PROJECT SUMMARY/ABSTRACT Social dysfunction is a core feature of schizophrenia. Many individuals with schizophrenia experience social disconnection, a lack of social contact with friends and family. Social disconnection is associated with reduced quality of life and many negative health effects, but most current treatments do little to address it. The development of new interventions is currently hindered by a lack of scientific understanding about how differences in the way individuals’ brains process information contribute to social disconnection, and a lack of biomarkers associated with social functioning. Recent research in non-clinical social neuroscience points to a compelling model that may help to explain social disconnection in schizophrenia and would provide the basis for a new biomarker of social dysfunction. Specifically, research using functional magnetic resonance imaging (fMRI) and inter-subject correlation (ISC) analysis methods shows that people whose brains tend to respond more normatively to dynamic, naturalistic stimuli (e.g., video clips) tend to have more social connections, perhaps because more other people experience the world in a similar way, whereas people with less normative responses tend to have fewer social connections. Converging evidence suggests that many individuals with schizophrenia are likely to have less normative responses to such naturalistic stimuli, which could help to explain why social disconnection is common in the disorder. However, the ISC method has not yet been used to study social dysfunction in schizophrenia. This project will fill this research gap by translating ISC research methods from non-clinical research in order to investigate how ISCs relate to social disconnection in schizophrenia. Individuals with schizophrenia (N=200) and matched healthy controls (N=100) will each complete one fMRI scan during which they will view naturalistic video stimuli and complete two established paradigms that assess important domains of social processing: social cue perception and mentalizing. We will characterize ISCs based on responses to the naturalistic video stimuli and characterize brain activity related to social cue perception and mentalizing using standard analyses. The study will test whether ISCs differ between the two participant groups and evaluate to what extent group ISC differences relate to individual differences in social connection. We will also characterize ISC normativity for each member of the schizophrenia group, using the control group as a reference, to assess whether brain response normativity is associated with social disconnection, and whether individuals’ degree of social disconnection can be predicted from it. The project will also test whether an ISC-based measure is more sensitive to individual differences in social disconnection than established fMRI measures. Results from this project will improve understanding of how brain activity relates to social dysfunction in schizophre...