Diffusion tensor imaging of the cerebellum and eyeblink conditioning in fetal alcohol spectrum disorder

Background: Prenatal alcohol exposure is related to a wide range of neurocognitive effects. Eyeblink conditioning (EBC), which involves temporal pairing of a conditioned with an unconditioned stimulus, has been shown to be a potential biomarker of fetal alcohol exposure. A growing body of evidence suggests that white matter may be a specific target of alcohol teratogenesis, and the neural circuitry underlying EBC is known to involve the cerebellar peduncles. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that has proven useful for assessing central nervous system white matter integrity. This study used DTI to examine the degree to which the fetal alcohol‐related deficit in EBC may be mediated by structural impairment in the cerebellar peduncles. Methods: Thirteen children with fetal alcohol spectrum disorder (FASD) and 12 matched controls were scanned using DTI and structural MRI sequences. The DTI data were processed using a voxelwise technique, and the structural data were used for volumetric analyses. Prenatal alcohol exposure group and EBC performance were examined in relation to brain volumes and outputs from the DTI analysis. Results: Fractional anisotropy (FA) and perpendicular diffusivity group differences between alcohol‐exposed and nonexposed children were identified in the left middle cerebellar peduncle. Alcohol exposure correlated with lower FA and greater perpendicular diffusivity in this region, and these correlations remained significant even after controlling for total brain and cerebellar volumes. Conversely, trace conditioning performance was related to higher FA and lower perpendicular diffusivity in the left middle peduncle. The effect of prenatal alcohol exposure on trace conditioning was partially mediated by lower FA in this region. Conclusions: This study extends recent findings that have used DTI to reveal microstructural deficits in white matter in children with FASD. This is the first DTI study to demonstrate mediation of a fetal alcohol‐related effect on neuropsychological function by deficits in white matter integrity.     

Brain Microstructure Is Related to Math Ability in Children With Fetal Alcohol Spectrum Disorder

Background: Children with fetal alcohol spectrum disorder (FASD) often demonstrate a variety of cognitive deficits, but mathematical ability seems to be particularly affected by prenatal alcohol exposure. Parietal brain regions have been implicated in both functional and structural studies of mathematical ability in healthy individuals, but little is known about the brain structure underlying mathematical deficits in children with FASD. The goal of this study was to use diffusion tensor imaging (DTI) to investigate the relationship between mathematical skill and brain white matter structure in children with FASD. Methods: Twenty‐one children aged 5 to 13 years diagnosed with FASD underwent DTI on a 1.5‐T MRI scanner and cognitive assessments including the Woodcock‐Johnson Quantitative Concepts test. Voxel‐based analysis was conducted by normalizing subject images to a template and correlating fractional anisotropy (FA) values across the brain white matter with age‐standardized math scores. Results: Voxel‐based analysis revealed 4 clusters with significant correlations between FA and math scores: 2 positively‐correlated clusters in the left parietal region, 1 positively‐correlated cluster in the left cerebellum, and 1 negatively‐correlated cluster in the bilateral brainstem. Diffusion tractography identified the specific white matter tracts passing through these clusters, namely the left superior longitudinal fasciculus, left corticospinal tract and body of the corpus callosum, middle cerebellar peduncle, and bilateral projection fibers including the anterior and posterior limbs of the internal capsule. Conclusions: These results identify 4 key regions related to mathematical ability and provide a link between brain microstructure and cognitive skills in children with FASD. Given previous findings in typically developing children and those with other abnormal conditions, our results highlight the consistent importance of the left parietal area for mathematical tasks across various populations, and also demonstrate other regions that may be specific to mathematical processing in children with FASD.     

Diffusion tensor imaging in children with fetal alcohol spectrum disorders

BACKGROUND: Prenatal alcohol exposure, which is associated with macrostructural brain abnormalities, neurocognitive deficits, and behavioral disturbances, is characterized as fetal alcohol syndrome (FAS) in severe cases. The only published study thus far using diffusion tensor imaging (DTI) showed microstructural abnormalities in patients with FAS. The current study investigated whether similar abnormalities are present in less severely affected, prenatally exposed patients who did not display all of the typical FAS physical stigmata. METHODS: Subjects included 14 children, ages 10 to 13, with fetal alcohol spectrum disorders (FASD) and 13 matched controls. Cases with full-criteria FAS, mental retardation, or microcephaly were excluded. Subjects underwent MRI scans including DTI. RESULTS: Although cases with microcephaly were excluded, there was a trend toward smaller total cerebral volume in the FASD group (p=0.057, Cohen's d effect size =0.73). Subjects with FASD had greater mean diffusivity (MD) in the isthmus of the corpus callosum than controls (p=0.013, effect size =1.05), suggesting microstructural abnormalities in this region. There were no group differences in 5 other regions of the corpus callosum. Correlations between MD in the isthmus and facial dysmorphology were nonsignificant. CONCLUSIONS: These results suggest that even relatively mild forms of fetal alcohol exposure may be associated with microstructural abnormalities in the posterior corpus callosum that are detectable with DTI.     

