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Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Drexler, Ben-Haim, Bien, Borger, Cardinale, Carpentier, Cendes, Chandra, Clusmann, Colon, Curtis, Delev, Didato, Dührsen, Farah, Guenot, Ghatan, Haegelen, Hamer, Hauptmann, Jeffree, Kalbhenn, Kegele, Krayenbühl, Lang, Mathon, Naros, Onken, Panov, Raftopoulos, Ricklefs, Rijkers, Rizzi, Rössler, Schijns, Schneider, Spyrantis, Strzelczyk, Stodieck, Tripathi, Vadera, Alonso-Vanegas, Vaz, Wellmer, Wehner, Westphal and Sauvigny.)

Introduction: It has been proposed that seizures induce IL-1β biosynthesis in astrocytes and increase blood brain barrier (BBB) permeability, even without the presence of blood borne inflammatory molecules and leukocytes. In the present study we investigate if seizures induce morphological changes typically observed in activated glial cells. Moreover, we will test if serum albumin extravasation into the brain parenchyma exacerbates neuronal hyperexcitability by inducing astrocytic and microglial activation. Methods: Epileptiform seizure-like events (SLEs) were induced in limbic regions by arterial perfusion of bicuculline methiodide (BMI; 50 μM) in the in vitro isolated guinea pig brain preparation. Field potentials were recorded in both the hippocampal CA1 region and the medial entorhinal cortex. BBB permeability changes were assessed by analyzing extravasation of arterially perfused fluorescein isothiocyanate (FITC)-albumin. Morphological changes in astrocytes and microglia were evaluated with tridimensional reconstruction and Sholl analysis in the ventral CA1 area of the hippocampus following application of BMI with or without co-perfusion of human serum albumin. Results: BMI-induced SLE promoted morphological changes of both astrocytes and microglia cells into an activated phenotype, confirmed by the quantification of the number and length of their processes. Human-recombinant albumin extravasation, due to SLE-induced BBB impairment, worsened both SLE duration and the activated glia phenotype. Discussion: Our study provides the first direct evidence that SLE activity per se is able to promote the activation of astro- and microglial cells, as observed by their changes in phenotype, in brain regions involved in seizure generation; we also hypothesize that gliosis, significantly intensified by h-recombinant albumin extravasation from the bloodstream to the brain parenchyma due to SLE-induced BBB disruption, is responsible for seizure activity reinforcement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor is currently organizing a Research Topic with one of the authors MC., (Copyright © 2021 Vila Verde, de Curtis and Librizzi.)

Introduction: To limit extrauterine growth restriction, recent guidelines on nutrition of preterm neonates recommended high protein intake since the first day of life (DOL). The impact of this nutritional strategy on the brain is still controversial. We aimed to evaluate the effects of protein intake on early cerebral growth in very low birth weight newborns. Materials and Methods: We performed serial cranial ultrasound (cUS) scans at 3-7 DOL and at 28 DOL in very low birth weight newborns consecutively observed in the neonatal intensive care unit. We analyzed the relation between protein intake and cerebral measurements at 28 DOL performed by cUS. Results: We enrolled 100 newborns (gestational age 29 ± 2 weeks, birth weight 1,274 ± 363 g). A significant ( p < 0.05) positive correlation between enteral protein intake and biparietal diameter ( r = 0.490 ** ), occipital-frontal diameter ( r = 0.608 ** ), corpus callosum (length r = 0.293 * , genu r = 0.301 * ), caudate head (right r = 0.528 ** , left r = 0.364 ** ), and cerebellum (transverse diameter r = 0.440 ** , vermis height r = 0.356 ** , vermis width r = 0.377 ** ) was observed at 28 DOL. Conversely, we found a significant negative correlation of protein intake given by parenteral nutrition (PN) with biparietal diameter ( r = -0.524 ** ), occipital-frontal diameter ( r = -0.568 ** ), body of corpus callosum ( r = -0.276 * ), caudate head (right r = -0.613 ** , left r = -0.444 ** ), and cerebellum (transverse diameter r = -0.403 ** , vermis height r = -0.274 * , vermis width r = -0.462 ** ) at 28 DOL. Multivariate regression analysis showed that measurements of occipital-frontal diameter, caudate head, and cerebellar vermis at 28 DOL depend positively on protein enteral intake ( r = 0.402 * , r = 0.305 * , and r = 0.271 * ) and negatively by protein parenteral intake ( r = -0.278 * , r = -0.488 * , and r = -0.342 * ). Conclusion: Brain development in neonatal life depends on early protein intake. High protein intake affects cerebral structures' measurements of preterm newborn when administered by PN. Positive impact on brain development encourages the administration of recommended protein intake mainly by enteral nutrition., (Copyright © 2020 Terrin, De Nardo, Boscarino, Di Chiara, Cellitti, Ciccarelli, Gasparini, Parisi, Urna, Ronchi, Russo, Sabatini and De Curtis.)

Objective: To observe and measure the morphological and temporal evolutionary features of the hypersynchronous (HYP) pattern in the mesial temporal seizure. Methods: The HYP patterns during preictal and interictal states of 16 mesial temporal epileptic patients were analyzed. The wave components of the HYP transients were firstly observed and measured. The dynamic deformations and parameter changes of the components were further analyzed along the preictal-ictal axis. The difference of emergence rate of HYP transients and typical interictal spike during interictal periods was also compared. Results: The HYP transients were invariably composed of slow-wave proper, sharp wave and post-slow component among studied patients for all the 93 seizures. During preictal epoch, all of the seizures incorporated present evolutionary manner of type 1 characterized by smooth modification of HYP transients in morphology, including gradual shortening of the inter-transient interval, increase of amplitude and time duration of slow-wave proper and sharp wave, amplitude decrease of the post-slow component, as well as amplitude increases of ripple and fast ripple, and 2/3 seizures showed some more sophisticated transitional manners (type 2) following type 1, including reduction in amplitude with decrease of inter-transient intervals, superimposed or followed by the emergent low amplitude rhythmic activities, or both of them. The HYP transients and typical interictal spikes were found to mutually "repelling" each other in interictal period. Conclusion: The HYP transients showed a combinational feature and temporal evolution manners during preictal state. The emergence of HYP transients in cluster reflects the transitional trend from interictal to ictal state. Significance: HYP should be viewed as an index of ictogenesis in the mesial temporal seizure. [ABSTRACT FROM AUTHOR]

Objective: The study aims to assess the relationship between epilepsy and circadian rhythms. Method: This study included a cohort of 7,410 participants sourced from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) database. The investigation focused on the comparative analysis of seven nonparametric indices associated with circadian rhythms (Interdaily Stability (IS), Intradaily Variability (IV), Relative Amplitude (RA), L5, M10, L5 start time, and M10 start time) between the overall population and patients with epilepsy. Logistic regression analysis was utilized to assess the potential correlation between the rest-activity circadian rhythm patterns and the presence of epilepsy within the cohort. Results: Compared to the general population, individuals with epilepsy exhibited lower values of IS and M10. Multivariable logistic regression analysis, when IS, RA, and M10 were categorized into four groups based on quartiles, revealed that the odds ratio (IS: OR = 0.36, 95% CI: 0.13, 0.89; RA: OR = 0.25, 95% CI: 0.06, 0.77; M10: OR = 0.24, 95% CI: 0.06, 0.73) for the highest quartile was lower than that for the lowest quartile. Furthermore, after adjustment for confounding factors, participants in the highest quartile compared to those in the lowest quartile of IV and M10 start time demonstrated a higher prevalence of epilepsy. Conclusion: Individuals with epilepsy demonstrate significant alterations in circadian rhythms. [ABSTRACT FROM AUTHOR]

Despite an abundance of pharmacologic and surgical epilepsy treatments, there remain millions of patients suffering from poorly controlled seizures. One approach to closing this treatment gap may be found through a deeper mechanistic understanding of the network alterations that underly this aberrant activity. Functional optical imaging in vertebrate models provides powerful advantages to this end, enabling the spatiotemporal acquisition of individual neuron activity patterns across multiple seizures. This coupled with the advent of genetically encoded indicators, be them for specific ions, neurotransmitters or voltage, grants researchers unparalleled access to the intact nervous system. Here, we will review how in vivo functional optical imaging in various vertebrate seizure models has advanced our knowledge of seizure dynamics, principally seizure initiation, propagation and termination. [ABSTRACT FROM AUTHOR]

