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The purpose of this thesis is to explore the animation production process and determine alignment and suitability to best practice educational approaches for an identified user group, in order to propose an engaging, multisensory educational intervention centred around creative storytelling and animation film making. It draws on knowledge and expertise from literature, professional and lived experience of a widely unknown and misunderstood condition, in order to challenge the lack of academic understanding beyond the realms of clinical evidence. It evolves from a place of passion, as I simply stumbled upon this condition at the beginning of my research journey, unaware of how the discovery would shape not only my research, but my career, as I went on to develop the UK's first educational intervention service for children and young people with Fetal Alcohol Spectrum Disorder (FASD) and complex neurodevelopmental profiles, before taking a role with the National Organisation for FASD to work on their education projects. The need for such works is growing as FASD is the 'most common preventable cause of learning disability/difficulty in the UK' (Carpenter 2011, 37) and estimates of its impact range between 6 - 17% (McQuire et al. 2019, 344) and 1.8-3.6% (McCarthy et al. 2021, 2271) of the UK's population, yet societal awareness and academic literature remains sparse almost 50 years after its identification. However, research does suggest benefits of engagement in creative, multisensory practices for this population, presenting opportunities for the development of educational interventions centred around such. People with FASD face numerous challenges, notably in the realms of education, which led this study to develop a mixed-method approach, required in order to address the significant gaps in knowledge and form much-needed foundations of understanding from which interventions and supports can evolve. Co-design is used through autoethnography, interviews and stakeholder consultation in the form of evaluative research to generate, collect, reflect on and analyse data around caregiver experience. This is then translated to an educational context from which an educational intervention can be hypothesized. The framework design is supported by environmental and facilitation recommendations and delivery guides to ensure transferability. With this knowledge in place, the study continues to propose a Learning Programme based on best practice approaches, a framework specifically designed to address the educational needs of individuals with FASD, with focus placed on individuals in upper primary and lower secondary (UK) school age ranges (approximately 7 - 14 years). The framework is an interactive and individualised intervention built on the animation production process, drawing on years of my own experience and academic study. My passion for, dedication to and fascination with the uses of this practice outside of the context of entertainment is a result of the process being a creative, visual method of narrative building. Its multisensory and adaptable nature, in this context encourages full individualisation of the programme dependent on the participants cognitive ability, forming the starting point of exploration for this research. Ward argues, "one of the key theoretical and practical considerations for anyone trying to offer an outline of animation - as a mode of practice, a pedagogy, a knowledge area - is its multi-sitedness." (Ward 2006, 230). Current academic literature provides extensive, and highly valued knowledge on the medical, neurological and scientific perspectives of FASD, but is yet to address the caregiver experience. This study therefore addresses a significant gap in knowledge where the current literature does not offer guidance or evidence from which studies beyond the science/medical fields such as this, can base their understanding and draw foundational knowledge from. As this intervention takes inspiration from such an unlikely source as animation production, it became imperative to consider facilitation, delivery as well as the knowledge and experience of the individual delivering the programme. Is the facilitator to be primarily trained and experienced in animation production, or FASD? Drawing heavily on my own unique experience and knowledge of both fields, later supported by data generated and gathered within this study, it became apparent that considering the knowledge and skillset of any potential facilitator and determining an appropriate training programme for facilitators to complete was imperative.

Background: Children's exposure to alcohol in pregnancy is a known risk factor for the development of life-long cognitive and neurobehavioural difficulties, collectively known as Fetal Alcohol Spectrum Disorders (FASDs). FASDs are more common in care-experienced children, who often have experiences of trauma and neglect. However, children with difficulties associated with prenatal alcohol exposure are frequently misdiagnosed or not identified, limiting their access to effective intervention. These factors have an impact on children's social, emotional and behavioural outcomes, as well as the experiences of their carers. Aims: This thesis had three aims: to review the behavioural profile of children with prenatal alcohol exposure (PAE); to investigate the association of care-experienced children's exposure to alcohol in pregnancy on carers' wellbeing, parenting stress and efficacy and child behaviour; and to evaluate the differences between kinship and foster carers experiences of wellbeing, parenting stress and efficacy. Methods: The aims are addressed in two journal articles. The first article presents a systematic review of the research regarding the behavioural profile of children with PAE compared to unexposed children. The second article presents findings from a quantitative cross-sectional study involving kinship and foster carers of children aged 6-18 years old, who completed self-report measures about their wellbeing, parenting stress and efficacy and provided data regarding their care-experienced child's behaviour and prenatal alcohol exposure. Results: The systematic review demonstrated that children with PAE have greater behavioural difficulties compared to typically developing unexposed controls, as reported by parent- and teacher-report measures. However, differences in behaviour between children with PAE and unexposed children with Attention Deficit Hyperacitivty Disorder (ADHD) was less clear. There were limitations to the research reviewed, particularly regarding the selection of subjects within PAE groups and the operationalisation of behavioural measures associated with neurobehavioural domains. Results from the empirical study highlight the difficulty in capturing PAE in care-experienced children, as many carers were unaware of their children's PAE status. Significant differences in wellbeing, parenting stress and efficacy were identified between carers of children with and without behaviours associated with PAE. Kinship and foster carers differed on measures of wellbeing and anxiety, but not on parenting stress and efficacy. Significant correlations were found between all carers measures and child behaviour. Due to a lack of robust PAE identification and the limitations to the sample size, these findings require further investigation. Conclusions: The results of the systematic review highlight the behavioural difficulties demonstrated by children with PAE as identified by parents and teachers. Further investigation of carer-report measures for the purpose of identifying and differentiating a profile of deficits for PAE compared to other neurodevelopmental disorders is needed. The empirical study highlights the association between child behaviour and carer's wellbeing and experiences of caring. Clinical implications for service providers regarding PAE, care-experienced children and family support are discussed.

