Abnormal Connectional Fingerprint in Schizophrenia: A Novel Network Analysis of Diffusion Tensor Imaging Data

The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal–frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder.

[1]  A. Anwander,et al.  Connectivity-Based Parcellation of Broca's Area. , 2006, Cerebral cortex.

[2]  Timothy Edward John Behrens,et al.  Quantitative Investigation of Connections of the Prefrontal Cortex in the Human and Macaque using Probabilistic Diffusion Tractography , 2005, The Journal of Neuroscience.

[3]  Osamu Abe,et al.  Reduced Gray Matter Volume of Pars Opercularis Is Associated with Impaired Social Communication in High-Functioning Autism Spectrum Disorders , 2010, Biological Psychiatry.

[4]  Desmond J. Higham,et al.  Connectivity-based parcellation of human cortex using diffusion MRI: Establishing reproducibility, validity and observer independence in BA 44/45 and SMA/pre-SMA , 2007, NeuroImage.

[5]  Mikail Rubinov,et al.  Schizophrenia and abnormal brain network hubs , 2013, Dialogues in clinical neuroscience.

[6]  Degang Zhang,et al.  Increased cortico-subcortical functional connectivity in schizophrenia , 2011, Brain Imaging and Behavior.

[7]  Karl J. Friston.  Disconnection and cognitive dysmetria in schizophrenia. , 2005, The American journal of psychiatry.

[8]  Thomas R. Knösche,et al.  White matter integrity, fiber count, and other fallacies: The do's and don'ts of diffusion MRI , 2013, NeuroImage.

[9]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[10]  Derek K. Jones.  Studying connections in the living human brain with diffusion MRI , 2008, Cortex.

[11]  Ingrid Agartz,et al.  Age-related cortical thickness differences in adolescents with early-onset schizophrenia compared with healthy adolescents , 2013, Psychiatry Research: Neuroimaging.

[12]  Klaas E. Stephan,et al.  The anatomical basis of functional localization in the cortex , 2002, Nature Reviews Neuroscience.

[13]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

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

[15]  S. Kay,et al.  Significance of Positive and Negative Syndromes in Chronic Schizophrenia , 1986, British Journal of Psychiatry.

[16]  Timothy Edward John Behrens,et al.  Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus. , 2005, Cerebral cortex.

[17]  J. Lindenmayer,et al.  Psychopathology of Schizophrenia: initial validation of a 5-factor model. , 1995, Psychopathology.

[18]  P. Barker,et al.  Diffusion magnetic resonance imaging: Its principle and applications , 1999, The Anatomical record.

[19]  V. Peralta,et al.  Psychopathological dimensions in schizophrenia. , 1995, Schizophrenia bulletin.

[20]  Mark E. Bastin,et al.  White matter integrity as an intermediate phenotype: Exploratory genome-wide association analysis in individuals at high risk of bipolar disorder , 2013, Psychiatry Research.

[21]  Tyrone D. Cannon,et al.  Dorsolateral prefrontal cortex activity during maintenance and manipulation of information in working memory in patients with schizophrenia. , 2005, Archives of general psychiatry.

[22]  Christophe Lenglet,et al.  Sex differences in the human connectome: 4-Tesla high angular resolution diffusion imaging (HARDI) tractography in 234 young adult twins , 2011, 2011 IEEE International Symposium on Biomedical Imaging: From Nano to Macro.

[23]  Christophe Lenglet,et al.  Hierarchical topological network analysis of anatomical human brain connectivity and differences related to sex and kinship , 2012, NeuroImage.

[24]  Matthias J. Müller,et al.  Dysconnectivity of the inferior frontal gyrus: Implications for an impaired self-other distinction in patients with schizophrenia , 2014, Psychiatry Research: Neuroimaging.

[25]  Peter Kirsch,et al.  Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia. , 2014, JAMA psychiatry.

[26]  Melissa J. Green,et al.  Task-related fronto-striatal functional connectivity during working memory performance in schizophrenia , 2013, Schizophrenia Research.

[27]  Timothy Edward John Behrens,et al.  Changes in connectivity profiles define functionally distinct regions in human medial frontal cortex. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Murray,et al.  Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder , 2011, BMC psychiatry.

[29]  Hae-Jeong Park,et al.  Prefrontal functional dissociation in the semantic network of patients with schizophrenia , 2008, Neuroreport.

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

[31]  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.

[32]  H. Karnath,et al.  Keeping Memory Clear and Stable—The Contribution of Human Basal Ganglia and Prefrontal Cortex to Working Memory , 2010, The Journal of Neuroscience.

[33]  Philip D. Harvey,et al.  White matter changes in schizophrenia: evidence for myelin-related dysfunction. , 2003, Archives of general psychiatry.

