Continuous spike-waves during slow-wave sleep in a mouse model of focal cortical dysplasia.

OBJECTIVE: To examine if mice with focal cortical dysplasia (FCD) develop spontaneous epileptic seizures and, if so, determine the key electroencephalography (EEG) features. METHODS: Unilateral single freeze lesions to the S1 region (SFLS1R) were made in postnatal day 0-1 pups to induce a neocortical microgyrus in the right cortical hemisphere. Continuous 24-h recordings with intracranial EEG electrodes and behavioral tests were performed in adult SFLS1R and sham-control mice to assess neurologic status. RESULTS: A high percentage of adult SFLS1R animals (89%, 40/45) exhibited at least one or more spontaneous nonconvulsive seizure events over the course of 24 h. Of these animals, 60% (27/45) presented with a chronic seizure state that was persistent throughout the recording session, consisting of bursts of rhythmic high-amplitude spike-wave activities and primarily occurring during periods of slow-wave sleep. In comparison, none of the control, age-matched, mice (0/12) developed seizures. The epileptic discharge pattern closely resembled a pattern of continuous spike-waves during slow-wave sleep (CSWS) of the human syndrome described as an electrical status epilepticus during slow-wave sleep (ESES). Key findings in the SFLS1R model indicated that the observed CSWS (1) were more prevalent in female (18/23) versus male (9/22, p < 0.05), (2) were strongest in the right S1 region although generalized to other brain regions, (3) were associated with significant cognitive and behavioral deficits, (4) were temporarily alleviated by ethosuximide treatment or optogenetic activation of cortical γ-aminobutyric acid (GABA)ergic neurons, and (5) theta and alpha band rhythms may play a key role in the generalization of spike-wave activities. SIGNIFICANCE: This is the first report of an in vivo animal FCD model that induces chronic spontaneous electrographic brain seizures. Further characterization of the abnormal oscillations in this mouse model may lead to a better understanding of the mechanisms of CSWS/ESES.

Increased resting functional connectivity in spike-wave epilepsy in WAG/Rij rats.

PURPOSE: Functional magnetic resonance imaging (fMRI)-based resting functional connectivity is well suited for measuring slow correlated activity throughout brain networks. Epilepsy involves chronic changes in normal brain networks, and recent work demonstrated enhanced resting fMRI connectivity between the hemispheres in childhood absence epilepsy. An animal model of this phenomenon would be valuable for investigating fundamental mechanisms and testing therapeutic interventions. METHODS: We used fMRI-based resting functional connectivity for studying brain networks involved in absence epilepsy. Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit spontaneous episodes of staring and unresponsiveness accompanied by spike-wave discharges (SWDs) resembling human absence seizures in behavior and electroencephalography (EEG). Simultaneous EEG-fMRI data in epileptic WAG/Rij rats in comparison to nonepileptic Wistar controls were acquired at 9.4 T. Regions showing cortical fMRI increases during SWDs were used to define reference regions for connectivity analysis to investigate whether chronic seizure activity is associated with changes in network resting functional connectivity. KEY FINDINGS: We observed high degrees of cortical-cortical correlations in all WAG/Rij rats at rest (when no SWDs were present), but not in nonepileptic controls. Strongest connectivity was seen between regions most intensely involved in seizures, mainly in the bilateral somatosensory and adjacent cortices. Group statistics revealed that resting interhemispheric cortical-cortical correlations were significantly higher in WAG/Rij rats compared to nonepileptic controls. SIGNIFICANCE: These findings suggest that activity-dependent plasticity may lead to long-term changes in epileptic networks even at rest. The results show a marked difference between the epileptic and nonepileptic animals in cortical-cortical connectivity, indicating that this may be a useful interictal biomarker associated with the epileptic state.