Brain networks linking the cortex to thalamus are critical for cognitive, sensory, and motor functioning. Dysruption of thalamocortical networks has been implicated in the pathophysiology of neurodevelopmental disorders, including psychosis, and mechanisms of clinical phenotypes, especially cognitive impairment. This view is supported by neuroimaging, including a series of studies by the Co-PIs, which consistently find a combination of reduced thalamic connectivity with the prefrontal cortex (PFC) and sensorimotor-thalamic hyper-connectivity in schizophrenia and bipolar disorder. While significant progress has been made, critical knowledge gaps remain with respect to the normal developmental trajectory of thalamocortical networks and onset of connectivity disturbances in psychosis; relationship between cognitive functions supported by thalamocortical circuits and thalamocortical connectivity biomarkers; and clinical utility of imaging thalamocortical networks. The availability of several large-scale cross-sectional datasets containing multi-modal neuroimaging data and extensive phenotypic data on healthy and at-risk individuals has created an unprecedented opportunity to address these critical knowledge gaps. They include the Cambridge Center for Ageing and Neuroscience (Cam-CAN: n=656, ages 18-88); Nathan Kline Institute-Rockland Sample (NKI- RS: n=932, ages 6-85); Pediatric Imaging, Neurocognition, and Genetics dataset (PING: N=1239, ages 3-20); Philadelphia Neurodevelopmental Cohort (PNC: n=1601, ages 8-21), which includes psychosis spectrum (PS) youth; and the North American Prodromal Longitudinal Study (NAPLS: n=397). Building on our prior work in clinical populations and leveraging the considerable resources of these datasets, we propose to chart the development of thalamocortical networks in healthy subjects (Aim 1) and youth with PS symptoms (Aim 2), characterize the associations between thalamocortical biomarkers and cognition (Aim 3), and investigate the clinical utility of thalamocortical connectivity biomarkers at identifying atypical brain development in individual subjects across the psychosis continuum and predicting conversion to psychosis in clinical high risk individuals (Aim 4). The proposed Aims will: 1) establish critical normative lifespan development data for refining and testing etiological models of not just psychosis, but other neurodevelopmental disorders, as well as aging- related disorders; 2) inform the pathophysiology of psychotic disorders and contribute to dimensional models of psychosis; 3) help define the neural basis of executive cognitive abilities thereby providing the necessary foundation for mechanistic models of normal cognitive function and cognitive impairment in psychosis; and 4) potentially provide risk biomarkers and intervention targets for youth at risk for developing a psychotic disorder.
Many psychiatric disorders emerge between childhood and early adulthood, a period when the brain is undergoing significant developmental changes, and are associated with cognitive impairment which leads to lifelong limitations in psychosocial functioning. Determining how and when premorbid brain development goes awry, clarifying the neural basis of cognitive impairment, and establishing the clinical utility of brain-based biomarkers at predicting illness onset in individuals at high risk for neuropsychiatric illness are essential to developing targeted interventions that prevent the onset of psychiatric disorders and cognitive impairment.
