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The cognitive and/or behavioural problems associated with Fetal Alcohol Spectrum Disorder (FASD) place this population at increased risk of involvement in the justice system. Although FASD poses challenges at each stage of the justice system, legal discussion and commentary have pinpointed the sentencing stage as the phase in which the issue of FASD is most commonly raised and considered. The purpose of this study is to examine if (and how) FASD is being taking into consideration at sentencing. To this end, a comparative analysis of 87 sentencing judgments (42 FASD offenders and 45 non-FASD offenders) reported in Quicklaw was conducted. Cases were matched on most serious offence (assault, robbery and sexual assault) and jurisdiction (Yukon, British Columbia and Ontario). Descriptions of FASD and non-FASD offenders as reported by judges were found to differ in a number of significant ways. Similarly, sentencing purposes applied to each offender group emerged as distinct. Despite these distinctions, no differences were found in the type and length of sentence handed down (even after controlling for criminal record and breaches). These findings indicate a need for further research and possible policy changes.

Objective: Fetal alcohol spectrum disorder (FASD) is a permanent developmental disorder that can occur if women drink alcohol while pregnant. Despite substantial variability in FASD as a population, anecdotal evidence and clinical reports suggest that affected individuals have difficulty learning from experience and generalizing information from one situation to another, and tend to make the same mistakes over and over. Consistent with research in cognitive and educational psychology, these difficulties were conceptualized as impairments in “transfer of learning.” This dissertation sought to measure transfer of learning using three experimental transfer measures and an exploratory parental transfer questionnaire. In addition, performance on the experimental transfer measures was investigated in relation to aspects of executive functioning, because abilities thought to underlie successful transfer bear much resemblance to aspects of executive functioning. Participants and Methods: The sample included 16 children diagnosed with FASD and 16 age- and gender-matched control children. Children were screened for intelligence and excluded if their performance on both Vocabulary and Matrix Reasoning from the WISC-IV fell below the 9th percentile. Children completed three transfer tasks: (1) a novel, experimental modification of the Tower of Hanoi involving nested plastic cups and Tupperware containers; (2) a variation of Chen’s (1996) Bead Retrieval Problem; and (3) the Purdue Pegboard. Participants also completed three executive functioning tasks that were selected to measure concept formation and flexibility: (1) Picture Concepts from the WISC-IV; (2) the D-KEFS Color-Word Interference Test; and (3) the Visual-Verbal Test. In addition, parents or caregivers completed an exploratory questionnaire designed to assess children’s transfer of learning abilities in everyday life, along with the ABAS-II, a standardized measure of adaptive functioning. Results: Children with FASD displayed significantly weaker performance on the Transfer Condition of the Tower of Hanoi, even after controlling for intelligence. Group differences were not observed on the Bead Retrieval Problem or on the Purdue Pegboard. On the measures of executive functioning, control children outperformed those with FASD on all measures before controlling for intelligence. In addition, there was a significant relationship between the Tower of Hanoi and the Visual-Verbal Test; the latter was the only executive functioning task related to transfer of learning. This finding, however, did not persist when intelligence was accounted for. After controlling for intelligence, significant group differences also were found on parental ratings of everyday transfer ability and on more complex aspects of adaptive functioning. Conclusions: Two out of four newly created measures in this exploratory dissertation provided partial support for weak transfer of learning in FASD. This was observed on the modified Tower of Hanoi, which shared an identical structure between conditions but differed in surface appearance. Parental ratings also indicated weak transfer of learning, although in children with FASD, these reports did not correlate with transfer abilities on the Tower of Hanoi. Children with FASD also demonstrated weak executive functioning, but this weakness was moderated significantly by intelligence. The relationship between transfer of learning and executive functioning appeared to be driven primarily by cognitive flexibility, although this relationship also was moderated by intelligence.

The cognitive and/or behavioural problems associated with Fetal Alcohol Spectrum Disorder (FASD) place this population at increased risk of involvement in the justice system. Although FASD poses challenges at each stage of the justice system, legal discussion and commentary have pinpointed the sentencing stage as the phase in which the issue of FASD is most commonly raised and considered. The purpose of this study is to examine if (and how) FASD is being taking into consideration at sentencing. To this end, a comparative analysis of 87 sentencing judgments (42 FASD offenders and 45 non-FASD offenders) reported in Quicklaw was conducted. Cases were matched on most serious offence (assault, robbery and sexual assault) and jurisdiction (Yukon, British Columbia and Ontario). Descriptions of FASD and non-FASD offenders as reported by judges were found to differ in a number of significant ways. Similarly, sentencing purposes applied to each offender group emerged as distinct. Despite these distinctions, no differences were found in the type and length of sentence handed down (even after controlling for criminal record and breaches). These findings indicate a need for further research and possible policy changes.