Extensive deep gray matter volume reductions in children and adolescents with fetal alcohol spectrum disorders

Background: The link between the numerous cognitive, motor, and behavioral difficulties of individuals with fetal alcohol spectrum disorders (FASD) and underlying specific structural brain injuries can be investigated using high‐resolution imaging. Differential sensitivity of the brain’s “relay” stations, namely the deep gray matter structures, may play a key factor given their multifaceted role in brain function. The purpose of our study was to analyze differences in deep gray matter volumes of children and adolescents with FASD relative to age/sex‐matched controls and to examine whether any volume differences were consistent across the age range of neurodevelopment. Methods: Children and adolescents (N = 28, 6 to 17 years) diagnosed with FASD and 56 age‐ and sex‐matched healthy controls (i.e., 2 matched controls per FASD subject) underwent 3‐dimensional T1‐weighted MRI scans that were used for the automated volume measurement (FreeSurfer) of the intracranial space, total white matter, cortical gray matter, and 6 deep gray matter structures, namely the hippocampus, amygdala, thalamus, caudate, putamen, and globus pallidus, with left and right measured separately. Volumes were compared between FASD and controls, as well as changes with age. Results: Significant reductions of volume in FASD were observed for the intracranial vault (7.6%), total white matter (8.6%), total cortical gray matter (7.8%), and total deep gray matter (13.1%). All 6 deep gray matter structures showed significant volume reductions bilaterally with the caudate (approximately 16%) and globus pallidus (approximately 18%) being most affected. The hippocampus, thalamus, and globus pallidus showed reductions in all 3 age subgroups (6 to 9, 10 to 13, and 14 to 17 years) but the caudate and putamen had smaller volumes for FASD only within the 2 youngest subgroups; the amygdala was only smaller for FASD in the 2 oldest subgroups. Conclusions: Significant, but variable, volume reductions throughout the deep gray matter are observed over a wide age range of 6 to 17 years in FASD.     

Neuropsychological characteristics of Italian children with fetal alcohol spectrum disorders

Background: Children with fetal alcohol spectrum disorders (FASD) display many problems ranging from deficits in intelligence to behavioral difficulties. Thus, many studies have aimed at defining the neuropsychological characteristics of children with FASD. The current article describes the neuropsychological characteristics of Italian children with severe diagnosis within FASD and compares them with controls. It was expected that intellectual functioning, language comprehension, academic skills, and inattention/hyperactivity would discriminate children with FASD from randomly selected peers without FASD. Methods: This article presents data from a second cohort of children examined in 2005 as part of an in‐school epidemiological study of FASD in Italy. Of 80 children, 23 diagnosed with a FASD, and 57 randomly selected control children from the same first‐grade classes, participated. After screening for FASD via growth and dysmorphology, the children were administered a test of general intelligence (WISC‐R) as well as tests of nonverbal reasoning (Raven Colored Progressive Matrices), language comprehension (Rustioni), academic achievement (IPDA), and problem behavior (Disruptive Behavior Disorder Rating Scale). Results: Children diagnosed with a FASD achieved lower scores than control children on Verbal, Performance, and Full Scale IQ. Profile analysis of the WISC‐R indicates overall differences between the groups. However, some intact functioning within the FASD group was found, as the Similarities and Vocabulary subtests were similar to the controls. After an alpha adjustment to 0.004, the Block Design, Object Assembly, and Mazes subtests were significantly different from controls. On tests of nonverbal reasoning, language comprehension, and academic achievement, the children with a FASD scored significantly lower. Moreover, teachers rated children with a severe diagnosis within FASD as showing more inattentive symptoms than controls, while hyperactive/impulsive characteristics among children with a FASD were comparable with the control children. Significant correlations between head circumference, child dysmorphology, WISC‐R, and Raven CPM scores are also reported. Conclusions: This study indicates that a sample of Italian children with a FASD, when compared with control children, display poorer functioning on measures of general intelligence, nonverbal reasoning, academic achievement, and teacher‐rated problem behaviors. The findings also contribute to the formulation of a neuropsychological profile of children diagnosed with a FASD.     

