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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 : 196885.pdf (Publisher’s version ) (Open Access) The hyperpolarization-activated inward current, Ih, plays a key role in the generation of rhythmic activities in thalamocortical relay (TC) neurons. Cyclic nucleotides, like 3', 5'-cyclic adenosine monophosphate (cAMP), facilitate voltage-dependent activation of HCN channels by shifting the activation curve of Ih to more positive values and thereby terminating the rhythmic burst activity. The role of 3', 5'- cyclic guanosine monophosphate (cGMP) in modulation of Ih is not well understood. To determine the possible role of the NO-sensitive cGMP-forming guanylyl cyclase 2 (NO-GC2) to the control of thalamic Ih, the voltage-dependency and cGMP/cAMP-sensitivity of Ih was analyzed in TC neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in WT and NO-GC2-deficit (NO-GC2-/-) mice. Whole cell voltage clamp recordings in brain slices revealed a more hyperpolarized half maximal activation (V1/2) of Ih in NO-GC2-/- TC neurons compared to wild type (WT). Different concentrations of 8-Br-cAMP / 8-Br-cGMP induced dose-dependent positive shifts of V1/2 in both strains. Treatment of WT slices with lyase enzyme inhibitors (SQ22536 and ODQ) resulted in further hyperpolarized V1/2. Under current clamp conditions NO-GC2-/- neurons exhibited a reduction in the Ih-dependent voltage sag and reduced action potential firing with hyperpolarizing and depolarizing current steps, respectively. Intrathalamic rhythmic bursting activity in brain slices and in a simplified mathematical model of the thalamic network was reduced in the absence of NO-GC2. In freely behaving NO-GC2-/- mice, delta and theta band activity was enhanced during active wakefulness (AW) and rapid eye movement sleep (REM) in cortical local field potential (LFP) in comparison to WT. These findings indicate that cGMP facilitates Ih activation and contributes to a tonic activity in TC neurons. On the network level basal cGMP production supports fast rhythmic activity in the cortex. 19 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.

Item does not contain fulltext Objective Glutamate and γ-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. Methods Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. Results Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. Significance These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA. 11 p.

Contains fulltext : 147446.pdf (Publisher’s version ) (Closed access) BACKGROUND: In patients with depression, as well as in patients with schizophrenia, both mood and working memory performance are often impaired. Both issues can only be addressed and improved with medication to some extent. OBJECTIVE: This study investigates the mood and the working memory performance in patients with depression or schizophrenia and whether acupuncture can improve these. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A pragmatic clinical trial design was used. The study was conducted in a psychiatric clinic. Fifty patients with depression and 50 with schizophrenia were randomly divided into an experimental and a waiting-list group. Additionally, 25 healthy control participants were included. Twelve weeks of individualized acupuncture treatment was used as the clinical intervention. MAIN OUTCOME MEASURES: All patients were tested before (T1) and after (T2) acupuncture treatment on a mood scale (Beck Depression Inventory-II, BDI-II), a simple working memory task (digit span), and a complex working memory task (letter-number sequencing); the healthy controls were tested at T1 only. RESULTS: Patients with depression scored worse than the others on the BDI-II, and patients with schizophrenia scored worse than the healthy controls. On the digit span, patients with schizophrenia did not differ from healthy controls whereas they scored worse of all on the letter-number sequencing. With respect to the acupuncture findings, first, the present study showed that the use of acupuncture to treat patients with schizophrenia was both practical and safe. Moreover, acupuncture had a positive effect on the BDI-II for the depression group, but acupuncture had no effect on the digit span and on the letter-number sequencing performance for the two clinical groups. CONCLUSION: The clinical improvement in patients with depression after acupuncture treatment was not accompanied by any significant change in a simple working memory task or in a more complex working memory task; the same was true for the patients with schizophrenia. 11 p.

