Early alterations of the neuronal network processing whisker-related sensory signal during absence epileptogenesis.

OBJECTIVE: Epileptogenesis is the particular process during which the epileptic network builds up progressively before the onset of the first seizures. Whether physiological functions are impacted by this development of epilepsy remains unclear. To explore this question, we used Genetic Absence Epilepsy Rats From Strasbourg (GAERS), in which spike-and-wave discharges are initiated in the whisker primary somatosensory cortex (wS1) and first occur during cortical maturation. We studied the development of both the epileptic and the physiological wS1 circuits during cortical maturation to understand the interactions between them and the consequences for the animals' behavior. METHODS: In sedated and immobilized rat pups, we recorded in vivo epileptic and whisker sensory evoked activities across the wS1 and thalamus using multicontact electrodes. We compared sensory evoked potentials based on current source density analysis. We then analyzed the multiunit activities evoked by whisker stimulation in GAERS and control rats. Finally, we evaluated behavioral performance dependent on the functionality of the wS1 cortex using the gap-crossing task. RESULTS: We showed that the epileptic circuit changed during the epileptogenesis period in GAERS, by involving different cortical layers of wS1. Neuronal activities evoked by whisker stimulation were reduced in the wS1 cortex at P15 and P30 in GAERS but increased in the ventral posteromedial nucleus of the thalamus at P15 and in the posterior medial nucleus at P30, when compared to control rats. Finally, we observed lower performance in GAERS versus controls, at both P15 and P30, in a whisker-mediated behavioral task. SIGNIFICANCE: Our data show that the functionality of wS1 cortex and thalamus is altered early during absence epileptogenesis in GAERS and then evolves before spike-and-wave discharges are fully expressed. They suggest that the development of the pathological circuit disturbs the physiological one and may be responsible for both the emergence of seizures and associated comorbidities.

Spike-wave seizures, slow-wave sleep EEG and morphology of substantia nigra pars compacta in WAG/Rij rats with genetic predisposition to absence epilepsy.

Spike-wave discharges (SWDs) are EEG hallmarks of absence epilepsy, and they spontaneously appear in adult WAG/Rij rats. SWDs are known to be vigilance-dependent and are modulated by monoaminergic mechanisms. It is also known that loss of neurons in the center of the nigrostriatal dopamine system, substantia nigra pars compacta (SNc), is associated with a variety of sleep disorders. We hypothesized that a disorder of the nigrostriatal dopamine system described for WAG/Rij rats might facilitate generation of SWDs through changes in vigilance state and the quality of sleep. Our study was conducted in 'epileptic' and 'non-epileptic' phenotype (less than 1 SWDs per h). Analysis included (1) EEG examination, i.e., analysis of SWDs, rudimentary SWDs and slow wave sleep EEG and (2) microstructural examination of SNc, i.e., measuring its size and the number of neurons and glial cells. No differences in size and cellular content of SNc were found between 'epileptic' and 'non-epileptic' phenotypes. Meanwhile in 'epileptic' subjects, the number of SWDs correlated with the number of neurons in SNc (SWDs more frequently occurred in subjects with fewer neurons in SNc). Rudimentary SWDs were found in both phenotypes. No differences in number and duration of rudimentary SWDs were found between 'epileptic' and 'non-epileptic' phenotypes. Spike-wave EEG activity showed strong association with the number of neurons in SNc: subjects with fewer neurons in SNc were characterized by higher number of SWDs and longer rudimentary SWDs. In sum, our data suggested that intense epileptic EEG activity (in the form of SWDs and rudimentary SWDs) might lead to sleep disruption. However, the lack of direct correlations between sleep parameters and SWDs number indicated that the link between sleep features, SNc cellularity and spike-wave EEG activity could be more complex than we had expected.

Ultrastructural GABA immunogold labeling in the substantia nigra pars reticulata of kindled genetic absence epilepsy rats.

Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a well-known animal model of absence epilepsy and they are resistant to electrical kindling stimulations. The present study aimed to examine possible differences in gamma-aminobutyric acid (GABA) levels and synapse counts in the substantia nigra pars reticulata anterior (SNRa) and posterior (SNRp) regions between GAERS and Wistar rats receiving kindling stimulations. Animals in the kindling group either received six stimulations in the amygdala and had grade 2 seizures or they were kindled, having grade five seizures. Rats were decapitated one hour after the last stimulation. SNR regions were obtained after vibratome sectioning of the brain tissue. GABA immunoreactivity was detected by immunogold method and synapses were counted. Sections were observed by transmission electron microscope and analyzed by Image J program. GABA density in the SNRa region of fully kindled GAERS and Wistar groups increased significantly compared to that of their corresponding grade 2 groups. The number of synapses increased significantly in kindled and grade 2 GAERS groups, compared to kindled and grade 2 Wistar groups, respectively, in the SNRa region. GABA density in the SNRp region of kindled GAERS group increased significantly compared to that of GAERS grade 2 group. In the SNRp region, both kindled and grade 2 GAERS groups were found to have increased number of synapses compared to that of GAERS control group. We concluded that both SNRa and SNRp regions may be important in modulating resistance of GAERS to kindling stimulations.

Gender-Dependent Effect of Maternal Methyl-Enriched Diet on the Expression of Genetic Absence Epilepsy and Comorbid Depression in Adult Offspring of WAG/Rij Rats.

In the present study it has been shown for the first time that maternal methyl-enriched diet (choline, betaine, folic acid, vitamin B12, L-methionine, zinc) during perinatal period reduces the expression of genetic absence epilepsy and comorbid depression in adult offspring of WAG/Rij rats. This beneficial effect was more pronounced in males compared with females. It is assumed that epigenetic modifications induced by maternal methyl-enriched diet in the offspring at the early stages of ontogenesis might be a possible mechanism underlying the correction of genetically-based pathologic phenotype in WAG/Rij rats. Results suggest that methyl-enriched diet during perinatal period can be potentially used for mitigation or prevention epileptogenesis and depression-like comorbid disorders in people genetically predisposed to absence epilepsy.

Slow-wave activity preceding the onset of 10-15-Hz sleep spindles and 5-9-Hz oscillations in electroencephalograms in rats with and without absence seizures.

Cortico-thalamocortical networks generate sleep spindles and slow waves during non-rapid eye movement sleep, as well as paroxysmal spike-wave discharges (i.e. electroencephalogram manifestation of absence epilepsy) and 5-9-Hz oscillations in genetic rat models (i.e. pro-epileptic activity). Absence epilepsy is a disorder of the thalamocortical network. We tested a hypothesis that absence epilepsy associates with changes in the slow-wave activity before the onset of sleep spindles and pro-epileptic 5-9-Hz oscillations. The study was performed in the WAG/Rij genetic rat model of absence epilepsy and Wistar rats at the age of 9-12 months. Electroencephalograms were recorded with epidural electrodes from the anterior cortex. Sleep spindles (10-15 Hz), 5-9-Hz oscillations and their slow-wave (2-7 Hz) precursors were automatically detected and analysed using continuous wavelet transform. Subjects with electroencephalogram seizures (the "epileptic" phenotype) and without seizure activity (the "non-epileptic" phenotype) were identified in both strains. It was found that time-amplitude features of sleep spindles and 5-9-Hz oscillations were similar in both rat strains and in both phenotypes. Sleep spindles in "epileptic" rats were more often preceded by the slow-wave (~4 Hz) activity than in "non-epileptic" rats. The intrinsic frequency of slow-wave precursors of sleep spindles and 5-9-Hz oscillations in "epileptic" rats was 1-1.5 Hz higher than in "non-epileptic" rats. In general, our results indicated that absence epilepsy associated with: (a) the reinforcement of slow waves immediately prior to normal sleep spindles; and (b) weakening of amplitude growth in transition "slow wave → spindle/5-9-Hz oscillation".

Unified analysis of global and focal aspects of absence epilepsy via neural field theory of the corticothalamic system.

