Nathan Phillip Stout

Autism Spectrum Disorder (ASD) is a complex and lifelong neurodevelopmental disorder that is widely variable in presentation and intensity of defining features. ASD affects 1 in 94 Canadians and is increasing in prevalence. The variety of professionals who work with children with ASD have an accumulation of experiences that can be instructive and inspiring for other practitioners. This study explored how their wealth of experiences might be encapsulated as short vignettes or stories that could be analyzed and used as resources for educating current and future professionals. Six stories were collected from diverse professionals, and themes were summarized in order to demonstrate the types of lessons that can be learned from a clinician’s story of a significant moment or event in working with a child with ASD. The stories highlighted challenges and breakthroughs in communication and managing the child’s challenging behaviours, as well as skills and techniques that professionals have found effective in practice. The study shows that clinicians’ stories hold valuable information that can be shared with professionals in an interesting and memorable manner. Future research could expand on this study to build larger collections of stories with additional viewpoints and specific professional insights and experiences with a variety of children in their practice. / Graduate / 0518 / 0727 / 0758

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication as well as ritualistic repetitive behaviors. Epidemiological studies suggest that maternal immune activation (MIA) during pregnancy may be a risk factor for ASD. To study MIA in a laboratory setting, we injected mouse dams (C57BL/6) with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly IC) during mid-gestation to mimic a bacterial or viral infection, respectively. We also performed the same Poly IC treatment on a mouse model of Fragile X syndrome (i.e. Fmr1 knockout), a genetic disease with high incidences of ASD. We found modest female-specific impairments in social interaction and striking male-specific increases in repetitive behavior in adult MIA offspring. Moreover, prenatal Poly IC treatment caused genotype-specific deficits in sociability in addition to reduced body weight and rearing in Fmr1 knockout mice only. Therefore, ASD-related behaviors caused by MIA may be sex, treatment, and/or genotype-dependent.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication as well as ritualistic repetitive behaviors. Epidemiological studies suggest that maternal immune activation (MIA) during pregnancy may be a risk factor for ASD. To study MIA in a laboratory setting, we injected mouse dams (C57BL/6) with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly IC) during mid-gestation to mimic a bacterial or viral infection, respectively. We also performed the same Poly IC treatment on a mouse model of Fragile X syndrome (i.e. Fmr1 knockout), a genetic disease with high incidences of ASD. We found modest female-specific impairments in social interaction and striking male-specific increases in repetitive behavior in adult MIA offspring. Moreover, prenatal Poly IC treatment caused genotype-specific deficits in sociability in addition to reduced body weight and rearing in Fmr1 knockout mice only. Therefore, ASD-related behaviors caused by MIA may be sex, treatment, and/or genotype-dependent.

For individuals with Autism Spectrum Disorder or ‘ASD’ the ability to accurately process and interpret auditory information is often difficult. Here we review behavioural, neurophysiological and neuroimaging literature pertaining to the field of auditory processing in ASD, with the aim of providing a comprehensive account of auditory processing in this population and thus an effective tool to aid further research. Literature was sourced from peer-reviewed journals published over the last two decades which best represent research conducted in these areas. Findings show substantial evidence for atypical processing of auditory information in ASD. Behavioural studies provide support for widespread abnormalities ranging from atypical perception of various low-level perceptual features (i.e. pitch) to processing of more complex auditory information such as prosody. Magnetic resonance imaging studies have identified functional abnormalities to a range of auditory stimuli in ASD while structural abnormalities have been observed in several brain regions implicated in auditory processing. Electrophysiological research has found evidence for atypical auditory processing within the cortex and brainstem of individuals with ASD in a variety of experimental paradigms. Trends across studies suggest auditory processing impairments in ASD are more likely to present during processing of complex auditory information and are more severe for speech than for non-speech stimuli. Moreover, atypical auditory processing in ASD may not always be viewed as an impairment and in some cases may reflect the use of a compensatory strategy to make sense of auditory information. To this end, there is an urgent need for further research aimed at understanding the behavioural and neural basis of auditory processing in ASD.

