The online version contains supplementary material
available at https://doi.org/10.1038/s41380-023-02039-6The human brain’s resting-state functional connectivity (rsFC) provides stable trait-like measures of differences in the perceptual,
cognitive, emotional, and social functioning of individuals. The rsFC of the prefrontal cortex is hypothesized to mediate a person’s
rational self-government, as is also measured by personality, so we tested whether its connectivity networks account for
vulnerability to psychosis and related personality configurations. Young adults were recruited as outpatients or controls from the
same communities around psychiatric clinics. Healthy controls (n = 30) and clinically stable outpatients with bipolar disorder
(n = 35) or schizophrenia (n = 27) were diagnosed by structured interviews, and then were assessed with standardized protocols of
the Human Connectome Project. Data-driven clustering identified five groups of patients with distinct patterns of rsFC regardless of
diagnosis. These groups were distinguished by rsFC networks that regulate specific biopsychosocial aspects of psychosis: sensory
hypersensitivity, negative emotional balance, impaired attentional control, avolition, and social mistrust. The rsFc group differences
were validated by independent measures of white matter microstructure, personality, and clinical features not used to identify the
subjects. We confirmed that each connectivity group was organized by differential collaborative interactions among six prefrontal
and eight other automatically-coactivated networks. The temperament and character traits of the members of these groups
strongly accounted for the differences in rsFC between groups, indicating that configurations of rsFC are internal representations of
personality organization. These representations involve weakly self-regulated emotional drives of fear, irrational desire, and
mistrust, which predispose to psychopathology. However, stable outpatients with different diagnoses (bipolar or schizophrenic
psychoses) were highly similar in rsFC and personality. This supports a diathesis-stress model in which different complex adaptive
systems regulate predisposition (which is similar in stable outpatients despite diagnosis) and stress-induced clinical dysfunction
(which differs by diagnosis).EU FEDER grants through the Spanish Ministry of Science and Technology
PID2021-125017OB-I00,
RTI2018-098983-B-I00,
D43 TW011793-06A1,
PID2021-125017OB-I00,
RTI2018-098983-B-I00,
D43 TW011793-06A1United States Department of Health & Human Services
National Institutes of Health (NIH) - USA
R01-MH124060Psychosis-Risk Outcomes Network
U01 MH12463
