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Assessing functional networks in human epileptic brains

Applicant Schindler Kaspar
Number 122010
Funding scheme Project funding (Div. I-III)
Research institution Klinik und Poliklinik für Neurologie Inselspital
Institution of higher education University of Berne - BE
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2009 - 31.07.2011
Approved amount 236'424.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Other disciplines of Physics

Keywords (7)

human epilepsy; neuronal networks; electroencephalogram; complex systems; networks; therapy; EEG

Lay Summary (German)

Lead
Lay summary
Kurzzusammenfassung: Das Ziel des Projektes ist es, funktionelle neuronale Netzwerke bei Epilepsiepatienten besser zu verstehen, um in Zukunft effektivere Therapien entwicklen zu können.Hintergrund: Epilepsie ist die zweithäufigste neurologische Erkrankung. In Europa leiden rund 6 Millionen Menschen an Epilepsie. Epileptische Anfälle bewirken eine erhöhte Sterblichkeit (zB durch anfallsbedingte Unfälle, oder durch besonders schwere epileptische Anfälle) und stellen eine ausgeprägte psychosoziale Belastung für den Patienten und seine Familie dar. Deshalb ist die vollständige Anfallsfreiheit das Ziel der modernen Epilepsietherapie. Gegenwärtig wird aber bei rund einem Viertel aller Patienten dieses Ziel nicht erreicht. Um die aktuellen Therapien zu verbessern und neue Therapieansätze zu entwickeln, ist ein tieferes Verständnis der krankmachenden Veränderungen im zentralen Nervensystem der Epilepsiepatienten unabdingbar. Dabei ist es sehr wichtig, zu beachten, dass epileptische Anfälle nicht durch Störungen einzelner oder einiger weniger Nervenzellen entstehen. Vielmehr sind epileptische Anfälle der Ausdruck einer kollektiven unkontrollierten elektrischen Aktivität in sehr grossen Nervenzellnetzwerken. Solche Netzwerke können als sogenannt komplexe Systeme aufgefasst werden wie sie zum Beispiel im Bereich der Physik seit längerer Zeit untersucht werden. Komplexe Systeme bestehen aus sehr vielen Elementen, die auf komplizierte Art miteinander wechselwirken und sich selbst zu vielfältigen Mustern organisieren können. Ziel: Das Ziel des Projektes ist es, die elektrische Aktivität ausgedehnter neuronaler Netzwerke bei Epilepsiepatienten besser zu verstehen. Zu diesem Zweck untersuchen wir Hirnstromsignale (elektroencephalographische Signale) mit Methoden, die zum Studium komplexer Systeme und Netzwerke in der Physik entwickelt wurden. Ein Hauptziel dabei ist, besser zu verstehen, wie einzelne lokale Teile der funktionellen Netzwerke die Netzwerkaktivität als Ganzes beeinflussen.Bedeutung: Das Projekt will dazu beitragen, dass wir besser verstehen, welche Veränderungen in der Aktivität funktioneller neuronaler Netzwerke zu Epilepsie führen. Ein besseres Verständnis dieser Veränderungen ist notwendige Voraussetzung, damit bessere, d.h. effektivere und gezieltere Therapien entwickelt werden können. In einem weiteren Kontext gesehen, ist das Verständnis des Zusammenhanges zwischen lokaler und globaler elektrischer Hirnaktivität auch ein konkretes Bespiel für das viel allgemeinere Problem, in einem komplexen System das Zusammenwirken zwischen den Systemelementen und den resultierenden emergenten (globalen) Eigenschaften des Gesamtsystemes zu verstehen.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Detecting determinism with improved sensitivity in time series: rank-based nonlinear predictability score.
Naro Daniel, Rummel Christian, Schindler Kaspar, Andrzejak Ralph G (2014), Detecting determinism with improved sensitivity in time series: rank-based nonlinear predictability score., in Physical review. E, Statistical, nonlinear, and soft matter physics, 90(3), 032913-032913.
A Systems-Level Approach to Human Epileptic Seizures
Rummel Christian, Goodfellow Marc, Gast Heidemarie, Hauf Martinus, Amor Frédérique, Stibal Alexander, Mariani Luigi, Wiest Roland, Schindler Kaspar (2013), A Systems-Level Approach to Human Epileptic Seizures, in Neuroinformatics, 11(2), 159-173.
Dynamics of linear and nonlinear interrelation networks in peri-ictal intracranial EEG: seizure onset and termination
Rummel Christian, Müller Markus, Hauf Martinus, Wiest Roland, Schindler Kaspar (2013), Dynamics of linear and nonlinear interrelation networks in peri-ictal intracranial EEG: seizure onset and termination, in Tetzlaff Roland (ed.), 162-174.