[34]  R. C. Oldfield.  The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[35]  H. Walter,et al.  Dorsolateral prefrontal cortex modulates striatal reward encoding during reappraisal of reward anticipation. , 2011, Cerebral cortex.

[36]  J. Lieberman,et al.  Anatomical Abnormalities in Gray and White Matter of the Cortical Surface in Persons with Schizophrenia , 2013, PloS one.

[37]  W. Dillo,et al.  Maladaptive connectivity of Broca’s area in schizophrenia during audiovisual speech perception: An fMRI study , 2011, Neuroscience.

[38]  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.

[39]  H. Heuer,et al.  Significance test for comparing complex microbial community fingerprints using pairwise similarity measures. , 2004, Journal of Microbiological Methods.

[40]  E. Bullmore,et al.  The relationship between regional and inter‐regional functional connectivity deficits in schizophrenia , 2012, Human brain mapping.

[41]  Yuan Zhou,et al.  Functional disintegration in paranoid schizophrenia using resting-state fMRI , 2007, Schizophrenia Research.

[42]  Timothy P. L. Roberts,et al.  Test-Retest Reliability of Computational Network Measurements Derived from the Structural Connectome of the Human Brain , 2013, Brain Connect..

[43]  Miseon Shim,et al.  Disruptions in small-world cortical functional connectivity network during an auditory oddball paradigm task in patients with schizophrenia , 2014, Schizophrenia Research.

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

[45]  Timothy Edward John Behrens,et al.  Diffusion-Weighted Imaging Tractography-Based Parcellation of the Human Lateral Premotor Cortex Identifies Dorsal and Ventral Subregions with Anatomical and Functional Specializations , 2007, The Journal of Neuroscience.

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

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

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

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

[50]  Michael W. Cole,et al.  Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change , 2015, The Journal of Neuroscience.

[51]  D. Barch,et al.  Basal ganglia and thalamic morphology in schizophrenia and bipolar disorder , 2014, Psychiatry Research: Neuroimaging.

[52]  Jonathan D. Power,et al.  Functional Brain Networks Develop from a “Local to Distributed” Organization , 2009, PLoS Comput. Biol..

[53]  Mark W. Woolrich,et al.  Probabilistic diffusion tractography with multiple fibre orientations: What can we gain? , 2007, NeuroImage.

[54]  Edward T. Bullmore,et al.  Overall brain connectivity maps show cortico subcortical abnormalities in schizophrenia , 2011 .

[55]  Marcus Kaiser,et al.  Integrating Temporal and Spatial Scales: Human Structural Network Motifs Across Age and Region of Interest Size , 2011, Front. Neuroinform..

[56]  Timothy Edward John Behrens,et al.  Reliable identification of the auditory thalamus using multi-modal structural analyses , 2006, NeuroImage.

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

[58]  Yuan Zhou,et al.  Anatomical insights into disrupted small-world networks in schizophrenia , 2012, NeuroImage.

[59]  W. Singer,et al.  Neuronal Dynamics and Neuropsychiatric Disorders: Toward a Translational Paradigm for Dysfunctional Large-Scale Networks , 2012, Neuron.

[60]  M. Chun,et al.  Functional connectome fingerprinting: Identifying individuals based on patterns of brain connectivity , 2015, Nature Neuroscience.

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

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

[63]  Philip D. Harvey,et al.  The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery , 2004, Schizophrenia Research.

[64]  Hongbing Lu,et al.  Anterior cingulate cortex-related connectivity in first-episode schizophrenia: a spectral dynamic causal modeling study with functional magnetic resonance imaging , 2015, Front. Hum. Neurosci..

[65]  D. Hubl,et al.  Pathways that make voices: white matter changes in auditory hallucinations. , 2004, Archives of general psychiatry.

[66]  B. Mulsant,et al.  Effects of antipsychotic D2 antagonists on long-term potentiation in animals and implications for human studies , 2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[67]  Mark S. Cohen,et al.  Decreased small-world functional network connectivity and clustering across resting state networks in schizophrenia: an fMRI classification tutorial , 2013, Front. Hum. Neurosci..

[68]  Timothy Edward John Behrens,et al.  Between session reproducibility and between subject variability of diffusion MR and tractography measures , 2006, NeuroImage.

[69]  Stephen M. Smith,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[70]  Thomas E. Nichols,et al.  Nonparametric permutation tests for functional neuroimaging: A primer with examples , 2002, Human brain mapping.

[71]  P. Thiran,et al.  Mapping Human Whole-Brain Structural Networks with Diffusion MRI , 2007, PloS one.

[72]  D. Weinberger,et al.  Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. , 1992, The American journal of psychiatry.

[73]  J. Coyle,et al.  Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia , 2011, Neuroscience & Biobehavioral Reviews.

[74]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

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

[76]  George Bartzokis,et al.  Schizophrenia: Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation , 2002, Neuropsychopharmacology.