Involvement of the contralateral hippocampus in ictal-like but not interictal epileptic activities in the kainate mouse model of temporal lobe epilepsy.

OBJECTIVE: Animal and human studies have shown that the seizure-generating region is vastly dependent on distant neuronal hubs that can decrease duration and propagation of ongoing seizures. However, we still lack a comprehensive understanding of the impact of distant brain areas on specific interictal and ictal epileptic activities (e.g., isolated spikes, spike trains, seizures). Such knowledge is critically needed, because all kinds of epileptic activities are not equivalent in terms of clinical expression and impact on the progression of the disease. METHODS: We used surface high-density electroencephalography and multisite intracortical recordings, combined with pharmacological silencing of specific brain regions in the well-known kainate mouse model of temporal lobe epilepsy. We tested the impact of selective regional silencing on the generation of epileptic activities within a continuum ranging from very transient to more sustained and long-lasting discharges reminiscent of seizures. RESULTS: Silencing the contralateral hippocampus completely suppresses sustained ictal activities in the focus, as efficiently as silencing the focus itself, but whereas focus silencing abolishes all focus activities, contralateral silencing fails to control transient spikes. In parallel, we observed that sustained focus epileptiform discharges in the focus are preceded by contralateral firing and more strongly phase-locked to bihippocampal delta/theta oscillations than transient spiking activities, reinforcing the presumed dominant role of the contralateral hippocampus in promoting long-lasting, but not transient, epileptic activities. SIGNIFICANCE: Altogether, our work provides suggestive evidence that the contralateral hippocampus is necessary for the interictal to ictal state transition and proposes that crosstalk between contralateral neuronal activity and ipsilateral delta/theta oscillation could be a candidate mechanism underlying the progression from short- to long-lasting epileptic activities.

Striatum- and Cerebellum-Modulated Epileptic Networks Varying Across States with and without Interictal Epileptic Discharges.

Idiopathic generalized epilepsy (IGE) is characterized by cryptogenic etiology and the striatum and cerebellum are recognized as modulators of epileptic network. We collected simultaneous electroencephalogram and functional magnetic resonance imaging data from 145 patients with IGE, 34 of whom recorded interictal epileptic discharges (IEDs) during scanning. In states without IEDs, hierarchical connectivity was performed to search core cortical regions which might be potentially modulated by striatum and cerebellum. Node-node and edge-edge moderation models were constructed to depict direct and indirect moderation effects in states with and without IEDs. Patients showed increased hierarchical connectivity with sensorimotor cortices (SMC) and decreased connectivity with regions in the default mode network (DMN). In the state without IEDs, striatum, cerebellum, and thalamus were linked to weaken the interactions of regions in the salience network (SN) with DMN and SMC. In periods with IEDs, overall increased moderation effects on the interaction between regions in SN and DMN, and between regions in DMN and SMC were observed. The thalamus and striatum were implicated in weakening interactions between regions in SN and SMC. The striatum and cerebellum moderated the cortical interaction among DMN, SN, and SMC in alliance with the thalamus, contributing to the dysfunction in states with and without IEDs in IGE. The current work revealed state-specific modulation effects of striatum and cerebellum on thalamocortical circuits and uncovered the potential core cortical targets which might contribute to develop new clinical neuromodulation techniques.

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method.