Synchronization and Desynchronization in Epilepsy: Controversies and Hypotheses.
Jiruska Premek, de Curtis Marco, Jefferys John, Schewon Catherine, Schiff Steve, Schindler Kaspar (2013), Synchronization and Desynchronization in Epilepsy: Controversies and Hypotheses., in Journal of Physiology, 15(591), 787-797.
Nonrandomness, nonlinear dependence, and nonstationarity of electroencephalographic recordings from epilepsy patients
Adrzejak Ralph, Schindler Kaspar, Rummel Christian (2012), Nonrandomness, nonlinear dependence, and nonstationarity of electroencephalographic recordings from epilepsy patients, in Phys. Rev. E, 86(4), 046206-17p.
On seeing the trees and the forest: Single-signal and multisignal analysis of periictal intracranial EEG.
Schindler K Gast H Goodfellow M Rummel C (2012), On seeing the trees and the forest: Single-signal and multisignal analysis of periictal intracranial EEG., in Epilepsia, 53(9), 1658-1668.
EEG correlation and power during maintenance of wakefulness test after sleep-deprivation.
Gast Heidermarie, Schindler Kaspar, Rummel Christian, Herrmann Uli S., Roth Corinne, Hess Christian W., Mathis Johannes (2011), EEG correlation and power during maintenance of wakefulness test after sleep-deprivation., in Clinical Neurophysiology, 122(10), 2025-2031.
Evolution of Genuine Cross-Correlation Strength of Focal Onset Seizures
Müller Markus, Baier Gerold, Jimenez Yurytzy Lopez, Marin Garcia Arlex, Rummel Christian, Schindler Kaspar (2011), Evolution of Genuine Cross-Correlation Strength of Focal Onset Seizures, in Journal of Clinical Neurophysiology, 28(5), 450-462.
Forbidden ordinal patterns of periictal intracranial EEG indicate deterministic dynamics in human epileptic seizures.
Schindler Kaspar, Gast Heidemarie, Stieglitz Lennart, Stibal Alexander, Hauf Martinus, Wiest Roland, Mariani Luigi, Rummel Christian (2011), Forbidden ordinal patterns of periictal intracranial EEG indicate deterministic dynamics in human epileptic seizures., in Epilepsia, 52(10), 1771-1780.
Uniform approach to linear and nonlinear interrelation patterns in multivariate time series
Rummel Christian, Abela Eugenio, Müller Markus, Hauf Martinus, Scheidegger Olivier, Wiest Roland, Schindler Kaspar (2011), Uniform approach to linear and nonlinear interrelation patterns in multivariate time series, in Physical Review E, 83, 066215-13.
Analyzing spatio-temporal patterns of genuine cross-correlations
Rummel Christian, Müller Markus, Baier Gerold, Amor Frédérique, Schindler Kaspar (2010), Analyzing spatio-temporal patterns of genuine cross-correlations, in Journal of Neuroscience Methods, 191(1), 094-100.
Assessing periodicity of periodic leg movements during sleep
Rummel Christian, Gast Heidemarie, Schindler Kaspar, Müller Markus, Amor Frédérique, Hess Christian, Mathis Johannes (2010), Assessing periodicity of periodic leg movements during sleep, in Frontiers in Neuroscience, 4, 1-14.
Frontallappenepilepsie – dorsolateral, orbital, polar
Schindler Kaspar, Rummel Christian, Gast Heidemarie, Amor Frédérique, Stibal Alexander, Stieglitz Lennart, Wiest Roland, Hauf Martinus, Mathis Johannes, Meyer Klaus, Rüegg Stefan, Mariani Luigi, Raabe Andreas, Hess Christian W. (2010), Frontallappenepilepsie – dorsolateral, orbital, polar, in Epileptologie, 27, 124-132.
Das Elektroenzephalogramm (EEG) in der prä-chirurgischen Epilepsiediagnostik
Schindler Kaspar, Rummel Christian, Gast Heidemarie, Amor Frédérique, Stibal Alexander, Wiest Roland, Hauf Martinus, Mathis Johannes, Rüegg Stefan, Mariani Luigi, Raabe Andreas, Hess Christian W. (2009), Das Elektroenzephalogramm (EEG) in der prä-chirurgischen Epilepsiediagnostik, in EpilepsieNewsletter, xxx(Juni 2010), 1-8.
Peri-ictal correlation dynamics of high-frequency (80-200 Hz) intracranial EEG.
Schindler Kaspar, Amor Frédérique, Gast Heidemarie, Müller Markus, Stibal Alexander, Mariani Luigi, Rummel Christian (2009), Peri-ictal correlation dynamics of high-frequency (80-200 Hz) intracranial EEG., in Epilepsy Research, 89(1), 72-81.
Epileptic seizures as condensed sleep: an analysis of network dynamics from elecetroencephalogram signals
Gast Heidemarie, Müller Markus, Rummel Christian, Roth Corinne, Mathis Johannes, Schindler Kaspar, Bassetti Claudio, Epileptic seizures as condensed sleep: an analysis of network dynamics from elecetroencephalogram signals, in Journal of Sleep Research.

