Interictal Spikes Research Articles

Clinical Relevance of Interictal Spikes in Tumor-Related Epilepsy: An Electrocorticographic Study.

Background and PurposeAlthough some surgeons utilize interictal spikes recorded via electrocorticography (ECoG) when planning extensive peritumoral resection in patients with tumor-related epilepsy, the association between interictal spikes and epileptogenesis has not been fully described. We investigated whether the resection of interictal spikes recorded by ECoG is associated with more favorable surgical outcomes in tumor-related epilepsy.MethodsOf 132 patients who underwent epilepsy surgery for tumor-related epilepsy from 2006 to 2013, seven patients who underwent extraoperative ECoG were included in this study. In each patient, ECoG interictal spike sources were localized using standardized low-resolution brain electromagnetic tomography and were co-registered into a reconstructed brain model. Correspondence to the resection volume was estimated by calculating the percentage of interictal spike sources in the resection volume.ResultsAll patients achieved gross total resection without oncological recurrence. Five patients achieved favorable surgical outcomes, whereas the surgical outcomes of two patients were unfavorable. Correspondence rates to the resection volume in the favorable and unfavorable surgical outcome groups were 44.6%±27.8% and 43.5%±22.8%, respectively (p=0.96). All patients had interictal spike source clusters outside the resection volume regardless of seizure outcome.ConclusionsIn these cases of tumor-related epilepsy, the extent of the resection of ECoG interictal spikes was not associated with postoperative seizure outcomes. Furthermore, the presence of interictal spike sources outside of the resection area was not related to seizure outcomes. Instead, concentrating more on the complete removal of the brain tumor appears to be a rational approach.

Electroencephalographic abnormalities are correlated with cognitive deficits in children with benign childhood epilepsy with centrotemporal spikes: A clinical study of 61 cases

ObjectiveThe objective of this study was to explore the effect of spikes on cognition in patients with benign childhood epilepsy with centrotemporal spikes (BECTS) and to identify electroencephalography (EEG) markers enabling early detection of cognitive impairment. MethodsSixty-one children with BECTS diagnoses and 60 age- and education-matched healthy controls were enrolled. Four-hour EEG recordings were analyzed for each patient to check for interictal spikes, high-frequency oscillations (HFOs), nondipole spikes, and other atypical EEG features and to examine the spike–wave index of nonrapid eye movement (NREM) sleep. All 121 children underwent a series of neuropsychological tests to assess cognitive function. ResultsPatients with a high NREM sleep discharge index (≥55%) in the first sleep cycle exhibited significantly lower scores for arithmetic calculation, executive function, and attention and memory tests than patients with a low discharge index (<55%). Eight patients with HFOs exhibited even poorer performance than HFO-negative patients for arithmetic calculation, executive function, vocabulary comprehension, visual perception, vocal perception, spatial memory ability, and response ability. Children with bilateral discharge exhibited poorer ability in three-dimensional spatial imaging test, poorer memory, and slower response than did those with unilateral discharge (P < .05). Nondipole spikes, multiple asynchronous discharges, and generalized spike–wave discharges respectively had an impact on calculation ability, memory, and reaction ability respectively (P < .05). ConclusionsSpike frequencies in stage 3 and 4 sleep varied from those observed in stage 1 and 2 sleep; the highest spike frequency was in stage 2 sleep. High NREM sleep discharge index (i.e., ≥55%) and HFOs were linked to the highest risk for cognitive deficit, while bilateral discharges, nondipole spikes, multiple asynchronous discharges, and generalized spike–wave discharges were less indicative of cognitive impairment.

