bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal Lobe Epileptogenesis
Authors: Sloviter Robert S. 
Published: July 2024

Abstract
In families with febrile seizures and temporal lobe epilepsy, mutations affecting different GABAergic mechanisms suggest that failure of chloride conductance to limit depolarization may be directly epileptogenic. This “GABAergic disinhibition” hypothesis has been discounted historically for two reasons. First, early attempts to produce hippocampal sclerosis and epilepsy simply by eliminating hippocampal GABA neurons consistently failed to do so. Second, the notion persists that because clinical epilepsy diagnosis is typically delayed for years or decades after brain injury, temporal lobe epileptogenesis should be presumed to involve a complex pathological transformation process that reaches completion during this “latent period.” Recent advances clarify both issues. Although spatially limited hippocampal GABA neuron ablation causes only submaximal granule cell hyperexcitability, more spatially extensive ablation maximizes granule cell hyperexcitability and triggers nonconvulsive granule cell status epilepticus, hippocampal sclerosis, and epilepsy. Recent studies also show that disinhibited granule cells begin to generate clinically subtle seizures immediately post-injury, and these seizures then gradually increase in duration to become clinically obvious. Therefore, rather than being a seizure-free “gestational” state of potentially interruptible epileptogenesis, the “latent period” is more likely an active epileptic state when barriers to seizure spread and clinical expression are gradually overcome by a kindling process. The likelihood that an epileptic brain state exists long before clinical diagnosis has significant implications for anti-epileptogenesis studies. The location, magnitude, and spatial extent of inherited, autoimmune, and injury-induced disinhibition may determine the latency to clinical diagnosis and establish the continuum between the benign, treatable, and refractory forms of temporal lobe epilepsy.
Neuroinflammation in Epilepsy
Authors: Dingledine Ray , Varvel Nicholas H. , Ravizza Teresa , Vezzani Annamaria 
Published: July 2024

Abstract
Neuroinflammation and epilepsy appear to exist in a self-reinforcing circular arrangement, whereby inflammatory pathways lower seizure threshold and the ensuing seizures trigger neuroinflammation. This forms the essential logic of anti-inflammatory therapies, which seek to interrupt the vicious cycle or to prevent it. Many if not all neuroinflammatory mediators are known to play physiological roles in the healthy brain, for example, regulation of astroglial potassium buffering by TGFβ, and the strength of excitatory synaptic transmission by PGE2 and IL-1β ανδ TNΦ. These neuromodulatory roles are usurped in epilepsy, when the neuroinflammatory mediators are transformed from their physiologic functions to agents of havoc as their local concentration rises or they persist too long in brain tissue. This chapter focuses on IL-1β, TNF, IL-6, PGE2, CXCL1, CCL2, and drivers of the complement pathway, which have all received substantial attention over the past decade. This chapter describes these inflammatory mediators and discusses how they may create a pathological milieu permissive for seizures, cell loss, and behavioral dysfunctions.
Role of Reactive Oxygen Species in Epilepsy
Authors: Hari Ashwini Sri , Walker Matthew C. , Patel Manisha 
Published: July 2024

Abstract
Since the last edition of this volume, there have been major advances in our understanding of redox mechanisms in epilepsies. The brain’s architecture, cell types, and function make it uniquely susceptible to oxidative damage. Animal models of acquired epilepsy have revealed reactive oxygen species generated by multiple cellular sources; oxidant damage to cellular lipids, proteins, and deoxyribonucleic acid; and an altered thiol redox status. Preclinical studies have identified several redox-based therapeutic strategies to improve epilepsy and/or its comorbidities. This chapter provides an overview of the role of redox dysregulation in epilepsy with emphasis on therapeutic targets.
Transcriptomic Alterations in Epileptogenesis
Authors: Brennan Gary P. , van Loo Karen M. J. 
Published: July 2024