Children with Fetal Alcohol Spectrum Disorders (FASDs) are a vulnerable population who can present with a wide range of complex educational needs. Whilst an accurate picture of the prevalence of FASDs globally, and in the UK, is somewhat unclear, incidence is currently estimated at approximately 1%. There is a need to develop an evidence-based understanding of how to meet the educational needs of children with FASD and this is a pertinent issue for those working in and around educational settings. A group of professionals who are likely to be key in meeting the educational needs of children with FASD are educational psychologists (EPs); however, very little is known regarding their practice in supporting children with FASDs or how the role might be developed. A systematic literature review (SLR) sought to draw together evidence from studies that have evaluated the effectiveness of interventions and considered factors related to the effective implementation of intervention over the last five years. 11 papers published between 2013-2018 were included in a broadly configurative synthesis. An empirical investigation sought to examine EPs' practice and discuss ways in which the EP role could be developed with regards to FASD. 31 EPs and trainee EPs (TEPs) were surveyed via an online questionnaire gathering quantitative data that were treated descriptively and qualitative data that were subject to content analysis using a deductive framework. SLR findings highlighted some promising intervention programmes and key processes centred on a theme of 'active collaboration' for effective implementation of intervention for children with FASD. SLR findings also indicated that the evidence base for effective FASD intervention is somewhat fragmented in its current state and future research directions are considered. The empirical investigation indicated that EPs are a professional group who are able to contribute to meeting the needs of children with FASD using a child-centred and holistic interactionist approach. Some possible barriers to EPs' effective and confident practice were highlighted including lack of FASD-related knowledge; the potential impact of role specialisation is discussed. Links to theory, practice and future research are considered and issues relating to the effective dissemination of research are discussed including the proposition of a dissemination strategy for the current research findings.

Ethanol exposure during pregnancy is one of the leading causes of preventable birth defects, leading to a range of symptoms collectively known as fetal alcohol spectrum disorder (FASD). More moderate levels of prenatal ethanol exposure (PNE) lead to a range of behavioural deficits including aggression, poor social interaction, poor cognitive performance and increased likelihood of addiction in later life. Current theories suggest that adaptation in the hypothalamic-pituitaryadrenal (HPA) axis and neuroendocrine systems contributes to mood alterations underlying behavioural deficits and vulnerability to addiction. This has led to the suggestion that corticotrophin-releasing factor (CRF) antagonists and glucocorticoid (steroid) inhibitors may be potential therapeutics to address the deficits of PNE and for the treatment of addiction. The zebrafish (Danio rerio) has several advantages over mammalian models, such as low cost of maintenance, short life cycle, easy embryological manipulation and the possibility of large-scale genetic screening. By using this model, our aim is to determine whether developmental ethanol exposure provokes changes in the HPA axis (HPI axis in fish), as it does in mammalian models, therefore opening the possibilities of using zebrafish to elucidate the mechanisms involved, and to test novel therapeutics to alleviate deleterious symptoms. Thus this thesis focuses solely on the effect of developmental ethanol exposure on the functioning of the HPI axis in zebrafish. Stress-reactivity in zebrafish larvae ethanol-treated 1-9 days post 4 fertilisation (dpf) was assessed using thigmotaxis and thigmotaxis following airstress. In both tests, lower stress-related responses were obtained with ethanol treated animals, in that they spent less time at the edges of the apparatus (P<0.01, n=3). They also showed lower total body cortisol (P=0.04, n=14). Larvae also showed the same behaviour pattern two weeks after ethanol exposure, (23dpf) (P=0.04, n=3), again with reduced total cortisol (P=0.03, n=4). HPI-related gene transcription was also assessed in 9dpf ethanol treated zebrafish larvae, by qRT-PCR. Revealing up-regulation of CRH, CRHBP and CRHR2, normalized against β-Actin, Elav1 and Gap43 housekeeping genes. In situ hybridization revealed no spatial changes in CRH, CRH-BP and POMC with animals at the same stage. Behavioural stress-reactivity differences in 6-months old adults that had been exposed developmentally to ethanol were assessed using novel tank diving and thigmotaxis. Both assays indicated a decrease in stress-like behaviour due to early ethanol exposure compared to controls (P<0.05, n=5 both). Finally, cortisol levels were assayed from 9dpf larvae and 6-month-old adults that had been treated with ethanol during early development showed a significant reduction in cortisol output when air-exposed stressed compared to controls (P=0.04, n=5). Conclusion: Early ethanol exposure produced significant changes in cortisol, HPI gene mRNA expression and stress-reactive behaviour in 9dpf animals. Changes in cortisol and behaviour were still detected in 6-months old adults, developmentally treated with ethanol, indicating that early ethanol exposure has permanent effects on the HPI axis. 5 As our data contradicts the findings in mammalian literature where early ethanol exposure increases stress-like behaviour in later life, it is also possible that more permanent effects of PNE in mammals may arise through maternal-offspring interactions, during and post gestation, such as breastfeeding and maternal grooming of the offspring, which are absent in the zebrafish model.

Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term for a group of diagnoses that result from exposure to alcohol in utero. Alcohol creates a spectrum of impacts on the developing brain, contributing to lifelong physical, cognitive and behavioral implications. The prevalence of children with FASD in the foster care system is approximately 60 per 1000 children (Lange et al., 2013). Prevalence rates are underestimated due to children not being diagnosed or receiving an alternative diagnosis. This relates to various emotional, behavioral, social, and cognitive struggles for children and their families. To best serve this population and their families, it is vital for psychologists and other health professionals to collaborate as an interdisciplinary team that is knowledgeable about symptoms, red flags, and the diagnostic process of FASD. Mental health professionals play an important role in increasing awareness of FASD and educating the general population about FASD prevention. The purpose of this dissertation is to emphasize the relationship between FASD and the foster care system through the creation of program curriculum. Emphasis on high prevalence rates within this population will highlight the need for an educational program to increase foster and adoptive parent knowledge about FASD. The curriculum will seek to educate foster and adoptive parents about FASD and instill confidence in their ability to successfully care for a child with FASD. Therefore, children with FASD in the foster care system may be more likely to receive the necessary support from caregivers and professionals which they need to thrive.

Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term describing a range of impairments following prenatal alcohol exposure (PAE). Difficulties with executive functioning (EF) are among the most common impairments in the condition. While research has traditionally focused on describing FASD, recently attention has turned to evaluating interventions. Two existing reviews suggest that there is promise with a range of approaches, although there is considerable variability noted in outcome measures and populations. The emerging problems associated with exposure to extensive adversity in early life has also been identified in this vulnerable population of children and young people. In the light of these concurrent foci, this thesis begins with a comprehensive systematic review and meta-analysis of interventions published across academic and grey literature that aimed to improve executive functioning in children aged 3-16 years (Study 1). A comprehensive search yielding 8,638 records resulted in identification of 11 eligible studies with results synthesised across 253 participants. Results showed no significant impact of intervention across all but one outcome measure: response inhibition. These findings need to be interpreted with caution as there were significant limitations with the published work. Nonetheless, the corpus of work to date suggests that interventions may need to move beyond a focus on supporting the development of EFs. Further consideration needs to be given to other co-occurring factors in children with FASD that may either limit or negate current approaches for supporting the development of EFs.

Abstract: In this manuscript-based thesis, I investigated the development of executive functioning (EF) in individuals with FASD, the types and intensity of services individuals with FASD and their caregivers access, and the associations between early EF, adaptive functioning, mental health, and later outcomes among individuals with FASD. Following a review of the relevant literature, two studies are presented. In Study 1, Longitudinal Development of EF Among Individuals with FASD, I investigated the developmental trajectory of EF among 16 individuals with FASD from adolescence (Mage = 13.1 years) into young adulthood (Mage = 19.4 years). EF was measured using both performance-based tasks (NEPSY and D-KEFS) and behavioural reports (BRIEF caregiver form). Associations between early EF skills and later outcomes were also investigated. Later outcomes included a measure of adaptive functioning (ABAS-II) and indicators of mental health (BASC-2). EF skills among this group are generally impaired and stable throughout this developmental period, with mean scores well below the normative average on the majority of measures. Only metacognitive skills, as measured via behavioural reports, increased significantly in severity during young adulthood. Notably, pockets of normative strength were indicated on a performance-based task of switching at both time points, and on a performance-based task of inhibition during young adulthood only. When intraindividual variation was examined, a large portion of the sample evidenced significant change in performance, with 30% experiencing change on the BRIEF and 45% experiencing change on at least one performance-based task. Finally, multiple significant correlations were found between early EF skills and later outcomes, particularly, adaptive functioning. Areas of EF also predicted later adaptive skills. Results highlight important areas of personal strength for this population while also emphasizing the importance of considering the heterogeneity of this disorder. Findings also shed light on important relationships between early EF skills and later functioning. Suggestions for future research and clinical implications are discussed. In study two, Supporting Individuals with FASD: Trends in Service Use, I investigated service use trends among the same sample at the same time points. Service use was measured across five domains: medical services, mental health services, social services, educational services, and caregiver services. I then explored the relationships between early EF, mental health, and adaptive functioning and later trends in service use. All services were accessed throughout both adolescence and young adulthood for this population, with education services accessed most frequently at both time points. The frequency of service used remained stable for all services except caregiver services, which increased significantly during young adulthood. Multiple significant associations were also found between early EF, adaptive skills, and mental health functioning and later service use. Findings highlight the importance of early functioning and the relationships with later supports. Suggestions for future research and clinical implications are discussed.

Abstract: Fetal Alcohol Spectrum Disorder (FASD) is a diagnostic term used to describe impacts resulting from alcohol exposure during prenatal development. Individuals with FASD have strengths they can use in and out of the classroom, yet much of the current FASD literature has largely focused on personal deficiencies such as deficits in thinking abilities, and challenges with behavioural functioning and emotional regulation. This study employed a qualitative descriptive design. Semi-structured interviews approximately 30 minutes in length were conducted with two adolescents from Alberta, ages 13 and 15, with FASD. These adolescents voiced what they wanted teachers to know about their perceived strengths and struggles across school, home, and community settings. Interviews were audio recorded using Google Meet, transcribed, and analyzed using thematic analysis. Interview data provided insight into lived experiences including the strengths adolescents with FASD have and the struggles they experience in and out of school settings. By engaging individuals with lived experiences, more can be learned about the unique perspectives of adolescents with FASD. Results revealed adolescents with FASD want teachers to know (1) they are aware of some ways to manage their emotions and some of what adds to their struggles, (2) they have preferences for the ways they learn, and (3) they value and desire meaningful relationships. These findings provide insight into how teachers can position themselves to provide high-quality instruction and specialized support for adolescents with FASD and appreciate the unique strengths and interests adolescents with FASD have to offer.