Effect of interictal epileptiform discharges on EEG-based functional connectivity networks

ObjectiveFunctional connectivity networks (FCNs) based on interictal electroencephalography (EEG) can identify pathological brain networks associated with epilepsy. FCNs are altered by interictal epileptiform discharges (IEDs), but it is unknown whether this is due to the morphology of the IED or the underlying pathological activity. Therefore, we characterized the impact of IEDs on the FCN through simulations and EEG analysis. MethodsWe introduced simulated IEDs to sleep EEG recordings of eight healthy controls and analyzed the effect of IED amplitude and rate on the FCN. We then generated FCNs based on epochs with and without IEDs and compared them to the analogous FCNs from eight subjects with infantile spasms (IS), based on 1340 visually marked IEDs. Differences in network structure and strength were assessed. ResultsIEDs in IS subjects caused increased connectivity strength but no change in network structure. In controls, simulated IEDs with physiological amplitudes and rates did not alter network strength or structure. ConclusionsIncreases in connectivity strength in IS subjects are not artifacts caused by the interictal spike waveform and may be related to the underlying pathophysiology of IS. SignificanceDynamic changes in EEG-based FCNs during IEDs may be valuable for identification of pathological networks associated with epilepsy.

Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding Slack (KNa1.1) Na+-activated K+ channels

Gain-of-function mutations in KCNT1, the gene encoding Slack (KNa1.1) channels, result in epilepsy of infancy with migrating focal seizures (EIMFS) and several other forms of epilepsy associated with severe intellectual disability. We have generated a mouse model of this condition by replacing the wild type gene with one encoding Kcnt1R455H, a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. We compared behavior patterns and seizure activity in these mice with those of wild type mice and Kcnt1−/− mice. Complete loss of Kcnt1 produced deficits in open field behavior and motor skill learning. Although their thresholds for electrically and chemically induced seizures were similar to those of wild type animals, Kcnt1−/− mice were significantly protected from death after maximum electroshock-induced seizures. In contrast, homozygous Kcnt1R455H/R455H mice were embryonic lethal. Video-EEG monitoring of heterozygous Kcnt1+/R455H animals revealed persistent interictal spikes, spontaneous seizures and a substantially decreased threshold for pentylenetetrazole-induced seizures. Surprisingly, Kcnt1+/R455H mice were not impaired in tasks of exploratory behavior or procedural motor learning. These findings provide an animal model for EIMFS and suggest that Slack channels are required for the development of procedural learning and of pathways that link cortical seizures to other regions required for animal survival.

QuPWM: Feature Extraction Method for Epileptic Spike Classification

Epilepsy is a neurological disorder ranked as the second most serious neurological disease known to humanity, after stroke. Inter-ictal spiking is an abnormal neuronal discharge after an epileptic seizure. This abnormal activity can originate from one or more cranial lobes, often travels from one lobe to another, and interferes with normal activity from the affected lobe. The common practice for Inter-ictal spike detection of brain signals is via visual scanning of the recordings, which is a subjective and a very time-consuming task. Motivated by that, this article focuses on using machine learning for epileptic spikes classification in magnetoencephalography (MEG) signals. First, we used the Position Weight Matrix (PWM) method combined with a uniform quantizer to generate useful features from time domain and frequency domain through a Fast Fourier Transform (FFT) of the framed raw MEG signals. Second, the extracted features are fed to standard classifiers for inter-ictel spikes classification. The proposed technique shows great potential in spike classification and reducing the feature vector size. Specifically, the proposed technique achieved average sensitivity up to 87% and specificity up to 97% using 5-folds cross-validation applied to a balanced dataset. These samples are extracted from nine epileptic subjects using a sliding frame of size 95 samples-points with a step-size of 8 sample-points.

KCC2 antagonism and gabaergic synchronization in the entorhinal cortex in the absence of ionotropic glutamatergic receptor signalling

γ-Aminobutyric acid (GABA), which is released by interneurons, plays an active role in generating interictal epileptiform spikes during blockade of ionotropic glutamatergic signalling, but it remains unclear whether and how the K+-Cl− cotransporter 2 (KCC2) influences these paroxysmal events. Therefore, we employed tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced interictal spikes that were pharmacologically isolated by applying ionotropic glutamatergic receptor antagonists. After the addition of VU0463271, these interictal spikes continued to occur at similar rates as in control (i.e., during application of 4AP with ionotropic glutamatergic receptor antagonists) but were smaller and shorter. Despite the absence of ionotropic glutamatergic receptor signalling, both interneurons and principal cells increased their firing during interictal spikes. Moreover, we found that KCC2 antagonism increased interneuron firing but decreased principal cell firing during the interictal spike rising phase; in contrast, during the falling phase, interneuron firing decreased in the presence of VU0463271 while no change was observed in principal cell firing. Overall, our results show that KCC2 antagonism enhances interneuron excitability at the onset of interictal spikes generated by the EC neuronal networks during blockade of ionotropic glutamatergic transmission but disrupts later neuronal recruitment.

