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

Purpose: 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. Methods: 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. Key Findings: 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. Significance: 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 are necessary for the expression of behavioral depression-like symptoms

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.     

Polygenic control of idiopathic generalized epilepsy phenotypes in the genetic absence rats from Strasbourg (GAERS)

PURPOSE: Generalized nonconvulsive absence seizures are characterized by the occurrence of synchronous and bilateral spike-and-wave discharges (SWDs) on electroencephalographic recordings, concomitant with behavioral arrest. The GAERS (genetic absence rats from Strasbourg) strain, a well-characterized inbred model for idiopathic generalized epilepsy, spontaneously develops EEG paroxysms that resemble those of typical absence seizures. The purpose of this study was to investigate the genetic control of SWD variables by using a combination of genetic analyses and electrophysiological measurements in an experimental cross derived from GAERS and Brown Norway (BN) rats. METHODS: SWD subphenotypes were quantified on EEG recordings performed at both 3 and 6 months in a cohort of 118 GAERS x BN F2 animals. A genome-wide scan of the F2 progenies was carried out with 146 microsatellite markers that were used to test each marker locus for evidence of genetic linkage to the SWD quantitative traits. RESULTS: We identified three quantitative trait loci (QTLs) in chromosomes 4, 7, and 8 controlling specific SWD variables in the cross, including frequency, amplitude, and severity of SWDs. Age was a major factor influencing the detection of genetic linkage to the various components of the SWDs. CONCLUSIONS: The identification of these QTLs demonstrates the polygenic control of SWDs in the GAERS strain. Genetic linkages to specific SWD features underline the complex mechanisms contributing to SWD development in idiopathic generalized epilepsy.     

Evaluation of two genetic animal models in behavioral tests of anxiety and depression

Anxiety- and depression-related disorders often appear associated and may be affected by common genetic factors. The inbred rat strains Lewis (LEW) and spontaneously hypertensive rats (SHR) and the outbred rat lines Floripa H and L, which were selectively bred for high and low locomotion in the central area of the open field (OF) test, respectively, have been proposed as experimental tools to study anxiety. The main goal of the present study was to characterize the behavior of these animals in two models of anxiety, elevated plus-maze (EPM) and OF, in two models of depression, forced swim test (FST) and tail suspension test (TST) and in their home-cages. Emotionality-related differences between LEW and SHR rats and between Floripa H and L rats were found in the EPM, OF and FST. Those lines showing low anxiety-like profiles in the EPM and OF (SHR and Floripa H) also showed low immobility in the FST. The TST failed to unveil any line differences. Factor analysis involving all tests revealed three independent factors with one of them associating anxiety-related measures from the OF and EPM to immobility in the FST. When observed in their home-cages, LEW and SHR rats showed no differences in general activity, but when acutely treated with imipramine (15mg/kg), only LEW rats were sensitive to its antidepressant effects. These results suggest the existence of a genetic link between two tests used in the screening of anxiolytic drugs and one test of antidepressant activity. Moreover, the LEW and SHR rat strains were shown to be an interesting model to study the comorbidity between anxiety- and depression-related disorders.     

Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenic seizures

Some rats of the WAG/Rij (Wistar Albino Glaxo from Rijswijk) and Wistar strain are susceptible for audiogenic (convulsive) seizures. In the present study, behavior of susceptible and non-susceptible rats from the WAG/Rij strain, genetically predisposed to absence epilepsy, and outbred Wistar strain, genetically not predisposed to absence epilepsy, was compared to assess the level of anxiety (in the open field, light-dark choice and elevated plus-maze tests) and the level of depression (in the sucrose consumption and forced swimming tests). Increased level of anxiety was found only in audiogenic susceptible rats both from WAG/Rij and Wistar strain, but increased level of depression was found only in WAG/Rij rats independently of their susceptibility to audiogenic seizures. The results suggest that enhanced level of depression in WAG/Rij strain rats is associated with absence epilepsy but enhanced level of anxiety with susceptibility to audiogenic seizures.     

