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Contains fulltext : 202738.pdf (Publisher’s version ) (Open Access) Sensory information processing and higher cognitive functions rely on the interactions between thalamus and cortex. Many types of neurological and psychiatric disorders are accompanied or driven by alterations in the brain connectivity. In the present study putative changes in functional and effective cortico-cortical (CC), thalamo-cortical (TC) and cortico-thalamic (CT) connectivity during wakefulness and slow-wave sleep in a model of thalamo-cortical dysrhythmia (TCD), TRIP8b-/- mice and in control (WT) mice are described. Coherence and nonlinear Granger Causality (GC) were calculated for twenty 10 s length epochs of slow-wave sleep and active-wakefulness of each animal. Coherence was reduced between 4 and ca 20 Hz in the cortex and between cortex and thalamus during slow-wave sleep compared to active-wakefulness in WT, but not in TRIP8b-/- mice. Moreover, TRIP8b-/- mice showed lower CT coherence during active-wakefulness compared to WT mice; these differences were no longer present during slow-wave sleep. Unconditional GC analysis also showed sleep related reductions in TC and CT couplings in WT mice, while TRIP8b-/- mice showed diminished wake and enhanced sleep CC coupling and rather strong CT directed coupling during wake and sleep, albeit smaller during sleep. Conditional GC coupling analysis confirmed the diminished CC and enhanced CT coupling in TRIP8b-/- mice. Our findings indicate that altered properties of HCN channels, characterizing TRIP8b-/- mice, have clear effects on CC, TC and CT networks. A more complete understanding of the function of the altered communication within these networks awaits detailed phenotyping of TRIP8b-/- mice aimed at specifics of sensory and attentional processes. 12 p.

Contains fulltext : 214178.pdf (Publisher’s version ) (Open Access) 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 (6mg/kg) or vehicle (olive oil). Injections (s.c.) took place 3 times per week during 2weeks. Electroencephalogram (EEG) recordings, each lasting 24h, were made 3 times: immediately before the first injection (baseline), immediately after the first injection (acute treatment), and after 2weeks 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. 10 p.

Contains fulltext : 219351.pdf (Publisher’s version ) (Open Access) 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 hours. 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 hours, 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 hours. 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 hours, 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 hours 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. 10 p.

Contains fulltext : 218080.pdf (Publisher’s version ) (Open Access) 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. 12 p.

Seizure prediction is the grand challenge of epileptology. Yet, effort was devoted to prediction of focal seizures, while generalized seizures were regarded as stochastic events. Long lasting 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 intrathalamic combinations, while predictions based on recordings in layer 4, 5 and 6 of the somatosensory-cortex significantly outreached all other combinations in terms of prediction sensitivity. In 24-hours out-of-sample recordings of 9 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 tradeoff 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.Significance statementSeizure prediction was declared the grand challenge of epileptology. While most effort was devoted to the prediction of focal seizures, generalized seizures were regarded as stochastic events. Results of this study demonstrate that above chance prediction of generalized spike and wave discharges (SWDs) is possible in long lasting, pseudoprospective 24 hours recordings of absence epileptic rats, by means of wavelet analysis of LFP traces acquired near the proposed cortical initiation network in S1 and further classification of true and false positive detections by a trained random forest machine learning algorithm. Moreover, as lower SWD prediction performance was achieved by analysis of LFP traces distant to S1, the study provides evidence supporting the cortical focus theory of absence epilepsy.

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I h, in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I h current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b−/−). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K+ current, I A, in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5–4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings. Electronic supplementary material The online version of this article (10.1007/s00429-017-1559-z) contains supplementary material, which is available to authorized users.

Contains fulltext : 178408.pdf (Publisher’s version ) (Open Access) Sleep spindles are phasic bursts of thalamo-cortical activity, visible in the cortex as transient oscillations in the sigma range (usually defined in humans as 12-14 or 9-16 Hz). They have been associated with sleep-dependent memory consolidation and sleep stability in humans and rodents. Occurrence, frequency, amplitude and duration of sleep spindles co-vary with age, sex and psychiatric conditions. Spindle analogue activity in dogs has been qualitatively described, but never quantified and related to function. In the present study we used an adjusted version of a detection method previously validated in children to test whether detections in the dogs show equivalent functional correlates as described in the human literature. We found that the density of EEG transients in the 9-16 Hz range during non-REM sleep relates to memory and is characterized by sexual dimorphism similarly as in humans. The number of transients/minute was larger in the learning condition and for female dogs, and correlated with the increase of performance during recall. It can be concluded that in dogs, automatic detections in the 9-16 Hz range, in particular the slow variant (

Contains fulltext : 219607.pdf (Publisher’s version ) (Closed access) 2 p.

Item does not contain fulltext 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. 9 p.

Contains fulltext : 203447.pdf (Publisher’s version ) (Open Access) Rapid changes in the light-dark cycle cause circadian desynchronization between rhythms of spike-wave discharges (SWDs) and motor activity in genetic epileptic rats, and this is accompanied by an increase in epileptic activity. Given the close relationship between absence seizures and sleep-wake states, the present study assessed firstly a putative relationship between vigilance rhythms and SWDs during re-synchronization, and secondly sleep-wake patterns responsible for increased epileptic activity. Lastly, in a view of existing evidence that melatonin and its agonists accelerate re-synchronization, the effects of agomelatine upon the speed of re-synchronization of different sleep-wake states and SWDs were investigated. Simultaneous electroencephalographic and electromyographic recordings were made in symptomatic WAG/Rij rats, before, during and 10 days following an 8 h light phase delay. Agomelatine was orally administered acutely and sub-chronically, during 10 post-shift days. The magnitude of the advance after the shift and the speed of re-synchronization were specific for various rhythms. Most prominent change was the increase in REM sleep duration during the dark phase. A post-shift increase in passive wakefulness and a reduction in deep slow-wave sleep coincided with an aggravation of SWDs during the light phase. Agomelatine showed neither an effect on sleep-wake parameters and SWDs, nor affected re-synchronization. The same speed of re-synchronization of SWDs and light slow-wave sleep suggests that both are controlled by a common circadian mechanism. The redistribution of SWDs and their increase in the light phase after the shift may be of importance for patients with absence epilepsy planning long trans-meridian flight across time zones. 12 p.

