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.
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