Item does not contain fulltext While epidemiological data suggest a female prevalence in human childhood- and adolescence-onset typical absence epilepsy syndromes, the sex difference is less clear in adult-onset syndromes. In addition, although there are more females than males diagnosed with typical absence epilepsy syndromes, there is a paucity of studies on sex differences in seizure frequency and semiology in patients diagnosed with any absence epilepsy syndrome. Moreover, it is unknown if there are sex differences in the prevalence or expression of atypical absence epilepsy syndromes. Surprisingly, most studies of animal models of absence epilepsy either did not investigate sex differences, or failed to find sex-dependent effects. However, various rodent models for atypical syndromes such as the AY9944 model (prepubertal females show a higher incidence than prepubertal males), BN model (also with a higher prevalence in males) and the Gabra1 deletion mouse in the C57BL/6J strain offer unique possibilities for the investigation of the mechanisms involved in sex differences. Although the mechanistic bases for the sex differences in humans or these three models are not yet known, studies of the effects of sex hormones on seizures have offered some possibilities. The sex hormones progesterone, estradiol and testosterone exert diametrically opposite effects in genetic absence epilepsy and pharmacologically-evoked convulsive types of epilepsy models. In addition, acute pharmacological effects of progesterone on absence seizures during proestrus are opposite to those seen during pregnancy. 17β-Estradiol has anti-absence seizure effects, but it is only active in atypical absence models. It is speculated that the pro-absence action of progesterone, and perhaps also the delayed pro-absence action of testosterone, are mediated through the neurosteroid allopregnanolone and its structural and functional homolog, androstanediol. These two steroids increase extrasynaptic thalamic tonic GABAergic inhibition by selectively targeting neurosteroid-selective subunits of GABAA receptors (GABAARs). Neurosteroids also modulate the expression of GABAAR containing the γ2, α4, and δ subunits. It is hypothesized that differences in subunit expression during pregnancy and ovarian cycle contribute to the opposite effects of progesterone in these two hormonal states. 13 p.

Thrombospondins, which are known to interact with the αWe measured the transcripts of thrombospondin-1 and αThrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged.These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs.

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.

Background: Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The α2δ subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and studies carried out in heterologous expression systems suggest that it may also associate with T channels. The α2δ subunit is also targeted by thrombospondins, which regulate synaptogenesis in the central nervous system. Objective: To discuss the potential role for the thrombospondin/α2δ axis in the pathophysiology of absence epilepsy. Methods: We searched PubMed articles for the terms “absence epilepsy”, “T-type voltage-sensitive calcium channels”, “α2δ subunit”, “ducky mice”, “pregabalin”, “gabapentin”, “thrombospondins”, and included papers focusing this Review's scope. Results: We moved from the evidence that mice lacking the α2δ-2 subunit show absence seizures and α2δ ligands (gabapentin and pregabalin) are detrimental in the treatment of absence epilepsy. This suggests that α2δ may be protective against absence epilepsy via a mechanism that does not involve T channels. We discuss the interaction between thrombospondins and α2δ and its potential relevance in the regulation of excitatory synaptic formation in the cortico-thalamo-cortical network. Conclusion: We speculate on the possibility that the thrombospondin/α2δ axis is critical for the correct functioning of the cortico-thalamo-cortical network, and that abnormalities in this axis may play a role in the pathophysiology of absence epilepsy.

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.

Item does not contain fulltext While previous studies on the MMPI-2 in patients with schizophrenia and depression have used mixed samples of both early stage and chronic psychiatric patients. Here, it is investigated whether chronicity itself might have a differential effect on the MMPI-2 profiles of these patients and whether demoralization associated with long-term illness' affects the scales of the MMPI-2. Thirty long-term patients with schizophrenia, 30 long-term patients with depression, and 30 healthy participants completed the MMPI-2. Groups were compared on Clinical Scales and on the Restructured Clinical (RC) Scales. Patients with schizophrenia differed from patients with depression on 14 MMPI-2 scales and from healthy controls on 10 scales, generally showing mean UT-scores < 65, indicating a subjective experience of (near) normal functioning. Patients with depression differed from healthy controls on 17 scales mostly with UT-scores > 65, indicating impaired functioning. Demoralization was higher in patients with depression than in patients with schizophrenia and both psychiatric groups differed from the healthy control group. It is concluded that long-term patients with depression show impaired functioning and high demoralization, while long-term patients with schizophrenia surprisingly show near normal functioning and less demoralization. 7 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.

