title: Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia.
abstract: Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical-subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.
authors.affiliation: The Mind Research Network, Albuquerque, NM, USA.
authors.forename: E
authors.initials: E
authors.lastname: Damaraju
authors.affiliation: The Mind Research Network, Albuquerque, NM, USA ; K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: E A
authors.initials: EA
authors.lastname: Allen
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Belger
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA ; San Francisco VA Medical Center, San Francisco, CA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: McEwen
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA ; San Francisco VA Medical Center, San Francisco, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Mathalon
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Mueller
authors.affiliation: Yale University, School of Medicine, New Haven, CT, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Pearlson
authors.affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Potkin
authors.affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Preda
authors.affiliation: Department of Psychology, Georgia State University, GA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Turner
authors.affiliation: Department of Psychiatry, University of Iowa, IA, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Vaidya
authors.affiliation: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: van Erp
authors.affiliation: The Mind Research Network, Albuquerque, NM, USA ; Department of ECE, University of New Mexico, NM, USA.
authors.forename: V D
authors.initials: VD
authors.lastname: Calhoun
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology*; D012559:Schizophrenia / Q000503:physiopathology*