Occurrence Of Spike-wave Discharges Research Articles

Posttraumatic and Idiopathic Spike-Wave Discharges in Rats: Discrimination by Morphology and Thalamus Involvement.

The possibility of epileptiform activity generation by the thalamocortical neuronal network after focal brain injuries, including traumatic brain injury (TBI), is actively debated. Presumably, posttraumatic spike-wave discharges (SWDs) involve a cortico-thalamocortical neuronal network. Differentiation of posttraumatic and idiopathic (i.e., spontaneously generated) SWDs is imperative for understanding posttraumatic epileptogenic mechanisms. Experiments were performed on male Sprague-Dawley rats with electrodes implanted into the somatosensory cortex and the thalamic ventral posterolateral nucleus. Local field potentials were recorded for 7 days before and 7 days after TBI (lateral fluid percussion injury, 2.5 atm). The morphology of 365 SWDs (89 idiopathic before craniotomy, and 262 posttraumatic that appeared only after TBI) and their appearance in the thalamus were analyzed. The occurrence of SWDs in the thalamus determined their spike-wave form and bilateral lateralization in the neocortex. Posttraumatic discharges were characterized by more "mature" characteristics as compared to spontaneously generated discharges: higher proportions of bilateral spreading, well-defined spike-wave form, and thalamus involvement. Based on SWD parameters, the etiology could be established with an accuracy of 75% (AUC 0.79). Our results support the hypothesis that the formation of posttraumatic SWDs involves a cortico-thalamocortical neuronal network. The results form a basis for further research of mechanisms associated with posttraumatic epileptiform activity and epileptogenesis.

The effect of GABAergic neurotransmission on the seizure-related activity of the laterodorsal thalamic nuclei and the somatosensory cortex in a genetic model of absence epilepsy

The present study aimed to investigate the alterations of the GABAergic system in the laterodorsal nucleus (LDN) of the thalamus and the somatosensory cortex (SC) in an experimental model of absence seizure. The effects of pharmacological manipulation of both GABAA and GABAB receptor subunits in the LDN on the generation of spike-wave discharges (SWD) were evaluated. The experiments were carried out in four groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. The expressions of various GABA receptor subunits were studied in the LDN and SC. Furthermore, recordings of unit activity from the LDN and electrocorticography were simultaneously monitored before, during, and after the application of GABAA and GABAB antagonists in the LDN. The generation of SWD in the older WAG/Rij rats was associated with significant alterations in the expression of GABAARα1, GABAARβ3, and GABABR2 subunits in the LDN as well as GABAARα1, GABAARβ3, GABAARγ2, and GABABR2 subunits in the SC. Furthermore, the occurrence of SWD was associated with a significant reduction of gene expression of GABAARα1 and increase of GABAARβ3 in the LDN as well as reduction of GABAARα1, GABAARβ3, GABAARγ2, and GABABR2 in the SC. The microionthophoretic application of the GABAA antagonist bicuculline resulted in a significant increase in the population firing rate of LDN neurons as well as the mean number and duration of SWD. The application of the GABAB antagonist CGP35348 significantly increased the population firing rate of LDN neurons but decreased the mean number of SWD. Our data indicate the regulatory effect of the GABAergic system of the LDN and SC in absence seizures.

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

Can absence seizures be predicted by vigilance states?: Advanced analysis of sleep–wake states and spike–wave discharges' occurrence in rats

Spike–wave discharges (SWDs) are the main manifestation of absence epilepsy. Their occurrence is dependent on the behavioral state, and they preferentially occur during unstable vigilance periods. The present study investigated whether the occurrence of SWDs can be predicted by the preceding behavioral state and whether this relationship is different between the light and the dark phases of the 24-h day.Twenty-four-hour (12:12 light/dark phases) electroencephalographic (EEG) recordings of 12 Wistar Albino Glaxo, originally bred in Rijswijk (WAG/Rij) rats, a well-known genetic model of absence epilepsy, were analyzed and transformed into sequences of 2-s length intervals of the following 6 possible states: active wakefulness (AW), passive wakefulness (PW), deep slow-wave sleep (DSWS), light slow-wave sleep (LSWS), rapid eye movement (REM) sleep, and SWDs, given discrete series of categorical data. Probabilities of all transitions between states and Shannon entropy of transitions were calculated for the light and dark phases separately and statistically analyzed.Common differences between the light and the dark phases were found regarding the time spent in AW, LSWS, DSWS, and SWDs. The most probable transitions were that AW was preceded and followed by PW and vice versa regardless of the phase of the photoperiod. A similar relationship was found for light and deep slow-wave sleep. The most probable transitions to and from SWDs were AW and LSWS, respectively, with these transition likelihoods being consistent across both circadian phases. The second most probable transitions around SWDs appeared more variable between light and dark. During the light phase, SWDs occurred around PW and participated exclusively in sleep initiation; in the dark phase, SWDs were seen on both, ascending and descending steps towards and from sleep. Conditional Shannon entropy showed that AW and DSWS are the most predictable events, while the possible prediction horizon of SWDs is not larger than 4 s and despite the higher occurrence of SWDs in the dark phase, did not differ between phases.It can be concluded that although SWDs show a stable, strong circadian rhythm with a peak in number during the dark phase, their occurrence cannot be reliably predicted by the preceding behavioral state, except at a very short time base.

