Developmental Trajectories for Visuo-Spatial Attention are Altered by Prenatal Alcohol Exposure: A Longitudinal FMRI Study.

Functional magnetic resonance imaging (fMRI) reveals brain activation abnormalities during visuo-spatial attention and working memory among those with fetal alcohol spectrum disorders (FASD) in cross-sectional reports, but little is known about how activation changes over time during development within FASD or typically developing children. We studied 30 controls and 31 individuals with FASD over 2 years (7-14 years at first participation) with a total of 122 scans, as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Despite comparable performance, there were significant group differences in visuo-spatial activation over time bilaterally in frontal, parietal, and temporal regions. Controls showed an increase in signal intensity in these multiple regions whereas FASD participants showed a decrease in brain activation. Effects were also found in 2 small independent samples from the USA, corroborating the findings from the larger group. Results suggest that the long-lasting effect of prenatal alcohol may impact the maturation of visuo-spatial attention and differentiate those with FASD from controls. Based on this first longitudinal fMRI study in FASD children, our novel findings suggest a possible neural mechanism for attention deficits common among individuals with FASD.

Prenatal alcohol exposure alters the patterns of facial asymmetry.

Directional asymmetry, the systematic differences between the left and right body sides, is widespread in human populations. Changes in directional asymmetry are associated with various disorders that affect craniofacial development. Because facial dysmorphology is a key criterion for diagnosing fetal alcohol syndrome (FAS), the question arises whether in utero alcohol exposure alters directional asymmetry in the face. Data on the relative position of 17 morphologic landmarks were obtained from facial scans of children who were classified as either FAS or control. Shape data obtained from the landmarks were analyzed with the methods of geometric morphometrics. Our analyses showed significant directional asymmetry of facial shape, consisting primarily of a shift of midline landmarks to the right and a displacement of the landmarks around the eyes to the left. The asymmetry of FAS and control groups differed significantly and average directional asymmetry was increased in those individuals exposed to alcohol in utero. These results suggest that the developmental consequences of fetal alcohol exposure affect a wide range of craniofacial features in addition to those generally recognized and used for diagnosis of FAS.

Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome).

We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions,

Automated diagnosis of fetal alcohol syndrome using 3D facial image analysis.

OBJECTIVES: Use three-dimensional (3D) facial laser scanned images from children with fetal alcohol syndrome (FAS) and controls to develop an automated diagnosis technique that can reliably and accurately identify individuals prenatally exposed to alcohol. METHODS: A detailed dysmorphology evaluation, history of prenatal alcohol exposure, and 3D facial laser scans were obtained from 149 individuals (86 FAS; 63 Control) recruited from two study sites (Cape Town, South Africa and Helsinki, Finland). Computer graphics, machine learning, and pattern recognition techniques were used to automatically identify a set of facial features that best discriminated individuals with FAS from controls in each sample. RESULTS: An automated feature detection and analysis technique was developed and applied to the two study populations. A unique set of facial regions and features were identified for each population that accurately discriminated FAS and control faces without any human intervention. CONCLUSION: Our results demonstrate that computer algorithms can be used to automatically detect facial features that can discriminate FAS and control faces.

Mapping callosal morphology and cognitive correlates: effects of heavy prenatal alcohol exposure.

