Structural brain network organization in children with prenatal alcohol exposure

We examined the effects of moderate prenatal alcohol exposure and/or prenatal stress exposure on (D1 R) binding in a non human primate model. The dopamine D1 R is involved in executive function, and it may play a role in cognitive behavioral deficits associated with prenatal alcohol and/or stress exposure. Little is known, however, about the effects of prenatal alcohol and/or stress exposure on the D1 R. We expected that prenatal insults would lead to alterations in D1 R binding in prefrontal cortex (PFC) and striatum in adulthood. Rhesus macaque females were randomly assigned to moderate alcohol exposure and/or mild prenatal stress as well as a control condition during pregnancy. Thirty-eight offspring were raised identically and studied as adults by noninvasive in vivo neuroimaging using positron emission tomography with the D1 antagonist radiotracer [(11) C]SCH 23390. Radiotracer binding in PFC and striatum was evaluated by 2 (alcohol)×2 (stress)×2 (sex) analysis of variance. In PFC, a significant alcohol×sex interaction was observed with prenatal alcohol exposure leading to increased [(11) C]SCH 23390 binding in male monkeys. No main effect of prenatal alcohol or prenatal stress exposure was observed. These results suggest that prenatal alcohol exposure results in long-term increases in prefrontal dopamine D1 R binding in males. This may help explain gender differences in the prevalence of neurodevelopmental disorders consequent to prenatal alcohol exposure.

Considering Prenatal Alcohol Exposure in a Developmental Origins of Health and Disease Framework.

Prenatal alcohol and tobacco exposure continue to have an impact on a significant portion of the U.S. population every year. Differences in neighborhood environment may be a contributing factor. The current study examines whether prenatal alcohol and tobacco exposure differ by neighborhood environment. We used neighborhood environment data linked to a U.S.-based, nationally representative cohort of adolescents (N = 8,731; 47.2% female; age: M = 118.6 months, SD = 7.4 months). Lower neighborhood deprivation, less air pollution, higher lead risk, and higher perceived neighborhood safety were associated with prenatal alcohol exposure, whereas higher neighborhood deprivation and lower perceived neighborhood safety were associated with prenatal tobacco exposure. Neighborhood environments differ between prenatal alcohol-exposed children and unexposed children, as well as between prenatal tobacco-exposed children and unexposed children. Future research should consider the cumulative and interactive effects of prenatal exposure to alcohol and tobacco and the neighborhood environment.

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. 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. 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. 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.

Prenatal alcohol exposure (PAE) can cause lasting physical damage to the developing foetus including the brain. This brain damage can manifest as cognitive dysfunction and behavioural difficulties, which can be diagnosed as foetal alcohol spectrum disorders (FASD). FASD is thought to be common in the UK, with estimates ranging from 3.24% up to 17% of the population affected, although rates of diagnosis are much lower than this. Children with FASD are at increased risk of a range of traumatic or adverse childhood experiences, such as neglect or abuse. Studies into the longterm effects of neglect or abuse show a similar range of cognitive dysfunction and behavioural difficulties as those seen in FASD, but there is a lack of evidence on the impact of a dual exposure of PAE and trauma. This is especially necessary for clinicians, who may need to use the presence of trauma to inform and potentially exclude a diagnosis on the foetal alcohol spectrum. This aim of this thesis was to investigate the impact of childhood trauma on the cognitive and behavioural functioning of children with FASD. A wide-ranging overview of the literature on the effects of PAE and trauma as separate exposures was conducted and was followed by a systematic literature review of studies into the dual exposure of PAE and trauma. The reviews showed that only five studies had investigated the impact of both exposures, although one further study was published more recently. The literature reviews, including the one new study showed that, although there had only been a small number of studies conducted, a pattern was emerging that children with both FASD and trauma were more similar to children with just FASD than they were to children with just trauma, in terms of their cognitive and behavioural functioning. The findings of the reviews were used to develop four original studies, which advanced the evidence in this area. The studies were designed to assess the damage caused by dual exposure at four levels: neurological, cognitive, behavioural, and finally the effect of behavioural problems on other people. A neuroimaging study measured task-related blood oxygenation in the prefrontal cortex in 15 children aged 8-14 years with FASD with and without a history of trauma. A series of cognitive tasks assessed verbal, non-verbal and overall intelligence, working memory and inhibitory control in 25 children aged 8-14 years with FASD with and without a history of trauma. An informant-report survey that assessed Adverse Childhood experiences, cognitive, affective and overall empathy, behavioural strengths and difficulties, and comorbid diagnoses was completed by the carers of children aged 4-16 years with FASD. A series of semi-structured interviews was conducted with caregivers of children aged 8-14 years with FASD, with and without a history of trauma. Children with FASD had high levels of adverse childhood experiences including neglect and abuse, poor empathy, high levels of behavioural difficulties, and high levels of comorbid diagnoses, particularly attention deficit hyperactivity disorder (ADHD). They also had verbal, non-verbal and overall intelligence in the average range, and working memory and inhibitory control scores that were similar to the scores of typically developing children of the same age. Children with both FASD and a history of trauma were found not to be significantly different from children with FASD without trauma in terms of their task-related prefrontal activity, verbal, non-verbal and overall intelligence, working memory, inhibitory control, and empathy. There was a slight tendency for children with higher numbers of adverse childhood experiences to exhibit more severe behavioural difficulties, particularly conduct problems. Caregivers of children with both exposures described experiences with the same themes as those whose children had FASD without trauma. Caregivers described their children as difficult to manage, but also described many strengths and rewarding moments. Caregivers were critical of service providers including medical and educational services, social services, adoption agencies and local authorities, who lacked knowledge and understanding of FASD. This led to their children being misunderstood and offered insufficient or inappropriate services. The findings of this thesis support previous research showing that children with FASD have high levels of behavioural difficulties, poor empathy, and high levels of comorbid diagnoses. It provides the first data on levels of adverse childhood experiences in children with FASD, which are also high. The main finding of the thesis is that the impact of traumatic childhood experiences on the cognitive and behavioural functioning of children with FASD may be very subtle, especially in terms of cognitive functioning. Clinicians and other professionals should be aware that a history of neglect or abuse does not appear to be a better explanation for cognitive dysfunction or behavioural difficulties than prenatal alcohol exposure. Where children have a history of both exposures, they should primarily be treated as children with FASD, and provided appropriate support and interventions specifically designed for FASD.

