UCLA

Neurodevelopmental syndromes such as schizophrenia and autism are driven by a confluence of genetic and environmental risk factors leading to differences in brain development. Rare copy number variants (CNVs) involving deletions or duplications of multiple genes can incur high risk for neuropsychiatric illness and represent a ‘genetic-first’ model for understanding important biological pathways contributing to risk. Investigation of brain phenotypes in populations with behaviorally defined risk factors for mental illness represents a complementary ‘top down’ approach for linking clinical symptoms to brain systems and underlying biology. In this dissertation, three separate studies apply magnetic resonance imaging (MRI) in cohorts with genetic and clinical risk factors to better understand the developmental differences in brain structure and function that contribute to neuropsychiatric risk. In the first study, we assessed longitudinal development of functional connectivity between the thalamus and cortex in individuals with 22q11.2 deletion syndrome (22qDel) who are at high risk for schizophrenia and autism compared to neurotypical controls. We found altered developmental trajectories in 22qDel, with children displaying a pattern of thalamocortical hyperconnectivity in somatomotor regions and hypoconnectivity in frontoparietal regions, which had been previously observed in studies of schizophrenia, clinical high risk (CHR) for psychosis, and a cross-sectional analysis of 22qDel. In the second study, we investigated gene dosage effects on maturation of subcortical brain volumes across 22qDel, neurotypical controls, and carriers of 22q11.2 duplications (22qDup) who are at high risk for autism but not schizophrenia. We found gene dosage effects on multiple subcortical structures and a wide range of developmental alterations across the two CNV groups, illuminating the role of the 22q11.2 locus in subcortical development. In the final study we compared resting-state functional MRI case-control phenotypes in 22qDel versus CHR for psychosis to better understand similarities between these two high-risk populations. We found broadly dissimilar effects on long-range connectivity, local connectivity, and brain signal variability in these two cohorts, and related 22qDel case-control differences to multiple established brain maps, most notably positron emission tomography maps of hemodynamics and metabolism from neurotypical adults. These three studies provide important new insights into brain development and neuropsychiatric risk.