Sex and age effects on gray matter volume trajectories in young children with prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) occurs in ~11% of North American pregnancies and is the most common known cause of neurodevelopmental disabilities such as fetal alcohol spectrum disorder (FASD; ~2-5% prevalence). PAE has been consistently associated with smaller gray matter volumes in children, adolescents, and adults. A small number of longitudinal studies show altered gray matter development trajectories in late childhood/early adolescence, but patterns in early childhood and potential sex differences have not been characterized in young children. Using longitudinal T1-weighted MRI, the present study characterized gray matter volume development in young children with PAE (N = 42, 84 scans, ages 3-8 years) compared to unexposed children (N = 127, 450 scans, ages 2-8.5 years). Overall, we observed altered global and regional gray matter development trajectories in the PAE group, wherein they had attenuated age-related increases and more volume decreases relative to unexposed children. Moreover, we found more pronounced sex differences in children with PAE; females with PAE having the smallest gray matter volumes and the least age-related changes of all groups. This pattern of altered development may indicate reduced brain plasticity and/or accelerated maturation and may underlie the cognitive/behavioral difficulties often experienced by children with PAE. In conjunction with previous research on older children, adolescents, and adults with PAE, our results suggest that gray matter volume differences associated with PAE vary by age and may become more apparent in older children.

Arcuate fasciculus and pre-reading language development in children with prenatal alcohol exposure.

Introduction: Prenatal alcohol exposure (PAE) contributes to widespread neurodevelopmental challenges, including reading, and has been associated with altered white matter. Here, we aimed to investigate whether arcuate fasciculus (AF) development is associated with pre-reading language skills in young children with PAE. Methods: A total of 51 children with confirmed PAE (25 males; 5.6 ± 1.1 years) and 116 unexposed controls (57 males; 4.6 ± 1.2 years) underwent longitudinal diffusion tensor imaging (DTI), for a total of 111 scans from participants with PAE and 381 scans in the unexposed control group. We delineated the left and right AF and extracted mean fractional anisotropy (FA) and mean diffusivity (MD). Pre-reading language ability was assessed using age-standardized phonological processing (PP) and speeded naming (SN) scores of the NEPSY-II. Linear mixed effects models were run to determine the relationship between diffusion metrics and age, group, sex, and age-by-group interactions, with subject modeled as a random factor. A secondary mixed effect model analysis assessed the influence of white matter microstructure and PAE on pre-reading language ability using diffusion metric-by-age-by-group interactions, with 51 age- and sex-matched unexposed controls. Results: Phonological processing (PP) and SN scores were significantly lower in the PAE group (p < 0.001). In the right AF, there were significant age-by-group interactions for FA (p < 0.001) and MD (p = 0.0173). In the left AF, there was a nominally significant age-by-group interaction for MD that failed to survive correction (p = 0.0418). For the pre-reading analysis, a significant diffusion-by-age-by-group interaction was found for left FA (p = 0.0029) in predicting SN scores, and for the right FA (p = 0.00691) in predicting PP scores. Discussion: Children with PAE showed altered developmental trajectories for the AF, compared with unexposed controls. Children with PAE, regardless of age, showed altered brain-language relationships that resembled those seen in younger typically developing children. Our findings support the contention that altered developmental trajectories in the AF may be associated with functional outcomes in young children with PAE.

Factors predicting general health concerns and atypical behaviours in children with prenatal alcohol exposure and other adverse exposures.