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 consumption during pregnancy is one potential risk factor for spontaneous abortion (SAb). Prior research suggested that heavy drinking during pregnancy was associated with significantly increased rates of SAb, but results for lower levels of drinking have been inconsistent. We examined the association between different levels and patterns of prenatal alcohol consumption and SAb in a high-risk inner-city sample. We hypothesized that higher levels, binge patterns, and more frequent drinking would be associated with increased rates of SAb. The quantity and frequency of self-reported peri-conceptional and repeated in-pregnancy maternal drinking volumes per beverage type were assessed with semi-structured interviews in a prospective subsample of 302 African-American mothers. Relations between various measures of prenatal alcohol exposure and SAb were assessed using logistic regression. After controlling for various potential confounders, there was a significant positive relation between average absolute alcohol use per day across pregnancy and SAb. Greater frequency of drinking episodes also predicted SAb: an average of even one day of drinking per week across pregnancy was associated with an increase in the incidence of SAb. However, contrary to our hypothesis, neither the amount of alcohol drunk per drinking day nor a measure of binge drinking was significantly related to SAb after controlling for confounders. Differences in when women who drank at risk levels initiated antenatal care may have under-estimated the impact of alcohol on SAb in this low-SES urban African-American sample. Some drinking measures averaged across pregnancy may have under-estimated consumption and overestimated risk of SAb, but other risk drinking measures that avoid this limitation show similar relations to SAb. Identifying fetal risk drinking in pregnant women is critical to increasing the effectiveness of interventions that reduce risk level alcohol consumption and protect from pregnancy loss.

Background: Fetal alcohol spectrum disorder (FASD) is a challenging public health problem. Previous studies have found an association between FASD and oxidative stress. In the present study, we assessed the role of oxidative stress in ethanol-induced embryonic damage and the effect of (-)-epigallocatechin-3-gallate (EGCG), a powerful antioxidant extracted from green tea, on the development of FASD in a murine model.Methods: Pregnant female mice were given intraperitoneal ethanol (25%, 0.005 to 0.02 ml/g) on gestational day 8 (G8) to establish the FASD model. On G10.25, mice were sacrificed and embryos were collected and photographed to determine head length (HL), head width (HW), and crown rump length (CRL). For mice given EGCG, administration was through a feeding tube on G7 and G8 (dose: 200, 300, or 400 mg/kg/d, the total amount for a day was divided into 2 equal portions). G10.25 embryos were evaluated morphologically. Brain tissues of G9.25 embryos were used for RT-PCR and western blotting of neural marker genes and proteins and detection of oxidative stress indicators.Results: Administration of ethanol to pregnant mice on G8 led to the retardation of embryonic growth and down-regulation of neural marker genes. In addition, administration of ethanol (0.02 ml/g) led to the elevation of oxidative stress indicators [hydrogen peroxide (H2O2) and malondialdehyde (MDA)]. Administration of EGCG on G7 and G8 along with ethanol on G8 ameliorated the ethanol-induced growth retardation. Mice given EGCG (400 mg/kg/d) along with ethanol had embryo sizes and neural marker genes expression similar to the normal controls. Furthermore, EGCG (400 mg/kg on G7 and G8) inhibited the increase in H2O2 and MDA.Conclusions: In a murine model, oxidative stress appears to play an important role in ethanol-induced embryonic growth retardation. EGCG can prevent some of the embryonic injuries caused by ethanol.