BACKGROUND: Abnormalities of the corpus callosum (CC) have been documented in fetal alcohol syndrome (FAS), ranging from subtle decrements in its size to partial and even complete agenesis. Prenatal exposure to alcohol is also known to result in neurocognitive deficits. OBJECTIVE: To 1) investigate abnormalities in size, shape, and location of the CC within the brain in individuals with FAS and in those exposed to high amounts of alcohol prenatally but without FAS (PEA group); and 2) determine if there is a relationship between callosal dysmorphology and cognitive test performance. METHODS: MRI and novel surface-based image analytic methods were used. Twenty alcohol-exposed subjects (8 to 22 years) along with 21 normal controls (8 to 25 years) were studied with high-resolution MRI and measures of verbal learning and visuospatial abilities. RESULTS: In addition to callosal area reductions, most severe in the splenium, the CC is significantly displaced in patients exposed to alcohol prenatally. In the alcohol-exposed group, this structure lies more anterior and inferior in posterior regions with relatively normal localization of anterior regions. These findings are significant in the FAS group, and a similar but less severe pattern is observed in the PEA patients. The authors show that the amount of CC displacement is correlated with impairment in verbal learning ability and that CC displacement is a better predictor of verbal learning than regional CC area. The brain-behavior relationship is only significant within the alcohol-exposed group, and the effect is not solely mediated by overall impaired verbal intellectual functioning. CONCLUSIONS: These results further emphasize the vulnerability of midline brain structures to prenatal alcohol exposure.

Verbal and nonverbal fluency in children with heavy prenatal alcohol exposure.

OBJECTIVE: Executive function deficits, including verbal fluency, have been documented in children with histories of prenatal alcohol exposure. Whereas nonverbal fluency impairments have been reported in adults with such exposure, these abilities have not been tested in children. Deficits in both verbal and nonverbal fluency were predicted and assessed in children and adolescents with histories of heavy prenatal alcohol exposure. METHOD: There was a total of 28 (54% female) subjects; children with heavy prenatal alcohol exposure with (n = 10) and without (n = 8) fetal alcohol syndrome (FAS) were compared to nonexposed controls (n = 10) on the design and verbal fluency measures from the Delis-Kaplan Executive Function System. Both fluency measures consist of three conditions, including a new set-shifting task. All tests require the generation of multiple responses within both rule and time constraints. RESULTS: Data were analyzed using repeated measures analyses of variance and hierarchical regression analyses. Compared to controls, children with heavy prenatal alcohol exposure with and without FAS displayed deficits in both fluency domains, but did not differ from each other. In addition, prenatal alcohol exposure was a significant predictor of performance on the set-shifting design fluency task above and beyond performance on more traditional fluency tasks. IQ was not a significant predictor for the traditional or set-shifting fluency measures, whereas diagnostic group remained a significant predictor when IQ was included in the model. CONCLUSIONS: This study adds to the literature on the integrity of executive functions in children with heavy prenatal alcohol exposure, documenting fluency impairment in both verbal and nonverbal domains. It is important to note that these impairments were demonstrated in higher functioning alcohol-exposed children, both with and without FAS, and that diagnostic group explained such deficiencies above and beyond general intellectual ability.

Brain dysmorphology in individuals with severe prenatal alcohol exposure.

Our previous studies revealed abnormalities on structural MRI (sMRI) in small groups of children exposed to alcohol prenatally. Microcephaly, disproportionately reduced basal ganglia volume, and abnormalities of the cerebellar vermis and corpus callosum were demonstrated. The present study used sMRI to examine in detail the regional pattern of brain hypoplasia resulting from prenatal exposure to alcohol using a higher resolution imaging protocol and larger sample sizes than reported previously. Fourteen participants (mean 11.4 years; eight females, six males) with fetal alcohol syndrome (FAS) and 12 participants (mean 14.8 years; four females, eight males) with prenatal exposure to alcohol (PEA) but without the facial features of FAS were compared to a group of 41 control participants (mean 12.8 years, 20 females, 21 males). Findings of significant microcephaly and disproportionately reduced basal ganglia volumes in the FAS group were confirmed. Novel findings were that in FAS participants, white matter volumes were more affected than gray matter volumes in the cerebrum, and parietal lobes were more affected than temporal and occipital lobes. Among subcortical structures, in contrast to the disproportionate effects on caudate nucleus, the hippocampus was relatively preserved in FAS participants. Differences between the PEA group and controls were generally non-significant; however, among a few of the structures most affected in FAS participants, there was some evidence for volume reduction in PEA participants as well, specifically in basal ganglia and the parietal lobe. There were no group differences in cerebral volume asymmetries. Severe prenatal alcohol exposure appears to produce a specific pattern of brain hypoplasia.

