Generalized Spike-and-wave Discharges Research Articles

Differences in generation and maintenance between ictal and interictal generalized spike-and-wave discharges in childhood absence epilepsy: A magnetoencephalography study

PurposeChildhood absence epilepsy (CAE) is characterized by impaired consciousness and distinct electroencephalogram (EEG) patterns. However, interictal epileptiform discharges (IEDs) do not lead to noticeable symptoms. This study examines the disparity between ictal and interictal generalized spike-and-wave discharges (GSWDs) to determine the mechanisms behind CAE and consciousness. MethodsWe enrolled 24 patients with ictal and interictal GSWDs in the study. The magnetoencephalography (MEG) data were recorded before and during GSWDs at a sampling rate of 6000 Hz and analyzed across six frequency bands. The absolute and relative spectral power were estimated with the Minimum Norm Estimate (MNE) combined with the Welch technique. All the statistical analyses were performed using paired-sample tests. ResultsDuring GSWDs, the right lateral occipital cortex indicated a significant difference in the theta band (5–7 Hz) with stronger power (P = 0.027). The interictal group possessed stronger spectral power in the delta band (P < 0.01) and weaker power in the alpha band (P < 0.01) as early as 10 s before GSWDs in absolute and relative spectral power. Additionally, the ictal group revealed enhanced spectral power inside the occipital cortex in the alpha band and stronger spectral power in the right frontal regions within beta (15–29 Hz), gamma 1 (30–59 Hz), and gamma 2 (60–90 Hz) bands. ConclusionsGSWDs seem to change gradually, with local neural activity changing even 10 s before discharge. During GSWDs, visual afferent stimulus insensitivity could be related to the impaired response state in CAE. The inhibitory signal in the low-frequency band can shorten GSWD duration, thereby achieving seizure control through inhibitory effect strengthening.

Altered brain state during episodic dystonia in tottering mice decouples primary motor cortex from limb kinematics.

Episodic Ataxia Type 2 (EA2) is a rare neurological disorder caused by a mutation in the CACNA1A gene, encoding the P/Q-type voltage-gated Ca2+ channel important for neurotransmitter release. Patients with this channelopathy exhibit both cerebellar and cerebral pathologies, suggesting the condition affects both regions. The tottering (tg/tg) mouse is the most commonly used EA2 model due to an orthologous mutation in the cacna1a gene. The tg/tg mouse has three prominent behavioral phenotypes: a dramatic episodic dystonia; absence seizures with generalized spike and wave discharges (GSWDs); and mild ataxia. We previously observed a novel brain state, transient low-frequency oscillations (LFOs) in the cerebellum and cerebral cortex under anesthesia. In this study, we examine the relationships among the dystonic attack, GSWDs, and LFOs in the cerebral cortex. Previous studies characterized LFOs in the motor cortex of anesthetized tg/tg mice using flavoprotein autofluorescence imaging testing the hypothesis that LFOs provide a mechanism for the paroxysmal dystonia. We sought to obtain a more direct understanding of motor cortex (M1) activity during the dystonic episodes. Using two-photon Ca2+ imaging to investigate neuronal activity in M1 before, during, and after the dystonic attack, we show that there is not a significant change in the activity of M1 neurons from baseline through the attack. We also conducted simultaneous, multi-electrode recordings to further understand how M1 cellular activity and local field potentials change throughout the progression of the dystonic attack. Neither putative pyramidal nor inhibitory interneuron firing rate changed during the dystonic attack. However, we did observe a near complete loss of GSWDs during the dystonic attack in M1. Finally, using spike triggered averaging to align simultaneously recorded limb kinematics to the peak Ca2+ response, and vice versa, revealed a reduction in the spike triggered average during the dystonic episodes. Both the loss of GSWDs and the reduction in the coupling suggest that, during the dystonic attack, M1 is effectively decoupled from other structures. Overall, these results indicate that the attack is not initiated or controlled in M1, but elsewhere in the motor circuitry. The findings also highlight that LFOs, GSWDs, and dystonic attacks represent three brain states in tg/tg mice.

The inhibition mechanism of epilepsy disease in a computational model.