Background: Fetal alcohol spectrum disorders (FASD), which are caused by prenatal alcohol exposure (PAE), affects people around the world. Certain communities in South Africa have among the highest reported incidences of fetal alcohol syndrome (FAS) in the world. Although PAE-related brain alterations have been widely documented, the mechanisms whereby alcohol affects the brain are not clearly understood. MRI relaxation parameters T1, T2, T2* and proton density (PD), are basic tissue properties that reflect the underlying biology. The present study aims to advance our understanding of how PAE alters the microstructural properties of tissue by examining PAE-related changes in these tissue parameters in adolescents with FASD. Methods: The final sample used in this study consisted of 53 children from a previously studied longitudinal cohort (Jacobson et al., 2008) and 12 additionally recruited subjects. Of the 65 participants, 18 were diagnosed with FAS or partial FAS (PFAS) and made up the FAS/PFAS group, 18 were diagnosed as heavily exposed non-syndromal (HE) and 29 were age matched controls. Subjects were scanned at the Cape Universities Body Imaging Centre (CUBIC) located at Groote Schuur Hospital on a 3T Siemens Skyra MRI. Structural images were obtained using the MEMPRAGE sequence. From these images T1, T2, T2* and PD parameter maps were constructed and segmented into 43 regions of interest (ROI) using Freesurfer, FSL and AFNI. Linear regression analyses were used to analyse group differences as well as correlations between parameter values and the amount of alcohol the mother consumed during pregnancy. Results: Significant T1 differences were found in the caudate, cerebellar cortex, hippocampus, accumbens, putamen, choroid plexus, ventral diencephalon (DC), right vessel and ventricles. Significant T2 differences were found in the caudate, brain stem, corpus callosum (CC), amygdala, cerebral cortex, choroid plexus, vessels and ventricles. Significant T2* differences were found in the cerebellar cortex, optic chiasm and ventricles. Significant PD differences were found in the hippocampus and left lateral ventricle. The exploratory nature of this study resulted in none of the results surviving FDR correction for multiple comparisons. Conclusions: Overall, our findings point to regional PAE-related increases in water content and cellular and molecular changes in underlying tissue of the anatomical structure. Exceptions were the right cerebral cortex, brain stem, hippocampus, amygdala and ventral diencephalon where our findings point to less free water and increased cell density, and cerebellar cortex where simultaneous reductions in T1 and T2* suggest the possibility of increased iron content. In highly myelinated white matter structures, such as the CC and optic chiasm, our results point to PAErelated demyelination, and possibly increased iron. These findings extend previous knowledge of effects of PAE and demonstrate that tissues are affected at a microstructural level.

Includes bibliographical references (leaves 73-79). / In vivo magnetic resonance spectroscopy (MRS) is an imaging technique that allows the chemical study of human tissue non-invasively. The method holds great promise as a diagnostic tool once its reliability has been established. Inter-scanner variability has, however, hampered this from happening as results cannot easily be compared if acquired on different scanners. In this study a phantom was constructed to determine the localisation efficiency of the 3 T Siemens Allegra MRI scanner located at the Cape Universities Brain Imaging Centre (CUBIC). Sufficient localisation is the key to acquiring useful spectroscopic data as only the signal from a small volume of interest (VOI) is typically acquired. The phantom consisted of a Perspex cube located inside a larger Perspex sphere. Solutions of the cerebral metabolites N-acetyl aspartate (NAA) and choline (Cho) were placed in the inner cube and outer sphere respectively. The phantom was scanned at a range of voxel sizes and echo times in order to determine parameters that typically indicate the performance of the scanner in question. The resultant full width at half maximum (FWHM) and signal to noise ratio (SNR) values indicated that optimal results were obtained for a voxel with dimensions 20 x 20 x 20 mm3. The selection efficiency could not be measured due to limitations in the scanner, but two other performance parameters ' extra volume suppression (EVS) and contamination ' could be determined. The EVS showed that the scanner was able to eliminate the entire background signal from the out-of-voxel region when voxel sizes with dimensions (20 mm)3 and (30 mm)3 were used. This performance decreased to 96.2% for a voxel size of (50 mm)3. The contamination indicated that the unwanted signal, weighted by the respective proton densities of the chemicals, ranged from 12% in the (20 mm)3 voxel to 24% in the (50 mm)3 voxel. These ranges are well within acceptable limits for proton MRS. Analysis of the water suppression achieved in the scanner showed an efficiency of 98.84%, which is acceptable for proton spectroscopy. It was also found that manual iv shimming of the scanner improved the spectra obtained, as compared to the automated shimming performed by the scanner. The second objective of the study was to quantify absolute metabolite concentrations in the familiar SI units of mM as results were previously mostly expressed as metabolite ratios. The LCModel software was used to assess two methods of determining absolute metabolite concentrations and the procedure using water scaling consistently showed superior performance to a method using a calibration factor. The method employing water scaling was then applied to a study of fetal alcohol spectrum disorder (FASD) where the deep cerebellar nuclei of children with FASD and a control group were scanned. The cerebellar nuclei were of interest as children with FASD show a remarkably consistent deficit in eye blink conditioning (EBC). The cerebellar deep nuclei is known to play a critical role in the EBC response. The results show significant decreases in the myo-inositol (mI) and total choline (tCho) concentrations of children with FASD in the deep cerebellar nuclei compared to control children. The FAS/PFAS subjects have a mean mI concentration of 4.6 mM as compared to a mean of 5.3 mM in the controls. A Pearson correlation showed that there was a significant relationship between decreasing mI concentrations with increasing prenatal alcohol exposure. The mean tCho concentrations are 1.3 mM for FAS/PFAS and 1.5 mM for the controls. There was no significant differences between the heavily exposed group and either the FAS/PFAS or the control subjects for either metabolite. The decreased mI and tCho concentrations may indicate deficient calcium signalling or decreased cell membrane integrity ' both of which can explain the compromised cerebellar learning in FASD subjects.