This manuscript outlines a model of Alzheimer's Disease (AD) pathophysiology in progressive layers, from its genesis to the development of biomarkers and then to symptom expression. Genetic predispositions are the major factor that leads to mitochondrial dysfunction and subsequent amyloid and tau protein accumulation, which have been identified as hallmarks of AD. Extending beyond these accumulations, we explore a broader spectrum of pathophysiological aspects, including the blood-brain barrier, blood flow, vascular health, gutbrain microbiodata, glymphatic flow, metabolic syndrome, energy deficit, oxidative stress, calcium overload, inflammation, neuronal and synaptic loss, brain matter atrophy, and reduced growth factors. Photobiomodulation (PBM), which delivers near-infrared light to selected brain regions using portable devices, is introduced as a therapeutic approach. PBM has the potential to address each of these pathophysiological aspects, with data provided by various studies. They provide mechanistic support for largely small published clinical studies that demonstrate improvements in memory and cognition. They inform of PBM's potential to treat AD pending validation by large randomized controlled studies. The presentation of brain network and waveform changes on electroencephalography (EEG) provide the opportunity to use these data as a guide for the application of various PBM parameters to improve outcomes. These parameters include wavelength, power density, treatment duration, LED positioning, and pulse frequency. Pulsing at specific frequencies has been found to influence the expression of waveforms and modifications of brain networks. The expression stems from the modulation of cellular and protein structures as revealed in recent studies. These findings provide an EEG-based guide for the use of artificial intelligence to personalize AD treatment through EEG data feedback. [ABSTRACT FROM AUTHOR]

Objective: The success rate of achieving seizure freedom after radiofrequency thermocoagulation surgery for patients with refractory focal epilepsy is about 20-40%. This study aims to enhance the prediction of surgical outcomes based on preoperative decisions through network model simulation, providing a reference for clinicians to validate and optimize surgical plans. Methods: Twelve patients with epilepsy who underwent radiofrequency thermocoagulation were retrospectively reviewed in this study. A coupled model based on model subsets of the neural mass model was constructed by calculating partial directed coherence as the coupling matrix from stereoelectroencephalography (SEEG) signals. Multi-channel time-varying model parameters of excitation and inhibitions were identified by fitting the real SEEG signals with the coupled model. Further incorporating these model parameters, the coupled model virtually removed contacts destroyed in radiofrequency thermocoagulation or selected randomly. Subsequently, the coupled model after virtual surgery was simulated. Results: The identified excitatory and inhibitory parameters showed significant difference before and after seizure onset (p < 0.05), and the trends of parameter changes aligned with the seizure process. Additionally, excitatory parameters of epileptogenic contacts were higher than that of non-epileptogenic contacts, and opposite findings were noticed for inhibitory parameters. The simulated signals of postoperative models to predict surgical outcomes yielded an area under the curve (AUC) of 83.33% and an accuracy of 91.67%. Conclusion: The multi-channel coupled model proposed in this study with physiological characteristics showed a desirable performance for preoperatively predicting patients' prognoses. [ABSTRACT FROM AUTHOR]

Epilepsy is characterized by abnormal synchronous electrical activity of neurons in the brain. The blood-brain barrier, which is mainly composed of endothelial cells, pericytes, astrocytes and other cell types and is formed by connections between a variety of cells, is the key physiological structure connecting the blood and brain tissue and is critical for maintaining the microenvironment in the brain. Physiologically, the blood-brain barrier controls the microenvironment in the brain mainly by regulating the passage of various substances. Disruption of the blood-brain barrier and increased leakage of specific substances, which ultimately leading to weakened cell junctions and abnormal regulation of ion concentrations, have been observed during the development and progression of epilepsy in both clinical studies and animal models. In addition, disruption of the blood-brain barrier increases drug resistance through interference with drug trafficking mechanisms. The changes in the blood-brain barrier in epilepsy mainly affect molecular pathways associated with angiogenesis, inflammation, and oxidative stress. Further research on biomarkers is a promising direction for the development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: New onset refractory status epilepticus (NORSE) is a rare and devastating condition characterised by the sudden onset of refractory status epilepticus (RSE) without an identifiable acute or active structural, toxic, or metabolic cause in an individual without a pre-existing diagnosis of epilepsy. Febrile infection-related epilepsy syndrome (FIRES) is considered a subcategory of NORSE and presents following a febrile illness prior to seizure onset. NORSE/FIRES is associated with high morbidity and mortality in children and adults. Methods and results: In this review we first briefly summarise the reported clinical, paraclinical, treatment and outcome data in the literature. We then report on existing knowledge of the underlying pathophysiology in relation to in vitro and in vivo pre-clinical seizure and epilepsy models of potential relevance to NORSE/FIRES. Discussion: We highlight how pre-clinical models can enhance our understanding of FIRES/NORSE and propose future directions for research. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the clinical application of 18F-FDG PET radiomics features for temporal lobe epilepsy and to create PET radiomics-based machine learning models for differentiating temporal lobe epilepsy (TLE) patients from healthy controls. Methods: A total of 347 subjects who underwent 18F-FDG PET scans from March 2014 to January 2020 (234 TLE patients: 25.50 ± 8.89 years, 141 male patients and 93 female patients; and 113 controls: 27.59 ± 6.94 years, 48 male individuals and 65 female individuals) were allocated to the training (n = 248) and test (n = 99) sets. All 3D PET images were registered to theMontreal Neurological Institute template. PyRadiomics was used to extract radiomics features from the temporal regions segmented according to the Automated Anatomical Labeling (AAL) atlas. The least absolute shrinkage and selection operator (LASSO) and Boruta algorithms were applied to select the radiomics features significantly associated with TLE. Eleven machine-learning algorithms were used to establish models and to select the best model in the training set. Results: The final radiomics features (n = 7) used for model training were selected through the combinations of the LASSO and the Boruta algorithms with cross-validation. All data were randomly divided into a training set (n = 248) and a testing set (n = 99). Among 11 machine-learning algorithms, the logistic regression (AUC 0.984, F1-Score 0.959)model performed the best in the training set. Then, we deployed the corresponding online website version (https://wane199.shinyapps.io/TLE_Classification/), showing the details of the LR model for convenience. The AUCs of the tuned logistic regression model in the training and test sets were 0.981 and 0.957, respectively. Furthermore, the calibration curves demonstrated satisfactory alignment (visually assessed) for identifying the TLE patients. Conclusion: The radiomics model from temporal regions can be a potential method for distinguishing TLE. Machine learning-based diagnosis of TLE from preoperative FDG PET images could serve as a useful preoperative diagnostic tool. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) stand as the prevailing sources of neurodegenerative dementia, impacting over 55 million individuals across the globe. Patients with AD and DLB exhibit a higher prevalence of epileptic activity compared to those with other forms of dementia. Seizures can accompany AD and DLB in early stages, and the associated epileptic activity can contribute to cognitive symptoms and exacerbate cognitive decline. Aberrant neuronal activity in AD and DLB may be caused by several mechanisms that are not yet understood. Hyperexcitability could be a biomarker for early detection of AD or DLB before the onset of dementia. In this review, we compare and contrast mechanisms of network hyperexcitability in AD and DLB. We examine the contributions of genetic risk factors, Ca2+ dysregulation, glutamate, AMPA and NMDA receptors, mTOR, pathological amyloid beta, tau and α-synuclein, altered microglial and astrocytic activity, and impaired inhibitory interneuron function. By gaining a deeper understanding of the molecular mechanisms that cause neuronal hyperexcitability, we might uncover therapeutic approaches to effectively ease symptoms and slow down the advancement of AD and DLB. [ABSTRACT FROM AUTHOR]

Absence status epilepticus is a prolonged, generalized absence seizure that lasts more than half an hour. The mechanisms underlying the absence of status epilepticus are still not entirely understood. In this study, the study concentrates on alpha2-adrenergic mechanisms of absence status using the WAG/Rij rat model. In this model, a prolonged spike-wave activity was associated with a specific behavioral state in transition between sedation («alpha2-wakefulness»)- resembled absence status in human patients. Pharmacological activation of alpha2-adrenoreceptors may target the locus coeruleus (presynaptic alpha2-adrenoreceptors) and the thalamic part of the seizure-generating thalamocortical system (postsynaptic alpha2B-adrenoreceptors). The duration of EEG-behavioral correlates of absence status was not dose-dependent and was predetermined by the intensity of absence seizures at baseline. This model could help scientists better understand the underlying causes of absence status and develop more effective and personalized treatments for each individual. [ABSTRACT FROM AUTHOR]