Neonatal tricyclic antidepressant clomipramine treatment reduces the spike-wave discharge activity of the adult WAG/Rij rat

Recently it was revealed that the absence-like epileptic activity of the WAG/Rij (Wistar Albino Glaxo/Rijswijk) rat is associated with depression-like behavioural symptoms. Whether these depressive-like symptoms are accompanying epileptic activity (manifested in spike-wave discharges, SWDs, in the EEG) or whether they are causative for each other are open questions. Neonatally administered tricyclic antidepressant clomipramine is a well characterized animal model of major depression. It evokes behavioural symptoms of depression and changes sleep pattern in normal adult rats. We investigated whether in the WAG/Rij rat the neonatally administered clomipramine would aggravate the depression-like behavioural symptoms and the SWD activity. Male WAG/Rij pups from postnatal day 8 (PD8) to PD21 were treated with clomipramine (20mg/kg) or saline (control animals) twice daily intraperitoneally (i.p.). In the 8 months old rats, sleep parameters and sucrose solution intake (as hedonic index) as well as the SWD activity were measured. While the neonatal clomipramine treatment significantly increased the rapid eye movement sleep (REM) amount and decreased the sucrose preference score, it surprisingly attenuated the adult (8 months old) SWD activity. We concluded that neonatal clomipramine treatment produced aggravation of depression-like symptoms while decreased the SWD activity in the adult (8 months old) WAG/Rij rat.     

Effect of lamotrigine treatment on epileptogenesis: an experimental study in rat

Prevention of epileptogenesis in patients with acute brain damaging insults like status epilepticus (SE) is a major challenge. We investigated whether lamotrigine (LTG) treatment started during SE is antiepileptogenic or disease-modifying. To mimic a clinical study design, LTG treatment (20 mg/kg) was started 2 h after the beginning of electrically induced SE in 14 rats and continued for 11 weeks (20 mg/kg per day for 2 weeks followed by 10 mg/kg per day for 9 weeks). One group of rats (n = 14) was treated with vehicle. Nine non-stimulated rats with vehicle treatment served as controls. Outcome measures were occurrence of epilepsy, severity of epilepsy, and histology (neuronal loss, mossy fiber sprouting). Clinical occurrence of seizures was assessed with 1-week continuous video-electroencephalography monitoring during the 11th (i.e. during treatment) and 14th week (i.e. after drug wash-out) after SE. LTG reduced the number of electrographic seizures during SE to 43% of that in the vehicle group (P < 0.05). In the vehicle group, 93% (13/14), and in the LTG group, 100% (14/14) of the animals, developed epilepsy. In both groups, 64% of the rats had severe epilepsy (seizure frequency >1 per day). The mean frequency of spontaneous seizures, seizure duration, or behavioral severity of seizures did not differ between groups. The severity of hippocampal neuronal damage and density of mossy fiber sprouting were similar. In LTG-treated rats with severe epilepsy, however, the duration of seizures was shorter (34 versus 54s, P < 0.05) and the behavioral seizure score was milder (1.4 versus 3.4, P < 0.05) during LTG treatment than after drug wash-out. LTG treatment started during SE and continued for 11 weeks was not antiepileptogenic but did not worsen the outcome. These data, together with earlier studies of other antiepileptic drugs, suggest that strategies other than Na(+)-channel blockade should be explored to modulate the molecular cascades leading to epileptogenesis after SE.     