Contains fulltext : 159466.pdf (Publisher’s version ) (Closed access) Genetic animal models for convulsive, non-convulsive and mixed types of generalized epilepsies were used to establish putative histaminergic brain sites involved in the control of different types of epilepsy. Age matched rats of the KM strain (audiogenic seizures, AGS), WAG/Rij strain (absence seizures) and the WAG/Rij-AGS substrain (mixed model) were compared with a control group of Wistar rats on regional binding densities of H1 histamine receptors. Coronal slices of adult brains of the four groups were labeled with 3H pyrilamine, an antagonist of H1 histamine receptor and density of receptors was quantified with image analyses. All three groups of epileptic rats showed an increase in the density of H1 histamine receptor binding in the frontal motor cortex and interposed nucleus of cerebellum compared to the non-epileptic control group. Audiogenic epilepsy was characterized by increased H1 histamine receptor density in the frontal cortical and hippocampal regions, and in two midbrain (interpedunculus and lateral vestibular) nuclei. Absence epilepsy was characterized by a decrease in substantia nigra pars compacta, while the mixed model showed an elevation of H1 histamine receptor binding density in limbic regions such as the shell of the nucleus accumbens and the ventral tegmental area. It can be concluded that common changes in H1 histamine receptors can be found in genetic epilepsy models irrespective of the seizure type, and that each type of generalized epilepsy has its own pattern of H1 histamine receptor changes. It is speculated that H1 histamine receptors play a role in the brain's endogenous epilepsy control system. 6 p.

Purpose: 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 lightdark 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 lightdark cycle, a condition known to induce internal desynchronization in the circadian timing system. Methods: Chronic electroencephalographic and motor activity recordings were made in adult WAG/Rij rats, kept in the 12:12 h lightdark 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. Key Findings: 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. Significance: 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.

Metabotropic glutamate (mGlu) receptors are positioned at synapses of the thalamocortical network that underlie the development of spike-and-wave discharges (SWDs) associated with absence epilepsy. The modulatory role of individual mGlu receptor subtypes on excitatory and inhibitory synaptic transmission in the cortico-thalamo-cortical circuitry makes subtype-selective mGlu receptor ligands potential candidates as novel antiabsence drugs. Some of these compounds are under clinical development for the treatment of numerous neurologic and psychiatric disorders, and might be soon available for clinical studies in patients with absence seizures refractory to conventional medications. Herein we review the growing evidence that links mGlu receptors to the pathophysiology of pathologic SWDs moving from the anatomic localization and function of distinct mGlu receptor subtypes in the cortico-thalamo-cortical network to in vivo studies in mouse and rat models of absence epilepsy.

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.

Item does not contain fulltext Comorbidity in the affective domain seems rather typical for idiopathic epilepsy. Whether seizures are causative for the behavioral abnormalities or whether they are a common genetic cause remains to be established. Although the most proper control groups are not always available, there seems to be some consistency in the behavioral patterns seen in rats with absence epilepsy. Formal behavioral testing has shown that genetic absence models such as WAG/Rij's and GAERS, but also other rat lines endowed with spontaneous occurring spike-wave discharges (APO-SUS and Long-Evans rats), show all signs of depression-like behavior, while some lines show an even more complex affective comorbidity. The availability of a treatment that prevents both the neurodevelopment of the genetically programmed seizure and the comorbid symptomatology may help in answering whether seizures are causative for or epiphenomena of changes in affective behavior. If absence seizures and depressive-like behavior is indeed caused by the same underlying factors, then it is predicted that preventing environmental stress in absence epileptic rats will also prevent the affective disturbances.

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.