BACKGROUND: The mechanism of prevention and treatment of epilepsy is a hot issue in theoretical research.OBJECTIVE: In this paper, we studied the control mechanism of the generalized spike-and-wave discharges (GSWD) by different types of external electrical stimulation acting on the subthalamic nucleus (STN) in a computational model.METHODS: Firstly, we analyzed the pathological mechanism of seizures, which were induced by different parameters in the thalamocortical (TC) circuit. Then, a voltage V was exerted in the STN. At last, we used the sine wave and square wave current stimulation in the STN.RESULTS: We found that seizures can be inhibited by tuning stimulus intensity into suitable range, and the direction of adjustment depended on the size of the parameter. We observed that the seizure can also be inhibited by tuning different parameters in current.CONCLUSIONS: Different inhibition mechanisms can be explained in this model, which may provide theoretical evidences for selecting the optimal treatment scheme in the clinical.

Effects of ketamine on EEG in baboons with genetic generalized epilepsy

Ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, used as an anesthetic has been reported to induce seizures both in humans and baboons predisposed to epilepsy. In this study, we aimed to characterize the acute effects of ketamine on scalp (sc-EEG) and intracranial EEG (ic-EEG) in the baboon, which offers a natural model of genetic generalized epilepsy (GGE). We evaluated the electroclinical response to ketamine in three epileptic baboons. The raw EEG data were analyzed within 10 min of intramuscular ketamine (5–6 mg/kg) administration. Earliest EEG changes occurred after 30 s in sc-EEG and after 15 s in ic-EEG of ketamine administration. These initial changes involved increased paroxysmal fast activity (PFA) followed by slowing, the latter emerging first occipitally, and then spreading more anteriorly. Generalized spike-and-wave discharges (GSWDs) were evident on both sc-EEG and ic-EEG within two minutes, but focal occipital discharges were already increased on ic-EEG after 15 s. Occipital slowing emerged on ic-EEG after 30 s, before spreading fronto-centrally and orbito-frontally. By 60–120 seconds post-injection, ic-EEG demonstrated a parieto-occipital burst suppression (BS), which was not noted on sc-EEG. Ketamine waves and seizures, especially if the latter were subclinical, also appeared earlier on ic-EEG. This study highlights the anesthetic and proconvulsant effects of ketamine originate in the occipital lobes before fronto-central regions. We speculate that NMDAR concentration difference in cortical regions, such as the occipital and frontal cortices, are mainly involved in the expression of ketamine’s EEG effects, both physiological and epileptic.

Synchronicity and Rhythmicity of Purkinje Cell Firing during Generalized Spike-and-Wave Discharges in a Natural Mouse Model of Absence Epilepsy.

Absence epilepsy is characterized by the occurrence of generalized spike and wave discharges (GSWDs) in electrocorticographical (ECoG) recordings representing oscillatory activity in thalamocortical networks. The oscillatory nature of GSWDs has been shown to be reflected in the simple spike activity of cerebellar Purkinje cells and in the activity of their target neurons in the cerebellar nuclei, but it is unclear to what extent complex spike activity is implicated in generalized epilepsy. Purkinje cell complex spike firing is elicited by climbing fiber activation and reflects action potential firing in the inferior olive. Here, we investigated to what extent modulation of complex spike firing is reflected in the temporal patterns of seizures. Extracellular single-unit recordings in awake, head-restrained homozygous tottering mice, which suffer from a mutation in the voltage-gated CaV2.1 calcium channel, revealed that a substantial proportion of Purkinje cells (26%) showed increased complex spike activity and rhythmicity during GSWDs. Moreover, Purkinje cells, recorded either electrophysiologically or by using Ca2+-imaging, showed a significant increase in complex spike synchronicity for both adjacent and remote Purkinje cells during ictal events. These seizure-related changes in firing frequency, rhythmicity and synchronicity were most prominent in the lateral cerebellum, a region known to receive cerebral input via the inferior olive. These data indicate profound and widespread changes in olivary firing that are most likely induced by seizure-related activity changes in the thalamocortical network, thereby highlighting the possibility that olivary neurons can compensate for pathological brain-state changes by dampening oscillations.

