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 taskbased 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 underand 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.