Epileptic high-frequency network activity in a model of non-lesional temporal lobe epilepsy

High-frequency cortical activity, particularly in the 250–600 Hz (fast ripple) band, has been implicated in playing a crucial role in epileptogenesis and seizure generation. Fast ripples are highly specific for the seizure initiation zone. However, evidence for the association of fast ripples with epileptic foci depends on animal models and human cases with substantial lesions in the form of hippocampal sclerosis, which suggests that neuronal loss may be required for fast ripples. In the present work, we tested whether cell loss is a necessary prerequisite for the generation of fast ripples, using a non-lesional model of temporal lobe epilepsy that lacks hippocampal sclerosis. The model is induced by unilateral intrahippocampal injection of tetanus toxin. Recordings from the hippocampi of freely-moving epileptic rats revealed high-frequency activity (4100 Hz), including fast ripples. High-frequency activity was present both during interictal discharges and seizure onset. Interictal fast ripples proved a significantly more reliable marker of the primary epileptogenic zone than the presence of either interictal discharges or ripples (100–250 Hz). These results suggest that fast ripple activity should be considered for its potential value in the pre-surgical workup of non-lesional temporal lobe epilepsy

Bayesian model comparison applied to the Explorer-Nautilus 2001 coincidence data

Bayesian reasoning is applied to the data by the ROG Collaboration, in which gravitational wave (g.w.) signals are searched for in a coincidence experiment between Explorer and Nautilus. The use of Bayesian reasoning allows, under well defined hypotheses, even tiny pieces of evidence in favor of each model to be extracted from the data. The combination of the data of several experiments can therefore be performed in an optimal and efficient way. Some models for Galactic sources are considered and, within each model, the experimental result is summarized with the likelihood rescaled to the insensitivity limit value (``${\cal R}$ function''). The model comparison result is given in in terms of Bayes factors, which quantify how the ratio of beliefs about two alternative models are modified by the experimental observationComment: 16 pages, 4 figures. Presented at the GWDAW2002 conference, held in Kyoto on Dec.,2002. This version includes comments by the referees of CQG, which has accepted the paper for pubblication in the special issue of the conference. In particular, note that in Eq. 12 there was a typeset error. As suggested by one of the referees, a uniform prior in Log(alpha) has also been considere

Can in vitro studies aid in the development and use of antiseizure therapies? A report of the ILAE/AES Joint Translational Task Force

In vitro preparations (defined here as cultured cells, brain slices, and isolated whole brains) offer a variety of approaches to modeling various aspects of seizures and epilepsy. Such models are particularly amenable to the application of anti-seizure compounds, and consequently are a valuable tool to screen the mechanisms of epileptiform activity, mode of action of known anti-seizure medications (ASMs), and the potential efficacy of putative new anti-seizure compounds. Despite these applications, all disease models are a simplification of reality and are therefore subject to limitations. In this review, we summarize the main types of in vitro models that can be used in epilepsy research, describing key methodologies as well as notable advantages and disadvantages of each. We argue that a well-designed battery of in vitro models can form an effective and potentially high-throughput screening platform to predict the clinical usefulness of ASMs, and that in vitro models are particularly useful for interrogating mechanisms of ASMs. To conclude, we offer several key recommendations that maximize the potential value of in vitro models in ASM screening. This includes the use of multiple in vitro tests that can complement each other, carefully combined with in vivo studies, the use of tissues from chronically epileptic (rather than naïve wild-type) animals, and the integration of human cell/tissue-derived preparations

Social inequalities in health- do they diminish with age? Revisiting the question in Sweden 1999

