title: Altered Hub Functioning and Compensatory Activations in the Connectome: A Meta-Analysis of Functional Neuroimaging Studies in Schizophrenia.
abstract: BACKGROUND
  Functional neuroimaging studies of schizophrenia have identified abnormal activations in many brain regions. In an effort to interpret these findings from a network perspective, we carried out a meta-analysis of this literature, mapping anatomical locations of under- and over-activation to the topology of a normative human functional connectome.
  
  
  METHODS
  We included 314 task-based functional neuroimaging studies including more than 5000 patients with schizophrenia and over 5000 controls. Coordinates of significant under- or over-activations in patients relative to controls were mapped to nodes of a normative connectome defined by a prior meta-analysis of 1641 functional neuroimaging studies of task-related activation in healthy volunteers.
  
  
  RESULTS
  Under-activations and over-activations were reported in a wide diversity of brain regions. Both under- and over-activations were significantly more likely to be located in hub nodes that constitute the "rich club" or core of the normative connectome. In a subset of 121 studies that reported both under- and over-activations in the same patients, we found that, in network terms, these abnormalities were located in close topological proximity to each other. Under-activation in a peripheral node was more frequently associated specifically with over-activation of core nodes than with over-activation of another peripheral node.
  
  
  CONCLUSIONS
  Although schizophrenia is associated with altered brain functional activation in a wide variety of regions, abnormal responses are concentrated in hubs of the normative connectome. Task-specific under-activation in schizophrenia is accompanied by over-activation of topologically central, less functionally specialized network nodes, which may represent a compensatory response.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; nicolas.crossley@kcl.ac.uk.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Crossley
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK;
authors.forename: Andrea
authors.initials: A
authors.lastname: Mechelli
authors.affiliation: Department of Neuroimaging Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Mathematics and Statistics, Boston University, Boston, MA;
authors.forename: Cedric
authors.initials: C
authors.lastname: Ginestet
authors.affiliation: Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, University of Cambridge, Cambridge, UK;
authors.forename: Mikail
authors.initials: M
authors.lastname: Rubinov
authors.affiliation: Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK; ImmunoPsychiatry, Alternative Discovery and Development, GlaxoSmithKline, Cambridge, UK These authors contributed equally to this work.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; These authors contributed equally to this work.
authors.forename: Philip
authors.initials: P
authors.lastname: McGuire
mesh_terms: D001921:Brain / Q000503:physiopathology*; D063132:Connectome; D006801:Humans; D012559:Schizophrenia / Q000503:physiopathology*
keywords: connectome; fMRI; graph analysis; hubs; schizophrenia