Voxel-based morphometric analyses of the brain in children and adolescents prenatally exposed to alcohol.

Children of mothers who abuse alcohol during pregnancy can suffer varying degrees of neurological abnormality, cognitive impairment, and behavioral problems, and in the worst case, are diagnosed with fetal alcohol syndrome (FAS). The purpose of the present study was to localize brain abnormalities in a group of children and adolescents prenatally exposed to alcohol using high resolution, 3D structural MRI data and whole-brain voxel-based morphometry (VBM). Data were collected for 21 children and adolescents with histories of prenatal alcohol exposure (ALC) and 21 normally developing individuals. Statistical parametric maps revealed abnormalities most prominent in the left hemisphere perisylvian cortices of the temporal and parietal lobes where the ALC patients tended to have too much gray matter and not enough white matter. These results provide further support for dysmorphology in temporo-parietal cortices above and beyond the overall microcephaly that results from severe prenatal alcohol exposure.

Teratogenic effects of alcohol on brain and behavior.

Children prenatally exposed to alcohol can suffer from serious cognitive deficits and behavioral problems as well as from alcohol-related changes in brain structure. Neuropsychological studies have identified deficits in learning and memory as well as in executive functioning both in children with fetal alcohol syndrome and in children with less severe impairments. Both groups of children also exhibit problem behaviors, such as alcohol and drug use, hyperactivity, impulsivity, and poor socialization and communication skills. Brain imaging studies have identified structural changes in various brain regions of these children--including the basal ganglia, corpus callosum, cerebellum, and hippocampus--that may account for the cognitive deficits. Functional brain imaging studies also have detected changes in alcohol-exposed children indicative of deficits in information processing and memory tasks.

Parent ratings of behavior in children with heavy prenatal alcohol exposure and IQ-matched controls.

BACKGROUND: Behavioral disturbances are well documented in children with heavy prenatal alcohol exposure. However, the degree to which these disturbances are related to factors other than alcohol, such as general intellectual functioning or socioeconomic status, is not known. METHODS: Using the Child Behavior Checklist, parent-rated behaviors of children with histories of heavy prenatal alcohol exposure were compared with those of a control group matched by age, sex, socioeconomic status, ethnicity, and verbal IQ score. Using this same questionnaire, children with fetal alcohol syndrome were compared with children with heavy prenatal alcohol exposure that did not meet the criteria for fetal alcohol syndrome classification. RESULTS: Data were analyzed by multivariate analyses of covariance. In the comparison of children with and without a history of prenatal alcohol exposure, significant differences were found on the competence, problem, and summary scales (all p < 0.05). For the secondary comparison between the fetal alcohol syndrome and the heavy prenatal alcohol exposure groups, there were no significant differences on any of the scales (allp > 0.10). CONCLUSIONS: These results suggest that prenatal alcohol exposure results in the significant and profound impairment of parent-rated behaviors and that these deficits are not explained entirely by the presence or absence of facial dysmorphology, general intellectual functioning, or demographic factors.

Executive functioning in children with heavy prenatal alcohol exposure.