Collaboration

Group / person Country
Types of collaboration
Facultad de Ciencias, Universidad Aut´onoma del Estado de Morelos Mexico (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Universitätsklinik für Neurochirurgie, Inselspital, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Insititut für Diagnostische und Interventionelle Neuroradiologie, Inselspital, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Universitätsklinik für Neurochirurgie, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Clinical Neuroscience Bern Poster Localizing value of EEG/fMRI in presurgical epilepsy: the influence of alternative tresholding strategies 22.11.2011 Bern, Switzerland Schindler Kaspar;
Clinical Neuroscience Bern Poster Does multivariate analysis of nonlinear EEG interrelation help delineate ictogenic brain tissue? 22.11.2011 Bern, Switzerland Schindler Kaspar;
5th International Workshop on Seizure Prediction Poster Spatio-­temporal dynamics of seizures characterized with genuine cross-­ correlations 19.09.2011 Dresden, Germany Schindler Kaspar;
5th International Workshop on Seizure Prediction Poster Linear and nonlinear interrelation dynamics in peri-ictal iEEG 19.09.2011 Dresden, Germany Schindler Kaspar;
5th International Workshop on Seizure Prediction Talk given at a conference Peri-ictal network phenomena in intracranial EEG: seizure onset and termination 19.09.2011 Dresden, Germany Schindler Kaspar;
Biosignal 2010 Poster Periodic Leg Movements during Sleep - Detecting hidden periodicities and data driven group formation 14.07.2011 Berlin, Germany
Clinical Neuroscience Bern Poster A systems perspective to peri-ictal iEEG dynamics of focal onset seizures 29.11.2010 Bern, Switzerland Schindler Kaspar;
Clinical Neuroscience Bern Poster Mapping resting-state functional connectivity of cytoarchitectonic areas using multivariate correlation analysis 29.11.2010 Bern, Switzerland Schindler Kaspar;
Syncline 2010 – Synchronization in Complex Networks Talk given at a conference Synchronization phenomena in human epileptic brain networks 26.05.2010 Bad Honnef, Germany
BrainModes: Meeting on the role of neuronal oscillations in neurological disorders Poster Spatial dynamics of genuine cross-correlations in intracranial multi-channel EEG of patients suffering from focal onset seizures 10.12.2009 Bristol, Great Britain and Northern Ireland Schindler Kaspar;
American Epilepsy Society 63rd Annual Meeting Poster Parameter-free extraction of the functional network topology from intracranial EEG recordings: a time-resolved study of graph properties in focal onset seizures 04.12.2009 Boston, United States of America
Clinical Neuroscience Meeting Poster Spatial dynamics of genuine cross-correlations in peri-ictal intracranial multi-channel EEG 01.12.2009 Bern, Switzerland
Synchronization and Multiscale Complex Dynamics in the Brain Poster Global and local disentangling of non-random from random cross-correlations in multi-channel EEG 02.11.2009 Dresden, Germany
28th International Epilepsy Congress Poster Presurgical Evaluation Using Combined fMRI/EEG in Temporal Lobe Epilepsy 29.06.2009 Budapest, Hungary
28th International Epilepsy Congress Poster Common Mechanisms of Auditory Hallucinations - Perfusion Studies in Epilepsy 29.06.2009 Budapest, Hungary Schindler Kaspar;
SAN SERVOLO Epilepsy Courses, Alumni Meeting 2009 Talk given at a conference Seizures and EEG correlation: A complex systems inspired approach 21.06.2009 Pecs, Ungarn, Hungary
Jahrestagung Schweizerische Gesellschaft für klinische Neurophysiologie SGKN Poster Synchronization flows in the epileptic brain: A preliminary study of pre-surgical intra-cerebral EEG recordings 14.05.2009 Luzern, Switzerland
Jahrestagung Schweizerische Gesellschaft für klinische Neurophysiologie SGKN Poster Assessing the Periodicity of Leg Movements during Sleep 14.05.2009 Luzern, Switzerland Amor Frédéerique; Schindler Kaspar;
Jahrestagung Schweizerische Gesellschaft für klinische Neurophysiologie SGKN Poster Spatio-temporal patterns of random and genuine cross-correlations during epileptic focal onset seizures. 14.05.2009 Luzern, Switzerland Schindler Kaspar; Amor Frédéerique;
53. Jahrestagung derDeutschen Gesellschaft für Klinische Neurophysiologie Poster Die gemeinsame Referenz bei der Elektroencephalografie: Medianwerte im Vergleich zu Mittelwerten 26.03.2009 München, Germany


