Abstract not available.

<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>

Due to the nature of the complexity of the diagnosis of autism spectrum disorder (ASD), elementary-aged students with this disorder require a holistic, team-based approach to education in the school setting. A review of current literature has found that while interprofessional collaborative practice (ICP) in the school setting is effective and often recommended for students with ASD, a variety of barriers have resulted in fragmented care. Additionally, there is limited research supporting a cohesive model of interprofessional collaborative practive when working with students with ASD in the elementary school setting. This problem is likely leading to decreased outcomes for elementary-aged students with ASD. Occupational therapy practitioners’ role as holistic, client-centered practitioners creates an ability to bridge the gaps between the often-fragmented goals of the members of an interprofessional team. Interprofessional collaboration in the school setting between occupational therapy practitioners, physical therapy practitioners, psychologists, speech and language pathologists, social workers, and teachers is crucial to addressing the multi-faceted needs of children with ASD and providing the highest level of service in accordance with the Occupational Therapy Practice Framework: Domain and Process, Fourth Edition. This doctoral project aims to add to the limited body of research in this area in order to fulfill this role. The TOPPSS Model of Interprofessional Collaboration is an evidence-based school-year long plan of structured collaboration between staff members working with students with ASD in an elementary school setting through a professional development workshop. The workshop will educate participants on the TOPPSS Model of Interprofessional Collaboration. The participants that are being targeted for this workshop include elementary school-based teachers (T), occupational therapy practitioners (O), physical therapy practitioners (P), psychologists (P), speech-language pathologists (S), and social workers (S). The overall aim of this program is to improve interprofessional collaborative practice (ICP) among the participants in order to increase positive outcomes for students with ASD.

No description available.

No description available.

Autism spectrum disorder (ASD) encompasses a broad range of neurodevelopmental disorders, with two core symptoms: deficits in social communication, and restrictive interests and repetitive behaviors. Genetics is thought to play a large role in ASD and currently there are hundreds of associated genes. We first studied the thousand and one amino acid kinase gene (TAOK2), which plays an important role in neurodevelopment. We found that loss of TAOK2 causes deficits in neuron development and activity, leading to morphological changes in various mouse brain regions and ASD-related behaviors. We studied the impact of de novo mutations identified in TAOK2, which caused aberrant neuron dendritic arborization and formation of synapses. To elucidate how TAOK2 regulates neuron development we used a proximity-labeling proteomics technique (BioID) to identify its protein-protein interaction (PPI) network. We applied this same methodology to a total of 41 ASD-risk genes and observed multiple convergent biological processes, including the less-studied mitochondrial and metabolic pathways. ASD-risk genes, including TAOK2, associated with mitochondrial proteins were found to have altered cellular respiration. The shared ASD-risk gene PPI network enriched for other ASD-risk genes and was used to group genes based on their shared PPI networks. These gene groups showed correlation between the clinical behavior scores of individuals that had mutations within the distinct gene groups. Lastly, we identified changes in the PPI networks of multiple ASD-risk genes through BioID, which we validated with various functional assays. In summary, we developed a proximity-labeling proteomics method that identified multiple convergent biological pathways associated with ASD. Studying the function of TAOK2 revealed multiple disease-relevant pathologies associated with the disorder, however proximity labeling has the potential to categorize multiple ASD-risk genes and elucidate their shared signaling pathways, which together, can advance the development of robust treatments for ASD. / Thesis / Doctor of Philosophy (PhD) / Autism spectrum disorder (ASD) is a group of brain disorders that affect more than 1% of children. Genetic variants are thought to cause ASD pathology, however there are currently hundreds of genes that have not been studied. We studied how disruption of one of those genes, TAOK2, alters brain development in mice and identified TAOK2 variants in multiple children with ASD. We then used BioID to find the shared disease-related mechanisms between multiple ASD-risk genes, and found that mitochondrial function and activity were connected to many of these genes. We showed that BioID can be used to study the effect of mutations in multiple ASD-risk genes simultaneously. Last, we could group children with ASD with similar behavior test scores based on the shared mechanisms of ASD-risk genes. Together our findings could be used to advance the development of robust treatments or new diagnostic tools for ASD.

Motor deficits in children who are diagnosed with Autism Spectrum Disorder (ASD) have started to become recognized as an area of concern. The purpose of this study was to examine practices of board-certified music therapists who address motor goals of children with ASD. A total of 168 current board certified music therapists completed an 18-item online survey regarding music therapy practices with children who have ASD, particularly the frequency with which they address motor goals and specific goals and interventions. Respondents reported addressing motor goals with children who have ASD more frequently than suggested by previous research. Motor goals most commonly addressed include imitation, upper limb coordination, hand/eye coordination, compliance, and praxis skills. The most common interventions used to address motor goals were instrument play, movement activities, dancing, using manipulatives, and task-oriented music games. Using information provided from the study, music therapists will be better equipped in helping children with ASD who have motor deficits by providing a list of commonly used interventions and which specific motor goals they are used most commonly with.