Despite the growing body of research for Fetal Alcohol Spectrum Disorder (FASD) within adults, there remains a lack of research addressing the prevalence of FASD in the legal system. Over the last several decades it has become apparent that alcohol consumption during pregnancy can have devastating long term impacts on the developing fetus including facial abnormalities, cognitive deficits, adverse life outcomes, and behavioral challenges (Brintnell et al., 2019; O’Neil, 2011; Sarman, 2018; Streissguth et al., 2004). Within the legal system, FASD is about 30 times higher than the general population (Lange et al., 2017). Initially, the prevalence of FASD was difficult to accurately track due to the lack of information regarding the mother’s alcohol consumption during pregnancy. One significant barrier in diagnosing FASD continues to be a systematic way to track and screen for FASD. This study examined the Behavioral Traits Survey: Self Report (DeVries et al., 2001) as a possible screener and the behavioral characteristics using the Personality Assessment Inventory (PAI; Morey, 1991). Participants were 25 justice-involved adults, recruited online and referred through probation program. Each participant completed an online survey that included the Behavioral Traits Survey: Self Report and the PAI. Results verified there was a relationship between the Behavioral Traits Survey: Self Report and the antisocial, aggression, alcohol, and drug scales of the PAI. Higher scores on the scales of the PAI were found in adults with FAS behavioral profiles, highlighting need for assessments to screen for FASD to provide interventions to address clinical needs and reduce recidivism risk. Concerns about the validity of the Behavioral Traits Survey: Self Report and PAI are raised and the need for further reliability and validity studies on these measures are discussed.

Prenatal alcohol exposure (PAE) is one of the leading preventable causes behind neurodevelopmental disorders- underlying intellectual disability, cognitive dysfunction, and numerous defects found within Fetal Alcohol Spectrum Disorder (FASD). Alcohol impacts diverse neural cell types; however, more specific pathophysiological effects on the human fetal cerebral cortex remain unclear. Here, we used cortical organoids, astrocytes, and primary fetal neurons to explore cellular alterations induced by ethanol exposure. Within our human neural models, EtOH altered apoptosis, cell cycle, and proliferation. Additionally, expression of co-localized synaptic puncta markers and synaptic proteins was reduced from early ethanol treatment. To potentially rescue these synaptic alterations, four drug compounds were employed; Donepezil, an acetylcholinesterase inhibitor commonly used to treat Alzheimer’s and dementia, produced promising results for improving synaptic expression. Our study contributes to preliminary neurodevelopmental modeling of PAE- further defining cellular phenotypic signatures and elucidating potential therapeutic options.

The effects of prenatal alcohol exposure on sleep quality have been understudied, and the possibility that sleep disturbances contribute to deficits in other domains has not been explored. The current study aimed to characterize sleep quality in children with fetal alcohol spectrum disorders (FASD) and understand relationships with neurobehavioral functioning.Participants aged 6-10 years with (alcohol-exposed [AE] = 27) and without (control [CON] = 27) prenatal alcohol exposure were included in the study. Objective sleep was measured via 24-hour actigraphy for two weeks. Parents completed sleep diaries and sleep questionnaires (Children’s Sleep Habits Questionnaire, Pediatric Sleep Questionnaire). Children completed neuropsychological testing (NIH Toolbox Cognition Battery) and parents completed the Child Behavior Checklist (CBCL) and Behavior Rating Inventory of Executive Functioning – Second Edition (BRIEF-2) as measures of problem behaviors and executive functioning skills. For a subset of participants (n = 31), neuropsychological assessment was modified and conducted remotely due to COVID-19. Multivariate analysis of variance was used to characterize the sleep profile (objective, subjective) and examine group differences. Multiple regression examined the relationships between sleep quality and neurobehavioral performance. There were no group differences on actigraphy metrics averaged across two weeks; however, AE showed significantly greater intraindividual variability on most actigraphy measures, particularly total sleep time. Parents reported significantly more sleep problems in AE than CON, primarily driven by sleep onset delay, night wakings, and daytime sleepiness. AE performed significantly lower than CON on the subset of cognitive measures administered to the full sample. CBCL and BRIEF-2 scores were significantly higher for AE compared to CON, reflecting more behavioral and executive functioning problems. Greater sleep time variability was significantly correlated with poorer memory performance and more behavior problems, but did not moderate effects of group. There were no significant differences between the pre-COVID and COVID samples. Despite similar two-week average sleep outcomes, children with FASD showed greater intraindividual sleep variability and parents reported more sleep problems. Across the sample, greater sleep time variability was associated with poorer episodic memory and more behavior problems. Interventions targeting variability in sleep, particularly sleep duration variability, may improve sleep quality and some aspects of cognition and behavior in children with FASD.

Abstract: This manuscript-based dissertation investigated the processes of resilience and thriving among youth and young adults with Fetal Alcohol Spectrum Disorder (FASD). Following a review of relevant literature, two studies are presented. Study 1 is a quantitative study focused on resilience among youth with FASD. The purpose of Study 1 was to provide a profile of youth- and caregiver-reported resilience resources and the association between these resources and concurrently reported emotional and behavioural functioning. This study included 19 youth with FASD (aged 13 to 23 years) and their caregivers (foster or adoptive parents). Youth with FASD were reported to have comparable relational resilience resources to a typically developing normative reference group, but lower contextual resources compared to the reference group. Caregivers reported youth to have low individual resilience resources, but youth with FASD reported individual resources commensurate with the normative reference group. Early childhood adversity, age, sex, and IQ were not significantly associated with resilience resources. However, earlier age of stable caregiving placement and earlier age at FASD diagnosis were associated with greater caregiver-reported relational and contextual resilience resources. Finally, higher youth- and caregiver-reported individual resources were associated with less mental health symptomology, and higher youth- and caregiver-reported individual and contextual resources were associated with better adaptive functioning behaviour. These findings complement previous research documenting the necessity of ensuring early stable relationships for youth with FASD and permitting timely access to diagnostic services. The results also highlight the need to better understand and strengthen individual and contextual resources. The second study is a qualitative study that explored what it means to thrive with FASD. Five youth and young adults with FASD (aged 16 to 24 years) and seven caregivers provided a rich understanding of how thriving is conceptualized and supported among young people with FASD. Participants described individual qualities that they believed characterized a thriving youth with FASD, as well as qualities of youth environments that supported the development of thriving. Individual markers of thriving with FASD were described by six themes: connection to others, competence and autonomy, meaningful participation, integrated identity, moving toward, and feeling happy. Four additional themes reflected the importance of youth environments in supporting thriving: context matters, affirming youth, understanding youth, and responsive to youth’s individual needs. Overall, thriving with FASD was conceptualized as an individualized, multidimensional, and interactive process. As the first study in this population to explore thriving, this research contributes to our understanding of how to define what it means to be successful with FASD, and how to support people with FASD to do well across the lifespan. The findings of Study 1 and 2 both support and expand upon the existing literature, shedding light on the individual, relational, and contextual strengths of individuals with FASD and how to best support successful trajectories that matter to individuals with FASD and their families. This dissertation concludes with a discussion and integration of key findings from Study 1 and 2, including how this research informs clinical practice and future research.