BACKGROUND: Individuals with low income have poorer health and should, therefore, have higher health expenditure than people with high income particularly in countries with a universal health care system. However, it has been discussed if social inequities in health diminish with age and we, hence, aimed to analyse this question. METHODS: We performed an age stratified cross-sectional analysis using averages, logistic and linear regression modelling of health care contacts, health care expenditures and mortality in relation to individual income in five groups by quintiles. The population consisted of all the 249,855 men aged 40 to 80 years living in the county of Skåne, Sweden during 1999. RESULTS: For working-age people (40-59 year old) we find a clear socioeconomic gradient with increasing probability of health care contact, relative expenditure and mortality as income decreased. The point estimations for 1st (highest)-2nd-3rd-4th and 5th (lowest) income groups were: (1.00-1.13-1.21-1.42 and 1.15), (1.00-1.16-1.29-1.69 and 1.89) and (1.00-1.35-1.44-2.82 and 4.12) for health care contact, relative expenditure and mortality respectively. However, in the elderly (75-80 year old) these point estimates were (1.00-0.83-0.59-0.61 and 0.39), (1.00-1.04-1.05-1.02 and 0.96) and (1.00-1.06-1.30-1.33 and 1.49). CONCLUSIONS: As expected among working-age individuals, lower income was associated with higher health care contact, relative expenditure and mortality. However, the existence of opposite socioeconomic gradients in health care utilisation and mortality in the elderly suggests that factors related to a high income might condition allocation of resources, or that current medical care is ineffective to treat determinants of income differences in mortality occurring earlier in the lifecourse

Controversies on the network theory of epilepsy : Debates held during the ICTALS 2019 conference

Acknowledgements We would like to acknowledge the contributions of the discussants to the exposition and discussion of the six debate topics. The discussants for debates 1-6 were Fabrice Wendling, Mark Cook, Mark Richardson, Thorsten Rings, Klaus Lehnertz and Piotr Suffczynski, respectively. Funding for ICTALS 2019 was received from the following foundations and industry partners: UCB S.A. (Belgium), American Epilepsy Society (AES), Epilepsy Innovation Institute (Ei2) and Epilepsy Foundation of America (EFA), NeuraLynx (Bozeman, MT, USA) and LivaNova (London, UK). The contribution of HZ was supported by award R01NS109062 from the National Institutes of Health, MG by the EPSRC via grants EP/P021417/1 and EP/N014391/1 and a Wellcome Trust Institutional Strategic Support Award (WT105618MA), and PJ by awards from the Ministry of Health of the Czech Republic AZV 17-28427A and the Czech Science Foundation 20-25298S. The opinions expressed in this article do not necessarily reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.Peer reviewedPostprin

Structural and functional substrates of tetanus toxin in an animal model of temporal lobe epilepsy

The effects of tetanus toxin (TeNT) both in the spinal cord, in clinical tetanus, and in the brain, in experimental focal epilepsy, suggest disruption of inhibitory synapses. TeNT is a zinc protease with selectivity for Vesicle Associated Membrane Protein (VAMP; previously synaptobrevin), with a reported selectivity for VAMP2 in rats. We found spatially heterogeneous expression of VAMP1 and VAMP2 in the hippocampus. Inhibitory terminals in stratum pyramidale expressed significantly more VAMP1 than VAMP2, while glutamatergic terminals in stratum radiatum expressed significantly more VAMP2 than VAMP1. Intrahippocampal injection of TeNT at doses that induce epileptic foci cleaved both isoforms in tissue around the injection site. The cleavage was modest at 2 days after injection and more substantial and extensive at 8 and 16 days. Whole-cell recordings from CA1 pyramidal cells close to the injection site, made 8–16 days after injection, showed that TeNT decreases spontaneous EPSC frequency to 38 % of control and VAMP2 immunoreactive axon terminals to 37 %. In contrast, TeNT almost completely abolished both spontaneous and evoked IPSCs while decreasing VAMP1 axon terminals to 45 %. We conclude that due to the functional selectivity of the toxin to the relative sparing of excitatory synaptic transmission shifts the network to pathogenically excitable state causing epilepsy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00429-013-0697-1) contains supplementary material, which is available to authorized users

Controversies in epilepsy: Debates held during the Fourth International Workshop on Seizure Prediction

Debates on six controversial topics were held during the Fourth International Workshop on Seizure Prediction (IWSP4) convened in Kansas City, KS, USA, July 4–7, 2009. The topics were (1) Ictogenesis: Focus versus Network? (2) Spikes and Seizures: Step-relatives or Siblings? (3) Ictogenesis: A Result of Hyposynchrony? (4) Can Focal Seizures Be Caused by Excessive Inhibition? (5) Do High-Frequency Oscillations Provide Relevant Independent Information? (6) Phase Synchronization: Is It Worthwhile as Measured? This article, written by the IWSP4 organizing committee and the debaters, summarizes the arguments presented during the debates

Opportunities for improving animal welfare in rodent models of epilepsy and seizures

Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs)

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin