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Background: Fetal alcohol spectrum disorders (FASD) are the most common preventable cause of birth defects and neurodevelopmental disorders worldwide. The placenta is the crucial interface between mother and fetus. Prenatal alcohol exposure (PAE) has been shown to alter placental structure and expression of genes in bulk placental tissue samples, but prior studies have not examined effects on placental cell-type composition or taken cell-type into consideration in transcriptome analyses., Methods: We leveraged an existent placenta single-cell RNA-seq dataset to perform cell-type deconvolution of bulk placental RNA-seq data from 35 heavy drinking pregnant women and 33 controls in a prospective birth cohort in Cape Town, South Africa. We used bivariate analyses and multivariable adjusted linear regression models to assess the relation of PAE on inferred placental cell-type proportions. We also examined differential expression of inflammatory response genes and PAE, using multivariable adjusted linear models., Results: Deconvolution analyses showed heterogeneous placenta cell-type composition in which stromal (27 %), endothelial (26 %) and cytotrophoblasts (18 %) were the predominant cell-types. PAE around conception was associated with a higher proportion of Hofbauer cells (B = 0.51, p = 0.035) in linear models adjusted for maternal age, infant sex, and gestational age. Among the 652 inflammatory genes examined, 35 were differential expressed in alcohol exposed placentas (FDR p < 0.05)., Conclusions: Our findings suggest that heavy alcohol exposure during pregnancy can influence the proportion of fetal placental villi macrophages (Hofbauer cells) and increased expression of inflammatory genes. Future studies are needed to further characterize these effects and to assess the potential functional roles of placental inflammation in FASD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

We have previously demonstrated prenatal alcohol exposure (PAE)-related alterations in maternal and infant iron homeostasis. Given that early iron deficiency and PAE both lead to growth restriction and deficits in recognition memory and processing speed, we hypothesized that PAE-related iron homeostasis alterations may mediate and/or moderate effects of PAE on growth and neurobehavior. We examined this hypothesis in a prenatally recruited, prospective longitudinal birth cohort [87 mother-infant pairs with heavy prenatal alcohol exposure (mean = 7.2 drinks/occasion on 1.4 days/week); 71 controls], with serial growth measures and infant neurobehavioral assessments. PAE was related to growth restriction at 2 weeks and 5 years, and, in infancy, poorer visual recognition memory, slower processing speed, lower complexity of symbolic play, and higher emotionality and shyness on a parental report temperament scale. Lower maternal hemoglobin-to-log(ferritin) ratio, which we have shown to be associated with PAE, appeared to exacerbate PAE-related 2-week head circumference reductions, and elevated maternal ferritin, which we have shown to be associated with PAE, appeared to exacerbate PAE-related visual recognition memory deficits. In causal inference analyses, PAE-related elevations in maternal ferritin and hemoglobin:log(ferritin) appeared to statistically mediate 22.6-82.3% of PAE-related growth restriction. These findings support potential mechanistic roles of iron homeostasis alterations in fetal alcohol spectrum disorders (FASD).

Background: Animal models have demonstrated that maternal nutrition can alter fetal vulnerability to prenatal alcohol exposure (PAE). Few human studies have examined the role of nutrition in fetal alcohol spectrum disorders (FASD)., Objectives: Our objectives were to examine whether fetal vulnerability to PAE-related growth restriction is modified by: 1) rate of gestational weight gain; or prenatal dietary intakes of 2) energy, 3) iron, or 4) choline., Methods: In a prospective longitudinal birth cohort in Cape Town, South Africa, 118 heavy-drinking and 71 abstaining/light-drinking pregnant women were weighed and interviewed regarding demographics, alcohol, cigarette/other drug use, and diet at prenatal visits. Infant length, weight, and head circumference were measured at 2 wk and 12 mo postpartum., Results: Heavy-drinking mothers reported a binge pattern of drinking [Mean = 129 mL (∼7.2 drinks)/occasion on 1.3 d/wk). Rate of gestational weight gain and average daily dietary energy, iron, and choline intakes were similar between heavy-drinking women and controls. In regression models adjusting for maternal age, socioeconomic status, cigarette use, and weeks gestation at delivery, PAE [ounces (30 mL) absolute alcohol per day] was related to smaller 2-wk length and head circumference and 12-mo length, weight, and head circumference z-scores (β = -0.43 to -0.67; all P values <0.05). In stratified analyses for each maternal nutritional measure (inadequate compared with adequate weight gain; tertiles for dietary energy, iron, and choline intakes), PAE-related growth restriction was more severe in women with poorer nutrition, with effect modification seen by weight gain, energy, iron, and/or choline for several anthropometric outcomes., Conclusions: Gestational weight gain and dietary intakes of energy, choline, and iron appeared to modify fetal vulnerability to PAE-related growth restriction. These findings suggest a need for screening programs for pregnant women at higher risk of having a child with FASD to identify alcohol-using women who could benefit from nutritional interventions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: The ability to identify and interpret facial emotions plays a critical role in effective social functioning, which may be impaired in individuals with fetal alcohol spectrum disorders (FASD). We previously reported deficits in children with fetal alcohol syndrome (FAS) and partial FAS (PFAS) on the "Reading the Mind in the Eyes" (RME) test, which assesses the interpretation of facial emotion. This follow-up study in adolescents was designed to determine whether this impairment persists or represents a developmental delay; to classify the RME stimuli by valence (positive, negative, or neutral) and determine whether RME deficits differ by affective valence; and to explore how components of executive function mediate these associations., Methods: The RME stimuli were rated and grouped according to valence. Sixty-two participants who had been administered the RME in late childhood (mean ± SD = 11.0 ± 0.4 years) were re-administered this test during adolescence (17.2 ± 0.6 years). Overall and valence-specific RME accuracy was examined in relation to prenatal alcohol exposure (PAE) and FASD diagnosis., Results: Children with FAS (n = 8) and PFAS (n = 15) performed more poorly on the RME than non-syndromal heavily exposed (HE; n = 19) and control individuals (n = 20). By adolescence, the PFAS group performed similarly to HE and controls, whereas the FAS group continued to perform more poorly. No deficits were seen for positively valenced items in any of the groups. For negative and neutral items, in late childhood individuals with FAS and PFAS performed more poorly than HE and controls, but by adolescence only the FAS group continued to perform more poorly. Test-retest reliability was moderate across the two ages. At both timepoints, the effects in the FAS group were partially mediated by Verbal Fluency but not by other aspects of executive function., Conclusions: Individuals with full FAS have greater difficulty interpreting facial emotions than those with non-syndromal HE and healthy controls in both childhood and adolescence. By contrast, RME deficits in individuals with PFAS in childhood represent developmental delay., (© 2022 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.)

Background: Individuals with fetal alcohol spectrum disorders may exhibit a distinct pattern of dysmorphic facial features, growth restriction, and cognitive deficits, particularly in arithmetic. Magnitude comparison, a fundamental element of numerical cognition, is modulated by the numerical distance effect, with numbers closer in value more difficult to compare than those further apart, and by the automaticity of the association of numerical values with their symbolic representations (Arabic numerals)., Methods: We examined event-related potentials acquired during the Numerical Stroop numerical and physical tasks administered to 24 alcohol-exposed adolescents (eight fetal alcohol syndrome (FAS), eight partial FAS (PFAS), eight heavily exposed (HE) nonsyndromal) and 23 typically developing (TD), same- age controls. The distance effect was assessed on the numerical task to examine differences in reaction time (RT) and accuracy when two numbers are close in value (e.g., 1 vs. 2) compared to when the numbers are less close (e.g., 1 vs. 6). Automaticity was assessed in the physical task by examining the degree to which RT and accuracy are reduced when the relative physical size of two numerals is incongruent with their numerical values (e.g., 1 vs. 6)., Results: Adolescents in all four groups performed behaviorally as expected on these relatively simple magnitude comparison tasks, but accuracy was poorer and RT was slower on both tasks in the FAS and PFAS than the HE and TD groups. At the neurophysiological level, in the numerical task, a higher level of prenatal alcohol exposure was associated with smaller P2p amplitude. In the physical task, only the TD and nonsyndromal HE groups exhibited the expected smaller P300 amplitude in the incongruent than the congruent condition., Conclusions: These findings suggest that magnitude comparison in alcohol-exposed individuals may be mediated by recruitment of alternative neural pathways that are likely to be inefficient when number processing becomes more challenging., (© 2022 by the Research Society on Alcoholism.)

