Background: Sleep disorders have been poorly described in children and adolescents diagnosed with FASD. The objective of this study is to describe the sleep and circadian rhythm characteristics of children with FASD using overnight polysomnography, sleep questionnaires, and the Dim Light Melatonin Onset (DLMO) test. To our knowledge, no comprehensive studies of this nature have been conducted. Methods: Children ages 6-18 years diagnosed with Fetal Alcohol Spectrum Disorder (FASD) were recruited from various FASD clinics to the Youthdale Child and Adolescent Sleep Centre in Toronto. After medical consultation, each participant had one night of overnight polysomnography, as well as an additional night of DLMO. Participants completed various sleep and FASD questionnaires. Results: Significant differences were found when comparing the sleep architecture of FASD participants to normative data. There was a high prevalence of sleep disorders in this sample. Most of the melatonin profiles of the FASD participants were found to be abnormal.

The purpose of this study was to investigate the work of three administrators and their staffs as they attempted to solve the ill-structured problem of integrating students with fetal alcohol spectrum disorders (FASD) into their schools. A further purpose of the study was to investigate the role played by schools in influencing community responses that would enhance the post-school lives of students with FASD.<p>The study was conducted throughout one academic year and involved three schools in northern Canada. The use of Problem Based Methodology (PBM) permitted research to be conducted within the schools to generate solutions to the problem. By working with their staff, administrators were afforded opportunities to examine their theories in action and engage in double-loop learning as they searched for new theories of action and alternate constraint constructs.<p>The data for the study were derived from interviews with participating practitioners, parents, health professionals, and District Educational Authority (DEA) members. This permitted the gathering of spontaneous comments and general opinions to be turned into systemic records and detailed statements. The use of PBM determined that data selection involved a search for behaviours in classes of interest. Potential classes of interest were identified prior to the beginning of the study. By the use of a constraint structure, parameters were established for acceptable solutions that generated a theory of action for the ill-structured problem. The four criteria of explanatory accuracy, effectiveness, coherence and improvability were used in theory adjudication (Robinson 1993). Critical dialogue was used between the researcher and participants to collectively make decisions and solve problems through the exchange of the best possible information.<p>The study suggested implications for organizational theory that could better enable administrators and staff to address this ill-structured problem. The isolation and lack of resources oblige staff to create conditions conducive to inquiry and learning (Schon 1983). In the case of initial solutions the theories in action were similar, suggesting that assumptions surrounding the role of contextual factors caused by the heterogeneous nature of the schools are misleading. Prior to the study by Godel et al. (2000) lack of diagnosis diffused the urgency of the problem. Following the publication of the data from that study the lack of screening and diagnosis was a major challenge to stakeholders. Generation of data on the children with FASD in northern communities is essential to generate an organizational and professional focus.

Introduction: The Canadian Medical Association (CMA) released guidelines for Fetal Alcohol Spectrum Diagnosis (FASD) in 2005 that attempted to equalize diagnostic practices across Canada. A multi-disciplinary neurodevelopmental assessment is expected and the occupational therapist must assess soft neurological signs, which includes sensory processing and motor development. In 2007, Northwest Partnership for FASD Research gathered a panel of OTs to consult on assessment tools who chose the Short Sensory Profile (SSP) as the main sensory processing assessment tool. Methods: Six qualitative interviews were completed for data collection. The inclusion criterion for the participants were involvement with a FASD diagnostic team and familiarity with the SSP. Qualitative data from the interviews was coded for likeness and analyzed for themes. Results: Three main themes developed from this research including: “Uncertainties about the FASD Diagnostic Process”, “Questioning the Validity of the Assessment Tool SSP” and “Strengths of the SSP”. The overaching theme that emerged was that the participants were attempting to find balance in many different ways throughout their assessments. While participants predominantly focused on concerns, they also indicated that the SSP is our best option at this time. Conclusions: Participants were not completely satisfied with using the SSP for FASD diagnostic assessments but will continue to use it. It was suggested that the panel of occupational therapists should reconvene and consider further options for assessment of sensory processing for FASD diagnostic assessments. There were also considerations for occupational therapy university education and continuing education.

