Experimental Traumatic Brain Injury Induces Bone Loss in Rats.

Few studies have investigated the influence of traumatic brain injury (TBI) on bone homeostasis; however, pathophysiological mechanisms involved in TBI have potential to be detrimental to bone. The current study assessed the effect of experimental TBI in rats on the quantity and quality of two different weight-bearing bones, the femur and humerus. Rats were randomly assigned into either sham or lateral fluid percussion injury (FPI) groups.

Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus.

Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes.

Reduced susceptibility to induced seizures in the Neuroligin-3(R451C) mouse model of autism.

Epilepsy is a common comorbidity in patients with autism spectrum disorder (ASD) and several gene mutations are associated with both of these disorders. In order to determine whether a point mutation in the gene for the synaptic protein, Neuroligin-3 (Nlgn3, R451C), identified in patients with ASD alters seizure susceptibility, we administered the proconvulsant pentylenetetrazole (PTZ) to adult male Neuroligin-3(R451C) (NL3(R451C)) and wild type (WT) mice. It has previously been reported that NL3(R451C) mice show altered inhibitory GABAergic activity in brain regions relevant to epilepsy, including the hippocampus and somatosensory cortex.

Epilepsy in 2014. Novel and large collaborations drive advances in epilepsy.

In 2014, novel, large-scale collaborative efforts and frameworks resulted in major advances in the epilepsy field, from publication of a new definition of epilepsy to important discoveries regarding aetiology, pathophysiology and management. These collaborative works provide a platform from which further advances are anticipated, and a model for future research.

Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats.

Autism is a complex neurodevelopmental disorder that is characterized by social abnormalities. Genetic, dietary and gut-related factors are implicated in autism, however the causal properties of these factors and how they may interact are unclear. Propionic acid (PPA) is a product of gut microbiota and a food preservative.

A novel treatment strategy for glioblastoma multiforme and glioma associated seizures: increasing glutamate uptake with PPARγ agonists.

The established role of glutamate in the pathogenesis of glioma-associated seizures (GAS) led us to investigate a novel treatment method using an established drug class, peroxisome proliferator activated receptor (PPAR) gamma agonists. Previously, sulfasalazine has been shown to prevent release of glutamate from glioma cells and prevent GAS in rodent models. However, raising protein mediated glutamate transport via excitatory amino acid transporter 2 (EAAT2) has not been investigated previously to our knowledge.

The dynamics of the epileptic brain reveal long-memory processes.

The pattern of epileptic seizures is often considered unpredictable and the interval between events without correlation. A number of studies have examined the possibility that seizure activity respects a power-law relationship, both in terms of event magnitude and inter-event intervals. Such relationships are found in a variety of natural and man-made systems, such as earthquakes or Internet traffic, and describe the relationship between the magnitude of an event and the number of events.

Seizure expression, behavior, and brain morphology differences in colonies of Genetic Absence Epilepsy Rats from Strasbourg.

Objective: Originally derived from a Wistar rat strain, a proportion of which displayed spontaneous absence-type seizures, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent the most widely utilized animal model of genetic generalized epilepsy. Here we compare the seizure, behavioral, and brain morphometric characteristics of four main GAERS colonies that are being actively studied internationally: two from Melbourne (MELB and STRAS-MELB), one from Grenoble (GREN), and one from Istanbul (ISTAN).

Methods: Electroencephalography (EEG) recordings, behavioral examinations, and structural magnetic resonance imaging (MRI) studies were conducted on GAERS and Non-Epileptic Control (NEC) rats to assess and compare the following: (1) characteristics of spike-and-wave discharges, (2) anxiety-like and depressive-like behaviors, and (3) MRI brain morphology of regions of interest.

Altered cortical thickness following prenatal sodium valproate exposure.

Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness.

Validation of a multigenic model to predict seizure control in newly treated epilepsy.

A multigenic classifier based on five single nucleotide polymorphisms (SNPs) was previously reported to predict treatment response in an Australian newly-diagnosed epilepsy cohort using a k-nearest neighbour (kNN) algorithm. We assessed the validity of this classifier in predicting response to initial antiepileptic drug (AED) treatment in two UK cohorts of newly-diagnosed epilepsy and investigated the utility of these five SNPs in predicting seizure control in general. The original Australian cohort constituted the training set for the classifier and was used to predict response to the first well-tolerated AED monotherapy in independently recruited UK cohorts (Glasgow, n=281; SANAD, n=491).

Interaction between sex and early-life stress: influence on epileptogenesis and epilepsy comorbidities.

Epilepsy is a common brain disorder which is characterised by recurring seizures. In addition to suffering from the constant stress of living with this neurological condition, patients also frequently experience comorbid psychiatric and cognitive disorders which significantly impact their quality of life. There is growing appreciation that stress, in particular occurring in early life, can negatively impact brain development, creating an enduring vulnerability to develop epilepsy.

The challenge and promise of anti-epileptic therapy development in animal models.

Translation of successful target and compound validation studies into clinically effective therapies is a major challenge, with potential for costly clinical trial failures. This situation holds true for the epilepsies-complex diseases with different causes and symptoms. Although the availability of predictive animal models has led to the development of effective antiseizure therapies that are routinely used in clinical practice, showing that translation can be successful, several important unmet therapeutic needs still exist.

Weight and fat distribution in patients taking valproate: a valproate-discordant gender-matched twin and sibling pair study.

Objectives: Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed.

Describing the genetic architecture of epilepsy through heritability analysis.

Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms.

Are alterations in transmitter receptor and ion channel expression responsible for epilepsies?

Neuronal voltage-gated ion channels and ligand-gated synaptic receptors play a critical role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks in the brain. Changes in expression of voltage-gated ion channels, in particular sodium, hyperpolarization-activated cyclic nucleotide-gated (HCN) and calcium channels, and ligand-gated synaptic receptors, in particular GABA and glutamate receptors, have been reported in many types of both genetic and acquired epilepsies, in animal models and in humans. In this chapter we review these and discuss the potential pathogenic role they may play in the epilepsies.

Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical γ oscillations.

Noncompetitive N-methyl-d-aspartate receptor (NMDAr) antagonists can elicit many of the symptoms observed in schizophrenia in healthy humans, and induce a behavioural phenotype in animals relevant to psychosis. These compounds also elevate the power and synchrony of gamma (γ) frequency (30-80 Hz) neural oscillations. Acute doses of antipsychotic medications have been shown to reduce ongoing γ power and to inhibit NMDAr antagonist-mediated psychosis-like behaviour in rodents.

The acute phase of mild traumatic brain injury is characterized by a distance-dependent neuronal hypoactivity.

The consequences of mild traumatic brain injury (TBI) on neuronal functionality are only now being elucidated. We have now examined the changes in sensory encoding in the whisker-recipient barrel cortex and the brain tissue damage in the acute phase (24 h) after induction of TBI (n=9), with sham controls receiving surgery only (n=5). Injury was induced using the lateral fluid percussion injury method, which causes a mixture of focal and diffuse brain injury.

Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.

Objective: To evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy.

Methods: This historical-controlled, double-blind study (NCT00520741) enrolled patients aged 16-70 years on stable doses of 1-2 antiepileptic drugs (AEDs) and experiencing 2-40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose.

IDH1 mutation is associated with seizures and protoplasmic subtype in patients with low-grade gliomas.

Objective: The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70-80%, but only 5-10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2-hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE.

Effects of aberrant gamma frequency oscillations on prepulse inhibition.

Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine).

Tumour associated epilepsy and glutamate excitotoxicity in patients with gliomas.

Tumour associated epilepsy (TAE) is common, debilitating and often not successfully controlled by surgical resection of the tumour and administration of multiple anti-epileptic drugs. It represents a cause of significant lost quality of life in an incurable disease and is therefore an important subject for ongoing research. The pathogenesis of TAE is likely to be multifactorial and involve, on the microscopic level, the interaction of genetic factors, changes in the peritumoural microenvironment, alterations in synaptic neurotransmitter release and re-uptake, and the excitotoxic effects of glutamate.

The effect of amygdala kindling on neuronal firing patterns in the lateral thalamus in the GAERS model of absence epilepsy.

Objective: The co-occurrence of absence and mesial temporal lobe epilepsy is rare in both humans and animal models. Consistent with this, rat models of absence epilepsy, including genetic absence epilepsy rats from Strasbourg (GAERS), are resistant to experimental temporal lobe epileptogenesis, in particular by amygdala kindling. Structures within the cortical-thalamocortical system are critically involved in the generation and maintenance of the electrographic spike-and-wave discharges (SWDs) that characterize absence seizures.

Early life maternal separation stress augmentation of limbic epileptogenesis: the role of corticosterone and HPA axis programming.

Early life stress causes long-lasting effects on the limbic system that may be relevant to the development of mesial temporal lobe epilepsy (MTLE) and its associated psychopathology. Recent studies in rats suggest that maternal separation (MS), a model of early life stress, confers enduring vulnerability to amygdala kindling limbic epileptogenesis. However, the mechanisms underlying this remain unknown.

HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models.

Objective: Evidence from animal and human studies indicates that epilepsy can affect cardiac function, although the molecular basis of this remains poorly understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate pacemaker activity and modulate cellular excitability in the brain and heart, with altered expression and function associated with epilepsy and cardiomyopathies. Whether HCN expression is altered in the heart in association with epilepsy has not been investigated previously.