Absence epilepsy is characterized by a sudden paroxysmal loss of consciousness accompanied by oscillatory activity propagating over many brain areas. Although primary generalized absence seizures are supported by the global corticothalamic system, converging experimental evidence supports a focal theory of absence epilepsy. Here a physiology-based corticothalamic model is investigated with spatial heterogeneity due to focal epilepsy to unify global and focal aspects of absence epilepsy. Numeric and analytic calculations are employed to investigate the emergent spatiotemporal dynamics as well as their underlying dynamical mechanisms. They can be categorized into three scenarios: suppressed epilepsy, focal seizures, or generalized seizures, as summarized from a phase diagram vs focal width and characteristic axon range. The corresponding temporal frequencies and spatial extents of cortical waves in generalized seizures and focal seizures agree well with experimental observations of global and focal aspects of absence epilepsy, respectively. The emergence of the spatiotemporal dynamics corresponding to focal seizures provides a biophysical explanation of the temporally higher frequency but spatially more localized cortical waves observed in genetic rat models that display characteristics of human absence epilepsy. Predictions are also presented for further experimental test.

Genetic absence epilepsy: Effective connectivity from piriform cortex to mediodorsal thalamus.

OBJECTIVE: The objective of the study was to quantify effective connectivity from the piriform cortex to mediodorsal thalamus, in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). METHODS: Local field potentials (LFPs) were recorded using microelectrode arrays implanted in the mediodorsal thalamus and piriform cortex, in three urethane anesthetized GAERS and three control rats. Screw electrodes were placed in the primary motor cortex to identify epileptiform discharges. We used transfer entropy to measure effective connectivity from piriform cortex to mediodorsal thalamus prior to and during generalized epileptiform discharges. RESULTS: We observed increased theta band effective connectivity from piriform cortex to mediodorsal thalamus, prior to and during epileptiform discharges in GAERS compared with controls. Increased effective connectivity was also observed in beta and gamma bands from the piriform cortex to mediodorsal thalamus, but only during epileptiform discharges. CONCLUSIONS: This preliminary study suggests that increased effective theta connectivity from the piriform cortex to the mediodorsal thalamus may be a feature of the 'epileptic network' associated with genetic absence epilepsy. Our findings indicate an underlying predisposition of this direct pathway to propagate epileptiform discharges in genetic absence epilepsy.

Statistical Properties and Predictability of Extreme Epileptic Events.

The use of extreme events theory for the analysis of spontaneous epileptic brain activity is a relevant multidisciplinary problem. It allows deeper understanding of pathological brain functioning and unraveling mechanisms underlying the epileptic seizure emergence along with its predictability. The latter is a desired goal in epileptology which might open the way for new therapies to control and prevent epileptic attacks. With this goal in mind, we applied the extreme event theory for studying statistical properties of electroencephalographic (EEG) recordings of WAG/Rij rats with genetic predisposition to absence epilepsy. Our approach allowed us to reveal extreme events inherent in this pathological spiking activity, highly pronounced in a particular frequency range. The return interval analysis showed that the epileptic seizures exhibit a highly-structural behavior during the active phase of the spiking activity. Obtained results evidenced a possibility for early (up to 7 s) prediction of epileptic seizures based on consideration of EEG statistical properties.

Differences in Neurodegeneration Between Kainic Acid-Injected GAERS and Wistar Rats.

AIM: To compare neurodegenerative changes using the Fluoro-Jade B staining, following status epilepticus induced by intraamygdaloid injection of kainic acid in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control Wistar rats. MATERIAL AND METHODS: A single unilateral intra-amygdaloid kainic acid (750 ng) was administered in adult male GAERS and Wistar rats to induce status epilepticus. We recorded electroencephalogram (EEG) and behavioral changes throughout the experiments. After 1 week of the kainic acid injection, rats were sacrificed, and the brains were removed. We obtained 20λm sections and processed them for Fluoro-Jade B and Nissl staining, which were evaluated semi-quantitatively. RESULTS: Following kainic acid injections, status epilepticus developed in all rats. In GAERS rats, motor seizures were considerably delayed, with no statistically significant difference in the number of seizures. However, statistically significant differences were observed in the Fluoro-Jade B staining in GAERS rats between contralateral and ipsilateral sides of the CA3, CA1, somatosensory cortex, entorhinal cortex, piriform cortex, reticular nucleus, putamen, and claustrum. In Wistar rats, the CA3, CA1, somatosensory cortex, entorhinal cortex, piriform cortex, reticular nucleus, amygdala, and laterodorsal nucleus exhibited significant differences. Comparing GAERS and Wistar rats, a statistically significant difference was observed for both sides of CA1. In both groups, the staining was prominent ipsilaterally, except for the claustrum in GAERS rats. However, the motor cortex remained unaffected in both groups. Neurodegenerative changes were not associated with the severity of seizures in both groups following the intra-amygdaloid kainic acid administration. CONCLUSION: This study demonstrates that CA1 is the only region exhibiting a statistically significant difference between Wistar and GAERS rats.