Ethosuximide (ETX) has become the drug of choice in the treatment of patients with absence seizures taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects treated with ETX failed in therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, acutely and chronically administered decreased seizures dose dependently in rats of the WAG/Rij strain, a genetic absence model. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172 as an anti-absence drug, and cognition is affected during and after chronic ETX treatment. Method: Male WAG/Rij rats were chronically treated with ETX for 4 months. EEG’s were recorded during and after treatment as well as challenged with VU0360172. Rats were also periodically exposed to a cue discrimination learning task in a Y-maze. mGlu5 receptors were quantified with Western Blot. Results: Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action. However, chronic ETX treated rats showed a decrease in absences both during and after the end treatment, without clear time and dose related effects. The decrease of sensitivity for VU0360172 was not accompanied by a change in mGluR5 expression in cortex and thalamus. Chronic ETX enhanced motivation to collect sucrose pallets and this was followed by an increase in cued discrimination learning. It is concluded that VU0360172 keeps its antiabsence effects after chronic treatment. Moreover, its differential effects in the two groups cannot be explained by a simple receptor down regulation suggesting a more downstream interaction between ETX and mGluR5. The cognitive enhancing effects of ETX, as found at the end of the experiment might be mediated to the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.

Contains fulltext : 200825.pdf (Publisher’s version ) (Open Access) Objective: The putative neuroprotective and disease-modifying effects of lamotrigine (LTG) and ethosuximide (ESM) were investigated in the lithium-pilocarpine (Li-Pc) model of temporal-lobe epilepsy (TLE) in rats. Then, spontaneous recurrent seizures (SRS), neuronal loss and astrogliosis were assessed. Methods: Status Epilepticus (SE) was induced by Li-Pc in five experimental groups: 24 h after SE, all rats received twice daily either a low (10 mg/kg) or high (20 mg/kg) dose of LTG, or a low (25 mg/kg) or high (50 mg/kg) dose of ESM, or solvent. The sixth group (control) did not receive Li-Pc and was given twice daily injections with solvent only. Drug administration lasted for 7 d. Rats were systematically observed in the 5th and 6th weeks, after that the brains were prepared for histology. Results: LTG dose-dependently decreased the frequency of SRS, and restricted neuronal loss, as well as astrogliosis in the hippocampus compared with the untreated SE control group. However, ESM had none of the above-mentioned effects. Conclusion: LTG had protective as well as disease-modifying effects in this TLE model. It was revealed that the disease-modifying effects were accompanied by the prevention of neuronal loss and astrogliosis. ESM was devoid of antiepileptogenic and its accompanying histological effects in this TLE model, in contrast to the antiepileptogenic effects found in the genetic absence epilepsy models, suggesting that different mechanisms are involved in the different models for epileptogenesis and antiepileptogenesis. 6 p.

Contains fulltext : 180954.pdf (Publisher’s version ) (Open Access) Purpose: The organization of neural networks and the mechanisms, which generate the highly stereotypical for absence epilepsy spike-wave discharges (SWDs) is heavily debated. Here we describe such a model which can both reproduce the characteristics of SWDs and dynamics of coupling between brain regions, relying mainly on properties of hierarchically organized networks of a large number of neuronal oscillators. Model: We used a two level mesoscale model. The first level consists of three structures: the nervus trigeminus serving as an input, the thalamus and the somatosensory cortex; the second level of a group of nearby situated neurons belonging to one of three modeled structures. Results: The model reproduces the main features of the transition from normal to epileptiformic activity and its spontaneous abortion: an increase in the oscillation amplitude, the emergence of the main frequency and its higher harmonics, and the ability to generate trains of seizures. The model was stable with respect to variations in the structure of couplings and to scaling. The analyzes of the interactions between model structures from their time series using Granger causality method showed that the model reproduced the preictal coupling increase detected previously from experimental data. Conclusion: SWDs can be generated by changes in network organization. It is proposed that a specific pathological architecture of couplings in the brain is necessary to allow the transition from normal to epileptiformic activity, next to by others modeled and reported factors referring to complex, intrinsic, and synaptic mechanisms. 12 p.

Contains fulltext : 190341.pdf (Publisher’s version ) (Open Access) A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. 3 p.

Contains fulltext : 182124.pdf (Author’s version preprint ) (Open Access) 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 perse 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 non-invasive 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 anti-absence 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 spike-and-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.

Contains fulltext : 166569.pdf (Publisher’s version ) (Open Access) Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce EEG-confirmed convulsive seizures. In a regulatory repeat-dose toxicity study violent episodes of "muscle spasms" were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. The aim of the present follow-up study was to investigate whether these violent movements were of an epileptic origin. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 hours. 25% of SLV326 treated animals showed 1 to 21 EEG-confirmed generalized convulsive seizures, whereas controls were seizure-free. The behavioral seizures were typical for a limbic origin. Moreover, interictal spikes were found in 38% of treated animals. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. It is concluded that long term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats. Additionally, SLV326 alters the frequency spectrum of the EEG when rats are highly active, suggesting effects on complex behavior and cognition. 16 p.

Contains fulltext : 175581.pdf (Publisher’s version ) (Open Access) We introduce a practical and computationally not demanding technique for inferring interactions at various microscopic levels between the units of a network from the measurements and the processing of macroscopic signals. Starting from a network model of Kuramoto phase oscillators which evolve adaptively according to homophilic and homeostatic adaptive principles, we give evidence that the increase of synchronization within groups of nodes (and the corresponding formation of synchronous clusters) causes also the defragmentation of the wavelet energy spectrum of the macroscopic signal. Our methodology is then applied for getting a glance to the microscopic interactions occurring in a neurophysiological system, namely, in the thalamo-cortical neural network of an epileptic brain of a rat, where the group electrical activity is registered by means of multichannel EEG. We demonstrate that it is possible to infer the degree of interaction between the interconnected regions of the brain during different types of brain activities, and to estimate the regions' participation in the generation of the different levels of consciousness. 9 p.

Contains fulltext : 173167.pdf (Publisher’s version ) (Open Access) The ultimate goal of epileptology is the complete abolishment of epileptic seizures. This might be achieved by a system that predicts seizure onset combined with a system that interferes with the process that leads to the onset of a seizure. Seizure prediction remains, as of yet, unresolved in absence-epilepsy, due to the sudden onset of seizures. We have developed a real-time absence seizure prediction algorithm, evaluated it and implemented it in an on-line, closed-loop brain stimulation system designed to prevent the spike-wave-discharges (SWDs), typical for absence epilepsy, in a genetic rat model. The algorithm corretly predicted 88% of the SWDs while the remaining were quickly detected. A high number of false-positive detections occurred mainly during light slow-wave-sleep. Inclusion of criteria to prevent false-positives greatly reduced the false alarm rate but decreased the sensitivity of the algoritm. Implementation of the latter version into a closed-loop brain-stimulation-system resulted in a 72% decrease in seizure activity. In contrast to long standing beliefs that SWDs are unpredictable, these results demonstrate that they can be predicted and that the development of closed-loop seizure prediction and prevention systems is a feasable step towards interventions to attain control and freedom from epileptic seizures. 8 p.

