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.

Limbic brain subregions associated with mental health symptoms in youth with and without prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) can result in reduced brain volume and an increased risk of mental health challenges. Limbic brain structures such as the hippocampus, thalamus, and amygdala often exhibit smaller volumes in youth with PAE, and similar volume reductions are observed in unexposed youth with symptoms of depression, bipolar disorder, anxiety, and schizophrenia. However, the role of volume reductions in these brain regions in mental health challenges remains unclear for individuals with PAE. METHODS: Thirty-four youth with PAE and 72 unexposed youth aged 7-16 years completed a T1-weighted magnetic resonance imaging scan. FreeSurfer was used to process and extract volumes for hippocampal subfields, thalamic subnuclei, and amygdalar subnuclei. Depression and anxiety symptoms were measured using the Behavioral Assessment System for Children (BASC-2/3-PRS), the Children's Depression Inventory, and the Multidimensional Anxiety Scale for Children. We tested whether limbic subregion volumes differed between youth with and those without PAE and whether volumes were associated with depression and/or anxiety symptoms, controlling for age and gender. RESULTS: Multiple hippocampal and thalamic subregions, but not amygdalar subnuclei, were smaller in individuals with PAE. Multiple group-brain interactions were observed for depression symptoms and subregion volumes. Negative associations between anxiety and limbic subregions were observed across groups. CONCLUSIONS: These findings show extensive volume reductions in the hippocampus and thalamus in youth with PAE. PAE also appears to disrupt the association between depression symptoms and limbic subregions in youth, which may have implications for interventions in these individuals. Anxiety symptoms in youth with and without PAE are similarly associated with limbic volumes.

Brain volume and magnetic susceptibility differences in children and adolescents with prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) can negatively affect brain development thereby increasing the risk of cognitive deficits, behavioral challenges, and mental health problems. Brain iron is important for a number of physiological processes for healthy brain development. Animal studies show that PAE reduced brain iron; however, this has not been investigated in human children with PAE. METHODS: We studied 20 children and adolescents with PAE and 44 unexposed children and adolescents aged 7.5 to 15 years. All children underwent quantitative susceptibility mapping and T1-weighted magnetic resonance imaging scans. Susceptibility and volume measurements of the caudate, putamen, pallidum, thalamus, amygdala, hippocampus, and nucleus accumbens were extracted using FreeSurfer. ANCOVAs were used to compare volume and susceptibility between groups for each region of interest, controlling for age and gender. For structures where susceptibility differed by group, we also tested for an association between intelligence quotient (IQ) and susceptibility. RESULTS: There were no significant group differences in susceptibility after multiple comparison correction, though the PAE group had higher susceptibility in the thalamus compared to unexposed participants before correction (p = 0.032, q = 0.230). There was no association between IQ and thalamus susceptibility. The PAE group had significantly lower volume in the bilateral caudate, bilateral pallidum, and left putamen. CONCLUSIONS: These findings suggest susceptibility may be altered in children and adolescents with PAE, though more research is needed. Volume reductions are consistent with previous literature and likely underlie cognitive and behavioral deficits associated with PAE.

