Abnormal Rich Club Organization and Functional Brain Dynamics in Schizophrenia

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Importance: The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain’s integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia.

Objective  To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics.

Design  Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls.

Results  Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity–functional connectivity coupling.

Conclusions  Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.

The human brain is a complex network of structurally and functionally interconnected regions. Studies examining the brain’s underlying network structure are motivated by the notion that brain function is not solely attributable to the properties of individual regions or individual connections but rather emerges from the network organization of the brain as a whole, the human connectome. Conversely, brain dysfunction may result from abnormal wiring of the brain’s network.

The notion that schizophrenia, a severe psychiatric disorder characterized by hallucinations, delusions, loss of initiative, and cognitive dysfunction, may relate to disconnectivity among brain regions has a long history. As cited by Stephan, Wernicke was among the first to suggest that schizophrenia may involve anatomical disruption of association pathways. Bleuler, who coined the term schizophrenia, hypothesized that decoupling of psychological processes might be the primary cause of the disease. Lately, studies using imaging techniques, such as diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI), have reported widespread disconnectivity in patients, in particular reduced integrity of frontal and temporal white matter connections and affected functional coupling of the default mode network.

A few highly connected and central regions, the so-called hub nodes, have a key role in the global topology of the brain’s network. Previous network studies report disruptions in the overall organization of structural connectivity (SC) and functional connectivity (FC) in patients with schizophrenia, together with a less centralized position of some of these hubs in the frontal, temporal, and parietal cortex. However, it remains unknown whether reduced connectivity of hubs constitutes a nonspecific generalized phenomenon involving white matter connectivity to and from all brain regions or whether this disruption disproportionally involves pathways that link highly connected regions. In the healthy brain, hubs have been found to be densely interconnected, together forming a central core or rich club, with rich club connections having a pivotal role in interregional brain communication. We test the hypothesis that disturbed wiring of this central rich club may contribute to the pathophysiology of schizophrenia.

Using neuroimaging data in a group of 48 patients and 45 healthy controls, we examined potentially abnormal connectivity of the brain’s rich club and the relationship of a disruption of this communication backbone to (reduced) levels of global communication capacity and changed functional dynamics in the brain networks of patients. An independently acquired data set of patients and controls (41 patients and 51 controls) was used to replicate possible findings.

Martijn P. van den Heuvel, PhD; Olaf Sporns, PhD; Guusje Collin, MD; Thomas Scheewe, PhD; René C. W. Mandl, PhD; Wiepke Cahn, MD, PhD; Joaquín Goñi, PhD; Hilleke E. Hulshoff Pol, PhD; René S. Kahn, MD, PhD

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