BACKGROUND: Epileptic seizures are an established comorbidity of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG. However, SEA might lead to faster cognitive decline in AD. AIMS: 1. To estimate the prevalence of SEA and interictal epileptic discharges (IEDs) in a well-defined cohort of participants belonging to the AD continuum, including preclinical AD subjects, as compared with cognitively healthy controls. 2. To evaluate whether long-term-EEG (LTM-EEG), high-density-EEG (hd-EEG) or MEG is superior to detect SEA in AD. 3. To characterise AD patients with SEA based on clinical, neuropsychological and neuroimaging parameters. METHODS: Subjects (n = 49) belonging to the AD continuum were diagnosed according to the 2011 NIA-AA research criteria, with a high likelihood of underlying AD pathophysiology. Healthy volunteers (n = 24) scored normal on neuropsychological testing and were amyloid negative. None of the participants experienced a seizure before. Subjects underwent LTM-EEG and/or 50-min MEG and/or 50-min hd-EEG to detect IEDs. RESULTS: We found an increased prevalence of SEA in AD subjects (31%) as compared to controls (8%) (p = 0.041; Fisher's exact test), with increasing prevalence over the disease course (50% in dementia, 27% in MCI and 25% in preclinical AD). Although MEG (25%) did not withhold a higher prevalence of SEA in AD as compared to LTM-EEG (19%) and hd-EEG (19%), MEG was significantly superior to detect spikes per 50 min (p = 0.002; Kruskall-Wallis test). AD patients with SEA scored worse on the RBANS visuospatial and attention subset (p = 0.009 and p = 0.05, respectively; Mann-Whitney U test) and had higher left frontal, (left) temporal and (left and right) entorhinal cortex volumes than those without. CONCLUSION: We confirmed that SEA is increased in the AD continuum as compared to controls, with increasing prevalence with AD disease stage. In AD patients, SEA is associated with more severe visuospatial and attention deficits and with increased left frontal, (left) temporal and entorhinal cortex volumes. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04131491. 12/02/2020.

Assessing 72 h vs. 24 h of long-term video-EEG monitoring to confirm the diagnosis of epilepsy: a retrospective observational study.

Introduction: Paroxysmal seizure-like events can be a diagnostic challenge. Inpatient video-electroencephalography (EEG) monitoring (VEM) can be a valuable diagnostic tool, but recommendations for the minimal duration of VEM to confirm or rule out epilepsy are inconsistent. In this study, we aim to determine whether VEM of 48 or 72 h was superior to 24 h. Methods: In this monocentric, retrospective study, we included 111 patients with paroxysmal, seizure-like events who underwent at least 72 h of VEM. Inclusion criteria were as follows: (1) Preliminary workup was inconclusive; (2) VEM admission occurred to confirm a diagnosis; (3) At discharge, the diagnosis of epilepsy was conclusively established. We analyzed the VEM recordings to determine the exact time point of the first occurrence of epileptic abnormalities (EAs; defined as interictal epileptiform discharges or electrographic seizures). Subgroup analyses were performed for epilepsy types and treatment status. Results: In our study population, 69.4% (77/111) of patients displayed EAs during VEM. In this group, the first occurrence of EAs was observed within 24 h in 92.2% (71/77) of patients and within 24-72 h in 7.8% (6/77). There was no statistically significant difference in the incidence of EA between medicated and non-medicated patients or between focal, generalized epilepsies and epilepsies of unknown type. Of the 19 recorded spontaneous electroclinical seizures, 6 (31.6%) occurred after 24 h. Discussion: A VEM of 24 h may be sufficient in the diagnostic workup of paroxysmal seizure-like events under most circumstances. Considering the few cases of first EA in the timeframe between 24 and 72 h, a prolonged VEM may be useful in cases with a high probability of epilepsy or where other strategies like sleep-EEG or ambulatory EEG show inconclusive results. Prolonged VEM increases the chance of recording spontaneous seizures. Our study also highlights a high share of subjects with epilepsy that do not exhibit EAs during 72 h of VEM.

Helium Optically Pumped Magnetometers Can Detect Epileptic Abnormalities as Well as SQUIDs as Shown by Intracerebral Recordings.

Magnetoencephalography based on superconducting quantum interference devices (SQUIDs) has been shown to improve the diagnosis and surgical treatment decision for presurgical evaluation of drug-resistant epilepsy. Still, its use remains limited because of several constraints such as cost, fixed helmet size, and the obligation of immobility. A new generation of sensors, optically pumped magnetometers (OPMs), could overcome these limitations. In this study, we validate the ability of helium-based OPM (4He-OPM) sensors to record epileptic brain activity thanks to simultaneous recordings with intracerebral EEG [stereotactic EEG (SEEG)]. We recorded simultaneous SQUIDs-SEEG and 4He-OPM-SEEG signals in one patient during two sessions. We show that epileptic activities on intracerebral EEG can be recorded by OPMs with a better signal-to noise ratio than classical SQUIDs. The OPM sensors open new venues for the widespread application of magnetoencephalography in the management of epilepsy and other neurologic diseases and fundamental neuroscience.

EEG-Findings during long-term treatment with everolimus in TSC-associated and therapy-resistant epilepsies in children.