Abstract: This dissertation explores the questions “What technology-based interventions are of most benefit in supporting the health and/or rehabilitation of individuals with substance use disorders? Where and how can they be most effectively embedded in the health system?” Chapter 1 begins with an introduction, presenting the need for change associated with the approach and management of substance use disorders (SUDs), and describes the role that digital technology can play in bridging gaps and enhancing care. Chapter 2 presents a brief historical synopsis of the social and clinical recognition of SUDs to provide a contextual introduction of the field of addiction, and to elucidate the need for change associated with the approach and management to these disorders, for which digital innovations hold promise. This chapter then describes the neurobiological foundations of addiction, followed by an overview of evidence supporting the theoretical and neurobiological mechanisms of treatment and intervention. This information provides a high-level evidentiary basis on which the chapters that follow are built. Chapter 3 is a review of digital technological addiction and mental health interventions, with an emphasis on interventions targeting SUDs. Evaluations on effectiveness are included where possible. This chapter concludes with a discussion addressing both the opportunities as well as possible negative implications of new innovations. Chapter 4 is divided into three sections: (1) a historical review of the social and clinical recognition of Fetal Alcohol Spectrum Disorder (FASD), which frames the landscape and context for the study that follows; (2) an original study examining the use of a specialized breathalyzer device, added as an additional service to the regular care for women who are pregnant and have a history of problematic alcohol use and/or are diagnosed with alcohol use disorder, with diagnosis of Fetal Alcohol Syndrome (FAS–the most severe form of FASD) as the primary outcome measure; and (3) a review that complements the discussion section of the study that precedes it, and explores issues posed for researchers, clinicians, and public policy leaders alike caused by the lack of standardization of diagnostic criteria for FASD. Chapter 5 provides an evaluation of the Text4Support program–a text messaging intervention using the principles of cognitive behavioural therapy–as a complementary service for individuals seeking addiction and mental health supports. Chapter 6, reflecting on the work that precedes it, explores the final query of this thesis (“where can technology-based interventions be most effectively embedded in the health system?”), and includes a discussion of public policy implications and considerations for further research.

The developmental origin of health and disease hypothesis (DOHaD) postulates that environmental and genetic factors present during prenatal and perinatal stages alter development and fundamentally influence adolescent and adult health. Adverse or stressful intrauterine events repeatedly associate with poor health outcomes, including psychiatric disease, neurobehavioral abnormalities, metabolic disease, and cardiovascular disorders. Prenatal alcohol exposure (PAE) is a common developmental stressor that can result in fetal alcohol spectrum disorder (FASD). At least 10% of pregnancies involve alcohol exposure, and recent estimates suggest that 2.5 - 5% of babies born from North America and Europe, and greater than 10% of those from South Africa, have FASD. Affected patients can present with behavioral and cognitive alterations, nerve and brain abnormalities, birth defects in organs such as the heart and kidney, and craniofacial anomalies. The teratogenic effects of EtOH are thought to have a lifelong impact on affected individuals; however, the consequences of PAE on adult metabolic health outcomes have yet to be characterized. Furthermore, the cellular and molecular mechanisms underlying EtOH’s teratogenicity are poorly understood. In Chapter 2, I investigate metabolic health outcomes in FASD. I demonstrate that adults with FASD have an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity, and recapitulate these findings in zebrafish model of embryonic alcohol exposure (EAE). Furthermore, I identify several consequences of EAE that may contribute to these phenotypes, including a reduction in adult swimming activity, diet-responsive transcriptional changes, and alterations in visceral adipocyte and hepatic development. In Chapter 3, I identify the proteasome as a critical target of EAE and demonstrate that EtOH-induced disruptions to the ubiquitin proteasome system (UPS) may contribute to neurodevelopmental disorder, craniofacial malformation, and endoderm defects following EAE. Finally, in Chapter 4, I interrogate the role of nuclear receptor nr5a2 in endoderm formation and demonstrate that it is required for hepatopancreas development. Taken together, this dissertation demonstrates the life-long impact of environmental and genetic perturbations during development, and provides clinically relevant insight into the metabolic health outcomes and molecular underpinnings of FASD.

Culturally relevant research has not kept pace with the most rapidly growing ethnic population in the United States. The Pacific Northwest consists of 1 million Mexican and Mexican Americans (López, 2015). Statistically, Latinos are considered one of the populations that is most often overrepresented within the lower socioeconomic status level. In addition, factors such as lack of resources, language barriers, and educational constraints play key obstacles to accessing medical treatment and mental health services in general and especially for specific groups such as those with Fetal Alcohol Syndrome (FAS; Lopez, 2015). Research has indicated high financial, emotional, and psychological expenses for society in order to care for people diagnosed with Fetal Alcohol Spectrum Disorders (FASD; Centers for Disease Control & Prevention, 2017). It is vital to provide this population with a tool that will be sensitive to the culture and help provide appropriate diagnoses and treatment for the family and community with individuals living with FASD. This study found 3 factors from the Culturally Correct FAS BeST (CCFAS BeST) that indicate behavioral differences in children born to younger mothers but no differences in behavior of children born to mothers who began drinking alcohol at a younger age. While the study was not able to establish validity or reliability for the CCFAS BeST due to the small homogenous sample, much was learned for continuing with the research.

