Summary Some of the most debilitating and detrimental aspects of serious mental illnesses (SMI) are the 1) social isolation (low numbers of social contacts) and 2) the subjective experiences of social disconnection (loneliness) that frequently accompany these conditions. Social isolation and loneliness have an immense impact on day-to-day functioning in SMI and are associated with an overall poor quality of life and early mortality. Currently there are no available interventions that can prevent or reverse these devastating consequences of SMI. This may be in part because the underlying neural and psychological mechanisms of social isolation and loneliness in SMI are poorly understood. However, recent clues from studies employing advanced neuroimaging and digital assessment approaches can provide the basis for a new approach to investigating such mechanisms. Prior work has indicated that objective isolation and loneliness are correlated but also somewhat independent. Recent neuroimaging findings support this model, revealing that social isolation and loneliness have both shared and distinct neural correlates. However, it is also clear that these are not static phenomena; smartphone-based assessments have revealed transient, dynamic changes in social isolation and loneliness. Individual differences in the anticipation of rejection are associated with momentary experiences of loneliness, greater avoidance and subsequent increases in social isolation. Thus, in the current proposal, we plan to comprehensively measure both the relatively stable neural and behavioral predictors of social isolation and loneliness, as well as the moment-to-moment changes in these experiences, in 60 individuals with SMI and 60 without SMI. In Aim 1 of the proposed project, we will show that the higher levels of social isolation and loneliness in SMI are linked to shared and distinct neural responses to social stimuli, with lower responses of social perception-related circuitry (medial temporal lobe regions) linked to social isolation, and lower responses of reward-related circuitry (basal ganglia regions) linked to loneliness. In Aim 2, we will measure transient changes in social isolation and loneliness with smartphone assessments using a longitudinal “burst” design. Lastly, in Aim 3, we will determine how the correlates of social isolation and loneliness identified in Aims 1 and 2 are linked to each other and to levels of functioning, and measure the stability of these associations over time. Therefore, in this project, we plan to demonstrate that fundamental neural and behavioral processes drive momentary variation in the experience of social isolation and loneliness, and directly impact functioning and quality of life in SMI. In follow-up work, these findings can be used as quantitative targets in studies of novel interventions which aim to address these major causes of disability and early mortality.