AIM: This prospective observational study evaluated the long-term EEG changes in children treated with everolimus (EVO) for refractory TSC-associated epilepsy. Changes in EEG-abnormalities were related to developmental outcomes. METHODS: Thirteen children treated with EVO were examined for EEG-recorded seizures and interictal epileptic discharges (IED) during a 72-hour-video-EEG-monitoring, which was performed at baseline and repeated at follow-up intervals of at least 9 months. Antiseizure medication was left unchanged for at least 27 months. Changes in cognitive developmental parameters were related to reduction of seizures and IED at the last monitoring. RESULTS: We found a significant reduction of recorded seizures and IED during sleep at the first as well as the last follow-up recording. The reduction of IED was especially prominent during sleep. For patients who continued for more than one monitoring under EVO (n = 8), number of seizures further decreased. In patients with developmental examination (n = 9), we observed that only (nearly) full cessation of IED was related to acquisition of new skills. DISCUSSION: In children with TSC, EVO was effective in reducing recorded seizures and IED; long-term EVO treatment led to a more pronounced reduction and an improvement of nocturnal IED even when the patient was initially not seizure-free. Cessation of IED in children with developmental improvement may point to the importance of healthy sleep for cognition.

EMHapp: a pipeline for the automatic detection, localization and visualization of epileptic magnetoencephalographic high-frequency oscillations.

Objective.High-frequency oscillations (HFOs) are promising biomarkers for localizing epileptogenic brain tissue. Previous studies have revealed that HFOs that present concurrence with interictal epileptic discharges (IEDs) better delineate epileptogenic brain tissue, particularly for epilepsy patients with multitype interictal discharges. However, the analysis of noninvasively recorded epileptic HFOs involves many complex procedures, such as data preprocessing, detection and source localization, impeding the translation of this approach to clinical practice.Approach.To address these problems, we developed a graphical user interface (GUI)-based pipeline called EMHapp, which can be used for the automatic detection, source localization and visualization of HFO events concurring with IEDs in magnetoencephalography (MEG) signals by using a beamformer-based virtual sensor (VS) technique. An improved VS reconstruction method was developed to enhance the amplitudes of both HFO and IED VS signals. To test the capability of our pipeline, we collected MEG data from 11 complex focal epilepsy patients with surgical resections or seizure onset zones (SOZs) that were identified by intracranial electroencephalography.Main results.Our results showed that the HFO sources of eight patients were concordant with their resection margins or SOZs. Our proposed VS signal reconstruction approach achieved an 83.2% improvement regarding the number of detected HFO events and a 17.3% improvement in terms of the spatial overlaps between the HFO sources and the resection margins or SOZs in comparison with conventional VS reconstruction approaches.Significance.EMHapp is the first GUI-based pipeline for the analysis of epileptic magnetoencephalographic HFOs, which conveniently obtains HFO source locations using clinical data and enables direct translation to clinical applications.

Vagus nerve stimulation for refractory posttraumatic epilepsy: Efficacy and predictors of seizure outcome.

Background: Traumatic brain injury (TBI) has been recognized as an important and common cause of epilepsy since antiquity. Posttraumatic epilepsy (PTE) is usually associated with drug resistance and poor surgical outcomes, thereby increasing the burden of the illness on patients and their families. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy. This study aimed to determine the efficacy of VNS for refractory PTE and to initially evaluate the potential predictors of efficacy. Methods: We retrospectively collected the outcomes of VNS with at least a 1-year follow-up in all patients with refractory PTE. Subgroups were classified as responders and non-responders according to the efficacy of VNS (≥50% or <50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS efficacy. Results: In total, forty-five patients with refractory PTE who underwent VNS therapy were enrolled. Responders were found in 64.4% of patients, and 15.6% of patients achieved seizure freedom at the last follow-up. In addition, the responder rate increased over time, with 37.8, 44.4, 60, and 67.6% at the 3-, 6-, 12-, and 24-month follow-ups, respectively. After multivariate analysis, generalized interictal epileptic discharges (IEDs) were found to be a negative predictor (OR: 4.861, 95% CI: 1.145-20.632) of VNS efficacy. Conclusion: The results indicated that VNS therapy was effective in refractory PTE patients and was well tolerated over a 1-year follow-up period. Patients with focal or multifocal IEDs were recognized to have better efficacy after VNS therapy.