Very little information is known about Fetal Alcohol Spectrum Disorders (FASD) within corrections populations, yet research suggests higher prevalence rates among these populations compared to the general population (Burd, Selfridge, Klug, & Bakko, 2004). In order to evaluate FASD within a corrections population, an established behavioral screener, FAS BeST (Robins & Andrews, 2009), was adapted for adults along with a selected protocol of cognitive and neuropsychological testing. The study aimed to identify testing performance and response patterns unique to individuals with an FASD in order to develop a cognitive and behavioral profile, and to evaluate the Self-Report and Adult Other version of the FAS BeST for reliability and validity. Participants included two groups: the first was recruited through a county drug court treatment program and probation offices (n = 13). The second group (n = 31) were recruited through social media Results verified reliability for the FAS BeST Self-Report and Adult Other versions as well as similarities in total scores between the Self-Report and Adult Other for the court population. Tactor analysis of the FAS BeST: Self-Report produced 3 significant components. Reliability of the measure for the online sample was not established and factor analysis components were weak. Further research is required in order to determine the validity of the FAS BeST: Self-Report and to generate a cognitive profile based upon neuropsychological testing.

Congenital heart disease/defects (CHDs) account for approximately one-third of all birth defects globally. Many of these will require invasive treatment within the first year of life, subsequent interventions, and a lifetime of monitoring. Alcohol has been known as a teratogen for several decades, and prenatal exposure alone is a significant cause of worldwide CHDs.Optical Coherence Tomography (OCT) has been used as an imaging modality for nearly three decades and is especially suited to the non-invasive imaging of small, semi-transparent tissue structures. Doppler OCT (DOCT) adds the ability to visualize and measure fluid flow and movement of reflective components within the tissue.This work presents the development of technology to further enable DOCT as a tool in measuring the function of anatomical structures. First, an interferometer design is described, which significantly reduces phase noise by incorporating a second, narrow band, continuous-wave light source as a phase-reference. By implementing this interferometer and related processing algorithms into a DOCT system, significant frequency noise reduction is demonstrated in reflective and scattering samples.Second, a modification to a DOCT system is presented using a single sample beam that provides velocity information from multiple angles within the beam. By introducing a delay element into part of the OCT beam path, the sample beam is divided into several components, each with a different group delay and each providing a separate interferogram with its own effective Doppler angle. By combining the Doppler shift measured in each of these component interferograms, the flow velocity vector is fully determined.OCT and DOCT are then applied to an embryonic avian model for Fetal Alcohol Spectrum Disorder (FASD) in order to study the effects of alcohol on early heart development. Folic acid is administered to a test group to learn more about its role in preventing CHDs. Through these embryonic studies, this work suggests that measurable changes in early-stage cardiac function could be not only an effect but also a cause of CHDs and that the introduction of substances such as folic acid could play a mitigative role at crucial junctures in cardiogenesis.

Prenatal alcohol exposure (PAE), the leading cause of childhood developmental disability, has long-lasting effects extending throughout the lifespan. The teratogenic effects of PAE, not always physically discernable, may corrupt brain structure resulting in neural dysfunction. These aberrant effects often result in executive functioning deficits, associated with social and academic difficulties, which hinder typical development. As maternal alcohol use during pregnancy is heavily stigmatized, children without physical dysmorphology often go unreported and untreated; resulting in increased deficiencies compared to those more severely affected who receive early life interventions. This phenomenon requires the discovery of neurophysiological makers of PAE in order to facilitate early identification and in turn early life interventions. Structural, functional, and behavioral deficits in individuals with PAE are well known. However, little research has been conducted assessing how these deficits in structure and function are associated together and with behavior. In this dissertation, we intend to show how white matter integrity as assessed by fractional anisotropy is associated with neural functioning, assed via magnetoencephalography, and how this association relates to behavior. It is well documented that children prenatally exposed to alcohol have difficulties inhibiting behavior and sustaining attention. Thus, the Sustained Attention to Response Task, a Go/No-go paradigm, is especially well suited to assess the behavioral and neural functioning characteristics of PAE children. This dissertation shows that children 8-12 years old with PAE have decreased associations between brain structure and functions, and that these deficits are associated with poorer performance on neuropsychological functioning.

Abstract: Ethanol (EtOH) exposure during development has been shown to lead to deficits in fine and gross motor control. In this study I used zebrafish embryos in the gastrulation stage to determine the developmental effects of a brief, 5-hour exposure to EtOH. I treated fertilized zebrafish eggs from 5.25 hours post fertilization (hpf) to 10.75 hpf, with 10 mM, 50 mM, 100 mM EtOH or 150 mM EtOH. Embryos were removed from the EtOH wash at the end of gastrulation and were allowed to develop. They were then examined for general animal morphology, the c-start reflex behavior, Mauthner cell morphology and motor neuron morphology in 2-day old embryos. EtOH treated animals exhibited a minor but significant increase in gross morphological deformities compared with untreated fish. Locomotor studies showed that EtOH treatment resulted in an increase in the average angular velocity of the tail bend during the escape response, and an increase in the peak speed of the tail. Furthermore, there was a marked increase in abnormally directed escape behaviors, with treated embryos showing greater incidences of c-starts in inappropriate directions. Immunolabelling of the Mauthner cells, which are born during gastrulation, showed them to be significantly smaller in fish treated with 100 mM EtOH and 150 mM EtOH compared with untreated animals. Immunolabelling of primary motor neurons using the anti-znp1antibody, showed no significant effect on axonal branching of primary motor neurons, whereas secondary motor axons possessed a greater number of branches in ethanol treated fish compared with controls. Together these findings indicate that ethanol exposure during gastrulation leads to alterations in behavior and neuronal morphology. The vitamin A derivative, RA, has been shown to prevent FASD in a number of preparations. Therefore, I determined whether co-treatment of alcohol and retinoic acid could prevent the effects of alcohol exposure during gastrulation. I exposed zebrafish embryos to either ethanol (150 mM) alone, retinoic acid (10-9 M) alone, or a combination of retinoic acid (10-9 M) plus ethanol (150 mM) for 5 hours from 5 hpf to 10.75 hpf (gastrulation). Ethanol treatment during gastrulation altered a range of features in embryonic zebrafish. Importantly, I found that co-treatment with retinoic acid prevented all of the effects of ethanol including survival, body length, M-cell morphology and escape response movements. Treatment with RA alone had no significant effect on any of these parameters. Together these findings show that ethanol exposure during the brief period of gastrulation has a significant effect on neuronal morphology, and that this can be prevented with retinoic acid co-treatment.