Diagnostic principles of immature epileptic (proepileptic) EEG activity in rats with genetic predisposition to absence epilepsy

Introduction:Absence epilepsy is a specific neurological disorder characterized by brief episodes of loss of consciousness (absence) accompanied by high-amplitude “spike-wave” discharges in the electroencephalogram (EEG). WAG/Rij rats with a genetic predisposition to absence epilepsy are used as a reliable model of this disease. This model is beneficial for investigating basic mechanisms of absence epilepsy, including the development of spike-wave seizures.Purpose:Establishing diagnostic principles for immature forms of spikewave activity in EEG (so-called proepileptic activity) of WAG/Rij rats.Results:Diagnostic criteria are proposed for proepileptic EEG activity in rats, based on time-frequency analysis with the continuous wavelet transform and skeletons of wavelet surfaces. The algorithm was tested in “epileptic” and “asymptomatic” individuals. Rats with the “epileptic” phenotype demonstrated a decrease in number of proepileptic patterns between 5 and 7 months of age in parallel to an increase in the number of epileptic discharges that might relate to the transformation of proepileptic activity to epileptic. In rats with the “asymptomatic” phenotype, the age-related decline in the number of proepileptic patterns was not accompanied by the occurrence of spike-wave discharges. A decrease in the instantaneous frequency was found in a larger number of proepileptic patterns in “epileptic” WAG/Rij rats as compared to “asymptomatic” individuals.Practical relevance:A similar approach can be used for early diagnosis of absence epilepsy at the preclinical stage in patients with genetic predisposition.

Increased cortical beta power and spike-wave discharges in middle-aged APP/PS1 mice.

Amyloid plaque-forming transgenic mice display neuronal hyperexcitability, epilepsy, and sudden deaths in early adulthood. However, it is unknown whether hyperexcitability persists until middle ages when memory impairment manifests. We recorded multichannel video electroencephalography (EEG), local field potentials, and auditory evoked potentials in transgenic mice carrying mutated human amyloid precursor protein (APP) and presenilin-1 (PS1) genes and wild-type littermates at 14-16months and compared the results with data we have earlier collected from 4-month-old mice. Furthermore, we monitored acoustic startle responses in other APP/PS1 and wild-type mice from 3 to 11months of age. Independent of the age APP/PS1 mice demonstrated increased cortical power at 8-60Hz. They also displayed over 5-fold increase in the occurrence of spike-wave discharges and augmented auditory evoked potentials compared with nontransgenic littermates. In contrast to evoked potentials, APP/PS1 mice showed normalization of acoustic startle responses with aging. Increased cortical power and spike-wave discharges provide powerful new biomarkers to monitor progression of amyloid pathology in preclinical intervention studies.

Differential response of hippocampal and prefrontal oscillations to systemic LPS application

The early electrophysiological phenomena linked to systemic inflammation are largely underexplored. We developed here local field analyses to detect prodromal oscillatory abnormalities. We identified early band-specific patterns in local field potential recorded from freely-moving rats injected intraperitoneally with lipopolysaccharide (LPS, 1 mg/kg). Theta frequency was significantly reduced and this effect was not related to the decreased locomotion of the animal. Furthermore, LPS-induced alterations show a region-specific response when compared between the hippocampal region and medial prefrontal cortex. Delta mean frequency increased in the hippocampal region but not in the prefrontal cortex. We explored also the hypothesis that systemic inflammation increases the propensity of abnormally synchronized brain activity. Our data indicate that the LPS-evoked alteration of delta and theta frequency parameters reflects the formation of abnormal synchronization in similar frequency ranges. The onset of abnormal brain activity was indicated by spike-wave discharges in the range of 1–10 Hz with three main frequency domains. Importantly, the occurrence of spike-wave discharges was observed in the hippocampus but not in the cortex. In summary, the hippocampal theta rhythm is an accurate indicator of the oscillatory changes evoked by LPS application. The findings offer clear patterns of altered brain function that will facilitate mechanistic investigations of brain dysfunction and delirium occurring during sepsis.