N-palmitoylethanolamine (PEA), an endogenous fatty acid ethanolamide, plays a key role in the regulation of the inflammatory response and pain through, among others, activation of nuclear peroxisome proliferator-activated receptors (PPAR-α). Endogenous cannabinoids play a protective role in several central nervous system (CNS) disorders, particularly those associated with neuronal hyperexcitability. We investigated the effects of PEA and the role of PPAR-α in absence epilepsy using the WAG/Rij rat model. PEA, anandamide (AEA), a PPAR-α antagonist (GW6471) and a synthetic CB1 receptor antagonist/inverse agonist (SR141716) were administered to WAG/Rij rats in order to evaluate the effects on epileptic spike-wave discharges (SWDs) on EEG recordings. We studied also the effects of PEA co-administration with SR141716 and GW6471 and compared these effects with those of AEA to evaluate PEA mechanism of action and focusing on CB1 receptors and PPAR-α. Both PEA and AEA administration significantly decreased SWDs parameters (absence seizures). In contrast, GW6471 was devoid of effects while SR141716 had pro-absence effects. The co-administration of SR141716 with PEA or AEA completely blocked the anti-absence effects of these compounds. GW6471 antagonized PEA's effects whereas it did not modify AEA's effects. Furthermore, we have also measured PEA, AEA and 2-AG (2-arachidonoylglycerol) brain levels identifying significant differences between epileptic and control rats such as decreased PEA levels in both thalamus and cortex that might contribute to absence epilepsy. Our data demonstrate that PEA has anti-absence properties in the WAG/Rij rat model and that such properties depend on PPAR-α and indirect activation of CB1 receptors. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.

Contains fulltext : 63867.pdf (Publisher’s version ) (Closed access) Purpose: The WAG/Rij rat is among the most appropriate models for the study of spontaneous childhood absence epilepsy, without complex neurologic disorders that are associated with some mouse models for absence epilepsy. Previous studies have allowed the identification of distinct types of spike-wave discharges (SWDs) characterizing seizures in this strain. The purpose of this study was to investigate the genetic basis of electroencephalographic (EEG) properties of SWDs. Methods: An intercross was derived from WAG/Rij and ACI inbred strains that are known to differ substantially in the number of SWDs. Phenotypic analyses based on 23-h EEG recording in all progenies allowed the quantification of type I and type II SWD phenotypes. A genome-wide scan was performed with 145 microsatellite markers, which were used to test for evidence of genetic linkage to SWD quantitative phenotypes. Results: We were able to map quantitative trait loci independently, controlling type I and type II SWD variables to rat chromosomes 5 and 9. Strongest linkages were obtained for D5Mgh15 and total duration of type II SWD (lod, 3.64) and for D9Rat103 and the average duration of type I SWD (lod, 3.91). These loci were denoted T2swd/wag and T1swd/wag, respectively. Conclusions: The independent genetic control of type I and type II SWDs underlines the complexity of the molecular mechanisms participating in SWDs. The identification of these genetic loci represents an important step in our fundamental knowledge of the architecture of SWDs and may provide new insights for resolving the genetic heterogeneity of absence epilepsy.

Contains fulltext : 157672.pdf (Publisher’s version ) (Closed access) PURPOSE: Although absence epilepsy is considered to be a prototypic type of generalized epilepsy, it is still under debate whether generalized 3 Hz spike-and-wave discharges (SWDs) might have a cortical focal origin. Here it is investigated whether focal interictal epileptiform discharges (IEDs), which typically occur in the electro- (EEG) and magnetoencephalogram (MEG) in case of focal epilepsy, are present in the MEG of children with absence epilepsy. Next, the location of the sources of the IEDs is established, and it is investigated whether the location is concordant to the earlier established focal cortical regions involved in the generalized SWDs of these children. METHODS: Whole head MEG recordings of seven children with absence epilepsy were reviewed with respect to the presence of IEDs (spikes and sharp waves). These IEDs were grouped into distinct clusters, in which each contribution to a cluster yields a comparable magnetic field distribution. Source localization was then performed onto the average signal of each cluster using an equivalent current dipole model and a realistic head model of the cortical surface. RESULTS: IEDs were detected in 6 out of 7 patients. Source reconstruction indicated most often frontal, central or parietal origins of the IED in either the left and or right hemisphere. Spatiotemporal assessment of the IEDs indicated a stable location of the averages of these discharges, indicating a single underlying cortical source. DISCUSSION: The outcome of this pilot study shows that MEG is well suited for the detection of IEDs and suggests that their estimated sources coincide rather well with the cortical regions involved during the spikes of the SWDs. It is discussed whether the presence of IEDs, classically seen as a marker of focal epilepsies, indicate that absence epilepsy should be considered as a focal type of epilepsy, in which changes in the network are evolving rapidly. 10 p.

Item does not contain fulltext The WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial 'insult' responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then non-genetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling. 21 p.

Item does not contain fulltext Objective: In order to unravel the mechanisms underlying the "sudden" onset of spontaneous absences in genetically prone subjects, we investigated the immediate precursors of spike-wave discharges (SWDs) produced in cortico-thalamo-cortical neuronal networks. Methods: A time-frequency analysis of the cortical and thalamic ECoG of WAG/Rij rats was accomplished with a continuous wavelet decomposition of SWDs, 3 s prior to the onset of SWDs (pre-SWD), and in control periods devoid of SWDs. Results: The pre-SWD ECoG consisted of delta and theta components in 80-90% of all SWDs simultaneously in cortex and thalamus, the co-occurrence of delta and theta was rare (7%) during control periods. The occurrence of delta and theta events in pre-SWDs in the cortex preceded that in the thalamus. The frequency of theta component in cortex correlated positively with that in thalamus, this correlation was less strong for delta. Conclusion: Precursors of SWDs comprise of delta and theta, their co-occurrence is typical for non-epileptic periods. Thalamic and cortical theta are strongly related. Rhythmic precursors appear earlier in cortex than in thalamus, and this is in line with the cortical origin of SWD. Significance: Simultaneous presence of delta and theta events in EEG is a condition for the occurrence of SWDs.

Contains fulltext : 99307.pdf (Publisher’s version ) (Open Access) The rhythms of spontaneously occurring seizures (spike-wave discharges, SWD) and motor activity, as well as the relationship between SWD and sleep-wake states were investigated in the WAG/Rij rat model of absence epilepsy. In order to establish whether SWD are controlled by external (Zeitgebers) or by endogenous factors such as circadian influences or the state of vigilance, the study was performed in entrained and constant dim light conditions. EEG and motor activity were recorded in the 12:12 light dark cycle and in constant dim light conditions. Circadian rhythmicity was found both for motor activity and the occurrence of SWD in conditions of entrainment. In constant dim light conditions also circadian rhythms emerged, however, the change in circadian parameters was opposite for the rhythm of SWD and motor activity. SWD were preceded mostly by passive wakefulness and by slow-wave sleep in both experimental conditions. It can be concluded that the rhythm of SWD seems to be generated and controlled by an endogenous mechanism distinct from that which controls the rhythm of motor activity. The relationship between SWD and sleep-wake states preceding their occurrences appeared to be unchanged, suggesting that the mechanism of generation of SWD is independent of the circadian timing system.

