Pathological High-Frequency Oscillations in Mesial Temporal Lobe Epilepsy

Allopregnanolone decreases interictal spiking and fast ripples in an animal model of mesial temporal lobe epilepsy

Interictal high-frequency oscillations over 200 Hz have been recorded with microelectrodes in the seizure onset zone of epileptic patients suffering from mesial temporal lobe epilepsy. Recent work suggests that similar high-frequency oscillations can be detected in the seizure onset zone using standard diagnostic macroelectrodes. However, only a few channels were examined in these studies, so little information is available on the spatial extent of high-frequency oscillations. Here, we present data on high-frequency oscillations recorded from a larger number of intracerebral contacts spatial (mean 38) in 16 patients. Data were obtained from 1 h of interictal recording sampled at 1024 Hz and was analysed using a new semi-automatic detection procedure based on a wavelet decomposition. A detailed frequency analysis permitted a rapid and reliable discrimination of high-frequency oscillations from other high-frequency events. A total of 1932 high-frequency oscillations were detected with an average frequency of 261 +/- 53 Hz, amplitude of 11.9 +/- 6.7 microV and duration of 22.7 +/- 11.6 ms. Records from a patient often showed several different high-frequency oscillation patterns. We classified 24 patterns from 11 patients. Usually (20/24 patterns) high-frequency oscillations were nested in an epileptic paroxysm, such as a spike or a sharp wave, and typically high-frequency oscillations (19/24) were recorded from just one recording contact. Unexpectedly in other cases, high-frequency oscillations (5/24) were detected simultaneously on two or three contacts, sometimes separated by large distances. This large spatial extent suggests that high-frequency oscillations may sometimes result from a neuronal synchrony manifest on a scale of centimetres. High-frequency oscillations were almost always recorded in seizure-generating structures of patients suffering from mesial (9/9) or polar (1/3) temporal lobe epilepsy. They were never found in the epileptic or healthy basal, lateral temporal or extra temporal neocortex nor in the healthy amygdalo-hippocampal complex. These findings confirm that the generation of oscillations at frequencies higher that 200 Hz is, at this scale, a specific, intrinsic property of seizure-generating networks in medial and polar temporal lobes, which have a common archaic phylogenetic origin. We show that this activity can be detected and its spatial extent determined with conventional intracranial electroencephalography electrodes in records from patients with temporal lobe epilepsy. It is a reliable marker of the seizure onset zone that should be considered in decisions on surgical treatment.

Neuronal synchronization supports different physiological states such as cognitive functions and sleep, and it is mirrored by identifiable EEG patterns ranging from gamma to delta oscillations. However, excessive neuronal synchronization is often the hallmark of epileptic activity in both generalized and partial epileptic disorders. Here, I will review the synchronizing mechanisms involved in generating epileptiform activity in the limbic system, which is closely involved in the pathophysiogenesis of temporal lobe epilepsy (TLE). TLE is often associated to a typical pattern of brain damage known as mesial temporal sclerosis, and it is one of the most refractory adult form of partial epilepsy. This epileptic disorder can be reproduced in animals by topical or systemic injection of pilocarpine or kainic acid, or by repetitive electrical stimulation; these procedures induce an initial status epilepticus and cause 1-4 weeks later a chronic condition of recurrent limbic seizures. Remarkably, a similar, seizure-free, latent period can be identified in TLE patients who suffered an initial insult in childhood and develop partial seizures in adolescence or early adulthood. Specifically, I will focus here on the neuronal mechanisms underlying three abnormal types of neuronal synchronization seen in both TLE patients and animal models mimicking this disorder: (i) interictal spikes; (ii) high frequency oscillations (80-500 Hz); and (iii) ictal (i.e., seizure) discharges. In addition, I will discuss the relationship between interictal spikes and ictal activity as well as recent evidence suggesting that specific seizure onsets in the pilocarpine model of TLE are characterized by distinctive patterns of spiking (also termed preictal) and high frequency oscillations.