Generalized paroxysmal fast activity in EEG: An unrecognized finding in genetic generalized epilepsy

ObjectiveTo study generalized paroxysmal fast activity (GPFA) in patients with genetic generalized epilepsy (GGE). IntroductionGPFA is an electroencephalographic (EEG) finding in patients with symptomatic generalized epilepsy consisting of 15-25Hz bifrontally predominant generalized fast activity seen predominantly in sleep. Historically GPFA is linked to epileptic encephalopathy with drug resistant epilepsy and intellectual disability. However, GPFA has been rarely described as an atypical finding in patients with GGE without negative prognostic implication. We report cognitive profile and seizure characteristics in seven patients with GGE and GPFA. MethodsThe Vanderbilt EMU and EEG reports were searched for the keywords “idiopathic generalized epilepsy”, “GPFA”and “generalized spike and wave discharges (GSWD)”. We reviewed the EEG tracings and the electronic medical records of patients thus identified. The seizure type, frequency, neurological work-up, clinical profile and imaging data were recorded. ResultsAwake and sleep states were captured on EEGs of all patients. On EEG tracing review six patients were confirmed to have GSWD and GPFA; one patient had GPFA but no GSWD. All patients had normal cognitive function. Four had a normal brain MRI and one a normal head CT (two were never imaged). None of the patients had tonic seizures. The main seizure type was generalized tonic-clonic seizures (GTCS) in five patients, absence in two. Age at onset of epilepsy ranged from 4 to 24years. The mean GTC seizure frequency at the time of EEG was 3; two patients were seizure free on two antiepileptic drugs (AEDs). ConclusionsGPFA can be an unrecognized electrographic finding in patients with genetic generalized epilepsy. While GPFA remains an important diagnostic EEG feature for epileptic encephalopathy (Lennox-Gastaut syndrome) it is not specific for this diagnosis. Thus, GPFA may have a spectrum of variable phenotypic expression. The finding of GPFA is not necessarily indicative of unfavorable outcome.

Analysis of epidemiological, clinical and therapeutic aspects. Epilepsy with absence seizures (EAS)

Objective: To analyse the epidemiological, clinical and therapeutic aspects of EAS to identify possible prognostic factors. Patients and methods: Retrospective descriptive study from January 2009 to December 2015 of patients <14 years diagnosed of epilepsy with EAS in a referral Centre. Results: We identified 42 cases; 34/42 were childhood absences epilepsy (CAE) and 8/42 were juvenile absence epilepsys (JAE). Mean time until diagnose after onset of symptoms was 6 months, with the majority (37/42) showing multiple daily seizuresattacks. EEG showed found 3 Hz generalized spike-and-wave (GSW) discharges in all cases with a mean duration of 10.2 s in CAE and 5 s in JAE with additional paroxysm in 12/42 (4/12 bifrontal,3/12 frontotemporal,2/12 biparietal and 3/13 temporal). Valproic acid was started in 39/42 and ethosuximide associated in 9/42 refractory cases. Refractory patients presented with spontaneous GSW discharges in 7/9 occasions in the EEG, with a mean duration of 14.7 s. Temporal paroxysms was found in 3/9. Mean time until diagnose was 8.5 months. Myoclonic seizures were present in 1/34 of CAE cases, tonic clonic seizures in 8/34 versus 4/8 of the JAE cases. Refractory crisis were present at 2 years in 3/42 cases, relapses in 4/42 cases, of which 3/4 did not reach optimal school level. Conclusions: We observed that a time until diagnose greater than 9 months, spontaneous 3 Hz GSW, duration of discharges greater than 15 s as well as temporal paroxysms were related to poor response to treatment. It is advisable to increase the study population to draw solid conclusions.

Brain correlates of spike and wave discharges in GLUT1 deficiency syndrome

PurposeTo provide imaging biomarkers of generalized spike-and-wave discharges (GSWD) in patients with GLUT1 deficiency syndrome (GLUT1DS).MethodsEighteen GLUT1DS patients with pathogenetic mutation in SLC2A1 gene were studied by means of Video-EEG simultaneously recorded with functional MRI (VideoEEG-fMRI). A control group of sex and age-matched patients affected by Genetic Generalized Epilepsy (GGE) with GSWD were investigated with the same protocol. Within and between groups comparison was performed as appropriated. For GLUT1DS, correlations analyses between the contrast of interest and the main clinical measurements were provided.ResultsEEG during fMRI revealed interictal GSWD in 10 GLUT1DS patients. Group-level analysis showed BOLD signal increases at the premotor cortex and putamen. With respect to GGE, GLUT1DS patients demonstrated increased neuronal activity in the putamen, precuneus, cingulate cortex, SMA and paracentral lobule. Whole-brain correlation analyses disclosed a linear relationship between the GSWD-related BOLD changes and the levels of glycorrhachia at diagnosis over the sensory-motor cortex and superior parietal lobuli.ConclusionThe BOLD dynamics related to GSWD in GLUT1DS are substantially different from typical GGE showing the former an increased activity in the premotor-striatal network and a decrease in the thalamus. The revealed hemodynamic maps might represent imaging biomarkers of GLUT1DS, being potentially useful for a precocious diagnosis of this genetic disorder.

