Altered functional-structural coupling of large-scale brain networks in idiopathic generalized epilepsy.

The human brain is a large-scale integrated network in the functional and structural domain. Graph theoretical analysis provides a novel framework for analysing such complex networks. While previous neuroimaging studies have uncovered abnormalities in several specific brain networks in patients with idiopathic generalized epilepsy characterized by tonic-clonic seizures, little is known about changes in whole-brain functional and structural connectivity networks. Regarding functional and structural connectivity, networks are intimately related and share common small-world topological features. We predict that patients with idiopathic generalized epilepsy would exhibit a decoupling between functional and structural networks. In this study, 26 patients with idiopathic generalized epilepsy characterized by tonic-clonic seizures and 26 age- and sex-matched healthy controls were recruited. Resting-state functional magnetic resonance imaging signal correlations and diffusion tensor image tractography were used to generate functional and structural connectivity networks. Graph theoretical analysis revealed that the patients lost optimal topological organization in both functional and structural connectivity networks. Moreover, the patients showed significant increases in nodal topological characteristics in several cortical and subcortical regions, including mesial frontal cortex, putamen, thalamus and amygdala relative to controls, supporting the hypothesis that regions playing important roles in the pathogenesis of epilepsy may display abnormal hub properties in network analysis. Relative to controls, patients showed further decreases in nodal topological characteristics in areas of the default mode network, such as the posterior cingulate gyrus and inferior temporal gyrus. Most importantly, the degree of coupling between functional and structural connectivity networks was decreased, and exhibited a negative correlation with epilepsy duration in patients. Our findings suggest that the decoupling of functional and structural connectivity may reflect the progress of long-term impairment in idiopathic generalized epilepsy, and may be used as a potential biomarker to detect subtle brain abnormalities in epilepsy. Overall, our results demonstrate for the first time that idiopathic generalized epilepsy is reflected in a disrupted topological organization in large-scale brain functional and structural networks, thus providing valuable information for better understanding the pathophysiological mechanisms of generalized tonic-clonic seizures.

[1]  Leonard M. Freeman,et al.  A set of measures of centrality based upon betweenness , 1977 .

[2]  R. Mattson,et al.  Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. , 1989, Epilepsia.

[3]  D. Mcintyre,et al.  Distribution of [14C]2-deoxyglucose after various forms and durations of status epilepticus induced by stimulation of a kindled amygdala focus in rats , 1991, Epilepsy Research.

[4]  G. Edelman,et al.  A measure for brain complexity: relating functional segregation and integration in the nervous system. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[6]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[7]  F Andermann,et al.  Idiopathic Generalized Epilepsy with Generalized and Other Seizures in Adolescence , 2001, Epilepsia.

[8]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[9]  Jerome Engel,et al.  A Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy: Report of the ILAE Task Force on Classification and Terminology , 2001, Epilepsia.

[10]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.

[11]  Derek K. Jones,et al.  Virtual in Vivo Interactive Dissection of White Matter Fasciculi in the Human Brain , 2002, NeuroImage.

[12]  Susumu Mori,et al.  Fiber tracking: principles and strategies – a technical review , 2002, NMR in biomedicine.

[13]  David G. Norris,et al.  An Investigation of Functional and Anatomical Connectivity Using Magnetic Resonance Imaging , 2002, NeuroImage.

[14]  Anthony B Waites,et al.  fMRI “deactivation” of the posterior cingulate during generalized spike and wave , 2003, NeuroImage.

[15]  Jason Freeman,et al.  Selective frontal, parietal, and temporal networks in generalized seizures , 2003, NeuroImage.

[16]  Hal Blumenfeld,et al.  From Molecules to Networks: Cortical/Subcortical Interactions in the Pathophysiology of Idiopathic Generalized Epilepsy , 2003, Epilepsia.

[17]  Hal Blumenfeld,et al.  Why do Seizures Cause Loss of Consciousness? , 2003, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[18]  Timothy Edward John Behrens,et al.  Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging , 2003, Nature Neuroscience.

[19]  R. Wennberg,et al.  Video-EEG evidence of lateralized clinical features in primary generalized epilepsy with tonic-clonic seizures. , 2003, Epileptic disorders : international epilepsy journal with videotape.

[20]  Mark E. J. Newman,et al.  The Structure and Function of Complex Networks , 2003, SIAM Rev..

[21]  J. Gotman,et al.  fMRI activation during spike and wave discharges in idiopathic generalized epilepsy. , 2004, Brain : a journal of neurology.

[22]  David W. Loring,et al.  COGNITIVE SIDE EFFECTS OF ANTIEPILEPTIC DRUGS , 2004 .

[23]  François Mauguière,et al.  Clinical Manifestations of Insular Lobe Seizures: A Stereo‐electroencephalographic Study , 2004 .

