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Dissecting Brain-Based Variability in Autism: Impact of Sex, Polygenic Risk, and Age


Autism spectrum disorder (ASD) is an extraordinarily heterogeneous neurodevelopmental condition which is characterized by challenges with social interaction and communication, the presence of restricted and repetitive behaviors, and differences in sensory processing. Other behavioral and cognitive domains are also impacted in ASD, including alterations in salience detection, social cognition, executive functioning, and social reward processing. Despite the high prevalence of ASD, its neurobiological basis remains poorly understood and there is a paucity of broadly effective treatments. Prior work has demonstrated that ASD is associated with neural atypicalities, but the exact nature of such alterations remains unclear and their association with individual differences has been insufficiently examined to date. This dissertation aims to elucidate the relationship between three sources of individual differences – participant sex, polygenic risk for ASD, and age – and variability in brain connectivity and activity among youth with ASD and typically developing (TD) youth. Chapter 1 describes a study that analyzed sex differences in functional connectivity within and between three brain networks which underlie salience perception, social cognition, and executive functions. Youth with ASD displayed altered sex differences in these networks, highlighting the importance of considering participant sex when characterizing the neural mechanisms underlying ASD. Chapter 2 describes a related study examining neural responsivity to social rewards among girls and boys with and without ASD. Girls with ASD displayed greater activity to socially rewarding stimuli than both boys with ASD and TD girls in brain regions associated with reward processing and salience detection. These findings indicate that girls with ASD may be more sensitive to social rewards, which may in turn have implications for the use and personalization of reinforcement-based interventions. Chapter 3 presents data investigating the association between polygenic risk for ASD and functional connectivity of the salience network. Polygenic load for ASD significantly influenced the functional connectivity of this network in boys with and without ASD, and such connectivity was furthermore significantly more sensitive to cumulative genetic risk among boys than girls. These results suggest a pathway through which polygenic risk may contribute to ASD and highlight a neurobiological mechanism for the reduced prevalence of ASD in females, thereby suggesting an area of investigation for future treatment studies. Chapter 4 describes a study which examined longitudinal trajectories of functional connectivity among adolescents with ASD and TD adolescents. Such developmental trajectories significantly differed between adolescents with and without ASD, underscoring the value of considering age in our understanding of brain connectivity in ASD. Taken together, the body of work presented in this dissertation demonstrates that participant sex, polygenic risk for ASD, and age all significantly impact the brain in ASD. As such, these findings improve our understanding of individual variability in ASD and may ultimately contribute to the future development and personalization of interventions.

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