Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

High‐frequency oscillations (HFOs) are a type of brain activity that is recorded from brain regions capable of generating seizures. Because of the close association of HFOs with epileptogenic tissue and ictogenesis, understanding their cellular and network mechanisms could provide valuable information about the organization of epileptogenic networks and how seizures emerge from the abnormal activity of these networks. In this review, we summarize the most recent advances in the field of HFOs and provide a critical evaluation of new observations within the context of already established knowledge. Recent improvements in recording technology and the introduction of optogenetics into epilepsy research have intensified experimental work on HFOs. Using advanced computer models, new cellular substrates of epileptic HFOs were identified and the role of specific neuronal subtypes in HFO genesis was determined. Traditionally, the pathogenesis of HFOs was explored mainly in patients with temporal lobe epilepsy and in animal models mimicking this condition. HFOs have also been reported to occur in other epileptic disorders and models such as neocortical epilepsy, genetically determined epilepsies, and infantile spasms, which further support the significance of HFOs in the pathophysiology of epilepsy. It is increasingly recognized that HFOs are generated by multiple mechanisms at both the cellular and network levels. Future studies on HFOs combining novel high‐resolution in vivo imaging techniques and precise control of neuronal behavior using optogenetics or chemogenetics will provide evidence about the causal role of HFOs in seizures and epileptogenesis. Detailed understanding of the pathophysiology of HFOs will propel better HFO classification and increase their information yield for clinical and diagnostic purposes.     

Electrophysiological Biomarkers of Epilepsy

In patients being evaluated for epilepsy and in animal models of epilepsy, electrophysiological recordings are carried to capture seizures to determine the existence of epilepsy. Electroencephalography recordings from the scalp, or sometimes directly from the brain, are also used to locate brain areas where seizure begins, and in surgical treatment help plan the area for resection. As seizures are unpredictable and can occur infrequently, ictal recordings are not ideal in terms of time, cost, or risk when, for example, determining the efficacy of existing or new anti-seizure drugs, evaluating potential anti-epileptogenic interventions, or for prolonged intracerebral electrode studies. Thus, there is a need to identify and validate other electrophysiological biomarkers of epilepsy that could be used to diagnose, treat, cure, and prevent epilepsy. Electroencephalography recordings in the epileptic brain contain other interictal electrophysiological disturbances that can occur more frequently than seizures, such as interictal spikes (IIS) and sharp waves, and from invasive studies using wide bandwidth recording and small diameter electrodes, the discovery of pathological high-frequency oscillations (HFOs) and microseizures. Of IIS, HFOs, and microseizures, a significant amount of recent research has focused on HFOs in the pathophysiology of epilepsy. Results from studies in animals with epilepsy and presurgical patients have consistently found a strong association between HFOs and epileptogenic brain tissue that suggest HFOs could be a potential biomarker of epileptogenicity and epileptogenesis. Here, we discuss several aspects of HFOs, as well as IIS and microseizures, and the evidence that supports their role as biomarkers of epilepsy.     

Spontaneous and evoked high-frequency oscillations in the tetanus toxin model of epilepsy

Purpose: High‐frequency oscillations (HFOs) are an emerging biomarker for epileptic tissue. Yet the mechanism by which HFOs are produced is unknown, and their rarity makes them difficult to study. Our objective was to examine the occurrence of HFOs in relation to action potentials (APs) and the effect of microstimulation in the tetanus toxin (TT) model of epilepsy, a nonlesional model with a short latency to spontaneous seizures. Methods: Rats were injected with TT into dorsal hippocampus and implanted with a 16‐channel (8 × 2) multielectrode array, one row each in CA3 and CA1. After onset of spontaneous seizures (3–9 days), recordings were begun of APs and local field potentials, analyzed for the occurrence of interictal spikes and HFOs. Recordings were made during microstimulation of each electrode using customized, open‐source software. Results: Population bursts of APs during interictal spikes were phase‐locked with HFOs, which were observable almost exclusively with high‐amplitude interictal spikes. Furthermore, HFOs could reliably be produced by microstimulation of the hippocampus, providing evidence that these oscillations can be controlled temporally by external means. Discussion: We show for the first time the occurrence of HFOs in the TT epilepsy model, an attractive preparation for their experimental investigation and, importantly, one with a different etiology than that of status models, providing further evidence of the generality of HFOs. The ability to provoke HFOs with microstimulation may prove useful for better understanding of HFOs by directly evoking them in the lab, and designing high‐throughput techniques for presurgical localization of the epileptic focus.     