[24]  T. Prescott,et al.  The brainstem reticular formation is a small-world, not scale-free, network , 2006, Proceedings of the Royal Society B: Biological Sciences.

[25]  H. Blumenfeld Cellular and Network Mechanisms of Spike‐Wave Seizures , 2005, Epilepsia.

[26]  J. Gotman,et al.  Generalized epileptic discharges show thalamocortical activation and suspension of the default state of the brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Fransson Spontaneous low‐frequency BOLD signal fluctuations: An fMRI investigation of the resting‐state default mode of brain function hypothesis , 2005, Human brain mapping.

[28]  Maurizio Corbetta,et al.  The human brain is intrinsically organized into dynamic, anticorrelated functional networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Bullmore,et al.  Neurophysiological architecture of functional magnetic resonance images of human brain. , 2005, Cerebral cortex.

[30]  K. Kaski,et al.  Intensity and coherence of motifs in weighted complex networks. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[31]  Marcus Kaiser,et al.  Nonoptimal Component Placement, but Short Processing Paths, due to Long-Distance Projections in Neural Systems , 2006, PLoS Comput. Biol..

[32]  E. Bullmore,et al.  A Resilient, Low-Frequency, Small-World Human Brain Functional Network with Highly Connected Association Cortical Hubs , 2006, The Journal of Neuroscience.

[33]  Danielle Smith Bassett,et al.  Small-World Brain Networks , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[34]  Alan C. Evans,et al.  Small-world anatomical networks in the human brain revealed by cortical thickness from MRI. , 2007, Cerebral cortex.

[35]  C. Stam,et al.  Small-world networks and epilepsy: Graph theoretical analysis of intracerebrally recorded mesial temporal lobe seizures , 2007, Clinical Neurophysiology.

[36]  O. Sporns,et al.  Identification and Classification of Hubs in Brain Networks , 2007, PloS one.

[37]  Edward T. Bullmore,et al.  Efficiency and Cost of Economical Brain Functional Networks , 2007, PLoS Comput. Biol..

[38]  G. Glover,et al.  Dissociable Intrinsic Connectivity Networks for Salience Processing and Executive Control , 2007, The Journal of Neuroscience.

[39]  M. Kramer,et al.  Emergent network topology at seizure onset in humans , 2008, Epilepsy Research.

[40]  Klaus Lehnertz,et al.  Evolving functional network properties and synchronizability during human epileptic seizures. , 2008, Chaos.

[41]  Oliver Granert,et al.  Changes in activity of striato–thalamo–cortical network precede generalized spike wave discharges , 2008, NeuroImage.

[42]  B. Biswal,et al.  Functional connectivity of human striatum: a resting state FMRI study. , 2008, Cerebral cortex.

[43]  E. Bullmore,et al.  Hierarchical Organization of Human Cortical Networks in Health and Schizophrenia , 2008, The Journal of Neuroscience.

[44]  Yong He,et al.  Disrupted small-world networks in schizophrenia. , 2008, Brain : a journal of neurology.

[45]  M. P. van den Heuvel,et al.  Microstructural Organization of the Cingulum Tract and the Level of Default Mode Functional Connectivity , 2008, The Journal of Neuroscience.

[46]  Kyungsik Kim,et al.  Comparison of the small-world topology between anatomical and functional connectivity in the human brain , 2008 .

[47]  Lester Melie-García,et al.  Studying the human brain anatomical network via diffusion-weighted MRI and Graph Theory , 2008, NeuroImage.

[48]  Olaf Sporns,et al.  Symbiotic relationship between brain structure and dynamics , 2009, BMC Neuroscience.

[49]  O. Sporns,et al.  Mapping the Structural Core of Human Cerebral Cortex , 2008, PLoS biology.

[50]  John S. Duncan,et al.  Tractography of the parahippocampal gyrus and material specific memory impairment in unilateral temporal lobe epilepsy , 2007, NeuroImage.

[51]  E. Trinka,et al.  Asymmetric seizure termination in primary and secondary generalized tonic–clonic seizures , 2009, Epilepsia.

[52]  J Gotman,et al.  Thalamic nuclei activity in idiopathic generalized epilepsy , 2009, Neurology.

[53]  Keith A. Johnson,et al.  Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease , 2009, The Journal of Neuroscience.

[54]  D. Velis,et al.  Long-Term Effects of Temporal Lobe Epilepsy on Local Neural Networks: A Graph Theoretical Analysis of Corticography Recordings , 2009, PloS one.

[55]  Heidi Johansen-Berg,et al.  Using diffusion imaging to study human connectional anatomy. , 2009, Annual review of neuroscience.