Contains fulltext : 90263.pdf (Publisher’s version ) (Closed access) Purpose: The WAG/Rij strain of rats, a well-established model for absence epilepsy, has comorbidity for depression. These rats exhibit depression-like behavioral symptoms such as increased immobility in the forced swimming test and decreased sucrose intake and preference (anhedonia). These depression-like behavioral symptoms are evident in WAG/Rij rats, both at 3-4 and 5-6 months of age, with a tendency to aggravate in parallel with an increase in seizure duration. Here we investigated whether the behavioral symptoms of depression could be prevented by the suppression of absence seizures. Methods: Ethosuximide (ETX; 300 mg/kg/day, in the drinking water) was chronically applied to WAG/Rij rats from postnatal day 21 until 5 months. Behavioral tests were done before the cessation of the treatment. Electroencephalography (EEG) recordings were made before and after cessation of treatment to measure seizure severity at serial time-points. Results: ETX-treated WAG/Rij rats exhibited no symptoms of depression-like behavior in contrast to untreated WAG/Rij rats of the same age. Moreover, treated WAG/Rij rats did not differ from control age-matched Wistar rats. ETX treatment led to almost complete suppression of spike-wave discharges (SWDs) in 5-6 month old WAG/Rij rats. Discontinuation of chronic treatment was accompanied by a gradual emergence of SWDs; however, a persistent reduction in seizure activity was still present 47 days after discontinuation of the chronic treatment. Discussion: The results suggest that seizure activity is necessary for the expression of depression-like behavioral symptoms and confirm that epileptogenesis can be prevented by early and chronic treatment.

Contains fulltext : 77009.pdf (Publisher’s version ) (Closed access) Periods in the electroencephalogram (EEG) that immediately precede the onset of spontaneous spike-wave discharges (SWD) were examined in WAG/Rij rat model of absence epilepsy. Precursors of SWD (preSWD) were classified based on the distribution of EEG power in delta-theta-alpha frequency bands as measured in the frontal cortex. In 95% of preSWD, an elevation of EEG power was detected in delta band (1-4 Hz). 73% of preSWD showed high power in theta frequencies (4.5-8 Hz); these preSWD might correspond to 5-9 Hz oscillations that were found in GAERS before SWD onset [Pinault, D., Vergnes, M., Marescaux, C., 2001. Medium-voltage 5-9 Hz oscillations give rise to spike-and-wave discharges in a genetic model of absence epilepsy: in vivo dual extracellular recording of thalamic relay and reticular neurons. Neuroscience 105, 181-201], however, theta component of preSWD in our WAG/Rij rats was not shaped into a single rhythm. It is concluded that a coalescence of delta and theta in the cortex is favorable for the occurrence of SWD. The onset of SWD was associated with strengthening of intracortical and thalamo-cortical coherence in 9.5-14 Hz and in double beta frequencies. No features of EEG coherence can be considered as unique for any of preSWD subtype. Reticular and ventroposteromedial thalamic nuclei were strongly coupled even before the onset of SWD. All this suggests that SWD derive from an intermixed delta-theto EEG background; seizure onset associates with reinforcement of intracortical and cortico-thalamic associations.

A large, negative wave which reaches its peak amplitude around 150 ms after stimulus onset, can be found in the Auditory Evoked Potential (AEP) recorded from the lateral amygdala in the rat. Previous studies in our laboratory have repeatedly shown that this N150 component increases during various aversive conditioning protocols and that this increase is attributable to both increases in emotional arousal that are inherent to aversive conditioning and to the formation of an association between the conditioned stimulus (CS) and the aversive unconditioned stimulus (US). Currently it is not known whether the N150 is also enhanced in conditioning procedures with positive reinforcement. To address this issue, we used a Pavlovian conditioning protocol in which an auditory CS signaled the delivery of a food US in food-deprived rats. AEPs evoked by the CS were recorded from the lateral amygdala while the animals were subjected to this appetitive conditioning procedure. Heart rate and N150 amplitude did not increase during conditioning relative to pre-conditioning baselines. In contrast, heart rate and N150 amplitude increases were present during an aversive conditioning protocol (tone-shock pairings) that was carried out after the appetitive conditioning. The present results suggest that the enhancement of the amygdalar N150 is specific for learning experiences that are accompanied by autonomic arousal and that this arousal is a prerequisite for the enhancement of the N150.

Differential composition of GABA A receptor (GABA A R) subunits underlies the variability of fast inhibitory synaptic transmission; alteration of specific GABA A R subunits in localized brain regions may contribute to abnormal brain states such as absence epilepsy. We combined immunocytochemistry and high-resolution ImmunoGold electron microscopy to study cellular and subcellular localization of GABA A R α1, α3, and β2/β3 subunits in ventral posterior nucleus (VP) and reticular nucleus (RTN) of control rats and WAG/Rij rats, a genetic model of absence epilepsy. In control rats, α1 subunits were prominent at inhibitory synapses in VP and much less prominent in RTN; in contrast, the α3 subunit was highly evident at inhibitory synapses in RTN. β2/β3 subunits were evenly distributed at inhibitory synapses in both VP and RTN. ImmunoGold particles representing all subunits were concentrated at postsynaptic densities with no extrasynaptic localization. Calculated mean number of particles for α1 subunit per postsynaptic density in nonepileptic VP was 6.1 ± 3.7, for α3 subunit in RTN it was 6.6 ± 3.4, and for β2/β3 subunits in VP and RTN the mean numbers were 3.7 ± 1.3 and 3.5 ± 1.2, respectively. In WAG/Rij rats, there was a specific loss of α3 subunit immunoreactivity at inhibitory synapses in RTN, without reduction in α3 subunit mRNA or significant change in immunostaining for other markers of RTN cell identity such as GABA or parvalbumin. α3 immunostaining in cortex was unchanged. Subtle, localized changes in GABA A R expression acting at highly specific points in the interconnected thalamocortical network lie at the heart of idiopathic generalized epilepsy.