Background: Acquired epilepsies are caused by an initial brain insult that is followed by epileptogenesis and finally the development of spontaneous recurrent seizures. The mechanisms underlying epileptogenesis are not fully understood. MicroRNAs regulate mRNA translation and stability and are frequently implicated in epilepsy. For example, antagonism of a specific microRNA, miR-324-5p, before brain insult and in a model of chronic epilepsy decreases seizure susceptibility and frequency, respectively. Here, we tested whether antagonism of miR-324-5p during epileptogenesis inhibits the development of epilepsy. Methods: We used the intrahippocampal kainic acid (IHpKa) model to initiate epileptogenesis in male wild type C57BL/6  J mice aged 6–8  weeks. Twentyfour hours after IHpKa, we administered a miR-324-5p or scrambled control antagomir intracerebroventricularly and implanted cortical surface electrodes for EEG monitoring. EEG data was collected for 28  days and analyzed for seizure frequency and duration, interictal spike activity, and EEG power. Brains were collected for histological analysis. Results: Histological analysis of brain tissue showed that IHpKa caused characteristic hippocampal damage in most mice regardless of treatment. Antagomir treatment did not affect latency to, frequency, or duration of spontaneous recurrent seizures or interictal spike activity but did alter the temporal development of frequency band-specific EEG power. Conclusion: These results suggest that miR-324-5p inhibition during epileptogenesis induced by status epilepticus does not convey anti-epileptogenic effects despite having subtle effects on EEG frequency bands. Our results highlight the importance of timing of intervention across epilepsy development and suggest that miR-324-5p may act primarily as a proconvulsant rather than a pro-epileptogenic regulator. [ABSTRACT FROM AUTHOR]

Despite advances in the understanding of cognitive dysfunction among people with epilepsy (PWE), evidence for cognitive rehabilitation in epilepsy (CoRE) remains scarce. We present the protocol of a randomized waitlist-controlled trial (ClinicalTrials.gov ID NCT05934786) of a psychological-behavioral intervention aiming to ameliorate quality of life as well as cognitive functioning in a mixed PWE sample. The study is set at Vilnius University Hospital Santaros Klinikos and will offer adult PWE six individual and two group sessions led by a certified psychologist and directed toward improving memory, attention, self-regulation, mood and quality of life. The trial is expected to address major gaps in the literature by providing novel evidence on the effectiveness of CoRE in patients with genetic generalized epilepsies, the importance of epilepsy-specific factors for the response to CoRE, the impact of CoRE on long-term memory as well as its maintenance effects. [ABSTRACT FROM AUTHOR]

Objective: Temporal lobe epilepsy (TLE) is the most common cause of drug-resistant epilepsy and can be treated surgically to control seizures. In this study, we analyzed the relevant research literature in the field of temporal lobe epilepsy (TLE) treatment to understand the background, hotspots, and trends in TLE treatment research. Methods: We discussed the trend, frontier, and hotspot of scientific output in TLE treatment research in the world in the last 20 years by searching the core collection of the Web of Science database. Excel and CiteSpace software were used to analyze the basic data of the literature. Result: We identified a total of 2,051 publications on TLE treatment from 75 countries between 2003 and 2023. We found that the publication rate was generally increasing. The United States was the most publishing country; among the research institutions on TLE treatment, the University of California system published the most relevant literature and collaborated the most with other institutions. The co-citation of literature, keyword co-occurrence, and its clustering analysis showed that the early studies focused on open surgical treatment, mainly by lobectomy. In recent years, the attention given to stereotactic, microsurgery, and other surgical techniques has gradually increased, and the burst analysis indicated that new research hotspots may appear in the future in the areas of improved surgical procedures and mechanism research. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic brain disease and, considering the amount of people affected of all ages worldwide, one of the most common neurological disorders. Over 20 novel antiseizure medications (ASMs) have been released since 1993, yet despite substantial advancements in our understanding of the molecular mechanisms behind epileptogenesis, over one-third of patients continue to be resistant to available therapies. This is partially explained by the fact that the majority of existing medicines only address seizure suppression rather than underlying processes. Understanding the origin of this neurological illness requires conducting human neurological and genetic studies. However, the limitation of sample sizes, ethical concerns, and the requirement for appropriate controls (many patients have already had anti-epileptic medication exposure) in human clinical trials underscore the requirement for supplemental models. So far, mammalian models of epilepsy have helped to shed light on the underlying causes of the condition, but the high costs related to breeding of the animals, low throughput, and regulatory restrictions on their research limit their usefulness in drug screening. Here, we present an overview of the state of art in epilepsy modeling describing gold standard animal models used up to date and review the possible alternatives for this research field. Our focus will be mainly on ex vivo, in vitro, and in vivo larval zebrafish models contributing to the 3R in epilepsy modeling and drug screening. We provide a description of pharmacological and genetic methods currently available but also on the possibilities offered by the continued development in gene editing methodologies, especially CRISPR/Cas9-based, for high-throughput disease modeling and anti-epileptic drugs testing. [ABSTRACT FROM AUTHOR]

Although many anti-seizure medications (ASMs) are available, treatment failure, known as drug-resistant epilepsy (DRE), still occurs in around 30% of children with epilepsy. Second-line ASMs are usually used as substitution therapy in DRE to control seizures, although international consensus is not available yet. Previous studies focus on comparing the ASMs, whether as add-on or substitution therapy, mainly conducted in newly diagnosed epilepsy. However, the study that investigated first-line ASMs as substitution therapy compared to second-line ones, particularly among DRE children, is still lacking. A randomized controlled trial (RCT) enrolling 102 participants, aged 1-18, at three referral hospitals in Indonesia will be conducted, dividing them into intervention and control groups. The intervention group will be treated with first-line ASMs as the substitution therapy, while the other in the control group will get second-line ASMs. The primary outcome measure is the proportion difference of responders between groups who get first-line and second-line ASMs in 14 weeks of intervention. Clinical trial registration: ClinicalTrials.gov, identifier NCT05697614. [ABSTRACT FROM AUTHOR]

The SCN1A gene is strongly associated with epilepsy and plays a central role for supporting cortical excitation-inhibition balance through the expression of NaV1.1 within inhibitory interneurons. The phenotype of SCN1A disorders has been conceptualized as driven primarily by impaired interneuron function that predisposes to disinhibition and cortical hyperexcitability. However, recent studies have identified SCN1A gain-of-function variants associated with epilepsy, and the presence of cellular and synaptic changes in mouse models that point toward homeostatic adaptations and complex network remodeling. These findings highlight the need to understand microcircuit-scale dysfunction in SCN1A disorders to contextualize genetic and cellular disease mechanisms. Targeting the restoration of microcircuit properties may be a fruitful strategy for the development of novel therapies. [ABSTRACT FROM AUTHOR]