Abstract
Epilepsy is associated with many transcriptomic alterations. In recent years, considerable progress has been made in the identification of epilepsy-associated genes, but we have only begun to understand the underlying mechanisms of epilepsy-driven transcriptional dysregulation. This chapter reviews the state of the current knowledge regarding the transcriptional mechanisms in experimental and human epilepsy and focuses on transcription factor–mediated dysregulation. The chapter describes how the expression of epilepsy-associated genes is affected, and it discusses the possible functional consequences of these alterations in the different phases of epileptogenesis.
Blood Biomarkers
Authors: Henshall David C. , Simonato Michele 
Published: July 2024

Abstract
The diagnosis of epilepsy and recent seizure remain important clinical challenges. Blood-based molecules represent potential circulating biomarkers that could provide simple, cheap, quick tests to support diagnosis, prognosis, monitoring, and decisions on choice and effectiveness of therapy. There have been recent and significant advances in identifying candidate molecules. A number of proteins hold promise, including HMGB1, matrix proteins, and neuron-enriched markers such as UCHL1. Small noncoding RNAs called microRNAs have more recently emerged, with interest stemming from their tissue-specific expression, suitability for rapid and quantitative assay, and link to mechanisms of disease and potential as treatments. Here we review why blood-based biomarkers are needed, the properties sought, and the quality and quantity of evidence obtained from clinical and experimental studies. We finish by identifying the necessary studies in the future that could bring these valuable supports to the clinic.
Sodium Channelopathies in Human and Animal Models of Epilepsy and Neurodevelopmental Disorders
Authors: Yamakawa Kazuhiro , Meisler Miriam H. , Isom Lori L. 
Published: July 2024

Abstract
The genes SCN1A, SCN2A, and SCN8A encode the voltage-gated sodium channel (VGSC) α-subunits Nav1.1, Nav1.2, and Nav1.6, respectively. Dravet syndrome is eat the severe end of the disease spectrum caused by SCN1A variants, and Nav1.1 haploinsufficiency in parvalbumin-positive inhibitory neurons has been proposed as a primary cause for the disease. Nav1.2 is predominantly expressed in excitatory neurons in neocortex and hippocampus. SCN2A is the gene with the largest number of de novo variants in patients with autism spectrum disorder and/or intellectual disability, and those are mainly truncations. SCN2A variants also appear in patients with epileptic encephalopathies, but those are mostly missense. Variants of SCN8A have been reported in a number of patients with variable epilepsies. Gain-of-function missense variants are the most common in SCN8A developmental and epileptic encephalopathy associated with motor manifestations such as ataxia and choreoathetosis in the most severe cases. SCN1B encodes the non-pore-forming VGSCβ1 and β1B subunits, which are multifunctional channel regulatory molecules expressed in excitatory and inhibitory neurons. SCN1B variants are reported in patients with epilepsies of multiple etiologies. In vitro and animal model studies have provided critical insights into pathological mechanisms of the diseases caused by genetic variation in these genes.
Transcriptional Regulation of Cortical Interneuron Development
Authors: Pai Emily Ling-Lin , Vogt Daniel , Hu Jia Sheng , Rubenstein John L. 
Published: July 2024

Abstract
GABAergic interneurons (INs) constitute 20%–30% of the pallial (neocortical and hippocampal) neurons. They are the main source of cortical and hippocampal synaptic inhibitory signals. Distinct IN subtypes inhibit different cellular and subcellular components of pallial circuits. INs are generated from different subdomains of the embryonic basal ganglia (ganglionic eminences, GEs). Transcription factors (TFs) through regulatory elements (REs) that they bind are integral in programming gene expression in a temporally and spatially diverse manner. This then programs cell fate-commitment, differentiation, migration, and maturation to generate different IN subtypes. Of note, the prevailing molecular and genetic knowledge about IN development has been established by decades of studies in rodent and is hypothesized to reflect many of the processes common to mammals. Research on human and primate brain development will test this hypothesis and also offers the opportunity to identify species-specific variations. In this chapter, we focus on discoveries derived from mouse research. This chapter reviews the histology of the GEs, fate-mapping tools, TFs that control regional patterning of the GEs, TFs that regulate IN maturation, and REs that are involved in IN development.
Gene–Genome Interactions
Authors: Kobow Katja , Mahoney John Matthew 
Published: July 2024