Prenatal alcohol exposure (PAE) has been linked to atypical brain and cognitive development, including poor academic performance in reading. This study utilized functional magnetic resonance imaging and diffusion tensor imaging to characterize functional and structural mechanisms mediating reading deficits in 26 adolescents with PAE-related facial dysmorphology (fetal alcohol syndrome (FAS)/partial FAS (PFAS)), 29 heavily-exposed (HE) non-syndromal adolescents, in comparison with 19 typically developing controls. The FAS/PFAS and HE groups were balanced in terms of levels of PAE and reading (dis)ability. While neural alterations in the posterior association cortices were evident in both PAE groups, distinctive neural correlates of reading (dis)abilities were observed between adolescents with and without facial dysmorphology. Specifically, compared to the HE and control groups, the syndromal adolescents showed greater activation in the right precentral gyrus during phonological processing and rightward lateralization in an important reading-related tract (inferior longitudinal fasciculus, ILF), suggesting an atypical reliance on the right hemisphere. By contrast, in the HE, better reading skills were positively correlated with neural activation in the left angular gyrus and white matter organization of the left ILF, although the brain function-behavior relation was weaker than among the controls, suggesting less efficient function of the typical reading network. Our findings provide converging evidence at both the neural functional and structural levels for distinctive brain mechanisms underlying atypical reading and phonological processing in PAE adolescents with and without facial dysmorphology., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Prenatal alcohol exposure (PAE) has been associated with compromised interhemispheric transfer of tactile stimuli in childhood and structural changes to the corpus callosum (CC). In this study, we used a finger localization task (FLT) to investigate whether interhemispheric transfer deficits persist in adolescence; whether effects of PAE on perceptual reasoning, working memory, and executive function are mediated by deficits in interhemispheric transfer of information; and whether CC size in childhood predicts FLT performance in adolescence., Methods: Participants, aged 16 to 17 years, were from the Cape Town Longitudinal Cohort, whose mothers were recruited during pregnancy and interviewed regarding their alcohol use using the timeline follow-back method. Diagnoses of fetal alcohol syndrome (FAS) and partial FAS (PFAS) were determined by two expert dysmorphologists; nonsyndromal exposed children were designated as heavily exposed (HE); those born to abstainers or light drinkers, as controls. The FLT was administered to 74 participants (12 FAS, 16 PFAS, 14 HE and 32 controls). CC size at age 9 to 12 years was available for 35 participants (7 FAS, 13 PFAS, 5 HE and 10 control)., Results: Although the degree of PAE was similar in the FAS, PFAS, and HE groups, only the adolescents with FAS showed more transfer-related errors than controls in conditions in which one finger was stimulated. FLT performance mediated the effects of FAS on perceptual reasoning and executive function. In the subsample for which neuroimaging data from childhood were available, there was an association among adolescents with PAE of smaller CC volumes with more transfer-related errors on the one-finger/hand hidden condition, suggesting that CC damage previously seen in childhood continues to impact function through adolescence., Conclusions: This study provides evidence of compromised interhemispheric transfer of information in adolescents with FAS, while those with PFAS or heavy exposed nonsyndromal individuals are apparently spared. It is the first to show that PAE effects on important aspects of cognitive function are partially mediated by deficits in the interhemispheric transfer of information., (© 2022 by the Research Society on Alcoholism.)

Despite several decades of research and prevention efforts, fetal alcohol spectrum disorders (FASD) remain the most common preventable cause of neurodevelopmental disabilities worldwide. Animal and human studies have implicated fetal alcohol-induced alterations in epigenetic programming as a chief mechanism in FASD. Several studies have demonstrated fetal alcohol-related alterations in methylation and expression of imprinted genes in placental, brain, and embryonic tissue. Imprinted genes are epigenetically regulated in a parent-of-origin-specific manner, in which only the maternal or paternal allele is expressed, and the other allele is silenced. The chief functions of imprinted genes are in placental development, somatic growth, and neurobehavior-three domains characteristically affected in FASD. In this review, we summarize the growing body of literature characterizing prenatal alcohol-related alterations in imprinted gene methylation and/or expression and discuss potential mechanistic roles for these alterations in the teratogenic effects of prenatal alcohol exposure. Future research is needed to examine potential physiologic mechanisms by which alterations in imprinted genes disrupt development in FASD, which may, in turn, elucidate novel targets for intervention. Furthermore, mechanistic alterations in imprinted gene expression and/or methylation in FASD may inform screening assays that identify individuals with FASD neurobehavioral deficits who may benefit from early interventions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Prenatal alcohol exposure (PAE) is associated with postnatal iron deficiency (ID), which has been shown to exacerbate deficits in growth, cognition, and behavior seen in fetal alcohol spectrum disorders. However, the mechanisms underlying PAE-related ID remain unknown., Objectives: We aimed to examine biochemical measures of iron homeostasis in the mother, placenta, neonate, and 6.5-month-old infant., Methods: In a prenatally recruited, prospective longitudinal birth cohort in South Africa, 206 gravidas (126 heavy drinkers and 80 controls) were interviewed regarding alcohol, cigarette, and drug use and diet at 3 prenatal visits. Hemoglobin, ferritin, and soluble transferrin receptor (sTfR) were assayed twice during pregnancy and urinary hepcidin:creatinine was assayed once. Infant ferritin and hemoglobin were measured at 2 weeks and 6.5 months and sTfR was measured at 6.5 months. Histopathological examinations were conducted on 125 placentas and iron transport assays (iron regulatory protein-2, transferrin receptor-1, divalent metal transporter-1, ferroportin-1, and iron concentrations) were conducted on 63., Results: In multivariable regression models, prenatal drinking frequency (days/week) was related to higher maternal hepcidin and to sequestration of iron into storage at the expense of erythropoiesis in mothers and neonates, as evidenced by a lower hemoglobin (g/dL)-to-log(ferritin) (ug/L) ratio [mothers: raw regression coefficient (β) = -0.21 (95% CI: -0.35 to -0.07); neonates: β = -0.15 (95% CI: -0.24 to -0.06)]. Drinking frequency was also related to decreased placental ferroportin-1:transferrin receptor-1 (β = -0.57 for logged values; 95% CI: -1.03 to -0.10), indicating iron-restricted placental iron transport. At 6.5 months, drinking frequency was associated with lower hemoglobin (β = -0.18; 95% CI: -0.33 to -0.02), and increased prevalences of ID (β = 0.09; 95% CI: 0.02-0.17) and ID anemia (IDA) (β = 0.13; 95% CI: 0.04-0.23). In causal inference analyses, the PAE-related increase in IDA was partially mediated by decreased neonatal hemoglobin:log(ferritin), and the decrease in neonatal hemoglobin:log(ferritin) was partially mediated by decreased maternal hemoglobin:log(ferritin)., Conclusions: In this study, greater PAE was associated with an unfavorable profile of maternal-fetal iron homeostasis, which may play mechanistic roles in PAE-related ID later in infancy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: This paper reports findings from the first longitudinal study on the evolution of the physical phenotypes of fetal alcohol syndrome (FAS) and partial FAS (PFAS) from early childhood through adolescence., Methods: The sample consisted of 155 children (78 males and 77 females) born to women recruited at an antenatal clinic serving a Cape Coloured (mixed ancestry) population in Cape Town, South Africa. Two expert FASD dysmorphologists, blind regarding prenatal alcohol exposure, independently evaluated each child's growth and dysmorphology at 4 clinics conducted over an 11-year period. Case conferences were held to reach consensus regarding which children had FAS or PFAS growth and physical features using the Revised Institute of Medicine (2005) guidelines., Results: The prevalence of the physical phenotype was stable across the 4 ages for about half of the children with FAS and about one-third of those with PFAS but more variable for the others. Test-retest reliability was substantial for the FAS phenotype, but poorer for PFAS. Two distinct patterns were seen: a "strong phenotype" that was consistently identified and a less consistent one in which dysmorphic features and/or anthropometric deficits fluctuated or diminished with age. The physical phenotype was most apparent during early childhood and least apparent during puberty, due to differences in timing of the growth spurt and the evolving adult face. Short palpebral features and small head circumference diminished with age, flat philtrum fluctuated, while thin vermilion and weight and height restriction were stable., Conclusions: Key facial features that characterize FASD in early childhood diminish or evolve in some individuals, making diagnostic examinations that rely on these characteristics most sensitive during early childhood and school age. Moreover, puberty poses classification problems due to variability in timing of the growth spurt. Given that several features and small head circumference diminished with age, many individuals would be misdiagnosed if only examined at a later age., (© 2020 by the Research Society on Alcoholism.)

