A nonsynaptic mechanism underlying interictal discharges in human epileptic neocortex.
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ABSTRACT:
SUBMITTER: Roopun AK
PROVIDER: S-EPMC2806783 | biostudies-literature | 2010 Jan
REPOSITORIES: biostudies-literature
Publications
A nonsynaptic mechanism underlying interictal discharges in human epileptic neocortex.
Roopun Anita K AK Simonotto Jennifer D JD Pierce Michelle L ML Jenkins Alistair A Nicholson Claire C Schofield Ian S IS Whittaker Roger G RG Kaiser Marcus M Whittington Miles A MA Traub Roger D RD Cunningham Mark O MO
Proceedings of the National Academy of Sciences of the United States of America 20091204 1
Very fast oscillations (VFOs, >80 Hz) are important for physiological brain processes and, in excess, with certain epilepsies. Putative mechanisms for VFO include interneuron spiking and network activity in coupled pyramidal cell axons. It is not known whether either, or both, of these apply in pathophysiological conditions. Spontaneously occurring interictal discharges occur in human tissue in vitro, resected from neocortical epileptic foci. VFO associated with these discharges was manifest in ...[more]
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Project description:ObjectiveTo explore the relationship between functional connectivity and presence of interictal epileptic discharges (IEDs) in different brain regions in intracranial EEG (iEEG).MethodsWe studied 38 focal epilepsy patients who underwent simultaneous EEG/fMRI scanning and subsequent intracerebral stereo-EEG investigation. In EEG/fMRI analysis, IEDs with different spatial distributions were considered independent studies and IED-related maximal BOLD responses were evaluated. Studies with iEEG electrodes inside the maximal responses were selected and divided into three groups: Studies with 1. distinct maximal BOLD highly concordant with seizure-onset-zone (SOZ); 2. Moderate maximal BOLD concordant with SOZ; 3. maximal BOLD discordant with SOZ. Using maximal BOLD as seed, its functionally connected zone (FCZ) was determined. IED rates in iEEG channels inside and outside the FCZ were compared in the three groups. The effect of laterality and distance between channels and maximal BOLD, and correlation between functional connectivity values and IED rates were analyzed.ResultsThirty-six studies in 25 patients were included. IED rates of intracranial EEG channels inside the FCZ were significantly higher than outside in Group 1 (p = 2.6×10-6) and Group 2 (p = 1.2×10-3) and the inside-outside difference remained after regressing distance and laterality factors. In Group 1, connectivity values were significantly correlated with IED rates in channels inside the FCZ (p < 0.05).SignificanceOur results indicate a higher probability of finding intracranial IEDs in the FCZ of SOZ-concordant maximal BOLD responses than in other regions, regardless of distance and laterality. In studies with distinct maximal BOLD, connectivity values can partially predict IED rates in intracranial EEG. It is thus feasible to non-invasively delineate brain regions that are likely to have high IED rates.
| S-EPMC6861611 | biostudies-literature
Project description:ObjectiveTo explore the relationship between functional connectivity and presence of interictal epileptic discharges (IEDs) in different brain regions in intracranial EEG (iEEG).MethodsWe studied 38 focal epilepsy patients who underwent simultaneous EEG/fMRI scanning and subsequent intracerebral stereo-EEG investigation. In EEG/fMRI analysis, IEDs with different spatial distributions were considered independent studies and IED-related maximal BOLD responses were evaluated. Studies with iEEG electrodes inside the maximal responses were selected and divided into three groups: Studies with 1. distinct maximal BOLD highly concordant with seizure-onset-zone (SOZ); 2. Moderate maximal BOLD concordant with SOZ; 3. maximal BOLD discordant with SOZ. Using maximal BOLD as seed, its functionally connected zone (FCZ) was determined. IED rates in iEEG channels inside and outside the FCZ were compared in the three groups. The effect of laterality and distance between channels and maximal BOLD, and correlation between functional connectivity values and IED rates were analyzed.ResultsThirty-six studies in 25 patients were included. IED rates of intracranial EEG channels inside the FCZ were significantly higher than outside in Group 1 (p = 2.6×10-6) and Group 2 (p = 1.2×10-3) and the inside-outside difference remained after regressing distance and laterality factors. In Group 1, connectivity values were significantly correlated with IED rates in channels inside the FCZ (p < 0.05).SignificanceOur results indicate a higher probability of finding intracranial IEDs in the FCZ of SOZ-concordant maximal BOLD responses than in other regions, regardless of distance and laterality. In studies with distinct maximal BOLD, connectivity values can partially predict IED rates in intracranial EEG. It is thus feasible to non-invasively delineate brain regions that are likely to have high IED rates.