Sinds Bradley (1969) het burn-outsyndroom voor het eerst beschreef, nu ruim 30 jaar geleden, heeft deze metafoor voor een toestand van psychologische uitputting sterk aan populariteit gewonnen. Recent onderzoek toont aan dat vier procent van de Nederlandse beroepsbevolking dusdanige symptomen van burn-out heeft dat ze zich eigenlijk onder professionele behandeling zouden moeten stellen (Houtman et al., 2000). Dit is een duidelijk teken dat burn-out een serieus probleem is, dat aangepakt moet worden. Het stellen van de diagnose burn-out is echter niet altijd gemakkelijk. Lastig is dat er geen objectieve neurobiologische markers bekend zijn voor burn-out. Daarnaast komt de diagnose burn-out niet voor in de DSM-IV (American Psychiatric Association, 1994). Burn-outpatienten kunnen binnen de DSM-IV gediagnosticeerd worden op basis van het kernsymptoom van burn-out, langdurige en medisch onverklaarbare vermoeidheid, als lijdende aan een ongedifferentieerde somatoforme stoornis. In de ICD-10 (World Health Organization, 1992) komt een op burn-out gelijkend syndroom, het neurastene syndroom, wel voor als onafhankelijke diagnose, maar diagnostische criteria ontbreken.

Purpose: Genetically epileptic WAGRij rats develop spontaneous absence-like seizures after 3 months of age. We used WAGRij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) receptors. Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of "presymptomatic" 2-month old and "symptomatic" 8-month-old WAGRij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAGRij rats systemically injected with the potent CB1 receptor agonist, R(+)WIN55,212-2 (3-12 mgkg, s.c.), given alone or combined with the CB1 receptor antagonistinverse agonist, AM251 (12 mgkg, s.c.). Results: Data showed a reduction of CB1 receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB 1 receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAGRij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB 1 receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 receptors are targeted by novel antiabsence drugs.

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.

The aim of this study was to examine whether patients with borderline personality disorder (BPD) have deficits in cognitive inhibition as measured with an anti-saccade eye task similar to patients with schizophrenia (Sz). Furthermore, we investigated whether these inhibition errors were more prominent among BPD patients with psychotic-like symptoms than among BPD patients without these symptoms.An anti-saccade task was administered in 32 BPD patients (among them, 20 had with psychotic-like symptoms), 21 patients with recent onset schizophrenia (Sz), and 25 healthy controls (HC). The percentage inhibition errors in the anti-saccade task were the primary outcome variable, in addition, the percentage of anticipatory errors was measured.Sz patients showed more inhibition errors than HC and BPD (p.001 and p.05 resp.), whereas BPD patients scored in between Sz and HC. The difference with HC was significant as well (p.05). BPD patients with psychotic-like symptoms showed more inhibition errors than BPD patients without these symptoms (p.05). BPD patients showed more anticipatory errors than HC (p.001), whereas Sz patients did not (p.26).The data demonstrate that inhibition deficits, as measured with anti-saccadic eye movement task, may be characteristic among BPD patients and in a larger extent in patients with psychotic-like symptoms. This inhibition deficit was distinct from a general predisposition to response impulsively as measured by anticipatory errors, which was found in the whole group of BPD patients. Psychotic-like symptoms may be an important target dimension for future BPD research and treatment.

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.

This work proposes a new method for automatic marking epileptic spike-wave discharges in local eld potential (LFP) signals. The method is based on empirical modelling using radial basis functions to approximate dependency of a further state on the current one. Number and type of radial basis functions used are adjusted to data based on statistical criteria. Due to this the method needs only a few manual eorts for its application to new data. The time resolution of the method is close to the sampling interval of the original data, and real time detection is possible. Detection accuracy of the proposed approach is validated analysing the LFP signals obtained using WAG/Rij rats.

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.

Anxiety and depression are component of interictal behavioral deteriorations that occur as a consequence of kindling, a procedure to induce chronic epilepsy. The aim of this study was to evaluate the possible effects of electrical stimulation (ES) of paleocerebellar cortex on anxiety and depressive-like behavior in a PTZ kindled epilepsy model. Kindling was induced via pentylenetetrazol (PTZ) (25.0 mg/kg IP daily) during three weeks. Locomotion in open field, elevated plus-maze (EPM) and Porsolt forced swimming test have been used for the assessment of anxiety and depression-like behavior. ES (100 Hz) has been delivered to V-VII lobules of vermal cortex of kindled rats. ES of paleocerebellum reversed kindling-induced reduction of crossings of central squares, increased rearings, and decreased the number of defecations in open field. The duration that kindled animals spent in the open arms of the EPM increased in post- ES period, and the number of enterings into the closed arms of the EPM decreased. The duration of the immobility response in the swimming test in kindled rats was reduced after ESs of paleocerebellum. In all: ES of paleocerebellar structures suppressed anxious and depressive-like behavior in PTZ-kindled rats.