Objective:Interictal high-frequency oscillations (HFOs) are a promising neurophysiological biomarker of the epileptogenic zone (EZ). However, objective criteria for distinguishing pathological from physiological HFOs remain elusive, hindering clinical application. We investigated whether the distinct mechanisms underlying pathological and physiological HFOs are encapsulated in their signal morphology in intracranial EEG (iEEG) recordings and whether this mechanism-driven distinction could be simulated by a deep generative model.Methods:In a retrospective cohort of 185 epilepsy patients who underwent iEEG monitoring, we analyzed 686,410 HFOs across 18,265 brain contacts. To learn morphological characteristics, each event was transformed into a time-frequency plot and input into a variational autoencoder. We characterized latent space clusters containing morphologically defined putative pathological HFOs (mpHFOs) using interpretability analysis, including latent space disentanglement and time-domain perturbation.Results:mpHFOs showed strong associations with expert-defined spikes and were predominantly located within the seizure onset zone (SOZ). Discovered novel pathological features included high power in the gamma (30–80 Hz) and ripple (>80 Hz) bands centered on the event. These characteristics were consistent across multiple variables, including institution, electrode type, and patient demographics. Predicting 12-month postoperative seizure outcomes using the resection ratio of mpHFOs outperformed unclassified HFOs (F1=0.72 vs. 0.68) and matched current clinical standards using SOZ resection (F1=0.74). Combining mpHFO data with demographic and SOZ resection status further improved prediction accuracy (F1=0.83).Interpretation:Our data-driven approach yielded a novel, explainable definition of pathological HFOs, which has the potential to further enhance the clinical use of HFOs for EZ delineation.

Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy.

We investigated whether entorhinal cortex (EC) layer IV neurons are hyperexcitable in the post-selfsustaining limbic status epilepticus (post-SSLSE) animal model of temporal lobe epilepsy. We studied naive rats (n = 44), epileptic rats that had experienced SSLSE resulting in spontaneous seizures (n = 45), and electrode controls (n = 7). There were no differences between electrode control and naive groups, which were pooled into a single control group. Intracellular and extracellular recordings were made from deep layers of EC, targeting layer IV, which was activated by stimulation of the superficial layers of EC or the angular bundle. There were no differences between epileptic and control neurons in basic cellular characteristics, and all neurons were quiescent under resting conditions. In control tissue, 77% of evoked intracellular responses consisted of a short-duration [8.6 +/- 1.3 (SE) ms] excitatory postsynaptic potential and a single action potential followed by gamma-aminobutyric acid-A (GABAA) and GABAB inhibitory post synaptic potentials (IPSPs). Ten percent of controls did not contain IPSPs. In chronically epileptic tissue, evoked intracellular responses demonstrated prolonged depolarizing potentials (256 +/- 39 ms), multiple action potentials (13 +/- 4), and no IPSPs. Ten percent of epileptic responses were followed by rhythmic "clonic" depolarizations. Epileptic responses exhibited an all-or-none response to progressive increases in stimulus intensity and required less stimulation to elicit action potentials. In both epileptic and control animals, intracellular responses correlated precisely in morphology and duration with extracellular field potentials. Severing the hippocampus from the EC did not alter the responses. Duration of intracellular epileptic responses was reduced 22% by the N-methyl--aspartate (NMDA) antagonist (-)-2-amino-5-phosphonovaleric acid (APV), but they did not return to normal and IPSPs were not restored. Epileptic and control responses were abolished by the non-NMDA antagonist 6, 7-dinitroquinoxaline-2-3-dione (DNQX). A monosynaptic IPSP protocol was used to test connectivity of inhibitory interneurons to primary cells by direct activation of interneurons with a stimulating electrode placed near the recording electrode in the presence of APV and DNQX. Using this protocol, IPSPs similar to control (P > 0.05) were seen in epileptic cells. The findings demonstrate that deep layer EC cells are hyperexcitable or "epileptiform" in this model. Hyperexcitability is not due to interactions with the hippocampus. It is due partially to augmented NMDA-mediated excitation. The lack of IPSPs in epileptic neurons may suggest inhibition is impaired, but we found evidence that inhibitory interneurons are connected to their target cells and are capable of inducing IPSPs.

In vitro Oscillation Patterns Throughout the Hippocampal Formation in a Rodent Model of Epilepsy

Glycine transporter 1 is a target for the treatment of epilepsy

Studies show that High frequency oscillations (HFOs) can be used as a reliable biomarker of epileptogenic zone, thus many algorithms have been proposed to detect HFOs. Among the wide variety of HFOs, fast ripples (FRs) are important transient oscillations occurring in the frequency band ranging from 250 Hz to 600 Hz. The automatic detection of FRs can be degenerated by the presence of some "pulse-like" events (commonly, the component of interictal epileptic spikes) associated with an increase of the signal energy in the high frequency bands, exactly as in the case of real FRs. The goal of this study is to propose a new method for automatic detection of fast ripples by using Hidden Markov Model (HMM). This method can separate fast ripples from interictal epileptic spikes and background EEG by classifying each segment of signal in three classes. The sensitivity and specificity show this method is reliable to detect fast ripples and avoids false detections caused by sharp transient events often present in raw signals.