Temporal current-source of spikes suggests initial treatment failure in childhood absence epilepsy

PurposeIn addition to the frontal lobe, the temporal lobe may also be involved in typical absence seizures. However, few studies have addressed the relationship between this involvement and drug responsiveness in childhood absence epilepsy (CAE). In this study, we observed the current-source distribution (CSD) of generalized spike-and-wave discharges (GSWDs) and investigated the relationship between temporal lobe involvement in the CSD and responsiveness to initial antiepileptic drug (AED) in CAE. MethodSeventeen consecutive patients with CAE were retrospectively enrolled in the study. Patients were divided into an initial-response group and an initial-failure group, according to their responsiveness to the initial AED treatment. For each patient, the spike peak CSD of an averaged GSWD was obtained from the initial electroencephalogram. We compared the incidence of temporal involvement in the CSD between the two groups. We also compared clinical variables, including age of onset, gender, type and dose of first AED, time to cessation of clinical seizures, and seizure-free status. ResultsThe initial-response and initial-failure groups contained 12 and five patients, respectively. Temporal lobe involvement was more frequent (80% vs. 17%, p=0.03), and time to cessation of clinical seizures was more prolonged (median 2.5 months vs. 8 months, p<0.01) in the initial-failure than in the initial-response group. None of the other variables studied differed between groups. ConclusionInitial AED failure was associated with temporal involvement in the CSD of CAE patients. This electrophysiological information may be helpful in clinical practice by estimating the efficacy of initial AED treatment in AED-naïve CAE patients in advance.

An EEG-fMRI Study on the Termination of Generalized Spike-And-Wave Discharges in Absence Epilepsy.

IntroductionDifferent studies have investigated by means of EEG-fMRI coregistration the brain networks related to generalized spike-and-wave discharges (GSWD) in patients with idiopathic generalized epilepsy (IGE). These studies revealed a widespread GSWD-related neural network that involves the thalamus and regions of the default mode network. In this study we investigated which brain regions are critically involved in the termination of absence seizures (AS) in a group of IGE patients.MethodsEighteen patients (6 male; mean age 25 years) with AS were included in the EEG-fMRI study. Functional data were acquired at 3T with continuous simultaneous video-EEG recording. Event-related analysis was performed with SPM8 software, using the following regressors: (1) GSWD onset and duration; (2) GSWD offset. Data were analyzed at single-subject and at group level with a second level random effect analysis.ResultsA mean of 17 events for patient was recorded (mean duration of 4.2 sec). Group-level analysis related to GSWD onset respect to rest confirmed previous findings revealing thalamic activation and a precuneus/posterior cingulate deactivation. At GSWD termination we observed a decrease in BOLD signal over the bilateral dorsolateral frontal cortex respect to the baseline (and respect to GSWD onset). The contrast GSWD offset versus onset showed a BOLD signal increase over the precuneus-posterior cingulate region bilaterally. Parametric correlations between electro-clinical variables and BOLD signal at GSWD offset did not reveal significant effects.ConclusionThe role of the decreased neural activity of lateral prefrontal cortex at GSWD termination deserve future investigations to ascertain if it has a role in promoting the discharge offset, as well as in the determination of the cognitive deficits often present in patients with AS. The increased BOLD signal at precuneal/posterior cingulate cortex might reflect the recovery of neural activity in regions that are “suspended” during spike and waves activity, as previously hypothesized.

Cerebellar output controls generalized spike-and-wave discharge occurrence.

ObjectiveDisrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike‐and‐wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures.MethodsTwo unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short‐lasting, on‐demand CN stimulation could disrupt epileptic seizures.ResultsWe found that a subset of CN neurons show phase‐locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ‐aminobutyric acid type A (GABA‐A) agonist muscimol increased GSWD occurrence up to 37‐fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA‐A antagonist gabazine decimated its occurrence. A single short‐lasting (30–300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed‐loop system, GSWDs were detected and stopped within 500 milliseconds.InterpretationCN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated. Ann Neurol 2015;77:1027–1049

Thalamocortical relationship in epileptic patients with generalized spike and wave discharges--A multimodal neuroimaging study.