Interictal spike quantification in continuous spike–wave of sleep (CSWS): Clinical usefulness of a wearable EEG device

IntroductionContinuous spike–wave of sleep (CSWS) syndrome is one of the most common epileptic encephalopathies of childhood. Because the associated cognitive/behavioral disturbances relate more to the amount of spike activity than of seizures, methods of spike quantification gained relevance in diagnosis and monitoring treatment. The conventional methodology for quantification of spike index (SI) relies on repeated full 10–20 long-term ambulatory electroencephalography (aEEG), which is both expensive and poorly tolerated. ObjectiveThe objectives of this study were to demonstrate the clinical value of repeated SI assessments in CSWS and to build and validate a wearable device allowing inexpensive and well-tolerated, repeated quantifications. MethodsA group of N = 38 patients with CSWS were submitted to repeated SI quantifications based on aEEG, as seen fit by the medical clinical assistant. Responses to therapy with corticosteroids (N = 10), sulthiame (N = 7), and the ketogenic diet (N = 3) were monitored. We used a conventional method based on a semiautomatic template match spike search. The individual variability in time spans of days (N = 4) or months (N = 10) was assessed and used to determine the meaningful neurophysiological responses to the diverse therapies.A wearable device capable of recording 2 bipolar EEG channels for 24 h was used to simplify SI quantification. ResultsCorticosteroids produced the most powerful SI reduction, but a large individual variability in both amount and time of onset of clinical response with some patients exhibiting recurrence shortly after therapy. A more frequent sampling of SI would provide a more accurate follow-up, with clinical benefit.The comparison of the SI obtained from standard 10–20 electrodes and 2 bipolar EEG channel subsets in aEEG or between the 10–20 and simultaneous wearable recordings, demonstrated that the new method provides an accurate SI quantification. ConclusionsA wearable EEG device with 2 bipolar channels simplifies the process of obtaining repeated SI quantification allowing a more accurate follow-up of spike activity in the clinical setting.

Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1+/− Mice

BackgroundLoss-of-function SYNGAP1 mutations cause a neurodevelopmental disorder characterized by intellectual disability and epilepsy. SYNGAP1 is a Ras GTPase-activating protein that underlies the formation and experience-dependent regulation of postsynaptic densities. The mechanisms that contribute to this proposed monogenic cause of intellectual disability and epilepsy remain unresolved. MethodsWe established the phenotype of the epileptogenesis in a Syngap1+/− mouse model using 24-hour video electroencephalography (vEEG)/electromyography recordings at advancing ages. We administered an acute low dose of perampanel, a Food and Drug Administration–approved AMPA receptor (AMPAR) antagonist, during a follow-on 24-hour vEEG to investigate the role of AMPARs in Syngap1 haploinsufficiency. Immunohistochemistry was performed to determine the region- and location-specific differences in the expression of the GluA2 AMPAR subunit. ResultsA progressive worsening of the epilepsy with emergence of multiple seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1+/− mice. Interictal spikes emerged predominantly during non–rapid eye movement sleep in 24-hour vEEG of Syngap1+/− mice. Myoclonic seizures occurred at behavioral-state transitions both in Syngap1+/− mice and during an overnight EEG from a child with SYNGAP1 haploinsufficiency. In Syngap1+/− mice, EEG spectral power analyses identified a significant loss of gamma power modulation during behavioral-state transitions. A significant region-specific increase of GluA2 AMPAR subunit expression in the somas of parvalbumin-positive interneurons was identified. ConclusionsAcute dosing with perampanel significantly rescued behavioral state–dependent cortical gamma homeostasis, identifying a novel mechanism implicating Ca2+-impermeable AMPARs on parvalbumin-positive interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.