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Epilepsie 2010
Talks/events/exhibitions Symposium Bern-Basel:Epilepsiechirurgie, diagnostische, therapeutische und wissenschaftliche Aspekte 2010

Associated projects

Number Title Start Funding scheme
155950 A Bayesian Inference Approach to Intracranial EEG Seizure Dynamics 01.11.2014 Project funding (Div. I-III)

Abstract

ContextEpilepsy is the second most common neurological disease. Recurrent epileptic seizures are associated with increased mortality, high morbidity, and a severe psycho-social burden for the patient and his/her family. Therefore the goal of epilepsy treatment is to render the patient seizure-free. However, since this goal is not achieved in one fourth of all patients, it is important to develop better therapies. To allow for a rational guidance of the development of improved therapies, a better understanding of the pathological changes of human epileptic brains is indispensable. In recent years, neuroimaging has provided important insights into structural changes associated with epilepsy and basic neuroscience has unravelled cellular and sub-cellular epileptogenic mechanisms. However, pathophysiological functioning is often not derivable from altered structure. Moreover, epileptic seizures are not produced by single neurons only, but result from excessive and aberrant collective activity and dynamic interaction of a very large number of nerve cells. Therefore it is important to study not only structure, but also function and to not only focus on single cells, but to strive to better understand large neural networks in the epileptic brain.General ObjectiveThe general objective of our study is to understand functional networks in human epileptic brains as a prerequisite for the rational development of more effective therapies. Our general study objective represents a specific example of one of the most fundamental problems of neuroscience, namely how segregated neuronal activity is integrated and coordinated, or, to widen the context even further, to the classical mereological problem of how parts are related to the whole. The understanding of this relationship, which is often discussed in an abstract way, may have very practical consequences in the present context of guiding the development of new therapies, because parts of the brain may be changed by surgical interventions, while the brain as a whole is affected by systemically applied drugs.MethodsIn the context of functional networks, the term "function" refers to neural electrical activity, which is recorded by the electroencephalogram (EEG). We will analyze multi-channel EEG recordings using quantitative methods originally developed in physics for the study of complex systems that consist of many interacting elements. A crucial characteristic of these methods is that they allow to study interdependencies on different scales. In other words, these methods allow to focus on parts of the functional networks as well as on the emergent activity produced by all the interacting functional networks as a whole. Specifically, mathematical tools from nuclear physics ("Random-Matrix Theory") and from graph theory will be applied, adjusted and further developed. These methods allow to detect dynamically formed "clusters", i.e. in our case those subsets of EEG channels that inter-depend more strongly with each other than with the rest. Furthermore, those EEG channels with an increased number of strong functional interactions with remote brain areas can be identified. Within the framework of graph theory such channels correspond to so-called "hubs", i.e. parts of a functional network that are specifically important to sustain and coordinate its activity. Linear (equal-time cross-correlation and finite-lag correlation) and nonlinear (mutual information) measures will be used to characterize the dynamic interdependencies between EEG channels. Rather than on bivariate relations between pairs of channels, emphasis will be put on multivariate relations of the entire set of channels. To this end, properties of the eigenvalues and eigenvectors of interdependence matrices as well as graph