Anne L Wheeler1, Michèle Wessa2, Philip R Szeszko3, George Foussias4, M Mallar Chakravarty5, Jason P Lerch6, Pamela DeRosse3, Gary Remington4, Benoit H Mulsant7, Julia Linke2, Anil K Malhotra3, Aristotle N Voineskos1. 1. Kimel Family Translational Imaging Genetics Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Schizophrenia Division of the Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto. 2. Department of Clinical Psychology and Neuropsychology, Psychological Institute, Johannes-Gutenberg University Mainz, Mainz, Germany. 3. Center for Translational Psychiatry, The Feinstein Institute for Medical Research, Manhasset, New York6Division of Psychiatry Research, The Zucker Hillside Hospital, Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York7Hofstra. 4. Schizophrenia Division of the Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada8Institute of Medical Science, University of Toronto, T. 5. Kimel Family Translational Imaging Genetics Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada10Institute of Biomaterials and Biom. 6. Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada12Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 7. Kimel Family Translational Imaging Genetics Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada9Campbell Family Research Institute.
Abstract
IMPORTANCE: The clinical heterogeneity of schizophrenia has hindered neurobiological investigations aimed at identifying neural correlates of the disorder. OBJECTIVE: To identify network-based biomarkers across the spectrum of impairment present in schizophrenia by separately evaluating individuals with deficit and nondeficit subtypes of this disorder. DESIGN, SETTING, AND PARTICIPANTS: A university hospital network-based neuroimaging study was conducted between February 1, 2007, and February 28, 2012. Participants included patients with schizophrenia (n = 128) and matched healthy controls (n = 130) from two academic centers and patients with bipolar I disorder (n = 39) and matched healthy controls (n = 43) from a third site. Patients with schizophrenia at each site in the top quartile on the proxy scale for the deficit syndrome were classified as having deficit schizophrenia and those in the bottom quartile were classified as having nondeficit schizophrenia. EXPOSURE: All participants underwent magnetic resonance brain imaging. MAIN OUTCOMES AND MEASURES: Network-level properties of cortical thickness were assessed in each group. Interregional cortexwide coupling was compared among the groups, and graph theoretical approaches were used to assess network density and node degree, betweenness, closeness, and eigenvector centrality. RESULTS: Stronger frontoparietal and frontotemporal coupling was found in patients with deficit schizophrenia compared with those with nondeficit schizophrenia (17 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate) and in patients with deficit schizophrenia compared with healthy controls (49 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate). Participants with nondeficit schizophrenia and bipolar I disorder did not show significant differences in coupling relative to those in the control groups (for both comparisons, 0 of 1326 pairwise relationships were significantly different, P > .05; 5% false discovery rate). The networks formed from patients with deficit schizophrenia demonstrated increased density of connections relative to controls and nondeficit patients (range, 0.07-0.45 in controls, 0.09-0.43 in the nondeficit group, and 0.18-0.67 in the deficit group). High centrality nodes were identified in the supramarginal, middle, and superior temporal and inferior frontal regions in deficit schizophrenia networks based on ranking of 4 centrality metrics. High centrality regions were identified as those that ranked in the top 10 in 50% or more of the thresholded networks in 3 or more of the centrality measures. Network properties were similar in patients with deficit schizophrenia from both study sites. CONCLUSIONS AND RELEVANCE: Patients with schizophrenia at one end of a spectrum show characteristic signatures of altered intracortical relationships compared with those at the other end of that spectrum, patients with bipolar I disorder, and healthy individuals. Cortical connectomic approaches can be used to reliably identify neural signatures in clinically heterogeneous groups of patients.
