The "Twin Peaks" method of automated Spike-Wave detection: A two-step, two-criteria Matlab application.

BACKGROUND: There are many automated spike-wave discharge detectors, but the known weaknesses of otherwise good methods and the varying working conditions of different research groups (mainly the access to hardware and software) invite further exploration into alternative approaches. NEW METHOD: The algorithm combines two criteria, one in the time-domain and one in the frequency-domain, exploiting morphological asymmetry and the presence of harmonics, respectively. The time-domain criterion is additionally adjusted by normal modelling between the first and second iterations. RESULTS: We report specificity, sensitivity and accuracy values for 20 recordings from 17 mature, male WAG/Rij rats. In addition, performance was preliminary tested with different hormones, pharmacological injections and species (mice) in a smaller sample. Accuracy and specificity were consistently above 91 %. The number of automatically detected spike-wave discharges was strongly correlated with the numbers derived from visual inspection. Sensitivity varied more strongly than specificity, but high values were observed in both rats and mice. COMPARISON WITH EXISTING METHODS: The algorithm avoids low-voltage movement artifacts, displays a lower false positive rate than many predecessors and appears to work across species, i.e. while designed initially with data from the WAG/Rij rat, the algorithm can pick up seizure activity in the mouse of considerably lower inter-spike frequency. Weaknesses of the proposed method include a lower sensitivity than several predecessors. CONCLUSION: The algorithm excels in being a selective and flexible (based on e.g. its performance across rats and mice) spike-wave discharge detector. Future work could attempt to increase the sensitivity of this approach.

The Metabotropic Glutamate 5 Receptor in Sleep and Wakefulness: Focus on the Cortico-Thalamo-Cortical Oscillations.

Sleep is an essential innate but complex behaviour which is ubiquitous in the animal kingdom. Our knowledge of the distinct neural circuit mechanisms that regulate sleep and wake states in the brain are, however, still limited. It is therefore important to understand how these circuits operate during health and disease. This review will highlight the function of mGlu5 receptors within the thalamocortical circuitry in physiological and pathological sleep states. We will also evaluate the potential of targeting mGlu5 receptors as a therapeutic strategy for sleep disorders that often co-occur with epileptic seizures.

Network analysis reveals a role of the hippocampus in absence seizures: The effects of a cannabinoid agonist.

The role of the hippocampus (Hp) in absence epileptic networks and the effect of endocannabinoid system on this network remain enigmatic. Here, using adapted nonlinear Granger causality, we compared the differences in network strength in four intervals (baseline or interictal, preictal, ictal and postictal) in two hours before (Epoch 1) and six hours (epochs 2, 3 and 4) after the administration of three different doses of the endocannabinoid agonist WIN55,212-2 (WIN) or solvent. Local field potentials were recorded for eight hours in 23 WAG/Rij rats in the Frontal (FC), Parietal PC), Occipital Cortex (OC) and in the hippocampus (Hp). The four intervals were visually marked by an expert neurophysiologist and the strength of couplings between electrode pairs were calculated in both directions. Ictally, a strong decrease in coupling strength was found between Hp and FC, as well as a large increase bidirectionally between PC and FC and unidirectionally from FC and PC to OC, and from FC to Hp over all epochs. The highest dose of WIN increased the couplings strength from FC to Hp and from OC to PC during 4 and 2 hr respectively in all intervals, and decreased the FC to PC coupling strength postictally in epoch 2. A single rat showed generalized convulsive seizures after the highest dose: this rat shared not only coupling changes with the other rats in the same condition, but showed many more. WIN reduced SWD number in epoch 2 and 3, their mean duration increased in epochs 3 and 4. Conclusions:during SWDs FC and PC are strongly coupled and drive OC, while at the same time the influence of Hp to FC is diminished. The first is in agreement with the cortical focus theory, the latter demonstrates an involvement of the hippocampus in SWD occurrence and that ictally the hippocampal control of the cortico-thalamo-cortical system is lost. WIN causes dramatic network changes which have major consequences for the decrease of SWDs, the occurrence of convulsive seizures, and the normal cortico-cortical and cortico-hippocampal interactions.

