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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: 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.)

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.

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.)

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.)

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.)

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.)

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.)

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.)

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.

Prenatal alcohol exposure is responsible for a broad range of brain structural malformations, which can be studied using magnetic resonance imaging (MRI). Advanced MRI methods have emerged to characterize brain abnormalities, but the teratogenic effects of alcohol on cortical morphology have received little attention to date. Twenty-four 9-year-old children with fetal alcohol spectrum disorders (9 with fetal alcohol syndrome, 15 heavy exposed nonsyndromal children) and 16 age-matched controls were studied to assess the effect of alcohol consumption during pregnancy on cortical morphology. An automated method was applied to 3D T1-weighted images to assess cortical gyrification using global and regional sulcal indices and two region-based morphological measurements, mean sulcal depth and fold opening. Increasing levels of alcohol exposure were related to reduced cortical folding complexity, even among children with normal brain size, indicating a reduction of buried cortical surface. Fold opening was the strongest anatomical correlate of prenatal alcohol intake, indicating a widening of sulci in all regions that were examined. These data identify cortical morphology as a suitable marker for further investigation of brain damage associated with prenatal alcohol exposure., (Copyright © 2013 Wiley Periodicals, Inc.)

Surface deformation-based analysis was used to assess local shape variations in the hippocampi and caudate nuclei of children with fetal alcohol spectrum disorders. High-resolution structural magnetic resonance imaging images were acquired for 31 children (19 controls and 12 children diagnosed with fetal alcohol syndrome/partial FAS). Hippocampi and caudate nuclei were manually segmented, and surface meshes were reconstructed. An iterative closest point algorithm was used to register the template of one control subject to all other shapes in order to capture the true geometry of the shape with a fixed number of landmark points. A point distribution model was used to quantify the shape variations in terms of a change in co-ordinate positions. Using the localized Hotelling T(2) method, regions of significant shape variations between the control and exposed subjects were identified and mapped onto the mean shapes. Binary masks of hippocampi and caudate nuclei were generated from the segmented volumes of each brain. These were used to compute the volumes and for further statistical analysis. The Mann-Whitney test was performed to predict volume differences between the groups. Although the exposed and control subjects did not differ significantly in their volumes, the shape analysis showed the hippocampus to be more deformed at the head and tail regions in the alcohol-exposed children. Between-group differences in caudate nucleus morphology were dispersed across the tail and head regions. Correlation analysis showed associations between the degree of compression and the level of alcohol exposure. These findings demonstrate that shape analysis using three-dimensional surface measures is sensitive to fetal alcohol exposure and provides additional information than volumetric measures alone., (Copyright © 2012 Wiley Periodicals, Inc.)

Although children with heavy prenatal alcohol exposure may exhibit the distinctive facial dysmorphology seen in full or partial fetal alcohol syndrome (FAS/PFAS), many lack that dysmorphology. This study examined the functional organization of working memory in the brain in three groups of children-those meeting diagnostic criteria for FAS or PFAS, heavily exposed (HE) nonsyndromal children, and healthy controls. A verbal n-back task (1-back and 0-back) was administered to 47 children (17 with FAS/PFAS, 13 HE, and 17 controls) during fMRI. Intra-group one-sample t-tests were used to identify activity regions of interest central to verbal working memory including the dorsal prefrontal cortex (dPFC), inferior frontal gyrus, caudate/putamen, parietal cortex, and cerebellar Crus I/lobule VI and lobule VIIB-IX. Whereas groups did not differ in task sensitivity, fMRI analyses suggested different patterns of sub-network recruitment across groups. Controls primarily recruited left inferior frontal gyrus (Broca's area). By contrast, HE primarily recruited an extensive set of fronto-striatal regions, including left dPFC and left caudate, and the FAS/PFAS group relied primarily on two cerebellar subregions and parietal cortex. This study is, to our knowledge, the first to demonstrate differential recruitment of critical brain regions that subserve basic function in children with different fetal alcohol spectrum disorders compared to controls. The distinct activation patterns seen in the two exposed groups may be related to substantial differences in alcohol dose/occasion to which these groups were exposed in utero., (Copyright © 2012 Wiley Periodicals, Inc.)

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]