Prenatal alcohol exposure (PAE) can result in cognitive and behavioral disabilities and growth deficits. Because alcohol-related neurobehavioral deficits may occur in the absence of overt dysmorphic features or growth deficits, there is a need to identify biomarkers of PAE that can predict neurobehavioral impairment. In this study, we assessed infant plasma extracellular, circulating miRNAs ( ex miRNAs) obtained from a heavily exposed Cape Town cohort to determine whether these can be used to predict PAE-related growth restriction and cognitive impairment. PAE, controlling for smoking as a covariate, altered 27% of expressed ex miRNAs with clinically-relevant effect sizes (Cohen's d ≥ 0.4). Moreover, at 2 weeks, PAE increased correlated expression of ex miRNAs across chromosomes, suggesting potential co-regulation. In confirmatory factor analysis, the variance in expression for PAE-altered ex miRNAs at 2 weeks and 6.5 months was best described by three-factor models. Pathway analysis found that factors at 2 weeks were associated with (F1) cell maturation, cell cycle inhibition, and somatic growth, (F2) cell survival, apoptosis, cardiac development, and metabolism, and (F3) cell proliferation, skeletal development, hematopoiesis, and inflammation, and at 6.5 months with (F1) neurodevelopment, neural crest/mesoderm-derivative development and growth, (F2) immune system and inflammation, and (F3) somatic growth and cardiovascular development. Factors F3 at 2 weeks and F2 at 6.5 months partially mediated PAE-induced growth deficits, and factor F3 at 2 weeks partially mediated effects of PAE on infant recognition memory at 6.5 months. These findings indicate that infant ex miRNAs can help identify infants who will exhibit PAE-related deficits in growth and cognition.

Background: Although deficits in the interpretation of affective facial expressions have been described clinically and in behavioral studies of fetal alcohol spectrum disorders (FASD), effects of prenatal alcohol exposure on the neural networks that mediate affective appraisal have not previously been examined., Methods: We administered a nonverbal event-related fMRI affective appraisal paradigm to 64 children (mean age = 12.5 years; 18 with fetal alcohol syndrome (FAS) or partial FAS (PFAS), 18 nonsyndromal heavily exposed (HE), and 28 controls). Happy, sad, angry, fearful, and neutral faces and pixelated control images were presented sequentially in a randomized order. The child indicated whether the currently displayed face showed the same or different affect as the previous one., Results: Data from whole-brain analyses showed that all groups activated the appropriate face processing neural networks. Region of interest analyses indicated that, compared to HE and control children, the FAS/PFAS group exhibited greater blood oxygenation level-dependent (BOLD) signal changes when processing neutral faces than pixelated images in 2 regions that form part of the visual sensory social brain network, which plays an important role in the initial processing of facial affect. By contrast, BOLD signal when processing angry faces was weaker for the FAS/PFAS group in a region involved in the processing of facial identity and facial expressions and in a region involved in the recognition and selection of behavioral responses to aggressive behavior., Conclusions: These findings of greater BOLD signal in the FAS/PFAS group in response to neutral faces suggest less efficient neural processing of more difficult to interpret emotions, and the weaker BOLD response to angry faces suggests altered processing of angry stimuli. Although behavioral performance did not differ in this relatively simple affective appraisal task, these data suggest that in children with FAS and PFAS, the appraisal of neutral affect and anger is likely to be more effortful in more challenging and dynamic social contexts., (© 2020 by the Research Society on Alcoholism.)

Prenatal alcohol exposure (PAE) is associated with physical anomalies, growth restriction, and a range of neurobehavioral deficits. Although declarative memory impairment has been documented extensively in individuals with fetal alcohol spectrum disorders (FASD), this cognitive process has been examined in only one functional magnetic resonance imaging (fMRI) study, and mechanisms underlying this impairment are not well understood. We used an event-related fMRI design to examine neural activations during visual scene encoding that predict subsequent scene memory in 51 right-handed children (age range = 10-14 years, M = 11.3, SD = 1.3) whose mothers had been recruited and interviewed prospectively about their alcohol use during pregnancy. Following examination by expert dysmorphologists, children were assigned to one of three FASD diagnostic groups: FAS/PFAS (n FAS  = 7; n PFAS  = 4), nonsyndromal heavily exposed (HE; n = 14), and Controls (n = 26). Subsequent memory was assessed in a post-scan recognition test, and subsequent memory activations were examined by contrasting activations during encoding of scenes that were subsequently remembered (hits) to those for incorrectly judged as 'new' (misses). Recognition accuracy did not differ between groups. Pooled across groups, we observed extensive bilateral subsequent memory effects in regions including the hippocampal formation, posterior parietal cortex, and occipital cortex-a pattern consistent with previous similar studies of typically developing children. Critically, in the group of children with FAS or PFAS, we observed activations in several additional regions compared to HE and Control groups. Given the absence of between-group differences in recognition accuracy, these data suggest that in achieving similar memory compared to children in the HE and Control groups, children with FAS and PFAS recruit more extensive neural resources to achieve successful memory formation., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Prenatal alcohol exposure (PAE) has been linked to poorer performance on the Morris water maze (MWM), a test of spatial navigation in rodents that is dependent on hippocampal functioning. We recently confirmed these findings in children with PAE on a human analog of the MWM, the virtual water maze (VWM). Previous studies have shown that the hippocampus is particularly sensitive to PAE. Our aim was to determine whether hippocampal volume mediates the relation between PAE and virtual navigation., Methods: VWM and MRI hippocampal data were collected from 50 right-handed 10-year-old children in a heavily exposed Cape Town, South African sample. PAE data had been collected from their mothers during pregnancy, and the children were examined by expert fetal alcohol spectrum disorder (FASD) dysmorphologists. In the VWM, the participant attempts to learn the location of a hidden platform in a virtual pool of water across a series of learning trials using only distal room cues. Hippocampal volumes were derived using FreeSurfer from MRI scans administered within 1 week of completing the VWM task., Results: Both the fetal alcohol syndrome (FAS)/partial FAS and nonsyndromal heavy-exposed (HE) groups had smaller hippocampal volumes than controls. PAE was associated with reduced right hippocampal volumes even after control for total intracranial volume (ICV). Hippocampal volume was also positively associated with VWM performance. The relation between PAE and VWM performance was partially mediated by right hippocampal volume but not by total ICV., Conclusions: These data confirm previous reports linking PAE to poorer spatial navigation on the VWM and are the first to provide direct evidence that volume reductions in this region partially mediate the relation of FASD diagnosis to place learning, suggesting that PAE specifically impairs the ability to encode the spatial information necessary for successful location of the hidden platform on a navigation task., (© 2020 by the Research Society on Alcoholism.)

Background: Arithmetic is the domain of academic achievement most consistently related to prenatal alcohol exposure (PAE). Error detection, an important aspect of arithmetic processing, can be examined in a mathematical verification task. Electroencephalographic (EEG) studies using such tasks have shown bursts of synchronized theta-band activity in response to errors. We assessed this activity for error detection in adolescents with PAE and typically developing (TD) matched controls. We predicted that the PAE group would show smaller theta bursts during error detection and weaker responses depending on the size of the error discrepancy., Methods: Participants' mothers were recruited during pregnancy and interviewed about their alcohol consumption using a timeline follow-back interview. Participants were followed from infancy and diagnosed for fetal alcohol syndrome (FAS) or partial FAS (PFAS) by expert dysmorphologists. EEGs were recorded for 48 adolescents during a verification task, which required differentiation between correct/incorrect solutions to simple equations; incorrect solutions had small or large deviations from correct solutions., Results: Performance was good-excellent. The PAE group showed lower accuracy than the TD group: Accuracy was inversely related to diagnosis severity. The TD and heavily exposed (HE) nonsyndromal groups showed the expected differentiation in theta-burst activity between correct/incorrect equations, but the FAS/PFAS groups did not. Degree of impairment in brain response to errors reflected severity of diagnosis: The HE group showed the same differentiation between correct/incorrect solutions as TD but failed to differentiate between levels of discrepancy; PFAS showed theta reactions only in response to large error discrepancies; and FAS did not respond to small or large discrepancies., Conclusions: Arithmetical error-related theta activity is altered by PAE and can be used to distinguish between exposed and nonexposed individuals and within diagnostic groups, supporting the use of numerical and quantitative processing patterns to derive a neurocognitive profile that could facilitate diagnosis and treatment of fetal alcohol spectrum disorders., (Copyright © 2019 by the Research Society on Alcoholism.)