Reduced REM sleep: a potential biomarker for epilepsy - a retrospective case-control study.

OBJECTIVE: Establishing the diagnosis of epilepsy can be challenging if interictal epileptic discharges (IEDs) or seizures are undetectable. Many individuals with epilepsy experience sleep disturbances. A reduced percentage of REM sleep (REM%) has been observed following seizures. We aimed to assess differences of REM% in individuals with epilepsy in comparison with differential diagnoses. METHODS: We performed a retrospective, monocentric, two-armed case-control study with 128 age-matched individuals who underwent ≥72 hours of continuous video-EEG monitoring at our epilepsy monitoring unit (EMU) for diagnostic evaluation. We assessed REM% on the first and last night of EMU admission. Logistic regressions models were used to evaluate the predictive value of REM%. RESULTS: We included 64 individuals diagnosed with epilepsy and 64 with a differential diagnosis. REM% in the epilepsy group was significantly lower [12.2% (±4.7) vs. 17.2% (±5.2), p<0.001]. We found no significant influence of sex, age, anti-seizure, or other medications. A REM%-based and an IED and seizure-based regression model were not significantly different [area under the curve (AUC) 0.791 (95% confidence interval (CI): 0.713-0.870) vs. 0.853 (95% CI: 0.788-0.919), p=0.23]. A combined model, based on IEDs, seizures, and REM%, was superior to the IED model alone [0.933 (0.891-0.975), p<0.01]. INTERPRETATION: Our study shows significantly reduced REM% in individuals with epilepsy. REM%-based models show a good predictive performance. REM% assessment could improve diagnostic accuracy - especially for challenging cases, e.g., when IEDs or seizures are absent and patient history and semiology appear ambiguous. REM% as a biomarker should be evaluated in prospective, multicentric trials.

Slow oscillations open susceptible time windows for epileptic discharges.

OBJECTIVE: In patients with epilepsy, interictal epileptic discharges are a diagnostic hallmark of epilepsy and represent abnormal, so-called "irritative" activity that disrupts normal cognitive functions. Despite their clinical relevance, their mechanisms of generation remain poorly understood. It is assumed that brain activity switches abruptly, unpredictably, and supposedly randomly to these epileptic transients. We aim to study the period preceding these epileptic discharges, to extract potential proepileptogenic mechanisms supporting their expression. METHODS: We used multisite intracortical recordings from patients who underwent intracranial monitoring for refractory epilepsy, the majority of whom had a mesial temporal lobe seizure onset zone. Our objective was to evaluate the existence of proepileptogenic windows before interictal epileptic discharges. We tested whether the amplitude and phase synchronization of slow oscillations (.5-4 Hz and 4-7 Hz) increase before epileptic discharges and whether the latter are phase-locked to slow oscillations. Then, we tested whether the phase-locking of neuronal activity (assessed by high-gamma activity, 60-160 Hz) to slow oscillations increases before epileptic discharges to provide a potential mechanism linking slow oscillations to interictal activities. RESULTS: Changes in widespread slow oscillations anticipate upcoming epileptic discharges. The network extends beyond the irritative zone, but the increase in amplitude and phase synchronization is rather specific to the irritative zone. In contrast, epileptic discharges are phase-locked to widespread slow oscillations and the degree of phase-locking tends to be higher outside the irritative zone. Then, within the irritative zone only, we observe an increased coupling between slow oscillations and neuronal discharges before epileptic discharges. SIGNIFICANCE: Our results show that epileptic discharges occur during vulnerable time windows set up by a specific phase of slow oscillations. The specificity of these permissive windows is further reinforced by the increased coupling of neuronal activity to slow oscillations. These findings contribute to our understanding of epilepsy as a distributed oscillopathy and open avenues for future neuromodulation strategies aiming at disrupting proepileptic mechanisms.

Interictal Heart Rate Variability Analysis Reveals Lateralization of Cardiac Autonomic Control in Temporal Lobe Epilepsy.

