean (SEM): 0.64 compared with 8.4-s SEM: 0.25] as well as in subchronically treated animals (11.5-s SEM: 1.00 compared with 8.4-s SEM: 0.25). Hazard rates were significantly lower for WIN-treated animals at SWD durations in the 5.04–20.16-s range on both occasions. No effects of WIN on the frequency spectrum of the ongoing EEG were found, neither acutely nor after repeated administration. Evidence for tolerance was not found. The results on the mean duration and hazard rates suggest that stimulating the endocannabinoid system affects the SWD stopping mechanism, resulting in more long SWDs. We speculate that this effect is likely to be a direct result of CB 1 receptor agonism and a subsequent decrease in the availability of gamma-aminobutyric acid (GABA) in the reticular thalamic nucleus, which further weakens, in WAG/Rij rats already disturbed, the stopping mechanism of the SWDs. • Stimulating the endocannabinoid system with CB 1 agonist R(+)WIN55,212-2 in WAG/Rij rats results in long SWDs for 24+ hours. • No effects of WIN on the frequency spectrum of the EEG or on behavior were found. • Tolerance for the effects of WIN did not develop. • We speculate that WIN reinforces a disturbed stopping mechanism. [ABSTRACT FROM AUTHOR]

Feed-forward inhibition (FFI) is an essential mechanism within the brain, to regulate neuronal firing and prevent runaway excitation. In the cortico-thalamocortical (CTC) network, fast spiking parvalbumin-expressing (PV+) inhibitory interneurons regulate the firing of pyramidal cells in the cortex and relay neurons in the thalamus. PV+ interneuron dysfunction has been implicated in several neurological disorders, including epilepsy. Previously, we demonstrated that loss of excitatory AMPA-receptors, specifically at synapses on PV+ interneurons in CTC feedforward microcircuits, occurs in the stargazer mouse model of absence epilepsy. These mice present with absence seizures characterized by spike and wave discharges (SWDs) on electroencephalogram (EEG) and concomitant behavioural arrest, similar to childhood absence epilepsy. The aim of the current study was to investigate the impact of loss of FFI within the CTC on absence seizure generation and behaviour using new Designer Receptor Exclusively Activated by Designer Drug (DREADD) technology. We crossed PV-Cre mice with Cre-dependent hM4Di DREADD strains of mice, which allowed Cre-recombinase-mediated restricted expression of inhibitory G i -DREADDs in PV+ interneurons. We then tested the impact of global and focal (within the CTC network) silencing of PV+ interneurons. CNO mediated silencing of all PV+ interneurons by intraperitoneal injection caused the impairment of motor control, decreased locomotion and increased anxiety in a dose-dependent manner. Such silencing generated pathological oscillations similar to absence-like seizures. Focal silencing of PV+ interneurons within cortical or thalamic feedforward microcircuits, induced SWD-like oscillations and associated behavioural arrest. Epileptiform activity on EEG appeared significantly sooner after focal injection compared to peripheral injection of CNO. However, the mean duration of each oscillatory burst and spike frequency was similar, irrespective of mode of CNO delivery. No significant changes were observed in vehicle-treated or non-DREADD wild-type control animals. These data suggest that dysfunctional feed-forward inhibition in CTC microcircuits may be an important target for future therapy strategies for some patients with absence seizures. Additionally, silencing of PV+ interneurons in other brain regions may contribute to anxiety related neurological and psychiatric disorders. • Silencing CTC PV+ interneurons generates epileptiform-activity similar to SWDs on EEG. • Oscillatory SWD-like bursts are associated with prolonged behavioural arrest. • Global silencing of PV+ interneurons causes motor function changes and anxiety. [ABSTRACT FROM AUTHOR]