The dark side of high-frequency oscillations in the developing brain

Adult brain networks generate a wide range of oscillations. Some of these are behaviourally relevant, whereas others occur during seizures and other pathological conditions. This raises the question of how physiological oscillations differ from pathogenic ones. In this review, this issue is discussed from a developmental standpoint. Indeed, both epileptic and physiological high-frequency oscillations (HFOs) appear progressively during maturation, and it is therefore possible to determine how this program corresponds to maturation of the neuronal populations that generate these oscillations. We review here important differences in the development of neuronal populations that might contribute to their different oscillatory properties. In particular, at an early stage, the density of glutamatergic synapses is too low for physiological HFOs but an additional drive can be provided by excitatory GABA, triggering epileptic HFOs and the cascades involved in long-lasting epileptogenic transformations. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).     

High-frequency oscillations recorded with surface EEG in neonates with seizures

ObjectiveNeonatal seizures are often the first symptom of perinatal brain injury. High-frequency oscillations (HFOs) are promising new biomarkers for epileptogenic tissue and can be found in intracranial and surface EEG. To date, we cannot reliably predict which neonates with seizures will develop childhood epilepsy. We questioned whether epileptic HFOs can be generated by the neonatal brain and potentially predict epilepsy.MethodsWe selected 24 surface EEGs sampled at 2048 Hz with 175 seizures from 16 neonates and visually reviewed them for HFOs. Interictal epochs were also reviewed.ResultsWe found HFOs in thirteen seizures (7%) from four neonates (25%). 5025 ictal ripples (rate 10 to 1311/min; mean frequency 135 Hz; mean duration 66 ms) and 1427 fast ripples (rate 8 to 356/min; mean frequency 298 Hz; mean duration 25 ms) were marked. Two neonates (13%) showed interictal HFOs (285 ripples and 25 fast ripples). Almost all HFOs co-occurred with sharp transients. We could not find a relationship between neonatal HFOs and outcome yet.ConclusionsNeonatal HFOs co-occur with ictal and interictal sharp transients.SignificanceThe neonatal brain can generate epileptic ripples and fast ripples, particularly during seizures, though their occurrence is not common and potential clinical value not evident yet.     

How to establish causality in epilepsy surgery

Focality in electro-clinical or neuroimaging data often motivates epileptologists to consider epilepsy surgery in patients with medically-uncontrolled seizures, while not all focal findings are causally associated with the generation of epileptic seizures. With the help of Hill’s criteria, we have discussed how to establish causality in the context of the presurgical evaluation of epilepsy. The strengths of EEG include the ability to determine the temporal relationship between cerebral activities and clinical events; thus, scalp video-EEG is necessary in the evaluation of the majority of surgical candidates. The presence of associated ictal discharges can confirm the epileptic nature of a particular spell and whether an observed neuroimaging abnormality is causally associated with the epileptic seizure. Conversely, one should be aware that scalp EEG has a limited spatial resolution and sometimes exhibits propagated epileptiform discharges more predominantly than in situ discharges generated at the seizure-onset zone. Intraoperative or extraoperative electrocorticography (ECoG) is utilized when noninvasive presurgical evaluation, including anatomical and functional neuroimaging, fails to determine the margin between the presumed epileptogenic zone and eloquent cortex. Retrospective as well as prospective studies have reported that complete resection of the seizure-onset zone on ECoG was associated with a better seizure outcome, but not all patients became seizure-free following such resective surgery. Some retrospective studies suggested that resection of sites showing high-frequency oscillations (HFOs) at >80 Hz on interictal or ictal ECoG was associated with a better seizure outcome. Others reported that functionally-important areas may generate HFOs of a physiological nature during rest as well as sensorimotor and cognitive tasks. Resection of sites showing task-related augmentation of HFOs has been reported to indeed result in functional loss following surgery. Thus, some but not all sites showing interictal HFOs are causally associated with seizure generation. Furthermore, evidence suggests that some task-related HFOs can be transiently suppressed by the prior occurrence of interictal spikes. The significance of interictal HFOs should be assessed by taking into account the eloquent cortex, seizure-onset zone, and cortical lesions. Video-EEG and ECoG generally provide useful but still limited information to establish causality in presurgical evaluation. A comprehensive assessment of data derived from multiple modalities is ultimately required for successful management.     

