Dynamic imaging of coherent sources reveals different network connectivity underlying the generation and perpetuation of epileptic seizures

The concept of focal epilepsies includes a seizure origin in brain regions with hyper synchronous activity (epileptogenic zone and seizure onset zone) and a complex epileptic network of different brain areas involved in the generation, propagation, and modulation of seizures. The purpose of this work was to study functional and effective connectivity between regions involved in networks of epileptic seizures. The beginning and middle part of focal seizures from ictal surface EEG data were analyzed using dynamic imaging of coherent sources (DICS), an inverse solution in the frequency domain which describes neuronal networks and coherences of oscillatory brain activities. The information flow (effective connectivity) between coherent sources was investigated using the renormalized partial directed coherence (RPDC) method. In 8/11 patients, the first and second source of epileptic activity as found by DICS were concordant with the operative resection site; these patients became seizure free after epilepsy surgery. In the remaining 3 patients, the results of DICS / RPDC calculations and the resection site were discordant; these patients had a poorer post-operative outcome. The first sources as found by DICS were located predominantly in cortical structures; subsequent sources included some subcortical structures: thalamus, Nucl. Subthalamicus and cerebellum. DICS seems to be a powerful tool to define the seizure onset zone and the epileptic networks involved. Seizure generation seems to be related to the propagation of epileptic activity from the primary source in the seizure onset zone, and maintenance of seizures is attributed to the perpetuation of epileptic activity between nodes in the epileptic network. Despite of these promising results, this proof of principle study needs further confirmation prior to the use of the described methods in the clinical praxis

Epilepsie im Kindesalter: Wann kann die antiepileptische Therapie abgesetzt werden?: Eine Meinungsäußerung des Königsteiner Arbeitskreises

Abstract : The Königsteiner Arbeitskreis (KA) discussed the optimal timing of discontinuation of antiepileptic drugs (AE) in children. Because the controlled trials are rare and inconsistent it was decided to publish the results of the discussion and the approach of the KA members. In neonates AE are usually withdrawn within 2-12 weeks after the last seizure. In infantile spasms, vigabatrin is discontinued 6-12 and sulthiam 6-36 months after the cessation of spasms. After steroids the majority of the KA members continue AE for 2 years. For Rolandic epilepsy 1-3 seizurefree years seem to be sufficient to stop AE, even when focal spike waves persist. In symptomatic focal epilepsy the decision of discontinuation is influenced by the underlying disease. In absence epilepsy AE are discontinued after 2 years; whereas in myoclonic astatic epilepsy most members prefer 2-5 seizure-free years before AE are tapered. Agreement exists about the high risk of relapse after withdrawal of AE in juvenile myoclonic epilepsy and the majority of the members never stop AE in patients with this syndrome. Some KA members however, consider discontinuation after 2-3 seizure-free years. With respect to the rate of withdrawal, most members prefer a slow (3-12 months) tapering. Rapid (< 3 months) tapering is practised only by 2 KA members. The role of EEG for the decision of AE discontinuation is limited to some epileptic syndromes (i.e. absence epilepsy). The paper reflects the opinion of the KA and is not feasible as a guideline. The decision to discontinue AE is always an individual decision based on the underlying disease, the kind of epilepsy and the psychosocial circumstances of the patien

TAN Classifiers Based on Decomposable Distributions

The original publication is available at www.springerlink.comIn this paper we present several Bayesian algorithms for learning Tree Augmented Naive Bayes (TAN) models. We extend the results in Meila & Jaakkola (2000a) to TANs by proving that accepting a prior decomposable distribution over TAN's, we can compute the exact Bayesian model averaging over TAN structures and parameters in polynomial time. Furthermore, we prove that the k-maximum a posteriori (MAP) TAN structures can also be computed in polynomial time. We use these results to correct minor errors in Meila & Jaakkola (2000a) and to construct several TAN based classifiers provide consistently better predictions over Irvine datasets and artificially generated data than TAN based classifiers proposed in the literature.Peer reviewe

Neuronal networks in children with continuous spikes and waves during slow sleep

Epileptic encephalopathy with continuous spikes and waves during slow sleep is an age-related disorder characterized by the presence of interictal epileptiform discharges during at least >85% of sleep and cognitive deficits associated with this electroencephalography pattern. The pathophysiological mechanisms of continuous spikes and waves during slow sleep and neuropsychological deficits associated with this condition are still poorly understood. Here, we investigated the haemodynamic changes associated with epileptic activity using simultaneous acquisitions of electroencephalography and functional magnetic resonance imaging in 12 children with symptomatic and cryptogenic continuous spikes and waves during slow sleep. We compared the results of magnetic resonance to electric source analysis carried out using a distributed linear inverse solution at two time points of the averaged epileptic spike. All patients demonstrated highly significant spike-related positive (activations) and negative (deactivations) blood oxygenation-level-dependent changes (P < 0.05, family-wise error corrected). The activations involved bilateral perisylvian region and cingulate gyrus in all cases, bilateral frontal cortex in five, bilateral parietal cortex in one and thalamus in five cases. Electrical source analysis demonstrated a similar involvement of the perisylvian brain regions in all patients, independent of the area of spike generation. The spike-related deactivations were found in structures of the default mode network (precuneus, parietal cortex and medial frontal cortex) in all patients and in caudate nucleus in four. Group analyses emphasized the described individual differences. Despite aetiological heterogeneity, patients with continuous spikes and waves during slow sleep were characterized by activation of the similar neuronal network: perisylvian region, insula and cingulate gyrus. Comparison with the electrical source analysis results suggests that the activations correspond to both initiation and propagation pathways. The deactivations in structures of the default mode network are consistent with the concept of epileptiform activity impacting on normal brain function by inducing repetitive interruptions of neurophysiological functio