Objective: To test the feasibility and reliability of intracranial electrophysiological recordings in an acute status epilepticus model on laboratory swine. Method: Intrahippocampal injection of kainic acid (KA) was performed on 17 male Bama pigs (Sus scrofa domestica) weighing between 25 and 35 kg. Two stereoelectroencephalography (SEEG) electrodes with a total of 16 channels were implanted bilaterally along the sensorimotor cortex to the hippocampus. Brain electrical activity was recorded 2 h daily for 9-28 days. Three KA dosages were tested to evaluate the quantities capable of evoking status epilepticus. Local field potentials (LFPs) were recorded and compared before and after the KA injection. We quantified the epileptic patterns, including the interictal spikes, seizures, and high-frequency oscillations (HFOs), up to 4 weeks after the KA injection. Test-retest reliability using intraclass correlation coefficients (ICCs) were performed on interictal HFO rates to evaluate the recording stability of this model. Results: The KA dosage test suggested that a 10 µl (1.0 µg/µl) intrahippocampal injection could successfully evoke status epilepticus lasting from 4 to 12 h. At this dosage, eight pigs (50% of total) had prolonged epileptic events (tonicchronic seizures + interictal spikes n = 5, interictal spikes alone n = 3) in the later 4 weeks of the video-SEEG recording period. Four pigs (25% of total) had no epileptic activities, and another four (25%) had lost the cap or did not complete the experiments. Animals that showed epileptiform events were grouped as E + (n = 8) and the four animals showing no signs of epileptic events were grouped as E-(n = 4). A total of 46 electrophysiological seizures were captured in the 4-week post-KA period from 4 E + animals, with the earliest onset on day 9. The seizure durations ranged from 12 to 45 s. A significant increase of hippocampal HFOs rate (num/min) was observed in the E+ group during the post-KA period (weeks 1, 2,4, p < 0.05) compared to the baseline. But the E-showed no change or a decrease (in week 2, p = 0.43) compared to their baseline rate. The between-group comparison showed much higher HFO rates in E + vs. E - (F = 35, p < 0.01). The high ICC value [ICC (1, k) = 0.81, p < 0.05] quantified from the HFO rate suggested that this model had a stable measurement of HFOs during the four-week post-KA periods. Significance: This study measured intracranial electrophysiological activity in a swine model of KA-induced mesial temporal lobe epilepsy (mTLE). Using the clinical SEEG electrode, we distinguished abnormal EEG patterns in the swine brain. The high test-retest reliability of HFO rates in the post-KA period suggests the utility of this model for studying mechanisms of epileptogenesis. The use of swine may provide satisfactory translational value for clinical epilepsy research. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic neurological disorder associated with severe social and psychological effects, and most epilepsy patients often report at least one comorbidity. Accumulating evidence have suggested that lacosamide, a new generation of anti-seizure medications, may exhibit efficacy in the management of both epilepsy and its related comorbidities. Therefore, this narrative review aimed to elucidate the recent advancements regarding the therapeutic role of lacosamide in epilepsy-associated comorbidities. The possible pathophysiological mechanisms between epilepsy and epilepsy-associated comorbidities have been also partially described. Whether lacosamide improves cognitive and behavioral functions in patients with epilepsy has not been conclusively established. Some studies support that lacosamide may alleviate anxiety and depression in epilepsy patients. In addition, lacosamide has been found to be safe and effective in the treatment of epilepsy in people with intellectual disabilities, epilepsy of cerebrovascular etiology, and epilepsy associated with brain tumors. Moreover, lacosamide treatment has demonstrated fewer side effects on other systems. Hence, future larger and higher quality clinical studies are needed to further explore both the safety and efficacy of lacosamide in the treatment of epilepsy-associated comorbidities. [ABSTRACT FROM AUTHOR]

Objective: To determine whether, in patients undergoing rehabilitation after traumatic or hemorrhagic brain injury, seizures and the use of antiepileptic drugs (AEDs) negatively impact on functional outcome, and, in turn, whether prophylactic AED therapy can prevent the development of seizures. Design: Observational retrospective study. Setting: Highly specialized inpatient neurorehabilitation clinic. Participants: Patients with traumatic brain injury (TBI), or hemorrhagic stroke (HS) consecutively admitted to our neurorehabilitation unit between January 1, 2009, and December 31, 2018. Mainmeasures and variables: Patients' demographic data, neurological status (Glasgow Coma Scale), and rehabilitation outcome (Functional Independence Measure scale), both assessed on admission and on discharge, associated neurosurgical procedures (craniectomy, or cranioplasty), AED use, early or late seizures occurrence, and death during hospitalization. Results: Of 740 patients, 162 (21.9%) had seizures, and prophylactic AEDs were started in 192 (25.9%). Multivariate logistic regression identified severity of brain injury as a risk factor for acute symptomatic seizures (ASS) in HS (OR = 1.800, 95%CI = 1.133-1.859, p = 0.013), and for unprovoked seizures (US) in TBI (OR = 1.679, 95%CI = 1.062-2.655, p = 0.027). Prophylaxis with AEDs reduced ASS frequency, but, if protracted for months, was associated with US occurrence (HS, p < 0.0001; TBI, p = 0.0002; vs. untreated patients). Presence of US (β = -0.12; p < 0.0001) and prophylaxis with AEDs (β = -0.09; p = 0.002), were associated with poor functional outcome, regardless of age, severity of brain insult, and HS vs. TBI subtype. Conclusions: Severity of brain injury and occurrence of seizures during neurorehabilitation are the main driver of poor outcome in both HS and TBI. The possible detrimental role on the epileptogenic and functional outcome played by seizures prophylaxis with AEDs, nonetheless useful to prevent ASS if administered over the first week after the brain injury, warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: Interictal epileptic discharges (IEDs) are known to affect cognitive function in patients with epilepsy, but the mechanism has not been elucidated. Sleep spindles appearing in synchronization with IEDs were recently demonstrated to impair memory consolidation in rat, but this has not been investigated in humans. On the other hand, the increase of sleep spindles at night after learning is positively correlated with amplified learning effects during sleep for motor sequence learning. In this study, we examined the effects of IEDs and IED-coupled spindles on motor sequence learning in patients with epilepsy, and clarified their pathological significance. Materials and methods: Patients undergoing long-term video-electroencephalography (LT-VEEG) at our hospital from June 2019 to November 2021 and age-matched healthy subjects were recruited. Motor sequence learning consisting of a finger-tapping task was performed before bedtime and the next morning, and the improvement rate of performance was defined as the sleep-dependent learning effect. We searched for factors associated with the changes in learning effect observed between the periods of when antiseizure medications (ASMs) were withdrawn for LT-VEEG and when they were returned to usual doses after LT-VEEG. Results: Excluding six patients who had epileptic seizures at night after learning, nine patients and 11 healthy subjects were included in the study. In the patient group, there was no significant learning effect when ASMs were withdrawn. The changes in learning effect of the patient group during ASM withdrawal were not correlated with changes in sleep duration or IED density; however, they were significantly negatively correlated with changes in IED-coupled spindle density. Conclusion: We found that the increase of IED-coupled spindles correlated with the decrease of sleep-dependent learning effects of procedural memory. Pathological IED-coupled sleep spindles could hinder memory consolidation, that is dependent on physiological sleep spindles, resulting in cognitive dysfunction in patients with epilepsy. [ABSTRACT FROM AUTHOR]

Background: Drug-resistance is a significant clinical issue in persons with epilepsy. In the past few years, many studies have been published investigating the management of drug-resistant epilepsy (DRE); however, no systematic and quantitative evaluation of this research has been performed. Therefore, a bibliometric analysis was conducted to demonstrate the current status of DRE research and to reflect the trends and hotspots within the field. Methods: We retrieved publications on DRE published between 2011 and 2021 from the Science Citation Index Expanded of the Web of Science Core Collection. All articles related to DRE were included in this study. VOSviewer, R software, and CiteSpace were used to perform bibliometric research. Results: A total of 3,088 original articles were included in this study. The number of publications on DRE has continued to increase over the past 11 years. The USA published the most papers with the highest number of citations and H-index. The National Institutes of Health and the University of Toronto were the most prolific funding agency and affiliation, respectively. Epilepsy b Behavior and Epilepsia ranked first as the most prolific and co-cited journals, respectively. The keywords "cannabidiol", "neuromodulation", "seeg" and "perampanel" revealed recent research hotspots. The top 100 most cited papers were classified into eight main topics, of which pharmacotherapy, disease mechanisms/pathophysiology, and neuromodulation were the three most important topics. Conclusions: This analysis of bibliometric data demonstrated that DRE has always been a topical area of research. The mechanisms of epilepsy and therapies have been the focus of DRE research, and innovative antiseizure medications and surgical approaches are fast-developing research trends. [ABSTRACT FROM AUTHOR]

Background: Restless Legs Syndrome (RLS) is a common neurological disorder. Growing evidence shows that dopaminergic dysfunction and iron deficiency are associated with the pathogenesis of RLS. Additionally, the dopaminergic system is linked with the hypothalamic-pituitary-thyroid (HPT) axis. Thus, the current study aimed to compare thyroid function between RLS patients and healthy subjects and investigate the associations with clinical characteristics of RLS. Methods: Serum levels of thyroid hormones were investigated in 102 first-episode drug-naïve RLS patients and 80 matched healthy controls (HCs). Baseline data and clinical characteristics were performed by professional personnel. In addition, multivariate regression was used to analyze the relationship between thyroid function and RLS. Results: Compared with control group, RLS patients had significantly higher serum thyroid-stimulating hormone (TSH) levels (p < 0.001), and higher prevalence of subclinical hypothyroidism [Odds ratio (OR) 8.00; 95% confidence interval (CI) = 3.50-18.30; p < 0.001]. The Subclinical hypothyroidism rate (47.1 vs. 10%, p < 0.001) in RLS patients was higher than the HCs group. Regression analysis revealed that serum TSH (OR = 1.77; 95% CI = 1.41-2.23; p < 0.001) was independently associated with RLS. There was a statistically significant positive correlation between TSH and the Pittsburgh sleep quality index (PSQI) scores (r = 0.728, p < 0.001), and the International Restless Legs Scales (IRLS) points (r = 0.627, p < 0.001). Spearman correlation analysis showed that FT3 was positive correlated with HAMA14 score (r = 0.239, p = 0.015). In addition, compared with the good-sleeper group, poor-sleeper patients had significantly higher serum TSH levels (p < 0.001). Conclusion: Serum levels of TSH and the prevalence of subclinical Hypothyroidism were higher in RLS patients, indicating the imbalance between thyroid hormones (TH) and the dopaminergic system may contribute to the development of primary RLS. Additionally, the TH axis may influence the quality of sleep in RLS patients. [ABSTRACT FROM AUTHOR]