Prenatal alcohol exposure (PAE) is associated with a range of physical, cognitive, and behavioral problems, particularly in arithmetic. We report ERP data collected from 32 infants (mean age = 6.8 mo; SD = 0.6; range = 6.1-8.1; 16 typically developing [TD]; 16 prenatally alcohol-exposed) during a task designed to assess error detection. Evidence of error monitoring at this early age suggests that precursors of the onset of executive control can already be detected in infancy. As predicted, the ERPs of the TD infants, time-locked to the presentation of the solution to simple arithmetic equations, showed greater negative activity for the incorrect solution condition at middle-frontal scalp areas. Spectral analysis indicated specificity to the 6-7 Hz frequency range. By contrast, the alcohol-exposed infants did not show the increased middle-frontal negativity seen in the TD group nor the increased power in the 6-7 Hz frequency, suggesting a marked developmental delay in error detection and/or early impairment in information processing of small quantities. Overall, our research demonstrates that (a) the brain network involved in error detection can be identified and highly specified in TD young infants, and (b) this effect is replicable and can be utilized for studying developmental psychopathology at very early ages., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Background: Rodent studies have consistently shown that prenatal alcohol exposure (PAE) impairs performance on the Morris water maze (MWM), a test of spatial navigation. A previous study comparing boys with fetal alcohol syndrome (FAS) to controls found poorer performance on the virtual water maze (VWM), a human analogue of the MWM. We examined PAE effects on virtual navigation in both sexes using the VWM in a moderately exposed Detroit cohort (N = 104; mean = 19.4 year) and a heavily exposed Cape Town, South African cohort (N = 62; mean = 10.4 year)., Methods: The task requires the participant to learn the location of a hidden platform in a virtual pool of water. The set of acquisition trials requires the participant to learn the location of the hidden platform and to return to that location repeatedly. The single-probe trial requires the participant to return to that location without knowing that the platform has been removed., Results: No effects of FASD diagnostic group or PAE were detected on virtual navigation in the Detroit moderately exposed cohort. By contrast, in the more heavily exposed Cape Town cohort, the FAS/partial FAS (PFAS) group took longer to locate the hidden platform during acquisition than nonsyndromal heavily exposed (HE) and control groups, an effect that persisted even after controlling for IQ. Among boys, both the FAS/PFAS and HE groups performed more poorly than controls during acquisition, and both boys and girls born to women who binge drank performed more poorly than those born to abstainers/light drinkers. Both amount and frequency of PAE were related to poorer performance during the probe trial at 10 years of age., Conclusions: These data demonstrate deficits in spatial navigation among heavily exposed syndromal boys and girls and in nonsyndromal exposed boys., (© 2019 by the Research Society on Alcoholism.)

Introduction: Although performance deficits in place learning have been reported in fetal alcohol spectrum disorders (FASD), neural correlates of these deficits have not been investigated. This functional magnetic resonance imaging (fMRI) study of 57 children (41 alcohol-exposed; 16 controls; mean age = 9.4 years; 29 boys) examined effects of prenatal alcohol exposure (PAE) on place learning in a virtual environment, the computer-generated (CG) arena., Methods: Functional magnetic resonance imaging data were acquired while children passively viewed a recording of an experimenter completing the task. Visible-target blocks involved navigation to a visible platform. During invisible-target blocks, the platform appeared only when the experimenter moved over it. After the scan, all children performed a post-test during which they had to navigate to the location of the invisible platform., Results: Although there were no group differences in post-test performance for sex or FASD diagnosis, PAE in boys was associated with poorer performance and reduced activation in the parahippocampal gyrus (PHG), precuneus, posterior cingulate, frontal and temporal lobes, caudate, insula, claustrum, lentiform nucleus, and thalamus. By contrast, PAE was not associated with performance or activation in any regions in girls., Discussion and Conclusion: Girls and boys are known to use different navigation strategies. Boys rely more on an allocentric navigational strategy and girls more on landmarks. Poorer recruitment of the PHG, a region known to mediate allocentric navigation, in more heavily exposed boys may explain the observed dose-dependent place learning deficit. The absence of PAE effects in girls suggests that landmark-based navigational strategies may be less affected by alcohol exposure., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Fetal alcohol spectrum disorders (FASD) are characterized by impairment in cognitive function that may or may not be accompanied by craniofacial anomalies, microcephaly, and/or growth retardation. Resting-state functional MRI (rs-fMRI), which examines the low-frequency component of the blood oxygen level dependent (BOLD) signal in the absence of an explicit task, provides an efficient and powerful mechanism for studying functional brain networks even in low-functioning and young subjects. Studies using independent component analysis (ICA) have identified a set of resting-state networks (RSNs) that have been linked to distinct domains of cognitive and perceptual function, which are believed to reflect the intrinsic functional architecture of the brain. This study is the first to examine resting-state functional connectivity within these RSNs in FASD. Rs-fMRI scans were performed on 38 children with FASD (19 with either full fetal alcohol syndrome (FAS) or partial FAS (PFAS), 19 nonsyndromal heavily exposed (HE)), and 19 controls, mean age 11.3 ± 0.9 years, from the Cape Town Longitudinal Cohort. Nine resting-state networks were generated by ICA. Voxelwise group comparison between a combined FAS/PFAS group and controls revealed localized dose-dependent functional connectivity reductions in five regions in separate networks: anterior default mode, salience, ventral and dorsal attention, and R executive control. The former three also showed lower connectivity in the HE group. Gray matter connectivity deficits in four of the five networks appear to be related to deficits in white matter tracts that provide intra-RSN connections. Hum Brain Mapp 38:5217-5233, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Our objective is to help clinicians detect the facial effects of prenatal alcohol exposure by developing computer-based tools for screening facial form., Methods: All 415 individuals considered were evaluated by expert dysmorphologists and categorized as (i) healthy control (HC), (ii) fetal alcohol syndrome (FAS), or (iii) heavily prenatally alcohol exposed (HE) but not clinically diagnosable as FAS; 3D facial photographs were used to build models of facial form to support discrimination studies. Surface curvature-based delineations of facial form were introduced., Results: (i) Facial growth in FAS, HE, and control subgroups is similar in both cohorts. (ii) Cohort consistency of agreement between clinical diagnosis and HC-FAS facial form classification is lower for midline facial regions and higher for nonmidline regions. (iii) Specific HC-FAS differences within and between the cohorts include: for HC, a smoother philtrum in Cape Coloured individuals; for FAS, a smoother philtrum in Caucasians; for control-FAS philtrum difference, greater homogeneity in Caucasians; for control-FAS face difference, greater homogeneity in Cape Coloured individuals. (iv) Curvature changes in facial profile induced by prenatal alcohol exposure are more homogeneous and greater in Cape Coloureds than in Caucasians. (v) The Caucasian HE subset divides into clusters with control-like and FAS-like facial dysmorphism. The Cape Coloured HE subset is similarly divided for nonmidline facial regions but not clearly for midline structures. (vi) The Cape Coloured HE subset with control-like facial dysmorphism shows orbital hypertelorism., Conclusions: Facial curvature assists the recognition of the effects of prenatal alcohol exposure and helps explain why different facial regions result in inconsistent control-FAS discrimination rates in disparate ethnic groups. Heavy prenatal alcohol exposure can give rise to orbital hypertelorism, supporting a long-standing suggestion that prenatal alcohol exposure at a particular time causes increased separation of the brain hemispheres with a concomitant increase in orbital separation., (Copyright © 2017 by the Research Society on Alcoholism.)

Prenatal alcohol exposure has been linked to a broad range of developmental deficits, with eyeblink classical conditioning (EBC) among the most sensitive endpoints. This fMRI study compared EBC-related brain activity in 47 children with fetal alcohol syndrome (FAS), partial FAS (PFAS), heavily exposed (HE) non-syndromal children, and healthy controls. All of the children had previously participated in two EBC studies conducted as part of our longitudinal study of fetal alcohol spectrum disorders. Although learning-related behavioral differences were seen in all groups during the scans, controls showed more conditioned responses (CR) than the alcohol-exposed groups. Despite lower conditioning levels relative to controls, the exposed groups exhibited extensive cerebellar activations. Specifically, children with FAS/PFAS showed increased activation of cerebellar lobule VI in session 2, while HE children showed increased activation in session 1. Continuous measures of prenatal alcohol use correlated with learning-related activations in cerebellum and frontal cortices. Only controls showed significant cerebellar activation-CR correlations in the deep nuclei and lateral lobule VI, suggesting that these key regions supporting EBC may be functionally disorganized in alcohol-exposed children. These findings are the first to characterize abnormalities in brain function associated with the behavioral conditioning deficits seen in children with prenatal alcohol exposure., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: The authors declare no conflict of interest.