Measuring clusters of spontaneous spike-wave discharges in absence epileptic rats

Spike-wave discharges (SWDs) characterizing absence epilepsy appear in closely packed aggregated sequences, which gave rise to the name "pyknolepsy" for this disease. In WAG/Rij rats, genetically prone to absence epilepsy, spontaneous SWDs seem to occur in clusters as well. Here, we aimed to quantify the seizures' clusters. SWDs sequences were extracted from long-term (complete estrous cycle) EEG recordings of adult female WAG/Rij rats. Spectral characteristics and half-decay time of autocorrelation functions (AC-tau) were calculated for time series of i(SWD) (proportion of time occupied by spike-wave activity), measured for subsequent periods. The clusters were characterized by means of AC-tau calculated for time series of i(SWD). The absence seizures were indeed clustered in a minute range. The clustering had a non-periodical character, since no significant and consistent periodicity was found in the minute range. AC-tau correlated positively with propensity of SWDs: i.e. the aggravation of absence epilepsy led to longer sequences of paroxysms and thus to a less random distribution. AC-tau was not sensitive to various phases of the estrous cycle, but was larger in the dark than in the light periods. We suggest that AC-tau can be used to quantify aggregation of epileptic events in the search for physiological basis of its temporal clustering.     

Interhemispheric desynchronization of spontaneous spike-wave discharges by corpus callosum transection in rats with petit mal-like epilepsy

Wistar rats of a strain inbred for spontaneous generalized non-convulsive seizures present EEG spike-wave discharges (SWDs), 7-10 c/sec, occurring about once/min and lasting about 15 sec. They are bilateral and synchronous and can be recorded over the entire neocortex and in the lateral thalamic nuclei. After corpus callosum section, only a few bilateral SWDs persisted. Asymmetrical SWDs were most often recorded: bilateral SWDs starting asynchronously, or unilateral SWDs, which were also seen to alternate abruptly between hemispheres. The thalamic SWDs were always synchronized with the ipsilateral cortical pattern. These findings suggest that while the corpus callosum has a major role in bilateral synchronization of SWD in this model of epilepsy, occasional synchronization may still occur through other pathways after callosal transection.     

Sex differences and phase of light cycle modify chronic stress effects on anxiety and depressive-like behavior

The experiment examined whether sex differences and the phase of the light cycle modified how chronic restraint stress influenced anxiety and depressive-like behavior. Rats were restrained (6 h/d/21 d) and tested on the open field (OF), elevated plus maze (EPM), forced swim test (FST), and sucrose preference (SP) test. Chronic stress increased anxiety in both males and females in different tasks during the dark phase, but not in the light phase. When tested during the dark, chronic stress decreased time and grid crossings in the center arena of the OF in males, whereas chronic stress decreased open arm entries and time in the EPM in females. For OF and EPM, an anxiety index calculation confirmed that chronic stress increased anxiety measures when taking into consideration locomotion metrics. For the FST and SP, chronic stress had a tendency to alter the immobility index and sucrose preference in both sexes, but did not reach statistical significance alone. Therefore, a separate z-score was computed for each task and summed to represent a combined z-score of depressive-like behavior. In the light phase, chronic stress increased depressive-like behavior in males, but decreased depressive-like behavior in females. Chronic stress had no statistically significant effects on depressive-like behavior in the dark phase, although the pattern of chronic stress effects on depressive-like behavior in females was similar for both light cycle phases. The results indicate that chronic restraint stress effects on anxiety and depressive-like behavior depend upon the type of task, phase of the light cycle and sex of the individual.     

Chromosomal mapping of genetic loci controlling absence epilepsy phenotypes in the WAG/Rij rat

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.     

The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected

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

Wistar audiogenic rats display abnormal behavioral traits associated with artificial selection for seizure susceptibility

