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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. [ABSTRACT FROM AUTHOR]

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. [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: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [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]

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 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. [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 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. [ABSTRACT FROM AUTHOR]

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. [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]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure has been linked to impairment in cerebellar structure and function, including eyeblink conditioning. The deep cerebellar nuclei, which play a critical role in cerebellar-mediated learning, receive extensive inputs from brain stem and cerebellar cortex and provide the point of origin for most of the output fibers to other regions of the brain. We used in vivo 1H magnetic resonance spectroscopy ( MRS) to examine effects of prenatal alcohol exposure on neurochemistry in this important cerebellar region. Methods MRS data from the deep cerebellar nuclei were acquired from 37 children with heavy prenatal alcohol exposure and 17 non- or minimally exposed controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa. Results Increased maternal alcohol consumption around time of conception was associated with lower N-Acetylaspartate ( NAA) levels in the deep nuclei ( r = −0.33, p < 0.05). Higher levels of alcohol consumption during pregnancy were related to lower levels of the choline-containing metabolites ( r = −0.37, p < 0.01), glycerophosphocholine plus phosphocholine (Cho). Alcohol consumption levels both at conception ( r = 0.35, p < 0.01) and during pregnancy ( r = 0.38, p < 0.01) were related to higher levels of glutamate plus glutamine (Glx). All these effects continued to be significant after controlling for potential confounders. Conclusions The lower NAA levels seen in relation to prenatal alcohol exposure may reflect impaired neuronal integrity in the deep cerebellar nuclei. Our finding of lower Cho points to disrupted Cho metabolism of membrane phospholipids, reflecting altered neuropil development with potentially reduced content of dendrites and synapses. The alcohol-related alterations in Glx may suggest a disruption of the glutamate-glutamine cycling involved in glutamatergic excitatory neurotransmission. [ABSTRACT FROM AUTHOR]

Day and colleagues have presented the first data showing that the behavioral effects of low to moderate prenatal alcohol exposure seen in childhood and adolescence persist into adulthood. Using the Achenbach Adult Self-Report, they found dose-dependent effects of prenatal exposure on internalizing, externalizing, and attention problems that persist in young adults and, thus, appear to be permanent. To date, few studies have attempted to identify thresholds at which prenatal alcohol exposure is harmful, although the animal literature suggests that even 1 to 2 binge episodes can result in adverse effects in the offspring. Four prospective longitudinal studies have reported adverse effects at what can be characterized as moderate exposure levels based on NIAAA criteria, but moderate drinking women often concentrate their alcohol use on 1 to 2 days per week, thereby engaging in binge drinking. In this study, binge drinking was not a strong predictor of adverse outcome when average daily dose was held constant, a conclusion that the authors note runs 'counter to studies that have reported that binge drinking has a greater effect.' This inconsistency may be due to the difficulty of allocating variance that is shared (overlapping) between average daily dose and binge drinking (i.e., dose/occasion). Data from laboratory animal studies, in which dosage can be manipulated experimentally, demonstrate that a higher dose per occasion, the key feature of binge drinking, leads to more severe adverse effects. Day and colleagues' findings of adverse effects at low levels of exposure provides clear evidence that there is no safe level of drinking during pregnancy and that, even at low levels, drinking results in irreversible behavioral impairment. On the other hand, given the evidence from the animal and most human studies, it is important for all women who drink during pregnancy, even at light to moderate levels, to recognize that minimizing their intake per occasion and refraining from binge drinking can reduce risk to the fetus. [ABSTRACT FROM AUTHOR]

Background Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown. Methods Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed ( n = 11, age 19.5 ± 0.3 years) and control ( n = 9, age 19.6 ± 0.5 years) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range. Results There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses. Conclusions These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood. [ABSTRACT FROM AUTHOR]