Variation is common in human birth defects and this variability is influenced by genes and the environment. How genes and the environment interact in causing birth defect variability is a fundamental question in biology. I sought to investigate these interactions using a zebrafish model of fetal alcohol spectrum disorder. Fetal alcohol spectrum disorder (FASD) is an umbrella term that describes all ethanol-induced fetal defects. It is highly variable and also highly prevalent, with an estimated 1% of the population being affected. FASD can cause variable defects, including those affecting the craniofacial skeleton, a neural crest- and mesoderm-derived structure. Although both timing and dosage can influence FASD variability, genetics is an underlying factor. Little is known of the genes that cause susceptibility to FASD, and so I sought to uncover these genes and the mechanism of their interaction with ethanol. Using a novel zebrafish genetic screen to uncover gene-ethanol interactions, we found a synergistic interaction between platelet-derived growth factor receptor alpha (pdgfra) and ethanol. Pdgfra is a receptor tyrosine kinase involved in cell migration, proliferation, and survival. Untreated pdgfra mutants display cleft palate. In a percentage of ethanol in which wildtype zebrafish are unaffected, pdgfra mutants display exacerbated loss of the entire palatal skeleton. Furthermore, pdgfra heterozygotes display variable craniofacial defects, uncovering latent haploinsufficiency. Genetic analysis of a group of children with and without FASD suggests that this interaction is highly conserved. In zebrafish, further analysis of the mechanism of this pdgfra-ethanol interaction revealed a protective role of pdgfra to ethanol-induced neural crest cell death. Analysis of the Pdgfra downstream pathway PI3K/AKT/mTOR revealed an inhibitory effect of ethanol at the level of mTOR. Together, these data suggest that genes functioning in growth factor signaling could predispose to ethanol-induced defects. Analysis of another growth factor signaling gene, fgf8a, supported this hypothesis. Ethanol interacts with fgf8a to cause posterior mesoderm-derived craniofacial defects. This phenotype can be recapitulated by blocking both fgf8a and fgf3, suggesting ethanol broadly attenuates growth factor signaling. Analysis of the fgf8a;fgf3 phenotype suggests that Fgf signaling is required for proper specification, via hyaluronan synthetase 2, of the mesoderm-derived posterior craniofacial skeleton. To test whether ethanol may also broadly attenuate Pdgf signaling, we analyzed pdgfra;pdgfrb mutant phenotypes and saw a recapitulation of the pdgfra-ethanol interaction. The synergistic pdgfra;pdgfrb phenotype may be due to a similar increase in neural crest cell death observed in the pdgfra-ethanol interaction. Together, these data reveal genes involved in growth factor signaling may act to protect against ethanol-induced craniofacial defects.

Maternal consumption of ethanol during pregnancy contributes to a set of pathologies, grouped together as the fetal alcohol spectrum disorders, affecting as many as 5% of live births in the United States annually. Ethanol acts widely in the developing embryo, affecting many tissues, but causing deficits in neuronal and neural crest populations particularly. These deleterious effects cause archetypical craniofacial expression and neurological deficits, including microcephaly and neuronal dysfunction. Severity of symptoms is linked to frequency of maternal alcohol consumption as well as the maximum blood alcohol concentration reached by the mother. The teratology of ethanol has been widely researched over the last four decades, with the link between the neural crest pathology and the fetal alcohol spectrum phenotype becoming clearer. Animal model studies have managed to replicate many of the symptoms seen in humans afflicted with fetal alcohol spectrum disorders, and have allowed us to elucidate the biochemical mechanisms behind the disease. There is no singular pathway responsible for the fetal alcohol spectrum disorders: over half a dozen models of dysfunction have been identified, and ethanol’s ability to react with a series of targets means that more pathways are likely to be discovered. Current theories regarding the effects of ethanol on the neural crest have implicated apoptosis of the cephalic neural crest, mediated by G-protein coupled receptors, activation of a phospholipase C pathway, and subsequent release of intracellular calcium; perturbations of the actin cytoskeleton leading to migration dysfunction of neural crest cells in the developing neural tube; lack of functional trophic molecules, specifically Shh, likely due to dysfunction of the cholesterol biosynthetic pathway; lack of retinoic acid production; oxidative stress, production of reactive oxygen species, and iron dysregulation; and genetics, which seems to confer greater susceptibility and resistance to ethanol in certain individuals. Ultimately, a global model for ethanol’s actions on the developing fetus eludes researchers, as do any potential treatments, and more research is required to further elucidate ethanol’s teratogenic mechanism.

