epilepsy pathophysiology

We have previously characterized the molecular mechanisms for variants in γ-aminobutyric acid transporter 1-encoding solute carrier family 6-member 1 ( SLC6A1 ) in vitro and concluded that a partial or complete loss of γ-aminobutyric acid uptake due to impaired protein trafficking is the primary aetiology. Impairment of γ-aminobutyric acid transporter 1 function could cause compensatory changes in the expression of γ-aminobutyric acid receptors, which, in turn, modify disease pathophysiology and phenotype...

INTRODUCTION: Hyperexcitability in Alzheimer's disease (AD) emerge early and contribute to disease progression. The dentate gyrus (DG) is implicated in hyperexcitability in AD. We hypothesized that mossy cells (MCs), regulators of DG excitability, contribute to early hyperexcitability in AD. Indeed, MCs generate hyperexcitability in epilepsy. METHODS: Using the Tg2576 model and WT mice (∼1month-old), we compared MCs electrophysiologically, assessed c-Fos activity marker, Aβ expression and mice performance in a hippocampal-dependent memory task...

BACKGROUND: Brain tumors are one of the leading causes of epilepsy, and brain tumor-related epilepsy (BTRE) is recognized as the major cause of intractable epilepsy, resulting in huge treatment cost and burden to patients, their families, and society. Although optimal treatment regimens are available, the majority of patients with BTRE show poor resolution of symptoms. BTRE has a very complex and multifactorial etiology, which includes several influencing factors such as genetic and molecular biomarkers...

A recently described type of neonatal diabetes mellitus is caused by mutations in the YIPF5 gene and is combined with manifestations from the central nervous system, including developmental delay, epilepsy, and microcephaly. The molecular pathophysiology behind this phenotype involves the breakdown of the endoplasmic reticulum stress response due to the loss of protein folding capacity. This results in overt diabetes present from very early in life. Herein, we describe a patient with a newly reported variant in the YIPF5 gene, who presented with short events of severe hyperglycemia, induced by the stress of common illnesses, which completely resolved after recovery...

Epilepsy is a complex disease spanning across multiple scales, from ion channels in neurons to neuronal circuits across the entire brain. Over the past decades, computational models have been used to describe the pathophysiological activity of the epileptic brain from different aspects. Traditionally, each computational model can aid in optimizing therapeutic interventions, therefore, providing a particular view to design strategies for treating epilepsy. As a result, most studies are concerned with generating specific models of the epileptic brain that can help us understand the certain machinery of the pathological state...

INTRODUCTION: Neuregulin-1 (NRG-1) appears to play a role in the pathogenesis of several neuropsychiatric disorders, including epilepsy. We conducted a study to investigate the effect of anti-seizure medication on NRG-1 mRNA and NRG-1 protein levels in patients with first-episode focal epilepsy. METHODS: The levels of NRG-1 mRNA isoforms (type I, II, III, and IV) in peripheral blood mononuclear cells (PBMCs) of 39 healthy controls, 39 first-episode focal epilepsy patients before anti-seizure medication (ASM) therapy and four weeks after administration of ASM were measured by RT-qPCR, and the levels of NRG-1 protein in the serum of samples of each group were determined using ELISA...

Humankind demonstrates boundless curiosity, mostly expressed through the activities of a small number of individuals, whose achievements affect all members of society. The extent and distribution of pre-historic trepanation and trepanation in contemporary unsophisticated societies are reviewed. In the great majority of cases the intention of trepanation has been therapeutic, even if the understanding of underlying pathophysiology is not the same as that which scientific societies now accept. This review demonstrates variation in surgical technique...

Pathogenic variants in genes encoding ion channels are causal for various pediatric and adult neurological conditions. In particular, several epilepsy syndromes have been identified to be caused by specific channelopathies. These encompass a spectrum from self-limited epilepsies to developmental and epileptic encephalopathies spanning genetic and acquired causes. Several of these channelopathies have exquisite responses to specific antiseizure medications (ASMs), while others ASMs may prove ineffective or even worsen seizures...

Deep brain stimulation (DBS) modulates local and widespread connectivity in dysfunctional networks. Positive results are observed in several patient populations; however, the precise mechanisms underlying treatment remain unknown. Translational DBS studies aim to answer these questions and provide knowledge for advancing the field. Here, we systematically review the literature on DBS studies involving models of neurological, developmental and neuropsychiatric disorders to provide a synthesis of the current scientific landscape surrounding this topic...

Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation plays a role in epilepsy and seizures, however few studies have specifically examined neuroinflammation in Dravet syndrome under conditions of a higher seizure burden. Here we used an established genetic mouse model of Dravet syndrome (Scn1a+/- mice), to examine whether a higher seizure burden impacts the number and morphology of microglia in the hippocampus...

Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extrasynaptic N-methyl-D-aspartate receptors with the contribution of astrocytes. These events are significantly slower than the excitatory postsynaptic currents. Parameters of slow inward currents are determined by several factors including the mechanisms of astrocytic activation and glutamate release, as well as the diffusion pathways from the release site towards the extrasynaptic receptors...

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area, and white matter subcortical periventricular áreas. Moreover, modeling these brain areas in a newborn is challenging due to significant variability in the intensities associated with HIE conditions. This paper aims to evaluate functional measurements and 3D machine learning models of a given HIE case by correlating the affected brain areas with the pathophysiology and clinical neurodevelopmental...

Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear...

Increasing pieces of evidence have suggested that astrocyte function has a strong influence on neuronal activity and plasticity, both in physiological and pathophysiological situations. In epilepsy, astrocytes have been shown to respond to epileptic neuronal seizures; however, whether they can act as a trigger for seizures has not been determined. Here, using the copper implantation method, spontaneous neuronal hyperactivity episodes were reliably induced during the week following implantation. With near 24-h continuous recording for over 1 week of the local field potential with in vivo electrophysiology and astrocyte cytosolic Ca2+ with the fiber photometry method, spontaneous occurrences of seizure episodes were captured...

PURPOSE: In developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis...

The endocannabinoid system (ECS) is an intricate network consisting of receptors, enzymes, and endogenous ligands that play a pivotal role in various neurological processes. It has been implicated in the pathophysiology of several neurological disorders, including epilepsy. Extensive research has demonstrated the involvement of genetic factors in influencing the susceptibility to and progression of epilepsy. In this study, we focused on investigating the connection between genetic variations in genes related to the ECS and the occurrence of epilepsy...

BACKGROUND: The hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN1) is predominantly located in key regions associated with epilepsy, such as the neocortex and hippocampus. Under normal physiological conditions, HCN1 plays a crucial role in the excitatory and inhibitory regulation of neuronal networks. In temporal lobe epilepsy, the expression of HCN1 is decreased in the hippocampi of both animal models and patients. However, whether HCN1 expression changes during epileptogenesis preceding spontaneous seizures remains unclear...

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1A L263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1a L263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization...

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date...

Myoclonic-tonic (MT) and spasm-tonic (ST) seizures represent distinctive features in late infantile epileptic encephalopathy (LIEE). This commentary aims to delineate the electroclinical characteristics of MT and ST seizures, setting them apart from other seizure types. Our analysis encompasses 211 ST and MT seizures observed in 31 patients diagnosed with LIEE, providing a comprehensive overview of video-EEG features and polygraphic signatures. In MT seizures, EEG findings reveal a high-voltage diffuse spike/polyspike and wave discharge, often succeeded by diffuse electrodecrements...