Interrogative suggestibility refers to the extent to which an individual internally accepts messages communicated during a formal questioning situation, as indicated by an external response. Research indicates low intelligence, poor memory and weak inhibitory control is associated with heightened suggestibility. Children with fetal alcohol spectrum disorder (FASD) may also display deficits in these key areas, indicating a potential vulnerability to suggestion. The present study compared levels of suggestibility among alcohol exposed and typical children. The findings indicate that children with FASD may be at heightened risk to suggestion following negative feedback or pressure. In addition, a large amount of the suggested material was elicited and internalized as truth by all children, dependent on question format. These findings have important consequences for future interrogative interactions with children with and without FASD, to ensure information is not presented and thus elicited in a suggestive manner. / Graduate

Indiana University-Purdue University Indianapolis (IUPUI) / The emerging field of epigenetics is expanding our understanding of how biological diversity is generated in the face of genetic limitations. One epigenetic mechanism in particular, DNA methylation, has demonstrated a dynamic range during neural development. Here, we provide evidence that DNA methylation occurs as a cell unique program aiding in the regulation of neurodevelopmental gene expression. DNA methylation has demonstrated sensitivity to external inputs ranging from stress to chemical exposure and dietary factors. To explore DNA methylation as a means of communicating early-life stress to the brain, we utilized a mouse model of fetal alcohol spectrum disorders (FASD). FASD presents a range of neurodevelopmental deficits and is a leading cause of neurodevelopmental disabilities in the United States. Predicated on the knowledge of alcohol's teratogenic role in brain development, we describe that the normal pattern of cortical DNA methylation and epigenetic correlates is similarly impacted by prenatal alcohol exposure. Due to the biochemical interaction of alcohol metabolism and the pathways regulating DNA methylation synthesis, we further investigated whether dietary manipulation could normalize the cortical DNA methylation program and aid in the protection of FASD characteristics. We found that the alcohol sensitive DNA methylation landscape is dually capable of registering dietary intervention, demonstrating normalization of disease-related patterns in the cortex and improved neurodevelopmental gene expression and morphology. Finally, we investigated the DNA methylation landscape in a crucial corticodevelopmental gene to more accurately define the breadth and scope of the environmental impacts at the nucleotide level. We found that alcohol and dietary supplementation are selective for regions associated with transcriptional control. Collectively, the evidence supports that DNA methylation plays a regulatory role in development and that its sensitivity to external inputs is dynamic and detectable at the smallest genomic level. Importantly, DNA methylation landscapes are adaptable and thus bear diagnostic and therapeutic potential.