| S-EPMC6861611 | biostudies-literature
Project description:ObjectiveTo explore the relationship between functional connectivity and presence of interictal epileptic discharges (IEDs) in different brain regions in intracranial EEG (iEEG).MethodsWe studied 38 focal epilepsy patients who underwent simultaneous EEG/fMRI scanning and subsequent intracerebral stereo-EEG investigation. In EEG/fMRI analysis, IEDs with different spatial distributions were considered independent studies and IED-related maximal BOLD responses were evaluated. Studies with iEEG electrodes inside the maximal responses were selected and divided into three groups: Studies with 1. distinct maximal BOLD highly concordant with seizure-onset-zone (SOZ); 2. Moderate maximal BOLD concordant with SOZ; 3. maximal BOLD discordant with SOZ. Using maximal BOLD as seed, its functionally connected zone (FCZ) was determined. IED rates in iEEG channels inside and outside the FCZ were compared in the three groups. The effect of laterality and distance between channels and maximal BOLD, and correlation between functional connectivity values and IED rates were analyzed.ResultsThirty-six studies in 25 patients were included. IED rates of intracranial EEG channels inside the FCZ were significantly higher than outside in Group 1 (p = 2.6×10-6) and Group 2 (p = 1.2×10-3) and the inside-outside difference remained after regressing distance and laterality factors. In Group 1, connectivity values were significantly correlated with IED rates in channels inside the FCZ (p < 0.05).SignificanceOur results indicate a higher probability of finding intracranial IEDs in the FCZ of SOZ-concordant maximal BOLD responses than in other regions, regardless of distance and laterality. In studies with distinct maximal BOLD, connectivity values can partially predict IED rates in intracranial EEG. It is thus feasible to non-invasively delineate brain regions that are likely to have high IED rates.
| S-EPMC6861611 | biostudies-literature
Project description:In EEG-fMRI studies, BOLD responses related to interictal epileptic discharges (IEDs) are most often the expected positive response (activation) but sometimes a surprising negative response (deactivation). The significance of deactivation in the region of IED generation is uncertain. The aim of this study was to determine if BOLD deactivation was caused by specific IED characteristics. Among focal epilepsy patients who underwent 3T EEG-fMRI from 2006 to 2011, those with negative BOLD having a maximum t-value in the IED generating region were selected. As controls, subjects with maximum activation in the IED generating region were selected. We established the relationship between the type of response (activation/deactivation) and (1) presence of slow wave in the IEDs, (2) lobe of epileptic focus, (3) occurrence as isolated events or bursts, (4) spatial extent of the EEG discharge. Fifteen patients with deactivation and 15 with activation were included. The IEDs were accompanied by a slow wave in 87 % of patients whose primary BOLD was a deactivation and only in 33 % of patients with activation. In the deactivation group, the epileptic focus was more frequently in the posterior quadrant and involved larger cortical areas, whereas in the activation group it was more frequently temporal. IEDs were more frequently of long duration in the deactivation group. The main factor responsible for focal deactivations is the presence of a slow wave, which is the likely electrographic correlate of prolonged inhibition. This adds a link to the relationship between electrophysiological and BOLD activities.
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Project description:Activation of astrocytes by neuronal signals plays a central role in the control of neuronal activity-dependent blood flow changes in the normal brain. The cellular pathways that mediate neurovascular coupling in the epileptic brain remain, however, poorly defined. In a cortical slice model of epilepsy, we found that the ictal, seizure-like discharge, and only to a minor extent the interictal discharge, evokes both a Ca(2+) increase in astrocyte endfeet and a vasomotor response. We also observed that rapid ictal discharge-induced arteriole responses were regularly preceded by Ca(2+) elevations in endfeet and were abolished by pharmacological inhibition of Ca(2+) signals in these astrocyte processes. Under these latter conditions, arterioles exhibited after the ictal discharge only slowly developing vasodilations. The poor efficacy of interictal discharges, compared with ictal discharges, to activate endfeet was confirmed also in the intact in vitro isolated guinea pig brain. Although the possibility of a direct contribution of neurons, in particular in the late response of cerebral blood vessels to epileptic discharges, should be taken into account, our study supports the view that astrocytes are central for neurovascular coupling also in the epileptic brain. The massive endfeet Ca(2+) elevations evoked by ictal discharges and the poor response to interictal events represent new information potentially relevant to interpret data from diagnostic brain imaging techniques, such as functional magnetic resonance, utilized in the clinic to localize neural activity and to optimize neurosurgery of untreatable epilepsies.
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Project description:IntroductionBlood oxygenation level-dependent (BOLD) signal changes at the time of interictal epileptic discharges (IEDs) identify their associated vascular/hemodynamic responses. BOLD activations and deactivations can be found within the epileptogenic zone but also at a distance. Source imaging identifies electric (ESI) and magnetic (MSI) sources of IEDs, with the advantage of a higher temporal resolution. Therefore, the objective of our study was to evaluate the spatial concordance between ESI/MSI and BOLD responses for similar IEDs.MethodsTwenty-one patients with similar IEDs in simultaneous electroencephalogram/functional magnetic resonance imaging (EEG/fMRI) and in simultaneous EEG/magnetoencephalogram (MEG) recordings were studied. IEDs in EEG/fMRI acquisition were analyzed in an event-related paradigm within a general linear model (GLM). ESI/MSI of averaged IEDs was performed using the Maximum Entropy on the Mean. We assessed the spatial concordance between ESI/MSI and clusters of BOLD activations/deactivations with surface-based metrics.ResultsESI/MSI were concordant with one BOLD cluster for 20/21 patients (concordance with activation: 14/21 patients, deactivation: 6/21 patients, no concordance: 1/21 patients; concordance with MSI only: 3/21, ESI only: 2/21). These BOLD clusters exhibited in 19/20 cases the most significant voxel. BOLD clusters that were spatially concordant with ESI/MSI were concordant with IEDs from invasive recordings in 8/11 patients (activations: 5/8, deactivations: 3/8).ConclusionAs the results of BOLD, ESI and MSI are often concordant, they reinforce our confidence in all of them. ESI and MSI confirm the most significant BOLD cluster within BOLD maps, emphasizing the importance of these clusters for the definition of the epileptic focus.