Background: Response inhibition is a distinct aspect of executive function that is frequently impaired in children with fetal alcohol spectrum disorders (FASD). We used a Go/NoGo (GNG) task in a functional MRI protocol to investigate differential activation of brain regions in the response inhibition network in children diagnosed with full or partial fetal alcohol syndrome (FAS/PFAS), compared with healthy controls., Methods: A rapid, event-related task with 120 Go and 60 NoGo trials was used to study children aged 8 to 12 years-8 with FAS/PFAS, 17 controls. Letters were projected sequentially, with Go and NoGo trials randomly interspersed across the task. BOLD signal in the whole brain was contrasted for the correct NoGo minus correct Go trials between the FAS/PFAS and control groups., Results: Compared to the FAS/PFAS group, controls showed greater activation of the inferior frontal and anterior cingulate network linked to response inhibition in typically developing children. By contrast, the FAS/PFAS group showed greater BOLD response in dorsolateral prefrontal cortex and other middle prefrontal regions, suggesting compensation for inefficient function of pathways that normally mediate inhibitory processing. All group differences were significant after control for potential confounding variables. None of the effects of prenatal alcohol exposure on activation of the regions associated with response inhibition were attributable to the effects of this exposure on IQ., Conclusions: This is the first FASD GNG study in which all participants in the exposed group met criteria for a diagnosis of full FAS or PFAS. Although FASD is frequently comorbid with attention deficit hyperactivity disorder, the pattern of brain activation seen in these disorders differs, suggesting that different neural pathways mediate response inhibition in FASD and that different interventions for FASD are, therefore, warranted., Competing Interests: None, (Copyright © 2017 by the Research Society on Alcoholism.)

Background: Previous event-related potential (ERP) studies of response inhibition in children with fetal alcohol spectrum disorder (FASD) have used a visual Go/NoGo task to study the impact of prenatal alcohol exposure on response inhibition. No studies exist using auditory versions of the task; thus, it is unclear how the deficits observed in visual tasks translate into the auditory domain., Methods: This study examined ERPs using an auditory Go/NoGo paradigm in a sample of 35 school-age children-18 with heavy prenatal alcohol exposure and 17 normally developing controls., Results: Alcohol-exposed children performed as well as controls in terms of inhibiting their responses; however, their reaction times were significantly slower under the Go condition. As in the ERP visual Go/NoGo task previously administered to these children, group differences were seen in early perceptual processing, specifically related to stimulus discrimination, with a decrease in P2 amplitude in the alcohol-exposed group. The control group exhibited greater N2 amplitude in the NoGo compared to the Go condition while the alcohol-exposed group did not, suggesting a group difference in the neural substrates underlying conflict monitoring. The alcohol-exposed group demonstrated longer latency P3 with reduced amplitude, suggesting poorer allocation of attention. The alcohol-exposed group also exhibited a late positive component (LPC) similar to the one observed in the previous visual ERP study. This LPC may indicate compensatory neurophysiological function related to resetting of attentional control networks in preparation for the next trial. None of the ERP outcomes in this study were related to potential confounders which included cognitive and socioeconomic measures as well as ADHD diagnosis., Conclusions: The observed ERP group differences point to elements of perceptual and attentional processing likely to be involved in the performance deficits often observed in children with FASD. We also observed changes in ERPs related to conflict monitoring/response inhibition, highlighting fetal alcohol-related effects on how the brain responds when there is need to identify and respond to environmental cues by switching away from a prepotent motor response to an inhibited state., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Although both fetal and long-term growth restriction are well documented in fetal alcohol spectrum disorders, effects on pattern of growth trajectory have not been characterized. Furthermore, the degree to which growth trajectories are related to fetal alcohol-related neurocognitive deficits is unknown., Methods: Ninety-three heavy drinking pregnant women and 64 controls were recruited at initiation of prenatal care in Cape Town, South Africa. Small for gestational age (SGA) was defined as birth weight <10th percentile. Length/height, weight, and head circumference were measured at 6.5 and 12 months and 5, 9, and 13 years. Four growth trajectories were identified: SGA with long-term postnatal growth restriction (length/height-for-age <10th percentile through 13 years); SGA with catch-up growth; no SGA or postnatal growth restriction; and late-onset postnatal stunting. IQ was assessed at 5 and 10 years, and learning, memory, and executive function at 10 years., Results: Children born SGA with postnatal growth restriction were most heavily exposed. Exposure was intermediate for those born SGA with catch-up growth and lowest for those without prenatal or postnatal growth restriction. Effects on neurocognition were strongest in children with both prenatal and long-term growth restriction, more moderate in those with fetal growth restriction and postnatal catch-up, and weakest in those without growth restriction., Conclusions: These findings validate the use of growth restriction in the diagnosis of fetal alcohol spectrum disorders and identify growth trajectory as a biomarker of which heavily exposed children are at greatest risk for cognitive developmental deficits., (Copyright © 2016 by the American Academy of Pediatrics.)

Fetal alcohol spectrum disorders comprise the spectrum of cognitive, behavioral, and neurological impairments caused by prenatal alcohol exposure (PAE). Diffusion tensor imaging (DTI) was performed on 54 children (age 10.1 ± 1.0 years) from the Cape Town Longitudinal Cohort, for whom detailed drinking histories obtained during pregnancy are available: 26 with full fetal alcohol syndrome (FAS) or partial FAS (PFAS), 15 nonsyndromal heavily exposed (HE), and 13 controls. Using voxelwise analyses, children with FAS/PFAS showed significantly lower fractional anisotropy (FA) in four white matter (WM) regions and higher mean diffusivity (MD) in seven; three regions of FA and MD differences (left inferior longitudinal fasciculus (ILF), splenium, and isthmus) overlapped, and the fourth FA cluster was located in the same WM bundle (right ILF) as an MD cluster. HE children showed lower FA and higher MD in a subset of these regions. Significant correlations were observed between three continuous alcohol measures and DTI values at cluster peaks, indicating that WM damage in several regions is dose dependent. Lower FA in the regions of interest was attributable primarily to increased radial diffusivity rather than decreased axonal diffusivity, suggesting poorer axon packing density and/or myelination. Multiple regression models indicated that this cortical WM impairment partially mediated adverse effects of PAE on information processing speed and eyeblink conditioning. Hum Brain Mapp 37:2943-2958, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Children with fetal alcohol spectrum disorders (FASD) may exhibit craniofacial dysmorphology, neurobehavioral deficits, and reduced brain volume. Studies of cortical thickness in FASD have yielded contradictory findings, with 3 reporting thicker cerebral cortex in frontal and temporal brain regions and 2 showing thinner cortex across multiple regions. All 5 studies included subjects spanning a broad age range, and none have examined continuous measures of prenatal alcohol exposure. We investigated the relation of extent of in utero alcohol exposure to cortical thickness in 78 preadolescent children with FASD and controls within a narrow age range. A whole-brain analysis using FreeSurfer revealed no significant clusters where cortical thickness differed by FASD diagnostic group. However, alcohol dose/occasion during pregnancy was inversely related to cortical thickness in 3 regions-right cuneus/pericalcarine/superior parietal lobe, fusiform/lingual gyrus, and supramarginal/postcentral gyrus. The effect of prenatal alcohol exposure on IQ was mediated by cortical thickness in the right occipitotemporal region. It is noteworthy that a continuous measure of maternal alcohol consumption during pregnancy was more sensitive than FASD diagnosis and that the effect on cortical thickness was most evident in relation to a measure of maternal binge drinking., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Prenatal alcohol exposure (PAE) is linked to impaired performance on tests of retrospective memory, but prospective memory (PM; the ability to remember and act on delayed intentions) has not been examined in alcohol-exposed children. We investigated event-based PM in children with heavy PAE and the degree to which associations between PAE and PM are influenced by IQ, executive functioning (EF), retrospective memory, and attention deficit/hyperactivity disorder (ADHD)., Methods: We administered a computerized PM task to 89 children (Mage = 11.1 years) whose mothers were recruited prenatally: 29 with fetal alcohol syndrome (FAS) or partial FAS (PFAS), 32 nonsyndromal heavily exposed (HE), and 28 Controls. We examined effects of diagnostic group, cue focality, and task difficulty on PM performance. The association between a continuous measure of alcohol exposure and PM performance was also examined after controlling for sociodemographic confounders. Mediation of alcohol effects on PM by IQ, EF, and retrospective memory scores was assessed as was the effect of ADHD on PM performance., Results: Children with FAS/PFAS made more PM errors than either HE or Control children. PAE was negatively related to PM performance even after adjusting for sociodemographic confounders, EF, and retrospective memory. This relation was only partially mediated by IQ. PAE was related to ADHD, but ADHD was not related to PM performance., Conclusions: Fetal alcohol-related impairment in event-based PM was seen in children with FAS/PFAS. The effect of PAE on PM was not attributable to impaired EF and retrospective memory and was not solely attributable to lower IQ. Consistent with previous studies, we found no effect of ADHD on event-based PM performance at this age. This is the first study documenting PM impairment in children with heavy PAE and identifies a new domain of impairment warranting attention in diagnosis and management of fetal alcohol spectrum disorders., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Theory of mind (ToM) refers to the ability to understand and make inferences about other people's intentions, feelings, and beliefs. Although children with fetal alcohol spectrum disorders (FASD) are known to have deficits in social-cognitive function, little is known about ToM in FASD., Methods: ToM ability was assessed using a developmentally sensitive ToM battery, including the reading the mind in the eyes (RME) test, a measure of mental inferential ability that has been found to be impaired in other clinical populations. IQ and executive function (EF) were assessed as potential mediating variables. The battery was administered to 63 children (aged 9 to 11 years) from Cape Town, South Africa, whose mothers had been prospectively recruited during pregnancy. Children with fetal alcohol syndrome (FAS; n = 8) and partial FAS (PFAS; n = 19), as well as nonsyndromal heavily exposed children (n = 17), were compared to children born to abstaining or light drinkers (n = 19) from the same community., Results: No FASD group differences were found on the less challenging ToM tasks. By contrast, children with FAS and PFAS performed more poorly than controls on a more challenging ToM task, the RME test. A continuous measure of prenatal alcohol exposure (PAE) was more sensitive than FASD diagnosis in that it was related to 4 higher-order ToM measures, particularly the ability to attribute mental states assessed on RME. IQ only partially mediated the effect of exposure on RME performance, and these effects were not mediated by EF. Hence, the data suggest that these ToM measures tap into a specific alcohol-related social-cognitive deficit that does not merely reflect poorer EF. FASD diagnosis and PAE were each also related to RME after control for attention deficit/hyperactivity disorder., Conclusions: These findings suggest that deficits in higher-order ToM function may play a significant role in the social-cognitive behavioral impairment in FASD., (Copyright © 2016 by the Research Society on Alcoholism.)

