Variable global dysconnectivity and individual differences in schizophrenia

Abstract

Background: A fundamental challenge for understanding neuropsychiatric disease is identifying sources of individual differences in psychopathology, especially when there is substantial heterogeneity of symptom expression, such as is found in schizophrenia (SCZ). We hypothesized that such heterogeneity might arise in part from consistently widespread yet variably patterned alterations in the connectivity of focal brain regions.

Methods: We used resting state functional connectivity magnetic resonance imaging to identify variable global dysconnectivity in 23 patients with DSM-IV SCZ relative to 22 age-, gender-, and parental socioeconomic status-matched control subjects with a novel global brain connectivity method that is robust to high variability across individuals. We examined cognitive functioning with a modified Sternberg task and subtests from the Wechsler Adult Intelligence Scale-Third Edition. We measured symptom severity with the Scale for Assessment of Positive and Negative Symptoms.

Results: We identified a dorsolateral prefrontal cortex (PFC) region with global and highly variable dysconnectivity involving within-PFC underconnectivity and non-PFC overconnectivity in patients. Variability in this "under/over" pattern of dysconnectivity strongly predicted the severity of cognitive deficits (matrix reasoning IQ, verbal IQ, and working memory performance) as well as individual differences in every cardinal symptom domain of SCZ (poverty, reality distortion, and disorganization).

Conclusions: These results suggest that global dysconnectivity underlies dorsolateral PFC involvement in the neuropathology of SCZ. Furthermore, these results demonstrate the possibility that specific patterns of dysconnectivity with a given network hub region might explain individual differences in symptom presentation in SCZ. Critically, such findings might extend to other neuropathologies with diverse presentation.

Figure 1

Within–prefrontal cortex (PFC) dysconnectivity in schizophrenia. (A) The weighted global brain connectivity method (14) was used to assess within-PFC dysconnectivity, which involves assigning each voxel its average connectivity to all other voxels. Two regions—right dorsolateral prefrontal cortex (DLPFC) and left inferior frontal junction (IFJ)—showed reduced within-PFC connectivity for patients compared with control subjects. (B) The average connection strengths for each voxel within the two regions are depicted in histograms. The between-group shift in distributions indicates both decreased positive connectivity and increased negative connectivity for patients. See Figure S4 in Supplement 1 for the basic connectivity pattern of the DLPFC region.

Figure 2

The DLPFC is underconnected with prefrontal cortex and overconnected with posterior cortex in schizophrenia (SCZ). (A) Individuals with SCZ had significantly reduced DLPFC connectivity with several other PFC regions compared with control subjects. In contrast, individuals with SCZ had significantly increased DLPFC connectivity with several regions of posterior cortex (except for right midtemporal cortex and posterior cerebellum), predominantly involving primary and secondary sensory regions. (B) Two representative regions are shown to illustrate the positive/negative shift in DLPFC connectivity for patients relative to control subjects. Region 1 is medial, superior, and anterior PFC, whereas Region 2 is superior occipital gyrus. See Figure S3 in Supplement 1 for the equivalent figure with inferior frontal junction as the seed region. Abbreviations as in Figure 1.

Figure 3

The DLPFC connectivity correlates with cognitive measures differentially for PFC and posterior cortex. Three cognitive measures (Wechsler Adult Intelligence Scale [WAIS] matrix IQ, WAIS vocabulary IQ, and working memory [WM] task accuracy) and three symptom domain measures (poverty, reality distortion, and disorganization) were included in a DLPFC-connectivity correlation analysis. Only the cognitive measures correlated significantly with the within-PFC/non-PFC DLPFC connectivity estimates (p < .05, false discovery rate corrected for multiple comparisons). None of these correlations were statistically significant in control subjects. This pattern of correlations is consistent with the pattern of DLPFC dysconnectivity (Figure 2) in that the more the connectivity patterns of patients resemble that of the control subjects, the more their cognitive abilities look like those of the control subjects. In other words, improved cognition is predicted by increased connectivity with underconnected PFC as well as decreased connectivity with overconnected posterior cortex. Abbreviations as in Figure 1.

Figure 4

Dorsolateral prefrontal cortex (DLPFC) connectivity correlates with all symptom domains of schizophrenia. The DLPFC connectivity correlations with symptoms and cognitive measures were assessed across all voxels. All symptom domains (and cognitive measures) (Table S3 in Supplement 1) were significantly correlated with multiple regions (p < .05, family-wise error corrected). In contrast, inferior frontal junction connectivity only correlated with disorganization in a single region (Table S5 in Supplement 1). These results demonstrate the utility of global brain connectivity for localizing globally dysconnected regions with high individual variability related to individual differences in symptoms.