Objective: For patients with drug-resistant focal epilepsy, intracranial monitoring remains the gold standard for surgical intervention. Focal cortical dysplasia (FCD) is the most common cause of pharmacoresistant focal epilepsy in pediatric patients who usually develop seizures in early childhood. Timely removal of the epileptogenic zone (EZ) is necessary to achieve lasting seizure freedom and favorable developmental and cognitive outcomes to improve the quality of life. We applied brain network analysis to investigate potential biomarkers for the diagnosis of EZ that will aid in the resection for pediatric focal epilepsy patients with FCD type II. Methods: Ten pediatric patients with focal epilepsy diagnosed as FCD type II and that had a follow-up after resection surgery (Engel class I [n = 9] and Engel class II [n = 1]) were retrospectively included. Time-frequency analysis of phase transfer entropy, graph theory analysis, and power spectrum compensation were combined to calculate brain network parameters based on interictal epileptiform discharges from ECoG. Results: Clustering coefficient, local efficiency, node out-degree, and node out-strength with higher values are the most reliable biomarkers for the delineation of EZ, and the differences between EZ and margin zone (MZ), and EZ and normal zone (NZ) were significant (p < 0.05; Mann-Whitney U-test, two-tailed). In particular, the difference between MZ and NZ was significant for patients with frontal FCD (MZ > NZ; p < 0.05) but was not significant for patients with extra-frontal FCD. Conclusions: Brain network analysis, based on the combination of time-frequency analysis of phase transfer entropy, graph theory analysis, and power spectrum compensation, can aid in the diagnosis of EZ for pediatric focal epilepsy patients with FCD type II. [ABSTRACT FROM AUTHOR]

Cognitive impairment and neuropsychiatric disorders are very common in patients with temporal lobe epilepsy (TLE). These comorbidities complicate the treatment of epilepsy and seriously affect the quality of life. So far, there is still no effective intervention to prevent the development of epilepsy-associated comorbidities. Gut dysbiosis has been recognized to be involved in the pathology of epilepsy development. Modulating gut microbiota by probiotics has shown an antiseizure effect on humans and animals with epilepsy. Whether this treatment strategy has a positive effect on epilepsy-associated comorbidities remains unclear. Therefore, this study aimed to objectively assess the effect of probiotics on cognitive function and neuropsychiatric performance of patients with TLE. Participants enrolled in an epilepsy clinic were randomly assigned to the probiotic and placebo groups. These two groups were treated with probiotics or placebo for 12 weeks, and then the cognitive function and psychological performance of participants were assessed. We enrolled 76 participants in this study, and 70 subjects were finally included in the study (35 in the probiotics group and 35 in the placebo group). Our results showed significant seizure reduction in patients with TLE treated with probiotics. No significant differences were observed on cognitive function (including intelligence and memory) between groups. For neuropsychiatric performances, supplementation of probiotics significantly decreased the Hamilton Anxiety Rating and Depression Scale scores and increased the 89-item Quality of Life in Epilepsy Inventory score in patients with TLE. In conclusion, probiotics have a positive impact on seizures control, and improve anxiety, depression, and quality of life in patients with TLE. [ABSTRACT FROM AUTHOR]

Epidemiological evidence shows that clinical features and comorbidities in temporal lobe epilepsy (TLE) may have different manifestations depending on the sex of patients. However, little is known about how sex-related mechanisms can interfere with the processes underlying the epileptic phenomenon. The findings of this study show that male rats with epilepsy in the pilocarpine model have longer-lasting and more severe epileptic seizures, while female rats have a higher frequency of epileptic seizures and a greater number of seizure clusters. Significant sex-linked pathological changes were also observed: epileptic brains of male and female rats showed differences in mass reduction of 41.8% in the amygdala and 18.2% in the olfactory bulb, while loss of neuronal cells was present in the hippocampus (12.3%), amygdala (18.1%), and olfactory bulb (7.5%). Another important sex-related finding was the changes in non-neuronal cells with increments for the hippocampus (36.1%), amygdala (14.7%), and olfactory bulb (37%). Taken together, our study suggests that these neuropathological changes may underlie the differences in the clinical features of epileptic seizures observed in male and female rats. [ABSTRACT FROM AUTHOR]

There is an urgent need for more informative quantitative techniques that non-invasively and objectively assess strategies for epilepsy surgery. Invasive intracranial electroencephalography (iEEG) remains the clinical gold standard to investigate the nature of the epileptogenic zone (EZ) before surgical resection. However, there are major limitations of iEEG, such as the limited spatial sampling and the degree of subjectivity inherent in the analysis and clinical interpretation of iEEG data. Recent advances in network analysis and dynamical network modeling provide a novel aspect toward a more objective assessment of the EZ. The advantage of such approaches is that they are data-driven and require less or no human input. Multiple studies have demonstrated success using these approaches when applied to iEEG data in characterizing the EZ and predicting surgical outcomes. However, the limitations of iEEG recordings equally apply to these studies—limited spatial sampling and the implicit assumption that iEEG electrodes, whether strip, grid, depth or stereo EEG (sEEG) arrays, are placed in the correct location. Therefore, it is of interest to clinicians and scientists to see whether the same analysis and modeling techniques can be applied to whole-brain, non-invasive neuroimaging data (from MRI-based techniques) and neurophysiological data (from MEG and scalp EEG recordings), thus removing the limitation of spatial sampling, while safely and objectively characterizing the EZ. This review aims to summarize current state of the art non-invasive methods that inform epilepsy surgery using network analysis and dynamical network models. We also present perspectives on future directions and clinical applications of these promising approaches. [ABSTRACT FROM AUTHOR]

Background: Patients with generalized epilepsy who had lateralized EEG abnormalities after corpus callosotomy (CC) occasionally undergo subsequent surgeries to control intractable epilepsy. Objectives: This study evaluated retrospectively the combination of EEG multiscale entropy (MSE) and FDG-PET for identifying lateralization of the epileptogenic zone after CC. Methods: This study included 14 patients with pharmacoresistant epilepsy who underwent curative epilepsy surgery after CC. Interictal scalp EEG and FDG-PET obtained after CC were investigated to determine (1) whether the MSE calculated from the EEG and FDG-PET findings was lateralized to the surgical side, and (2) whether the lateralization was associated with seizure outcomes. Results: Seizure reduction rate was higher in patients with lateralized findings to the surgical side than those without (MSE: p < 0.05, FDG-PET: p < 0.05, both: p < 0.01). Seizure free rate was higher in patients with lateralized findings in both MSE and FDG-PET than in those without (p < 0.05). Conclusions: This study demonstrated that patients with lateralization of MSE and FDG-PET to the surgical side had better seizure outcomes. The combination of MSE and conventional FDG-PET may help to select surgical candidates for additional surgery after CC with good postoperative seizure outcomes. [ABSTRACT FROM AUTHOR]