Interictal magnetoencephalography in parietal lobe epilepsy – Comparison of equivalent current dipole and beamformer (SAMepi) analysis

ObjectiveTo evaluate a novel analysis method (SAMepi) in the localization of interictal epileptiform magnetoencephalographic (MEG) activity in parietal lobe epilepsy (PLE) patients in comparison with equivalent current dipole (ECD) analysis. MethodsWe analyzed the preoperative interictal MEG of 17 operated PLE patients utilizing visual analysis and: (1) ECD with a spherical conductor model; (2) ECD with a boundary element method (BEM) conductor model; and (3) SAMepi – a kurtosis beamformer method. Localization results were compared between the three methods, to the location of the resection and to the clinical outcome. ResultsFourteen patients had an epileptiform finding in the visual analysis; SAMepi detected spikes in 11 of them. A unifocal finding in both the ECD and in the SAMepi analysis was associated with a better chance of seizure-freedom (p = 0.02). There was no significant difference in the distances from the unifocal MEG localizations to the nearest border of the resection between the different analysis methods. ConclusionsLocalizations of unifocal interictal spikes detected by SAMepi did not significantly differ from the conventional ECD localizations. SignificanceSAMepi – a novel semiautomatic analysis method – is useful in localizing interictal epileptiform MEG activity in the presurgical evaluation of parietal lobe epilepsy patients.

Induction of Temporal Lobe Epilepsy in Mice with Pilocarpine.

In the pilocarpine model of temporal lobe epilepsy (TLE) in rodents, systemic injections of pilocarpine induce continuous, prolonged limbic seizures, a condition termed "Status Epilepticus" (SE). With appropriate doses, many inbred strains of mice show behavioral seizures within an hour after pilocarpine is injected. With the behavioral scoring system based on a modification of the original Racine scale, one can monitor the seizures behaviorally, as they develop into more prolonged seizures and SE. SE is typically associated with damage to subsets of hippocampal neurons and other structural changes in the hippocampus and generally subsides on its own. However, more precise control of the duration of SE is commonly achieved by injecting a benzodiazepine into the mouse 1 to 3 h after the onset of SE to suppress the seizures. Several days following pilocarpine-induced SE, electrographic and behavioral seizures begin to occur spontaneously. The goal of this protocol is to reliably generate mice that develop spontaneous recurrent seizures (SRS) and show the typical neuropathological changes in the brain characteristic of severe human mesial temporal lobe epilepsy (mTLE), without high mortality. To reduce mortality, multiple subthreshold injections of pilocarpine are administered, which increases the percentage of mice developing SE without concomitant mortality. Precise control of the duration of SE (1 or 3 h) is achieved by suppressing SE with the benzodiazepine Midazolam (Versed). We have found that this protocol is an efficient means for generating mice that subsequently develop characteristics of human mTLE including high-frequency interictal spike and wave activity and SRS. In addition, we and others have shown that this protocol produces mice that show excitotoxic cell death of subsets of hippocampal GABAergic interneurons, particularly in the dentate gyrus and compensatory sprouting of excitatory projections from dentate granule cells (mossy fiber sprouting). Aspects of this protocol have been described in several of our previous publications.

The Significance of Interictal Spike Frequency in Temporal Lobe Epilepsy.

Purpose. In this study, the frequency of interictal epileptiform discharges (IEDs) in patients with drug-resistant temporal lobe epilepsy (TLE) was measured to determine its correlation with epilepsy duration, seizure frequency, brain magnetic resonance imaging (MRI) findings, and recent occurrence of focal to bilateral tonic clonic seizures (FBTCS). Methods. Our study was performed on TLE patients, who admitted to epilepsy monitoring unit of Loghman-Hakim hospital, Tehran, from 2016 to 2018. The patients' IEDs frequency were measured from their scalp EEG recording during no-rapid eye movement (NREM) sleep. The IEDs frequency was classified into 3 groups of rare, occasional, and frequent. Results. A total of 142 patients, with the mean age of 33.95 ± 12.73 years, were included in the study. The patients' mean epilepsy duration was 17.27 ± 12.19 years and the mean seizure frequency was 10.56 ± 12.95 attacks per month. The mean IEDs frequency was 123.48 ± 513.01 per hour. Thirty-five (24.6%) patients had history of FBTCS in the past year. Our findings revealed no significant association between IEDs frequency with epilepsy duration (P = .22), the recent occurrence of FBTCS (P = .42), and the type of MRI abnormalities (P = .66). There was only a weak positive correlation between seizure frequency and interictal spike density (r = 0.2, P = .007). Conclusions. In patients with TLE, standard EEG recording may not be a reliable method to predict the probability of occurring future seizures.