Frontoparietal and temporal white matter diffusion MRI in children and youth with prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is associated with brain alterations and neurocognitive deficits, but relationships between brain alterations and neurocognitive deficits remain unclear. METHODS: Diffusion tensor imaging (DTI) data were obtained from 31 participants with PAE and 31 unexposed controls aged 7-15 years. Mean diffusivity (MD) and fractional anisotropy (FA) were derived from the genu, body, and splenium of the corpus callosum (CC), bilateral cingulum, and inferior and superior longitudinal fasciculus (ILF, SLF). Participants completed language subtests from the NEPSY-II. Executive functioning was measured using the Behavior Rating Inventory of Executive Functioning (BRIEF-PR) and verbal learning was assessed using the California Verbal Learning Test-Children's Version (CVLT-C) only in children with PAE. Group differences in diffusion metrics and cognitive scores were tested. Principal component analysis was used to reduce redundancy in cognitive and behavior variables; associations between components and brain measures were then assessed. RESULTS: Children with PAE had lower MD in the right SLF compared with unexposed controls. FA was positively related to age in 6 of 9 tracts and MD negatively related to age in all tracts; there were no significant age-by-group interactions. Participants with PAE scored lower than unexposed peers on the NEPSY-II Comprehension of Instructions and Phonological Processing and above population norms (indicating worse performance) on the BRIEF-PR. Children with PAE had a negative association between a principal component closely associated with Speeded Naming and FA in the left SLF (PAE: p = 0.002) and left ILF (PAE: p = 0.002); unexposed controls showed no significant associations. CONCLUSION: We found widespread cognitive difficulties in children with PAE, but relatively limited differences in brain metrics and associations with age. Different brain-cognitive relationships were found in children with PAE compared with controls. Overall, the results provide additional evidence that PAE may lead to cognitive difficulties and disrupt typical brain-function relationships.

Attachment Theory: A Barrier for Indigenous Children Involved with Child Protection.

BACKGROUND: Attachment theory is an established theoretical understanding of the intimate relationships between parental figures and children. The theory frames the ways in which a child can be supported to develop within a secure base that prepares them for adulthood, including entering into and sustaining intimate relationships. The theory, built on the work of John Bowlby following World War II, has extensive literature supporting its application across multiple cultures and nations, although its roots are heavily tied to Eurocentric familial understandings. However, the theory has also been heavily criticized as not being appropriate for child intervention decision-making. Further, its application to Indigenous caregiving systems is also under question. Yet courts rely heavily on applying the theory to questions of sustaining Indigenous children in non-Indigenous care when return to biological parents is deemed impossible. METHODS: This article draws upon the consistent arguments used in leading Canadian child welfare legal decisions and case examples to show how Attachment Theory is applied relative to Indigenous children and families. RESULTS: Attachment Theory drawing upon Eurocentric framing, and as applied in Canadian child protection systems, as seen in precedent court decisions, is given priority over living in culture. This occurs even though the research reviewed has shown that the traditional dyadic version of the theory is not valid for Indigenous peoples. CONCLUSIONS: While all children will attach to a caregiver or caregiving system, such as kinship or community, leading legal decisions in Canada tend to rely on Eurocentric versions of the theory, which is contrary to the best interests of Indigenous children. Child protection needs to reconsider how attachment can be used from appropriate cultural lenses that involve the communal or extended caregiving systems common to many Canadian Indigenous communities. Child protection should also recognize that there is not a pan-Indigenous definition of attachment and child-rearing, so efforts to build working relationships with various Indigenous communities will be needed to accomplish culturally informed caregiving plans. In addition, continued advocacy in Canada is needed to have child protection decision-making conducted by the Indigenous communities, as opposed to Eurocentric provincial or territorial agencies.

Effects of prenatal alcohol exposure on neurobehavioural development and volume of rostral cingulate cortex subregions.

BACKGROUND: Maternal alcohol consumption during pregnancy can have widespread and long-lasting effects on children's cognition, behaviour, brain function and structure. The pregenual anterior cingulate cortex (ACC) and the anterior midcingulate cortex (MCC) mediate emotional and cognitive behaviours that are affected by prenatal alcohol exposure. However, the neurobehavioural development of the pregenual ACC and anterior MCC has not been examined in people with prenatal alcohol exposure. METHODS: We recruited 30 children and adolescents with prenatal alcohol exposure and 50 age- and gender-matched unexposed controls. We acquired structural MRI data sets on a 3 T scanner. We manually delineated 2 areas of the rostral cingulate cortex - the pregenual ACC and the anterior MCC - and compared them between groups. We measured behavioural and emotional problems using the Behaviour Assessment System for Children, 2nd Edition, Parent Rating Scale, and then explored their associations with rostral cingulate cortex volumes. RESULTS: Intracranial-normalized volumes of the right pregenual ACC and the right total rostral cingulate cortex were significantly smaller in individuals with prenatal alcohol exposure than in unexposed controls. The volume of the right anterior MCC had a significant positive association with scores on the Internalizing Problems scale in individuals with prenatal alcohol exposure. LIMITATIONS: This study was cross-sectional, and detailed information about the timing and amount of exposure was not always available. CONCLUSION: Prenatal alcohol exposure is associated with lower volumes in the right pregenual ACC. This finding may underlie some of the emotional and behavioural problems experienced by individuals with prenatal alcohol exposure.