BACKGROUND: Children with heavy prenatal alcohol exposure have well documented deficits in overall cognitive ability. Recently, attention has turned to the executive function (EF) domain in this population. Until recently, comprehensive measures of EF have not been available within one test battery. This study used a battery of tests to assess four domains of EF in alcohol-exposed children. METHODS: The Delis-Kaplan Executive Function Scale was used to evaluate EF in 18 children with heavy prenatal alcohol exposure, with and without a diagnosis of fetal alcohol syndrome (FAS), and 10 nonexposed controls. Children ranged in age from 8 to 15 years. Measures from four domains of executive functioning were analyzed: planning ability, cognitive flexibility, selective inhibition, and concept formation and reasoning. Tasks consisted of primary EF measures as well as measures of secondary component skills. RESULTS: Alcohol-exposed children were deficient on EF measures compared with nonexposed controls. Furthermore, in most cases, children with and without the FAS diagnosis did not differ from one another. These deficits were not entirely explainable by concomitant deficits on component skills. Specific impairments were identified within the domains of planning and response inhibition, with additional deficits in abstract thinking and flexibility. CONCLUSIONS: Deficits in executive functioning were observed in alcohol-exposed children with or without the diagnosis of FAS and in the absence of mental retardation. Performance on these EF tasks provides insight into the cognitive processes driving overall performance and has implications for adaptive and daily functions. These results are consistent with anecdotal and empirical reports of deficits in behavioral control and with neuroanatomical evidence of volumetric reductions in structures within the frontal-subcortical system in children with heavy prenatal alcohol exposure.

Implicit and explicit memory functioning in children with heavy prenatal alcohol exposure.

Prenatal alcohol exposure is associated with widespread and devastating neurodevelopmental deficits. Numerous reports have suggested memory deficits in both humans and animals exposed prenatally to alcohol. However, the nature of these memory deficits remains to be characterized. Recently children with fetal alcohol syndrome were shown to have learning and memory deficits on a verbal learning and memory measure that involved free recall and recognition memory. The current study seeks to further characterize memory functioning in children with heavy prenatal alcohol exposure by evaluating priming performance. The choice of task is also relevant given previous studies of memory performance in patient groups with and without involvement of the basal ganglia, a group of structures known to be affected in fetal alcohol syndrome. Three groups were evaluated for lexical priming, free recall, recognition memory, and verbal fluency: (1) children with heavy prenatal alcohol exposure; (2) children with Down syndrome; and (3) nonexposed controls. The children with Down syndrome showed significantly less priming than alcohol-exposed children, who did not differ from controls. In addition, the alcohol-exposed children were impaired on the free recall task but not on the recognition memory task, whereas the children with Down syndrome performed significantly worse than the alcohol-exposed group on both tasks. Finally, on the verbal fluency task, children with heavy prenatal alcohol exposure were impaired on both category and letter fluency, but the degree of impairment was greater for letter fluency. These results further characterize the memory deficits in children with heavy prenatal alcohol exposure suggesting that in spite of learning and memory deficits, they are able to benefit from priming of verbal information.

Behavioral and psychosocial profiles of alcohol-exposed children.

BACKGROUND: It is widely known that prenatal alcohol exposure is related to cognitive and behavioral deficits throughout childhood and adolescence. Much research has focused on understanding and quantifying the cognitive profile of children with fetal alcohol syndrome (FAS) with relatively less empirical research on behavioral or psychosocial adjustment. The primary purpose of this study was to examine the behavioral and psychosocial profile of children exposed to heavy amounts of alcohol prenatally. METHOD: Two groups of subjects were evaluated: an alcohol-exposed group (ALC) and a nonexposed control group (NC) each made up of 32 subjects matched for age, gender, and ethnicity. The alcohol-exposed group consisted of children heavily exposed to alcohol in utero, including 19 children diagnosed with FAS. The Personality Inventory for Children (PIC) was completed by the caretaker of each child. Four validity/screening scales and 12 clinical scales were scored for all subjects. RESULTS: Analyses revealed significant group differences on four validity/screening scales and 12 substantive scales. Within the ALC group, the profile of children without FAS was similar to that of children with FAS, with the exception that their profiles were consistent with less cognitive impairment. CONCLUSIONS: These findings indicate that in addition to previously reported cognitive impairments, heavy prenatal alcohol exposure is related to significant impairments in psychosocial functioning. Even children without alcohol-related physical anomalies suffer from impaired psychosocial functioning. Because impairments of this nature can interfere with functioning across multiple domains, effective early intervention programs should be considered for families of alcohol-exposed children. Furthermore, given the similarities of alcohol-exposed children with and without FAS, it is imperative to obtain prenatal alcohol exposure histories on all children experiencing cognitive or psychosocial deficits.