Cardiac Magnetic Resonance Imaging in Individuals With Prenatal Alcohol Exposure.

Alcohol, tobacco and marijuana use among pregnant teenagers: 6-year follow-up of offspring growth effects

Objectives This review aims to determine the connection between developmental alcohol exposure and its potential impact on Alzheimer's disease (AD) later in life. We employ a network meta-analysis approach and examine gene fold changes from literature and Gene Expression Omnibus (GEO) datasets. Our goal is to investigate whether prenatal alcohol exposure (PAE) and/or adolescent alcohol exposure (AAE) could activate specific neuroinflammatory genes, potentially increasing the risk of AD development. Content We conducted a comprehensive analysis of brain datasets using a network meta-analysis approach. By synthesizing gene fold changes from literature and GEO datasets, we examined the potential impact of developmental alcohol exposure on increased risk of developing AD in the future. Summary Our findings reveal significant associations between alcohol exposure and critical functional categories and diseases in the brain. Alcohol exposure was strongly linked to the “Inflammatory Response” and “Nervous System Development and Function” categories, indicative of inflammatory reactions in the brain and detrimental effects on nervous system integrity. Furthermore, we observed links with “Organismal Injury and Abnormalities” and “Cell Death and Survival.” Pathway analysis revealed dysregulation in neuroinflammatory, ERK/MAPK signaling, amyloid processing, IL-1 signaling and calcium signaling pathways, suggesting their potential involvement in alcohol-induced neurotoxicity. Outlook This review highlights the necessity of recognizing developmental alcohol exposure as a potential risk factor for AD and shed light on the underlying mechanisms that may contribute to alcohol-induced neurotoxicity. By expanding our understanding of these mechanisms, we can better address the complex relationship between developmental alcohol exposure and neurodegenerative disorders like AD.

Annotated Abstracts

Computed tomography assessment of peripubertal craniofacial morphology in a sheep model of binge alcohol drinking in the first trimester

Background This study examined the association between prenatal alcohol exposure and attachment behavior in 4‐ and 5‐year‐old children. Prenatal alcohol exposure was hypothesized to be associated with insecure attachment behavior of the child toward the mother. It was also hypothesized that children with heavier prenatal alcohol exposure would exhibit higher levels of negative affect as well as poorer coping skills. The quality of maternal support in interaction with the child was predicted to mediate prenatal exposure effects.Methods Participants were 42 mother‐child dyads, the majority of whom came from poverty backgrounds in which the mother was a single parent. Attachment security was measured using the Attachment Q‐Set.Results Results revealed that prenatal alcohol exposure was highly related to attachment insecurity. Eighty percent of children who were exposed to alcohol during gestation were insecure, whereas 36% of unexposed children were insecure. Prenatal alcohol exposure also predicted child negative affect, which was related to lower levels of maternal emotional support of the child. However, when the mothers of the prenatally exposed children provided high levels of support, these children evidenced better coping skills and more secure attachment relations.Conclusions Although prenatal alcohol exposure was found to relate to higher levels of insecure attachment, children of mothers who provided them with emotional support were more able to deal with frustration. These children also exhibited higher levels of attachment security. Thus, the mother's supportive presence may mediate the association between prenatal alcohol exposure and the child's security of attachment.