Fetal alcohol spectrum disorders (FASD) are characterized by a range of neurodevelopmental deficits that result from prenatal exposure to alcohol. These can include cognitive, behavioural, and neurological impairment, as well as structural and functional brain damage. Eyeblink conditioning (EBC) is among the most sensitive endpoints affected in FASD. The cerebellar peduncles, large bundles of myelinated nerve fibers that connect the cerebellum to the brainstem, constitute the principal white matter element of the EBC circuit. Diffusion tensor imaging (DTI) is used to assess white matter integrity in fibre pathways linking brain regions. DTI scans of 54 children with FASD and 23 healthy controls, mean age 10.1 ± 1.0 years, from the Cape Town Longitudinal Cohort were processed using voxelwise group comparisons. Prenatal alcohol exposure was related to lower fractional anisotropy (FA) bilaterally in the superior cerebellar peduncles and higher mean diffusivity (MD) in the left middle peduncle, effects that remained significant after controlling for potential confounding variables. Lower FA and higher MD in these regions were associated with poorer EBC performance. Moreover, effects of alcohol exposure on EBC decreased significantly after inclusion of these DTI measures in regression models, suggesting that these white matter deficits partially mediate the relation of prenatal alcohol exposure to EBC. The associations of greater alcohol consumption with these DTI measures are largely attributable to greater radial diffusivity, possibly indicating poorer myelination. Thus, these data suggest that fetal alcohol-related deficits in EBC are attributable, in part, to poorer myelination in key regions of the cerebellar peduncles., (© 2015 Wiley Periodicals, Inc.)

Background: Previous studies using the California Verbal Learning Test-Children's Version (CVLT-C) to examine effects of heavy prenatal alcohol exposure on verbal learning and memory have reported impaired information acquisition (i.e., encoding), rather than retrieval, as the primary mechanism underlying learning and memory impairment. We administered the CVLT-C to 2 independent cohorts to determine whether (i) effects on encoding are also seen at moderate exposure levels, using both categorical (diagnostic/exposure group) and continuous exposure measures; (ii) these deficits are specific or secondary to alcohol-related impairment in IQ; (iii) effects on retrieval can be detected over and above effects on initial encoding; and (iv) effects on learning are attributable to less efficient learning strategy use., Methods: We administered the CVLT-C and Wechsler Intelligence Scale for Children to 151 Cape Town heavy and nonexposed children (M = 10.3 years), and 291 Detroit adolescents recruited to over-represent moderate-to-heavy prenatal alcohol exposure (M = 14.4 years)., Results: Effects on encoding in the heavily exposed Cape Town cohort and on retrieval in both cohorts were significant after adjustment for IQ. Although effects on retrieval were no longer significant in Cape Town after control for initial encoding, effects on recognition memory continued to be evident in Detroit. Children with full or partial fetal alcohol syndrome were less able to use the semantic cluster encoding strategy implicit in the CVLT-C., Conclusions: Effects on verbal learning were seen primarily in the more heavily exposed Cape Town cohort; effects on recall and recognition memory were also seen at moderate exposure levels in Detroit. These effects were not attributable to alcohol-related impairment in overall intellectual competence. The finding that effects on retention continued to be evident after statistical adjustment for initial encoding in Detroit suggests that a fetal alcohol-related deficit in retrieval is not secondary to a failure to encode the initial information. These data confirm that this impairment in initial learning is mediated, in part, by failure to use the semantic cluster learning strategy., (Copyright © 2015 by the Research Society on Alcoholism.)

Objectives: Classical eyeblink conditioning (EBC), an elemental form of learning, is among the most sensitive indicators of fetal alcohol spectrum disorders. The cerebellum plays a key role in maintaining timed movements with millisecond accuracy required for EBC. Functional MRI (fMRI) was used to identify cerebellar regions that mediate timing in healthy controls and the degree to which these areas are also recruited in children with prenatal alcohol exposure., Experimental Design: fMRI data were acquired during an auditory rhythmic/non-rhythmic finger tapping task. We present results for 17 children with fetal alcohol syndrome (FAS) or partial FAS, 17 heavily exposed (HE) nonsyndromal children and 16 non- or minimally exposed controls., Principal Observations: Controls showed greater cerebellar blood oxygen level dependent (BOLD) activation in right crus I, vermis IV-VI, and right lobule VI during rhythmic than non-rhythmic finger tapping. The alcohol-exposed children showed smaller activation increases during rhythmic tapping in right crus I than the control children and the most severely affected children with either FAS or PFAS showed smaller increases in vermis IV-V. Higher levels of maternal alcohol intake per occasion during pregnancy were associated with reduced activation increases during rhythmic tapping in all four regions associated with rhythmic tapping in controls., Conclusions: The four cerebellar areas activated by the controls more during rhythmic than non-rhythmic tapping have been implicated in the production of timed responses in several previous studies. These data provide evidence linking binge-like drinking during pregnancy to poorer function in cerebellar regions involved in timing and somatosensory processing needed for complex tasks requiring precise timing.

