The impact of X-chromosome loss on brain structure and function in infancy

Abstract

Many childhood-onset behavioral disorders are male-biased, including autism spectrum disorders, attention-deficit hyperactivity disorder, and early onset persistent antisocial behavior. It has been hypothesized that these differences result from sex chromosome effects on the development of brain structure and function. Behavioral and neuroimaging studies of individuals with partial or complete X monosomy (Turner Syndrome or TS) provide an unparalleled opportunity to test this hypothesis. However, all studies of TS to date have been carried out in adults and older children. The study presented here is the first to test whether brain structure and function is altered in infants with TS. Our central hypothesis was that infants with TS would show altered gray matter volumes, anatomical connectivity, and functional connectivity in the neural circuits for social cognition and executive function. High-resolution structural magnetic resonance imaging revealed that infants with TS had decreased gray matter volumes in parietal cortex and increased gray matter volumes in insular cortex compared to XX females. Findings are highly similar to neuroanatomical studies of older children with TS, suggesting a stable phenotype with origins in the prenatal or early postnatal period. Diffusion tensor imaging (DTI) revealed that infants with TS did not exhibit the extensive reductions in FA seen in older children, but did show focal reductions in FA in several regions, suggesting that global reductions in FA arise after two years of age. Resting state functional connectivity analyses suggested reduced fronto-parietal connectivity in infants with TS, a lack of typical connectivity between caudate and frontal lobe, and increased connectivity with the insula. Results provide new insight into the impact of X-chromosome loss on neurodevelopment in early life.