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 effects of catecholamine reuptake blocker methylphenidate (Ritalin®, 20 mg) and the benzodiazepine diazepam (Valium®, 10 mg) on the acoustic eye blink reflex were investigated in healthy volunteers. Stand alone as well as prepulse trials were presented and three intensities of stand-alone stimuli and three intensities of prepulses were used in an double blind cross-over study (n=12). Measured were the amplitude, area under the curve, onset and peak latencies of the blink reflex. It was found that the amplitude, area under the curve, and the onset latency were dependent on the intensity of the stand-alone and prepulse trials. The amplitude of the startle reflex was not changed by methylphenidate, diazepam showed a large reduction in the amplitude. The amplitude of prepulse trials was not reduced by methylphenidate, but strongly by diazepam. The onset latencies were prolonged in loud prepulse trials and after diazepam. The diazepam data not only suggest that firm reductions in stand-alone trials might have major consequences for the amplitude in prepulse inhibition trials, they equally show that sedation may affect the reflex amplitude in prepulse inhibition trials and that large reduction of the amplitude in prepulse inhibition trials are not exclusive for DA agents.

Whiplash staat nogal in de belangstelling omdat het, evenals chronische vermoeidheid en burn-out, een welvaartsziekte lijkt te zijn. Mensen die aangereden worden door een auto, maken, vooral bij een kop-staartbotsing, een onverhoedse beweging met het hoofd en de nek, een whiplash. Als gevolg van deze beweging treedt een zogenaamd benig- of wekedelenletsel op dat onder andere nek- en hoofdpijn, accommodatiestoornissen en duizeligheid kan veroorzaken. Geheugen- en aandachtsklachten worden vaak gerapporteerd, evenals psychische symptomen als prikkelbaarheid, angst en depressie. Ook overgevoeligheid voor licht en geluid, vermoeidheid en slaapproblemen worden genoemd. Het geheel van symptomen dat door een whiplashbeweging wordt veroorzaakt noemt men wel het whiplashsyndroom. Met moderne beeldvormende technieken is bij weinig patienten iets te zien, maar met neuropsychologische tests worden nogal eens afwijkingen gevonden.

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 Purpose: While decades of research were devoted to study generation mechanisms of spontaneous spike and wave discharges (SWD), little attention has been paid to network mechanisms associated with the spontaneous termination of SWD. In the current study coupling-dynamics at the onset and termination of SWD were studied in an extended part of the cortico-thalamo-cortical system of freely moving, genetic absence epileptic WAG/Rij rats. Methods: Local-field potential recordings of 16 male WAG/Rij rats, equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex (ctx4, ctx5, ctx6), rostral and caudal reticular thalamic nucleus (rRTN & cRTN), ventral postero medial (VPM), anterior- (ATN) and posterior (Po) thalamic nucleus, were obtained. Six seconds lasting pre-SWD- > SWD, SWD- > post SWD and control periods were analyzed with time-frequency methods, and between-region interactions were quantified with frequency-resolved Granger Causality (GC) analysis. Results: Most channel pairs showed increases in GC lasting from onset to offset of the SWD. While for most thalamo-thalamic pairs a dominant coupling direction was found during the complete SWD, most corticothalamic pairs only showed a dominant directional drive (always from cortex to thalamus) during the first 500 ms of SWD. Channel pair ctx4-rRTN showed a longer lasting dominant cortical drive, which stopped 1.5 sec prior to SWD offset. This early decrease in directional coupling was followed by an increase in directional coupling from cRTN to rRTN 1 sec prior to SWD offset. For channel pairs ctx5-Po and ctx6-Po the heightened cortex- > thalamus coupling remained until 1.5 sec following SWD offset, while the thalamus- > cortex coupling for these pairs stopped at SWD offset. Conclusion: The high directional coupling from somatosensory cortex to the thalamus at SWD onset is in good agreement with the idea of a cortical epileptic focus that initiates and entrains other brain structures into seizure activity. The decrease of cortex to rRTN coupling as well as the increased coupling from cRTN to rRTN preceding SWD termination demonstrates that SWD termination is a gradual process that involves both cortico-thalamic as well as intrathalamic processes. The rostral RTN seems to be an important resonator for SWD and relevant for maintenance, while the cRTN might inhibit this oscillation. The somatosensory cortex seems to attempt to reinitiate SVVD following its offset via its strong coupling to the posterior thalamus. 11 p.