Abstract
The advent of high-throughput molecular technologies has fundamentally transformed epilepsy research. It is now possible to simultaneously measure tens of thousands of biomolecules in a stunning array of biological contexts to discern mechanistic drivers of molecular dysregulation in seizure disorders. Correspondingly, there has been an increased appreciation that the relationship between molecular perturbations (e.g., gene mutations) and their corresponding functional outcome is highly nonlinear and mediated through vast regulatory networks. Overcoming the immense complexity of biological systems to “reverse engineer” the pathological functioning of molecular networks is one of the fundamental tasks of epilepsy research over the next 10 years. This chapter discusses how to address the yet underappreciated gene–genome interactions. It provides a comprehensive overview of both specific experimental approaches and most recent advances in analytical methods to disentangle the nonlinear relationship between a complex molecular trait and its functional consequences leading to a specific phenotype, for example, epilepsy.
Progressive Myoclonus Epilepsy of Lafora
Authors: Serratosa José M. , Burgos Daniel F. , Zafra-Puerta Luis , Iglesias-Cabeza Nerea , Sanz Pascual , Sánchez Marina P. 
Published: July 2024

Abstract
Metformin is a biguanide drug that is commonly used as a first-line treatment for type 2 diabetes. This chemical works by activating the energy sensor AMPK that inhibits hepatic gluconeogenesis. Metformin’s therapeutic properties go beyond its use as an antidiabetic compound. As a result, a large number of publications have recently reported promising results in a variety of neurological diseases. Although several hypotheses have been formulated regarding the specific mechanisms of action of metformin in the central nervous system, such as a decrease of neuroinflammation or a reduction of oxidative stress, the underlying pathways of these positive effects remain obscure. In this chapter, we review the newly discovered benefits of metformin as a neuroprotective agent for Lafora disease, a rare form of progressive myoclonus epilepsy caused by mutations in the EPM2A or EPM2B genes. The aggregation of Lafora bodies, abnormal glycogen inclusions that accumulate in the brain and other tissues, is the major histopathological characteristic. Treatment with metformin in Lafora disease knockout mice reduced the number of Lafora bodies, decreased neuronal loss and reactive astrogliosis, and improved the functional and epileptic symptoms.
Antisense Oligonucleotide Therapy for Progressive Myoclonus Epilepsies
Authors: Nitschke Silvia , Minassian Berge A. 
Published: July 2024

Abstract
Progressive myoclonus epilepsies (PMEs) are genetic diseases that together account for about 1% of all epilepsies in childhood and adolescence. Even though the age of onset, symptom spectrum, and severity vary among different PMEs, all patients experience myoclonic seizures, generalized epilepsy, and progressive neurological decline, often intractable and fatal. Antisense oligonucleotides (ASOs) are synthetic single-stranded chemically modified nucleic acid polymers that target RNA to alter splicing, modulate translation, or promote/prevent mRNA degradation. Their gene-specific action and versatility has made ASO-based therapeutics one of the major pillars of drug development for genetic diseases with more than a dozen ASO drugs FDA-approved and many more in development and clinical trials. Advances in ASO technology already paved the way toward “N of 1” patient-customized therapies and hold great promise for personalized drug development that is much needed to treat rare genetic diseases such as PMEs. This chapter discusses the potential of ASO therapies for PMEs by giving an overview of the possible mechanisms of action employed to target disease genes and by reviewing ASO studies aimed to treat neuromuscular or neurodegenerative diseases, including PMEs.
What Rodent Models Teach Us about the Association of Autism and Epilepsy
Authors: Golshani Peyman 
Published: July 2024