Indiana University-Purdue University Indianapolis (IUPUI) / Fetal alcohol spectrum disorder (FASD) is a result of prenatal alcohol exposure, producing a wide range of defects including craniofacial, sensory, motor and cognitive deficits. Many ocular abnormalities are frequently associated with FASD including microphthalmia, optic nerve hypoplasia, and cataracts. FASD is highly prevalent in low socioeconomic populations, where it is also accompanied by higher rates of malnutrition and alcoholism. Using zebrafish as a model to study FASD retinal defects has been extremely insightful in understanding the ethanol-induced retinal defects at the cellular level. Zebrafish embryos treated with ethanol from mid-blastula transition through somitogenesis (2-24 hours post fertilization; hpf) showed defects similar to human ocular deficits including microphthalmia, optic nerve hypoplasia, and photoreceptor differentiation defects. Ethanol exposure altered critical transcription factor expression involved in retinal cell differentiation. Retinoic acid (RA) and folic acid (FA) nutrient co-supplementation rescued optic nerve and photoreceptor differentiation defects. Ethanol exposure during retinal morphogenesis stages (16-24 hpf), produced retinal defects like those seen with ethanol exposure between 2-24 hpf. Significantly, during ethanol-sensitive time window (16-24 hpf), RA co-supplementation moderately rescued these defects, whereas, FA cosupplementation showed significant rescue of optic nerve and photoreceptor differentiation. RA, but not FA, supplementation after ethanol exposure could restore ethanol-induced optic nerve and photoreceptor differentiation defects. Ethanol exposure did not affect timing of retinal cell differentiation induction, but later increased retinal cell death and proliferation. Ethanol-treated embryos showed increased retinal proliferation in the outer nuclear layer (ONL), inner nuclear layer (INL), and ciliary marginal zone (CMZ) at 48 hpf and 72 hpf. In order to identify the genesis of ethanol-induced persistent retinal defects, ethanol effects on retinal stem cell populations in the CMZ and the Müller glial cells (MGCs) were examined. Ethanol treated retinas had an expanded CMZ indicated by histology and Alcama, a retinal stem cell marker, immunolabeling, but reduced expression of rx1 and the cell cycle exit marker, cdkn1c. Ethanol treated retinas also showed reduced MGCs. At 72 hpf, ONL of ethanol exposed fish showed fewer photoreceptors expressing terminal differentiation markers. Importantly, these poorly differentiated photoreceptors co-expressed the basic helix-loop-helix (bHLH) proneural differentiation factor, neurod, indicating that ethanol exposure produced immature and undifferentiated photoreceptors. Reduced differentiation along with increased progenitor marker expression and proliferation suggest cell cycle exit failure due to ethanol exposure. These results suggested that ethanol exposure disrupted stem cell differentiation progression. Wnt, Notch and proneural gene expression regulate retinal stem cell proliferation and transition into progenitor cells. Ethanol exposure disrupted Wnt activity in the CMZ as well as Notch activity and neurod gene expression in the retina. RA and FA co-supplementation were able to rescue Wnt activity in the CMZ and rescue downstream Notch activity. To test whether the rescue of these Wnt-active cells could restore the retinal cell differentiation pathways, ethanol treated embryos were treated with Wnt agonist. This treatment could restore Wnt-active cells in the CMZ, Notch-active cells in the retina, proliferation, and photoreceptor terminal differentiation. We conclude that ethanol exposure produced persistent defects in the stem cell Wnt signaling, a critical pathway in retinal cell differentiation. Further analysis of underlying molecular mechanisms will provide insight into the embryonic origins of ethanol-induced retinal defects and potential therapeutic targets to cure this disorder.