PurposeWe investigated the distribution of spikes and HFOs recorded during intraoperative electrocorticography (ioECoG) and tried to elaborate a predictive model for postsurgical outcomes of patients with lateral neocortical temporal lobe epilepsy (TLE) whose mesiotemporal structures are left in situ.MethodsWe selected patients with temporal lateral neocortical epilepsy focus who underwent ioECoG-tailored resections without amygdalo–hippocampectomies. We visually marked spikes, ripples (80–250 Hz), and fast ripples (FRs; 250–500 Hz) on neocortical and mesiotemporal channels before and after resections. We looked for differences in event rates and resection ratios between good (Engel 1A) and poor outcome groups and performed logistic regression analysis to identify outcome predictors.ResultsFourteen out of 24 included patients had a good outcome. The poor-outcome patients showed higher rates of ripples on neocortical channels distant from the resection in pre- and post-ioECoG than people with good outcomes (ppre = 0.04, ppost = 0.05). Post-ioECoG FRs were found only in poor-outcome patients (N = 3). A prediction model based on regression analysis showed low rates of mesiotemporal post-ioECoG ripples (ORmesio = 0.13, pmesio = 0.04) and older age at epilepsy onset (OR = 1.76, p = 0.04) to be predictors of good seizure outcome.ConclusionHFOs in ioECoG may help to inform the neurosurgeon of the hippocampus-sparing resection success chance in patients with lateral neocortical TLE.

Event Abstract Back to Event Wireless telemetry as an ideal tool for continuous intrahippocampal EEG recording in chronic epilepsy mouse models Yana Van Den Herrewegen1*, An Buckinx1*, Gino De Smet1, Ilse J. Smolders1 and Dimitri De Bundel1 1 Vrije Universiteit Brussel, Experimental Pharmacology (EFAR), cluster Neurosciences, Belgium Tethered recording systems are routinely used as a method for long-term continuous EEG monitoring in animal models of epilepsy. Nevertheless, tethered systems display some disadvantages when chronically used in mice, in some cases even compromising experiments and behavioral follow-up of the mice. Therefore, wireless telemetry systems are increasingly being used as an alternative method to precisely measure biopotentials in the rodent brain. As EEG recordings are the most powerful read-outs in animal models of epilepsy, we evaluated the use of wireless radio-telemetry in the intrahippocampal post-status epilepticus kainic acid model, an established mouse model for studying temporal lobe epilepsy and epileptogenesis. Via intraperitoneal implantation of a radiofrequency transmitter (ETA-F10, DSI) and electrodes positioned in the hippocampus, we were able to record intrahippocampal signals for up to two months. We could clearly monitor the epileptic activity during the status epilepticus, followed by a short latent period and the subsequent occurrence of the typical spontaneous epileptic discharges. This study discusses the advantages of telemetric EEG recordings and strategies to maximize the signal-to-noise ratio in order to obtain high-quality deep-brain EEG recordings. In conclusion, wireless telemetry systems are a valuable EEG monitoring method in the intrahippocampal kainic acid mouse model and other models of chronic epilepsy in mice. References Bouilleret V, Ridoux V, Depaulis A, et al. Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience. 1999; Mar;89(3):717-29. Duveau V, Pouyatos B, Bressand K, et al. Differential Effects of Antiepileptic Drugs on Focal Seizures in the Intrahippocampal Kainate Mouse Model of Mesial Temporal Lobe Epilepsy. CNS Neuroscience & Therapeutics: CNS Neurosci Ther. 2016;(22):497-50. doi: 10.1111/cns.12523 Lundt A, Wormuth C, Siwek ME, et al. EEG Radiotelemetry in Small Laboratory Rodents: A Powerful State-of-the Art Approach in Neuropsychiatric, Neurodegenerative, and Epilepsy Research. Neural Plasticity. 2016;2016:8213878. doi:10.1155/2016/8213878. Twele F, Tollner K, Bankstahl M, Loscher W, et al. The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain. Epilepsia Open, 2016; 1(1):45–60,. doi: 10.1002/epi4.2 Zayachkivsky A, Lehmkuhle MJ, Dudek FE. Long-term Continuous EEG Monitoring in Small Rodent Models of Human Disease Using the Epoch Wireless Transmitter System. Journal of Visualized Experiments : JoVE. 2015;(101):52554. doi:10.3791/52554. Keywords: wireless radio-telemetry, EEG, Epilepsy, Temporal Lobe, mouse models, Seizures Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Poster Presentation Topic: Novel Methods and Technology Development Citation: Van Den Herrewegen Y, Buckinx A, De Smet G, Smolders IJ and De Bundel D (2019). Wireless telemetry as an ideal tool for continuous intrahippocampal EEG recording in chronic epilepsy mouse models. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00001 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 02 May 2017; Published Online: 25 Jan 2019. * Correspondence: Miss. Yana Van Den Herrewegen, Vrije Universiteit Brussel, Experimental Pharmacology (EFAR), cluster Neurosciences, Brussels, 1090, Belgium, yana.van.den.herrewegen@vub.ac.be Miss. An Buckinx, Vrije Universiteit Brussel, Experimental Pharmacology (EFAR), cluster Neurosciences, Brussels, 1090, Belgium, an.buckinx@vub.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Yana Van Den Herrewegen An Buckinx Gino De Smet Ilse J Smolders Dimitri De Bundel Google Yana Van Den Herrewegen An Buckinx Gino De Smet Ilse J Smolders Dimitri De Bundel Google Scholar Yana Van Den Herrewegen An Buckinx Gino De Smet Ilse J Smolders Dimitri De Bundel PubMed Yana Van Den Herrewegen An Buckinx Gino De Smet Ilse J Smolders Dimitri De Bundel Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