Fast oxygen dynamics as a potential biomarker for epilepsy.

Changes in brain activity can entrain cerebrovascular dynamics, though this has not been extensively investigated in pathophysiology. We assessed whether pathological network activation (i.e. seizures) in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) could alter dynamic fluctuations in local oxygenation. Spontaneous absence seizures in an epileptic rat model robustly resulted in brief dips in cortical oxygenation and increased spectral oxygen power at frequencies greater than 0.08 Hz. Filtering oxygen data for these fast dynamics was sufficient to distinguish epileptic vs. non-epileptic rats. Furthermore, this approach distinguished brain regions with seizures from seizure-free brain regions in the epileptic rat strain. We suggest that fast oxygen dynamics may be a useful biomarker for seizure network identification and could be translated to commonly used clinical tools that measure cerebral hemodynamics.

Alterations in hippocampal and cortical densities of functionally different interneurons in rat models of absence epilepsy.

Recent data from absence epileptic patients and animal models provide evidence for significant impairments of attention, memory, and psychosocial functioning. Here, we outline aspects of the electrophysiological and structural background of these dysfunctions by investigating changes in hippocampal and cortical GABAergic inhibitory interneurons in two genetically absence epileptic rat strains: the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Using simultaneously recorded field potentials from the primary somatosensory cortex (S1 cortex, seizure focus) and the hippocampal hilus, we demonstrated that typical frequencies of spike-wave discharges (SWDs; 7-8 Hz, GAERS; 7-9 Hz, WAG/Rij) and their harmonics appeared and their EEG spectral power markedly increased on recordings not only from the S1 cortex, but also from the hilus in both GAERS and WAG/Rij rats during SWDs. Moreover, we observed an increased synchronization between S1 cortex and hilus at 7-8 Hz (GAERS) and 7-9 Hz (WAG/Rij) and at their harmonics when SWDs occurred in the S1 cortex in both rat strains. In addition, using immunohistochemistry we demonstrated changes in the densities of perisomatic (parvalbumin-immunopositive, PV+) and interneuron-selective (calretinin-immunopositive, CR+) GABAergic inhibitory interneuron somata. Specifically, GAERS and WAG/Rij rats displayed lower densities of PV-immunopositivity in the hippocampal hilus compared to non-epileptic control (NEC) and normal Wistar rats. GAERS and WAG/Rij rats also show a marked reduction in the density of CR + interneurons in the same region in comparison with NEC rats. Data from the S1 cortex reveals bidirectional differences in PV + density, with GAERS displaying a significant increase, whereas WAG/Rij a reduction compared to control rat strains. Our results suggest an enhanced synchronization and functional connections between the hippocampus and S1 cortex as well as thalamocortical activities during SWDs and a functional alteration of inhibitory mechanisms in the hippocampus and S1 cortex of two genetic models of absence epilepsy, presumably in relation with increased neuronal activity and seizure-induced neuronal injury.

Whole-brain MEG connectivity-based analyses reveals critical hubs in childhood absence epilepsy.