Objective: The subiculum, one major output structure in the hippocampus, is considered to participate in seizure generation and modulation in temporal lobe epilepsy (TLE) since stimulation of the subiculum was found to suppress seizures in a seizure model. The current study aimed to investigate whether acute scheduled or responsive stimulation of the subiculum can suppress spontaneous seizures and affect local excitability of the subiculum in a chronic TLE model. Methods: Wistar rats were administrated intraperitoneally with kainic acid (KA) repeatedly to induce status epilepticus (SE). 4 months later the rats were implanted with stimulation electrodes in the subiculum. After one-week baseline recording, they received either responsive or scheduled high frequency stimulation (HFS, 125 Hz) for two days and then were swapped to the other type of stimulation for two days with one-week interval. All the rats also received pulse stimuli (100 μs, interval of 5-7 s) at different intensities (20, 50, 100 mA) before and after stimulation while evoked responses were elicited. Results: Acute HFS of the subiculum-both scheduled and responsive stimulation-suppressed spontaneous focal seizures in rats. The excitability of the subiculum, measured by evoked responses, did not show obvious changes before and after HFS. Conclusion: The preliminary outcomes revealed the anticonvulsant effects of subicular stimulation on spontaneous seizures, suggesting that the subiculum is a promising target candidate for deep brain stimulation to control seizures in TLE. The absence of changes in subicular excitability indicates that HFS affects the hippocampal network rather than the excitability of the subiculum per se.

Item does not contain fulltext Background: Advanced methods of signal analysis of the preictal and ictal activity dynamics characterizing absence epilepsy in humans with absences and in genetic animal models have revealed new and unknown electroencephalographic characteristics, that has led to new insights and theories. New method: Taking into account that some network associations can be considered as nonlinear, an adaptive nonlinear Granger causality approach was developed and applied to analyze cortico-cortical, cortico-thalamic and intrathalamic network interactions from local field potentials (LFPs). The outcomes of adaptive nonlinear models, constructed based on the properties of electroencephalographic signal and on statistical criteria to optimize the number of coefficients in the models, were compared with the outcomes of linear Granger causality. Results: The nonlinear adaptive method showed statistically significant preictal changes in Granger causality in almost all pairs of channels, as well as ictal changes in cortico-cortical, cortico-thalamic and intrathalamic networks. Current results suggest rearrangement of interactions in the thalamo-cortical network accompanied the transition from preictal to ictal phase. Comparison with existing method(s): The linear method revealed no preictal and less ictal changes in causality. Conclusions: Achieved results suggest that this proposed adaptive nonlinear method is more sensitive than the linear one to dynamics of network properties. Since changes in coupling were found before the seizure-related increase of LFP signal amplitude and also based on some additional tests it seems likely that they were not spurious and could not result from signal to noise ratio change. 9 p.

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.

The interest of psychiatric patients for complementary medicine, such as acupuncture, is stable, but effect studies in psychiatry remain scarce. In this pilot study, the effects of 3 months of acupuncture treatment on sleep were evaluated and compared between a group of patients with schizophrenia (n=16) and a group with depression (n=16). Healthy controls were included in order to establish reference values (n=8). Patients with schizophrenia and depression were randomly assigned to either a waiting list or a treatment condition. The Pittsburgh Sleep Quality Inventory was completed before and after the acupuncture treatment (individualized and according to traditional Chinese medicine principles) or the waiting list condition. Both acupuncture groups showed significant lower scores on the sleep inventory, which was not the case for the waiting list condition. Moreover, it was found that the effectiveness of the acupuncture treatment was higher in the patients with schizophrenia than in the patients with depression. Acupuncture seems able to improve sleep in this convenient sample of patients with long-lasting psychiatric problems and may be a suitable and cost-effective add-on treatment for this group, particularly if conducted group-wise.

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.