Accurate mapping of the seizure onset zone (SOZ) is critical to the success of epilepsy surgery outcomes. Epileptogenicity index (EI) is a statistical method that delineates hyperexcitable brain regions involved in the generation and early propagation of seizures. However, EI can overestimate the SOZ for particular electrographic seizure onset patterns. Therefore, using direct cortical stimulation (DCS) as a probing tool to identify seizure generators, we systematically evaluated the causality of the high EI nodes (>0.3) in replicating the patient's habitual seizures. Specifically, we assessed the diagnostic yield of high EI nodes, i.e., the proportion of high EI nodes that evoked habitual seizures. A retrospective single-center study that included post-stereo encephalography (SEEG) confirmed TLE patients (n = 37) that had all high EI nodes stimulated, intending to induce a seizure. We evaluated the nodal responses (true and false responder rate) to stimulation and correlated with electrographic seizure onset patterns (hypersynchronous-HYP and low amplitude fast activity patterns-LAFA) and clinically defined SOZ. The ictogenicity (i.e., the propensity to induce the patient's habitual seizure) of a high EI node was only 44.5%. The LAFA onset pattern had a significantly higher response rate to DCS (i.e., higher evoked seizures). The concordance of an evoked habitual seizure with a clinically defined SOZ with good outcomes was over 50% (p = 0.0025). These results support targeted mapping of SOZ in LAFA onset patterns by performing DCS in high EI nodes to distinguish seizure generators (true responders) from hyperexcitable nodes that may be involved in early propagation. [ABSTRACT FROM AUTHOR]

Epilepsy surgery can be a very effective therapy in medication refractory patients. During patient evaluation intracranial EEG is analyzed by clinical experts to identify the brain tissue generating epileptiform events. Quantitative EEG analysis increasingly complements this approach in research settings, but not yet in clinical routine. We investigate the correspondence between epileptiform events and a specific quantitative EEG marker. We analyzed 99 preictal epochs of multichannel intracranial EEG of 40 patients with mixed etiologies. Time and channel of occurrence of epileptiform events (spikes, slow waves, sharp waves, fast oscillations) were annotated by a human expert and non-linear excess interrelations were calculated as a quantitative EEG marker. We assessed whether the visually identified preictal events predicted channels that belonged to the seizure onset zone, that were later resected or that showed strong non-linear interrelations. We also investigated whether the seizure onset zone or the resection were predicted by channels with strong non-linear interrelations. In patients with temporal lobe epilepsy (32 of 40), epileptic spikes and the seizure onset zone predicted the resected brain tissue much better in patients with favorable seizure control after surgery than in unfavorable outcomes. Beyond that, our analysis did not reveal any significant associations with epileptiform EEG events. Specifically, none of the epileptiform event types did predict non-linear interrelations. In contrast, channels with strong non-linear excess EEG interrelations predicted the resected channels better in patients with temporal lobe epilepsy and favorable outcome. Also in the small number of patients with seizure onset in the frontal and parietal lobes, no association between epileptiform events and channels with strong non-linear excess EEG interrelations was detectable. In contrast to patients with temporal seizure onset, EEG channels with strong non-linear excess interrelations did neither predict the seizure onset zone nor the resection of these patients or allow separation between patients with favorable and unfavorable seizure control. Our study indicates that non-linear excess EEG interrelations are not strictly associated with epileptiform events, which are one key concept of current clinical EEG assessment. Rather, they may provide information relevant for surgery planning in temporal lobe epilepsy. Our study suggests to incorporate quantitative EEG analysis in the workup of clinical cases. We make the EEG epochs and expert annotations publicly available in anonymized form to foster similar analyses for other quantitative EEG methods. [ABSTRACT FROM AUTHOR]

Background: Epileptic seizures are caused by abnormal brain wave hypersynchronization leading to a range of signs and symptoms. Tools for detecting seizures in everyday life typically focus on cardiac rhythm, electrodermal activity, or movement (EMG, accelerometry); however, these modalities are not very effective for non-motor seizures. Ultra long-term subcutaneous EEG-devices can detect the electrographic changes that do not depend on clinical changes. Nonetheless, this also means that it is not possible to assess whether a seizure is clinical or subclinical based on an EEG signal alone. Therefore, we combine EEG and movement-related modalities in this work. We focus on whether it is possible to define an individual "multimodal ictal fingerprint" which can be exploited in different epilepsy management purposes. Methods: This study used ultra long-term data from an outpatient monitoring trial of persons with temporal lobe epilepsy obtained with a subcutaneous EEG recording system. Subcutaneous EEG, an EMG estimate and chest-mounted accelerometry were extracted from four persons showing more than 10 well-defined electrographic seizures each. Numerous features were computed from all three modalities. Based on these, the Gini impurity measure of a Random Forest classifier was used to select the most discriminative features for the ictal fingerprint. A total of 74 electrographic seizures were analyzed. Results: The optimal individual ictal fingerprints included features extracted from all three tested modalities: an acceleration component; the power of the estimated EMG activity; and the relative power in the delta (0.5–4 Hz), low theta (4–6 Hz), and high theta (6–8 Hz) bands of the subcutaneous EEG. Multimodal ictal fingerprints were established for all persons, clustering seizures within persons, while separating seizures across persons. Conclusion: The existence of multimodal ictal fingerprints illustrates the benefits of combining multiple modalities such as EEG, EMG, and accelerometry in future epilepsy management. Multimodal ictal fingerprints could be used by doctors to get a better understanding of the individual seizure semiology of people with epilepsy. Furthermore, the multimodal ictal fingerprint gives a better understanding of how seizures manifest simultaneously in different modalities. A knowledge that could be used to improve seizure acknowledgment when reviewing EEG without video. [ABSTRACT FROM AUTHOR]

Secondary epileptogenesis is a common phenomenon in epilepsy, characterized by epileptiform discharges from the regions outside the primary focus. It is one of the major reasons for pharmacoresistance and surgical failure. Compared with primary epileptogenesis, the mechanism of secondary epileptogenesis is usually more complex and diverse. In this review, we aim to summarize the characteristics of secondary epileptogenesis from both clinical and laboratory studies in a historical view. Mechanisms of secondary epileptogenesis in molecular, cellular, and circuity levels are further presented. Potential treatments targeting the process are discussed as well. At last, we highlight the importance of circuitry studies, which would further illustrate precise treatments of secondary epileptogenesis in the future. [ABSTRACT FROM AUTHOR]

Objective: Accurate estimation of the epileptogenic zone (EZ) is essential for favorable outcomes in epilepsy surgery. Conventional ictal electrocorticography (ECoG) onset is generally used to detect the EZ but is insufficient in achieving seizure-free outcomes. By contrast, high-frequency oscillations (HFOs) could be useful markers of the EZ. Hence, we aimed to detect the EZ using interictal spikes and investigated whether the onset area of interictal spike-related HFOs was within the EZ. Methods: The EZ is considered to be included in the resection area among patients with seizure-free outcomes after surgery. Using a complex demodulation technique, we developed a method to determine the onset channels of interictal spike-related ripples (HFOs of 80–200 Hz) and investigated whether they are within the resection area. Results: We retrospectively examined 12 serial patients who achieved seizure-free status after focal resection surgery. Using the method that we developed, we determined the onset channels of interictal spike-related ripples and found that for all 12 patients, they were among the resection channels. The onset frequencies of ripples were in the range of 80–150 Hz. However, the ictal onset channels (evaluated based on ictal ECoG patterns) and ripple onset channels coincided in only 3 of 12 patients. Conclusions: Determining the onset area of interictal spike-related ripples could facilitate EZ estimation. This simple method that utilizes interictal ECoG may aid in preoperative evaluation and improve epilepsy surgery outcomes. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to investigate the dynamics of functional connectivity (FC) networks during seizure termination in patients with childhood absence epilepsy (CAE) using magnetoencephalography (MEG) and graph theory (GT) analysis. Methods: MEG data were recorded from 22 drug-naïve patients diagnosed with CAE. FC analysis was performed to evaluate the FC networks in seven frequency bands of the MEG data. GT analysis was used to assess the topological properties of FC networks in different frequency bands. Results: The patterns of FC networks involving the frontal cortex were altered significantly during seizure termination compared with those during the ictal period. Changes in the topological parameters of FC networks were observed in specific frequency bands during seizure termination compared with those in the ictal period. In addition, the connectivity strength at 250–500 Hz during the ictal period was negatively correlated with seizure frequency. Conclusions: FC networks associated with the frontal cortex were involved in the termination of absence seizures. The topological properties of FC networks in different frequency bands could be used as new biomarkers to characterize the dynamics of FC networks related to seizure termination. [ABSTRACT FROM AUTHOR]