Fetal Alcohol Spectrum Disorder (FASD) encompasses the deleterious consequences of Prenatal Alcohol Exposure (PAE), including developmental delay, microcephaly, dysmorphologies, and cognitive and behavioral issues. The dose and timing of alcohol exposure, maternal and environmental factors, and genetics all impact FASD outcomes, but differential susceptibility and resiliency to PAE remains poorly understood. In this study, we examined the differential effects of PAE during early mouse development on brain growth and gene expression. Brains were weighed and collected either 24 hours or five days after treatment. We then performed transcriptomics to determine whether offspring differentially affected by PAE, by brain weight, also differ in gene expression, despite having the same genetic background, alcohol exposure, and maternal factors. We found within litter variation in brain weights after PAE, and classified offspring as having normal, middle, and low-weight brains relative to saline-treated controls. The normal-weight brains showed no significant differences in gene expression, suggesting these offspring were both phenotypically and transcriptionally unaffected by PAE. While both middle- and low-weight brains showed changes in gene expression, the middle-weight brains showed the most robust transcriptome differences. Twenty-four hours after PAE, we saw an upregulation of cell cycle and apoptosis in affected offspring, whereas at roughly a week later, we saw a downregulation of metabolic processes. Overall, these findings highlight variability in response to PAE and demonstrate the molecular processes involved in offspring phenotypically affected by alcohol.

Context: In 2003, UCLA introduced a new, systems-based, integrated curricular structure for first year medical students. The curriculum emphasises small group and independent learning, limiting lectures to 10 h per week. A problem-based learning (PBL) case presents the clinical theme of each week, and provides the framework for incorporating the basic science learning. The exemplary case: In an integrated curriculum organised around a clinical case, the ideal case simultaneously serves as an exemplar that assists students in integrating their knowledge, while teaching them about commonly encountered diseases. Fetal Alcohol Syndrome (FAS) was chosen as a commonly encountered clinical disorder, which was able to carry teaching about the basic sciences of embryology, neuroanatomy and brain development, and epidemiology, as well as other important clinical topics such as ethics and law, counselling, and health behaviour. During the portion of the curriculum covering the neurosciences, a week was designed to address ‘Nurture or Nature’ using FAS as an exemplar clinical case. A PBL case began the week with a web-administered presentation of a school-aged child with physical features and learning and behaviour problems potentially attributable to a number of prenatal (including alcohol, cocaine, and nicotine exposure) and postnatal factors. An evidence-based portion of PBL required students to investigate the literature to either research a related learning issue or to defend or refute the position that ‘It is safe for a woman to drink a little during pregnancy’. The PBL case ended with a discussion of the impact of fetal alcohol exposure on child development and ‘hands-on’ practice screening a child for FAS, including conducting a facial dysmorphology exam to assess physical features associated with prenatal alcohol exposure. In another exercise, small groups of students worked with a standardised patient case learning to screen adolescents for alcohol and drug use and practising a brief intervention to reduce binge drinking. A portion of a Law and Order television episode in which a woman is prosecuted for drinking while pregnant facilitated students' consideration of legal and ethical issues as they formed juries and wrestled with a verdict. Evaluation: Results of assessments and course evaluations by the 146 students completing the FAS elements of the curriculum suggest increased awareness, knowledge and appreciation of the potential damage alcohol causes to the developing embryo and fetus and the consequences of FAS to the family and broader society. On a quiz testing knowledge of alcohol's effect on the fetus, students completing the embryology lab had a mean score of 5.65 (maximum = 6) and rated the lab's effectiveness as 4.11 (maximum = 5). Students attained a mean score of 4.31 (maximum = 5) on the FAS items in the weekly quiz. Students' end of course evaluations yielded mean ratings of 3.7 and 3.6 on the FAS-related PBL and standardised patient cases, respectively, using a 5-point scale (1 = not effective; 5 = very effective). These rating compared favourably to ratings of other first year cases in the curriculum.

Deficits in response inhibition correlate with oculomotor control in children with fetal alcohol spectrum disorder and prenatal alcohol exposure

Prenatal alcohol exposure causes a variety of impairments to the fetus called Fetal Alcohol Spectrum Disorders (FASD). Since it is very difficult to identify women that consume alcohol during pregnancy, different methods have been studied to evaluate alcohol exposure. Ethyl Glucuronide (EtG) and Fatty Acid Ethyl Esters (FAEEs) are commonly used to measure alcohol consumption in individuals at-risk for alcohol abuse, including pregnant women. We conducted a study of two cohorts of 1.5 year-old infants (of mothers without a history of alcohol abuse) with or without meconium samples positive to both EtG and FAEEs and we evaluated their cognitive-behavioral development by the Griffiths Mental Developmental Scale (GMDS) method. Our protocol included 8 infants with meconium positive to alcohol metabolites (EtG and FAEEs) and 7 with meconium negative to alcohol metabolites. None of the 8 alcohol metabolites positive meconium infants exhibited distinctive facial features and growth retardation of severe FASD, showing that other factors may contribute to the FASD onset but elevations in EtG and FAEEs in the meconium were significantly associated with disrupted neurodevelopment and adaptive functions within the first year and a half of life. Indeed, we found out that infants with meconium positive for both EtG and FAEEs, although without displaying any FASD morphological features, had a delay in the fine regulation of their own locomotory capabilities. Further analyses and larger studies are needed to estimate the right link between prenatal alcohol exposure and the different range of disorders connected but this study provides an additional step in the field of FASD in order to suggest early treatments for at-risk newborns and infants.