Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Role of L- and T-Type Calcium Channels in Regulation of Absence Seizures in WAG/Rij Rats

In chronic experiments on five groups of WAG/Rij rats (a genetic model of absence epilepsy; six animals in each group), we recorded EEG activity from the S1po cortical area through implanted electrodes and subjected the cortex to the action of four agents affecting L- and T-type calcium channels (injections through an implanted cannula). A blocker of L-type channels, verapamil hydrochloride, an agonist of these channels, Bay K8644, an antagonist of T-type calcium channels, L-ascorbate, and an agonist of the latter channels, PMA, were used. The parameters of 7- to 10-Hz spike-wave discharges, SWDs, spontaneously generated in the cortex of this rat strain (frequency of SWDs, mean duration of the latter, and their number) were measured within the baseline interval (before injections) and within three subsequent 20-min-long post-injection intervals. Normal saline was injected in the control group. There were no significant differences in the mean peak frequency in SWDs between all examined groups (P > 0.05 in all cases). Verapamil significantly (by more than 40%; P < 0.05) decreased the mean SWD duration throughout the entire period of post-injection observation. The dynamics of the Bay K8644 effects were rather similar, but the intensity of SWD duration changes was somewhat smaller. Both the above agents in the doses used dramatically decreased the number (frequency of appearance) of SWDs within the observation period. L-ascorbate also suppressed SWD generation. The duration of these phenomena decreased mildly, while their number dropped dramatically. In the PMA group, the number of SWDs increased significantly (by 50%, P < 0.05) within the first 20-min-long interval, but this was not observed within subsequent intervals. These findings confirm that blocking or activating of L- and T-type Ca2+ channels in the S1po area (cortical focus area) can significantly control generation of SWDs during absence seizures. Possible mechanisms underlying actions of the tested agents are discussed.У хронічних експериментах на п’яти групах щурів лінії WAG/Rij (генетична модель абсанс-епілепсії; шість тварин у кожній групі) ми відводили ЕЕГ-активність від кортикальної зони S1po через імплантовані електроди і піддавали кору дії чотирьох агентів, що впливають на кальцієві канали L- та T-типів (ін’єкції через імплантовану канюлю). Використовували блокатор кальцієвих каналів L-типу верапамілу гідрохлорид, агоніст цих каналів Bay K8644, антагоніст кальцієвих каналів T-типу L-аскорбат та агоніст останніх каналів PMA. Вимірювали параметри розрядів пік-хвиля (РПХ, частота 7–10 Гц), котрі спонтанно генеруються у корі головного мозку щурів указаної лінії (частоту в межах РПХ, середню тривалість останніх та їх кількість) протягом інтервалу порівняння (перед ін’єкціями) та трьох послідовних 20-хвилинних інтервалів після ін’єкцій. Щурам контрольної групи ін’єкували фізіологічний розчин. Істотних різниць між величинами частоти в межах РПХ у всіх досліджених групах не спостерігалося (P > 0.05 у всіх випадках). Верапаміл істотно (більш ніж на 40 %; P < 0.05) зменшував середню тривалість РПХ протягом усього періоду спостереження після ін’єкцій. Динаміка ефектів Bay K8644 була вельми подібною, але інтенсивність скорочення тривалості РПХ – дещо меншою. Обидва вказані агенти у використаних дозах зумовлювали драматичне зменшення кількості (тобто частоти виникнення) РПХ протягом усього періоду спостереження. L-аскорбат також істотно пригнічував генерацію РПХ. Тривалість цих феноменів зменшувалася помірно, а їх кількість скорочувалася дуже сильно. У групі РМА кількість РПХ протягом першого 20-хвилинного інтервалу спостереження істотно зростала (на 50 % , P < 0.05), але цього не спостерігалося в межах наступних інтервалів. Наші результати підтверджують, що блокування або активація кальцієвих каналів L- та T-типів у фокальній кортикальній зоні S1po здатні істотно контролювати генерацію РПХ під час прояву абсансних судом. Обговорюються можливі механізми дії тестованих агентів

Dynamics on networks: the role of local dynamics and global networks on the emergence of hypersynchronous neural activity.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tGraph theory has evolved into a useful tool for studying complex brain networks inferred from a variety of measures of neural activity, including fMRI, DTI, MEG and EEG. In the study of neurological disorders, recent work has discovered differences in the structure of graphs inferred from patient and control cohorts. However, most of these studies pursue a purely observational approach; identifying correlations between properties of graphs and the cohort which they describe, without consideration of the underlying mechanisms. To move beyond this necessitates the development of computational modeling approaches to appropriately interpret network interactions and the alterations in brain dynamics they permit, which in the field of complexity sciences is known as dynamics on networks. In this study we describe the development and application of this framework using modular networks of Kuramoto oscillators. We use this framework to understand functional networks inferred from resting state EEG recordings of a cohort of 35 adults with heterogeneous idiopathic generalized epilepsies and 40 healthy adult controls. Taking emergent synchrony across the global network as a proxy for seizures, our study finds that the critical strength of coupling required to synchronize the global network is significantly decreased for the epilepsy cohort for functional networks inferred from both theta (3-6 Hz) and low-alpha (6-9 Hz) bands. We further identify left frontal regions as a potential driver of seizure activity within these networks. We also explore the ability of our method to identify individuals with epilepsy, observing up to 80% predictive power through use of receiver operating characteristic analysis. Collectively these findings demonstrate that a computer model based analysis of routine clinical EEG provides significant additional information beyond standard clinical interpretation, which should ultimately enable a more appropriate mechanistic stratification of people with epilepsy leading to improved diagnostics and therapeutics.Funding was from Epilepsy Research UK (http://www.epilepsyresearch.org.uk) via grant number A1007 and the Medical Research Council (http://www.mrc.ac.uk) via grants (MR/K013998/1 and G0701310)