Background: Prenatal alcohol exposure (PAE) can have significant negative consequences on the health outcomes of children. Children with PAE often experience other prenatal and postnatal adverse exposures. Increased rates of general health concerns and atypical behaviours are seen in both children with PAE as well as with other patterns of adverse exposures, although these have not been systematically described. The association between multiple adverse exposures and adverse health concerns and atypical behaviours in children with PAE is unknown. Methods: Demographic information, medical history, adverse exposures, health concerns, and atypical behaviours were collected from children with confirmed PAE (n = 22; 14 males, age range = 7.9-15.9 years) and their caregivers. Support vector machine learning classification models were used to predict the presence of health concerns and atypical behaviours based on adverse exposures. Associations between the sums of adverse exposures, health concerns, and atypical behaviours were examined using correlation analysis. Results: All children experienced health concerns, the most common being sensitivity to sensory inputs (64%; 14/22). Similarly, all children engaged in atypical behaviours, with atypical sensory behaviour (50%; 11/22) being the most common. Prenatal alcohol exposure was most important factor for predicting some health concerns and atypical behaviours, and alone and in combination with other factors. Simple associations between adverse exposures could not be identified for many health concerns and atypical behaviours. Conclusion: Children with PAE and other adverse exposures experience high rates of health concerns and atypical behaviours. This study demonstrates the complex effects of multiple adverse exposures on health and behaviour in children.

Trajectories of brain white matter development in young children with prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) is associated with alterations to brain white matter microstructure. Previous studies of PAE have demonstrated different findings in young children compared to older children and adolescents, suggesting altered developmental trajectories and highlighting the need for longitudinal research. 122 datasets in 54 children with PAE (27 males) and 196 datasets in 89 children without PAE (45 males) were included in this analysis. Children underwent diffusion tensor imaging between 2 and 8 years of age, returning approximately every 6 months. Mean fractional anisotropy (FA) and mean diffusivity (MD) were obtained for 10 major brain white matter tracts and examined for age-related changes using linear mixed effects models with age, sex, group (PAE vs. control) and an age-by-group interaction. Children with PAE had slower decreases of MD over time in the genu of the corpus callosum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus. No significant age-by-group interactions were noted for FA. These findings show slower white matter development in young children with PAE than in unexposed controls. This connects previous cross-sectional findings of lower MD in young children with PAE to findings of higher MD in older children and adolescents with PAE, and further helps to understand brain development in children with PAE. This deviation from typical development trajectories may reflect altered brain plasticity, which has implications for cognitive and behavioral learning in children with PAE.

Alcohol and substance use in pregnancy during the COVID-19 pandemic.

BACKGROUND: The impact of the COVID-19 pandemic on alcohol and substance use has been a topic of concern. Pregnant women are currently experiencing elevated anxiety and depression symptoms, which may increase risk of substance use, and potentially result in poor perinatal and neurodevelopmental outcomes for children. METHODS: Survey results were analyzed from an ongoing study of 7470 pregnant individuals in Canada: Pregnancy during the COVID-19 Pandemic. Participants were asked about current use of alcohol and substances, symptoms of depression and anxiety, and COVID-19 concerns: how much they worry about COVID-19 threatening their baby's life, threatening their own life, care for themselves or the baby, feelings of social isolation, and financial difficulties. RESULTS: The percentage of participants who reported use during pregnancy was 6.7 % for alcohol, 4.3 % for cannabis, 4.9 % for tobacco, and 0.3 % for illicit drugs; 2.6 % were using multiple substances. Higher depression symptoms and financial difficulties were associated with more cannabis and/or tobacco use as well as the co-use of substances. There were no associations between alcohol use and mental health or COVID-19 concerns. CONCLUSIONS: Self-reported rates of use and co-use were lower or comparable to previous research, perhaps reflecting pandemic-related circumstances or the demographics of this sample. Depression symptoms and pandemic-related financial difficulties were associated with more tobacco use, cannabis use, and substance co-use. It remains important to maintain access to perinatal, mental health, and financial supports during the pandemic to mitigate prenatal alcohol and substance use and prevent poor perinatal and long-term neurodevelopmental outcomes for children.