High-frequency oscillations as a new biomarker in epilepsy

The discovery that electroencephalography (EEG) contains useful information at frequencies above the traditional 80Hz limit has had a profound impact on our understanding of brain function. In epilepsy, high-frequency oscillations (HFOs, >80Hz) have proven particularly important and useful. This literature review describes the morphology, clinical meaning, and pathophysiology of epileptic HFOs. To record HFOs, the intracranial EEG needs to be sampled at least at 2,000Hz. The oscillatory events can be visualized by applying a high-pass filter and increasing the time and amplitude scales, or EEG time-frequency maps can show the amount of high-frequency activity. HFOs appear excellent markers for the epileptogenic zone. In patients with focal epilepsy who can benefit from surgery, invasive EEG is often required to identify the epileptic cortex, but current information is sometimes inadequate. Removal of brain tissue generating HFOs has been related to better postsurgical outcome than removing the seizure onset zone, indicating that HFOs may mark cortex that needs to be removed to achieve seizure control. The pathophysiology of epileptic HFOs is challenging, probably involving populations of neurons firing asynchronously. They differ from physiological HFOs in not being paced by rhythmic inhibitory activity and in their possible origin from population spikes. Their link to the epileptogenic zone argues that their study will teach us much about the pathophysiology of epileptogenesis and ictogenesis. HFOs show promise for improving surgical outcome and accelerating intracranial EEG investigations. Their potential needs to be assessed by future research.     

Epileptic high‐frequency oscillations in intraoperative electrocorticography: The effect of propofol

Purpose: Epileptic high‐frequency oscillations (HFOs; 80–500 Hz) may be used to guide neurosurgeons during epilepsy surgery to identify epileptogenic tissue. We studied the effect of the anesthetic agent propofol on the occurrence of HFOs in intraoperative electrocorticography (ECoG). Methods: We selected patients who were undergoing surgery for temporal lobe epilepsy with a standardized electrode grid placement. Intraoperative ECoG was recorded at 2,048 Hz following cessation of propofol. The number and distribution of interictal spikes, ripples (R [80–250 Hz]), and fast ripples (FRs; 250–500 Hz) were analyzed. The amount of events on mesiotemporal channels and lateral neocortical channels were compared between patients with a suspected mesiotemporal and lateral epileptogenic area (Student’s t‐test), and HFOs were compared with the irritative zone, using correlation between amounts of events per channel, to provide evidence for the epileptic nature of the HFOs. Next, the amount of events within the first minute and the last minute were compared to each other and the change in events over the entire epochs was analyzed using correlation analyses of 10 epochs during the emergence periods (Spearman rank test). We studied whether the duration of HFOs changed over time. The change in events within presumed epileptogenic area was compared to the change outside this area (Student’s t‐test). Periods of burst suppression and continuous background activity were compared between and within patients (t‐test). Key Findings: Twelve patients were included: five with suspected mesiotemporal epileptogenic area and three with suspected lateral epileptogenic area (and four were “other”). Spikes, ripples, and FRs were related to the suspected epileptogenic areas, and HFO zones were related to the irritative zones. Ripples and FRs increased during emergence from propofol anesthesia (mean number of ripples from first minute–last minute: 61.5–73.0, R = 0.46, p < 0.01; FRs: 3.1–5.7, R = 0.30, p < 0.01) and spikes remained unchanged (80.1–79.9, R = ?0.05, p = 0.59). There was a decrease in number of channels with spikes (R = ?0.18, p = 0.05), but no change in ripples (R = ?0.13, p = 0.16) or FRs (R = 0.11, p = 0.45). There was no change in the durations of HFOs. The amount of HFOs in the presumed epileptogenic areas did not change more than the amount outside the presumed epileptogenic area, whereas spikes paradoxically decreased more within the suspected epileptogenic area. Six patients showing burst‐suppression had lower rates of ripples than six other patients with continuous background activity (p = 0.02). No significant difference was found between burst suppression and continuous background activity in four patients, but there was a trend toward showing more ripples during continuous background activity (p = 0.16). Significance: Propofol, known for its antiepileptic effects, reduces the number of epileptic HFOs, but has no effect on spikes. This enforces the hypothesis that, in epilepsy, HFOs mirror the disease activity and HFOs might be useful for monitoring antiepileptic drug treatment. It is feasible to record HFOs during surgery, but propofol infusion should be interrupted for some minutes to improve detection.     