Striatal Patchwork of D1-like and D2-like Receptors Binding Densities in Rats with Genetic Audiogenic and Absence Epilepsies.

Binding densities to dopamine D1-like and D2-like receptors (D1DR and D2DR) were studied in brain regions of animals with genetic generalized audiogenic (AGS) and/or absence (AbS) epilepsy (KM, WAG/Rij-AGS, and WAG/Rij rats, respectively) as compared to non-epileptic Wistar (WS) rats. Convulsive epilepsy (AGS) exerted a major effect on the striatal subregional binding densities for D1DR and D2DR. An increased binding density to D1DR was found in the dorsal striatal subregions of AGS-prone rats. Similar changes were seen for D2DR in the central and dorsal striatal territories. Subregions of the nucleus accumbens demonstrated consistent subregional decreases in the binding densities of D1DR and D2DR in epileptic animals, irrespective of epilepsy types. This was seen for D1DR in the dorsal core, dorsal, and ventrolateral shell; and for D2DR in the dorsal, dorsolateral, and ventrolateral shell. An increased density of D2DR was found in the motor cortex of AGS-prone rats. An AGS-related increase in binding densities to D1DR and D2DR in the dorsal striatum and motor cortex, areas responsible for motor activity, possibly reflects the activation of brain anticonvulsive loops. General epilepsy-related decreases in binding densities to D1DR and D2DR in the accumbal subregions might contribute to behavioral comorbidities of epilepsy.

An online platform and a dynamic database for neuropsychological assessment in Indonesia.

Proper use of neuropsychological tests in Indonesia is hindered by a lack of properly adapted neurocognitive tests as well as an absence of normative data. In 2016, we started adapting ten of these tests for use in Indonesia and collected data from healthy participants in Java. Here we introduce and propose a system that will facilitate the proper usage and interpretation of test scores: an online platform and a dynamic database. Newly collected data (492 healthy adults) of the Indonesian version of the Boston Naming Test (I-BNT) were used to illustrate the usefulness of the two functions. Analysis of variances, post-hoc tests, and a simulation study revealed the effects of age and education on the I-BNT, indicating that it is imperative to fine-tune the reference group based on these demographic factors. Putative inadequate sample size issues for obtaining reliable normative scores were overcome by employing regression analyses and the prediction of normative scores. It can be concluded that a flexible online platform is available for the calculation of normative scores either based on the whole population, on fine-tuned reference groups, or on predicted scores. The dynamic database's growth will allow to obtain even more fine-tuned and more reliable reference data as well as more accurate predictions. Fine-tuned reference data are badly needed for the heterogenous Indonesian population.

The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities.

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.

Feasibility and potential of a bedside mini-EEG for diagnosing delirium superimposed on dementia.

OBJECTIVE: Delirium superimposed on dementia (DSD) is difficult to diagnose because symptoms of delirium might be interpreted as symptoms of dementia. To improve diagnostic accuracy, we investigated the potential of a brief point-of-care EEG measurement. METHODS: Thirty older patients were included, all with Major Neurocognitive Disorder (i.e. dementia) according to DSM-5 criteria. EEG was registered at right prefrontal and right temporal site, with eyes either open or closed for three minutes, simultaneously with the Discomfort Scale for Dementia of Alzheimer Type. The Confusion Assessment Method for the Intensive Care Unit was administered to determine the presence of symptoms of a delirium at the time of EEG administration. Video registrations were reviewed independently by two delirium experts. RESULTS: Higher activities of delta and theta1, and lower activities of theta2, alpha, and beta activity, were found in DSD when compared to dementia only. The ratio of delta and theta power during eyes-open conditions had the highest accuracy (AUC = 0.80 [0.63-0.94]; p <.001) to distinguish DSD from dementia alone. All subjects were on benzodiazepines and half on clozapine, thus the effects of psychotropics on EEG cannot be fully excluded. CONCLUSIONS: A brief point-of-care EEG at two sites of the head has the potential to aid in the detection of DSD. SIGNIFICANCE: The diagnostic accuracy of EEG in recognizing or excluding delirium in patients who already have dementia is of large potential given the lack of proper diagnostic tools.