Brain Iron and Mental Health Symptoms in Youth with and without Prenatal Alcohol Exposure.

Prenatal alcohol exposure (PAE) negatively affects brain development and increases the risk of poor mental health. We investigated if brain volumes or magnetic susceptibility, an indirect measure of brain iron, were associated with internalizing or externalizing symptoms in youth with and without PAE. T1-weighted and quantitative susceptibility mapping (QSM) MRI scans were collected for 19 PAE and 40 unexposed participants aged 7.5-15 years. Magnetic susceptibility and volume of basal ganglia and limbic structures were extracted using FreeSurfer. Internalizing and Externalizing Problems were assessed using the Behavioural Assessment System for Children (BASC-2-PRS). Susceptibility in the nucleus accumbens was negatively associated with Internalizing Problems, while amygdala susceptibility was positively associated with Internalizing Problems across groups. PAE moderated the relationship between thalamus susceptibility and internalizing symptoms as well as the relationship between putamen susceptibility and externalizing symptoms. Brain volume was not related to internalizing or externalizing symptoms. These findings highlight that brain iron is related to internalizing and externalizing symptoms differently in some brain regions for youth with and without PAE. Atypical iron levels (high or low) may indicate mental health issues across individuals, and iron in the thalamus may be particularly important for behavior in individuals with PAE.

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.

Prenatal Exposure And Child brain and mental Health (PEACH) study: protocol for a cohort study of children and youth with prenatal alcohol exposure.

INTRODUCTION: Fetal alcohol spectrum disorder (FASD), which is caused by prenatal alcohol exposure (PAE), affects an estimated 4% of North Americans, and is the most common preventable cause of intellectual disability. Mental health problems, including anxiety and depression, are experienced by nearly all individuals with FASD. However, there is very limited knowledge about effective mental health treatments for individuals with FASD; effective treatments are hindered in part due to a lack of understanding of the basic neurobiology underlying internalising disorders in youth with FASD. METHODS AND ANALYSIS: The Prenatal Exposure And Child brain and mental Health (PEACH) study includes children aged 7-18 years. We will use longitudinal neuroimaging (anatomical T1-weighted, diffusion and passive viewing function MRI) and mental health assessments (Behaviour Assessment Scale for Children, Multi-dimensional Anxiety Scale for Children, Children's Depression Inventory (CDI-2), Kiddie Scale of Affective Disorders) to: (1) characterise brain development trajectories in youth with FASD, (2) determine whether brain alterations mediate increased anxiety and depression in youth with FASD and (3) identify baseline brain features that predict changes of anxiety and depression symptoms over the next 2 years. All of this will be done while considering sex and adverse postnatal experiences, which can significantly impact mental health and brain outcomes. This project will forge new understanding of FASD and mental health from a neurobiological perspective, highlighting key time periods (ie, sensitive windows) and brain regions (ie, that may be susceptible to neurostimulation), while identifying factors that predict individual trajectories of anxiety and depression symptoms. ETHICS AND DISSEMINATION: This study was approved by the University of Calgary Conjoint Health Research Ethics Board and the University of Alberta Health Research Ethics Board. Study results will be disseminated in peer-reviewed journals, at relevant conferences and in conjunction with our knowledge mobilisation partners.

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.

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.