Absence seizures are thought to be linked to abnormal interplays between regions of a thalamocortical network. However, the complexity of this widespread network makes characterizing the functional interactions among various brain regions challenging. Using whole-brain functional connectivity and network analysis of magnetoencephalography (MEG) data, we explored pre-treatment brain hubs ("highly connected nodes") of patients aged 6 to 12 years with childhood absence epilepsy. We analyzed ictal MEG data of 74 seizures from 16 patients. We employed a time-domain beamformer technique to estimate MEG sources in broadband (1-40 Hz) where the greatest power changes between ictal and preictal periods were identified. A phase synchrony measure, phase locking value, and a graph theory metric, eigenvector centrality (EVC), were utilized to quantify voxel-level connectivity and network hubs of ictal > preictal periods, respectively. A volumetric atlas containing 116 regions of interests (ROIs) was utilized to summarize the network measures. ROIs with EVC (z-score) > 1.96 were reported as critical hubs. ROIs analysis revealed functional-anatomical hubs in a widespread network containing bilateral precuneus (right/left, z = 2.39, 2.18), left thalamus (z = 2.28), and three anterior cerebellar subunits of lobule "IV-V" (z = 3.9), vermis "IV-V" (z = 3.57), and lobule "III" (z = 2.03). Findings suggest that highly connected brain areas or hubs are present in focal cortical, subcortical, and cerebellar regions during absence seizures. Hubs in thalami, precuneus and cingulate cortex generally support a theory of rapidly engaging and bilaterally distributed networks of cortical and subcortical regions responsible for seizures generation, whereas hubs in anterior cerebellar regions may be linked to terminating motor automatisms frequently seen during typical absence seizures. Whole-brain network connectivity is a powerful analytic tool to reveal focal components of absence seizures in MEG. Our investigations can lead to a better understanding of the pathophysiology of CAE.

Comparison of cerebral ventricular volumes and cortical thicknesses in normal rats and Genetic Absence Epilepsy (GAERS): A developmental study.

Ventricular enlargement and cortical atrophy have been associated with various central nervous system diseases. The aim of the present study was to measure the volumes of the lateral (LV) and third (3V) ventricles and to determine the cortical thickness for the motor (MCx), somatosensory (SSCx), visual (VCx) and auditory (AuCx) cortex and the striatum of Wistar rats, in a developmental series at 10, 20, 30, and 60 days postnatal, and to compare them with similar data from genetic absence epilepsy rats from Strasbourg (GAERS). Serial sections were taken from the brains of Wistar and GAERS animals and were Nissl stained. Photographs were taken from specific sections of the brain for measurements of ventricular volume, cortical and striatal thickness. The image-j computer program was used for the volume and thickness measurements. The data was statistically analyzed by 3-way ANOVA using SPSS 15. Comparison of the measurements of GAERS and Wistar animals showed no statistically significant differences at any of the developmental stages regarding the ventricular (LV and 3V) volumes. However, at P60 and P30 of the MCx, P30 of the SSCx, P20 of the VCx and AuCx showed a significantly thinner cortical thickness in the GAERS than in the Wistar animals. The striatal measurements showed significant decrease in thickness of the striatum at P30 and P60. Further, brain size measurements (between the two temporal poles) showed significant decrease in the size at P30 and P60 of GAERS animals. The presence of thinner cortical and striatal thicknesses and smaller brain size in GAERS animals may suggests that these changes could be involved in the mechanism of epileptogenicity or be a result of the epileptogenicity.

Dependence of absence seizure dynamics on physiological parameter evolution.

A neural field model of the corticothalamic system is applied to investigate the temporal and spectral characteristics of absence seizures in the presence of a temporally varying connection strength between the cerebral cortex and thalamus. Increasing connection strength drives the system into an absence seizure-like state once a threshold is passed and a supercritical Hopf bifurcation occurs. The dynamics and spectral characteristics of the resulting model seizures are explored as functions of maximum connection strength, time above threshold, and the rate at which the connection strength increases (ramp rate). Our results enable spectral and temporal characteristics of seizures to be related to changes in the underlying physiological evolution of connections via nonlinear dynamics and neural field theory. Spectral analysis reveals that the power of the harmonics and the duration of the oscillations increase as the maximum connection strength and the time above threshold increase. It is also found that the time to reach the stable limit-cycle seizure oscillation from the instability threshold decreases with the square root of the ramp rate.