Ovarian hormones play an important role in the regulation of absence seizures in patients as well as in animal models. The present study examined whether chronic progesterone exposure would induce tolerance for the occurrence of absence seizures and whether reduction in gonadal steroids (via ovariectomy) would alter the number of basal and stress induced absence seizures in WAG/Rij rats, a genetic model for absence epilepsy. Methods: In Experiment 1, female WAG/Rij rats equipped with EEG electrodes received progesterone (P) (20 mg/kg) or cyclodextrin (CD, solvent) i.p. injections once a day for 3 days while a third group received CD injections on Days 1 and 2 and P on Day 3. The EEG was recorded on the day preceding the injections and at each day after injections. In Experiment 2, female WAG/Rij rats equipped with EEG electrodes, were ovariectomized (OVX) or sham operated. EEG recordings were made before and at the 4th, 8th, 10th, 20th, and 35th day after surgery. Rats were then exposed to three series of 10 foot-shocks (FS, 1.5 mA, 1 s) over 3 days. The EEG was recorded 1 h before and 2 h after each FS series. Results: Tolerance developed after a single P injection and the effect of P on SWDs was facilitated by two preceding control injections. No differences were found between OVX and sham-operated females in the occurrence of SWDs either in resting conditions or after acute FS exposure. However, OVX females showed a more prominent day-to-day aggravation in SWDs after repeated FS administration. Conclusions: The data suggest an important interaction between hormones of the hypothalamo-pituitary-adrenal and hypothalamo-pituitarygonadal axes in seizure control. On the one hand, stress interferes with and facilitates the acute effects of progesterone on the occurrence of SWDs and, on the other hand, rats with an intact hypothalamo-pituitary-gonadal axis can better regulate the stress response and develop tolerance to the stressor. © 2007 Elsevier Ltd. All rights reserved.

Contains fulltext : 139822.pdf (Publisher’s version ) (Open Access) Network mechanisms relevant for the generation, maintenance and termination of spike-wave discharges (SWD), the neurophysiological hallmark of absence epilepsy, are still enigmatic and widely discussed. Within the last years, however, improvements in signal analytical techniques, applied to both animal and human fMRI, EEG, MEG, and ECoG data, greatly increased our understanding and challenged several, dogmatic concepts of SWD. This review will summarize these recent data, demonstrating that SWD are not primary generalized, are not sudden and unpredictable events. It will disentangle different functional contributions of structures within the cortico-thalamo-cortical system, relevant for the generation, generalization, maintenance, and termination of SWD and will present a new "network based" scenario for these oscillations. Similarities and differences between rodent and human data are presented demonstrating that in both species a local cortical onset zone of SWD exists, although with different locations; that in both some forms of cortical and thalamic precursor activity can be found, and that SWD occur through repetitive cyclic activity between cortex and thalamus. The focal onset zone in human data could differ between patients with varying spatial and temporal dynamics; in rats the latter is still poorly investigated. 17 p.

Contains fulltext : 143482.pdf (Publisher’s version ) (Open Access) Research Question Recent discoveries have challenged the traditional view that the thalamus is the primary source driving spike-and-wave discharges (SWDs). At odds, SWDs in genetic absence models have a cortical focal origin in the deep layers of the perioral region of the somatosensory cortex. The present study examines the effect of unilateral and bilateral surgical resection of the assumed focal cortical region on the occurrence of SWDs in anesthetized WAG/Rij rats, a well described and validated genetic absence model. Methods Male WAG/Rij rats were used: 9 in the resected and 6 in the control group. EEG recordings were made before and after craniectomy, after unilateral and after bilateral removal of the focal region. Results SWDs decreased after unilateral cortical resection, while SWDs were no longer noticed after bilateral resection. This was also the case when the resected areas were restricted to layers I-IV with layers V and VI intact. Conclusions These results suggest that SWDs are completely abolished after bilateral removal of the focal region, most likely by interference with an intracortical columnar circuit. The evidence suggests that absence epilepsy is a network type of epilepsy since interference with only the local cortical network abolishes all seizures. 10 p.

The study examines cortico-cortical and cortico-thalamic network synchronization at the onset of spike-wave discharges (SWD) in a genetic model of absence epilepsy, WAG/Rij rats. Coherence was measured between multiple cortical areas (intracortical), reticular and rely thalamic nuclei (intrathalamic) and between the cortex and the thalamus. SWD-related increase of coherence (5-60 Hz) was found in all investigated pairs. The highest increase of coherence was around the mean frequency of SWD (8-11.5 Hz) and in the harmonic band 16-21.5 Hz with two central maxima around 10 and 20 Hz. The frequency profile of coherence was different in different intracortical networks, therefore latter were divided into local, global and transhemispheric networks. The presumable source of SWD in the somatosensory cortex and its closest surroundings formed a minimal (local) circuit, in which occurrence of SWD was facilitated by a consistent shift of network synchrony from delta to alpha/beta frequencies. Transhemispheric coherence revealed the largest increase with an additional 16 Hz peak, suggesting a crucial involvement of the corpus callosum in the pathophysiology of absence seizures. The increase in interhemispheric coherence was largest between relatively remote somatosensory or frontal areas, supporting the assumption that SWD originate from the lateral fronto-parietal cortical area.

The distinction between generalized and partial epilepsies is probably one, if not the most, pregnant assertions in modern epileptology. Both absence and generalized tonic-clonic seizures, the prototypic seizures found in generalized epilepsies, are classically seen as the result of a rapid, synchronous recruitment of neuronal networks resulting in impairment of consciousness and/or convulsive semiology. The term generalized also refers to electroencephalographic presentation, with bilateral, synchronous activity, such as the classical 3 Hz spike and wave discharges of typical absence epilepsy. However, findings obtained from electrophysiological and functional imaging studies over the last few years, contradict this view, showing a rather focal onset for most of the so-called generalized seizure types. Therefore, we ask here the question whether "generalized epilepsy" does indeed exist.

The distinction between generalized and partial epilepsies is probably one, if not the most, pregnant assertions in modern epileptology. Both absence and generalized tonic-clonic seizures, the prototypic seizures found in generalized epilepsies, are classically seen as the result of a rapid, synchronous recruitment of neuronal networks resulting in impairment of consciousness and/or convulsive semiology. The term generalized also refers to electroencephalographic presentation, with bilateral, synchronous activity, such as the classical 3 Hz spike and wave discharges of typical absence epilepsy. However, findings obtained from electrophysiological and functional imaging studies over the last few years, contradict this view, showing a rather focal onset for most of the so-called generalized seizure types. Therefore, we ask here the question whether “generalized epilepsy” does indeed exist.