Background: Fetal alcohol spectrum disorders (FASD) include a range of neurocognitive and behavioral impairments resulting from prenatal alcohol exposure (PAE). Among the PAE‐related cognitive deficits, number processing is particularly affected. This study examines alterations in number processing networks and whether changes in functional connectivity mediate the adverse effects of PAE on arithmetic performance. Methods: Magnetic resonance imaging (MRI) was acquired in 57 children (mean (SD) age = 11.3 (+0.9) yr), 38 with FASD (19 fetal alcohol syndrome (FAS) or partial FAS (PFAS), 19 heavily exposed (HE)) and 19 controls. Whole‐brain correlation analyses were performed from five seeds located in regions involved in number processing. Results: Children with FAS/PFAS showed dose‐dependent reductions in resting state functional connectivity between the seed in the right (R) posterior superior parietal lobule and a cluster in the left (L) inferior frontal gyrus, and between a seed in the R horizontal intraparietal sulcus and clusters in the R precentral gyrus and L cerebellar lobule VI. HE children showed lower resting state functional connectivity in a subset of these regions. Lower functional connectivity in the two fronto‐parietal connections partially mediated the adverse effects of PAE on arithmetic performance. Conclusion: This study demonstrates PAE‐related functional connectivity impairments in functional networks involved in number processing. The weaker connectivity between the R posterior superior parietal lobule and the L inferior frontal gyrus suggests that impaired verbal processing and visuospatial working memory may play a role in number processing deficits, while weaker connectivity between the R intraparietal sulcus and the R precentral gyrus points to poorer finger‐based numerical representation, which has been linked to arithmetic computational skills. [ABSTRACT FROM AUTHOR]

Background: Most studies of the effects of prenatal alcohol exposure (PAE) on cognitive function have assumed that the dose-response curve is linear. However, data from a few animal and human studies suggest that there may be an inflection point in the dose-response curve above which PAE effects are markedly stronger and that there may be differences associated with pattern of exposure, assessed in terms of alcohol dose per drinking occasion and drinking frequency. Methods: We performed second-order confirmatory factor analysis on data obtained at school age, adolescence, and early adulthood from 2227 participants in six US longitudinal cohorts to derive a composite measure of cognitive function. Regression models were constructed to examine effects of PAE on cognitive function, adjusted for propensity scores. Analyses based on a single predictor (absolute alcohol (AA)/day) were compared with analyses based on two predictors (dose/occasion and drinking frequency), using (1) linear models and (2) nonparametric general additive models (GAM) that allow for both linear and nonlinear effects. Results: The single-predictor GAM model showed virtually no nonlinearity in the effect of AA/day on cognitive function. However, the two-predictor GAM model revealed differential effects of maternal drinking pattern. Among offspring of infrequent drinkers, PAE effects on cognitive function were markedly stronger in those whose mothers drank more than ~3 drinks/occasion, and the effect of dose/occasion was strongest among the very frequent drinkers. Frequency of drinking did not appear to alter the PAE effect on cognitive function among participants born to mothers who limited their drinking to ~1 drink/occasion or less. Conclusions: These findings suggest that linear models based on total AA/day are appropriate for assessing whether PAE affects a given cognitive outcome. However, examination of alcohol dose/occasion and drinking frequency is needed to fully characterize the impact of different levels of alcohol intake on cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta‐analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. Methods: Meta‐analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores. Results: The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle‐class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent‐ and teacher‐reported behavior problems and not significant for sustained attention. In a meta‐analysis of five aspects of executive function, the strongest effect was on set‐shifting. Conclusions: The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle‐class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition—learning/memory and set‐shifting—that are particularly affected by PAE, and one, sustained attention, which is apparently spared. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence in animal models has implicated alcohol-induced alterations in epigenetic programming as an important mechanism in fetal alcohol spectrum disorders (FASD). Imprinted genes, a subset of epigenetically regulated genes that are sensitive to the prenatal environment, are chiefly involved in growth and neurobehavior. We tested the hypothesis that alterations in placental imprinted gene expression mediate fetal alcohol growth restriction. Methods: Placental expression of 109 genes previously shown to be imprinted and expressed in the placenta was assessed using the NanoStringTM nCounter Analysis System in flash-frozen samples from 34 heavy drinkers and 31 control women in Cape Town, South Africa, from whom prospective pregnancy alcohol consumption data had been obtained. Length/height, weight, and head circumference were measured at 6.5 and 12 months and at an FASD diagnostic clinic (at ages 1.1 to 4.6 years) that we organized. Imprinted gene expression between exposed and control placentas was compared using the limma R package. The relation of alcohol exposure to World Health Organization length-for-age z-scores was examined before and after inclusion of expression for each alcohol-related imprinted gene, using hierarchical mixed regression models with repeated measures. Results: Heavy drinkers averaged 8 standard drinks on 2 to 3 days/wk (vs. 0 for controls). Prenatal alcohol exposure was associated with smaller length/height and weight during the postnatal period. Heavy exposure was related to alterations in expression of 11 of 93 expressed imprinted genes, including increased expression of 5 genes found to be negatively associated with growth and decreased expression of 3 genes positively associated with growth. Alcohol-related alterations in expression of 5 genes statistically mediated the effect of prenatal alcohol exposure on length. Conclusions: These findings identify alcohol-related alterations in placental imprinted gene expression as potential biomarkers of adverse effect in FASD and suggest that these alterations may play a mechanistic role in fetal alcohol growth restriction. Future studies are needed to determine whether alterations in imprinted gene expression also mediate FASD neurobehavioral deficits and whether such alterations are amenable to intervention. [ABSTRACT FROM AUTHOR]

Background: We recently demonstrated the acceptability and feasibility of a randomized, double‐blind choline supplementation intervention for heavy drinking women during pregnancy. In this study, we report our results relating to the efficacy of this intervention in mitigating adverse effects of prenatal alcohol exposure (PAE) on infant growth and cognitive function. Methods: Sixty‐nine Cape Coloured (mixed ancestry) heavy drinkers in Cape Town, South Africa, recruited in mid‐pregnancy, were randomly assigned to receive a daily oral dose of either 2 g of choline or placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape‐flavored drink. The primary outcome, eyeblink conditioning (EBC), was assessed at 6.5 months. Somatic growth was measured at birth, 6.5, and 12 months, recognition memory and processing speed on the Fagan Test of Infant Intelligence, at 6.5 and 12 months. Results: Infants born to choline‐treated mothers were more likely to meet criterion for conditioning on EBC than the placebo group. Moreover, within the choline arm, degree of maternal adherence to the supplementation protocol strongly predicted EBC performance. Both groups were small at birth, but choline‐treated infants showed considerable catch‐up growth in weight and head circumference at 6.5 and 12 months. At 12 months, the infants in the choline treatment arm had higher novelty preference scores, indicating better visual recognition memory. Conclusions: This exploratory study is the first to provide evidence that a high dose of choline administered early in pregnancy can mitigate adverse effects of heavy PAE on EBC, postnatal growth, and cognition in human infants. These findings are consistent with studies of alcohol‐exposed animals that have demonstrated beneficial effects of choline supplementation on classical conditioning, learning, and memory. [ABSTRACT FROM AUTHOR]

Background: Choline, an essential nutrient, serves as a methyl‐group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies suggest that choline supplementation during pregnancy can mitigate adverse effects of prenatal alcohol exposure on growth and neurocognitive function. We conducted a randomized, double‐blind exploratory trial to examine feasibility and acceptability of a choline supplementation intervention during pregnancy. Methods: Seventy heavy drinkers, recruited in mid‐pregnancy, were randomly assigned to receive a daily oral dose of 2 g of choline or a placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape‐flavored drink. Adherence was assessed by collecting used and unused drink packets on a monthly basis and tabulating the number used. Side effects were assessed in monthly interviews. Blood samples obtained at enrollment and at 4 and 12 weeks after randomization were assayed for plasma choline concentration. Results: Adherence was good‐to‐excellent (median doses taken = 74.0%; interquartile range = 53.9 to 88.7%) and was not related to a range of sociodemographic characteristics or to alcohol consumption ascertained using a timeline follow‐back interview. By 4 weeks, plasma choline concentrations were significantly higher in the choline supplementation than the placebo arm, and this group difference continued to be evident at 12 weeks. The only side effect was a small increase in nausea/dyspepsia. No effects were seen for diarrhea, vomiting, muscle stiffness, blood pressure, or body odor changes. Conclusions: This study demonstrated that a choline supplementation program with very heavy drinkers during pregnancy is feasible even among highly disadvantaged, poorly educated women. The broad acceptability of this intervention is indicated by our finding that adherence was not related to maternal education, intellectual function, depression, nutritional status, or alcohol use. [ABSTRACT FROM AUTHOR]

