Default-mode network dysfunction and self-referential processing in healthy siblings of schizophrenia patients

Abstract The default-mode network (DMN) of the brain shows highly coherent intrinsic activity in healthy subjects and is implicated in self-referential processing important for social cognitive functioning. Schizophrenia patients show abnormal resting-state connectivity within the DMN and this aberrant connectivity is thought to contribute to difficulties in self-referential and introspective processing. Subjects at increased genetic risk of developing schizophrenia, including unaffected siblings of patients, also exhibit brain abnormalities and impaired social cognitive processing. However, it is unclear whether resting-state connectivity within the DMN is abnormal in these subjects. Here, we investigate resting-state DMN connectivity in siblings and whether this is related to the functioning of the network during self-referential processing. Brain activity was measured using functional MRI in 25 unaffected siblings of patients with schizophrenia and 25 healthy controls during an 8-minute resting-state period and during a self-referential processing task in which the subjects had to indicate whether a trait adjective (e.g. “lazy”) described their personality (self-referential condition) or whether the trait was socially desirable (non-referential condition). Compared with controls, siblings showed exaggerated connectivity during resting-state between the midline areas of the DMN. Moreover, they failed to adequately modulate connectivity between these areas during self-referential processing. No abnormalities in activation during self-referential processing were observed. These findings suggest that subjects at increased genetic risk of developing schizophrenia exhibit abnormal intrinsic connectivity within the midline DMN and that this is associated with aberrant interactions between these regions during self-referential processing.