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In children with typical AS, we have confirmed a core network of structures involved in generalized epileptiform activity that includes the reticular structures of the brainstem. Furthermore, we have identified changes in parietal BOLD signal which precede the onset of epileptiform activity, suggesting the parietal cortex has a role in the initiation of epileptiform activity.

SUMMARYObjective: Lennox-Gastaut syndrome (LGS) is a severe epilepsy phenotype with characteristic electroclinical features despite diverse etiologies. We previously found common cerebral networks involved during slow spike-and-wave (SSW) and generalized paroxysmal fast activity (PFA), characteristic interictal discharges. Some patients have a Lennox-Gastaut-like phenotype and cortical lesions. We wished to explore the interaction between cerebral networks and lesions in this group. Methods: 3 Tesla electroencephalography-functional magnetic resonance imaging (EEG-fMRI) on six subjects with Lennox-Gastaut phenotype and a structural lesion. Timings of SSW and PFA events were used in an event-related fMRI analysis, and to estimate the time course of the hemodynamic response from key regions. Results: (1) PFA-robust fMRI signal increases were observed in frontal and parietal association cortical areas, thalamus, and pons, with simultaneous increases in both "attention" and resting-state (default mode) networks, a highly unusual pattern. (2) SSW showed mixed increased and decreased fMRI activity, with preevent increases in association cortex and thalamus, and then prominent postevent reduction. There was decreased fMRI activity in primary cortical areas. (3) Lesion-variable fMRI increases were observed during PFA and SSW discharges. Three subjects who proceeded to lesionectomy are >1 year seizure-free. Significance: We conceptualize Lennox-Gastaut phenotype as a being a network epilepsy, where key cerebral networks become autonomously unstable. Epileptiform activity in Lennox-Gastaut phenotype, and by implication in LGS, appears to be amplified and expressed through association cortical areas, possibly because the attention and default-mode networks are widely interconnected, fundamental brain networks. Seizure freedom in the subjects who proceeded to lesionectomy suggests that cortical lesions are able to establish and maintain this abnormal unstable network behavior.LGS may be considered a secondary network epilepsy because the unifying epileptic manifestations of the disorder, including PFA and SSW, reflect network dysfunction, rather than the specific initiating process.

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SUMMARYPurpose: The aim of this study was to provide better spatiotemporal description of the brain activity observed during generalized spike-and-wave (GSW) discharges. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) studies of these epileptiform events have shown regional differences in the timing of fMRI signal changes, which suggests activities within multiple interacting networks rather than a single unified network. Methods: EEG-fMRI recordings from eight patients with childhood absence epilepsy (CAE) were studied using event-related independent components analysis (eICA). This technique separates the fMRI signal changes observed during GSW discharges into different spatial components, each showing different event-related timing. Unlike standard independent components analysis (ICA), which is applied to the entire fMRI time series, the eICA method is applied only to the event-related time courses at each voxel, which means that only a small number of components are generated that are all explicitly related to the event of interest. Key Findings: Six eICA components were identified, representing distinct GSW-related subnetworks. Activations were detected in a number of brain regions, including the striatum, which have not previously been reported in association with GSW in CAE patients. Significance: The eICA results support previous findings that the earliest activity associated with GSW may be in posterior cortical regions and provide new evidence that the thalamostriate network may play a more important role in the generation of GSW than suggested by previous studies. KEY WORDS: Event-related independent components analysis, Hemodynamic response, Generalized spike and wave, Thalamus, Striatum.Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) studies of childhood absence epilepsy (CAE) have shown that the characteristic generalized spike-and-wave (GSW) discharges are associated with "activations" and "deactivations" within a network of cortical and subcortical brain regions (Labate et al., 2005;Moeller et al., 2008a;Bai et al., 2010;Carney et al., 2010). The event-related fMRI signal changes within these regions, however, show marked differences to a standard evoked fMRI response (Moeller et al., 2008b;Bai et al., 2010;Carney et al., 2010); the underlying brain activity is therefore not easily classified in terms of activation or deactivation (Carney et al., 2012). Furthermore, there are significant differences between the timing of GSW-related fMRI signal changes in different regions (Moeller et al., 2008b;Bai et al., 2010;Carney et al., 2010), which suggests activities within multiple interacting networks rather than a single unified network.These findings of complex GSW-related brain responses suggest that standard fMRI analyses-based on a "canonical" model of the hemodynamic response function (HRF)-are unsuitable for studying these events. An alternative approach, as used in some previous studies (Moeller et al., 2008b;Bai...

These observations suggest that there may be at least 2 mechanisms underpinning AS in individuals with absence epilepsy. This may have phenotypic and genetic implications for understanding epilepsy syndromes.

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