Stimulus-induced transitions between spike-wave discharges and spindles with the modulation of thalamic reticular nucleus.

It is believed that thalamic reticular nucleus (TRN) controls spindles and spike-wave discharges (SWD) in seizure or sleeping processes. The dynamical mechanisms of spatiotemporal evolutions between these two types of activity, however, are not well understood. In light of this, we first use a single-compartment thalamocortical neural field model to investigate the effects of TRN on occurrence of SWD and its transition. Results show that the increasing inhibition from TRN to specific relay nuclei (SRN) can lead to the transition of system from SWD to slow-wave oscillation. Specially, it is shown that stimulations applied in the cortical neuronal populations can also initiate the SWD and slow-wave oscillation from the resting states under the typical inhibitory intensity from TRN to SRN. Then, we expand into a 3-compartment coupled thalamocortical model network in linear and circular structures, respectively, to explore the spatiotemporal evolutions of wave states in different compartments. The main results are: (i) for the open-ended model network, SWD induced by stimulus in the first compartment can be transformed into sleep-like slow UP-DOWN and spindle states as it propagates into the downstream compartments; (ii) for the close-ended model network, weak stimulations performed in the first compartment can result in the consistent experimentally observed spindle oscillations in all three compartments; in contrast, stronger periodic single-pulse stimulations applied in the first compartment can induce periodic transitions between SWD and spindle oscillations. Detailed investigations reveal that multi-attractor coexistence mechanism composed of SWD, spindles and background state underlies these state evolutions. What's more, in order to demonstrate the state evolution stability with respect to the topological structures of neural network, we further expand the 3-compartment coupled network into 10-compartment coupled one, with linear and circular structures, and nearest-neighbor (NN) coupled network as well as its realization of small-world (SW) topology via random rewiring, respectively. Interestingly, for the cases of linear and circular connetivities, qualitatively similar results were obtained in addition to the more irregularity of firings. However, SWD can be eventually transformed into the consistent low-amplitude oscillations for both NN and SW networks. In particular, SWD evolves into the slow spindling oscillations and background tonic oscillations within the NN and SW network, respectively. Our modeling and simulation studies highlight the effect of network topology in the evolutions of SWD and spindling oscillations, which provides new insights into the mechanisms of cortical seizures development.

Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy

WAG/Rij rats are genetic animal model of absence epilepsy with comorbidity of depression. The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at the age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main index of absence epilepsy. Previously it has been shown that the extensive absence epilepsy in 5-6 months old WAG/Rij rats is accompanied by decrease of dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms, and impairments of the learning and memory processes. In 36 days old WAG/Rij rats, SWDs are not manifested, deficiency of the mesolimbic dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior in the open field, light-dark choice, forced swimming tests, monoamines and their metabolites concentrations in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) were investigated in two months old WAG/Rij rats in comparison with age-matched Wistar rats. Reduced concentration of the dopamine and its metabolites, and increased concentration of the serotonin was found in WAG/Rij rats compared with Wistar rats only in the prefrontal cortex, indicating that the prefrontal cortex is the brain structure where neurochemical abnormalities appear first. No substantial changes in the monoamine and their metabolites concentrations have been revealed in other brain structures. Two months old WAG/Rij rats didn’t exhibit depression-like behavior in the forced swimming test, and learning/memory deficits in the passive avoidance test, but they showed behavioral changes, indicating increase anxiety/stress-reactivity, and alterations in learning/memory in the active avoidance test. Results suggest that two month-old WAG/Rij rats are at the stage of so called “pre-pathology” (increased anxiety and stress reactivity) preceding the development of depression-like behavior and substantial cognitive impairments which are co-morbid to fully expressed absence epilepsy in 5-6 months old rats of this strain.