theoretical measures will be studied in this tripartite project. First, in order to assess the multivariate effect of lag correlations between signals recorded from different sites of the brain, the concept of the equal-time cross-correlation matrix will be generalized to finite time lags, in a way that conserves the practically important mathematical property of real and non-negative eigenvalues. Comparing the equal-time and the finite-lag correlation structure will allow to assess propagation of activity through functional networks. Second, to be sensitive not only to linear but also to nonlinear interdependencies, we will define functional networks based on the mutual information between EEG channels. Characteristics defined within the framework of Random Matrix Theory will be investigated for the multivariate generalization of mutual information. Based on preliminary results we expect that the nonlinear interdependencies are more sensitive to changes within the functional networks in epileptic brains. As a third part of the project, graph theoretical measures will be applied in a time resolved manner to interdependence matrices constructed from EEG recordings on the basis of equal-time cross-correlation, finite-lag correlation and mutual information. As a central methodological point, the results will be constantly interpreted in the context of clinical neurophysiology. Using the EEG data base of the Clinic of Neurology of the Inselspital in Bern, the methods can thus be evaluated for their practical utility, which will influence their further development.Clinical QuestionsThe following clinically important questions will be addressed:1. Is it possible to identify local parts ("clusters" and/or "hubs") within the functional networks in epileptic brains that show specific activity in the interictal and during different ictal stages, i.e. before and at seizure onset, during seizure propagation, before, at and following seizure termination?2. How does the emergent global activity of the functional networks as a whole differ between interictal and ictal stages?3. How do functional neuronal networks differ between patients suffering from focal-onset seizures vs. those suffering from primary generalized seizures?4. Are the functional networks of epileptic brains different in the interictal stages in those patients who have rare (or no more) seizures compared to those who have frequent seizures?5. How do anti-convulsive drugs act on the functional networks?6. Do brain regions, that have been surgically removed in patients who are post-operatively seizure-free, correspond to specific parts of functional networks (i.e. "clusters" and/or "hubs")?RelevanceA better understanding of functional networks in human epileptic brains is highly relevant in regard to improving existing or developing new therapeutic approaches. This study will contribute to this goal in at least a twofold way: First, signal analysis tools to assess neuronal network activity will be advanced, and second, the analysis results will be interpreted in the context of clinically relevant questions. The detection of clusters/hubs and the understanding of their relationship to the activity of the epileptic brain as a whole may have direct practical consequences. For example the goal of epilepsy surgery is to remove the so-called "epileptogenic zone", which often appears structurally normal. Especially in these cases it would be highly relevant to be able to identify those parts of the neuronal networks that are crucial for seizure generation based on EEG analysis. In addition, our study may be helpful by identifying also those parts of the functional networks that are important for seizure termination and may potentially be stabilized by modern tools such as electric brain stimulation. The characteristics of the emergent global activity of functional networks are highly important in regard to understanding the effects of anti-convulsive drugs. Better understanding of how drugs affect global network activity would be specifically relevant for assessing the anti-convulsive potential of new drugs.
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