Unlike focal or partial epilepsy, which has a confined range of influence, idiopathic generalized epilepsy (IGE) often affects the whole or a larger portion of the brain without obvious, known cause. It is important to understand the underlying network which generates epileptic activity and through which epileptic activity propagates. The aim of the present study was to investigate the thalamocortical relationship using non-invasive imaging modalities in a group of IGE patients. We specifically investigated the roles of the mediodorsal nuclei in the thalami and the medial frontal cortex in generating and spreading IGE activities. We hypothesized that the connectivity between these two structures is key in understanding the generation and propagation of epileptic activity in brains affected by IGE. Using three imaging techniques of EEG, fMRI and EEG-informed fMRI, we identified important players in generation and propagation of generalized spike-and-wave discharges (GSWDs). EEG-informed fMRI suggested multiple regions including the medial frontal area near to the anterior cingulate cortex, mediodorsal nuclei of the thalamus, caudate nucleus among others that related to the GSWDs. The subsequent seed-based fMRI analysis revealed a reciprocal cortical and bi-thalamic functional connection. Through EEG-based Granger Causality analysis using (DTF) and adaptive DTF, within the reciprocal thalamocortical circuitry, thalamus seems to serve as a stronger source in driving cortical activity from initiation to the propagation of a GSWD. Such connectivity change starts before the GSWDs and continues till the end of the slow wave discharge. Thalamus, especially the mediodorsal nuclei, may serve as potential targets for deep brain stimulation to provide more effective treatment options for patients with drug-resistant generalized epilepsy.

Analysis of generalized interictal discharges using quantitative EEG

Experimental evidence from animal models of the absence seizures suggests a focal source for the initiation of generalized spike-and-wave (GSW) discharges. Furthermore, clinical studies indicate that patients diagnosed with idiopathic generalized epilepsy (IGE) exhibit focal electroencephalographic abnormalities, which involve the thalamo-cortical circuitry. This circuitry is a key network that has been implicated in the initiation of generalized discharges, and may contribute to the pathophysiology of GSW discharges. Quantitative electroencephalogram (qEEG) analysis may be able to detect abnormalities associated with the initiation of GSW discharges. The objective of this study was to determine whether interictal GSW discharges exhibit focal characteristics using qEEG analysis. In this study, 75 EEG recordings from 64 patients were analyzed. All EEG recordings analyzed contained at least one GSW discharge. EEG recordings were obtained by a 22-channel recorder with electrodes positioned according to the international 10-20 system of electrode placement. EEG activity was recorded for 20 min including photic stimulation and hyperventilation. The EEG recordings were visually inspected, and the first unequivocally confirmed generalized spike was marked for each discharge. Three methods of source imaging analysis were applied: dipole source imaging (DSI), classical LORETA analysis recursively applied (CLARA), and equivalent dipole of independent components with cluster analysis. A total of 753 GSW discharges were identified and spatiotemporally analyzed. Source evaluation analysis using all three techniques revealed that the frontal lobe was the principal source of GSW discharges (70%), followed by the parietal and occipital lobes (14%), and the basal ganglia (12%). The main anatomical sources of GSW discharges were the anterior cingulate cortex (36%) and the medial frontal gyrus (23%). Source analysis did not reveal a common focal source of GSW discharges. However, there was a predominance of GSW discharges originating from the cingulate gyrus and the frontal lobe.