Accumulating evidence from different animal models has contributed to the understanding of the bidirectional comorbidity associations between the epileptic condition and behavioral abnormalities. A strain of animals inbred to enhance seizure predisposition to high-intensity sound stimulation, the Wistar audiogenic rat (WAR), underwent several behavioral tests: forced swim test (FST), open-field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), social preference (SP), marble burying test (MBT), inhibitory avoidance (IAT), and two-way active avoidance (TWAA). The choice of tests aimed to investigate the correlation between underlying circuits believed to be participating in both WAR's innate susceptibility to sound-triggered seizures and the neurobiological substrates associated with test performance. Comparing WAR with its Wistar counterpart (i.e., resistant to audiogenic seizures) showed that WARs present behavioral despair traits (e.g., increased FST immobility) but no evidence of anhedonic behavior (e.g., increased sucrose consumption in SPT) or social impairment (e.g., no difference regarding juvenile exploration in SP). In addition, tests suggested that WARs are unable to properly evaluate degrees of aversiveness (e.g., performance on OFT, EPM, MBT, IAT, and TWAA). The particularities of the WAR model opens new venues to further untangle the neurobiology underlying the co-morbidity of behavioral disorders and epilepsy.This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".     

IL-1β is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence

Interleukin (IL)-1β plays a crucial role in the mechanisms of limbic seizures in rodent models of temporal lobe epilepsy. We addressed whether activation of the IL-1β signaling occurs in rats with genetic absence epilepsy (GAERS) during the development of spike-and-wave discharges (SWDs). Moreover, we studied whether inhibition of IL-1β biosynthesis in GAERS could affect SWD activity.IL-1β expression and glia activation were studied by immunocytochemistry in the forebrain of GAERS at postnatal days (PN)14, PN20, and PN90 and in age-matched non-epileptic control Wistar rats. In PN14 GAERS, when no SWDs have developed yet, IL-1β immunostaining was undetectable, and astrocytes and microglia showed a resting phenotype similar to control Wistar rats. In 3 out of 9 PN20 GAERS, IL-1β was observed in activated astrocytes of the somatosensory cortex; the cytokine expression was associated with the occurrence of immature-type of SWDs. In all adult PN90 GAERS, when mature SWDs are established, IL-1β was observed in reactive astrocytes of the somatosensory cortex but not in adjacent cortical areas or in extra-cortical regions.An age-dependent c-fos activation was found in the somatosensory cortex of GAERS with maximal levels reached in PN90 rats; c-fos was also induced in some thalamic nuclei in PN20 and PN90 GAERS.Inhibition of IL-1β biosynthesis in PN90 GAERS by 4-day systemic administration of a specific ICE/Caspase-1 blocker, significantly reduced both SWD number and duration.These results show that IL-1β is induced in reactive astrocytes of the somatosensory cortex of GAERS at the onset of SWDs. IL-1β has pro-ictogenic properties in this model, and thus it may play a contributing role in the mechanisms underlying the occurrence of absence seizures.     

The influence of gender on the aggravation of absence seizures by carbamazepine in the low-dose pentylenetetrazol rat model.

OBJECTIVES: To determine whether carbamazepine (CBZ) aggravates absence seizures in the low-dose pentylenetetrazol (PTZ) rat model in both male and female animals, and investigate for gender differences. METHODS: Inbred Sprague-Dawley rats were implanted with EEG electrodes. Seven days later PTZ (20 mg/kg, i.p.) was administered following pre-treatment with vehicle or CBZ (20 mg/kg, i.p.) and the occurrence of spike-and-wave discharges (SWDs) on the EEG quantified. RESULTS: The cumulative SWD for 90-minute post-PTZ was higher in the CBZ versus vehicle pre-treatment arm for both female (mean 110 seconds vs. 62 seconds; P = 0.03) and male (mean 89 seconds vs. 60 seconds; P = 0.03) rats. The increase in SWD duration in the CBZ arm was greater in female rats for the first five 15-minute intervals, but none attained statistical significance (P > 0.05). CBZ pre-treatment resulted in reductions in both SWD frequency (Hz) (male, P = 0.003; female, P < 0.0001) and latency to onset of SWD (male, P = 0.002). The frequency of SWD in CBZ pre-treated rats was lower in females (5.8 Hz vs. 6.1 Hz, P = 0.002) as was the decrease in the SWD burst duration following CBZ versus vehicle pre-treatment (-0.05 seconds vs. -0.25 seconds, P = 0.046). CONCLUSIONS: CBZ consistently aggravates absence seizures in the low-dose PTZ model in both female and male rats. However, while some gender differences were found, the results failed to support the hypothesis that females are significantly more susceptible to aggravation of the number or duration of absence seizures by CBZ.     