The role of thalamic nuclei in genetic generalized epilepsies.

There is no doubt on the participation of the thalamus in the various types of genetic generalized epilepsies as evidenced by multiple non-invasive imaging studies in humans as well as invasive studies in animal models of GGE. Based on human and mostly animal data gathered in early 2000 a so called 'three compartment model' on seizure generation was proposed conceptualizing the existence of a hyperexcitable cortical seizure onset zone providing excitation to relay cells of the relay thalamus and the inhibitory reticular thalamic nucleus (RTn). The interplay of corticothalamic excitation and feedforward inhibition via RTn is supposed to entrain thalamic relay neurons into synchronous, oscillatory activity for SWD sustainment. With the emergence of more fine-tuned experimental techniques and analyses, however, it becomes apparent that this model is too simplistic as the thalamus cannot be regarded as unity. Rather, different thalamic nuclei, being integrated in different thalamocortical and other subcortical subloops, need to be differentiated, which take over different functions for seizure generation, generalization and maintenance. Moreover, these networks are not necessarily the same for different classes of patients with GGE and can even be antagonistic between seizure types. This review will summarize data concerning different nuclei and their participation in GGE in order to extend this model and create a more detailed concept on seizure generation, generalization and maintenance.

Thalamo-Cortical and Thalamo-Thalamic Coupling During Sleep and Wakefulness in Rats.

Introduction: The thalamus, a heterogeneous brain structure, is involved in the generation of sleep-related thalamo-cortical oscillations. Higher order nuclei might possess a distinct function compared with first-order nuclei in brain communication. Here it is investigated whether this distinction can also be found during the process of falling asleep and deepening of slow-wave sleep. Methods: A nonlinear version of Granger causality was used to describe changes in directed network activity between the somatosensory cortex and rostral reticular thalamic nucleus (rRTN) and caudal reticular thalamic nucleus (cRTN), the higher order posterior (PO)- and anterior-thalamic nuclei (ATN), and the first-order ventral posteromedial thalamic nucleus (VPM) as assessed in local field potential recordings acquired during passive wakefulness (PW), light slow-wave sleep (LSWS), and deep slow-wave sleep (DSWS) in freely behaving rats. Surrogate statistics was used to assess significance. Results: Decreases in cortico-thalamo-cortical couplings were found. In contrast, multiple increases in intrathalamic couplings were observed. In particular, the rRTN increased its inhibition on the ATN from PW to LSWS, and this was further strengthened from LSWS to DSWS. The cRTN increased its coupling to VPM and PO from PW to LSWS, but the coupling from cRTN to VPM weakened at the transition from LSWS to DSWS, while its coupling to PO strengthened. Furthermore, intra-RTN coupling from PW to LSWS was differently changed compared with the change from LSWS to DSWS. Discussion: It can be inferred that higher order (ATN and PO) and first-order nuclei (VPM) are differentially inhibited during DSWS, which might be relevant for a proper functioning of sleep-related processes. Impact statement The functionally heterogeneous thalamus is affected by the different sleep/wake states. Changes in directed functional coupling between the thalamus and cortex and between functional different thalamic nuclei during the process of falling asleep and deepening to slow-wave sleep were investigated. It was revealed that the rostral and caudal subparts of the reticular thalamic nucleus, constituting the major source of intrathalamic inhibition, decouple from each other and show different coupling profiles with other thalamic nuclei. Specifically, higher order nuclei were found to be more inhibited than first-order nuclei during deep slow-wave sleep. These differences might be relevant for a proper coordination of sleep-related processes such as housekeeping, forgetting of irrelevant information, and consolidation of episodic memory.

Seizure Prediction in Genetic Rat Models of Absence Epilepsy: Improved Performance through Multiple-Site Cortico-Thalamic Recordings Combined with Machine Learning.