Spatial distribution of interictal spikes fluctuates over time and localizes seizure onset.

The location of interictal spikes is used to aid surgical planning in patients with medically refractory epilepsy; however, their spatial and temporal dynamics are poorly understood. In this study, we analysed the spatial distribution of interictal spikes over time in 20 adult and paediatric patients (12 females, mean age = 34.5 years, range = 5-58) who underwent intracranial EEG evaluation for epilepsy surgery. Interictal spikes were detected in the 24 h surrounding each seizure and spikes were clustered based on spatial location. The temporal dynamics of spike spatial distribution were calculated for each patient and the effects of sleep and seizures on these dynamics were evaluated. Finally, spike location was assessed in relation to seizure onset location. We found that spike spatial distribution fluctuated significantly over time in 14/20 patients (with a significant aggregate effect across patients, Fisher's method: P < 0.001). A median of 12 sequential hours were required to capture 80% of the variability in spike spatial distribution. Sleep and postictal state affected the spike spatial distribution in 8/20 and 4/20 patients, respectively, with a significant aggregate effect (Fisher's method: P < 0.001 for each). There was no evidence of pre-ictal change in the spike spatial distribution for any patient or in aggregate (Fisher's method: P = 0.99). The electrode with the highest spike frequency and the electrode with the largest area of downstream spike propagation both localized the seizure onset zone better than predicted by chance (Wilcoxon signed-rank test: P = 0.005 and P = 0.002, respectively). In conclusion, spikes localize seizure onset. However, temporal fluctuations in spike spatial distribution, particularly in relation to sleep and post-ictal state, can confound localization. An adequate duration of intracranial recording-ideally at least 12 sequential hours-capturing both sleep and wakefulness should be obtained to sufficiently sample the interictal network.

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of “self-limited focal epilepsies.” In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: “individual CTS” in model 1 and “CTS density” in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical–subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood–oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.

Localizing non-epileptiform abnormal brain function in children using high density EEG: Electric Source Imaging of focal slowing

BackgroundElectric Source Imaging (ESI) of interictal epileptiform discharges (IED) is increasingly validated for localizing epileptic activity. In children, IED can be absent or multifocal even in cases of a focal epileptogenic zone and additional electrophysiological markers are needed. Here, we investigated ESI of pathological focal slowing (FS) recorded on EEG as a new localizing marker in children with drug-resistant epilepsy. MethodsWe selected 15 children (median: 12; range: 4-18yrs), with high-density EEG (hdEEG), presurgical evaluation and surgical resection. One patient had a non-lesional MRI. ESI of patient-specific focal slow activity was performed (distributed linear inverse solution and individual head model). The maximal average power in the band of interest was considered as the source of focal slowing (ESI-FS). The Euclidian distance between ESI-FS and the resection (5 mm margin) was compared to the localization of maximal ESI of interictal epileptiform discharges (ESI-IED), interictal FDG-PET and ictal SPECT/SISCOM. ResultsIn 9/15 patients (60%), ESI of focal slowing (ESI-FS) was inside or ≤5 mm from resection margins. The remaining 6/15 cases had distances ≤15 mm. In 9/15 patients with interictal spikes, the ESI-IED was concordant with the resection. 6/15 patients with concordant ESI-FS showed also interictal concordant ESI of IED; in 3/15 patients, ESI-FS but not ESI-IED was concordant with the resection. In 10/15 patients, ESI-FS was concordant with MRI lesion and for ESI-IED this concordance was on 8/15 patients. Maximal hypometabolism and SISCOM were concordant with the resection for 7/15 and 7/12, respectively. ConclusionThese findings suggest that “non-epileptiform” EEG activity, such as focal slowing, could be a complementary useful marker to localize the epileptogenic zone. ESI-FS may notably be applied in young patients without focal interictal spikes or multifocal spikes. This potential new marker of brain dysfunction has potential applications to other neurological disorders associated with slow EEG activity.