Elevated anxiety and depressive-like behavior in a rat model of genetic generalized epilepsy suggesting common causation

The explanation for the increased prevalence of neuropsychiatric disorders in epilepsy patients is uncertain, with both biological and psychosocial factors proposed. Increasing evidence supports the idea of shared neurobiological processes leading both to seizures and to behavioral, emotional and cognitive disturbance. This study addresses this using Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of human generalized epilepsy. We subjected GAERS (n=47) and Non-Epileptic Control rats (NEC; n=73) to behavioral measures of depression and anxiety at 7 and 13 weeks of age, ages prior to and after seizure onset. We employed the Sucrose-Preference Test (SPT), the Elevated Plus Maze (EPM), and the Open Field Arena (OFA). GAERS exhibited significantly greater levels of both depression- and anxiety-like behaviors on all measures, including reduced consumption of sucrose solution in the SPT; lower percentage of time in the open arms of the EPM; and reduced exploratory activity and less time spent in the inner area of the OFA. These differences were evident at both 7 and 13 weeks of age, before and after the onset of epilepsy. Increased anxiety- and depressive-like behaviors are observed in GAERS. These behavioral differences exist before the onset of seizures indicating that they are not secondary consequences of seizures, and suggest shared factors in the biological diathesis underlying the two kinds of disorder. Studying affective disturbance in animal models of epilepsy may illuminate the pathogenesis of affective disorder more generally, as well as modeling psychiatric comorbidities common in epilepsy patients.     

Simultaneous EEG,fMRI, and behavior in typical childhood absence seizures

Purpose: Absence seizures cause transient impairment of consciousness. Typical absence seizures occur in children, and are accompanied by 3–4‐Hz spike–wave discharges (SWDs) on electroencephalography (EEG). Prior EEG–functional magnetic resonance imaging (fMRI) studies of SWDs have shown a network of cortical and subcortical changes during these electrical events. However, fMRI during typical childhood absence seizures with confirmed impaired consciousness has not been previously investigated. Methods: We performed EEG‐fMRI with simultaneous behavioral testing in 37 children with typical childhood absence epilepsy (CAE). Attentional vigilance was evaluated by a continuous performance task (CPT), and simpler motor performance was evaluated by a repetitive tapping task (RTT). Results: SWD episodes were obtained during fMRI scanning from 9 patients among the 37 studied. fMRI signal increases during SWDs were observed in the thalamus, frontal cortex, primary visual, auditory, somatosensory, and motor cortex, and fMRI decreases were seen in the lateral and medial parietal cortex, cingulate gyrus, and basal ganglia. Omission error rate (missed targets) with SWDs during fMRI was 81% on CPT and 39% on RTT. For those seizure epochs during which CPT performance was impaired, fMRI changes were seen in cortical and subcortical structures typically involved in SWDs, whereas minimal changes were observed for the few epochs during which performance was spared. Discussion: These findings suggest that typical absence seizures involve a network of cortical–subcortical areas necessary for normal attention and primary information processing. Identification of this network may improve understanding of cognitive impairments in CAE, and may help guide development of new therapies for this disorder.     

Oxcarbazepine and its active metabolite, (S)‐licarbazepine,exacerbate seizures in a mouse model of genetic generalized epilepsy

