Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia

Abstract

We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.

Fig. 1.

Task-related suppression in default network regions. (A) Greater activation during rest than task (2-back WM) in PCC/precuneus and MPFC for controls (CON), relatives (REL), and patients (SZ). (B) MPFC region (peak: [12, 57, −6]) showing significant task-related suppression differences among groups. (C) Task-related suppression (with 95% confidence intervals) of MPFC region during 2-back and 0-back conditions. There was significantly more task suppression for controls than for relatives and patients on both WM tasks. The [x, y, z] locations are listed in Montreal Neurological Institute coordinates.

Fig. 2.

Functional connectivity with default network during rest. (A) Areas showing positive connectivity with default network areas (averaged across 4 ROI seeds) in controls (CON), relatives (REL), and patients (SZ). (B) (Middle) Regions within default network showing significant connectivity differences between groups. Connectivity with default network (with 95% confidence intervals) in MPFC (Right, peak: [−12, 54, 15]) and PCC/precuneus (Left, peak: [−9, −51, 48]). There was significantly more connectivity with MPFC for relatives and patients than for controls and significantly more connectivity with PCC/precuneus for patients than for controls.

Fig. 3.

Functional connectivity during rest correlated with psychopathology in patients. (Middle) Whole-brain correlation between severity of psychopathology (composite SAPS score of positive symptomology) and strength of connectivity with the MPFC seed z-maps. Peaks in PCC/precuneus BA7 [−3, −57, 36], P = 0.003, r = 0.76 (Left) and in MPFC [−6, 51, 6], P < 0.001, r = 0.88 (Right).