Autism spectrum disorder (ASD) is pervasive neurodevelopment disorder characterized by a broad range of social abnormalities and deficit in motor skills, many times referred to as clumsiness. These abnormal social characteristics result in a restricted repertoire of activity and interests that also may affect the motor learning process. Therefore, fewer opportunities to practice motor skills can lead to a delay in achieving motor proficiency. It is well known that physical activity and motor proficiency are positively correlated and the amount of time spent in a physical activity is directly related to the level of expertise in neurotypical children. Hence, the specific aim of this study is to quantify the amount of physical activity in children with ASD and compare this value to that of non-diagnosed siblings (ASD siblings) and neurotypical controls (NT), as well as to compare the amount of physical activity between neurotypical controls and ASD siblings. In this study, it was hypothesized that: 1) children with ASD would have lower scores than their non-diagnosed sibling and also than the NT controls in the amount of physical activity; 2) non-diagnosed siblings and neurotypical children would not be different in the amount of physical activity; 3) children with ASD's general score on the motor skills assessments would be lower than the non-diagnosed siblings and lower than NT controls; 4) There would not be a difference in the general score on motor skills assessments between non-diagnosed siblings and neurotypical children and 5) the motor assessments scores would be positively correlated (p < 0.05) to the amount of physical activity. There were differences between ASD and NT groups regarding to the amount of physical activity and also regarding to the motor proficiency scores. Although those differences were not statistically significant, they definitely are clinically relevant as showed that the children on the autism spectrum presented a clear motor delay. Likewise, the correlation between amount of physical activity and motor proficiency was showed not to be significant. These results can be explained by the small sample size. Further studies with a larger sample size would be crucial to verify these hypotheses proposed in the present study. / text

Introduction: Children with a learning disability (LD) and/or Autism Spectrum Disorder (ASD) are known to suffer from significantly more sleep problems, anxiety and challenging behaviour (CB) than typically developing children, yet little is known about the relationships between these factors in the child LD/ASD population. Aims and Hypotheses: The aim of the current study was to examine the relationships between sleep problems, anxiety and CB in children with LD and/or ASD. It was hypothesised that there would be differences between levels of sleep problems, anxiety and CB in children with LD alone, LD and ASD, and ASD alone. It was further hypothesised that there would be significant positive correlations between the three factors and that sleep problems and anxiety would predict a significant amount of the variance in levels of CB. Method: Postal questionnaires were returned by parents of one hundred and sixty seven parents of children with LD and/or ASD. Questionnaires consisted of parental report measures of sleep problems, anxiety and CB, in addition to general demographic variables. Results and Discussion: Statistical analysis revealed no difference between groups (LD, LD+ASD, ASD) in relation to sleep problems, however, some differences were found between the groups in relation to anxiety and CB. Correlational analysis revealed significant positive associations between the three factors. A hierarchical multiple regression showed that medication, sleep problems and anxiety accounted for 42% of the variance in CB, with a large effect size. These findings suggest that the relationships between sleep, anxiety and CB found in the TD child and adult LD/ASD populations are also evident in the child LD/ASD population and that these relationships should be considered during clinical practice, particularly in the case of CB interventions where sleep problems and/or anxiety are also present.

Thesis advisor: Ruth McRoy / Thesis advisor: Linnie Green Wright / Autism spectrum disorder (ASD) prevalence rates have risen dramatically over the past decade and boys are five times more likely to be diagnosed than girls. Prior research on children with ASD includes samples that are overwhelmingly male, but does indicate that girls with high-functioning ASD may have distinct needs and profiles. This study begins to address this gap in the research through a qualitative study of eleven families with an adolescent daughter with high-functioning autism spectrum disorder. The family is the primary unit of analysis and the study focuses on the following: (a) families' experience with the diagnostic process (b) families' management of their daughter's adjustment to adolescence, and(c) the impact of the ASD on family well-being. Family stress theory was the conceptual framework used to guide the study. Using grounded theory with a supplemental quantitative data strand, the study involved forty in-depth semi-structured interviews. Parents completed the Stress Index for Parents of Adolescents (SIPA) and a demographic questionnaire. Findings indicate that parenting a daughter with ASD could be categorized as a chronic stressor. The majority of parents endorsed clinically significant levels of stress on the SIPA. The mean age of ASD diagnosis was 8.7 years, well above the most recent (2014) Centers for Disease Control findings (6.3 years). Delayed and misdiagnosis for girls with ASD resulted in significant stress for families and reduced access to appropriate intervention. A shift in perception of the ASD from an acute to a chronic stressor allowed families to move toward acceptance and adaptation. The study findings support the need for a family centered model of assessment and intervention. Social workers in schools and in early intervention programs can play a critical role in providing education and support for families. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Social Work. / Discipline: Social Work.