IMPORTANCE: The clinical heterogeneity of schizophrenia has hindered neurobiological investigations aimed at identifying neural correlates of the disorder. OBJECTIVE: To identify network-based biomarkers across the spectrum of impairment present in schizophrenia by separately evaluating individuals with deficit and nondeficit subtypes of this disorder. DESIGN, SETTING, AND PARTICIPANTS: A university hospital network-based neuroimaging study was conducted between February 1, 2007, and February 28, 2012. Participants included patients with schizophrenia (n = 128) and matched healthy controls (n = 130) from two academic centers and patients with bipolar I disorder (n = 39) and matched healthy controls (n = 43) from a third site. Patients with schizophrenia at each site in the top quartile on the proxy scale for the deficit syndrome were classified as having deficit schizophrenia and those in the bottom quartile were classified as having nondeficit schizophrenia. EXPOSURE: All participants underwent magnetic resonance brain imaging. MAIN OUTCOMES AND MEASURES: Network-level properties of cortical thickness were assessed in each group. Interregional cortexwide coupling was compared among the groups, and graph theoretical approaches were used to assess network density and node degree, betweenness, closeness, and eigenvector centrality. RESULTS: Stronger frontoparietal and frontotemporal coupling was found in patients with deficit schizophrenia compared with those with nondeficit schizophrenia (17 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate) and in patients with deficit schizophrenia compared with healthy controls (49 of 1326 pairwise relationships were significantly different, P < .05; 5% false discovery rate). Participants with nondeficit schizophrenia and bipolar I disorder did not show significant differences in coupling relative to those in the control groups (for both comparisons, 0 of 1326 pairwise relationships were significantly different, P > .05; 5% false discovery rate). The networks formed from patients with deficit schizophrenia demonstrated increased density of connections relative to controls and nondeficit patients (range, 0.07-0.45 in controls, 0.09-0.43 in the nondeficit group, and 0.18-0.67 in the deficit group). High centrality nodes were identified in the supramarginal, middle, and superior temporal and inferior frontal regions in deficit schizophrenia networks based on ranking of 4 centrality metrics. High centrality regions were identified as those that ranked in the top 10 in 50% or more of the thresholded networks in 3 or more of the centrality measures. Network properties were similar in patients with deficit schizophrenia from both study sites. CONCLUSIONS AND RELEVANCE: Patients with schizophrenia at one end of a spectrum show characteristic signatures of altered intracortical relationships compared with those at the other end of that spectrum, patients with bipolar I disorder, and healthy individuals. Cortical connectomic approaches can be used to reliably identify neural signatures in clinically heterogeneous groups of patients.
Authors: Colin Hawco; Joseph D Viviano; Sofia Chavez; Erin W Dickie; Navona Calarco; Peter Kochunov; Miklos Argyelan; Jessica A Turner; Anil K Malhotra; Robert W Buchanan; Aristotle N Voineskos Journal: Psychiatry Res Neuroimaging Date: 2018-06-09 Impact factor: 2.376
Authors: Carolina Makowski; John D Lewis; Claude Lepage; Ashok K Malla; Ridha Joober; Martin Lepage; Alan C Evans Journal: Cereb Cortex Date: 2019-12-17 Impact factor: 5.357
Authors: Aristotle N Voineskos; Daniel Felsky; Anne L Wheeler; David J Rotenberg; Melissa Levesque; Sejal Patel; Philip R Szeszko; James L Kennedy; Todd Lencz; Anil K Malhotra Journal: Schizophr Bull Date: 2015-12-27 Impact factor: 9.306
Authors: Joseph D Viviano; Robert W Buchanan; Navona Calarco; James M Gold; George Foussias; Nikhil Bhagwat; Laura Stefanik; Colin Hawco; Pamela DeRosse; Miklos Argyelan; Jessica Turner; Sofia Chavez; Peter Kochunov; Peter Kingsley; Xiangzhi Zhou; Anil K Malhotra; Aristotle N Voineskos Journal: Biol Psychiatry Date: 2018-04-13 Impact factor: 13.382
Authors: Javier Gomez-Pilar; Rodrigo de Luis-García; Alba Lubeiro; Henar de la Red; Jesús Poza; Pablo Núñez; Roberto Hornero; Vicente Molina Journal: Hum Brain Mapp Date: 2018-04-02 Impact factor: 5.038