Purpose: The temporal lobe, a critical hub for cognition, also plays a central role in the regulation of autonomic cardiovascular functions. Lesions in this area are usually associated with abnormalities in the regulation of heart rate (HR) and blood pressure (BP). The analysis of the heart rate variability (HRV) is useful to evaluate the cardiac parasympathetic nervous system activity. This study aims at comparing HRV changes occurring in two groups of patients suffering from Temporal Lobe Epilepsy (TLE). To that aim, we evaluated patients differentiated by the right or left location of the epileptic foci. Materials and Methods: Fifty-two adult patients with a diagnosis of TLE were enrolled. Each patient underwent a 20-min EEG + EKG recording in resting state. According to the localization of epileptic focus, patients were divided into two subgroups: right TLE (R-TLE) and left TLE (L-TLE). HRV parameters were calculated with a short-lasting analysis of EKG recordings. Time-domain and frequency domain-related, as well as non-linear analysis, parameters, were compared between the two groups. Results: Compared to the R-TLE group, L-TLE subjects showed a significant decrease in low frequency (LF) (p < 0.01) and low frequency/high-frequency ratio (LF/HF) (p < 0.001) as well as increased HF values (p < 0.01), a parameter indicative of the presence of an increased cardiac vagal tone. These results were also confirmed in the subgroup analysis that took into account the seizure types, responses to antiepileptic drugs, seizure frequencies, and etiology. Conclusions: The main finding of the study is that, compared to R-TLE, L-TLE is associated with increased cardiac vagal tone. These results indicate that patients with TLE exhibit a lateralized cardiac autonomic control. L-TLE patients may have a lower risk of developing cardiac dysfunctions and less susceptible to develop Sudden Death for Epilepsy (SUDEP).

Extent of Single-Neuron Activity Modulation by Hippocampal Interictal Discharges Predicts Declarative Memory Disruption in Humans.

Memory deficits are common in epilepsy patients. In these patients, the interictal EEG commonly shows interictal epileptiform discharges (IEDs). While IEDs are associated with transient cognitive impairments, it remains poorly understood why this is. We investigated the effects of human (male and female) hippocampal IEDs on single-neuron activity during a memory task in patients with medically refractory epilepsy undergoing depth electrode monitoring. We quantified the effects of hippocampal IEDs on single-neuron activity and the impact of this modulation on subjectively declared memory strength. Across all recorded neurons, the activity of 50 of 728 neurons were significantly modulated by IEDs, with the strongest modulation in the medial temporal lobe (33 of 416) and in particular the right hippocampus (12 of 58). Putative inhibitory neurons, as identified by their extracellular signature, were more likely to be modulated by IEDs than putative excitatory neurons (19 of 157 vs 31 of 571). Behaviorally, the occurrence of hippocampal IEDs was accompanied by a disruption of recognition of familiar images only if they occurred up to 2 s before stimulus onset. In contrast, IEDs did not impair encoding or recognition of novel images, indicating high temporal and task specificity of the effects of IEDs. The degree of modulation of individual neurons by an IED correlated with the declared confidence of a retrieval trial, with higher firing rates indicative of reduced confidence. Together, these data link the transient modulation of individual neurons by IEDs to specific declarative memory deficits in specific cell types, thereby revealing a mechanism by which IEDs disrupt medial temporal lobe-dependent declarative memory retrieval processes.SIGNIFICANCE STATEMENT Interictal epileptiform discharges (IEDs) are thought to be a cause of memory deficits in chronic epilepsy patients, but the underlying mechanisms are not understood. Utilizing single-neuron recordings in epilepsy patients, we found that hippocampal IEDs transiently change firing of hippocampal neurons and disrupted selectively the retrieval, but not encoding, of declarative memories. The extent of the modulation of the individual firing of hippocampal neurons by an IED predicted the extent of reduction of subjective retrieval confidence. Together, these data reveal a specific kind of transient cognitive impairment caused by IEDs and link this impairment to the modulation of the activity of individual neurons. Understanding the mechanisms by which IEDs impact memory is critical for understanding memory impairments in epilepsy patients.

Valproic acid potently inhibits interictal-like epileptiform activity in prefrontal cortex pyramidal neurons.