Improved identification and differentiation from epileptiform activity of human hippocampal sharp wave ripples during NREM sleep.

In rodents, pyramidal cell firing patterns from waking may be replayed in nonrapid eye movement sleep (NREM) sleep during hippocampal sharp wave ripples (HC-SWR). In humans, HC-SWR have only been recorded with electrodes implanted to localize epileptogenicity. Here, we characterize human HC-SWR with rigorous rejection of epileptiform activity, requiring multiple oscillations and coordinated sharp waves. We demonstrated typical SWR in those rare HC recordings which lack interictal epileptiform spikes (IIS) and with no or minimal seizure involvement. These HC-SWR have a similar rate (~12 min-1 on average, variable across NREM stages and anterior/posterior HC) and apparent intra-HC topography (ripple maximum in putative stratum pyramidale, slow wave in radiatum) as rodents, though with lower frequency (~85 Hz compared to ~140 Hz in rodents). Similar SWR are found in HC with IIS, but no significant seizure involvement. These SWR were modulated by behavior, being largely absent (<2 min-1 ) except during NREM sleep in both Stage 2 (~9 min-1 ) and Stage 3 (~15 min-1 ), distinguishing them from IIS. This study quantifies the basic characteristics of a strictly selected sample of SWR recorded in relatively healthy human hippocampi.

Tripolar concentric EEG electrodes reduce noise

ObjectiveTo assay EEG signal quality recorded with tripolar concentric ring electrodes (TCREs) compared to regular EEG electrodes. MethodsEEG segments were recorded simultaneously by TCREs and regular electrodes, low-pass filtered at 35 Hz (REG35) and 70 Hz (REG70). Clips were rated blindly by nine electroencephalographers for presence or absence of key EEG features, relative to the “gold-standard” of the clinical report. ResultsTCRE showed less EMG artifact (F = 15.4, p < 0.0001). Overall quality rankings were not significantly different. Focal slowing was better detected by TCRE and spikes were better detected by regular electrodes. Seizures (n = 85) were detected by TCRE in 64 cases (75.3%), by REG70 in 75 (88.2%) and REG35 in 69 (81.2%) electrodes. TCRE detected 9 (10.6%) seizures not detected by one of the other 2 methods. In contrast, 14 seizures (16.5%) were not detected by TCRE, but were by REG35 electrodes. Each electrode detected interictal spikes when the other did not. ConclusionsTCRE produced similar overall quality and confidence ratings versus regular electrodes, but less muscle artifact. TCRE recordings detected seizures in 7% of instances where regular electrodes did not. SignificanceThe combination of the two types increased detection of epileptiform events compared to either alone.

Layer- and Cell-Specific Recruitment Dynamics during Epileptic Seizures In Vivo.

To investigate the network dynamics mechanisms underlying differential initiation of epileptic interictal spikes and seizures. We performed combined in vivo 2-photon calcium imaging from different targeted neuronal subpopulations and extracellular electrophysiological recordings during 4-aminopyridine-induced neocortical spikes and seizures. Both spikes and seizures were associated with intense synchronized activation of excitatory layer 2/3 pyramidal neurons (PNs) and to a lesser degree layer 4 neurons, as well as inhibitory parvalbumin-expressing interneurons (INs). In sharp contrast, layer 5 PNs and somatostatin-expressing INs were gradually and asynchronously recruited into the ictal activity during the course of seizures. Within layer 2/3, the main difference between onset of spikes and seizures lay in the relative recruitment dynamics of excitatory PNs compared to parvalbumin- and somatostatin-expressing inhibitory INs. Whereas spikes exhibited balanced recruitment of PNs and parvalbumin-expressing INs, during seizures IN responses were reduced and less synchronized than in layer 2/3 PNs. Similar imbalance was not observed in layers 4 or 5 of the neocortex. Machine learning-based algorithms we developed were able to distinguish spikes from seizures based solely on activation dynamics of layer 2/3 PNs at discharge onset. During onset of seizures, the recruitment dynamics markedly differed between neuronal subpopulations, with rapid synchronous recruitment of layer 2/3 PNs, layer 4 neurons, and parvalbumin-expressing INs and gradual asynchronous recruitment of layer 5 PNs and somatostatin-expressing INs. Seizures initiated in layer 2/3 due to a dynamic mismatch between local PNs and inhibitory INs, and only later spread to layer 5 by gradually and asynchronously recruiting PNs in this layer. ANN NEUROL 2020;87:97-115.