Normative data for 4-year-old children on the California Verbal Learning Test-Children's Version.

This study presents normative data for 4-year-old children on the California Verbal Learning Test-Children's Version (CVLT-C), a measure of verbal learning and memory. Norms are currently available for children 5 years and older; however, normative data are unavailable for this younger population. Forty males and 40 females comprise this normative sample of 4-year-old children. The mean number of words recalled increased from the first to the fifth learning trial, and a consistent level of recall was maintained across delay recall trials. Extra-list intrusion responses were common and these responses were more frequent than correct responses on cued but not free recall conditions. Finally, yes/no recognition testing resulted in the greatest mean number of words remembered compared to the other trials. Overall, the pattern of performance across the learning and memory variables in this younger population was similar to that of older children, but at a lower level. These data suggest that 4-year-old children are able to perform this task, making possible the use of the CVLT-C in normal and clinical populations in this age group.

A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol.

Fetal alcohol syndrome is a devastating developmental disorder caused by prenatal exposure to high amounts of alcohol. In addition to structural abnormalities and growth deficits, fetal alcohol syndrome is associated with a broad spectrum of neurobehavioral anomalies. This paper reviews the behavioral and cognitive effects of prenatal alcohol exposure. More than 20 years of research are discussed, with a focus on IQ, activity, attention, learning, memory, language, motor, and visuospatial abilities in children prenatally exposed to varying amounts of alcohol, including those with fetal alcohol syndrome.

A review of the neuroanatomical findings in children with fetal alcohol syndrome or prenatal exposure to alcohol.

Human and animal studies have clearly demonstrated that alcohol is both a physical and behavioral teratogen and that heavy prenatal alcohol exposure can lead to a distinct pattern of birth defects termed the fetal alcohol syndrome. Underlying the behavioral and cognitive anomalies seen in fetal alcohol syndrome are alterations in brain structure and/or function. This paper reviews the literature examining brain anomalies attributable to prenatal alcohol exposure, beginning with a survey of autopsy studies and leading up to current findings using magnetic resonance imaging and positron emission tomography studies. Autopsy reports clearly illustrate the wide and devastating influence alcohol has on the developing brain, although for the most part no specific pattern of brain malformation has been identified. More recent magnetic resonance imaging studies, particularly when combined with quantitative analysis, have indicated that specific brain areas--such as the basal ganglia, the corpus callosum, and parts of the cerebellum--might be especially susceptible to alcohol's teratogenic effects. Further studies using functional brain imaging techniques may provide even more information about the unique effects prenatal alcohol exposure has on the developing brain. Discovering specific areas of the brain that are affected by alcohol may allow clinicians and researchers to look for patterns of vulnerable regions in the brain, thereby helping in the future detection of children who are prenatally exposed to alcohol.

Comparison of social abilities of children with fetal alcohol syndrome to those of children with similar IQ scores and normal controls.

Children diagnosed with fetal alcohol syndrome (FAS) were assessed with items from the social skills domain of the Vineland Adaptive Behavior Scales (VABS) via interviews with their caregivers. Their scores were compared with scores from children in two control groups. The control groups included children matched for IQ to the FAS group (specifically on verbal IQ, henceforth, the VIQ group) and children with IQ scores in the average to above-average range (normal control group). Forty-five children (age range, 5 years 7 months to 12 years 11 months) were assessed (n/group = 15). All groups differed with regard to social ability, as measured by the VABS (NC > VIQ > FAS), even when the effects of socioeconomic status were held constant. The three subdomains of the VABS social scale (interpersonal relationship skills, use of play and leisure time, and coping skills) were assessed, and results showed that the children with FAS were most impaired on the subdomain that assessed interpersonal relationship skills. An additional measure was constructed by obtaining an age-equivalent score for the VABS social scale and calculating a difference score by subtracting the child's chronological age from his/her age-equivalent score. There was a significant correlation between chronological age and difference scores for children in the FAS group but not for children in the two control groups. Specifically, in older children with FAS, there was an increased discrepancy between their ages and their age-equivalent scores, a discrepancy that was not present in children in the control groups. These results suggest that social deficits in children with FAS are beyond what can be explained by low IQ scores and indicate that there may be arrested, and not simply delayed, development of social abilities in children with FAS.