High-frequency oscillations of ictal muscle activity and epileptogenic discharges on intracranial EEG in a temporal lobe epilepsy patient.

OBJECTIVE: During seizures, intracranial EEG electrodes can record ictal muscle movements. Our purpose was to differentiate the high-frequency oscillations (HFOs) of extracranial muscle contractions from those of intracranial epileptogenic discharges. METHODS: Using intracranial video-EEG (IVEEG), we recorded seizures in a 17-year-old boy with left mesial-temporal lobe epilepsy. We used multiple band frequency analysis (MBFA) to differentiate extracranial HFOs of craniofacial muscle activities from intracranial HFOs recorded ictally and interictally. RESULTS: During 11 seizures, IVEEG showed low-amplitude fast waves ( approximately 60Hz) starting at the left mesial-temporal electrodes. Ictal facial grimacing projected low-amplitude ( approximately 20muV) fast waves ( approximately 160Hz) on inferior lateral-temporal electrodes. Interictal chewing projected medium-amplitude ( approximately 100muV) fast waves ( approximately 140Hz) correlating to mouth movements. MBFA topographic power spectrograms revealed a sustained, consistent ictal fast-frequency band from electrodes in the seizure-onset zone and randomly scattered HFOs without a specific frequency band from ictal and interictal extracranial muscle contractions. CONCLUSIONS: MBFA power spectrograms differentiated randomly scattered muscle HFOs without a specific frequency band at electrodes close to temporal muscles from ictal epileptic HFOs with a sustained, fast-frequency band in the seizure-onset zone. SIGNIFICANCE: The pattern and distribution of frequency power spectrograms of extracranial HFOs differ from those of intracranial HFOs.     

High-frequency (80-500 Hz) oscillations and epileptogenesis in temporal lobe epilepsy

High-frequency oscillations (HFOs), termed ripples (80-200 Hz) and fast ripples (250-600 Hz), are recorded in the EEG of epileptic patients and in animal epilepsy models; HFOs are thought to reflect pathological activity and seizure onset zones. Here, we analyzed the temporal and spatial evolution of interictal spikes with and without HFOs in the rat pilocarpine model of temporal lobe epilepsy. Depth electrode recordings from dentate gyrus (DG), CA3 region, subiculum and entorhinal cortex (EC), were obtained from rats between the 4th and 15th day after a status epilepticus (SE) induced by i.p. injection of pilocarpine. The first seizure occurred 6.1 ± 2.5 days after SE (n = 7 rats). Five of 7 animals exhibited interictal spikes that co-occurred with fast ripples accounting for 4.9 ± 4.6% of all analyzed interictal spikes (n = 12,886) while all rats showed interictal spikes co-occurring with ripples, accounting for 14.3 ± 3.4% of all events. Increased rates of interictal spikes without HFOs in the EC predicted upcoming seizures on the following day, while rates of interictal spikes with fast ripples in CA3 reflected periods of high seizure occurrence. Finally, interictal spikes co-occurring with ripples did not show any specific relation to seizure occurrence. Our findings identify different temporal and spatial developmental patterns for the rates of interictal spikes with or without HFOs in relation with seizure occurrence. These distinct categories of interictal spikes point at dynamic processes that should bring neuronal networks close to seizure generation.     