Progress and Outlooks in a Genetic Absence Epilepsy Model (WAG/Rij)

The WAG/Rij model is a well characterized and validated genetic animal epilepsy model in which the for absence epilepsy highly characteristic spike-wave discharges (SWDs) develop spontaneously. In this review we discuss first some older and many new studies, with an emphasis on pharmacological and neurochemical studies towards the role of GABA and glutamate and the ion channels involved in the pathological firing patterns. Next, new insights and highlights from the last 5-10 years of reaearch in WAG/Rij rats are discussed. First, early environmental factors modulate SWD characteristics and antiepileptogenesis is possible. Also new is that the classically assumed association between sleep spindles and SWDs seems no longer valid as an explanatory role for the occurrence of SWDs in the genetic rodent models. A role of cortical and thalamic glial cells has been revealed, indicating a putative role for inflammatory cytokines. Neurophysiologic and signal analytical studies in this and in another rodent model (GAERS) point towards a cortical site of origin, that SWDs do not have a sudden onset, and propose a more important role for the posterior thalamus than was previously assumed. Finally it is proposed that the reticular nucleus of the thalamus might be heterogeneous with respect to its role in propagation and maintenance of SWDs. The presence of a well-established cortical region in which SWDs are elicited allows for research towards new non-invasive treatment options, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). The first results show the feasibility of this new approach.

Internal desynchronization facilitates seizures

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.

Effect of intracranial administration of ethosuximide in rats with spontaneous or pentylenetetrazol-induced spike-wave discharges

Generalized absence seizures are characterized by bilateral spike-wave discharges (SWDs), particularly in the frontoparietal cortical region. In WAG/Rij and GAERS rats with absence epilepsy, recent evidence indicates that SWDs arise first from the lateral somatosensory cortex (LSC), that is, the cortical focus theory. To further understand the cortical role in SWD generation, two epileptic rat models were assessed. Two models, Long-Evans rats with spontaneous SWDs and Wistar rats with low-dose pentylenetetrazol-induced SWDs (20 mg/kg, i.p.), were administered intracortical or intrathalamic ethosuximide (ESM) or saline. Electroencephalographic recordings were analyzed before and after intracranial microinfusion to evaluate onset, frequency, and duration of SWDs. In both epileptic rat models, ESM in the LSC significantly reduced SWD number, shortened SWD duration, and delayed SWD onset compared to saline. By contrast, ESM in the medial somatosensory cortex had little effect compared to saline. Intrathalamic infusion of ESM only delayed SWD onset. These findings suggest that the LSC may be essential for the occurrence of SWDs. Our data support the cortical focus theory for the generation of absence seizures.

Spike–wave discharges in WAG/Rij rats are preceded by delta and theta precursor activity in cortex and thalamus

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.

The role of perioral afferentation in the occurrenceof spike-wave discharges in the WAG/Rij modelof absence epilepsy

According to the focal cortical theory of absence epilepsy, spike-and-wave discharges (SWDs) have a cortical focal origin in the perioral region of the somatosensory cortex in rats. In the present study the role of peripheral afferents of the perioral (snout) region in the occurrence of spontaneous SWDs was investigated in the WAG/Rij (Wistar Albino Glaxo from Rijswijk) rat model of absence epilepsy in order to examine whether an input from peripheral sources is imperative for the occurrence of SWDs. Twelve male WAG/Rij rats were chronically equipped with cortical EEG electrodes. Peripheral afferents of the perioral region of the snout nervus trigeminus were pharmacologically blocked with a local injection of 2% Novocain, a blockade of nervus facialis and saline injections were used as controls. ECoGs were recorded before and after bilateral injection of the drug. Blockade of the n. trigeminus decreased the incidence and duration of SWD, while similar injections with Novocain near the n. facialis had no effect . Injections with saline were also not effective. Our data demonstrate that intact peripheral afferent input may be primarily involved in the initiation of SWDs. It suggests that the cortico-thalamo-cortical circuits need the peripheral stimulations from the snout and vibrissae for an initiation of the spontaneous SWDs.

Does arousal interfere with operant conditioning of spike-wave discharges in genetic epileptic rats?

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.