White matter alterations in young children with prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) can lead to cognitive, behavioural, and social-emotional challenges. Previous neuroimaging research has identified structural brain alterations in newborns, older children, adolescents, and adults with PAE; however, little is known about brain structure in young children. Extensive brain development occurs during early childhood; therefore, understanding the neurological profiles of young children with PAE is critical for early identification and effective intervention. We studied 54 children (5.21 ± 1.11 years; 27 males) with confirmed PAE (94% also had other prenatal exposures, 74% had adverse postnatal experiences) compared with 54 age- and sex-matched children without PAE. Children underwent diffusion tensor imaging between 2 and 7 years of age. Mean fractional anisotropy (FA) and mean diffusivity (MD) were obtained for 10 major white matter tracts. Univariate analyses of covariance were used to test group differences (PAE vs. control) controlling for age and sex. The PAE group had higher FA in the genu of the corpus callosum and lower MD in the bilateral uncinate fasciculus. The PAE group also had lower tract volume in the corpus callosum, the bilateral inferior fronto-occipital fasciculi, and the right superior longitudinal fasciculus. Our findings align with studies of newborns with PAE reporting lower diffusivity, but contrast those in older populations with PAE, which consistently report lower FA and higher MD. Further research is needed to understand trajectories of white matter development and how our results of higher FA/lower MD in young children connect with lower FA/higher MD observed at older ages.

Association between breastfeeding during infancy and white matter microstructure in early childhood.

INTRODUCTION: Associations between breastfeeding and brain development, in the context of child, perinatal, and sociodemographic variables, remain unclear. This study investigated whether exclusive breastfeeding for the first 6 months and total duration of breastfeeding were associated with brain white matter microstructure in young children. METHODS: This study included 85 typically developing children (42 males) born to 83 mothers that were predominantly white, highly educated, and in high income households. Children underwent their first diffusion tensor imaging scan between ages 2.34 and 6.97 years; some children returned multiple times, providing a total of 331 datasets. Feeding information was collected from mothers at 3, 6, and 12 months postpartum and at their child's scan to calculate breastfeeding status at 6 months (exclusive or not) as well as total duration of any breastfeeding. Linear regression was used to investigate associations between breastfeeding exclusivity/duration and fractional anisotropy (FA) for the whole brain and 10 individual white matter tracts. RESULTS: Breastfeeding exclusivity and duration were associated with global and regional white matter microstructure, even after controlling for perinatal and sociodemographic factors. Greater exclusivity was associated with higher FA in females and lower FA in males. CONCLUSIONS: These findings suggest white matter differences associated with breastfeeding that differ by sex. These may stem from different trajectories in white matter development between males and females in early childhood and suggest possible long-term white matter differences associated with breastfeeding.

Different brain profiles in children with prenatal alcohol exposure with or without early adverse exposures.

Prenatal alcohol exposure (PAE) can alter brain development and impact mental health outcomes, and often occurs in conjunction with postnatal adversity (e.g., maltreatment). However, it is unclear how postnatal adverse exposures may moderate mental health and brain outcomes in children with PAE. T1-weighted and diffusion magnetic resonance imaging were obtained from 66 participants aged 7-16 years. Twenty-one participants had PAE and adverse postnatal exposures (PAE+), 12 had PAE without adverse postnatal exposures (PAE-), and 33 were age- and gender-matched controls unexposed to either prenatal alcohol or postnatal adversity. Internalizing and externalizing mental health symptoms were assessed using the Behavioral Assessment System for Children II, Parent-Rating Scale. ANCOVAs were used to compare mental health symptoms, limbic and prefrontal cortical volumes, and diffusion parameters of cortico-limbic white matter tracts between groups, and to assess brain-mental health relationships. Both PAE groups had worse externalizing behavior (higher scores) than controls. The PAE- group had lower fractional anisotropy (FA) in the bilateral cingulum and left uncinate fasciculus, and smaller volumes in the left anterior cingulate cortex than controls and the PAE+ group. The PAE- group also had higher mean diffusivity (MD) in the left uncinate than the PAE+ group, and smaller right anterior cingulate and superior frontal gyrus volumes than controls. These findings show different brain structure and mental health symptom profiles in children with PAE with and without postnatal adversity, highlighting the need to consider adverse postnatal exposures in individuals with PAE.