Seizure prediction is the grand challenge of epileptology. However, effort was devoted to prediction of focal seizures, while generalized seizures were regarded as stochastic events. Long-lasting local field potential (LFP) recordings containing several hundred generalized spike and wave discharges (SWDs), acquired at eight locations in the cortico-thalamic system of absence epileptic rats, were iteratively analyzed in all possible combinations of either two or three recording sites, by a wavelet-based algorithm, calculating the product of the wavelet-energy signaling increases in synchronicity. Sensitivity and false alarm rate of prediction were compared between various combinations, and wavelet spectra of true and false positive predictions were fed to a random forest machine learning algorithm to further differentiate between them. Wavelet analysis of intracortical and cortico-thalamic LFP traces showed a significantly smaller number of false alarms compared with intrathalamic combinations, while predictions based on recordings in Layers IV, V, and VI of the somatosensory-cortex significantly outreached all other combinations in terms of prediction sensitivity. In 24-h out-of-sample recordings of nine Genetic Absence Epilepsy Rats from Strasbourg (GAERS), containing diurnal fluctuations of SWD occurrence, classification of true and false positives by the trained random forest further reduced the false alarm rate by 71%, although at some trade-off between false alarms and sensitivity of prediction, as reflected in relatively low F1 score values. Results provide support for the cortical-focus theory of absence epilepsy and allow the conclusion that SWDs are predictable to some degree. The latter paves the way for the development of closed-loop SWD prediction-prevention systems. Suggestions for a possible translation to human data are outlined.

Group I metabotropic glutamate receptor-mediated long term depression is disrupted in the hippocampus of WAG/Rij rats modelling absence epilepsy.

Absence epilepsy is frequently associated with cognitive dysfunction, although the underlying mechanisms are not well understood. Here we report that some forms of hippocampal synaptic plasticity are abnormal in symptomatic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Metabotropic Glu 1/5 receptor-mediated long term depression (LTD) at Schaffer collateral CA1 synapses is significantly reduced in symptomatic, 5-6 months old WAG/Rij rats compared to age-matched non epileptic control rats. There were no significant changes in mGlu1/5-dependent LTD in pre-symptomatic, 4-6 weeks old WAG/Rij rats compared to age matched controls. The changes in LTD found in symptomatic WAG/Rij forms are not indicative of general deficits in all forms of synaptic plasticity as long term potentiation (LTP) was unchanged. Immunoblot analysis of hippocampal tissue showed a significant reduction in mGlu5 receptor expression, a trend to an increase in pan Homer protein levels and a decrease in GluA1 receptor expression in the hippocampus of symptomatic WAG/Rij rats vs non-epileptic control rats. There were no changes in mGlu1α receptor or GluA2 protein levels. These findings suggest that abnormalities in hippocampal mGlu5 receptor-dependent synaptic plasticity are associated with the pathological phenotype of WAG/Rij rats. This lays the groundwork for the study of mGlu5 receptors as a candidate drug target for the treatment of cognitive dysfunction linked to absence epilepsy.

Pharmacological activation of mGlu5 receptors with the positive allosteric modulator VU0360172, modulates thalamic GABAergic transmission.

Previous studies have shown that injection of the mGlu5 receptor positive allosteric modulator (PAM) VU0360172 into either the thalamus or somatosensory cortex markedly reduces the frequency of spike-and-wave discharges (SWDs) in the WAG/Rij model of absence epilepsy. Here we have investigated the effects of VU0360172 on GABA transport in the thalamus and somatosensory cortex, as possible modes of action underlying the suppression of SWDs. Systemic VU0360172 injections increase GABA uptake in thalamic synaptosomes from epileptic WAG/Rij rats. Consistent with this observation, VU0360172 could also enhance thalamic GAT-1 protein expression, depending on the dosing regimen. This increase in GAT-1 expression was also observed in the thalamus from non-epileptic rats (presymptomatic WAG/Rij and Wistar) and appeared to occur selectively in neurons. The tonic GABAA receptor current present in ventrobasal thalamocortical neurons was significantly reduced by VU0360172 consistent with changes in GAT-1 and GABA uptake. The in vivo effects of VU0360172 (reduction in tonic GABA current and increase in GAT-1 expression) could be reproduced in vitro by treating thalamic slices with VU0360172 for at least 1 h and appeared to be dependent on the activation of PLC. Thus, the effects of VU0360172 do not require an intact thalamocortical circuit. In the somatosensory cortex, VU0360172 reduced GABA uptake but did not cause significant changes in GAT-1 protein levels. These findings reveal a novel mechanism of regulation mediated by mGlu5 receptors, which could underlie the powerful anti-absence effect of mGlu5 receptor enhancers in animal models.