Granger causality: Cortico-thalamic interdependencies during absence seizures in WAG/Rij rats

Linear Granger causality was used to identify the coupling strength and directionality of information transport between frontal cortex and thalamus during spontaneous absence seizures in a genetic model, the WAG/Rij rats. Electroencephalograms were recorded at the cortical surface and from the specific thalamus. Granger coupling strength was measured before, during and after the occurrence of spike-wave discharges (SWD). Before the onset of SWD, coupling strength was low, but associations from thalamus-to-cortex were stronger than vice versa. The onset of SWD was associated with a rapid and significant increase of coupling strength in both directions. There were no changes in Granger causalities before the onset of SWD. The strength of thalamus-to-cortex coupling remained constantly high during the seizures. The strength of cortex-to-thalamus coupling gradually diminished shortly after the onset of SWD and returned to the pre-SWD level when SWD stopped. In contrast, the strength of thalamus-to-cortex coupling remained elevated even after cessation of SWD. The strong and sustained influence of thalamus-to-cortex may facilitate propagation and maintenance of seizure activity, while rapid reduction of cortex-to-thalamus coupling strength may prompt the cessation of SWD. However, the linear estimation of Granger coupling strength does not seem to be sufficient for predicting episodes with absence epilepsy.

Effects of non-competitive AMPA receptor antagonists injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy

CFM-2 [1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one] and THIQ-10c [ N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline], are two non-competitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) receptor antagonists, which demonstrated to antagonize generalized tonic-clonic seizures in different animal models. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were focally microinjected into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs) and better characterize the role of AMPA neurotransmission in this animal model. The focal microinjection of the two AMPA antagonists into some thalamic nuclei (ventralis posteromedialis (VPM), reticularis (NRT), ventralis posterolateralis (VPL) and the primary somatosensory forelimb region (S1FL)) was, generally, not able to significantly modify the occurrence of SWDs. Whereas, both compounds were able to reduce the number and duration of SWDs dose-dependently when microinjected into the peri-oral region of the primary somatosensory cortex (S1po). These findings suggest that AMPA receptor antagonists might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.

Cortical and thalamic coherence during spike–wave seizures in WAG/Rij 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.

Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy

Neurosteroids are synthesized in the brain and have been demonstrated to modulate various cerebral functions. Allopregnanolone (3α-hydroxy-5α-pregnan-20-one), a naturally occurring neurosteroid, and ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), a synthetic derivative, are two neurosteroids acting as positive allosteric modulators of the GABA A receptor complex acting on a specific steroid recognition site. Both agents antagonize generalized tonic-clonic seizures in various animal models of epilepsy. Pregnenolone sulphate (3β-hydroxy-5α-pregnen-20-one 3-sulphate; PS) is a negative allosteric modulator of GABA A receptors and a positive modulator of the NMDA receptors. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were chronically implanted with five frontoparietal cortical electrodes for electrocorticogram (EEG) recordings and bilateral guide cannulae into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs). The focal and bilateral microinjection of the two GABA A positive modulators into some thalamic nuclei (nucleus ventralis posteromedialis, nucleus reticularis thalami, nucleus ventralis posterolateralis was usually able to significantly worsen the occurrence of SWDs in WAG/Rij rats. Whereas both compounds were able to reduce the number and duration of SWDs when microinjected into the peri-oral region of the primary somatosensory cortex. The effects of PS were more complex depending on both the dose and the site of administration, generally, at low doses in thalamic nuclei and cortex, PS induced an increase of absence activity and a reduction at higher doses. These findings suggest that neurosteroids might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.

Cortical control of generalized absence seizures: effect of lidocaine applied to the somatosensory cortex in WAG/Rij rats

The role of the somatosensory cortex (SmI) in the incidence of spike–wave discharges (SWDs) was studied in a genetic model of absence epilepsy, WAG/Rij rats. SWDs were recently shown to initiate at the perioral area of the SmI and spread over the cortex and thalamus within a few milliseconds [J. Neurosci. 22 (2002) 1480]. It was hypothesized that functional deactivation of the SmI might reduce the appearance of SWDs. This was tested using unilateral microinjections (1 μl) of 2% lidocaine into the SmI in 13 WAG/Rij rats. Electrocorticogram (ECoG) was recorded in free moving animals from four cortical sites after lidocaine and control (saline) injections. Lidocaine effectively diminished the power of the ECoG spectra mostly in the area surrounding the injection site. Deactivation of the perioral region of the SmI reduced the incidence of SWDs at the entire cortex in both hemispheres. The number of SWDs gradually reached control level at the end of the second hour after injections of lidocaine. These data show that proper functioning of SmI is important for the occurrence of SWDs, supporting the idea that absence seizures might have a focal cortical origin.