Children with Autism Spectrum Disorder (ASD) language repertoire development varies greatly amongst each individual especially in one’s ability to understand emotions. One way to increase language development and further understand emotions is through stimulus equivalence. Theis present study examined the effefficacy of a stimulus equivalence training procedure in bringing the recognition of others’ emotions under multiple contextual control, and also evaluated co-occurring changes in the flexibility of participant responses to common questions requiring emotional recognition that is multiply controlled. The procedures were taken from the Promoting the Emergence of Advanced Knowledge Equivalence Module (PEAK-E) to aid in replication both clinically and in research. The results suggest that each of the three participants, all with an autism diagnosis, were able to identify the facial expressions of others when provided with a person and a context (i.e., What face does Person A feel at Location B?). In addition, two of the three participants were able to correctly identify an individual when provided with a context and an emotion (i.e., Who feels Emotion A at Location C?). Results from the flexibility probes throughout the study however indicate that the participants did not demonstrate an increase vin flexible responding following equivalence training. ectiveness of stimulus equivalence under multiple control to promote the emergence of an untrained relation via the PEAK – E Curriculum: Feelings in Context. Three participants diagnosed with autism, between the ages 12 and 17, were directly trained nine relations that established under a specific context a person will make a certain facial expression. Results indicate that all three participants demonstrated mastery in the training condition; however, when tested for equivalence only two of three participants were able to do so.

Abstract not available.

Autism spectrum disorder (ASD) is a complex disorder with large individual variability, where every case has differences in the type and severity of symptoms. Despite the recent increase in diagnoses, scientists have advanced considerably less in their understanding of the mechanisms of ASD because few individual genes that are implicated in ASD are mutated in much more than 1% of patients. One proposed mechanism is that the dysfunction of GABAergic interneurons may play a role in the development and progression of the disorder by interrupting the excitatory and inhibitory balance of neural networks. In our research, we elucidate the role of one class of interneurons in ASD by knocking out a high-risk gene (phosphatase and tensin homologue on chromosome ten, or PTEN) selectively in somatostatinexpressing (SOM+) interneurons. Since many symptoms of autism spectrum disorder present themselves as social anxieties, we test our mouse model in a variety of settings to observe social interaction and social preference, anxiety-like behavior, and repetitive stereotyped behavior. We found that in the SOM+ conditional knockout of PTEN, mice had elevated levels of anxiety and fear recall, suggesting a potential disruption of amygdala function. We then investigated potential dysfunction at the cellular and circuit levels using confocal microscopy, electrophysiology, and 2P local circuit mapping. We found that SOM+ cells lacking PTEN were overgrown morphologically, with larger cell bodies and larger, more complex dendritic arbors. Additionally, SOM+ cells in the central amygdala (CeA) lacking PTEN had elevated levels of excitatory drive from the basolateral amygdala (BLA) as well as a drastic disruption of lateral inhibition within the CeA, seen by decreased connection probability and reduced inhibitory post synaptic currents. Given what is known about central amygdala circuitry, these deficits in CeA SOM+ neuron activity conceivably underlie the fear and anxiety-related phenotype observed in mice with a conditional SOM+ PTEN knockout. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

Parent knowledge of ASD may be relevant to early identification and intervention services for children with ASD. By understanding how knowledgeable parents of young children are about ASD, researchers and practitioners can intervene and educate this population. This study sought to determine the knowledge base of ASD among parents with children five years and younger and if developmental, behavioral, and autism-related concerns predict knowledge of ASD. The sample of parents consisted of 167 mothers and fathers. All participants completed a knowledge questionnaire (i.e., ASKSG) and reported their level of developmental, behavioral, and autism-related concerns of their oldest child between the ages of 2 and five years. Results revealed that the sample of parents had a relatively low knowledge base of ASD, as determined by a percentage correct on the ASKSG of 43.9% (SD=20.1). Additionally, developmental, behavioral, and autism-related concerns did not collectively predict the sample’s knowledge of ASD; however, autism-related concerns independently predicted knowledge. The results of this study provide information to researchers and practitioners that can be used to educate parents of young children regarding ASD. By doing so, early and appropriate identification of ASD may be improved. In turn, children and families may have increased access to early intervention services and thus may result in better developmental outcomes.