Valproic acid has a long-standing reputation of effectively treating the symptoms of not only epilepsy but also psychiatric conditions. In the latter, the exact mechanism by which valproate exerts its effect remains unclear. In this study, epileptiform bursts were recorded from pyramidal neurons in the prefrontal cortex (the brain region thought to be involved in psychiatric disorders) using the patch-clamp technique. An extracellular solution with no magnesium ions and elevated potassium levels that is known to induce epileptiform activity in vitro was used. Because of their short durations, the epileptiform bursts were regarded as interictal-like epileptiform activity, which is believed to be involved in cognitive impairment. Interictal discharges occur in many neuropsychiatric disorders as well as in healthy population. Epileptic activity in prefrontal cortex pyramidal neurons was potently inhibited by two therapeutic concentrations of valproic acid (20 µM and 200 µM). Moreover, valproate suppressed spontaneous excitatory postsynaptic potentials. Epileptiform bursts were fully inhibited by NMDA receptor antagonist, which suggests that epileptiform activity is driven by NMDA receptors. The inhibition of excitability in prefrontal cortex pyramidal neurons by valproate was also shown. This study shows that it is possible to evoke NMDA-dependent epileptiform activity in prefrontal cortex pyramidal neurons in vitro. We suggest that the prefrontal cortex is a good region for studying the influence of drugs on interictal epileptiform activity.

Antiepileptic Effects of a Novel Non-invasive Neuromodulation Treatment in a Subject With Early-Onset Epileptic Encephalopathy: Case Report With 20 Sessions of HD-tDCS Intervention.

The current clinical investigation examined high-definition transcranial direct current stimulation (HD-tDCS) as a focal, non-invasive, anti-epileptic treatment in a child with early-onset epileptic encephalopathy. We investigated the clinical impact of repetitive (20 daily sessions) cathode-centered 4 × 1 HD-tDCS (1 mA, 20 min, 4 mm ring radius) over the dominant seizure-generating cortical zone in a 40-month-old child suffering from a severe neonatal epileptic syndrome known as Ohtahara syndrome (OS). Seizures and epileptiform activity were monitored and quantified using video-EEG over multiple days of baseline, intervention, and post-intervention periods. Primary outcome measures were changes in seizure frequency and duration on the last day of intervention versus the last baseline day, preceding the intervention. In particular, we examined changes in tonic spasms, tonic-myoclonic seizures (TM-S), and myoclonic seizures from baseline to post-intervention. A trend in TM-S frequency was observed indicating a reduction of 73% in TM-S frequency, which was non-significant [t(4) = 2.05, p = 0.1], and denoted a clinically significant change. Myoclonic seizure (M-S) frequency was significantly reduced [t(4) = 3.83, p = 0.019] by 68.42%, compared to baseline, and indicated a significant clinical change as well. A 73% decrease in interictal epileptic discharges (IEDs) frequency was also observed immediately after the intervention period, compared to IED frequency at 3 days prior to intervention. Post-intervention seizure-related peak delta desynchronization was reduced by 57%. Our findings represent a case-specific significant clinical response, reduction in IED, and change in seizure-related delta activity following the application of HD-tDCS. The clinical outcomes, as noted in the current study, encourage the further investigation of this focal, non-invasive neuromodulation procedure in other severe electroclinical syndromes (e.g., West syndrome) and in larger pediatric populations diagnosed with early-onset epileptic encephalopathy. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02960347, protocol ID: Meiron 2013-4.

Perisylvian epileptic network revisited.

We overview here the new data about the epileptic spectrum disorders within the frame of perisylvian epileptic network since our first trial to synthetize knowledge about this system epilepsy (Halász et al., 2005). We found evidences for a continual features relating together syndromes constituting this spectrum disorder in several fields: in sharing genetic origin, in common perisylvian human communication circuitry, in NREM sleep related potentiation of interictal epileptiform discharges of the centro-temporal spike phenomenon and in the discharge related cognitive impairment, reflecting functional deficits in human communication abilities. The transformation of a part of the children to develop into a malignant course with different degree of residual cognitive loss, through compromising sleep plastic functions, by the epileptic discharges during sleep, beside pure genetic origin, is still under research. Both factual data and new conceptual approaches helps understand better the developmental childhood epilepsies.

Modeling of intracerebral interictal epileptic discharges: Evidence for network interactions.

