Disrupted axonal fiber connectivity in schizophrenia

Abstract

Background: Schizophrenia is believed to result from abnormal functional integration of neural processes thought to arise from aberrant brain connectivity. However, evidence for anatomical dysconnectivity has been equivocal, and few studies have examined axonal fiber connectivity in schizophrenia at the level of whole-brain networks.

Methods: Cortico-cortical anatomical connectivity at the scale of axonal fiber bundles was modeled as a network. Eighty-two network nodes demarcated functionally specific cortical regions. Sixty-four direction diffusion tensor-imaging coupled with whole-brain tractography was performed to map the architecture via which network nodes were interconnected in each of 74 patients with schizophrenia and 32 age- and gender-matched control subjects. Testing was performed to identify pairs of nodes between which connectivity was impaired in the patient group. The connectional architecture of patients was tested for changes in five network attributes: nodal degree, small-worldness, efficiency, path length, and clustering.

Results: Impaired connectivity in the patient group was found to involve a distributed network of nodes comprising medial frontal, parietal/occipital, and the left temporal lobe. Although small-world attributes were conserved in schizophrenia, the cortex was interconnected more sparsely and up to 20% less efficiently in patients. Intellectual performance was found to be associated with brain efficiency in control subjects but not in patients.

Conclusions: This study presents evidence of widespread dysconnectivity in white-matter connectional architecture in a large sample of patients with schizophrenia. When considered from the perspective of recent evidence for impaired synaptic plasticity, this study points to a multifaceted pathophysiology in schizophrenia encompassing axonal as well as putative synaptic mechanisms.

Conflict of interest statement

All other authors reported no biomedical financial interests or potential conflicts of interest.

Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Overview of methodology. (I) The tractographic maps show the set of all cortico-cortical streamlines (normalized to Montreal Neurological Institute space). II. Connectivity matrices were populated and (III) binarized, where matrix element (i,j) quantifies the connectivity (i.e., number of interconnecting streamlines) between node pair (i,j). The rows/columns of the connectivity matrix and the binarized connectivity matrix were ordered such that all left hemisphere nodes occupied the first 41 rows/columns. Hence, the two strongly interconnected sub-blocks along the matrix diagonal exclusively involve intrahemispheric connections, whereas the two off-diagonal sub-blocks involve interhemispheric connections. Note the strong contralateral connection profile indicated by the connections along the main diagonal of each interhemispheric sub-block. All matrices represent group averages. (IV) The network-based statistic (Methods and Materials) was used to identify impaired connections.

Figure 2

Graph measures describing topological attributes of corticocortical connectivity were quantified in a sample of patients with schizophrenia. The binarizing threshold (horizontal axis) determined the minimum number of streamlines that needed to interconnect a pair of nodes for a connection to be assumed. Data points marked with a star indicate a significant difference (p < .05) between patients and control subjects. Because the same hypothesis was tested at each threshold, correction for multiple comparisons was not performed. Note that T = 0 indicates at least one or more streamlines must be present for a link to be drawn. (I) Nodal degree and (II) network efficiency were reduced in schizophrenia for all binarizing thresholds considered. A trend for increased: (III) clustering, (IV) path length, and (V) small-worldness was demonstrated in patients but was not significant at most thresholds. For binarizing thresholds exceeding T = 4, the graph for at least one subject broke apart into two or more disconnected subgraphs. The binarizing threshold was therefore constrained when considering path length, clustering, and small-worldness. The clustering coefficient and path length were normalized with degree-matched random graphs.

Figure 3

A linear association was found in the control group between intelligence quotient (IQ), estimated with the Wechsler test of adult reading, and three attributes of network organization: namely, (I) global efficiency, (II) characteristic path length, and (III) average clustering coefficient. No associations with IQ were found in the patient group. Spearman’s rank correlation coefficient (rs) was used to assess the significance of an association. Two control subjects were excluded from this correlation analysis, because IQ data were not available for them.

Figure 4

Impaired connections in patients with schizophrenia satisfying a 10% false discovery rate. Anterior-posterior fibers: green; left–right: red; and superior-inferior: blue. Node abbreviations: (D) right angular; (J) left cuneus; (K) right cuneus; (O) right superior frontal; (P) left superior frontal; (Q) right superior occipital; (R) right middle temporal; (S) left inferior triangularis frontal; and (T) left insula.

Figure 5

Schematic of the frontal-parietal/occipital network that was impaired in schizophrenia (p = .021 ± .004, corrected). Each connection comprising this network was impaired in patients but not in control subjects. Left: uniquely colored nodes and streamline representation of interconnecting fiber bundles. Anterior-posterior fibers: green; left–right: red; and superior-inferior: blue. Right: planar graph representation, where each node is depicted as a circle positioned at its node’s center of gravity. Note that the positioning of some posterior nodes was slightly shifted from the true center of gravity to avert overlapping. Top: sagittal, left hemisphere. Bottom: axial. Node abbreviations: (A) right medial orbital frontal, (B) left superior medial frontal, (C) left anterior cingulate, (D) right angular, (E) right superior occipital, (F) left precuneus, (G) right superior temporal, (H) right calcarine, (I) left calcarine, (J) left cuneus, (K) right cuneus, (L) left middle occipital, (M) left lingual, and (N) left fusiform.