L’exposition du fœtus à l’éthanol est reconnue comme étant la principale cause de maladies évitables lors du développement. Une forte exposition à l’alcool durant la gestation peut occasionner des dysmorphies cranio-faciales et des retards mentaux, ainsi que des troubles d’apprentissages et du comportement. Le développement du système visuel est également perturbé chez une grande majorité d’enfants qui ont été exposés à l’alcool. Lorsque les doses prises sont élevées, le système visuel peut présenter une panoplie de symptômes comme une augmentation de la tortuosité des vaisseaux rétiniens, de la myopie, de l’hypermétropie, du strabisme et une hypoplasie du nerf optique. Cependant, très peu d’études se sont penchées sur les effets de plus faibles doses sur le développement du système visuel du primate. Le singe est un excellent modèle pour étudier le système visuel car il possède plusieurs similitudes avec l’humain tant au niveau développemental qu’au niveau structurel. De plus, le singe utilisé, le Chlrocebus aethiops sabeus, possède l’avantage que des individus de cette espèce ont une consommation naturelle et volontaire à l’alcool. Une étude (Clarren et al., 1990) a suggéré qu’une faible exposition à l’alcool du fœtus du primate non humain occasionnait une diminution du nombre de cellules ganglionnaires de la rétine (CGRs). Étant donné que le corps genouillé latéral dorsal (CGLd) reçoit la plupart de ses intrants de la rétine, il est raisonnable d’assumer que les couches rétino-récipientes du CGLd devraient être aussi affectées. Nous avons alors émis l’hypothèse que le CGLd devrait également subir une diminution du nombre de neurones. Pour la première fois, nous avons utilisé une méthode stéréologique pour quantifier le nombre de cellules dans les couches parvo- (P) et magnocellulaires (M) du CGLd. Contrairement à notre hypothèse de départ, nous n’avons pas observé de diminution dans le nombre global de neurones dans le CGLd des animaux exposés à l’alcool par rapport à des sujets contrôles, ni une diminution de son volume. Nous avons toutefois observé une diminution de la taille du corps cellulaire seulement dans la population M du CGLd. Ces résultats suggèrent que le système visuel est affecté par une faible exposition à l’alcool durant son développement qui devrait se traduire sur le comportement par des déficits dans les fonctions de la voie M. / An alcohol exposition during the gestation is recognized as the leading causes of preventable developmental disorders. A heavy exposure to ethanol can lead to a litany of symptoms ranging from cranio-facial dysmorphology and mental retardation to developmental learning and behavioural disorders. The visual system development is also the target for a high percentage of children exposed prenatally to alcohol. When the concentrations are relatively high, the visual system can show signs of increased tortuosity of the retina vessels, myopia, hyperopia, strabismus and hypoplasia of the optic nerve. Few studies have examined the effects of a moderate exposure to alcohol on the development of the primate visual system. The monkey is an excellent model to study the visual system because this model owns a lot of similarities with human at the developmental and structural levels. Moreover, the monkey used for this study, Chlrocebus sabeus, naturally and voluntarily consumes alcohol. One study (Clarren et al., 1990) suggested that a low dose exposure of alcohol induce a diminution of neurons in the ganglion retinal cell population. But, no information is given about the numbers and the cell population of neurons. We hypothesized that the lateral geniculate nucleus (LGN) should show a decrease in the number of neurons after moderate prenatal exposure to alcohol. The LGN is a key region because it is situated between the region that receives visual information, the retina, and the first visual region that analyzes the visual information, the primary visual cortex (V1). We utilized a stereological method to study the effects of moderate doses of alcohol on the neuronal population of the LGN in the non-human primate. In opposition to our hypothesis, we have not observed any diminution in the number of neurons or the volume of the LGN. However, we have found a diminution in the neuronal volume of only the magnocellular (M) region. These results suggest that the visual system is affected by a low dose of alcohol that should translate into deficits in the functions of the M pathway.

L’exposition du fœtus à l’éthanol est reconnue comme étant la principale cause de maladies évitables lors du développement. Une forte exposition à l’alcool durant la gestation peut occasionner des dysmorphies cranio-faciales et des retards mentaux, ainsi que des troubles d’apprentissages et du comportement. Le développement du système visuel est également perturbé chez une grande majorité d’enfants qui ont été exposés à l’alcool. Lorsque les doses prises sont élevées, le système visuel peut présenter une panoplie de symptômes comme une augmentation de la tortuosité des vaisseaux rétiniens, de la myopie, de l’hypermétropie, du strabisme et une hypoplasie du nerf optique. Cependant, très peu d’études se sont penchées sur les effets de plus faibles doses sur le développement du système visuel du primate. Le singe est un excellent modèle pour étudier le système visuel car il possède plusieurs similitudes avec l’humain tant au niveau développemental qu’au niveau structurel. De plus, le singe utilisé, le Chlrocebus aethiops sabeus, possède l’avantage que des individus de cette espèce ont une consommation naturelle et volontaire à l’alcool. Une étude (Clarren et al., 1990) a suggéré qu’une faible exposition à l’alcool du fœtus du primate non humain occasionnait une diminution du nombre de cellules ganglionnaires de la rétine (CGRs). Étant donné que le corps genouillé latéral dorsal (CGLd) reçoit la plupart de ses intrants de la rétine, il est raisonnable d’assumer que les couches rétino-récipientes du CGLd devraient être aussi affectées. Nous avons alors émis l’hypothèse que le CGLd devrait également subir une diminution du nombre de neurones. Pour la première fois, nous avons utilisé une méthode stéréologique pour quantifier le nombre de cellules dans les couches parvo- (P) et magnocellulaires (M) du CGLd. Contrairement à notre hypothèse de départ, nous n’avons pas observé de diminution dans le nombre global de neurones dans le CGLd des animaux exposés à l’alcool par rapport à des sujets contrôles, ni une diminution de son volume. Nous avons toutefois observé une diminution de la taille du corps cellulaire seulement dans la population M du CGLd. Ces résultats suggèrent que le système visuel est affecté par une faible exposition à l’alcool durant son développement qui devrait se traduire sur le comportement par des déficits dans les fonctions de la voie M. / An alcohol exposition during the gestation is recognized as the leading causes of preventable developmental disorders. A heavy exposure to ethanol can lead to a litany of symptoms ranging from cranio-facial dysmorphology and mental retardation to developmental learning and behavioural disorders. The visual system development is also the target for a high percentage of children exposed prenatally to alcohol. When the concentrations are relatively high, the visual system can show signs of increased tortuosity of the retina vessels, myopia, hyperopia, strabismus and hypoplasia of the optic nerve. Few studies have examined the effects of a moderate exposure to alcohol on the development of the primate visual system. The monkey is an excellent model to study the visual system because this model owns a lot of similarities with human at the developmental and structural levels. Moreover, the monkey used for this study, Chlrocebus sabeus, naturally and voluntarily consumes alcohol. One study (Clarren et al., 1990) suggested that a low dose exposure of alcohol induce a diminution of neurons in the ganglion retinal cell population. But, no information is given about the numbers and the cell population of neurons. We hypothesized that the lateral geniculate nucleus (LGN) should show a decrease in the number of neurons after moderate prenatal exposure to alcohol. The LGN is a key region because it is situated between the region that receives visual information, the retina, and the first visual region that analyzes the visual information, the primary visual cortex (V1). We utilized a stereological method to study the effects of moderate doses of alcohol on the neuronal population of the LGN in the non-human primate. In opposition to our hypothesis, we have not observed any diminution in the number of neurons or the volume of the LGN. However, we have found a diminution in the neuronal volume of only the magnocellular (M) region. These results suggest that the visual system is affected by a low dose of alcohol that should translate into deficits in the functions of the M pathway.