Developmental changes of GABA immunoreactivity in cortico-thalamic networks of an absence seizure model.

Absence seizures (ASs) are associated with abnormalities in gamma-aminobutyric acid (GABA) neurotransmission in the thalamus and the cortex. In the present study, we used light microscopy GABA immunocytochemistry to quantify the GABA-immunoreactive (GABA-IR) neurons and neuropil in the thalamic ventral basal (VB) nucleus, the nucleus reticularis thalami (NRT), the dorsal lateral geniculate (dLGN), the primary motor cortex (M1) and perioral region of the somatosensory cortex (S1po) of genetic absence epilepsy rats from Strasbourg (GAERS). We used both the relative non-epileptic control (NEC) and normal Wistar rats as control strains, and investigated GABA immunostaining at postnatal day 15 (P15), P25, and P90. The main findings were i) an increase in GABA-IR neuropil in the VB at P25 and P90 in GAERS but not in NEC and Wistar rats; ii) an increase in NRT GABA-IR neurons in GAERS and NEC, but not Wistar, rats at both P25 and P90; and iii) an increase in GABA-IR neuron density in S1po of GAERS at P25 and P90 and in Wistar at P90. These results indicate that the increased GABAergic innervation in the VB at P25 most likely contributes to the enhanced tonic inhibition observed in GAERS prior to AS onset, whereas the lack of any anatomo-morphological GABAergic differences in GAERS S1po suggests that functional more than structural abnormalities underlie the origin of cortical paroxysms in S1po of this AS model. This article is part of the "Special Issue Dedicated to Norman G. Bowery".

[Reactive changes in morphological and morphometric parameters of immunopositive astrocytes of the amygdala in response to hormone level in absence epilepsy]. / Reaktivnye izmeneniia astrotsitov mindalevidnogo tela golovnogo mozga v otvet na raznyi uroven' polovykh gormonov pri absansnoi épilepsii.

AIM: To study the changes in the morphological and morphometric parameters of immunopositive astrocytes of the amygdala in absence epilepsy depending on hormonal profile. MATERIAL AND METHODS: Adult female WAG/Rij rats were used as experimental subjects. The astrocytes were detected on serial sections using a reaction to glial fibrillary acidic protein (GFAP) with pre-stained hematoxylin. Quantitative analysis was carried out for a 204.8´153.6 µm2 field of view. RESULTS: In the control group, astrocytes had a relatively regular stellate form and GFAP was moderately expressed in their bodies and processes. The number of astrocytes was 18.20±2.87, and their area was 164±3.29 µm2. After ovariectomy, a high expression of the protein, both in the bodies and in the processes of astrocytes, increasing the cell size to 188.85±4.97 µm2 (p<0.05) was observed. The astrocytes increased to 34.55±3.03 (p<0.05). In addition, the deformation of the processes and their diffuse defibration were observed. After hormone replacement therapy, a decrease in GFAP expression was detected, the area of astrocytes became smaller in comparison with the group after ovariectomy: 173.54±5.48 µm2 (p<0.05). Morphological changes in glial cells were manifested as a decrease in the size of their bodies, the processes became smooth without diffuse sprouting and swelling, which is probably associated with neuroprotective functions of estradiol. CONCLUSION: Thus, the results of our study demonstrated that the deficiency of female sex hormones led to the increase in both the amount and area of astrocytes in the anterior cortical nucleus of the amygdala, and hormone replacement therapy positively affected the structural and quantitative characteristics of astrocytes due to the endogenous protective role of estradiol.

Modeling pathogenesis and treatment response in childhood absence epilepsy.

OBJECTIVE: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. METHODS: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. RESULTS: Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. SIGNIFICANCE: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.

Postnatal expression of thalamic GABAA receptor subunits in the stargazer mouse model of absence epilepsy.