Oxcarbazepine (OXC), widely used to treat focal epilepsy, is reported to exacerbate seizures in patients with generalized epilepsy. OXC is metabolized to monohydroxy derivatives in two enantiomeric forms: (R)‐licarbazepine and (S)‐licarbazepine. Eslicarbazepine acetate is a recently approved antiepileptic drug that is rapidly metabolized to (S)‐licarbazepine. It is not known whether (S)‐licarbazepine exacerbates seizures. Here, we test whether OXC or either of its enantiomers exacerbates the number of spike‐and‐wave discharges (SWDs) in mice harboring the human γ‐aminobutyric acid A receptor (GABA_A)γ2(R43Q) mutation. OXC (20 mg/kg), (S)‐licarbazepine (20 mg/kg), and (R)‐licarbazepine (20 mg/kg) all significantly increased the number of SWDs, while their duration was unaffected. The potential for (S)‐licarbazepine to exacerbate SWDs suggests that eslicarbazepine acetate should be used with caution in generalized epilepsy. Furthermore, generalized seizure exacerbation for first‐, second‐, and third‐generation carbamazepine‐based compounds is likely to occur through a common mechanism.     

Quantitative trait locus on distal chromosome 1 regulates the occurrence of spontaneous spike-wave discharges in DBA/2 mice

Purpose: Most common forms of human epilepsy result from a complex combination of polygenetic and environmental factors. Quantitative trait locus (QTL) mapping is a first step toward the nonbiased discovery of epilepsy-related candidate genes. QTL studies of susceptibility to induced seizures in mouse strains have consistently converged on a distal region of chromosome 1 as a major phenotypic determinant; however, its influence on spontaneous epilepsy remains unclear. In the present study we characterized the influence of allelic variations within this QTL, termed Szs1, on the occurrence of spontaneous spike-wave discharges (SWDs) characteristic of absence seizures in DBA/2 (D2) mice. Methods: We analyzed SWD occurrence and patterns in freely behaving D2, C57BL/6 (B6) and the congenic strains D2.B6-Szs1 and B6.D2-Szs1. Key Findings: We showed that congenic manipulation of the Szs1 locus drastically reduced the number and the duration of SWDs in D2.B6-Szs1 mice, which are homozygous for Szs1 from B6 strain on a D2 strain background. However, it failed to induce the full expression of SWDs in the reverse congenic animals B6.D2-Szs1. Significance: Our results demonstrate that the occurrence of SWDs in D2 animals is under polygenic control and, therefore, the D2 and B6 strains might be a useful model to dissect the genetic determinants of polygenic SWDs characteristic of typical absence seizures. Furthermore, we point to the existence of epistatic interactions between at least one modifier gene within Szs1 and genes within unlinked QTLs in regulating the occurrence of spontaneous nonconvulsive forms of epilepsies.     

Predictors of pharmacoresistant epilepsy: pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy

Purpose: Patients with intractable temporal lobe epilepsy (TLE) exhibit an increased risk of psychiatric comorbidity, including depression, anxiety, psychosis, and learning disorders. Furthermore, a history of psychiatric comorbidity has been suggested as a predictor of lack of response to therapy with antiepileptic drugs (AEDs) in patients with epilepsy. However, clinical studies on predictors of pharmacoresistant epilepsy are affected by several confounding variables, which may complicate conclusions. In the present study, we evaluated whether behavioral alterations in epileptic rats are different in AED nonresponders versus responders. Methods: For this purpose, we used an animal model of TLE in which AED responders and nonresponders can be selected by prolonged treatment of epileptic rats with phenobarbital (PB). Behavioral and cognitive abnormalities were compared between responders and nonresponders as well as between epileptic rats and nonepileptic controls in a battery of tests. Results: Fifteen epileptic rats with spontaneous recurrent seizures (SRS) either responding (11 rats) or not responding (4 rats) to PB were used for this study. The nonresponders differed markedly in behavioral and cognitive abnormalities from responders and nonepileptic controls in tests of anxiety (open field, elevated‐plus maze test), behavioral hyperexcitability (approach‐response, touch‐response, pick‐up tests), and learning and memory (Morris water maze). Discussion: Our hypothesis that AED‐resistant rats will show more severe behavioral and cognitive changes than AED‐responsive rats was confirmed by the present experiments. The data substantiate that rodent models of TLE are useful to delineate predictors of pharmacoresistant epilepsy.