In vivo evidence of microstructural hypo-connectivity of brain white matter in 22q11.2 deletion syndrome

Abstract

Abstract22q11.2 deletion syndrome, or 22q11.2DS, is a genetic syndrome associated with high rates of schizophrenia and autism spectrum disorders, in addition to widespread structural and functional abnormalities throughout the brain. Experimental animal models have identified neuronal connectivity deficits, e.g., decreased axonal length and complexity of axonal branching, as a primary mechanism underlying atypical brain development in 22q11.2DS. However, it is still unclear whether deficits in axonal morphology can also be observed in people with 22q11.2DS. Here, we provide an unparalleled in vivo characterization of white matter microstructure in participants with 22q11.2DS (12–15 years) and those undergoing typical development (8–18 years) using a customized magnetic resonance imaging scanner which is sensitive to axonal morphology. A rich array of diffusion MRI metrics are extracted to present microstructural profiles of typical and atypical white matter development, and provide new evidence of connectivity differences in individuals with 22q11.2DS. A recent, large-scale consortium study of 22q11.2DS identified higher diffusion anisotropy and reduced overall diffusion mobility of water as hallmark microstructural alterations of white matter in individuals across a wide age range (6–52 years). We observed similar findings across the white matter tracts included in this study, in addition to identifying deficits in axonal morphology. This, in combination with reduced tract volume measurements, supports the hypothesis that abnormal microstructural connectivity in 22q11.2DS may be mediated by densely packed axons with disproportionately small diameters. Our findings provide insight into the in vivo white matter phenotype of 22q11.2DS, and promote the continued investigation of shared features in neurodevelopmental and psychiatric disorders.