<p>  </p> <p>Recent advancements in genetics have revealed that <em>SCN2A</em> is one of the leading genes associated with neurodevelopmental disorders including autism spectrum disorder and epilepsy. In particular, loss-of-function and truncation variants account for a majority of cases. As there are no current treatments specific for <em>SCN2A</em>, the neuropharmacogenomics field has strived to further elucidate the role of <em>SCN2A</em> in neurodevelopment to identify intervention targets. Rodent models offer <em>in vivo</em>, pre-clinical insight into the effects of genetic variation on behavior, biochemistry, and electrophysiology as well as the mechanisms on molecular, cellular, and circuitry levels. Due to <em>SCN2A</em>’s critical involvement in the initiation and propagation of action potential neuronal firing early in neurological development, full null homozygous knockout of <em>Scn2a</em> in mice is perinatal lethal. Furthermore, canonical heterozygous knockout of <em>Scn2a </em>in mice does not render phenotypes that recapitulate <em>SCN2A</em> deficiency in humans. Therefore my dissertation aims at developing a mouse model that better parallels the human condition, then using that pre-clinical platform to explore precision medicine.</p> <p>  </p> <p>Using the unconventional strategy of gene trapping, we generated mice with a severe reduction in <em>Scn2a</em> expression, resulting in significant behavioral and electrophysiological differences from neurotypical wild-type mice with full <em>Scn2a</em> expression, but enough residual expression that the <em>Scn2a</em>-deficient mice survived into adulthood. The severely decreased sociability accompanied by increased high and low order repetitive behaviors observed with the <em>Scn2a</em>-deficient mice suggest autism-like phenotypes. In addition, <em>Scn2a</em>-deficient mice also displayed other co-morbidities of neurodevelopmental disorders including atypical innate behavior, increased anxiety, increased sensitivity to stimuli, motor discoordination, and impaired learning and memory. On the electrophysiological level, these mice displayed enhanced intrinsic excitabilities of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in seizures and social behavior. This increased excitability was autonomous and reversible by the genetic restoration of <em>Scn2a</em> expression in adult mice. Further, RNA-sequencing revealed a downregulation of multiple potassium channels as well as differential expression of glutamate excitatory and GABA inhibitory signaling, which led to the pursuit of targeting these pathways. Indeed, the use of potassium channel openers alleviated the hyperexcitability of <em>Scn2a</em>-deficient neurons, thus supporting the pursuit of these targets.  </p> <p>Since characterization of the <em>Scn2a</em>-deficient mouse model revealed disruption in excitatory and inhibitory pathways, excitatory/inhibitory balance was examined further as a precision medicine target. Increasing <em>Scn2a</em> expression throughout the whole brain by excising the gene trap, as well as specific targeting of the striatum and the neurons that project to it using a retrograde viral vector, rescued social deficits. However the striatum-specific injection did not lead to a social rescue. This shifted the focus to the neurons that project to the striatum such as the medial prefrontal cortex. Using chemogenetics to reduce excitatory signaling in the prelimbic region of the medial prefrontal cortex, we were able to increase the social behavior in <em>Scn2a</em>-deficient mice. Synthesizing the results from the retrograde striatum and prelimbic-specific rescue, the next hypothesis tested was a circuity-level manipulation of the medial prefrontal cortex projections to the striatum. Retrograde control (striatum) of chemogenetics (medial prefrontal cortex) decreased the excitatory signaling in the medial prefrontal cortex neurons that project to the striatum, which also led to improved sociability. On the other side of the excitatory/inhibitory balance, increasing inhibitory signaling through acute exposure to small-molecule GABA receptor positive allosteric modulators, clonazepam and AZD7325, rescued sociability.</p> <p>This dissertation opens up new avenues of research by supporting the use of a pre-clinical mouse model of <em>Scn2a</em> deficiency to advance the study of underlying mechanisms behind <em>SCN2A</em>-related neurodevelopmental disorders. Although the results of this dissertation need additional validation such as cellular support, the data and results in this dissertation can serve as a guide to further explore excitatory/inhibitory balance as a neuropharmacogenomics precision medicine target to treat <em>SCN2A</em>-related neurodevelopmental disorders. </p> <p><br></p> <p><br></p>