Alcohol use and abuse has many harmful effects, especially to children exposed prenatally, including fetal alcohol spectrum disorders (FASDs). The disabilities due to fetal alcohol exposure continue throughout life and cause major financial burdens to society. The molecular mechanisms underlying FASDs are not well understood. We have taken a genetic approach to characterize ethanol’s effect on changing a discrete cell fate decision during embryogenesis in the nematode, Caenorhabditis elegans (C. elegans). Our preliminary data suggest that ethanol can affect the development of AWC neurons, a pair of olfactory neurons in C. elegans. We suggest that lipids can protect AWC neurons from ethanol’s effects. Importantly, we show that altering the metabolism of triacylglycerols (TAGs) can rescue this cell fate change in behavioral assays. By identifying molecular causes of fetal alcohol damage in humans we hope to be able to develop a greater understanding of how to prevent these detrimental effects.

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.

Prenatal alcohol exposure (Fetal Alcohol Syndrome [FAS] and Fetal Alcohol Spectrum Disorders [FASD’s]) represents the leading preventable cause of intellectual disabilities in the western world, with FASDs estimated to affect approximately 2-5% of live births in the United States at an approximate annual cost of $3.6 billion (CDC, 2015; May et al., 2009). Ethanol (ETOH) exposure during development can lead to a variety of long-term behavioral impairments including problems with executive functioning, motor coordination, spatial learning, attention, and hyperactivity (Jones, 2011; Mattson & Riley, 1998). Much research has been conducted to develop pharmacological and/or environmental interventions to reduce these deficits, however, there are currently no clinically approved medications to treat the deficits related to fetal ETOH exposure. The current study used a developmental “3rd trimester” ETOH exposure model in neonatal rats to test the hypothesis that compounds targeting the nicotinic system will reduce deficits associated with ETOH exposure. Both compounds demonstrated promise in reducing some of the effects of developmental ethanol exposure, with DMXB-A treatment after ethanol exposure reducing balance deficits in females and spatial memory deficits in males. Solidago nemoralis treatment after ETOH exposure reduced learning and memory deficits in males and balance and executive functioning deficits in both sexes. With these results and previous work in this lab and others there appears to be ample evidence for their usefulness in reducing various forms of neurotoxicity. The long-term goal of this research is to evaluate the usefulness of both DMXB-A & Solidago nemoralis (SN) in treating deficits related to developmental ETOH exposure in humans and hopefully develop a treatment for these disorders.