Abnormal rich club organization and functional brain dynamics in schizophrenia.

IMPORTANCE The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain's integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia. OBJECTIVE To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics. DESIGN Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls. SETTING Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. PARTICIPANTS Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. MAIN OUTCOME(S) AND MEASURES: Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics. RESULTS Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity-functional connectivity coupling. CONCLUSIONS Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.

[1]  Alessandro Vespignani,et al.  Detecting rich-club ordering in complex networks , 2006, physics/0602134.

[2]  Morten L. Kringelbach,et al.  Modeling the outcome of structural disconnection on resting-state functional connectivity , 2012, NeuroImage.

[3]  René S. Kahn,et al.  Impaired Cerebellar Functional Connectivity in Schizophrenia Patients and Their Healthy Siblings , 2011, Front. Psychiatry.

[4]  D. Bassett,et al.  Emerging Evidence of Connectomic Abnormalities in Schizophrenia , 2011, The Journal of Neuroscience.

[5]  J. Gabrieli,et al.  Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia , 2009, Proceedings of the National Academy of Sciences.

[6]  Philip K. McGuire,et al.  Diffusion Tensor Imaging in Schizophrenia , 2005, Biological Psychiatry.

[7]  Danielle S Bassett,et al.  Cognitive fitness of cost-efficient brain functional networks , 2009, Proceedings of the National Academy of Sciences.

[8]  Luciano da Fontoura Costa,et al.  Rich-club phenomenon across complex network hierarchies , 2007 .

[9]  R. Kahn,et al.  Tract-based analysis of magnetization transfer ratio and diffusion tensor imaging of the frontal and frontotemporal connections in schizophrenia. , 2010, Schizophrenia bulletin.

[10]  M. P. van den Heuvel,et al.  Estimating false positives and negatives in brain networks. , 2013, NeuroImage.

[11]  E. Bullmore,et al.  Undirected graphs of frequency-dependent functional connectivity in whole brain networks , 2005, Philosophical Transactions of the Royal Society B: Biological Sciences.

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

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

[14]  O. Sporns,et al.  Organization, development and function of complex brain networks , 2004, Trends in Cognitive Sciences.

[15]  Danielle S. Bassett,et al.  Conserved and variable architecture of human white matter connectivity , 2011, NeuroImage.

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

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

[18]  E. Bleuler.  [Dementia praecox or the group of schizophrenias]. , 1968, Vertex.

[19]  Mert R. Sabuncu,et al.  The influence of head motion on intrinsic functional connectivity MRI , 2012, NeuroImage.

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

[21]  O. Sporns,et al.  Rich Club Organization of Macaque Cerebral Cortex and Its Role in Network Communication , 2012, PloS one.

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

[23]  Carl-Fredrik Westin,et al.  DTI and MTR abnormalities in schizophrenia: Analysis of white matter integrity , 2005, NeuroImage.

[24]  J. Kurths,et al.  Exploring Brain Function from Anatomical Connectivity , 2011, Front. Neurosci..

[25]  R. Kahn,et al.  Abnormal Brain Wiring as a Pathogenetic Mechanism in Schizophrenia , 2011, Biological Psychiatry.

[26]  Peter Williamson,et al.  Are anticorrelated networks in the brain relevant to schizophrenia? , 2007, Schizophrenia bulletin.

[27]  E. Bullmore,et al.  Meta-analysis of diffusion tensor imaging studies in schizophrenia , 2009, Schizophrenia Research.

[28]  Hang Joon Jo,et al.  Trouble at Rest: How Correlation Patterns and Group Differences Become Distorted After Global Signal Regression , 2012, Brain Connect..

[29]  O. Sporns,et al.  Network centrality in the human functional connectome. , 2012, Cerebral cortex.

[30]  Tore Opsahl,et al.  Prominence and control: the weighted rich-club effect. , 2008, Physical review letters.

[31]  Nikos Makris,et al.  Automatically parcellating the human cerebral cortex. , 2004, Cerebral cortex.

[32]  M. P. van den Heuvel,et al.  Normalized Cut Group Clustering of Resting-State fMRI Data , 2008, PloS one.

[33]  N. Schuff,et al.  Headache and cerebral venous air embolism , 2007, Neurology.

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

[35]  Marek Kubicki,et al.  Attentional networks and cingulum bundle in chronic schizophrenia , 2007, Schizophrenia Research.

[36]  Olaf Sporns,et al.  The Human Connectome: A Structural Description of the Human Brain , 2005, PLoS Comput. Biol..

[37]  R. Kikinis,et al.  Uncinate fasciculus findings in schizophrenia: a magnetic resonance diffusion tensor imaging study. , 2002, The American journal of psychiatry.

[38]  N. Volkow,et al.  Functional connectivity density mapping , 2010, Proceedings of the National Academy of Sciences.

[39]  Andrew J. Saykin,et al.  Age-related deficits in fronto-temporal connections in schizophrenia: A diffusion tensor imaging study , 2008, Schizophrenia Research.

[40]  R. Bluhm,et al.  Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. , 2007, Schizophrenia bulletin.

[41]  Edward T. Bullmore,et al.  Schizophrenia, neuroimaging and connectomics , 2012, NeuroImage.

[42]  E. Bullmore,et al.  Functional Connectivity and Brain Networks in Schizophrenia , 2010, The Journal of Neuroscience.

[43]  Hidenao Fukuyama,et al.  Anterior and posterior cingulum abnormalities and their association with psychopathology in schizophrenia: A diffusion tensor imaging study , 2007, Schizophrenia Research.

[44]  S. Debener,et al.  Default-mode brain dysfunction in mental disorders: A systematic review , 2009, Neuroscience & Biobehavioral Reviews.

[45]  M E J Newman,et al.  Modularity and community structure in networks. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

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

[47]  O. Sporns,et al.  High-cost, high-capacity backbone for global brain communication , 2012, Proceedings of the National Academy of Sciences.

[48]  Karl J. Friston,et al.  Synaptic Plasticity and Dysconnection in Schizophrenia , 2006, Biological Psychiatry.

[49]  R. Kikinis,et al.  A review of diffusion tensor imaging studies in schizophrenia. , 2007, Journal of psychiatric research.

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

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

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

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

[54]  Wolfgang Rosenstiel,et al.  Quantifying the Link between Anatomical Connectivity, Gray Matter Volume and Regional Cerebral Blood Flow: An Integrative MRI Study , 2011, PloS one.

[55]  Abraham Z. Snyder,et al.  Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion , 2012, NeuroImage.

[56]  Gorka Zamora-López,et al.  Cortical Hubs Form a Module for Multisensory Integration on Top of the Hierarchy of Cortical Networks , 2009, Front. Neuroinform..

[57]  V. Calhoun,et al.  Aberrant "default mode" functional connectivity in schizophrenia. , 2007, The American journal of psychiatry.

[58]  Vince D Calhoun,et al.  Resting state and task‐induced deactivation: A methodological comparison in patients with schizophrenia and healthy controls , 2009, Human brain mapping.

[59]  Patric Hagmann,et al.  Mapping the human connectome at multiple scales with diffusion spectrum MRI , 2012, Journal of Neuroscience Methods.

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

[61]  Cornelis J. Stam,et al.  Small-world and scale-free organization of voxel-based resting-state functional connectivity in the human brain , 2008, NeuroImage.

[62]  O. Sporns,et al.  Rich-Club Organization of the Human Connectome , 2011, The Journal of Neuroscience.

[63]  B. Pollock,et al.  Diffusion tensor tractography findings in schizophrenia across the adult lifespan. , 2010, Brain : a journal of neurology.

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

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