Immediate versus late effects of vigabatrin on spike and wave discharges.

Vigabatrin increases GABA concentrations by inhibiting GABA transaminase. In previous studies, it was shown that vigabatrin increases the incidence of Spike and Wave Discharges (SWD) in the WAG/Rij rat model for absence epilepsy. Since following a single dose of vigabatrin GABA concentrations are known to be increased for several days, the present study sheds light on how the previously described changes in SWD characteristics develop over a longer time frame. To achieve this, we injected adult WAG/Rij rats with 500 mg/kg and recorded their EEG for 48 h. SWD were quantified, and their peak frequencies were calculated. Our results showed three rapid onset effects: a sharp increase in SWD incidence, from 12.5 /hour to 133/hour), this increase lasted only 4.4 h, an increase in mean SWD duration, from 4.6 s to 8.1 s and a drop in peak frequency, from 8 to 6 Hz. Since it takes several hours before GABA concentrations are sufficiently increased, we propose that these immediate effects are caused by direct stimulation of both GABAA and GABAB receptors by the molecule vigabatrin. Next, the mean SWD duration decreased below baseline values after 4.4 h. Hazard rate analysis showed that this is caused by an increased probability of short SWD. We argue that these changes are caused by increased activation of both GABAA and GABAB receptors in the frontal cortex and the thalamus, and more specifically, in the Reticular Thalamic Nucleus (RTN). After approximately 34 h, the probability of short SWD returned to normal. This suggests the occurrence of downregulation of GABA receptors. The decrease in peak frequency was still present 48 h after injection. It has been argued that the balance between GABAA and GABAB receptor-mediated activity in the RTN is crucial for controlling this SWD characteristic. It can be concluded that a single dose of vigabatrin results in remarkable and opposite effects over time: an initial, proabsence effect is followed by an antiabsence effect.

Establishing Drug Effects on Electrocorticographic Activity in a Genetic Absence Epilepsy Model: Advances and Pitfalls.

The genetic rat models such as rats of the WAG/Rij strain and GAERS were developed as models for generalized genetic epilepsy and in particular for childhood absence epilepsy. These animal models were described in the eighties of the previous century and both models have, among others, face, construct and predictive validity. Both models were and are currently used as models to predict the action of antiepileptic medication and other experimental treatments, to elucidate neurobiological mechanisms of spike-wave discharges and epileptogenesis. Although the electroencephalagram (EEG)/electrocorticogram (ECoG) is imperative for establishing absence seizures and to quantify the for absence epilepsy typical spike-wave discharges, monitoring the animals behavior is equally necessary. Here an overview is given regarding the design of drug evaluation studies, which animals to use, classical and new EEG variables, the monitoring and quantification of the behavior of the rats, some pitfalls regarding the interpretation of the data, and some developments in EEG technology.

Circadian Rhythms and Epilepsy: A Suitable Case for Absence Epilepsy.

Many physiological processes such as sleep, hormonal secretion, or thermoregulation, are expressed as daily rhythms orchestrated by the circadian timing system. A powerful internal clock mechanism ensures proper synchronization of vital functions within an organism on the one hand, and between the organism and the external environment on the other. Some of the pathological processes developing in the brain and body are subjected to circadian modulation as well. Epilepsy is one of the conditions which symptoms often worsen at a very specific time of a day. Variation in peak occurrence depends on the syndrome and localization of the epileptic focus. Moreover, the timing of some types of seizures is closely related to the sleep-wake cycle, one of the most prominent circadian rhythms. This review focuses on childhood absence epilepsy (CAE), a genetic generalized epilepsy syndrome, in which both, the circadian and sleep influences play a significant role in manifestation of symptoms. Human and animal studies report rhythmical occurrence of spike-wave discharges (SWDs), an EEG hallmark of CAE. The endogenous nature of the SWDs rhythm has been confirmed experimentally in a genetic animal model of the disease, rats of the WAG/Rij strain. Well-known detrimental effects of circadian misalignment were demonstrated to impact the severity of ongoing epileptic activity. SWDs are vigilance-dependent in both humans and animal models, occurring most frequently during passive behavioral states and light slow-wave sleep. The relationship with the sleep-wake cycle seems to be bidirectional, while sleep shapes the rhythm of seizures, epileptic phenotype changes sleep architecture. Circadian factors and the sleep-wake states dependency have a potential as add-ons in seizures' forecasting. Stability of the rhythm of recurrent seizures in individual patients has been already used as a variable which refines existing algorithms for seizures' prediction. On the other hand, apart from successful pharmacological approach, circadian hygiene including sufficient sleep and avoidance of internal desynchronization or sleep loss, may be beneficial for patients with epilepsy in everyday management of seizures.

Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2.

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 CB1 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 CB1 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.

Neonatal exposure to AY-9944 increases typical spike and wave discharges in WAG/Rij and Wistar rats.

Absence-epileptic seizures appear in the EEG as Spike and Wave Discharges (SWDs). Typical SWDs develop spontaneously in WAG/Rij rats, an inbred Wistar strain. Atypical SWDs however were reported in studies in which the cholesterol synthesis inhibitor AY-9944 was administered to neonatal Wistar rats, causing absence-like seizures later in life. Atypical SWDs seemed to differ from typical SWDs in 3 aspects: lower peak frequency, longer duration, and involvement of the hippocampus. The aim of the present study was to investigate the effect of AY-9944 on typical SWDs. Male Wistar and WAG/Rij rats were injected with 7.5 mg/kg AY-9944 or saline postnatally. After 6 months, EEGs were recorded from the cortex and the hippocampus. Incidence, duration and peak frequency of the SWDs were determined. The SWD stopping probability was estimated by hazard rate analysis. Hippocampal involvement was assessed by cross correlation analysis of the hippocampus and cortex channels. The Wistar rats unexpectedly showed a high incidence of spontaneous SWDs. The AY-treatment increased the total SWD duration in both Wistar and WAG/Rij rats: the incidence was 1.6 times higher and the mean SWD duration was 1.4 times longer than in the saline-treated rats. The peak frequency of the SWDs did not change. The hazard rates were lower in the AY-treated rats, so some very long SWDs were observed. Cross correlations of spiky activity in the hippocampus pointed to volume conduction rather than to genuine SWD activity in this area. In summary, we found no indication that SWDs in AY-treated animals differ from typical SWDs. However, since saline-treated rats had many spontaneous SWDs, other rat strains might respond differently. With respect to the mechanism, the appearance of long SWDs suggests that the SWD stopping mechanism is affected by the treatment. We speculate that this effect is due to changes in the distribution of GABA-ergic and glutamatergic receptors in lipid rafts.

A network approach to investigate the bi-hemispheric synchrony in absence epilepsy.

OBJECTIVE: Our objective was to unravel the dynamics underlying spike-and-wave discharges (SWDs) characteristic for childhood absence epilepsy. METHODS: SWDs were recorded for a cohort of 28 children using magnetoencephalography. Non-linear association analyses and a graph theoretical metric of local connectedness (LoC) were utilized in a sliding window starting one s before till four s after ictal onset. RESULTS: A focal pattern of bilateral frontal and parietal areas with high LoC during the spikes alternated by generalized patterns during the waves was found for all children studied during generalization of the SWDs. In the interval preceding the generalization a focal parietal region was most often (16/28) encountered and less often an occipital (4/28), temporal (5/28) or frontal (3/28) region. 55% of the children with a parietal/occipital focal onset became seizure free after the administration of two anti-epileptic drugs, and only 12.5% with a temporal/frontal focal onset. CONCLUSIONS: The transition from the interictal to the ictal state is for some of the children characterized by dominant LoC at either the parietal/occipital and for others at the frontal/temporal region. SIGNIFICANCE: The focal onset of the SWDs varies in location among the children with a clinical similar profile, who, however, seemingly are differing with regard to seizure control.