Item does not contain fulltext Effects of i.p. administration of the neurosteroids, allopregnanolone and pregnenolone sulfate, were studied in WAG/Rij rats, a genetic model for generalized absence epilepsy. EEG recordings showed that allopregnanolone a positive modulator of the GABAa receptor, in doses ranging from 5 to 20 mg/kg, increased dose-dependently the number and total duration of spike-wave discharges. pregnenolone sulfate, a positive modulator of NMDA receptors, also increased those parameters, though only at the highest dose used (100 mg/kg). Significant changes in spike-wave discharges occurred during the first hour post-injection and were not accompanied with behavioral alterations. The obtained data indicate that both these neurosteroids aggravate the spike-wave activity. This finding contrasts with the anti-convulsant effects of some neurosteroids and they point to a different pharmacological profile of epilepsy with convulsive or non-convulsive seizure.

Item does not contain fulltext Purpose The site specific effects of two different types of electrical stimulation of the thalamus on electroencephalic epileptic activity as generated in the cortico-thalamo-cortical system were investigated in genetic epileptic WAG/Rij rats, a well characterized and validated absence model. Methods First, 12 male rats received low frequency (double-pulse pairs of 2.5 Hz, 150 μA intensity and 30 s inter-pair-interval) open-loop stimulation to either the Ventral-Postero-Medial (VPM) or the Anterior Thalamic Nucleus (ATN) for 8 h. Second, rats received high frequency (130 Hz, pulse train of 1 s) closed-loop stimulation applied to either VPM or ATN whenever a spike-wave discharge (SWD) was automatically detected. Results Low frequency stimulation induced 8 Hz SWD-like afterdischarges (AD). AD were frequently seen in VPM but rarely in ATN stimulated rats. AD, recorded in cortex and thalamus, showed a strong temporal coherence (visually assessed) and opposite spike polarities. Properties of AD and spontaneous SWD were equally affected by the stimulation. Closed-loop high frequency stimulation disrupted spontaneous SWD with no difference between ATN and VPM stimulated rats. 89% of SWD could be disrupted leading to a decrease in average SWD duration from 9 to 1.5 s. Conclusion Low frequency stimulation induced AD, which strongly mimic SWD. Moreover, the effects were site-specific. High frequency thalamic stimulation disrupts ongoing SWD probable by interfering with the slow firing pattern of cortico-thalamo-cortical neurons seen during SWD cycle. The absence of stimulation site specificity for high frequency stimulation might be due to the fact that stimulation only started on average 1 s after SWD onset when SWD are already fully expressed in the bidirectional cortico-thalamo-cortical resonance system.

Item does not contain fulltext Typical and atypical seizures of absence epilepsy are thought to be generated by a rhythmogenic interplay between the cortex and the thalamus. However, the question remains as to which other subcortical and extrathalamic structures are involved in the pathophysiology of typical and atypical absence epilepsy. Limbic structures are not thought to be involved in typical absence seizures, since in animal models and human patients there is no evidence for the occurrence of spike-and-wave discharges of absence seizures in the limbic regions. However, there are a number of observations from animal models of absence epilepsy that point to a possibly important link between absence seizure mechanisms and limbic structures. Atypical absence seizures are distinct in many ways from typical absence seizures although they bear considerable clinical, EEG, and pharmacological resemblance to typical absence seizures. The differences between typical and atypical seizures of absence epilepsy appear to be circuitry dependent. While both typical and atypical absence seizures involve the cortico-thalamo-cortical circuitry, they each engage different neuronal networks within that circuitry. This review examines the involvement of limbic structures in typical and atypical absence seizures, shows that limbic circuitry forms an integral component of the absence epilepsy network and concludes that further knowledge of this component is important for understanding the complex relationships involved in absence epilepsy.

Item does not contain fulltext The beneficial effects of chronic and early pharmacological treatment with ethosuximide on epileptogenesis were studied in a genetic absence epilepsy model comorbid for depression. It was also investigated whether there is a critical treatment period and treatment length. Cortical excitability in the form of electrical evoked potentials, but also to cortico-thalamo-cortical network activity (spike-wave discharges, SWD and afterdischarges), white matter changes representing extra cortico-thalamic functions and depressive-like behavior were investigated. WAG/Rij rats received either ethosuximide for 2 months (post natal months 2-3 or 4-5), or ethosuximide for 4 months (2-5) in their drinking water, while control rats drank plain water. EEG measurements were made during treatment, and 6 days and 2 months post treatment. Behavioral test were also done 6 days post treatment. DTI was performed ex vivo post treatment. SWD were suppressed during treatment, and 6 days and 2 months post treatment in the 4 month treated group, as well as the duration of AD elicited by cortical electrical stimulation 6 days post treatment Increased fractional anisotropy in corpus callosum and internal capsula on DTI was found, an increased P8 evoked potential amplitude and a decreased immobility in the forced swim test. Shorter treatments with ETX had no large effects on any parameter. Chronic ETX has widespread effects not only within but also outside the circuitry in which SWD are initiated and generated, including preventing epileptogenesis and reducing depressive-like symptoms. The treatment of patients before symptom onset might prevent many of the adverse consequences of chronic epilepsy. 13 p.

Item does not contain fulltext Purpose: The brain is a highly interconnected neuronal assembly in which network analyses can greatly enlarge our knowledge on seizure generation. The cortico-thalamo-cortical network is the brain-network of interest in absence epilepsy. Here, network synchronization is assessed in a genetic absence model during 5 s long pre-ictal-> ictal transition periods. Method: 16 male WAG/Rij rats were equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex, rostral and caudal RTN, VPM, anterior-(ATN) and posterior (Po) thalamic nucleus. Local field potentials measured during pre-ictal-> ictal transition and during control periods were subjected to time-frequency and pairwise phase consistency analysis. Results: Pre-ictally, all channels showed spike-wave discharge (SWD) precursor activity (increases in spectral power), which were earliest and most pronounced in the somatosensory cortex. The caudal RTN decoupled from VPM, Po and cortical layer 4. Strong increases in synchrony were found between cortex and thalamus during SWD. Although increases between cortex and VPM were seen in SWD frequencies and its harmonics, boarder spectral increases (6-48 Hz) were seen between cortex and Po. All thalamic nuclei showed increased phase synchronization with Po but not with VPM. Conclusion: Absence seizures are not sudden and unpredictable phenomena: the somatosensory cortex shows highest and earliest precursor activity. The pre-ictal decoupling of the caudal RTN might be a prerequisite of SWD generation. Po nucleus might be the primary thalamic counterpart to the somatosensory-cortex in the generation of the cortico-thalamic-cortical oscillations referred to as SWD. 13 p.