Interictal high-frequency oscillations,spikes, and connectivity profiles: A fingerprint of epileptogenic brain pathologies

Objective

Focal cortical dysplasia (FCD), hippocampal sclerosis (HS), nonspecific gliosis (NG), and normal tissue (NT) comprise the majority of histopathological results of surgically treated drug-resistant epilepsy patients. Epileptic spikes, high-frequency oscillations (HFOs), and connectivity measures are valuable biomarkers of epileptogenicity. The question remains whether they could also be utilized for preresective differentiation of the underlying brain pathology. This study explored spikes and HFOs together with functional connectivity in various epileptogenic pathologies.

Methods

Interictal awake stereoelectroencephalographic recordings of 33 patients with focal drug-resistant epilepsy with seizure-free postoperative outcomes were analyzed (15 FCD, 8 HS, 6 NT, and 4 NG). Interictal spikes and HFOs were automatically identified in the channels contained in the overlap of seizure onset zone and resected tissue. Functional connectivity measures (relative entropy, linear correlation, cross-correlation, and phase consistency) were computed for neighboring electrode pairs.

Results

Statistically significant differences were found between the individual pathologies in HFO rates, spikes, and their characteristics, together with functional connectivity measures, with the highest values in the case of HS and NG/NT. A model to predict brain pathology based on all interictal measures achieved up to 84.0% prediction accuracy.

Significance

The electrophysiological profile of the various epileptogenic lesions in epilepsy surgery patients was analyzed. Based on this profile, a predictive model was developed. This model offers excellent potential to identify the nature of the underlying lesion prior to resection. If validated, this model may be particularly valuable for counseling patients, as depending on the lesion type, different outcomes are achieved after epilepsy surgery.     

Critical evaluation of animal models for localization-related epilepsies

There are many forms of human partial seizures and many human localization-related epilepsies. Idiopathic epilepsies undoubtedly have pathophysiologic substrates different from those of symptomatic epilepsies, and there is evidence that some forms of limbic epilepsy involve different epileptogenic mechanisms than neocortical epilepsies. Although these mechanisms are best studied and understood by direct investigations of patients, this is often impractical and experimental animal models are also necessary. The use of experimental animals requires that the relevance of each model to a human condition be determined. Human epilepsies are comprised of multiple component parts which can be modeled independently. For instance, acute animal models provide opportunities to study epileptic seizures, but chronic models are necessary for investigation of processes relevant to epileptic conditions, such as epileptogenesis, transition from interictal to ictal state, and long-term consequences of epilepsy. Interactions between localized epileptic activity and cerebral maturation can also be studied in the animal laboratory. Experimental animal models of human partial seizures and localization-related epilepsies can be used to further investigations on basic mechanisms that cannot be pursued in patients, and to develop hypotheses concerning the fundamental neuronal processes underlying epilepsy and epilepsy-related phenomena that subsequently can be validated in patients. In addition, it would be of great clinical utility to develop animal models of partial seizures or localization-related epilepsy that could be used cost-effectively to screen potential antiepileptic drugs.Original research reported by the author was supported in part by Grants NS-02808, NS-15654 and GM-24839, from the National Institutes of Health, and Contract DE-AC03-76-SF00012 from the Department of Energy.     