Chapter Sleep Spindles – As a Biomarker of Brain Function and Plasticity

Alternative & renewable energy sources & technolog

Sleep Spindles – As a Biomarker of Brain Function and Plasticity

Alternative & renewable energy sources & technolog

Ictal Functional Neuroimaging of Childhood Absence Epilepsy

Absence seizures in Childhood Absence Epilepsy (CAE) are 5 10 second episodes of impaired consciousness that are characterized on electroencephalography (EEG) by frontally-predominant, 3 4 Hz spike and wave discharges (SWD). The aims of this study were to use simultaneous EEG, functional magnetic resonance imaging (fMRI), and behavioral testing to identify the neural networks involved in absence seizures as well as to examine the timecourse of those ictal fMRI changes. It was hypothesized that absence seizures involve wide-reaching neural networks including the areas traditionally associated with normal attention processing and that absence seizures produce fMRI signal changes not only during the seizure, but before and after it as well. In this study, we recorded 88 absence seizures from a cohort of 42 children with pure CAE. These seizures were recorded as subjects participated in simultaneous EEG-fMRI scanning while engaged in a continuous performance task (CPT) of attentional vigilance or a repetitive tapping task (RTT) requiring repetitive motor activity. Using a novel, voxel-based percent fMRI change analysis combined with a volume of interest analysis, the second-by-second fMRI signal timecourse of the absence seizures were examined across numerous brain regions of interest, from 20 seconds before seizure onset through 40 seconds after seizure onset. EEG frequency analysis revealed seizures with a mean duration of 6.6 seconds and an abrupt onset and ending that were comprised of frontally-predominant, 3 4 Hz SWD. Ictal behavioral testing demonstrated abrupt onset of impairments during periods of SWD. These behavioral impairments were typical of CAE absence seizures in that impairments were greater in the CPT of attentional vigilance (omission error rate, OER = 81%) than in RTT testing (OER = 39 %) (p \u3c 0.003). The ictal fMRI changes we observed varied depending upon the method of fMRI signal analysis used. Using the traditional general liner model, and assuming the standard hemodynamic response (HRF) function, this study replicated results consistent with previous ictal absence fMRI studies showing ictal activations primarily in the thalamus and ictal deactivations in traditional default mode areas. Using a more data-driven, novel voxel-based fMRI percentage change analysis to examine the ictal fMRI timecourse on a second-by-second basis, both ictally as well as pre- and post- ictally, this study, however, demonstrated ictal involvement of diverse brain regions before, during, and after the seizure. Activation was demonstrated up to 16 seconds before seizure onset, starting first in the parietal and orbital-medial frontal cortices and progressing to lateral frontal and lateral temporal cortices followed by the occipital and Rolandic cortices and finally the thalamus. Deactivation followed a similar anatomic progression and lasted up to 17 seconds after the end of SWD. These findings reveal a complex and long-lasting sequence of fMRI changes in CAE absence seizures that are not detectable by conventional HRF modeling and are important in the understanding and eventual treatment of absence seizures associated with CAE

Cortical local and long-range synchronization interplay in human absence seizure initiation

Brain activity relies on transient, fluctuating interactions between segregated neuronal populations. Synchronization within a single and between distributed neuronal clusters reflects the dynamics of these cooperative patterns. Thus absence epilepsy can be used as a model for integrated, large-scale investigation of the emergence of pathological collective dynamics in the brain. Indeed, spike-wave discharges (SWD) of an absence seizure are thought to reflect abnormal cortical hypersynchronization. In this paper, we address two questions: how and where do SWD arise in the human brain? Therefore, we explored the spatio-temporal dynamics of interactions within and between widely distributed cortical sites using magneto-encephalographic recordings of spontaneous absence seizures. We then extracted, from their time-frequency analysis, local synchronization of cortical sources and long-range synchronization linking distant sites. Our analyses revealed a reproducible sequence of 1) long-range desynchronization, 2) increased local synchronization and 3) increased long-range synchronization. Although both local and long-range synchronization displayed different spatio-temporal profiles, their cortical projection within an initiation time window overlap and reveal a multifocal fronto-central network. These observations contradict the classical view of sudden generalized synchronous activities in absence epilepsy. Furthermore, they suggest that brain states transition may rely on multi-scale processes involving both local and distant interactions