The occurrence of spike-wave discharges (SWDs) in WAG/Rij rats is modulated by the circadian timing system and is shaped by the presence of a light-dark cycle, motor activity, and state of vigilance. Here it is investigated whether the response to a phase shift is different between the SWDs and general motor activity rhythm. The process of reentrainment of both rhythms and its effect on number of absences was compared after a phase shift in the light-dark cycle, a condition known to induce internal desynchronization in the circadian timing system.Chronic electroencephalographic and motor activity recordings were made in adult WAG/Rij rats, kept in the 12:12 h light-dark cycle. After four baseline days, rats were exposed to an 8-h phase delay by shifting the light onset. Recordings were continuously made for another 10 consecutive days.An immediate effect of the phase shift on both rhythms was observed: the acrophases were 7.5 h advanced. Next, they gradually returned to the baseline level, however, with a different speed. The more robust motor activity rhythm stabilizes first, whereas the weaker rhythm of SWDs adapted more slowly. The phase shift caused a prolonged aggravation of epileptic activity, observed mostly during the light phase.Different speed and character of reentrainment suggests that the occurrence of seizures and motor activity are controlled by distinct circadian oscillators. The prolonged increase in absences after the phase shift has immediate practical consequences.

Item does not contain fulltext Purpose Generalized spike and wave discharges (SWD) are generated within the cortico-thalamo-cortical system. However the exact interactions between cortex and different thalamic nuclei needed for the generation and maintenance of SWD are still to be elucidated. This study aims to shed more light on these interactions via multisite cortical and thalamic local-field-potential recordings. Methods WAG/Rij rats were equipped with multiple electrodes targeting layers 4 to 6 of the somatosensory-cortex, rostral and caudal RTN, VPM, anterior (ATN)- and posterior (Po) thalamic nucleus. The maximal-association-strength between signals was calculated for pre-ictal → ictal transition periods and in control periods using non-linear-association-analysis. Dynamics of changes in coupling-direction and time-delays between channels were analyzed. Results Earliest and strongest increases in coupling-strength were seen between cortical layers 5/6 and Po. Other thalamic nuclei became later involved in SWD activity. During the first 500 ms of SWDs the cortex guided most thalamic nuclei while cortex and Po kept a bidirectional crosstalk. Most thalamic nuclei started to guide the Po until the end of the SWD. While the rostral RTN showed increased coupling with Po, the caudal RTN decoupled. Instead, it directed its activity to the rostral RTN. Conclusions Next to the focal cortical instigator zone of SWDs, the Po seems crucial for their occurrence. This nucleus shows early increases in coupling and is the only nucleus which keeps a bidirectional crosstalk to the cortex within the first 500 ms of SWDs. Other thalamic nuclei seem to have only a function in SWD maintenance. Rostral and caudal-RTN have opposite roles in SWD occurrence. 12 p.

Contains fulltext : 102917.pdf (Publisher’s version ) (Closed access) 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. 5 p.

Haloperidol treatment during pre- and post-natal period affects maternal behavior and this may have long-term effects on the offspring. We examined whether early haloperidol administration to Wistar-Albino-Glaxo dams from Rijswijk (WAG/Rij) and in Wistar control rats would affect maternal care and as a consequence, seizure susceptibility and behavior in the WAG/Rij's offspring at 3-4 months of age. Nursing dams of this well-validated genetic animal model of absence epilepsy and control dams were injected with haloperidol or saline at PPD 1 to 6. Maternal behavior was evaluated at PPD 7 to 9. Haloperidol-injected WAG/Rij dams showed more pup carryings compared with saline-injected mothers, this effect was not noticed in control Wistar dams. The offspring of haloperidol-treated WAG/Rij dams, tested during adulthood, showed heightened behavioral activity (time spent into the open arms, head dips) in the elevated plus-maze, as well as shorter spike-wave discharges (SWD) as measured in their electroencephalographic activity compared with saline-treated rats. Overall, it can be concluded that deviancies in the DA system as induced by haloperidol facilitates pup carrying/retrieval behavior in WAG/Rij rats and reduces seizure activity of the offspring in adulthood. Therefore, inter-individual differences in seizure properties and behavior in genetically predisposed animals may be due to differences in maternal behavior of the dams.

Item does not contain fulltext A great number of clinical observations show a relationship between epilepsy and depression. Idiopathic generalized epilepsy, including absence epilepsy, has a genetic basis. The review provides evidence that WAG/Rij rats can be regarded as a valid genetic animal model of absence epilepsy with comorbidity of depression. WAG/Rij rats, originally developed as an animal model of human absence epilepsy, share many EEG and behavioral characteristics resembling absence epilepsy in humans, including the similarity of action of various antiepileptic drugs. Behavioral studies indicate that WAG/Rij rats exhibit depression-like symptoms: decreased investigative activity in the open field test, increased immobility in the forced swimming test, and decreased sucrose consumption and preference (anhedonia). In addition, WAG/Rij rats adopt passive strategies in stressful situations, express some cognitive disturbances (reduced long-term memory), helplessness, and submissiveness, inability to make choice and overcome obstacles, which are typical for depressed patients. Elevated anxiety is not a characteristic (specific) feature of WAG/Rij rats; it is a characteristic for only a sub-strain of WAG/Rij rats susceptible to audiogenic seizures. Interestingly, WAG/Rij rats display a hyper-response to amphetamine similar to anhedonic depressed patients. WAG/Rij rats are sensitive only to chronic, but not acute, antidepressant treatments, suggesting that WAG/Rij rats fulfill a criterion of predictive validity for a putative animal model of depression. However, more and different antidepressant drugs still await evaluation. Depression-like behavioral symptoms in WAG/Rij rats are evident at baseline conditions, not exclusively after stress. Experiments with foot-shock stress do not point towards higher stress sensitivity at both behavioral and hormonal levels. However, freezing behavior (coping deficits) and blunted response of 5HT in the frontal cortex to uncontrollable sound stress, increased c-fos expression in the terminal regions of the meso-cortico-limbic brain systems and greater DA response of the mesolimbic system to forced swim stress suggest that WAG/Rij rats are vulnerable to some, but not to all types of stressors. We propose that genetic absence epileptic WAG/Rij rats have behavioral depression-like symptoms, are vulnerable to stress and might represent a model of chronic low-grade depression (dysthymia). Both 5HT and DAergic abnormalities detected in the brain of WAG/Rij rats are involved in modulation of vulnerability to stress and provocation of behavioral depression-like symptoms. The same neurotransmitter systems modulate SWDs as well. Recent studies suggest that the occurrence and repetition of absence seizures are a precipitant of depression-like behavior. Whether the neurochemical changes are primary to depression-like behavioral alterations remains to be determined. In conclusion, the WAG/Rij rats can be considered as a genetic animal model for absence epilepsy with comorbidity of dysthymia. This model can be used to investigate etiology, pathogenic mechanisms and treatment of a psychiatric comorbidity, such as depression in absence epilepsy, to reveal putative genes contributing to comorbid depressive disorder, and to screen novel psychotropic drugs with a selective and/or complex (dual) action on both pathologies.

