UCLA

Autism spectrum disorders (ASD) are heterogeneous yet highly heritable neurodevelopmental disorders characterized by atypical social behavior, delayed and/or abnormal verbal and nonverbal communication, as well as unusual repetitive behaviors and restricted interests. In vivo neuroimaging studies have consistently reported reductions in functional and structural connectivity of large-scale brain networks and recent genetic and neurobiological work suggests that ASD are related to altered synaptic and local-circuit connectivity. This dissertation seeks to provide insight into the neurobiological basis of ASD by using a network approach and by characterizing risk factors to ultimately aid in the development of more effective diagnostic tools and biologically-based treatments and interventions.

In chapter 1, we examine functional connectivity of brain systems involved in social and emotional processing in ASD during an emotion-processing task. We use the amygdala and right inferior frontal gyrus, pars opercularis, as seeds in whole-brain functional connectivity analyses. We show that ASD is related to reduced integration within and segregation between distinct functional systems, which indicates that brain networks may partially reflect immature patterns of connectivity

In chapter 2, we examine intrinsic functional connectivity with resting-state fMRI (rsfMRI) and structural connectivity with diffusion tensor imaging (DTI) using a complex network approach. Using graph theoretical methods, we show that pairwise differences in functional connectivity are reflected in network level reductions in modularity and local efficiency, yet higher global efficiency. Structural networks displayed lower levels of white matter integrity and atypical age-related changes in global efficiency. By combining functional and structural network properties we further show that there is an age-related imbalance between structure and function in ASD.

In chapter 3 we examine the neural correlates of an established autism risk polymorphism in Met receptor tyrosine kinase (MET). We show that this polymorphism is a potent modulator of key social brain circuitry in children and adolescents with and without ASD as MET risk genotype was associated with atypical fMRI activation and deactivation patterns to social stimuli (i.e., emotional faces), as well as reduced functional and structural connectivity in temporo-parietal regions known to have high MET expression, particularly within the DMN.