MEG-EEG Fusion by Kalman Filtering within a Source Analysis Framework*

Abstract-The fusion of data from multiple neuroimaging modalities may improve the temporal and spatial resolution of non-invasive brain imaging. In this paper, we present a novel method for the fusion of simultaneously recorded electroencephalograms (EEG) and magnetoencephalograms (MEG) within the framework of source analysis. This method represents an extension of a previously published spatio-temporal inverse solution method to the case of MEG or combined MEG-EEG signals. Moreover, we use a state-of-the-art realistic finite element (FE) head model especially calibrated for the MEG-EEG fusion problem. Using a real data set containing an epileptic spike, we validate the source analysis results of the spatio-temporal inverse solution using the results of the LORETA method and the findings from other structural and functional modalities. We show that the proposed fusion method, despite the low signal-to-noise ratio (SNR) of single spikes, points to the same brain area that was found by the other modalities. Furthermore, it correctly identifies the same source as the main generator for the MEG and EEG spikes

Professor Dr. Kikunosuke Ohno : His Personality and Works (Ohno Commemorative Issue)

At the sensor level many aspects, such as spectral power, functional and effective connectivity as well as relative-power-ratio ratio (RPR) and spatial resolution have been comprehensively investigated through both electroencephalography (EEG) and magnetoencephalography (MEG). Despite this, differences between both modalities have not yet been systematically studied by direct comparison. It remains an open question as to whether the integration of EEG and MEG data would improve the information obtained from the above mentioned parameters. Here, EEG (64-channel system) and MEG (275 sensor system) were recorded simultaneously in conditions with eyes open (EO) and eyes closed (EC) in 29 healthy adults. Spectral power, functional and effective connectivity, RPR, and spatial resolution were analyzed at five different frequency bands (delta, theta, alpha, beta and gamma). Networks of functional and effective connectivity were described using a spatial filter approach called the dynamic imaging of coherent sources (DICS) followed by the renormalized partial directed coherence (RPDC). Absolute mean power at the sensor level was significantly higher in EEG than in MEG data in both EO and EC conditions. At the source level, there was a trend towards a better performance of the combined EEG+MEG analysis compared with separate EEG or MEG analyses for the source mean power, functional correlation, effective connectivity for both EO and EC. The network of coherent sources and the spatial resolution were similar for both the EEG and MEG data if they were analyzed separately. Results indicate that the combined approach has several advantages over the separate analyses of both EEG and MEG. Moreover, by a direct comparison of EEG and MEG, EEG was characterized by significantly higher values in all measured parameters in both sensor and source level. All the above conclusions are specific to the resting state task and the specific analysis used in this study to have general conclusion multi-center studies would be helpful

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial

IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT0292689

Special Issue: Recent advances (2008 – 2015) in the study of ground ice and cryostratigraphy

Cryostratigraphy involves the description, interpretation and correlation of ground-ice 17 structures (cryostructures) and their relationship to the host deposits. Recent advances in the 18 study of ground ice and cryostratigraphy concern permafrost aggradation and degradation, 19 massive-ice formation and evaluation of ground-ice content. Field studies have increased our 20 knowledge of cryostructures and massive ground ice in epigenetic and syngenetic permafrost. 21 Epigenetic permafrost deposits are relatively ice-poor and composed primarily of pore-filled 22 cryostructures, apart from an ice-enriched upper section and intermediate layer. Syngenetic 23 permafrost deposits are commonly identified from cryostructures indicative of an aggrading 24 permafrost table and are characterized by a high ice content, ice-rich cryofacies, and nested 25 wedge ice. Degradation of ice-rich permafrost can be marked by thaw unconformities, 26 truncated buried ice wedges, ice-wedge pseudomorphs, and organic-rich ‘forest beds’. 27 Studies of massive ground ice have focused on wedge ice, thermokarst-cave ice, intrusive ice, 28 and buried ice. Significant advances have been made in methods for differentiating between 29 tabular massive ice bodies of glacier and intrasedimental origin. Recent studies have utilized 30 palynology, isotope geochemistry and hydrochemistry, in addition to sedimentary and 31 cryostratigraphic analyses. The application of remote sensing techniques and laboratory 32 methods such as CT scanning has improved estimations of the ice content of frozen 33 sediments