Polymicrogyria (PMG) is a common malformation of cortical development associated with a higher susceptibility to epileptic seizures. Seizures secondary to PMG are characterized by difficult-to-localize cerebral sources due to the complex and widespread lesion structure. Tracing the dynamics of interictal epileptiform discharges (IEDs) in patients with epilepsy has been shown to reveal the location of epileptic activity sources, crucial for successful treatment in cases of focal drug-resistant epilepsy. In this case series IED dynamics were evaluated with simultaneous EEG-fMRI recordings in four patients with unilateral peri-sylvian polymicrogyria (PSPMG) by tracking BOLD activations over time: before, during and following IED appearance on scalp EEG. In all cases, focal BOLD activations within the lesion itself preceded the activity associated with the time of IED appearance on EEG, which showed stronger and more widespread activations. We therefore propose that early hemodynamic activity corresponding to IEDs may hold important localizing information potentially leading to the cerebral sources of epileptic activity. IEDs are suggested to develop within a small area in the PSPMG lesion with structural properties obscuring the appearance of their electric field on the scalp and only later engage widespread structures which allow the production of large currents which are recognized as IEDs on EEG. [ABSTRACT FROM AUTHOR]

Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the global burden of neurological disease. Although epilepsy can result from a variety of brain insults, in many cases the cause is unknown and, in a significant proportion of cases, seizures cannot be controlled by available treatments. Understanding the molecular alterations that underlie or are triggered by epileptogenesis would help to identify therapeutics to prevent or control progression to epilepsy. To this end, the moderate throughput technique of Reverse Phase Protein Arrays (RPPA) was used to profile changes in protein expression in a pilocarpine mouse model of acquired epilepsy. Levels of 54 proteins, comprising phosphorylation-dependent and phosphorylation-independent components of major signaling pathways and cellular complexes, were measured in hippocampus, cortex and cerebellum of mice at six time points, spanning 15 min to 2 weeks after induction of status epilepticus. Results illustrate the time dependence of levels of the commonly studied MTOR pathway component, pS6, and show, for the first time, detailed responses during epileptogenesis of multiple components of the MTOR, MAPK, JAK/STAT and apoptosis pathways, NMDA receptors, and additional cellular complexes. Also noted are time- and brain region- specific changes in correlations among levels of functionally related proteins affecting both neurons and glia. While hippocampus and cortex are primary areas studied in pilocarpine-induced epilepsy, cerebellum also shows significant time-dependent molecular responses. [ABSTRACT FROM AUTHOR]

The propagation of epileptiform events is a highly interesting phenomenon from the pathophysiological point of view, as it involves several mechanisms of recruitment of neural networks. Extensive in vivo and in vitro research has been performed, suggesting that multiple networks as well as cellular candidate mechanisms govern this process, including the co-existence of wave propagation, coupled oscillator dynamics, and more. The clinical importance of seizure propagation stems mainly from the fact that the epileptic manifestations cannot be attributed solely to the activity in the seizure focus itself, but rather to the propagation of epileptic activity to other brain structures. Propagation, especially when causing secondary generalizations, poses a risk to patients due to recurrent falls, traumatic injuries, and poor neurological outcome. Anti-seizure medications (ASMs) affect propagation in diverse ways and with different potencies. Importantly, for drug-resistant patients, targeting seizure propagation may improve the quality of life even without a major reduction in simple focal events. Motivated by the extensive impact of this phenomenon, we sought to review the literature regarding the propagation of epileptic activity and specifically the effect of commonly used ASMs on it. Based on this body of knowledge, we propose a novel classification of ASMs into three main categories: major, minor, and intermediate efficacy in reducing the propagation of epileptiform activity. [ABSTRACT FROM AUTHOR]

Great strides have been made recently in documenting that machine-learning programs can predict seizure occurrence in people who have epilepsy. Along with this progress have come claims that appear to us to be a bit premature. We anticipate that many people will benefit from seizure prediction. We also doubt that all will benefit. Although machine learning is a useful tool for aiding discovery, we believe that the greatest progress will come from deeper understanding of seizures, epilepsy, and the EEG features that enable seizure prediction. In this essay, we lay out reasons for optimism and skepticism. [ABSTRACT FROM AUTHOR]

Introduction: Approximately 25–30% of veterans deployed to Kuwait, 1990-91, report persistent multi-symptom Gulf War Illness (GWI) likely from neurotoxicant exposures. Photobiomodulation (PBM) in red/near-infrared (NIR) wavelengths is a safe, non-invasive modality shown to help repair hypoxic/stressed cells. Red/NIR wavelengths are absorbed by cytochrome C oxidase in mitochondria, releasing nitric oxide (increasing local vasodilation), and increasing adenosine tri-phosphate production. We investigated whether PBM applied transcranially could improve cognition, and health symptoms in GWI. Materials and Methods: Forty-eight (40 M) participants completed this blinded, randomized, sham-controlled trial using Sham or Real, red/NIR light-emitting diodes (LED) applied transcranially. Fifteen, half-hour transcranial LED (tLED) treatments were twice a week (7.5 weeks, in-office). Goggles worn by participant and assistant maintained blinding for visible red. Pre-/Post- testing was at Entry, 1 week and 1 month post- 15th treatment. Primary outcome measures were neuropsychological (NP) tests; secondary outcomes, Psychosocial Questionnaires, including PTSD. Results: Primary Analyses (all participants), showed improvement for Real vs. Sham, for Digit Span Forwards (p < 0.01); and a trend for Trails 4, Number/Letter Sequencing (p < 0.10). For secondary outcomes, Real group reported more improvement on the SF-36V Plus, Physical Component Score (p < 0.08). Secondary Analyses included only subjects scoring below norm (50%ile) at Entry, on specific NP test/s. Real and Sham improved at 1 week after 15th treatment; however, at 1 month, only those receiving Real improved further: Digit Span Total, Forwards and Backwards; Trails 4, Number/Letter Sequencing; California Verbal Learning Test-II, long delay free recall; Continuous Performance Test-II, False Alarm Rate; and Color-Word Interference, Stroop, Trial 3, Inhibition; Sham group worsened, toward Entry values. Only those with more post-traumatic stress disorder (PTSD) symptomatology at Entry, receiving Real, continued to have additional PTSD reduction at 1 month; Sham regressed. Conclusion: This study was underpowered (n = 48), with large heterogeneity at Entry. This likely contributed to significance or trend to significance, for only two of the NP tests (Digit Span Forwards; Trails 4, Number/Letter Sequencing) and only one general health measure, the SF-36V Plus, Physical Component Score. More subjects receiving Real, self-reported increased concentration, relaxation and sleep. Controlled studies with newer, transcranial LED home treatment devices are warranted; this is expected to increase enrollment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01782378. [ABSTRACT FROM AUTHOR]

Intracranial electroencephalography (EEG) studies using stereotactic EEG (SEEG) have shown that during seizures, epileptic activity spreads across several anatomical regions from the seizure onset zone toward remote brain areas. A full and objective characterization of this patient-specific time-varying network is crucial for optimal surgical treatment. Functional connectivity (FC) analysis of SEEG signals recorded during seizures enables to describe the statistical relations between all pairs of recorded signals. However, extracting meaningful information from those large datasets is time consuming and requires high expertise. In the present study, we first propose a novel method named Brain-wide Time-varying Network Decomposition (BTND) to characterize the dynamic epileptogenic networks activated during seizures in individual patients recorded with SEEG electrodes. The method provides a number of pathological FC subgraphs with their temporal course of activation. The method can be applied to several seizures of the patient to extract reproducible subgraphs. Second, we compare the activated subgraphs obtained by the BTND method with visual interpretation of SEEG signals recorded in 27 seizures from nine different patients. As a whole, we found that activated subgraphs corresponded to brain regions involved during the course of the seizures and their time course was highly consistent with classical visual interpretation. We believe that the proposed method can complement the visual analysis of SEEG signals recorded during seizures by highlighting and characterizing the most significant parts of epileptic networks with their activation dynamics. [ABSTRACT FROM AUTHOR]

Background: Laser interstitial thermal therapy (LiTT) has emerged as a minimally invasive option for surgical treatment of refractory epilepsy. However, LiTT of the mesial temporal (MT) structures is still inferior to anterior temporal lobectomy (ATL) in terms of postoperative outcome. In this pilot study, we identify intracranial EEG (iEEG) biomarkers that distinguish patients with favorable outcome from those with poor outcome after MT LiTT. Methods: We performed a retrospective review of 9 adult refractory epilepsy patients who underwent stereotactic electroencephalography (sEEG) followed by LiTT of MT structures. Their iEEG was retrospectively reviewed in both time and frequency domains. Results: In the time-domain, the presence of sustained 14–30 Hz in MT electrodes coupled with its absence from extra-MT electrodes at ictal onset was highly correlated with favorable outcomes, whereas the appearance of sustained 14–30 Hz or >30 Hz activity in extra-MT sites was negatively correlated to favorable outcomes. In the frequency domain, a declining spectral phase, beginning at the high frequency range (>14 Hz) at ictal onset and following a smooth progressive decline toward lower frequencies as the seizure further evolved, was positively correlated with improved outcomes. On the contrary, low frequency (<14 Hz) patterns and "crescendo-decrescendo" patterns with an early increasing frequency component at ictal onset that reaches the high-beta and low gamma bands before decreasing smoothly, were both correlated with poor surgical outcomes. Conclusions: This pilot study demonstrates the first evidence that iEEG analysis can provide neurophysiological markers for successful MT LiTT and therefore we strongly advocate for systematic sEEG investigations before offering MT LiTT to TLE and MTLE patients. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation. [ABSTRACT FROM AUTHOR]

Objective: Characterization of the spatial and temporal dynamics of interictal epileptic discharges (IED) using time-frequency analysis (TFA) and electrical-source localization (ESL). Methods: TFA was performed on IED (spikes, spike waves, and polyspike waves) recorded by high-density-EEG (HD-EEG) in 19 refractory focal epileptic children. Temporal modulations related to IEDs were analyzed in a time window around the IED peaks [−1,000 to 1,000 ms]. Spatial modulations were analyzed by ESL in the time-frequency and time domains. Results: IED were associated with complex power spectral modulations. We observed increases in power spectrum (IPS) patterns specific to IED type. For spikes, the TFA pattern consisted of an IPS (−100 to +100 ms, 4–50 Hz). For spike waves, the IPS was followed by a second IPS (+100 to +400 ms, 4–10 Hz), corresponding to the slow wave. IPS patterns were preceded (−400 to −100 ms, 4–40 Hz), and followed (+100 to +400 ms) by a decrease in the power spectrum (DPS) (n = 8). For 14 out of 19 patients, at least one ESL method was concordant with the epileptogenic area. For the remaining five patients, all of them had temporal epilepsies. ESL in the time-frequency domain (DPS/IPS) provided concordant (n = 6) or complementary (n = 4) information to the ESL in the time domain concerning the epileptogenic zone. ESL in time-frequency domain (DPS/IPS) was the only method to provide concordant information concerning the epileptogenic zone in three patients. Significance: TFA demonstrates complex time-frequency modulations of the neuronal networks around IED, suggesting that the pathological mechanisms are initiated well before onset of the classical hyper-synchronization of the IED. Combining time and time-frequency analysis of the ESL provides complementary information to define the epileptogenic zone in refractory focal epilepsy. [ABSTRACT FROM AUTHOR]

We previously demonstrated that seizure occurrences at different zeitgeber times alter sleep and circadian rhythm differently. On the other hand, the synchronized delta wave of electroencephalogram (EEG) during non-rapid eye movement (NREM) sleep facilitates seizure, while the desynchronized EEG of rapid eye movement (REM) sleep suppresses it. We also elucidated that unilateral deep brain stimulation (DBS) of the anterior nucleus of thalamus (ANT) suppresses seizure recurrence. In the present study, we intraperitoneally injected pentylenetetrazol (PTZ, 40 mg/kg) for 14 consecutive days (PTZ kindling) to induce spontaneous seizure in rats, and a 30-min (delivered 10 min before each PTZ injection) or a 3-h DBS of unilateral ANT (delivered 1 h before each PTZ injection) was applied to suppress seizure. The frequency of DBS stimulation was 200 Hz and the electrical current consisted of biphasic square pulses with 50-μA intensity, 100-μs pulse width, and 4.1-ms stimulation interval. Our results found that PTZ-induced spontaneous seizure did not cause a significant change in the quantity of NREM sleep but suppressed the amount of REM sleep. Unilateral ANT DBS prolonged the onset latency of ictal seizure, decreased the spontaneous seizure duration, and increased the survival rate but did not change the amplitude of epileptiform EEGs during ictal period. Unilateral ANT DBS did not significantly alter NREM sleep but increased the amount of REM sleep. An analysis of the spectrograms of fast Fourier transform indicated that the intensities of all frequencies were enhanced during the PTZ-induced ictal period and the subsequent spontaneous seizure. Thirty minutes of unilateral ANT DBS suppressed the augmentation of low-frequency (<10 Hz) intensities during the spontaneous seizure induced by PTZ kindling. We further found that consecutive injections of PTZ progressively increased the enhancement of the delta powers during NREM sleep, whereas unilateral ANT DBS inhibited this progressive enhancement. It was also noticed that 30 min of ANT DBS exhibited a better efficacy in epilepsy suppression than 3 h of ANT DBS. These results elucidated that unilateral ANT DBS enhanced the seizure threshold by increasing the amount of REM sleep and decreasing the progressive enhancement of delta power during NREM sleep to suppress spontaneous seizure recurrences in PTZ kindling-induced epileptic rats. [ABSTRACT FROM AUTHOR]

The relationship between circadian rhythm and epilepsy has been recognized for decades. Yet many questions underlying the complex mechanisms of their interaction remain elusive. A better understanding on this topic allows the development of accurate seizure-detection algorithm and alternative precise therapeutic strategies. Preclinical laboratory studies based on epileptic animal models, with controllable epileptogenic pathology and an array of intervention strategies, shed light on the bidirectional effects between circadian rhythm and epileptic seizures as well as their underlying mechanisms. Here, we reviewed findings on the interaction between circadian rhythm and epileptic seizures in the preclinical setting. We present the possible mechanisms at molecular, cellular and circuitry levels. We propose that future experimental designs should take into account the relationship between circadian rhythm and epilepsy as well as the underlying mechanisms in different types of animal models, which may have a translational significance as stepping stones for clinical benefits. [ABSTRACT FROM AUTHOR]

Growing evidence shows the bidirectional interactions between sleep, circadian rhythm, and epilepsy. Comprehending how these interact with each other may help to advance our understanding of the pathophysiology of epilepsy and develop new treatment strategies to improve seizure control by reducing the medication side effects and the risks associated with seizures. In this review, we present the overview of different temporal patterns of interictal epileptiform discharges and epileptic seizures over a period of 24 consecutive hours. Furthermore, we discuss the underlying mechanism of the core-clock gene in periodic seizure occurrences. Finally, we outline the role of circadian patterns of seizures on seizure forecasting models and its implication for chronotherapy in epilepsy. [ABSTRACT FROM AUTHOR]

The Wistar Audiogenic Rat (WAR) and the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) strains are audiogenic epilepsy models, in which seizures are triggered by acoustic stimulation. These strains were developed by selective reproduction and have a genetic background with minimal or no variation. In the current study, we evaluated the transcriptome of the inferior colliculus, the epileptogenic nucleus, of both audiogenic models, in order to get insights into common molecular aspects associated to their epileptic phenotype. Based on GASH/Sal RNA-Seq and WAR microarray data, we performed a comparative analysis that includes selection and functional annotation of differentially regulated genes in each model, transcriptional evaluation by quantitative reverse transcription PCR of common genes identified in both transcriptomes and immunohistochemistry. The microarray data revealed 71 genes with differential expression in WAR, and the RNA-Seq data revealed 64 genes in GASH/Sal, showing common genes in both models. Analysis of transcripts showed that Egr3 was overexpressed in WAR and GASH/Sal after audiogenic seizures. The Npy, Rgs2, Ttr , and Abcb1a genes presented the same transcriptional profile in the WAR, being overexpressed in the naïve and stimulated WAR in relation to their controls. Npy appeared overexpressed only in the naïve GASH/Sal compared to its control, while Rgs2 and Ttr genes appeared overexpressed in naïve GASH/Sal and overexpressed after audiogenic seizure. No statistical difference was observed in the expression of Abcb1a in the GASH/Sal model. Compared to control animals, the immunohistochemical analysis of the inferior colliculus showed an increased immunoreactivity for NPY, RGS2, and TTR in both audiogenic models. Our data suggest that WAR and GASH/Sal strains have a difference in the timing of gene expression after seizure, in which GASH/Sal seems to respond more quickly. The transcriptional profile of the Npy, Rgs2 , and Ttr genes under free-seizure conditions in both audiogenic models indicates an intrinsic expression already established in the strains. Our findings suggest that these genes may be causing small changes in different biological processes involved in seizure occurrence and response, and indirectly contributing to the susceptibility of the WAR and GASH/Sal models to audiogenic seizures. [ABSTRACT FROM AUTHOR]