[56]  M. Greicius,et al.  Greater than the sum of its parts: a review of studies combining structural connectivity and resting-state functional connectivity , 2009, Brain Structure and Function.

[57]  A. Cavanna,et al.  Brain mechanisms of altered conscious states during epileptic seizures , 2009, Nature Reviews Neurology.

[58]  R. Kahn,et al.  Efficiency of Functional Brain Networks and Intellectual Performance , 2009, The Journal of Neuroscience.

[59]  Yong Liu,et al.  Altered Anatomical Network in Early Blindness Revealed by Diffusion Tensor Tractography , 2009, PloS one.

[60]  Alan C. Evans,et al.  Uncovering Intrinsic Modular Organization of Spontaneous Brain Activity in Humans , 2009, PloS one.

[61]  Liang Wang,et al.  Parcellation‐dependent small‐world brain functional networks: A resting‐state fMRI study , 2009, Human brain mapping.

[62]  M. Greicius,et al.  Resting-state functional connectivity reflects structural connectivity in the default mode network. , 2009, Cerebral cortex.

[63]  G. Shehata,et al.  Cognitive function, mood, behavioral aspects, and personality traits of adult males with idiopathic epilepsy , 2009, Epilepsy & Behavior.

[64]  W. Liao,et al.  Impaired perceptual networks in temporal lobe epilepsy revealed by resting fMRI , 2009, Journal of Neurology.

[65]  Joshua E. Motelow,et al.  Cortical and subcortical networks in human secondarily generalized tonic-clonic seizures. , 2009, Brain : a journal of neurology.

[66]  R. Kahn,et al.  Functionally linked resting‐state networks reflect the underlying structural connectivity architecture of the human brain , 2009, Human brain mapping.

[67]  Alan C. Evans,et al.  Age- and Gender-Related Differences in the Cortical Anatomical Network , 2009, The Journal of Neuroscience.

[68]  C. J. Honeya,et al.  Predicting human resting-state functional connectivity from structural connectivity , 2009 .

[69]  O. Sporns,et al.  Complex brain networks: graph theoretical analysis of structural and functional systems , 2009, Nature Reviews Neuroscience.

[70]  C. Stam,et al.  Indications for network regularization during absence seizures: Weighted and unweighted graph theoretical analyses , 2009, Experimental Neurology.

[71]  Alan C. Evans,et al.  Mapping anatomical connectivity patterns of human cerebral cortex using in vivo diffusion tensor imaging tractography. , 2009, Cerebral cortex.

[72]  Stefan Rampp,et al.  Network characteristics of idiopathic generalized epilepsies in combined MEG/EEG , 2009, Epilepsy Research.

[73]  M. Fox,et al.  The global signal and observed anticorrelated resting state brain networks. , 2009, Journal of neurophysiology.

[74]  Jun Li,et al.  Brain Anatomical Network and Intelligence , 2009, NeuroImage.

[75]  M. Symms,et al.  Preoperative amygdala fMRI in temporal lobe epilepsy , 2009, Epilepsia.

[76]  Boris C. Bernhardt,et al.  Thalamo–cortical network pathology in idiopathic generalized epilepsy: Insights from MRI-based morphometric correlation analysis , 2009, NeuroImage.

[77]  R. Kahn,et al.  Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: A Graph Theoretical Analysis , 2010, The Journal of Neuroscience.

[78]  Edward T. Bullmore,et al.  Whole-brain anatomical networks: Does the choice of nodes matter? , 2010, NeuroImage.

[79]  O. Sporns Networks of the Brain , 2010 .

[80]  Michael D. Greicius,et al.  Development of functional and structural connectivity within the default mode network in young children , 2010, NeuroImage.

[81]  Yong He,et al.  Graph theoretical modeling of brain connectivity. , 2010, Current opinion in neurology.

[82]  Yong He,et al.  Diffusion Tensor Tractography Reveals Abnormal Topological Organization in Structural Cortical Networks in Alzheimer's Disease , 2010, The Journal of Neuroscience.

[83]  Liang Wang,et al.  Dynamic functional reorganization of the motor execution network after stroke. , 2010, Brain : a journal of neurology.

[84]  M. Kramer,et al.  Coalescence and Fragmentation of Cortical Networks during Focal Seizures , 2010, The Journal of Neuroscience.

[85]  T. Jiang,et al.  Cerebellum Abnormalities in Idiopathic Generalized Epilepsy with Generalized Tonic-Clonic Seizures Revealed by Diffusion Tensor Imaging , 2010, PloS one.

[86]  Fabrice Bartolomei,et al.  Graph theoretical analysis of structural and functional connectivity MRI in normal and pathological brain networks , 2010, Magnetic Resonance Materials in Physics, Biology and Medicine.