ObjectivePathological high-frequency oscillations (HFOs) in intracranial EEG are promising biomarkers of epileptogenic tissue, and their physiological counterparts play a role in sensorimotor and cognitive function. HFOs have also been found in scalp EEG, but an overview of all studies is lacking. In this systematic review, we assessed the methodology to detect scalp HFOs and their clinical potential. MethodsWe searched PubMed, Embase and the Cochrane Library for studies on HFOs in scalp EEG, and extracted methodological and clinical data. ResultsWe included 60 studies with data from 1149 unique individuals. Two-thirds of studies analyzed HFOs visually in the time or time–frequency domain, and one-third automatically with visual validation. Most studies evaluated interictal ripples during sleep in children. Pathological HFOs were overall better than spikes in localizing the epileptogenic zone and predicting outcome, correlated negatively with cognition and positively with disease activity and severity, and decreased after medical and surgical treatment. ConclusionsThe methodologies of the 60 studies were heterogeneous, but pathological scalp HFOs were clinically valuable as biomarkers in various situations, particularly in children with epilepsy. SignificanceThis systematic review gives an extensive overview of methodological and clinical data on scalp HFOs, establishing their clinical potential and discussing their limitations.

Ondansetron reduces seizures and improves cognitive impairment in a rat model of temporal lobe epilepsy

Pathological high frequency oscillations (HFOs) are putative neurophysiological biomarkers of epileptogenic brain tissue. Utilizing HFOs for epilepsy surgery planning offers the promise of improved seizure outcomes for patients with medically refractory epilepsy. This review discusses possible machine learning strategies that can be applied to HFO biomarkers to better identify epileptogenic regions. We discuss the role of HFO rate, and utilizing features such as explicit HFO properties (spectral content, duration, and power) and phase-amplitude coupling for distinguishing pathological HFO (pHFO) events from physiological HFO events. In addition, the review highlights the importance of neuroanatomical localization in machine learning strategies.

BackgroundThe expression pattern and function of miRNAs in the rat model of temporal lobe epilepsy have not been well defined. Profiling miRNA expression in the rat model of temporal lobe epilepsy and investigating the function of specific miRNAs in epilepsy offers the prospect of a deeper understanding of the mechanisms of epilepsy.MethodsThe lithium-pilocarpine-induced status epilepticus model and the temporal lobe epilepsy model were established in Sprague–Dawley rats. Samples were analysed to detect deregulated miRNAs in the hippocampal temporal lobe, and several of these deregulated miRNAs were confirmed by qPCR. The expression of the pro-apoptotic miR-34a was detected at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. The antagomir of miR-34a was then utilised. The expression of miR-34a after targeting and the expression change of activated caspase-3 protein were examined. The effects of altering the expression of miR-34a and activated caspase-3 protein on neuronal survival and neuronal death or apoptosis post-status epilepticus were assessed.ResultsThe miRNA microarray detected 9 up-regulated miRNAs (miR-146a, -211, -203, -210, -152, -31, -23a, -34a, -27a) and 15 down-regulated miRNAs (miR-138*, -301a, -136, -153, -19a, -135b, -325-5p, -380, -190, -542-3p, -33, -144, -542-5p, -543, -296*). Some of the deregulated miRNAs (miR-146a, miR-210, miR-27a, miR-135b and miR-33) were confirmed using qPCR. Furthermore, an increase in expression of the pro-apoptotic miR-34a was demonstrated in the post-status epilepticus rat hippocampus. miR-34a was significantly up-regulated at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. Experiments with the miR-34a antagomir revealed that targeting miR-34a led to an inhibition of activated caspase-3 protein expression, which may contribute to increased neuronal survival and reduced neuronal death or apoptosis.ConclusionsOur study showed the expression profile of miRNAs in the hippocampus in a rat model of temporal lobe epilepsy and an increase in the expression of the pro-apoptotic miR-34a in post-status epilepticus rats. The results show that miR-34a is up-regulated during seizure-induced neuronal death or apoptosis, and targeting miR-34a is neuroprotective and is associated with an inhibition of an increase in activated caspase-3 protein.