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Project description:PurposeInterictal epileptic discharges (IEDs) are known to affect cognitive function in patients with epilepsy, but the mechanism has not been elucidated. Sleep spindles appearing in synchronization with IEDs were recently demonstrated to impair memory consolidation in rat, but this has not been investigated in humans. On the other hand, the increase of sleep spindles at night after learning is positively correlated with amplified learning effects during sleep for motor sequence learning. In this study, we examined the effects of IEDs and IED-coupled spindles on motor sequence learning in patients with epilepsy, and clarified their pathological significance.Materials and methodsPatients undergoing long-term video-electroencephalography (LT-VEEG) at our hospital from June 2019 to November 2021 and age-matched healthy subjects were recruited. Motor sequence learning consisting of a finger-tapping task was performed before bedtime and the next morning, and the improvement rate of performance was defined as the sleep-dependent learning effect. We searched for factors associated with the changes in learning effect observed between the periods of when antiseizure medications (ASMs) were withdrawn for LT-VEEG and when they were returned to usual doses after LT-VEEG.ResultsExcluding six patients who had epileptic seizures at night after learning, nine patients and 11 healthy subjects were included in the study. In the patient group, there was no significant learning effect when ASMs were withdrawn. The changes in learning effect of the patient group during ASM withdrawal were not correlated with changes in sleep duration or IED density; however, they were significantly negatively correlated with changes in IED-coupled spindle density.ConclusionWe found that the increase of IED-coupled spindles correlated with the decrease of sleep-dependent learning effects of procedural memory. Pathological IED-coupled sleep spindles could hinder memory consolidation, that is dependent on physiological sleep spindles, resulting in cognitive dysfunction in patients with epilepsy.
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Project description:Epilepsy is a common neurological disorder, which is not well understood at the molecular level. Exactly why some brain regions produce epileptic discharges and others do not is not known. Patients who fail to respond to antiseizure medication (refractory epilepsy) can benefit from surgical removal of brain regions to reduce seizure frequency. The tissue removed in these surgeries offers an invaluable resource to uncover the molecular and cellular basis of human epilepsy. Here, we report a proteomic study to determine whether there are common proteomic patterns in human brain regions that produce epileptic discharges. We analyzed human brain samples, as part of the Systems Biology of Epilepsy Project (SBEP). These brain pieces are in vivo electrophysiologically characterized human brain samples withdrawn from the neocortex of six patients with refractory epilepsy. This study is unique in that for each of these six patients the comparison of protein expression was made within the same patient: a more epileptic region was compared to a less epileptic brain region. The amount of epileptic activity was defined for each patient as the frequency of their interictal spikes (electric activity between seizures that is a parameter strongly linked to epilepsy). Proteins were resolved from three subcellular fractions, using a 2D differential gel electrophoresis (2D-DIGE), revealing 31 identified protein spots that changed significantly. Interestingly, glial fibrillary acidic protein (GFAP) was found to be consistently down regulated in high spiking brain tissue and showed a strong negative correlation with spike frequency. We also developed a two-step analysis method to select for protein species that changed frequently among the patients and identified these proteins. A total of 397 protein spots of interest (SOI) were clustered by protein expression patterns across all samples. These clusters were used as markers and this analysis predicted proteomic changes due to both histological differences and molecular pathways, revealed by examination of gene ontology clusters. Our experimental design and proteomic data analysis predicts novel glial changes, increased angiogenesis, and changes in cytoskeleton and neuronal projections between high and low interictal spiking regions. Quantitative histological staining of these same tissues for both the vascular and glial changes confirmed these findings, which provide new insights into the structural and functional basis of neocortical epilepsy.
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Project description:Dynamic interactions between remote but functionally specialized brain regions enable complex information processing. This intercortical communication is disrupted in the neural networks of patients with focal epilepsy, and epileptic activity can exert widespread effects within the brain. Using large-scale human intracranial electroencephalography recordings, we show that interictal epileptiform discharges (IEDs) are significantly coupled with spindles in discrete, individualized brain regions outside of the epileptic network. We found that a substantial proportion of these localized spindles travel across the cortical surface. Brain regions that participate in this IED-driven oscillatory coupling express spindles that have a broader spatial extent and higher tendency to propagate than spindles occurring in uncoupled regions. These altered spatiotemporal oscillatory properties identify areas that are shaped by epileptic activity independent of IED or seizure detection. Our findings suggest that IED-spindle coupling may be an important mechanism of interictal global network dysfunction that could be targeted to prevent disruption of normal neural activity.
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