Abstract
Autism is strongly associated with epilepsy, but the mechanisms that drive this association are poorly understood. Are autism-related behaviors and epilepsy different manifestations of pathological excitability or altered synaptic transmission induced by the same genetic changes in different brain structures? Or do early-life seizures themselves drive activity-dependent changes in circuits and induce or exacerbate deficits in social interaction? This chapter will review work done in the last 10 years in mouse models of Dravet syndrome, CACNA1a deficiency, several potassium channelopathies, and the CNTNAP2 knockout model of cortical dysplasia focal epilepsy syndrome to dissect mechanisms that drive the epilepsy and autism-relevant behaviors. It will also review the evidence for the causal role of epilepsy in autism. To conclude, it will discuss new directions for research in the coming decade, driven by the development of new technologies.
Drug Combinations for Antiepileptogenesis
Authors: Löscher Wolfgang 
Published: July 2024

Abstract
Prevention of epilepsy in patients at risk is an urgent global unmet need. In theory, the latent period between an epileptogenic brain insult and the onset of epilepsy may offer a therapeutic window to interfere with epileptogenesis. Numerous preclinical and a few clinical studies on antiepileptogenesis have been performed in the past 20-plus years. The vast majority of these studies used treatments with single, often highly selective drugs shortly after epileptogenic brain injuries, mostly without any success. The negative results may be due to the complex mechanisms of epileptogenesis, which complicate any strategy to interfere with this process. It was therefore proposed to apply principles of network pharmacology to the search for antiepileptogenic treatments. Here the outcome of preclinical studies using rationally chosen drug combinations for antiepileptogenesis is reviewed. Of 24 drug combinations that are discussed here, only four exerted persistent antiepileptogenic efficacy in rodent models of acquired epilepsy. For three of these effective combinations, clinically approved drugs were used, which would facilitate translation into clinical trials. The chapter also discusses future advancements in the search for antiepileptogenic drugs or drug combinations, including the subsequent use of in silico, in vitro, and in vivo platforms as well as “big data” mining approaches and machine learning.
Purinergic Signaling in Epilepsy
Authors: Engel Tobias , Dale Nicholas 
Published: July 2024

Abstract
Despite the availability of numerous antiseizure drugs (ASDs), treatment of epilepsy remains a clinical challenge, with over 30% of patients not responding to any pharmacological intervention. In addition, ASDs are mainly symptomatic without significantly impacting on disease progression. Thus, there is a strong focus on the identification of drug targets with a novel mechanism of action that are independent on GABAergic and glutamatergic neurotransmission and that possess a disease-modifying potential. That extracellular released purines such as adenosine triphosphate (ATP) and adenosine act as signaling molecules in the brain has been known for decades. While the anticonvulsant potential of adenosine is well established, increasing evidence suggests also an important role for ATP during the generation of seizures and the development of epilepsy. Usually present at low extracellular concentrations, ATP is released in response to several pathological stimuli including increased neuronal activity acting as danger signal and activating specific purinergic P2 receptors divided into the metabotropic P2Y and ionotropic P2X receptors. Suggesting a role during seizures and epilepsy, data from experimental models and patients show widespread expression changes of both P2Y and P2X receptor family members during epilepsy and, critically, drugs targeting both receptor subtypes, in particular, the P2Y1 and P2X7 receptors, confer both anticonvulsive and antiepileptic effects. This chapter provides a detailed summary of the current evidence suggesting ATP-gated receptors as novel drug targets for epilepsy, discusses the possible mechanisms for how these receptors contribute to increased hyperexcitability, and briefly outlines how the purinergic system can be used as novel tool for the diagnosis of epilepsy.
Targeted Augmentation of Nuclear Gene Output (TANGO)
Authors: Isom Lori L. , Knupp Kelly G. 
Published: July 2024

