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The chronic and severe executive functioning (EF) and self regulation deficits experienced by children with fetal alcohol spectrum disorders (FASD) are well documented and EF and self regulation have been identified as core targets for intervention. The goals of this dissertation were to: (i) examine the effects of a self regulation treatment for children with FASD on a range of EF measures (ii) examine neural markers of treatment outcome and determine if functional magnetic resonance imaging (fMRI) can differentiate treatment responders from nonresponders; (iii) determine if treatment effects generalize to child compliance and qualitatively examine the treatment process. Twenty-five children with FASD participated. Using a wait-list control design children were assigned to an immediate treatment (TXT; n = 12) or delayed treatment control (DTC; n = 13) condition. All children received an evaluation of EF and fMRI at baseline and 12-week follow-up. Parents also completed questionnaires assessing EF and behavior as well as a feedback questionnaire upon completion of treatment. A subset of parents tracked compliance over the course of their child’s therapy. For the TXT group only, parent questionnaires were readministered at 6 month follow-up. At 12-week follow-up, children in the TXT group displayed significant improvements in inhibitory control and social cognition. Additionally, parents reported improved behavioral and emotional regulation. This improvement, along with a further improvement in parent-rated inhibitory control, was maintained at the 6-month follow-up. Neuroplastic changes were also observed as the TXT group showed increased BOLD response in the right prefrontal cortex (PFC) and left caudate on a task of inhibitory control. When treatment responders were compared to nonresponders a pattern of increased BOLD response was found bilaterally in the PFC and left caudate. Compliance tracking revealed that self regulation therapy generalized to improved child compliance at home. Qualitative analysis indicated that perceived clinician competence, caregiver insight about child’s problems and caregiver perceptions of child’s insight about their problems, were the most commonly endorsed themes by caregivers. Results from this research signify that children with FASD are responsive to psychotherapy and following a brief intervention, showed improvements in self regulatory abilities that generalize to other EF areas and parent-reported behaviors.

A serious consequence of maternal consumption of alcohol during pregnancy is the fetal alcohol syndrome (FAS): characterized by growth deficiency (both pre- and post-natal), craniofacial dysmorphology and central nervous system (CNS) dysfunction. However, in the absence of the characteristic facial features, and without confirmed history of alcohol exposure, clinical diagnosis remains a significant challenge. Recently, the term fetal alcohol spectrum disorders (FASD) has been adopted to encompass all diagnoses relating to a history of prenatal alcohol exposure. The purpose of this study was to test the following three general hypotheses: Children with FASD 1) demonstrate specific deficits in oculomotor control that can be measured using saccadic eye movement tasks, 2) display specific deficiencies in multiple domains of executive function that can be determined using standardized neuropsychological tasks, and 3) reveal deficits in oculomotor control that correlate with deficiencies in executive function as measured using standardized neuropsychological tasks. A preliminary study revealed significant deficits in saccadic eye movement tasks and provided the foundation for a large, multi-centered study assessing oculomotor control and neuropsychological function in children with FASD. A mobile laboratory was created, which facilitated recruitment of 92 control subjects and 89 subjects with FASD. We found significant evidence for oculomotor deficits across multiple outcome measures following the saccadic eye movement experiments, especially for oculomotor tasks that probe aspects of executive function. Additionally, children with FASD exhibited performance deficits in neuropsychological tasks that assess planning, attention, spatial working memory and strategy; cognitive skills also included within the domain of executive function. Finally, significant correlations between these two objective measures were found for children with FASD, which were not evident in the control sample. These findings are consistent with significant frontal lobe dysfunction. This is an exciting area of research that may hold promise in developing effective screening tools that can assist in the diagnosis of individuals with a history of prenatal alcohol exposure. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2008-08-28 15:41:20.595