OBJECTIVE: The interictal epileptic discharges (IEDs) occurring in stereotactic EEG (SEEG) recordings are in general abundant compared to ictal discharges, but difficult to interpret due to complex underlying network interactions. A framework is developed to model these network interactions. METHODS: To identify the synchronized neuronal activity underlying the IEDs, the variation in correlation over time of the SEEG signals is related to the occurrence of IEDs using the general linear model. The interdependency is assessed of the brain areas that reflect highly synchronized neural activity by applying independent component analysis, followed by cluster analysis of the spatial distributions of the independent components. The spatiotemporal interactions of the spike clusters reveal the leading or lagging of brain areas. RESULTS: The analysis framework was evaluated for five successfully operated patients, showing that the spike cluster that was related to the MRI-visible brain lesions coincided with the seizure onset zone. The additional value of the framework was demonstrated for two more patients, who were MRI-negative and for whom surgery was not successful. CONCLUSIONS: A network approach is promising in case of complex epilepsies. SIGNIFICANCE: Analysis of IEDs is considered a valuable addition to routine review of SEEG recordings, with the potential to increase the success rate of epilepsy surgery.

Electrophysiological Evidence for the Development of a Self-Sustained Large-Scale Epileptic Network in the Kainate Mouse Model of Temporal Lobe Epilepsy.

Most research on focal epilepsy focuses on mechanisms of seizure generation in the primary epileptic focus (EF). However, neurological deficits that are not directly linked to seizure activity and that may persist after focus removal are frequent. The recruitment of remote brain regions of an epileptic network (EN) is recognized as a possible cause, but a profound lack of experimental evidence exists concerning their recruitment and the type of pathological activities they exhibit. We studied the development of epileptic activities at the large-scale in male mice of the kainate model of unilateral temporal lobe epilepsy using high-density surface EEG and multiple-site intracortical recordings. We show that, along with focal spikes and fast ripples that remain localized to the injected hippocampus (i.e., the EF), a subpopulation of spikes that propagate across the brain progressively emerges even before the expression of seizures. The spatiotemporal propagation of these generalized spikes (GSs) is highly stable within and across animals, defining a large-scale EN comprising both hippocampal regions and frontal cortices. Interestingly, GSs are often concomitant with muscular twitches. In addition, while fast ripples are, as expected, highly frequent in the EF, they also emerge in remote cortical regions and in particular in frontal regions where GSs propagate. Finally, we demonstrate that these remote interictal activities are dependent on the focus in the early phase of the disease but continue to be expressed after focus silencing at later stages. Our results provide evidence that neuronal networks outside the initial focus are progressively altered during epileptogenesis.SIGNIFICANCE STATEMENT It has long been held that the epileptic focus is responsible for triggering seizures and driving interictal activities. However, focal epilepsies are associated with heterogeneous symptoms, calling into question the concept of a strictly focal disease. Using the mouse model of hippocampal sclerosis, this work demonstrates that focal epilepsy leads to the development of pathological activities specific to the epileptic condition, notably fast ripples, that appear outside of the primary epileptic focus. Whereas these activities are dependent on the focus early in the disease, focus silencing fails to control them in the chronic stage. Thus, dynamical changes specific to the epileptic condition are built up outside of the epileptic focus along with disease progression, which provides supporting evidence for network alterations in focal epilepsy.

An unaware agenda: interictal consciousness impairments in epileptic patients.

Consciousness impairments have been described as a cornerstone of epilepsy. Generalized seizures are usually characterized by a complete loss of consciousness, whereas focal seizures have more variable degrees of responsiveness. In addition to these impairments that occur during ictal episodes, alterations of consciousness have also been repeatedly observed between seizures (i.e. during interictal periods). In this opinion article, we review evidence supporting the novel hypothesis that epilepsy produces consciousness impairments which remain present interictally. Then, we discuss therapies aimed to reduce seizure frequency, which may modulate consciousness between epileptic seizures. We conclude with a consideration of relevant pathophysiological mechanisms. In particular, the thalamocortical network seems to be involved in both seizure generation and interictal consciousness impairments, which could inaugurate a promising translational agenda for epilepsy studies.

Complex patterns of spatially extended generators of epileptic activity: Comparison of source localization methods cMEM and 4-ExSo-MUSIC on high resolution EEG and MEG data.