Scalp‐recorded high‐frequency oscillations in childhood sleep‐induced electrical status epilepticus

Because high‐frequency oscillations (HFOs) may affect normal brain functions, we examined them using electroencephalography (EEG) in epilepsy with continuous spike‐waves during slow‐wave sleep (CSWS), a condition that can cause neuropsychological regression. In 10 children between 6 and 9 years of age with epilepsy with CSWS or related disorders, we investigated HFOs in scalp EEG spikes during slow‐wave sleep through temporal expansion of the EEG traces with a low‐cut frequency filter at 70 Hz as well as through time‐frequency power spectral analysis. HFOs (ripples) concurrent with spikes were detected in the temporally expanded traces, and the frequency of the high‐frequency peak with the greatest power in each patient’s spectra ranged from 97.7 to 140.6 Hz. This is the first report on the detection of HFOs from scalp EEG recordings in epileptic patients. We speculate that epileptic HFOs may interfere with higher brain functions in epilepsy with CSWS.     

Computational models of epilepsy

PurposeApproximately 30% of epilepsy patients suffer from medically refractory epilepsy, in which seizures can not controlled by the use of anti-epileptic drugs (AEDs). Understanding the mechanisms underlying these forms of drug-resistant epileptic seizures and the development of alternative effective treatment strategies are fundamental challenges for modern epilepsy research. In this context, computational modeling has gained prominence as an important tool for tackling the complexity of the epileptic phenomenon. In this review article, we present a survey of computational models of epilepsy from the point of view that epilepsy is a dynamical brain disease that is primarily characterized by unprovoked spontaneous epileptic seizures.MethodWe introduce key concepts from the mathematical theory of dynamical systems, such as multi-stability and bifurcations, and explain how these concepts aid in our understanding of the brain mechanisms involved in the emergence of epileptic seizures.ResultsWe present a literature survey of the different computational modeling approaches that are used in the study of epilepsy. Special emphasis is placed on highlighting the fine balance between the degree of model simplification and the extent of biological realism that modelers seek in order to address relevant questions. In this context, we discuss three specific examples from published literature, which exemplify different approaches used for developing computational models of epilepsy. We further explore the potential of recently developed optogenetics tools to provide novel avenue for seizure control.ConclusionWe conclude with a discussion on the utility of computational models for the development of new epilepsy treatment protocols.     

L-Type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue

Purpose: Human hypothalamic hamartomas (HHs) are associated with gelastic seizures, intrinsically epileptogenic, and notoriously refractory to medical therapy. We previously reported that the L‐type calcium channel antagonist nifedipine blocks spontaneous firing and γ‐aminobutyric acid (GABA)_A–induced depolarization of single cells in HH tissue slices. In this study, we examined whether blocking L‐type calcium channels attenuates emergent activity of HH neuronal networks. Methods: A high‐density multielectrode array was used to record extracellular signals from surgically resected HH tissue slices. High‐frequency oscillations (HFOs, ripples and fast ripples), field potentials, and multiunit activity (MUA) were studied (1) under normal and provoked [4‐aminopyridine (4‐AP)] conditions; and (2) following nifedipine treatment. Key Findings: Spontaneous activity occurred during normal artificial cerebrospinal fluid (aCSF) conditions. Nifedipine reduced the total number and duration of HFOs, abolished the association of HFOs with field potentials, and increased the inter‐HFO burst intervals. Notably, the number of active regions was decreased by 45 ± 9% (mean ± SEM) after nifedipine treatment. When considering electrodes that detected activity, nifedipine increased MUA in 58% of electrodes and reduced the number of field potentials in 67% of electrodes. Provocation with 4‐AP increased the number of events and, as the number of electrodes that detected activity increased 248 ± 62%, promoted tissue‐wide propagation of activity. During provocation with 4‐AP, nifedipine effectively reduced HFOs, the association of HFOs with field potentials, field potentials, MUA, and the number of active regions, and limited propagation. Significance: This is the first study to report (1) the presence of HFOs in human subcortical epileptic brain tissue in vitro; (2) the modulation of “pathologic” high‐frequency oscillations (i.e., fast ripples) in human epileptic tissue by L‐type calcium channel blockers; and (3) the modulation of network physiology and synchrony of emergent activity in human epileptic tissue following blockade of L‐type calcium channels. Attenuation of activity in HH tissue during normal and provoked conditions supports a potential therapeutic usefulness of L‐type calcium channel blockers in epileptic patients with HH.     

