Displacement of extracellular chloride by immobile anionic constituents of the brain's extracellular matrix.

GABA is the primary inhibitory neurotransmitter. Membrane currents evoked by GABA receptor activation have uniquely small driving forces: their reversal potential (E) is very close to the resting membrane potential. As a consequence, GABA currents can flow in either direction, depending on both the membrane potential and the local intra and extracellular concentrations of the primary permeant ion, chloride (Cl).

Timing of interventions to control neuronal chloride elevation in a model of neonatal seizures after hippocampal injury.

Objective: Following hypoxic-ischemic (HI) brain injury, neuronal cytoplasmic chloride concentration ([Cl]) increases, potentially contributing to depolarizing γ-aminobutyric acid (GABA) responses, onset of seizures, and the failure of antiepileptic drugs that target inhibitory chloride-permeable GABA receptors. Post-HI seizures characteristically begin hours after injury, by which time substantial accumulation of [Cl] may have already occurred. In immature neurons, a major pathway for Cl influx is the reversible Na-K-2Cl cotransporter NKCC1.

Intraventricular haemorrhage in premature infants: the role of immature neuronal salt and water transport.

Intraventricular haemorrhage is a common complication of premature birth. Survivors are often left with cerebral palsy, intellectual disability and/or hydrocephalus. Animal models suggest that brain tissue shrinkage, with subsequent vascular stretch and tear, is an important step in the pathophysiology, but the cause of this shrinkage is unknown.

Cellular resolution contributions to ictal population signals.

Objective: The increased amplitude of ictal activity is a common feature of epileptic seizures, but the determinants of this amplitude have not been identified. Clinically, ictal amplitudes are measured electrographically (using, e.g.

Synthesis and Characterization of a Novel Concentration-Independent Fluorescent Chloride Indicator, ABP-Dextran, Optimized for Extracellular Chloride Measurement.

GABA, the primary inhibitory neurotransmitter, stimulates GABAA receptors (GABAARs) to increase the chloride conductance of the cytosolic membrane. The driving forces for membrane chloride currents are determined by the local differences between intracellular and extracellular chloride concentrations (Cli and Clo, respectively). While several strategies exist for the measurement of Cli, the field lacks tools for non-invasive measurement of Clo.

2-Photon imaging of fluorescent proteins in living swine.

A common point of failure in translation of preclinical neurological research to successful clinical trials comes in the giant leap from rodent models to humans. Non-human primates are phylogenetically close to humans, but cost and ethical considerations prohibit their widespread usage in preclinical trials. Swine have large, gyrencencephalic brains, which are biofidelic to human brains.

Effect of neonatal seizure burden and etiology on the long-term outcome: data from a randomized, controlled trial.

Background: Neonatal seizures are common, but the impact of neonatal seizures on long-term neurologic outcome remains unclear. We addressed this question by analyzing data from an early-phase controlled trial of bumetanide to treat neonatal seizures.

Methods: Neonatal seizure burden was calculated from continuous video-EEG data.

2-Photon imaging of fluorescent proteins in living swine.

A common point of failure in translation of preclinical neurological research to successful clinical trials comes in the giant leap from rodent models to humans. Non-human primates are phylogenetically close to humans, but cost and ethical considerations prohibit their widespread usage in preclinical trials. Swine have large, gyrencencephalic brains, which are biofidelic to human brains.

Clinical Reasoning: An 8-Year-Old With Acute Onset Ataxia.

Acute ataxia is a common neurologic presentation in the pediatric population that carries a broad differential diagnosis. The tempo of the presentation, distribution of the ataxia (focal or diffuse), examination findings, and paraclinical testing may be helpful in guiding diagnosis and management. Although Guillain-Barré syndrome (GBS) and its variant, Miller Fisher syndrome (MFS), are well defined, frequently encountered acute autoimmune neuropathies, the GBS/MFS spectrum have at least 12 different phenotypes with distinct neurologic features, 4 of which include ataxia.

Clarifications regarding bumetanide for neonatal seizures.

A recent Phase II randomized, controlled trial of bumetanide as an adjunctive treatment for neonatal seizures showed a robust efficacy signal and no evidence of toxicity. Concerns regarding bumetanide as an adjunctive anticonvulsant are addressed here. An adequately powered multi-institutional trial is needed to accurately determine efficacy.

Analysis of brain region-specific mRNA synthesis and stability by utilizing adult mouse brain slice culture.

