BRAIN CONNECTIVITY AND THE ROLE OF MYELIN IN AUTISM SPECTRUM DISORDERS ABSTRACT The maturation of the myelin sheath is a cornerstone to human brain development and function. Myelination plays a critical role in the establishment and maintenance of efficient communication between discrete brain regions (i.e. brain connectivity) and is additionally believed to underlie a variety of neurological and psychiatric disorders, including autism spectrum disorder (ASD). However, the current understanding of myelin in ASD is exceptionally limited. Thus, the goal of this proposed research is to examine whether differences in the myelinated white matter microstructure exist between individuals ASD and typical development and to investigate the extent to which the myelinated white matter and its development influences structural and functional connectivity in these two groups. We aim to achieve this goal in two solid steps. In the first phase (K99), we will leverage an ongoing longitudinal magnetic resonance imaging study to measure both structural and functional connectivity characteristics in the brain of 40 individuals diagnosed with autism spectrum disorder and 40 typically developing subjects. We will additionally utilize advancements in the field of quantitative MRI to implement and acquire measurements of the myelin water fraction, a surrogate measure of myelin content, from these subjects. This data will allow us to perform the first investigation about the role of myelin in autism spectrum disorders and allow us to examine how myelin influences the relationships between structural and functional brain connectivity. In the next phase (R00), we measure and interrogate brain microstructure during early brain development in infants at heightened risk for developing autism. We will examine the cross-sectional neurodevelopmental trajectories of brain connectivity and myelin content in order to provide knowledge and new insights regarding the neurodevelopmental mechanisms that underlie this escalating disorder. We expect that this detailed analysis will result in invaluable information about the structure-function relationships of the brain as well as provide new understanding into the critical role that myelinated white matter has on mediating connectivity relationships of the brain. Our results will reveal new neurobiological mechanisms of the pathogenesis of autism and advance our comprehension about the earliest manifestations of this impairing disorder. The results from the proposed project are thus significant to new understanding of brain imaging phenotypes of autism spectrum disorders and will have direct implications for the development of earlier and targeted intervention strategies.