The brain's functional connectome in young children with prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) can lead to altered brain function and structure, as well as lifelong cognitive, behavioral, and mental health difficulties. Previous research has shown reduced brain network efficiency in older children and adolescents with PAE, but no imaging studies have examined brain differences in young children with PAE, at an age when cognitive and behavioral problems often first become apparent. The present study aimed to investigate the brain's functional connectome in young children with PAE using passive viewing fMRI. We analyzed 34 datasets from 26 children with PAE aged 2-7 years and 215 datasets from 87 unexposed typically-developing children in the same age range. The whole brain functional connectome was constructed using functional connectivity analysis across 90 regions for each dataset. We examined intra- and inter-participant stability of the functional connectome, graph theoretical measurements, and their correlations with age. Children with PAE had similar inter- and intra-participant stability to controls. However, children with PAE, but not controls, showed increasing intra-participant stability with age, suggesting a lack of variability of intrinsic brain activity over time. Inter-participant stability increased with age in controls but not in children with PAE, indicating more variability of brain function across the PAE population. Global graph metrics were similar between children with PAE and controls, in line with previous studies in older children. This study characterizes the functional connectome in young children with PAE for the first time, suggesting that the increased brain variability seen in older children develops early in childhood, when participants with PAE fail to show the expected age-related increases in inter-individual stability.

Characterizing adverse prenatal and postnatal experiences in children.

BACKGROUND: Prenatal and postnatal adversities, including prenatal alcohol exposure (PAE), prenatal exposure to other substances, toxic stress, lack of adequate resources, and postnatal abuse or neglect, often co-occur. These exposures can have cumulative effects, or interact with each other, leading to worse outcomes than single exposures. However, given their complexity and heterogeneity, exposures can be difficult to characterize. Clinical services and research often overlook additional exposures and attribute outcomes solely to one factor. METHODS: We propose a framework for characterizing adverse prenatal and postnatal exposures and apply it to a cohort of 77 children. Our approach considers type, timing, and frequency to quantify PAE, other prenatal substance exposure, prenatal toxic stress, postnatal threat (harm or threat of harm), and postnatal deprivation (failure to meet basic needs) using a 4-point Likert-type scale. Postnatal deprivation and harm were separated into early (<24 months of age) and late (≥24 months) time periods, giving seven exposure variables. Exposures were ascertained via health records, child welfare records, interviews with birth parents, caregivers, and/or close family/friends. RESULTS: Nearly all children had co-occurring prenatal exposures, and two-thirds had both prenatal and postnatal adversities. Children with high PAE were more likely to experience late postnatal adversities, and children with other prenatal substance exposure were more likely to have early postnatal deprivation. Postnatal adversities were more likely to co-occur. CONCLUSION: This framework provides a comprehensive picture of a child's adverse exposures, which can inform assessment and intervention approaches and policy and will be useful for future research.

Disease-modifying effects of ganglioside GM1 in Huntington's disease models.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD In this study, we provide evidence that intraventricular administration of GM1 has profound disease-modifying effects across HD mouse models with different genetic background. GM1 administration results in decreased levels of mutant huntingtin, the protein that causes HD, and in a wide array of beneficial effects that include changes in levels of DARPP32, ferritin, Iba1 and GFAP, modulation of dopamine and serotonin metabolism, and restoration of normal levels of glutamate, GABA, L-Ser and D-Ser. Treatment with GM1 slows down neurodegeneration, white matter atrophy and body weight loss in R6/2 mice. Motor functions are significantly improved in R6/2 mice and restored to normal in Q140 mice, including gait abnormalities that are often resistant to treatments. Psychiatric-like and cognitive dysfunctions are also ameliorated by GM1 administration in Q140 and YAC128 mice. The widespread benefits of GM1 administration, at molecular, cellular and behavioural levels, indicate that this ganglioside has strong therapeutic and disease-modifying potential in HD.