The Triple Network Model of psychopathology identifies the salience network (SN), central executive network (CEN), and default mode network (DMN) as key networks underlying the pathophysiology of psychiatric disorders. In particular, abnormal SN-initiated network switching impacts the engagement and disengagement of the CEN and DMN, and is proposed to lead to the generation of psychosis symptoms. Between-network connectivity has been shown to be abnormal in both substance use disorders (SUD) and psychosis. However, none have studied how SUD affects connectivity between sub-networks of the DMN, SN, and CEN in early stage psychosis (ESP) patients. In this study, we collected data from 113 ESP patients and 50 healthy controls to investigate the effect of SUD on between-network connectivity. In addition, we performed sub-group analysis by exploring whether past SUD vs current SUD co-morbidity, or diagnosis (affective vs non-affective psychosis) had a modulatory effect. Connectivity between four network-pairs, consisting of sub-networks of the SN, CEN, and DMN, was significantly different between ESP patients and controls. Two patterns of connectivity were observed when patients were divided into sub-groups with current vs past SUD. In particular, connectivity between right CEN and the cingulo-opercular salience sub-network (rCEN-CON) showed a gradient effect where the severity of abnormalities increased from no history of SUD to past+ to current+. We also observed diagnosis-specific effects, suggesting non-affective psychosis patients were particularly vulnerable to effects of substance use on rCEN-CON connectivity. Our findings reveal insights into how comorbid SUD affects between-network connectivity and symptom severity in ESP.