Prenatal exposure to alcohol affects the ability to maintain postural balance.

Prenatal exposure to alcohol is known to affect gross motor functioning. Animal studies have shown that balance is particularly affected, and there is some evidence that similar deficits exist in alcohol-exposed children. In the current study, postural balance, or the ability to maintain equilibrium, was assessed in a group of alcohol-exposed children (ALC group; n = 11) and controls (NC group; n = 11) individually matched for age and sex. Balance was measured across six conditions designed to systematically manipulate or eliminate visual or somatosensory information. Equilibrium and strategy scores for each condition and a derived composite balance score were analyzed. Although the ALC group had a lower mean composite balance score, their performance was similar to that of the NC group on all conditions where somatosensory input was reliable. However, when somatosensory input was manipulated, and when both somatosensory and visual input were inaccurate, the ALC group performed more poorly than controls. Interestingly, there were no differences between the ALC group and NC group in the type of control strategy used to maintain balance. These results suggest that alcohol-exposed children are overly reliant on somatosensory input. When this input is atypical, alcohol-exposed children display significantly greater anterior-posterior body sway and are unable to compensate using available visual or vestibular information. These deficits may be related to cerebellar anomalies previously reported in fetal alcohol syndrome children.

Neuropsychological comparison of alcohol-exposed children with or without physical features of fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) is associated with behavioral and cognitive deficits. However, the majority of children born to alcohol-abusing women do not meet the formal criteria for FAS and it is not known if the cognitive abilities of these children differ from those of children with FAS. Using a set of neuropsychological tests, 3 groups were compared: (a) children with FAS, (b) children without FAS who were born to alcohol-abusing women (the PEA group), and (c) normal controls. The results indicated that, relative to controls, both the FAS and the PEA groups were impaired on tests of language, verbal learning and memory, academic skills, fine-motor speed, and visual-motor integration. These data suggest that heavy prenatal alcohol exposure is related to a consistent pattern of neuropsychological deficits and the degree of these deficits may be independent of the presence of physical features associated with FAS.

Neuromuscular responses to disturbance of balance in children with prenatal exposure to alcohol.

Alcohol-exposed children display delayed motor development and impaired fine- and gross-motor skills, including deficits in the maintenance of balance. In a recent study, we assessed the contribution of visual, somatosensory, and vestibular information to the ability to maintain balance. Our findings suggested that alcohol-exposed children were overly reliant on somatosensory information and were unable to compensate by using the visual and/or vestibular systems. To understand the nature of these observed balance deficits, corrective postural reactions were examined by exposing standing subjects to rapid toe-up movements of the support surface. Subjects for this study were alcohol-exposed (ALC) and normal control (NC) children matched for age and sex. Postural reactions were quantified by measuring electromyographic activity of the triceps surae and anterior tibialis muscles. Analyses revealed no differences between the ALC and NC groups on short- and medium-latency electromyographic responses, which are thought to be involuntary mono- and polysynaptic spinal reflexes, respectively. However, when compared with the NC group, the ALC group displayed increased long-latency responses, which are thought to involve a transcortical pathway. Although we are not able to rule out the possibility of additional peripheral (e.g., vestibular) disturbance as a contributing factor to postural instability, our findings suggest that the balance deficits seen in alcohol-exposed children are, at least in part, central in nature.