An Automatic HFO Detection Method Combining Visual Inspection Features with Multi-Domain Features

As an important promising biomarker, high frequency oscillations (HFOs) can be used to track epileptic activity and localize epileptogenic zones. However, visual marking of HFOs from a large amount of intracranial electroencephalogram (iEEG) data requires a great deal of time and effort from researchers, and is also very dependent on visual features and easily influenced by subjective factors. Therefore, we proposed an automatic epileptic HFO detection method based on visual features and non-intuitive multi-domain features. To eliminate the interference of continuous oscillatory activity in detected sporadic short HFO events, the iEEG signals adjacent to the detected events were set as the neighboring environmental range while the number of oscillations and the peak–valley differences were calculated as the environmental reference features. The proposed method was developed as a MatLab-based HFO detector to automatically detect HFOs in multi-channel, long-distance iEEG signals. The performance of our detector was evaluated on iEEG recordings from epileptic mice and patients with intractable epilepsy. More than 90% of the HFO events detected by this method were confirmed by experts, while the average missed-detection rate was < 10%. Compared with recent related research, the proposed method achieved a synchronous improvement of sensitivity and specificity, and a balance between low false-alarm rate and high detection rate. Detection results demonstrated that the proposed method performs well in sensitivity, specificity, and precision. As an auxiliary tool, our detector can greatly improve the efficiency of clinical experts in inspecting HFO events during the diagnosis and treatment of epilepsy.     

Potential new roles for glycogen in epilepsy

Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue often show low signals with ¹⁸fluorodeoxyglucose (FDG) positron emission tomography (PET) in many epileptic patients, even when there are no radiologically detectable structural abnormalities. Low FDG-PET signals are thought to reflect glucose hypometabolism. Here, we review knowledge about metabolism of glucose and glycogen and oxidative stress in people with epilepsy and in acute and chronic rodent seizure models. Interictal brain glucose levels are normal and do not cause apparent glucose hypometabolism, which remains unexplained. During seizures, high amounts of fuel are needed to satisfy increased energy demands. Astrocytes consume glycogen as an additional emergency fuel to supplement glucose during high metabolic demand, such as during brain stimulation, stress, and seizures. In rodents, brain glycogen levels drop during induced seizures and increase to higher levels thereafter. Interictally, in people with epilepsy and in chronic epilepsy models, normal glucose but high glycogen levels have been found in the presumed brain areas involved in seizure generation. We present our new hypothesis that as an adaptive response to repeated episodes of high metabolic demand, high interictal glycogen levels in epileptogenic brain areas are used to support energy metabolism and potentially interictal neuronal activity. Glycogenolysis, which can be triggered by stress or oxidative stress, leads to decreased utilization of plasma glucose in epileptogenic brain areas, resulting in low FDG signals that are related to functional changes underlying seizure onset and propagation. This is (partially) reversible after successful surgery. Last, we propose that potential interictal glycogen depletion in epileptogenic and surrounding areas may cause energy shortages in astrocytes, which may impair potassium buffering and contribute to seizure generation. Based on these hypotheses, auxiliary fuels or treatments that support glycogen metabolism may be useful to treat epilepsy.     

Dipole analysis in a case with tumor-related epilepsy.

In order to evaluate the effectiveness of presurgical dipole analysis of interictal spikes as a non-invasive technique for the determination of epileptogenic area, we compared the results of this method with those of electrocorticography (ECoG) localization in the diagnosis of a patient with tumor-related epilepsy. A preoperative MRI revealed a temporal lobe tumor on the right side. The individual dipoles estimated from the interictal spikes were located mainly in the anterolateral region of the right temporal lobe, although some were located in the mesial side. The ECoG recorded frequent spikes in the anterolateral region of the right temporal lobe consistent with the location estimated by dipole analysis. After surgery, the patient suffered from residual seizures. Therefore, the residual epileptogenic area was examined by dipole analysis using a four-layered head model instead of the previous three-layered head model. As a result, the dipole analysis was able to pinpoint the epileptic focus in the area directly adjacent to the resected area, and in the mesial temporal lobe. In conclusion, EEG dipole analysis appears to hold promise as a non-invasive presurgical evaluation technique for locating epileptogenic areas as well as for postsurgical evaluation of residual epileptic focus.     