The chronic and severe executive functioning (EF) and self regulation deficits experienced by children with fetal alcohol spectrum disorders (FASD) are well documented and EF and self regulation have been identified as core targets for intervention. The goals of this dissertation were to: (i) examine the effects of a self regulation treatment for children with FASD on a range of EF measures (ii) examine neural markers of treatment outcome and determine if functional magnetic resonance imaging (fMRI) can differentiate treatment responders from nonresponders; (iii) determine if treatment effects generalize to child compliance and qualitatively examine the treatment process. Twenty-five children with FASD participated. Using a wait-list control design children were assigned to an immediate treatment (TXT; n = 12) or delayed treatment control (DTC; n = 13) condition. All children received an evaluation of EF and fMRI at baseline and 12-week follow-up. Parents also completed questionnaires assessing EF and behavior as well as a feedback questionnaire upon completion of treatment. A subset of parents tracked compliance over the course of their child’s therapy. For the TXT group only, parent questionnaires were readministered at 6 month follow-up. At 12-week follow-up, children in the TXT group displayed significant improvements in inhibitory control and social cognition. Additionally, parents reported improved behavioral and emotional regulation. This improvement, along with a further improvement in parent-rated inhibitory control, was maintained at the 6-month follow-up. Neuroplastic changes were also observed as the TXT group showed increased BOLD response in the right prefrontal cortex (PFC) and left caudate on a task of inhibitory control. When treatment responders were compared to nonresponders a pattern of increased BOLD response was found bilaterally in the PFC and left caudate. Compliance tracking revealed that self regulation therapy generalized to improved child compliance at home. Qualitative analysis indicated that perceived clinician competence, caregiver insight about child’s problems and caregiver perceptions of child’s insight about their problems, were the most commonly endorsed themes by caregivers. Results from this research signify that children with FASD are responsive to psychotherapy and following a brief intervention, showed improvements in self regulatory abilities that generalize to other EF areas and parent-reported behaviors.

Background: Prenatal ethanol exposure (PNEE) causes irreversible intellectual and behavioral disabilities, clinically known as fetal alcohol spectrum disorder. Few neuropathologic studies of human brain exist. Hypotheses: First, markers of oxidative stress persist following PNEE. Second, PNEE is associated with inhibitory and excitatory neuron changes. Methods: Human brain autopsies (153) with known PNEE were reviewed; 18 cases (fetus to adult) and controls were selected. Oxidative stress and neuronal differentiation markers were used for immunohistochemistry. Results: There were no obvious differences between control and PNEE brains using oxidative stress markers. In human PNEE brains, glutamatergic neurons were reduced 15.96 % and 18.03% in dentate gyrus and temporal cortex, respectively. GABAergic neurons reactive for parvalbumin were reduced in all hippocampal regions (CA1= 57.86%, CA3= 65.15%, and DG= 53.39%) and temporal cortex (44.13%) in all age groups. Conclusion: GABAergic neuron reduction in human following PNEE could explain motor and behavior distractibility in FASD individuals.

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.

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.

Alcohol consumption during pregnancy can result in fetal alcohol spectrum disorders (FASD), which encompass a range of physical, behavioral, learning, emotional and social disturbances. Many mechanisms for this array of alcohol-derived fetal injuries have been proposed, but none fully accounts for the deficiencies observed. Alcohol is a ubiquitous drug that may affect the brain at any or all stages of development and at multiple sites; regional differences in vulnerability of different brain structures during different periods of exposure have been demonstrated. This study investigates possible mechanisms for the alcohol induced neurodevelopment damage seen as a result of prenatal alcohol exposure, and also includes evaluation of a potential intervention strategy (glutamine). These experiments all utilized the sheep model, which has distinct advantages over the rodent model for third trimester-equivalent studies (a time of increased vulnerability to the effects of alcohol). The fetal hippocampal formation (pyramidal cells in the CA1 and CA2/3 fields and granule cells of the dentate gyrus) and olfactory bulb (mitral cells) have been altered in response to alcohol exposure in rodent model studies. This study examined the effects on the fetal hippocampal formation and olfactory bulb in response to all three trimester-equivalent alcohol exposure in the sheep model, a species in which the third trimester-equivalent occurs in utero (as opposed to post-natal as occurs in the rodent). It is known that both maternal and fetal cortisol levels increase in response to alcohol. The role of cortisol in mediating fetal cerebellar Purkinje cell loss (known to occur with alcohol exposure) was analyzed. Lastly, the availability of circulating amino acids, both maternal and fetal, in response to alcohol are reported. The results of administration of a single acute dose of glutamine to the ewe, concurrent with alcohol, was evaluated for its ability to prevent the amino acid and pH perturbations known to occur in response to alcohol.