Abstract
Most development and epileptic encephalopathies (DEEs) are genetic in origin. Drug-resistant epilepsy is often the most notable feature of the DEEs, although numerous other symptoms are present that have significant impact on patients’ quality of life. Despite novel, third-generation antiseizure drug treatment options becoming available over the last several years, seizure freedom is often not attained and nonseizure symptoms remain. Therapeutic approaches such as antisense oligonucleotides and adeno-associated virus delivered gene modulation offers realistic hope for seizure freedom in some DEEs with an underlying genetic etiology, with several approaches demonstrating preclinical success and now transitioning to clinical trials. Several of these therapeutic strategies risk the exacerbation of gain-of-function variants and may not be reversible, thus emphasizing the need for functional testing of variants and more reliable prediction tools for pathogenicity. Dravet syndrome, Rett syndrome, and Angelman syndrome are presented here as examples of how these techniques are being applied and the nuances and challenges of each unique genetic disorder. Additionally, with so many gene regulatory therapeutic options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease.
Warps and breaks in circumbinary discs
Authors: Rabago Ian , Zhu Zhaohuan , Lubow Stephen , Martin Rebecca G 
Published: July 2024

ABSTRACT
Disc warping, and possibly disc breaking, has been observed in protoplanetary discs around both single and multiple stars. Large warps can break the disc, producing multiple observational signatures. In this work, we use comparisons of disc time-scales to derive updated formulae for disc breaking, with better predictions as to when and where a disc is expected to break and how many breaks could occur. Disc breaking is more likely for discs with small inner cavities, cooler temperatures, and steeper power-law profiles, such that thin, polar-aligning discs are more likely to break. We test our analytical formulae using three-dimensional grid-based simulations of protoplanetary discs warped by the gravitational torque of an inner binary. We reproduce the expected warp behaviours in different viscosity regimes and observe disc breaking at locations in agreement with our derived equations. As our simulations only show disc breaking when disc viscosity is low, we also consider a viscous criterion for disc breaking, where rapid alignment to the precession vector can prevent a break by reducing the maximum misalignment between neighbouring rings. We apply these results to the GW Orionis circumtriple disc and find that the precession induced from the central stars can break the disc if it is relatively thin. We expect repeated or multiple disc breaking to occur for discs with sufficiently steep power-law profiles. We simulate a polar-aligning disc around an eccentric binary with steep power-law profiles and observe two separate breaking events at locations in rough agreement with our analytical predictions.
Radiation hydrodynamical simulations of super-Eddington mass transfer and black hole growth in close binaries
Authors: Toyouchi Daisuke , Hotokezaka Kenta , Inayoshi Kohei , Kuiper Rolf 
Published: July 2024

ABSTRACT
Radiation-driven outflows play a crucial role in extracting mass and angular momentum from binary systems undergoing rapid mass transfer at super-Eddington rates. To study the mass transfer process from a massive donor star to a stellar-mass black hole (BH), we perform multidimensional radiation-hydrodynamical simulations that follow accretion flows from the first Lagrange point down to about a hundred times the Schwarzschild radius of the accreting BH. Our simulations reveal that rapid mass transfer occurring at over a thousand times the Eddington rate leads to significant mass-loss from the accretion disc via radiation-driven outflows. Consequently, the inflow rates at the innermost radius are regulated by two orders of magnitude smaller than the transfer rates. We find that convective motions within the accretion disc drive outward energy and momentum transport, enhancing the radiation pressure in the outskirts of the disc and ultimately generating large-scale outflows with sufficient energy to leave the binary. Furthermore, we observe strong anisotropy in the outflows, which occur preferentially toward both the closest and furthest points from the donor star. However, when averaged over all directions, the specific angular momentum of the outflows is nearly comparable to the value predicted in the isotropic emission case. Based on our simulation results, we propose a formula that quantifies the mass growth rates on BHs and the mass-loss rates from binaries due to radiation-driven outflows. This formula provides important implications for the binary evolution and the formation of merging binary BHs.