Background The identification of individuals exposed prenatally to alcohol can be challenging, with only those having the characteristic pattern of facial features, central nervous system abnormality, and growth retardation receiving a clinical diagnosis of fetal alcohol syndrome ( FAS). Methods Seventeen anthropometric measurements were obtained at 5 and 9 years from 125 Cape Town, South African children, studied since birth. The children were divided into 3 groups: FAS or partial FAS ( PFAS), heavily exposed nonsyndromal ( HE), and non-alcohol-exposed controls ( C). Anthropometric measurements were evaluated for mean group differences. Logistic regression models were used to identify the subset of anthropometric measures that best predicted group membership. Anthropometric measurements were examined at the 2 ages in relation to prenatal alcohol exposure obtained prospectively from the mothers during pregnancy. Correlation of these facial measurements with key neurobehavioral outcomes including Wechsler Intelligence Scales for Children-IV IQ and eyeblink conditioning was used to assess their utility as indicators of alcohol-related central nervous system impairment. Results Significant group differences were found for the majority of the anthropometric measures, with means of these measures smaller in the FAS/ PFAS compared with HE or C. Upper facial widths, ear length, lower facial depth, and eye widths were consistent predictors distinguishing those exposed to alcohol from those who were not. Using longitudinal data, unique measures were identified that predicted facial anomalies at one age but not the other, suggesting the face changes as the individual matures. And 41% of the FAS/ PFAS group met criteria for microtia at both ages. Three of the predictive anthropometric measures were negatively related to measures of prenatal alcohol consumption, and all were positively related to at least 1 neurobehavioral outcome. Conclusions The analysis of longitudinal data identified a common set of predictors, as well as some that are unique at each age. Prenatal alcohol exposure appears to have its primary effect on brain growth, reflected by smaller forehead widths, and may suppress neural crest migration to the branchial arches, reflected by deficits in ear length and mandibular dimensions. These results may improve diagnostic resolution and enhance our understanding of the relation between the face and the neuropsychological deficits that occur. [ABSTRACT FROM AUTHOR]

Background: The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes. Methods: We recorded event-related potentials (ERPs) during a Go/No-go response inhibition task in young adults with prospectively obtained histories of prenatal alcohol exposure and childhood ADHD. Results: Regardless of prenatal alcohol exposure, participants with childhood ADHD were less accurate at inhibiting responses. However, only the ADHD group without prenatal alcohol exposure showed a markedly diminished P3 difference between No-go and Go, which may reflect a more effortful strategy related to inhibitory control at the neural processing level. Conclusion: This finding supports a growing body of evidence suggesting that the manifestation of idiopathic ADHD symptoms may stem from a neurophysiologic process that is different from the ADHD symptomatology associated with prenatal alcohol exposure. Individuals who have been prenatally exposed to alcohol and present with ADHD symptomatology may represent a unique endophenotype of the disorder, which may require different treatment approaches from those found to be effective with idiopathic ADHD. [ABSTRACT FROM AUTHOR]

Background: Both executive function deficits and slower processing speed are characteristic of children with fetal alcohol exposure, but the temporal dynamics of neural activity underlying cognitive processing deficits in fetal alcohol spectrum disorder have rarely been studied. To this end, event-related potentials (ERPs) were used to examine the nature of alcohol-related effects on response inhibition by identifying differences in neural activation during task performance. Methods: We recorded ERPs during a Go/No-go response inhibition task in 2 groups of children in Cape Town, South Africa ( M age = 11.7 years; range = 10 to 13)—one diagnosed with fetal alcohol syndrome (FAS) or partial FAS (FAS/PFAS; n = 7); the other, a control group whose mothers abstained or drank only minimally during pregnancy ( n = 6). Children were instructed to press a “Go” response button to all letter stimuli presented except for the letter “X,” the “No-go” stimulus, which occurred relatively infrequently. Results: Task performance accuracy and reaction time did not differ between groups, but differences emerged for 3 ERP components—P2, N2, and P3. The FAS/PFAS group showed a slower latency to peak P2, suggesting less efficient processing of visual information at a relatively early stage (∼200 ms after stimulus onset). Moreover, controls showed a larger P2 amplitude to Go versus No-go, indicating an early discrimination between conditions that was not seen in the FAS/PFAS group. Consistent with previous literature on tasks related to cognitive control, the control group showed a well-defined, larger N2 to No-go versus Go, which was not evident in the FAS/PFAS group. Both groups showed the expected larger P3 amplitude to No-go versus Go, but this condition difference persisted in a late slow wave for the FAS/PFAS group, suggesting increased cognitive effort. Conclusions: The timing and amplitude differences in the ERP measures suggest that slower, less efficient processing characterizes the FAS/PFAS group during initial stimulus identification. Moreover, the exposed children showed less sharply defined components throughout the stimulus and response evaluation processes involved in successful response inhibition. Although both groups were able to inhibit their responses equally well, the level of neural activation in the children with FAS/PFAS was greater, suggesting more cognitive effort. The specific deficits in response inhibition processing at discrete stages of neural activation may have implications for understanding the nature of alcohol-related deficits in other cognitive domains as well. [ABSTRACT FROM AUTHOR]