Jeavons syndrome in China

ObjectivesJeavons syndrome (JS) is one of the underreported epileptic syndromes and is characterized by eyelid myoclonia (EM), eye closure-induced seizures or electroencephalography (EEG) paroxysms, and photosensitivity. In the Western populations, it has been reported to be characterized by focal posterior, occipital predominant epileptiform discharges (OPEDs) or frontal predominant epileptiform discharges (FPEDs) followed by generalized EDs in both interictal and ictal EEG recordings. However, it is not clear if there are different clinical manifestations between OPEDs and FPEDs. The clinical and electrographic presentations in the Chinese population are largely unknown. Here, we report the clinical and electroencephalographic features of 50 Chinese patients with JS and evaluate for the presence of different clinical features between patients with OPEDs and patients with FPEDs. MethodsWe identified 50 cases who met the Jeavons syndrome criteria from 4230 patients with epilepsy at Xijing Hospital, Xi'an, China from the period of January 2010 to November 2011. These patients underwent long-term 24-hour video-EEG recording. Brain imaging was performed using magnetic resonance imaging (MRI) or computerized tomography (CT). Webster IQ testing was performed to determine intellectual development. We reviewed and described the interictal abnormalities, ictal EEG pattern, and demographic, clinical, and neuroimaging findings of these 50 Chinese patients in Xi'an. We divided the 50 patients into two groups according to the predominance of EDs and analyzed their clinical features. ResultsTwenty-five of these 50 patients were male. Twenty-two out of 32 patients in the group with FPEDs were male, and 3/18 patients in the group with OPEDs were male. The median age of EMA–EM onset in FPEDs was 8years and that in OPEDs was 5.8years. Eyelid myoclonia occurred in all the 50 patients. Twenty-one out of 32 patients in the group with FPEDs had EM with absences, and 14/32 of them had EM with eyeball rolling up. Two out of 18 patients in the group with OPEDs had EM with absences, and only 1 of 18 had EM with eyeball rolling up. ConclusionEyelid myoclonia with or without absences or JS diagnosis is easily missed and underreported in China. As an IGE, either the frontal or the occipital lobe may initiate generalized spike-and-wave discharges (GSWDs) and generalized seizures (GSs). There may be two subtypes of JS with distinctive clinical and electroencephalogrphic features: a predominantly male group with frontal predominant epileptiform discharges, eyelid myoclonia, and eyes rolling up and a predominantly female group with occipital predominant epileptiform discharges with eyelid myoclonia alone.

Differences in paracingulate connectivity associated with epileptiform discharges and uncontrolled seizures in genetic generalized epilepsy

Patients with genetic generalized epilepsy (GGE) frequently continue to have seizures despite appropriate clinical management. GGE is associated with changes in the resting-state networks modulated by clinical factors such as duration of disease and response to treatment. However, the effect of generalized spike and wave discharges (GSWDs) and/or seizures on resting-state functional connectivity (RSFC) is not well understood. We investigated the effects of GSWD frequency (in GGE patients), GGE (patients vs. healthy controls), and seizures (uncontrolled vs. controlled) on RSFC using seed-based voxel correlation in simultaneous electroencephalography (EEG) and resting-state functional magnetic resonance imaging (fMRI) (EEG/fMRI) data from 72 GGE patients (23 with uncontrolled seizures) and 38 healthy controls. We used seeds in paracingulate cortex, thalamus, cerebellum, and posterior cingulate cortex to examine changes in cortical-subcortical resting-state networks and the default mode network (DMN). We excluded from analyses time points surrounding GSWDs to avoid possible contamination of the resting state. (1) Higher frequency of GSWDs was associated with an increase in seed-based voxel correlation with cortical and subcortical brain regions associated with executive function, attention, and the DMN; (2) RSFC in patients with GGE, when compared to healthy controls, was increased between paracingulate cortex and anterior, but not posterior, thalamus; and (3) GGE patients with uncontrolled seizures exhibited decreased cerebellar RSFC. Our findings in this large sample of patients with GGE (1) demonstrate an effect of interictal GSWDs on resting-state networks, (2) provide evidence that different thalamic nuclei may be affected differently by GGE, and (3) suggest that cerebellum is a modulator of ictogenic circuits.

Epileptic discharges specifically affect intrinsic connectivity networks during absence seizures

Intrinsic connectivity network (ICN) technique provides a feasible way for evaluating cognitive impairments in epilepsy. This EEG–fMRI study aims to comprehensively assess the alterations of ICNs affected by generalized spike-and-wave discharge (GSWD) during absence seizure (AS). Twelve fMRI sessions with GSWD, and individually paired non-GSWD sessions were acquired from 16 patients with AS. Ten ICNs corresponding to seizure origination and cognitive processes were extracted using independent component analysis. Intra- and inter-network connectivity alterations of the ICNs were observed through comparisons between GSWD and non-GSWD sessions. Sequential correlation analysis between GSWD and the ICN time courses addressed the immediate effects of GSWD on ICNs during AS. GSWD-related increase of intra-network connectivity was found only in the thalamus, and extensive decreases were found in the ICNs corresponding to higher-order cognitive processes including the default-mode network, dorsal attention network, central executive network and salience network. The perceptive networks and motor network were less affected by GSWD. Sequential correlation analysis further demonstrated different responses of the ICNs to GSWD. In addition to GSWD-related functional excitation in the thalamus and functional suspension in the default-mode network, this study revealed extensive inhibitions in the other ICNs corresponding to higher-order cognitive processes, and spared perceptive and motor processes in AS. GSWD elevated synchronization of brain network activity and sequentially affected the ICNs.