Electric Source Imaging (ESI) and Magnetic Source Imaging (MSI) of EEG and MEG signals are widely used to determine the origin of interictal epileptic discharges during the pre-surgical evaluation of patients with epilepsy. Epileptic discharges are detectable on EEG/MEG scalp recordings only when associated with a spatially extended cortical generator of several square centimeters, therefore it is essential to assess the ability of source localization methods to recover such spatial extent. In this study we evaluated two source localization methods that have been developed for localizing spatially extended sources using EEG/MEG data: coherent Maximum Entropy on the Mean (cMEM) and 4th order Extended Source Multiple Signal Classification (4-ExSo-MUSIC). In order to propose a fair comparison of the performances of the two methods in MEG versus EEG, this study considered realistic simulations of simultaneous EEG/MEG acquisitions taking into account an equivalent number of channels in EEG (257 electrodes) and MEG (275 sensors), involving a biophysical computational neural mass model of neuronal discharges and realistically shaped head models. cMEM and 4-ExSo-MUSIC were evaluated for their sensitivity to localize complex patterns of epileptic discharges which includes (a) different locations and spatial extents of multiple synchronous sources, and (b) propagation patterns exhibited by epileptic discharges. Performance of the source localization methods was assessed using a detection accuracy index (Area Under receiver operating characteristic Curve, AUC) and a Spatial Dispersion (SD) metric. Finally, we also presented two examples illustrating the performance of cMEM and 4-ExSo-MUSIC on clinical data recorded using high resolution EEG and MEG. When simulating single sources at different locations, both 4-ExSo-MUSIC and cMEM exhibited excellent performance (median AUC significantly larger than 0.8 for EEG and MEG), whereas, only for EEG, 4-ExSo-MUSIC showed significantly larger AUC values than cMEM. On the other hand, cMEM showed significantly lower SD values than 4-ExSo-MUSIC for both EEG and MEG. When assessing the impact of the source spatial extent, both methods provided consistent and reliable detection accuracy for a wide range of source spatial extents (source sizes ranging from 3 to 20cm2 for MEG and 3 to 30cm2 for EEG). For both EEG and MEG, 4-ExSo-MUSIC localized single source of large signal-to-noise ratio better than cMEM. In the presence of two synchronous sources, cMEM was able to distinguish well the two sources (their location and spatial extent), while 4-ExSo-MUSIC only retrieved one of them. cMEM was able to detect the spatio-temporal propagation patterns of two synchronous activities while 4-ExSo-MUSIC favored the strongest source activity. Overall, in the context of localizing sources of epileptic discharges from EEG and MEG data, 4-ExSo-MUSIC and cMEM were found accurately sensitive to the location and spatial extent of the sources, with some complementarities. Therefore, they are both eligible for application on clinical data.

Nocturnal interictal epileptic discharges in adult Lennox-Gastaut syndrome: the effect of sleep stage and time of night.

Lennox-Gastaut syndrome (LGS) is characterized by interictal epileptiform discharges (IEDs) occurring during sleep. The aim of this study was to determine whether sleep influences not only the frequency of seizures and IEDs, but also the time-dependent evolution that may support the hypothesis of homeostatic influences on epileptic threshold. Video polysomnography data from our database were reviewed to identify adult LGS patients with at least seven hours of nocturnal recording. Thirteen patients were identified and a second polysomnography was available for nine. The number, duration and index of IEDs, relative to total sleep, sleep stages, and time during the night, were calculated. The majority of IEDs occurred during non-rapid eye movement sleep, mainly in stage 2 and slow-wave sleep. Adjusting for time spent in each sleep stage, we found 45 IEDs/hour in stage 1, 123/hour in stage 2, 106/hour in slow-wave sleep, and 26/hour in rapid eye movement sleep. The temporal distribution of IEDs showed a significant rise in the first three hours of sleep, followed by a progressive decrease at the end of the night (F=85.6; p<0.0001). Interictal epileptiform discharges occurrence in adult LGS is facilitated by non-rapid eye movement sleep with an evident effect of stage 2 and slow-wave sleep. The significant IED occurrence in the first part of the night and the subsequent decline suggests a link between epileptic threshold and homeostatic sleep mechanisms. The latter should be considered regarding choice of therapy.