Brain connectivity is not only lower but different in schizophrenia: a combined anatomical and functional approach

Abstract

Background: Schizophrenia is hypothesized to involve disordered connectivity between brain regions. Currently, there are no direct measures of brain connectivity; functional and structural connectivity used separately provide only limited insight. Simultaneous measure of anatomical and functional connectivity and its interactions allow for better understanding of schizophrenia-related alternations in brain connectivity.

Methods: Twenty-seven schizophrenia patients and 27 healthy control subjects underwent magnetic resonance imaging with resting state functional magnetic resonance imaging and diffusion tensor imaging. Separate functional and anatomical connectivity maps were calculated and combined for each subject. Global, regional, and voxel measures and K-means network analysis were employed to identify group differences and correlation with clinical symptoms.

Results: A global connectivity analysis indicated that patients had lower anatomical connectivity and lower coherence between the two imaging modalities. In schizophrenia these group differences correlated with clinical symptom severity. Although anatomical connectivity nearly uniformly decreased, functional connectivity in schizophrenia was lower for some connections (e.g., middle temporal gyrus) and higher for others (e.g., cingulate and thalamus). Within the default mode network (DMN) two separate subsystems can be identified. Schizophrenia patients showed decoupling between structural and functional connectivity that can be localized to networks originating in posterior cingulate cortex as well as in the task-positive network and one of the DMN components.

Conclusions: Combining two measures of brain connectivity provides more comprehensive descriptions of altered brain connectivity underlying schizophrenia. Patients show deficits in white matter anatomy, but functional connectivity alterations are more complex. Fusion of both methods allows identification of subsystems showing both increased and decreased functional connectivity.

Figure 1

Connections between brain regions that differ between schizophrenia patients and controls in measure of anatomical (measured with DTI) connectivity (Table 2). Only connections for which anatomical connectivity was lower in patients than control were significant at p<0.01 for both the group difference and for correlation to clinical symptoms in clinical group.

Figure 2

Connections between brain regions that differ between schizophrenia patients and controls in measure of functional connectivity (Table 2). Red lines represent connections for which the functional connectivity was higher in patients, while for green line connectivity was higher in controls. All shown connections showed significance of p<0.02 for both the group difference and for correlation to clinical symptoms in clinical group.

Figure 3

Components detected by k-means cluster analysis of connectivity. The functional resting connectivity led to identification of the default mode network (DMN), depicted in red and orange and its counter part – the task-positive network shown in yellow. The anatomical connectivity analysis further subdivided the DMN into two components : DMN-1 includes anterior cingulate and portions of posterior cingulate, shown in orange, is characterized by higher functional connectivity in schizophrenia and no change in anatomical connectivity between groups. DMN-2 includes parts of bilateral parietal cortices and bilateral dorsolateral prefrontal cortex (DLPFC) is characterized anatomical connectivity lower in schizophrenia.

Figure 4

Mean functional (left column) and anatomical (right column) connectivity averaged over all voxel pairs within the DMN-1 (top row) and DMN-2 (bottom row) subcomponent of Default Mode Network. Green crosses represent values for healthy controls. Only voxel pairs separated by distance of more than 24 mm are included in component averaging.