Localization of Generalized Spike and Wave Discharge and Valproate Response

Investigators at Universities of Cincinnati, OH, and Birmingham, Alabama; and Montreal Neurological Institute, Canada, studied the EEG and functional magnetic resonance imaging (fMRI) in 89 patients with idiopathic generalized epilepsy (IGE), (25 with generalized spike and wave discharges (GSWD) identified in EEG), and compared patients with valproate (VPA)-refractory and VPA-responsive IGE.

Absence epilepsy subnetworks revealed by event‐related independent components analysis of functional magnetic resonance imaging

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. 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. 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. 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.

The relationship between the localization of the generalized spike and wave discharge generators and the response to valproate

Up to 30% of patients with idiopathic generalized epilepsy (IGE) have seizures that are refractory to medication despite appropriate therapy that commonly includes valproate (VPA). The aim of this study was to compare patients with VPA-refractory and VPA-responsive IGE in order to determine whether there are group differences in generalized spike and wave discharge (GSWD) generators that may be associated with VPA resistance. Of 89 IGE patients who underwent electroencephalography (EEG) combined with functional magnetic resonance imaging (fMRI; EEG/fMRI), 25 with GSWDs identified in EEG/fMRI data were included. Simultaneous acquisition of 64 channels of EEG data at 10 kHz was performed using an MRI-compatible EEG cap and amplifier at 4T. VPA resistance was defined as lack of seizure control despite therapeutic dose of VPA. The fMRI blood oxygen-level dependent (BOLD) correlates of GSWD in the entire group involved midline thalamus, frontal regions comprising Brodmann areas 6, 24, and 32, and temporal lobes diffusely. When VPA-responsive and VPA-resistant patients were compared, BOLD signal increases were noted in the VPA-resistant patients in medial frontal cortex, along the paracingulate gyrus (Montreal Neurological Institute; MNI x = 2, y = 13.6, z = 45.9), and anterior insula bilaterally (right MNI x = 37.6, y = 7.8, z = 0.6, left MNI x = -35.3, y = 13.6, z = -5.3). Our findings support the hypothesis that VPA-resistant and VPA-responsive patients may have different GSWD generators. Furthermore, we hypothesize that these differences in GSWD generators may be the reason for different responses to VPA.

Analysis of Generalized Interictal Discharges Using Dipole Source Imaging (P04.014)

Objective: The objective of this study was to investigate focal spatiotemporal characteristics of the scalp interictal generalized spike and wave (GSW) discharges in patients with idiopathic generalized epilepsies (IGE) using quantitative electroencephalogram (qEEG). Background Investigations have shown that patients with IGE have mild focalities. These focal abnormalities probably are related with IGE mechanisms which involves the thalamo-cortical circuitry. Experimental investigations points to a focal onset of the GSW discharges in models of absence seizure. qEEG analysis may be able to detect subtle focalities in these patients. Design/Methods: 21 patients (8 woman, mean age 29±12 years) with IGE were investigated. Subjects underwent routine EEG which was performed with a 19-channel recorder, 20 minutes duration, 10-20 system of electrode placement, photic stimulation and hyperventilation. EEGLAB software was used for EEG processing and analysis. All GSW discharges were entirely selected and stored. Discharges were submitted to decomposition into temporally independent and spatially fixed components by independent component analysis. For dipole fitting a spherical four-shell head model and nonlinear adjustment were used. A single equivalent dipole source model was calculated for each component. To identify common patterns of discharge propagation cluster analysis of the equivalent dipole obtained for each component was used. Closely located dipole sources were classified into same subsets (clusters). Results: 207 discharges (mean 10±16 per patient, range 1-73) were evaluated. In 14 patients (81%) source analysis showed the main independent component cluster (ICC) centroid localized in the cingulate gyrus. In 5 patients ICC centroid was localized in basal ganglia and in 2 patients ICC centroid was in the frontal lobe (orbital and middle frontal gyrus). Conclusions: There is not a common source for the GSW discharges in patients with IGE. However, it was disclosed a clear-cut focal predominance in the cingulate gyrus and frontal regions. Supported by: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP). Disclosure: Dr. Betting has nothing to disclose. Dr. Blasque has nothing to disclose. Dr. Pereira has nothing to disclose. Dr. Fonseca has nothing to disclose. Dr. Betting has nothing to disclose.