[87]  Walter H Backes,et al.  Functional MRI in chronic epilepsy: associations with cognitive impairment , 2010, The Lancet Neurology.

[88]  Edward T. Bullmore,et al.  SYSTEMS NEUROSCIENCE Original Research Article , 2009 .

[89]  T. Hanakawa,et al.  Amygdalar enlargement in patients with temporal lobe epilepsy , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[90]  Klaus Lehnertz,et al.  Controversies in epilepsy: Debates held during the Fourth International Workshop on Seizure Prediction , 2010, Epilepsy & Behavior.

[91]  Huafu Chen,et al.  Altered Functional Connectivity and Small-World in Mesial Temporal Lobe Epilepsy , 2010, PloS one.

[92]  Olaf Sporns,et al.  Complex network measures of brain connectivity: Uses and interpretations , 2010, NeuroImage.

[93]  Olaf Sporns,et al.  Can structure predict function in the human brain? , 2010, NeuroImage.

[94]  P. Skudlarski,et al.  Brain Connectivity Is Not Only Lower but Different in Schizophrenia: A Combined Anatomical and Functional Approach , 2010, Biological Psychiatry.

[95]  Efstathios D. Gennatas,et al.  Network-level structural covariance in the developing brain , 2010, Proceedings of the National Academy of Sciences.

[96]  O. Sporns,et al.  White matter maturation reshapes structural connectivity in the late developing human brain , 2010, Proceedings of the National Academy of Sciences.

[97]  J Martinerie,et al.  Functional modularity of background activities in normal and epileptic brain networks. , 2008, Physical review letters.

[98]  Huafu Chen,et al.  Altered spontaneous neuronal activity of the default-mode network in mesial temporal lobe epilepsy , 2010, Brain Research.

[99]  Fernando Cendes,et al.  Correlation between quantitative EEG and MRI in idiopathic generalized epilepsy , 2010, Human brain mapping.

[100]  K. Lehnertz,et al.  State dependent properties of epileptic brain networks: Comparative graph–theoretical analyses of simultaneously recorded EEG and MEG , 2010, Clinical Neurophysiology.

[101]  M. V. D. Heuvel,et al.  Exploring the brain network: A review on resting-state fMRI functional connectivity , 2010, European Neuropsychopharmacology.

[102]  Neda Bernasconi,et al.  Graph-theoretical analysis reveals disrupted small-world organization of cortical thickness correlation networks in temporal lobe epilepsy. , 2011, Cerebral cortex.

[103]  Yong He,et al.  Hemisphere- and gender-related differences in small-world brain networks: A resting-state functional MRI study , 2011, NeuroImage.

[104]  Tianzi Jiang,et al.  Impaired Resting-State Functional Integrations within Default Mode Network of Generalized Tonic-Clonic Seizures Epilepsy , 2011, PloS one.

[105]  Q. Gong,et al.  Altered functional connectivity in default mode network in absence epilepsy: A resting‐state fMRI study , 2011, Human brain mapping.

[106]  Wei Liao,et al.  Altered resting state networks in epileptic patients with generalized tonic–clonic seizures , 2011, Brain Research.

[107]  Jean Gotman,et al.  Functional connectivity in patients with idiopathic generalized epilepsy , 2011, Epilepsia.

[108]  S. Petersen,et al.  Concepts and principles in the analysis of brain networks , 2011, Annals of the New York Academy of Sciences.

[109]  N. Volkow,et al.  Association between functional connectivity hubs and brain networks. , 2011, Cerebral cortex.

[110]  E. Bullmore,et al.  Disrupted Axonal Fiber Connectivity in Schizophrenia , 2011, Biological Psychiatry.

[111]  Yong He,et al.  Discrete Neuroanatomical Networks Are Associated with Specific Cognitive Abilities in Old Age , 2011, The Journal of Neuroscience.

[112]  Danielle S Bassett,et al.  Brain graphs: graphical models of the human brain connectome. , 2011, Annual review of clinical psychology.

[113]  Yong He,et al.  Sex- and brain size-related small-world structural cortical networks in young adults: a DTI tractography study. , 2011, Cerebral cortex.

[114]  Yong He,et al.  Diffusion tensor tractography reveals disrupted topological efficiency in white matter structural networks in multiple sclerosis. , 2011, Cerebral cortex.

[115]  Huafu Chen,et al.  Default mode network abnormalities in mesial temporal lobe epilepsy: A study combining fMRI and DTI , 2011, Human brain mapping.

[116]  Olaf Sporns,et al.  THE HUMAN CONNECTOME: A COMPLEX NETWORK , 2011, Schizophrenia Research.

[117]  Q. Gong,et al.  Resting state basal ganglia network in idiopathic generalized epilepsy , 2012, Human brain mapping.