Alcohol is a potent teratogen to the developing CNS, and moderate-heavy alcohol intake during pregnancy causes fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD). These patients display CNS symptoms associated with developmental deficits, cognitive impairment and social abnormalities, with structural impairments in several brain regions. In this dissertation, we investigated the role of FASD in neurogenic functional deficits in the adult hippocampal dentate gyrus. The dentate gyrus is a subregion of the hippocampus that displays unique plasticity, in that new dentate granule neurons are continuously produced throughout life. Adult hippocampal neurogenesis is thought to play key roles in pattern separation and associative learning and in depression-like behaviors. Interestingly, adult neurogenesis is stimulated by physical and social enrichment (enriched environments) and learning. It is becoming increasingly apparent that prenatal alcohol exposure produces long-lasting impairments in postnatal hippocampal neurogenesis and learning impairment. My dissertation research addressed the hypothesis that prenatal alcohol exposure (FASD) impairs the EE-mediated survival and electrophysiological properties of newborn DGCs in the adult hippocampus. Utilizing a combination of histological, behavioral and electrophysiological approaches, we addressed the following specific aims Specific Aim 1: To determine whether prenatal alcohol (FASD) impairs the neurogenic response to environmental enrichment in adult Nestin:CreERT2:YFP bitransgenic mice; and if so, to delineate the stage of neural stem cell lineage most impacted by prenatal alcohol exposure. Specific Aim 2: To determine whether adult-generated DGCs in FASD mice display normal electrophysiological properties after developing under standard and enriched conditions. Specific Aim 3: To determine whether adult-generated DGCs in FASD mice display dendritic morphological plasticity in response to enriched environment. My overall findings indicate that FASD severely impairs the late-stage survival of adult-generated DGCs and disrupts the electrophysiological response to EE in the existing granule cell layer, and that this is accompanied by heightened excitatory synaptic transmission in surviving DGCs. These findings suggest that FASD imparts resistance to the full benefits of social and physical enrichment therapies through both impairment of neurogenic and GCL circuitry mechanisms.

Embryonic ethanol exposure is known to cause birth defects and neurodevelopmental disorders in many vertebrates, including humans. In this study, zebrafish (D. rerio) were used to investigate the affects of embryonic ethanol exposure on embryo/larval development and the subsequent adult behavior. Although zebrafish have become a widely used model for prenatal alcohol exposure, in many cases the concentrations used are high and the period of observation is short. In order to record both larval and adult measures, this study utilized a low concentration of ethanol (0.4%) throughout the embryonic period of development (0-72 days post fertilization). Anatomical and physiological data was collected from larvae (including eye and heart measures) to investigate the affects of ethanol on embryonic development and an aggression/avoidance assay was used to determine if embryonic ethanol exposure influenced adult behavioral phenotypes. Exposure to ethanol throughout embryonic development resulted in decreased eye size, increased ventricle area, increased cardiovascular function, and reduced size in the larvae. In the adult fish, neither measures of size nor behavior of the treatment group were found to be significantly different from that of the control. In conclusion, low levels of embryonic ethanol exposure can result in changes in both form and function of larval anatomy and physiology. However, this affect does not seem to carry into adulthood through size or behavioral aggression/avoidance behaviors.

Children with Fetal Alcohol Spectrum Disorder exhibit long lasting behavioral impairments, such as learning disabilities, problems in executive functioning and memory deficits. Currently, there are no rationally designed, clinically available pharmacological tools to circumvent prenatal alcohol-induced cognitive deficits. Recently, using a rat model of voluntary drinking during pregnancy, Savage and collaborators (2010) showed that the inverse agonist of histamine H3 receptors reverses fetal ethanol-induced deficits in learning and memory, without further increasing cognition in control rats. These differential effects and the notion that H3 receptors reside in presynaptic nerve terminals to inhibit neurotransmitter release, led to the hypothesis that fetal alcohol exposure elevates histamine H3 receptor-mediated depression of glutamate release from perforant path nerve terminals in the dentate gyrus, and that this effect may contribute to the observed long-term potentiation (LTP) deficit in these animals. In the present study, this hypothesis was examined using a combination of electrophysiological and radiohistochemical approaches. Long-Evans rat dams voluntarily consumed between 2.40 and 2.82 g/kg/day of 5% sweetened ethanol solution throughout gestation. This level of consumption produced a mean peak serum ethanol concentration of 84 mg/dL. No differences in offspring birthweight or litter size were observed. Prenatal alcohol exposure did not significantly affect electrophysiological raw measures of granule cell responsiveness or baseline probability of glutamate release in the dentate gyrus, but significantly impaired coupling of population spikes-to-fEPSP slopes and LTP of perforant path-to-granule cell synapses. Prenatal alcohol-induced LTP deficit was reversed by systemic injection of the inverse agonist of H3 receptors ABT-239 in-vivo, without further improvement in control rats. Conversely, agonism of these receptors by systemic injection of methimepip mimicked the LTP deficit in control offspring both in-vivo and in-vitro, without further decreasing LTP in prenatal alcohol exposed rats. Measurement of methimepip-stimulated binding of [35S]-GTPyS in the dentate gyrus in prenatal alcohol exposed rats suggested an increased H3 receptor-effector coupling in these animals. This increased receptor-effector coupling resulted in heightened agonist inhibition of glutamate release in-vitro, but not in-vivo. No differences were found in the density of histamine H3 receptors in the dentate gyrus. Taken together, these results suggest that heightened H3 receptor-mediated modulation of glutamate release in the dentate gyrus of fetal-ethanol exposed rats is a possible contributing mechanism for LTP deficit observed in these animals. It is expected that these experiments will provide insights into the mechanisms by which prenatal ethanol exposure affects hippocampal-dependent learning and memory. A better understanding of this phenomenon may provide targets for therapeutic intervention in children with alcohol-related neurodevelopmental disorders.