Developmental ethanol exposure causes both structural and functional changes in the brain that can result in cognitive and behavioral abnormalities. The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of ethanol. Research in this thesis focused on uncovering the effects of developmental ethanol exposure on hippocampal function in adulthood, particularly synaptic plasticity (a putative neurobiological mechanism of learning and memory). The first experiment sought to determine the temporal vulnerability of hippocampal synaptic plasticity as a function of exposure to ethanol during a single trimester. Ethanol exposure during the 1st or 3rd trimester equivalent resulted in minor changes in synaptic plasticity in adult offspring. In contrast, ethanol exposure during the 2nd trimester equivalent resulted in a pronounced decrease in long-term potentiation (LTP), indicating that the timing of exposure determines the severity of the deficit. The second experiment was aimed at determining the effects of prenatal ethanol exposure (1st and 2nd trimester equivalent combined) on bidirectional synaptic plasticity. Prenatal ethanol exposure resulted in a profound reduction in LTP but did not affect long-term depression. These findings show that prenatal ethanol exposure creates an imbalance in bidirectional synaptic plasticity. The third experiment sought to determine if prenatal ethanol exposure alters the affect of acute ethanol exposure in adulthood on synaptic plasticity. Acute exposure to ethanol in adulthood attenuated LTP in control offspring. Conversely, the magnitude of LTP was not affected by acute ethanol application in prenatal ethanol offspring. These results suggest that prenatal ethanol exposure alters the physiological response to ethanol in adulthood. Together, the results from the experiments undertaken in this thesis demonstrate long-lasting alterations in synaptic plasticity as the result of developmental ethanol exposure. Furthermore, these results allude to a malfunction of neural circuits within the hippocampal formation, perhaps relating to the learning and memory deficits observed in individuals with fetal alcohol spectrum disorders. / Graduate

Prenatal alcohol exposure (PAE) is associated with a range of physical, growth, and neurobehavioral deficits characteristic of individuals with fetal alcohol spectrum disorders (FASD). Although declarative memory impairment is a key feature of the neurocognitive profile of FASD, the mechanisms underlying this deficit require further clarification. The aim of this cross-sectional research was to examine, both directly and indirectly (via bottom-up and top-down processes), a critical cognitive mechanism that supports successful declarative memory functioning (viz., memory encoding), in children with FASD. Data were collected from a sample (N = 88) of South African children with and without PAE. In Study I, I used a blocked design functional magnetic resonance imaging (fMRI) paradigm to investigate neural activation during visual perception, a lower-order cognitive process essential to memory encoding. The task elicited bilateral category-specific activation during the visual perception of objects and scenes in all participants. The absence of between-group differences suggests that functional recruitment of brain regions during basic visual perception is less susceptible to the effects of PAE than during higher-order processes supporting memory encoding. In Study II, I used an event-related fMRI paradigm to investigate neural activation during memory encoding itself. All participants demonstrated similar memory performance accuracy and recruited extensive bilateral networks during memory encoding. However, participants with a diagnosis of fetal alcohol syndrome (FAS) or partial FAS (PFAS) activated additional regions associated with attentional function. Within the FAS/PFAS group, higher exposure levels were associated with smaller activation increases in the parahippocampal gyri and greater activation increases in the right hippocampal formation during encoding. Data from this study therefore suggest that children with FAS/PFAS recruited more extensive neural resources to support successful memory encoding during this task. In Study III, I used a behavioral source memory paradigm to investigate higher-order executive processes essential for memory encoding. Despite similar recognition accuracy across all diagnostic groups, participants in the FAS/PFAS group showed impaired memory for source details. This pattern of impairment was only partially mediated by working memory performance. These three studies provide novel clarification of the neural and cognitive mechanisms underlying declarative memory impairments in children with FASD.