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Original Investigation |

Abnormal Rich Club Organization and Functional Brain Dynamics in Schizophrenia

Martijn P. van den Heuvel, PhD1; Olaf Sporns, PhD2; Guusje Collin, MD1; Thomas Scheewe, PhD1; René C. W. Mandl, PhD1; Wiepke Cahn, MD, PhD1; Joaquín Goñi, PhD2; Hilleke E. Hulshoff Pol, PhD1; René S. Kahn, MD, PhD1
[+] Author Affiliations
1Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands
2Department of Psychological and Brain Sciences, Indiana University, Bloomington
JAMA Psychiatry. 2013;70(8):783-792. doi:10.1001/jamapsychiatry.2013.1328.
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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.

Setting  Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.

Participants  Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings.

Main Outcome(s) and Measures  Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics.

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.

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Figures

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Figure 1.
The Analysis Steps

A, Individual T1 images were used for automatic classification of gray and white matter tissue and parcellation of the cortex into 68 distinct brain regions, forming the nodes of the individual brain networks. B, Streamline tractography was applied to the diffusion tension imaging (DTI) data to reconstruct cortico-cortical white matter pathways. From the set of reconstructed streamlines, streamlines that interconnected region i and j from the set of 68 or 82 regions were taken as an edge between node i and j in the structural brain network. Streamline count was taken to represent the weight of the connection and was aggregated into a structural connectivity (SC) matrix. C, Functional connectivity (FC) between node i and j was computed as their level of correlation between their resting-state function magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) time series, resulting in a matrix FC. D, The topologic organization of the resulting individual structural brain networks was examined, including (among other metrics) measurements of the rich club, global strength, and global efficiency (top). The level of coupling between SC and FC was examined by computing the level of correlation between the weights of (existing) structural connections and their functional counterparts. This correlation is referred to as the level of SC-FC coupling. At the group level, values were examined between the patient and control groups (for both the principal and replication data sets). Statistical evaluation was performed using permutation testing (see Methods and eMethods in Supplement).

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Figure 2.
Rich Club Organization

A, Group-averaged rich club curve for controls (white) and patients (blue). Patients had a significantly reduced rich club organization for the range k = 26 to k = 28, reflecting a lower level of connectivity between central hubs of the brain (cortical: P = .003; whole brain: P = .04; 10 000 permutations) B, Confirming previous findings, rich club members included the bilateral precuneus, superior frontal cortex, superior parietal cortex, and the insula in both the healthy and patient populations. This figure is based on the group-averaged cortical network in controls (at a rich club level of k >15).53 C, Edges across individual brain networks (both controls and patients) were divided into 3 distinct classes: rich club connections linking rich club members (red), feeder connections linking rich club members to non–rich club members (orange), and local connections connecting non–rich club members (yellow edges). Examining the density of rich club, feeder, and local connections between the populations of controls and patients revealed a significant reduction in rich club density in patients but no significant effect in density of feeder and local connections. The figure shows mean (SD) density values for each of the 3 classes, scaled to the mean density values of the control group. ROI indicates region of interest.

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Figure 3.
Replication Data Set

A, Group-averaged rich club curve of controls (white) and patients (blue) of the replication data set (n = 41 patients and 51 controls). B, Global graph metrics (cortex network) of controls (dark blue) and patients (light blue). No differences were found between patients and controls on connectivity strength (S), global efficiency (GE), or clustering (C). mod indicates modularity. C, Density of rich club, feeder, and local connections. Confirming the findings of the principal data set, patients had a significant reduction in rich club density (*P < .05). D, Structural connectivity (SC)–functional connectivity (FC) coupling for patients and controls (data of 39 patients and 35 controls). Confirming the findings of the principal data set, patients had an increased level of SC-FC coupling.

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Figure 4.
Global Efficiency and Rich Club Density

A, General topologic graph metrics. Patients had reduced levels of connectivity strength (S) and global efficiency (GE) and increased levels of local clustering (C) and modularity (mod) (*P < .05, permutation testing, 10 000 permutations, effects of GE remained significant after volume and global S correction, cortex network). B, Across the control (top) and patient (bottom) populations, global efficiency (y-axis) was significantly correlated with rich club density (x-axis), after correcting for overall differences in global connectivity S.

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Figure 5.
Structural Connectivity (SC)–Functional Connectivity (FC) Coupling

A, Patients revealed a significant increase in SC-FC coupling compared with healthy controls (*P < .05, permutation testing, 10 000 permutations). B, In the patient population (bottom), lower levels of normalized rich club density (measured as the fraction of streamlines inside the rich club relative to the total number of streamlines, corrected for volume effects, blue) were associated with increased SC-FC coupling. This association was absent in the control population (top).

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