Item does not contain fulltext Recently it was established that early long lasting treatment with the anti-absence drug ethosuximide (ETX) delays the occurrence of absences and reduces depressive-like symptoms in a genetic model for absence epilepsy, rats of the WAG/Rij strain. Here it is investigated whether anti-epileptogenesis (chronic treatments with ETX for 2 and 4 months) affects REM sleep in this model. Four groups of weaned male WAG/Rij rats were treated with ETX for 4 months, two groups for 2 months (at 2–3 and 4–5 months of age), the fourth group was untreated. Next, the rats were recorded 6 days after the last day of the treatment for 22.5 h. Non-REM sleep and REM sleep parameters and delta power were analyzed in four characteristic and representative hours of the recoding period. Four months treatment with ETX reduced the amount of REM sleep and REM sleep as percentage of total sleep time. Other sleep parameters were not affected by the treatment. Clear differences between the various hours of the light–dark phase in amounts of non-REM and REM sleep and delta power were found, in line with commonly reported circadian sleep patterns. It can be concluded that the reduction of REM sleep is unique for the early and long lasting chronic treatment. The outcomes may explain our earlier finding that a reduction of REM sleep might alleviate depressive like symptoms. 6 p.

Contains fulltext : 90212.pdf (Publisher’s version ) (Closed access) The concept of burnout remains enigmatic since it is only determined by behavioral characteristics. Moreover, the differential diagnosis with depression and chronic fatigue syndrome is difficult. EEG-related variables in 13 patients diagnosed with burnout syndrome were compared with 13 healthy comparison subjects in order to explore the existence of neurobiological markers for burnout. Burnout patients showed reduced P300 amplitude, a lower alpha peak frequency and reduced beta power. These EEG-related differences in burnout patients differ from those described in the literature in depression and chronic fatigue patients. Our preliminary findings suggest that burnout might be considered as a separate clinical syndrome. 10 p.

Contains fulltext : 89806.pdf (Publisher’s version ) (Closed access) PURPOSE: Brain-type creatine kinase (CK-B) and ubiquitous mitochondrial creatine kinase (UbCKmit) act as components of local phosphocreatine ATP shuttles that help in the compartmentalization and maintenance of pools of high-energy phosphate molecules in both neurons and glial cells. We investigated the role of these brain-type creatine kinases during extreme energy-demanding conditions in vivo (generalized tonic-clonic seizures) and in vitro. METHODS: The physiologic response of wild-types and mice lacking both CK-B and UbCKmit (CK--/--mice) to pentylenetetrazole (PTZ)-induced seizures was measured using electroencephalography (EEG) recordings and behavioral monitoring. In vitro intracellular Ca(2+) kinetics in hippocampal granule neurons were monitored upon single and repetitive depolarizations. RESULTS: PTZ induced in only a few CK--/-- mice PTZ seizure-like behavior, but in all wild-types a full-blown seizure. EEG analysis showed that preseizure jerking was associated with high-amplitude discharges. Wild-type EEG recordings showed continuous runs of rhythmic 4-6 Hz activity, whereas no rhythmic EEG activities were observed in the few CK--/-- mice that developed a behavioral seizure. All other CK--/-- mice displayed a sudden postictal depression without any development of a generalized seizure. Hippocampal granule neurons of CK--/-- mice displayed a higher Ca(2+) removal speed following repetitive KCl-induced depolarizations. DISCUSSION: Deficiency for creatine kinase is affecting brain energy metabolism and will likely contribute to the disturbance of seizure development. Because CK--/-- hippocampal neurons exhibited an increase in Ca(2+) removal rate of elevated intracellular levels, we conclude that altered Ca(2+) clearance in CK--/-- neurons could play a role in the abnormal EEG and seizure activity. 01 januari 2010

Contains fulltext : 90188.pdf (Publisher’s version ) (Closed access) One of the ways in which brain computer interfaces can be used is neurofeedback (NF). Subjects use their brain activation to control an external device, and with this technique it is also possible to learn to control aspects of the brain activity by operant conditioning. Beneficial effects of NF training on seizure occurrence have been described in epileptic patients. Little research has been done about differentiating NF effectiveness by type of epilepsy, particularly, whether idiopathic generalized seizures are susceptible to NF. In this experiment, seizures that manifest themselves as spike-wave discharges (SWDs) in the EEG were reinforced during 10 sessions in 6 rats of the WAG/Rij strain, an animal model for absence epilepsy. EEG's were recorded before and after the training sessions. Reinforcing SWDs let to decreased SWD occurrences during training; however, the changes during training were not persistent in the post-training sessions. Because behavioural states are known to have an influence on the occurrence of SWDs, it is proposed that the reinforcement situation increased arousal which resulted in fewer SWDs. Additional tests supported this hypothesis. The outcomes have implications for the possibility to train SWDs with operant learning techniques. 8 p.

Contains fulltext : 90685.pdf (Publisher’s version ) (Closed access) The automatic real-time detection of spike-wave discharges (SWDs), the electroencephalographic hallmark of absence seizures, would provide a complementary tool for rapid interference with electrical deep brain stimulation in both patients and animal models. This paper describes a real-time detection algorithm for SWDs based on continuous wavelet analyses in rodents. It has been implemented in a commercially available data acquisition system and its performance experimentally verified. ECoG recordings lasting 5–8 h from rats (n = 8) of the WAG/Rij strain were analyzed using the real-time SWD detection system. The results indicate that the algorithm is able to detect SWDs within 1 s with 100% sensitivity and with a precision of 96.6% for the number of SWDs. Similar results are achieved for 24-h ECoG recordings of two rats. The dependence of accuracy and speed of detection on program settings and attributes of ECoG are discussed. It is concluded that the wavelet based real-time detecting algorithm is well suited for automatic, real-time detection of SWDs in rodents. 7 p.

Contains fulltext : 76693.pdf (Publisher’s version ) (Closed access) The role of the cholinergic innervated nucleus basalis of Meynert (NB) and reticular thalamic nucleus (RT) in the generation or modulation of spontaneously occurring spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The cholinergic agonist carbachol and the muscarinic antagonist scopolamine were injected in the NB and RT in the doses of 0.55 and 5.5 nmol while the EEG was recorded. Carbachol injected in the NB decreased the number and the mean duration of SWDs. Scopolamine alone had no influence on SWDs, but could antagonize the effects of carbachol if administered simultaneously in NB. Injections of carbachol in the RT inhibited the occurrence of SWDs, but did not affect the mean duration. Scopolamine administered in the RT had no influence on seizure activity. It is concluded that cholinergic stimulation of the NB or the RT inhibits the cortical synchronous activity characterizing SWDs.