High‐frequency oscillations: The state of clinical research

Modern electroencephalographic (EEG) technology contributed to the appreciation that the EEG signal outside the classical Berger frequency band contains important information. In epilepsy, research of the past decade focused particularly on interictal high‐frequency oscillations (HFOs) > 80 Hz. The first large application of HFOs was in the context of epilepsy surgery. This is now followed by other applications such as assessment of epilepsy severity and monitoring of antiepileptic therapy. This article reviews the evidence on the clinical use of HFOs in epilepsy with an emphasis on the latest developments. It highlights the growing literature on the association between HFOs and postsurgical seizure outcome. A recent meta‐analysis confirmed a higher resection ratio for HFOs in seizure‐free versus non–seizure‐free patients. Residual HFOs in the postoperative electrocorticogram were shown to predict epilepsy surgery outcome better than preoperative HFO rates. The review further discusses the different attempts to separate physiological from epileptic HFOs, as this might increase the specificity of HFOs. As an example, analysis of sleep microstructure demonstrated a different coupling between HFOs inside and outside the epileptogenic zone. Moreover, there is increasing evidence that HFOs are useful to measure disease activity and assess treatment response using noninvasive EEG and magnetoencephalography. This approach is particularly promising in children, because they show high scalp HFO rates. HFO rates in West syndrome decrease after adrenocorticotropic hormone treatment. Presence of HFOs at the time of rolandic spikes correlates with seizure frequency. The time‐consuming visual assessment of HFOs, which prevented their clinical application in the past, is now overcome by validated computer‐assisted algorithms. HFO research has considerably advanced over the past decade, and use of noninvasive methods will make HFOs accessible to large numbers of patients. Prospective multicenter trials are awaited to gather information over long recording periods in large patient samples.     

Dynamic changes of ictal high-frequency oscillations in neocortical epilepsy: using multiple band frequency analysis

PURPOSE: To characterize the spatial and temporal course of ictal high-frequency oscillations (HFOs) recorded by subdural EEG in children with intractable neocortical epilepsy. METHODS: We retrospectively studied nine children (four girls, five boys; 4-17 yr) who presented with intractable extrahippocampal localization-related epilepsy and who underwent extraoperative video subdural EEG (1000 Hz sampling rate) and cortical resection. We performed multiple band frequency analysis (MBFA) to evaluate the frequency, time course, and distribution of ictal HFOs. We compared ictal HFO changes before and after clinical onset and postsurgical seizure outcomes. RESULTS: Seventy-eight of 79 seizures showed HFOs. We observed wide-band HFOs ( approximately 250 Hz, approximately 120 electrodes) in six patients either with partial seizures alone (three patients) or with epileptic spasms (three patients). Three patients with partial seizures that secondarily generalized had wide-band HFOs ( approximately 170 Hz) before clinical onset and sustained narrow-band HFOs (60-164 Hz) with electrodecremental events after clinical onset ( approximately 28 electrodes). In four postoperatively seizure-free patients, more electrodes recorded higher-frequency HFOs inside the resection area than outside before and after clinical seizure onset. In five patients with residual seizures, electrodes recorded more HFOs that were of higher or equal frequency outside the surgical area than inside after clinical onset. CONCLUSION: For partial seizures alone and epileptic spasms, more electrodes recorded only wide-band HFOs; for partial seizures that secondarily generalized, fewer electrodes recorded wide-band HFOs, but in these seizures electrodes also recorded subsequent sustained narrow-band ictal HFOs. Resection of those brain regions having electrodes with ictal, higher HFOs resulted in postsurgical seizure-free outcomes.