Disproportionate volume reductions in the basal ganglia, corpus callosum (CC) and hippocampus have been reported in children with prenatal alcohol exposure (PAE). However, few studies have investigated these reductions in high prevalence communities, such as the Western Cape Province of South Africa, and only one study made use of manual tracing, the gold standard of volumetric analysis. The present study examined the effects of PAE on subcortical neuroanatomy using manual tracing and the relation of volumetric reductions in these regions to IQ and performance on the California Verbal Learning Test-Children's Version (CVLT-C), a list learning task sensitive to PAE. High-resolution T1-weighted images were acquired, using a sequence optimized for morphometric neuroanatomical analysis, on a Siemens 3T Allegra MRI scanner from 71 right-handed, 9- to 11-year-old children [9 fetal alcohol syndrome (FAS), 19 partial FAS (PFAS), 24 non-syndromal heavily exposed (HE) and 19 non-exposed controls]. Frequency of maternal drinking was ascertained prospectively during pregnancy using timeline follow-back interviews. PAE was examined in relation to volumes of the CC and left and right caudate nuclei, nucleus accumbens and hippocampi. All structures were manually traced using Multitracer. Higher levels of PAE were associated with reductions in CC volume after adjustment for TIV. Although the effect of PAE on CC was confounded with smoking and lead exposure, additional analyses showed that it was not accounted for by these exposures. Amongst dysmorphic children, smaller CC was associated with poorer IQ and CVLT-C scores and statistically mediated the effect of PAE on IQ. In addition, higher levels of PAE were associated with bilateral volume reductions in caudate nuclei and hippocampi, effects that remained significant after control for TIV, child sex and age, socioeconomic status, maternal smoking during pregnancy, and childhood lead exposure. These data confirm previous findings showing that PAE is associated with decreases in subcortical volumes and is the first study to show that decreases in callosal volume may play a role in fetal alcohol-related impairment in cognitive function seen in childhood. [ABSTRACT FROM AUTHOR]

Number processing is a cognitive domain particularly sensitive to prenatal alcohol exposure, which relies on intact parietal functioning. Alcohol-related alterations in brain activation have been found in the parietal lobe during symbolic number processing. However, the effects of prenatal alcohol exposure on the neural correlates of non- symbolic number comparison and the numerical distance effect have not been investigated. Using functional magnetic resonance imaging (fMRI), we examined differences in brain activation associated with prenatal alcohol exposure in five parietal regions involved in number processing during a non-symbolic number comparison task with varying degrees of difficulty. fMRI results are presented for 27 Cape Colored children (6 fetal alcohol syndome (FAS)/partial FAS, 5 heavily exposed (HE) non-sydromal, 16 controls; mean age ± SD = 11.7 ± 1.1 years). Fetal alcohol exposure was assessed by interviewing mothers using a timeline follow-back approach. Separate subject analyses were performed in each of five regions of interest, bilateral horizontal intraparietal sulci (IPS), bilateral posterior superior parietal lobules (PSPL), and left angular gyrus (left AG), using the general linear model with predictors for number comparison and difficulty level. Mean percent signal change for each predictor was extracted for each subject for each region to examine group differences and associations with continuous measures of alcohol exposure. Although groups did not differ in performance, controls activated the right PSPL more during non-symbolic number comparison than exposed children, but this was not significant after controlling for maternal smoking, and the right IPS more than children with fetal alcohol syndrome (FAS) or partial FAS. More heavily exposed children recruited the left AG to a greater extent as task difficulty increased, possibly to compensate, in part, for impairments in function in the PSPL and IPS. Notably, in non-syndromal heavily exposed children activation was impaired in the right PSPL, but spared in the right IPS. These results extend previous findings of poor right IPS recruitment during symbolic number processing in FAS/PFAS, indicating that mental representation of relative quantity is affected by prenatal alcohol exposure for both symbolic and non-symbolic representations of quantity. [ABSTRACT FROM AUTHOR]

Background Despite known risks of prenatal nutritional deficiencies and studies documenting increased prevalence of poor dietary intake among nonpregnant alcohol abusers, the nutritional status of heavy drinking pregnant women remains largely unstudied. Animal models have found interactions between prenatal ethanol exposure and micronutrients, such as choline, folate, B12, and iron, and human studies have reported that lower maternal weight and body mass confer increased fetal alcohol-related risk. Methods One hundred and twenty-three heavy drinking Cape Coloured pregnant women and 83 abstaining controls were recruited at their first antenatal clinic visit. At 3 prenatal study visits, each gravida was interviewed about alcohol, smoking, and drug use and weight, height, and arm skinfolds were measured. Dietary intakes of energy, protein, fat, and major micronutrients were assessed from three 24-hour recall interviews. Results The majority of women gained less than the recommended 0.42 kg/wk during pregnancy. Whereas methamphetamine use was associated with smaller biceps skinfolds, an indicator of body fat, alcohol consumption was not related to any anthropometric indicator. Alcohol was related to higher intake of phosphorus, choline, and vitamins B12 and D. Alcohol, cigarette, and methamphetamine use were related to lower vitamin C intake. Insufficient intake was reported by >85% of women for 10 of 22 key nutrients, and >50% for an additional 3 nutrients. Conclusions Alcohol consumption during pregnancy was not associated with meaningful changes in diet or anthropometric measures in this population, suggesting that poor nutrition among drinkers does not confound the extensively reported effects of prenatal alcohol exposure on growth and neurobehavior. The poor gestational weight gain and high rates of insufficient intake for several nutrients in both the alcohol-exposed and control groups are also of public health importance. [ABSTRACT FROM AUTHOR]

Background Magnetic resonance imaging (MRI) studies have consistently demonstrated disproportionately smaller corpus callosa in individuals with a history of prenatal alcohol exposure (PAE) but have not previously examined the feasibility of detecting this effect in infants. Tissue segmentation of the newborn brain is challenging because analysis techniques developed for the adult brain are not directly transferable, and segmentation for cerebral morphometry is difficult in neonates, due to the latter's incomplete myelination. This study is the first to use volumetric structural MRI to investigate PAE effects in newborns using manual tracing and to examine the cross-sectional area of the corpus callosum ( CC). Methods Forty-three nonsedated infants born to 32 Cape Coloured heavy drinkers and 11 controls recruited prospectively during pregnancy were scanned using a custom-designed birdcage coil for infants, which increases signal-to-noise ratio almost 2-fold compared to the standard head coil. Alcohol use was ascertained prospectively during pregnancy, and fetal alcohol spectrum disorders diagnosis was conducted by expert dysmorphologists. Data were acquired using a multi-echo FLASH protocol adapted for newborns, and a knowledge-based procedure was used to hand-segment the neonatal brains. Results CC was disproportionately smaller in alcohol-exposed neonates than controls after controlling for intracranial volume. By contrast, CC area was unrelated to infant sex, gestational age, age at scan, or maternal smoking, marijuana, or methamphetamine use during pregnancy. Conclusions Given that midline craniofacial anomalies have been recognized as a hallmark of fetal alcohol syndrome in humans and animal models since this syndrome was first identified, the CC deficit identified here in newborns may support early identification of a range of midline structural impairments. Smaller CC during the newborn period may provide an early indicator of fetal alcohol-related cognitive deficits that have been linked to this critically important brain structure in childhood and adolescence. [ABSTRACT FROM AUTHOR]

Background Animal studies have demonstrated adverse effects of prenatal alcohol exposure on placental development, but few studies have examined these effects in humans. Little is known about effects of prenatal exposure to methamphetamine, marijuana, and cigarette smoking on placental development. Methods Placentas were collected from 103 Cape Coloured (mixed ancestry) pregnant women recruited at their first antenatal clinic visit in Cape Town, South Africa. Sixty-six heavy drinkers and 37 nondrinkers were interviewed about their alcohol, cigarette smoking, and drug use at 3 antenatal visits. A senior pathologist, blinded to exposure status, performed comprehensive pathology examinations on each placenta using a standardized protocol. In multivariable regression models, effects of prenatal exposure were examined on placental size, structure, and presence of infections and meconium. Results Drinkers reported a binge pattern of heavy drinking, averaging 8.0 drinks/occasion across pregnancy on 1.4 d/wk. 79.6% smoked cigarettes; 22.3% used marijuana; and 17.5% used methamphetamine. Alcohol exposure was related to decreased placental weight and a smaller placenta-to-birthweight ratio. By contrast, methamphetamine was associated with larger placental weight and a larger placenta-to-birthweight ratio. Marijuana was also associated with larger placental weight. Alcohol exposure was associated with increased risk of placental hemorrhage. Prenatal alcohol, drug, and cigarette use were not associated with chorioamnionitis, villitis, deciduitis, or maternal vascular underperfusion. Alcohol and cigarette smoking were associated with a decreased risk of intrauterine passing of meconium, a sign of acute fetal stress and/or hypoxia; methamphetamine, with an increased risk. Conclusions This is the first human study to show that alcohol, methamphetamine, and marijuana were associated with distinct patterns of pathology, suggesting different mechanisms mediating their effects on placental development. Given the growing body of evidence linking placental abnormalities to neurodevelopmental deficits, these findings may be important in the long-term teratogenic effects of prenatal alcohol and drug exposure. [ABSTRACT FROM AUTHOR]