Absence seizures are known to originate from disruptions within the corticothalamocortical network; however, the precise underlying cellular and molecular mechanisms that induce hypersynchronicity and hyperexcitability are debated and likely to be complex and multifactorial. Recent studies implicate impaired thalamic GABAergic inhibition as a common feature in multiple animal models of absence epilepsy, including the well-established stargazer mouse model. Recently, we demonstrated region-specific increases in the whole tissue and synaptic levels of GABAA receptor (GABAAR) subunits α1 and ß2, within the ventral posterior region of the thalamus in adult epileptic stargazer mice compared with nonepileptic control littermates. The objective of this study was to investigate whether such changes in GABAAR subunits α1 and ß2 can be observed before the initiation of seizures, which occur around postnatal (PN) days 16-18 in stargazers. Semiquantitative western blotting was used to analyze the relative tissue level expression of GABAAR α1 and ß2 subunits in the thalamus of juvenile stargazer mice compared with their nonepileptic control littermates at three different time points before the initiation of seizures. We show that there is a statistically significant increase in the expression of α1 and ß2 subunits in the thalamus of stargazer mice, at the PN7-9 stage, compared with the control littermates, but not at PN10-12 and PN13-15 stages. These results suggest that an aberrant expression of GABAAR subunits α1 and ß2 in the stargazers does not occur immediately before seizure onset and therefore is unlikely to directly contribute to the initiation of absence seizures.

Experimental Treatment Options in Absence Epilepsy.

BACKGROUND: The benign character of absence epilepsy compared to other genetic generalized epilepsy syndromes has often hampered the search for new treatment options. Absence epilepsy is most often treated with ethosuximide or valproic acid. However, both drugs are not always well tolerated or fail, and seizure freedom for a larger proportion of patients remains to be achieved. The availability of genuine animal models of epilepsy does allow to search for new treatment options not only for absence epilepsy per se but also for other genetic - previously called idiopathic - forms of epilepsy. The recent discovery of a highly excitable cortical zone in these models is considered as a new therapeutic target area. METHODS: Here, we provide an overview regarding the search for new therapeutical options as has been investigated in the genetic rodent models (mainly WAG/Rij and GAERS) including drugs and whether antiepileptogenesis can be achieved, various types of electrical and optogenetical invasive stimulations, different types of noninvasive stimulation and finally whether absence seizures can be predicted and prevented. RESULTS: Many factors determine either the cortical and or thalamic excitability or the interaction between cortex and thalamus and offer new possibilities for new anti-absence drugs, among others metabotropic glutamatergic positive and negative allosteric modulators. The inhibition of epileptogenesis by various drugs with its widespread consequences seems feasible, although its mechanisms remain obscure and seems different from the antiabsence action. Surgical intervention on the cortical zone initiating seizures, either with radiosurgery using synchrotron- generated microbeams, or ablation techniques might reduce spike-and-wave discharges in the rodent models. High frequency electrical subcortical or cortical stimulation might be a good way to abort ongoing spikeand- wave discharges. In addition, possibilities for prevention with real-time EEG analyses in combination with electrical stimulation could also be a way to fully control these seizures. CONCLUSION: Although it is obvious that some of these treatment possibilities will not be used for absence epilepsy and/or need to be further developed, all can be considered as proof of principle and provide clear directives for further developments.

Disrupted topological organization of structural brain networks in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is the most common paediatric epilepsy syndrome and is characterized by frequent and transient impairment of consciousness. In this study, we explored structural brain network alterations in CAE and their association with clinical characteristics. A whole-brain structural network was constructed for each participant based on diffusion-weighted MRI and probabilistic tractography. The topological metrics were then evaluated. For the first time, we uncovered modular topology in CAE patients that was similar to healthy controls. However, the strength, efficiency and small-world properties of the structural network in CAE were seriously damaged. At the whole brain level, decreased strength, global efficiency, local efficiency, clustering coefficient, normalized clustering coefficient and small-worldness values of the network were detected in CAE, while the values of characteristic path length and normalized characteristic path length were abnormally increased. At the regional level, especially the prominent regions of the bilateral precuneus showed reduced nodal efficiency, and the reduction of efficiency was significantly correlated with disease duration. The current results demonstrate significant alterations of structural networks in CAE patients, and the impairments tend to grow worse over time. Our findings may provide a new way to understand the pathophysiological mechanism of CAE.