Autism Spectrum Disorder Within Neurodevelopmental Disorders Catching Heterogeneity Specificity And Comorbidity In Clinical Phenotypes And Neurobiological Bases PDF Download

Autism Spectrum Disorder (ASD) is a heritable neurodevelopmental disorder in which manifestations of behavioral symptomology vary widely. Core behavioral deficits associated with the disorder include impairments in social communication and social interactions, along with the presence of repetitive patterns of behavior, restricted interests, and/or altered sensory responsivity to external stimuli. The last decade has seen the rate of ASD diagnosis rise to an estimated 1 in every 59 children, making early diagnosis and effective treatment a critical public health concern. However, the neurobiological and phenotypic heterogeneity present in individuals with ASD makes discerning ASD etiologies and developing effective treatments very challenging. This dissertation seeks to examine the neurobiological underpinnings of ASD from a multidimensional perspective - investigating how brain function and connectivity are altered in ASD and how they vary among affected individuals, which may ultimately contribute to the development of targeted, individualized treatment. Chapter 1 provides an Introduction to the research conducted in the following chapters and gives a review of the neurobiological basis of ASD, describing neuroimaging findings related to altered brain structure, function, and connectivity. Chapter 2 describes a study which investigated how functional connectivity of the brain's reward network varies as a function of genetic heterogeneity in a predominantly male cohort of youth with and without ASD. Using a seed in the subcortical hub of the reward network, the nucleus accumbens, this study showed that genetic variability in the oxytocin receptor gene (OXTR) is linked to distinct patterns of reward network connectivity in neurotypical children and in children with ASD. In ASD youth, increased genetic risk in the OXTR was associated with reduced within network connectivity, whereas neurotypical youth showed compensatory upregulation of connectivity between the nucleus accumbens and frontal cortex. These findings elucidate the neural mechanisms of risk and resilience in youth with and without autism. Chapter 2 describes a related study which used an imaging-genetics approach to examine sex-differences in ASD by investigating gender-specific effects of OXTR variants on reward network connectivity. Here, the results showed that under the same OXTR genetic risk load, females with ASD and neurotypical males display similar neuroplastic upregulation of functional connectivity between the reward network and frontal brain regions, with identical positive effects on social behavior. In addition, variability in the OXTR had distinct effects in male and female ASD youth, underscoring the importance of including females in studies of gene-brain interactions in ASD. Finally, Chapter 3 presents data from a study which explored how behavioral variability in auditory sensory responsivity affects discourse processing and social attention in youth with and without ASD. Study findings showed that in neurotypical youth, listening to conversations shrouded in distracting environmental noises was associated with increased activity in canonical left hemisphere language regions, likely reflecting the automatic engagement of selective attention mechanisms due to the social salience of speech. Conversely, in ASD youth with high levels of auditory sensory over-responsivity, listening to such conversations was associated with recruitment of contralateral right hemisphere language homologues, reflecting the increased difficulty of processing the speech signal in the context of competing auditory input. These data indicate that youth with and without ASD, particularly ASD youth with high auditory sensitivity, use different neural mechanisms to "hone-in" on socially relevant information in the presence of distracting stimuli, suggesting that the intrinsic salience of speech is disrupted in individuals with ASD and high sensory-over responsivity.