The Role of the Posterior Cerebellum in Mentalizing During Early Psychosis: Linking Neural Features to Social Dysfunction

About This Grant

PROJECT SUMMARY Individuals with psychotic disorders often experience significant social dysfunction that contributes to both individual suffering and societal burden – even during the initial onset of illness (i.e., early psychosis; EP). Social cognition is a key predictor of social and functional outcomes in EP, and mentalizing – the social cognitive ability to make inferences about the perspectives and mental states of other people – is both robustly impaired and particularly associated with social functioning. Unfortunately, mentalizing impairments are not addressed by psychiatric medications and psychosocial interventions for social cognitive dysfunction are often difficult to access or inconsistent with regard to improving real-world outcomes. Though mentalizing has known neural underpinnings in the cerebral brain regions that comprise the mentalizing network (MN; i.e., medial prefrontal cortex, precuneus, temporoparietal junction), emerging data indicate that a specific region of the posterior cerebellum (Crus II) plays a critical role in mentalizing that has been overlooked in models of social dysfunction in psychosis. Recent data from the neuroanatomical and developmental literatures further demonstrate that the posterior cerebellum undergoes a unique, protracted process of development from the years spanning adolescence and early adulthood – which intersects with the years of life when EP tends to emerge and escalate. Despite evidence of structural and functional abnormalities of the cerebellum in psychosis, how these alterations manifest in EP and their contribution to social dysfunction remain unknown. In this proposal, we utilize a neurodevelopmental framework to clarify the impact of the posterior cerebellum on social dysfunction and further characterize the comprehensive functional brain circuitry of mentalizing during EP. We will recruit a large sample (n=120) of EP participants, as well as 60 age-matched non-clinical control participants for comparison purposes. Participants will undergo MRI to delineate the structural and functional posterior cerebellum features underlying mentalizing dysfunction. Participants will also complete a comprehensive clinical assessment of social cognition, psychiatric symptoms, neurocognition, and functional outcomes. The specific aims of this proposal are to: i) elucidate the nature of localized alterations of the posterior cerebellum during early psychosis (EP); ii) to delineate the functional network dynamics underlying posterior cerebellum-cerebrum interactions during mentalizing in EP; and iii) to parse the specific impact of posterior cerebellum dysfunction on social outcomes in EP. Successful completion of these aims will advance our understanding of how the posterior cerebellum influences social dysfunction during key developmental phases within the early time-course of psychosis, further informing translational interventions during a critical period of illness and thus advancing NIMH strategic goals to define brain mechanisms underlying complex behavior and examine mental illness trajectories across the lifespan.