Utilization of live animals for mechanistic study is challenging yet pivotal to elucidate pathogenesis of neurological diseases. Here, we present a protocol that employs cultured brain slices derived from adult mice to examine mRNA metabolism. We describe the preparation of acute brain slices and the treatments of RNA synthesis inhibitor and nucleotide analog to examine the effects of ataxin-1 loss-of-function on mRNA stability and transcription in cortex.

In vitro ictogenesis is stochastic at the single neuron level.

Seizure initiation is the least understood and most disabling element of epilepsy. Studies of ictogenesis require high speed recordings at cellular resolution in the area of seizure onset. However, in vivo seizure onset areas cannot be determined at the level of resolution necessary to enable such studies.

Unique Actions of GABA Arising from Cytoplasmic Chloride Microdomains.

Developmental, cellular, and subcellular variations in the direction of neuronal Cl currents elicited by GABA receptor activation have been frequently reported. We found a corresponding variance in the GABA receptor reversal potential (E) for synapses originating from individual interneurons onto a single pyramidal cell. These findings suggest a similar heterogeneity in the cytoplasmic intracellular concentration of chloride ([Cl]) in individual dendrites.

KCC2 Chloride Transport Contributes to the Termination of Ictal Epileptiform Activity.

Recurrent seizures intensely activate GABA receptors (GABA-Rs), which induces transient neuronal chloride ([Cl]) elevations and depolarizing GABA responses that contribute to the failure of inhibition that engenders further seizures and anticonvulsant resistance. The K-Cl cotransporter KCC2 is responsible for Cl extrusion and restoration of [Cl] equilibrium (E) after synaptic activity, but at the cost of increased extracellular potassium which may retard K-Cl extrusion, depolarize neurons, and potentiate seizures. Thus, KCC2 may either diminish or facilitate seizure activity, and both proconvulsant and anticonvulsant effects of KCC2 inhibition have been reported.

A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.

Objective: In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group.

Methods: A randomized, double-blind, dose-escalation design was employed.

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen.

Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects.

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches.

Scalp recorded spike ripples predict seizure risk in childhood epilepsy better than spikes.

In the past decade, brief bursts of fast oscillations in the ripple range have been identified in the scalp EEG as a promising non-invasive biomarker for epilepsy. However, investigation and clinical application of this biomarker have been limited because standard approaches to identify these brief, low amplitude events are difficult, time consuming, and subjective. Recent studies have demonstrated that ripples co-occurring with epileptiform discharges ('spike ripple events') are easier to detect than ripples alone and have greater pathological significance.

A Proposed Mechanism for Spontaneous Transitions between Interictal and Ictal Activity.

Epileptic networks are characterized by two outputs: brief interictal spikes and rarer, more prolonged seizures. Although either output state is readily modeled and induced experimentally, the transition mechanisms are unknown, in part because no models exhibit both output states spontaneously. small-world neural networks were built using single-compartment neurons whose physiological parameters were derived from dual whole-cell recordings of pyramidal cells in organotypic hippocampal slice cultures that were generating spontaneous seizure-like activity.

Epileptiform activity in traumatic brain injury predicts post-traumatic epilepsy.

We hypothesize that epileptiform abnormalities (EAs) in the electroencephalogram (EEG) during the acute period following traumatic brain injury (TBI) independently predict first-year post-traumatic epilepsy (PTE ). We analyze PTE risk factors in two cohorts matched for TBI severity and age (n = 50). EAs independently predict risk for PTE (odds ratio [OR], 3.

Epileptogenesis in organotypic hippocampal cultures has limited dependence on culture medium composition.

Rodent organotypic hippocampal cultures spontaneously develop epileptiform activity after approximately 2 weeks in vitro and are increasingly used as a model of chronic post-traumatic epilepsy. However, organotypic cultures are maintained in an artificial environment (culture medium), which contains electrolytes, glucose, amino acids and other components that are not present at the same concentrations in cerebrospinal fluid (CSF). Therefore, it is possible that epileptogenesis in organotypic cultures is driven by these components.

Staged anticonvulsant screening for chronic epilepsy.

Objective: Current anticonvulsant screening programs are based on seizures evoked in normal animals. One-third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high-throughput in vitro models to low-throughput in vivo models.

A semi-automated method for rapid detection of ripple events on interictal voltage discharges in the scalp electroencephalogram.

Background: High frequency oscillations are emerging as a clinically important indicator of epileptic networks. However, manual detection of these high frequency oscillations is difficult, time consuming, and subjective, especially in the scalp EEG, thus hindering further clinical exploration and application. Semi-automated detection methods augment manual detection by reducing inspection to a subset of time intervals.