Hemispherectomy in adults and adolescents: Seizure and functional outcomes in 47 patients.

To examine longitudinal seizure and functional outcomes after hemispherectomy in adults and adolescents. We reviewed 47 consecutive patients older than 16years who underwent hemispherectomy between 1996 and 2016 at our center. Clinical, electroencephalographic (EEG), imaging, neuropsychological, surgical, and functional status data were analyzed. Thirty-six patients were 18 years or older at surgery; 11 were aged between 16 and 18years. Brain injury leading to hemispheric epilepsy occurred before 10years of age in 41 (87%) patients. At a mean follow-up of 5.3 postoperative years (median = 2.9years), 36 (77%) had Engel class I outcome. Longitudinal outcome analysis showed 84% seizure freedom (Engel IA) at 6months, 76% at 2years, and 76% at 5years and beyond, with stable longitudinal outcomes up to 12years from surgery. Multivariate analysis demonstrated that acute postoperative seizures and contralateral interictal spikes at 6-month follow-up EEG were associated with seizure recurrence. Patients who could walk unaided preoperatively and had no cerebral peduncle atrophy on brain magnetic resonance imaging were more likely to experience worsening of motor function postoperatively. Otherwise, postoperative ambulatory status and hand function were unchanged. Of the 19 patients who completed neuropsychological testing, 17 demonstrated stable or improved postoperative outcomes. Hemispherectomy in adults is a safe and effective procedure, with seizure freedom rates and functional outcome similar to those observed in children.

Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability.

Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function and, at the extreme, their susceptibility to seizure. We have developed a sensitive, quantitative estimate of network excitability in freely behaving mice using a novel optogenetic intensity-response procedure. Synchronous activation of deep sublayer CA1 pyramidal cells produces abnormal network-wide epileptiform population discharges (PDs) that are nearly indistinguishable from spontaneously-occurring interictal spikes (IISs). By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (LEV; 40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced PD threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations.

Generalized quasiperiodic epileptiform activity in sleep is associated with cognitive impairment in children with drug-resistant focal lesional epilepsy.

To evaluate the impact of generalized quasiperiodic epileptiform discharges ("hurdles") observed in non-rapid eye movement (NREM) sleep on cognitive function in children with intractable focal epilepsy. "Hurdles" pattern does not meet the criteria of the electrical status epilepticus in slow-wave sleep (ESES). In a retrospective analysis, 24 patients with "hurdles" and their 24 peers matched for demographic and epilepsy-related variables were compared in terms of neuropsychological domains and electroencephalography (EEG)-derived quantifiers. Both "hurdles" and controls were children between 2 and 19years of age who had intractable focal epilepsy evaluated as candidates of resective epilepsy surgery. Full-scale intelligence quotient/developmental quotient (FSIQ/DQ) (P=.002) and visuoconstructional skills (P=.004) were significantly lower in children with "hurdles" compared to controls. Patients with "hurdles" presented with higher interictal spike indexes in sleep (P<.001, median difference -0.9, 95% confidence interval [CI] -1.4, -0.6) and wakefulness (P<.001, median difference -0.3, 95% CI -0.5, -1). Relative time of sleep spindles in NREM sleep was significantly reduced (P<.001, median difference 0.1, 95% CI 0.0, 0.1) in the "hurdles" group. The time proportion of sleep spindles represented a significant positive (P=.008) and spike index of generalized spikes in sleep a significant negative explanatory variable (P=.004) of FSIQ/DQ scores. The proportion of seizure-free patients 2 years after epilepsy surgery did not differ significantly between the two groups (P=.19). Although the "hurdles" pattern does not fulfill the criteria of ESES, it is associated with a pronounced cognitive dysfunction. Disturbed sleep structure marked by reduced sleep spindles and generalized spiking in sleep is associated with worse cognitive performance. Despite having a generalized nature, we did not find a lower probability of postsurgical seizure freedom in patients with "hurdles" pattern.