Atypical Morphometry and Connectivity of the Cortico-Striatal-Thalamo-Cortical Circuit in Children and Adolescents with Chromosome 22q11.2 Deletion Syndrome: A Population at Ultra-High Risk for Developing Obsessive-Compulsive and Schizophrenia Spectr

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a complex neurodevelopmental disorder associated with serious medical, cognitive, and psychiatric conditions, including significantly elevated risk for obsessive-compulsive (OCD) and/or schizophrenia spectrum disorders (SCZ). The cortico-striato-thalamo-cortical (CSTC) neural circuit is critical for cognitive and emotional processing. Dysfunction of the CSTC circuit is implicated in the etiopathology of both OCD and SCZ but has not been specifically examined in individuals with 22q11.2DS. This study used structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), along with standardized psychological and cognitive measures, to investigate atypical morphometry and white matter connectivity within CSTC-related brain regions in children and adolescents with 22q11.2DS compared to typically developing (TD) controls. Structural analyses included 23 participants with 22q11.2DS and 21 TD controls, while DTI analyses involved 17 participants with 22q11.2DS and 14 TD controls. Findings revealed significant volumetric reductions in grey and white matter within CSTC-associated regions among participants with 22q11.2DS relative to TD controls in regions including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), striatum, and thalamus. Additionally, DTI analyses demonstrated altered white matter connectivity characterized by increased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) metrics within tracts connecting the OFC, striatum, and thalamus. Decreased grey and white matter volumes and altered white matter connectivity were significantly associated with elevated levels of anxiety, atypicality, and withdrawal, as well as deficits in attention, learning, and functional communication. Reduced cognitive performance, particularly in working memory and processing speed, also correlated strongly with these neuroanatomical and connective disruptions. Overall, these findings provide critical insights into the neuroanatomical and connectivity disruptions within the CSTC circuitry in a developing population, highlighting their significance for cognitive, emotional, and psychiatric vulnerability in 22q11.2DS. The results highlight the need for longitudinal and integrative approaches to identify an OCD and/or SCZ endophenotype in 22q11.2DS to aid with early identification and informing targeted interventions in this population at risk for serious psychiatric illness.