Impaired eyeblink conditioning in children with fetal alcohol syndrome

Background: Eyeblink conditioning (EBC) is a Pavlovian paradigm that involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Animal studies have shown that binge consumption of alcohol during pregnancy impairs EBC and that this impairment is likely mediated by a loss of neurons in the inferior olive and the cerebellar cortex and deep nuclei, as well as by a reduction in neural plasticity in the cerebellar deep nuclei. Methods: Short delay EBC was examined in 98 5‐year‐old children born to women from the Coloured (mixed ancestry) community in Cape Town, South Africa, who were recruited prenatally and are participating in the first prospective longitudinal study of children with fetal alcohol syndrome (FAS). FAS status was assessed at 5 years by expert dysmorphologists. Two sessions of 50 trials each were administered to the children; a third session was administered the following day to those children who did not meet criterion of 40% conditioned responses in session 2. Results: Not a single child with FAS met criterion for conditioning as contrasted with 75.0% of the controls. Whereas 86.7% of the controls who were conditioned met criterion by the end of Session 2, a large proportion of the relatively few alcohol‐exposed nonsyndromal children who conditioned did not do so until Session 3. These alcohol effects on EBC persisted after controlling for IQ. Three of 4 microcephalic children who were not exposed to alcohol were successfully conditioned. Conclusions: This is the first prospective study to demonstrate impaired EBC in children diagnosed with FAS. Successful EBC in a microcephalic group supports the inference that the EBC deficit is specific to prenatal alcohol exposure and a potential biomarker for diagnosis of exposed children lacking the distinctive FAS dysmorphology. Delay EBC has a high sensitivity for identifying individuals with a diagnosis of probable FAS.     

Brain metabolic alterations in adolescents and young adults with fetal alcohol spectrum disorders

BACKGROUND: Prenatal alcohol exposure affects brain structure and function. This study examined brain metabolism using magnetic resonance spectroscopy (MRS) and searched for regions of specific vulnerability in adolescents and young adults prenatally exposed to alcohol. METHODS: Ten adolescents and young adults with confirmed heavy prenatal alcohol exposure and a diagnosis within the fetal alcohol spectrum disorders (FASD) were included. Three of them had fetal alcohol syndrome (FAS), 3 had partial FAS (PFAS), and 4 had alcohol-related neurobehavioral disorder (ARND). The control group consisted of 10 adolescents matched for age, sex, head circumference, handedness, and body mass. Exclusionary criteria were learning disorders and prenatal alcohol exposure. Three-dimensional (1)H magnetic resonance spectroscopic imaging ((1)H MRSI) was performed in the cerebrum and cerebellum. Metabolite ratios N-acetylaspartate/choline (NAA/Cho), NAA/creatine (Cr) and Cho/Cr, and absolute metabolite intensities were calculated for several anatomic regions. RESULTS: In patients with FASD, lower NAA/Cho and/or NAA/Cr compared with controls were found in parietal and frontal cortices, frontal white matter, corpus callosum, thalamus, and cerebellar dentate nucleus. There was an increase in the absolute intensity of the glial markers Cho and Cr but no change in the neuronal marker NAA. CONCLUSIONS: Our results suggest that prenatal alcohol exposure alters brain metabolism in a long-standing or permanent manner in multiple brain areas. These changes are in accordance with previous findings from structural and functional studies. Metabolic alterations represent changes in the glial cell pool rather than in the neurons.     

Neurobehavioral characteristics of children with fetal alcohol spectrum disorders in communities from Italy: Preliminary results

BACKGROUND: There has been considerable effort expended on defining neurobehavioral characteristics of children with fetal alcohol spectrum disorders (FASD). Children with FASD display a range of cognitive deficits and behavioral problems. In this article, we report on the neurobehavioral characteristics of children with FASD in selected communities in Italy. It was expected that both inattentive and hyperactive/impulsive characteristics would discriminate children with FASD from controls and that the groups would also differ on intellectual functioning, language comprehension, and academic skills. METHODS: Eighty-two children, 22 diagnosed with FASD and 60 control children, participated in this study. The children were administered tests of nonverbal reasoning, language comprehension, academic achievement, and behavior. RESULTS: On tests of nonverbal reasoning and language comprehension, the FASD group earned lower scores than did controls. Moreover, on a test of academic achievement the FASD group scored lower. When comparing these 2 groups on disruptive behavioral symptomatology, similar results were obtained, the FASD group showing greater attentional difficulties and hyperactivity/impulsivity behaviors and more overall behavioral problems. Stepwise logistic regression analysis showed that a model containing inattention and error scores on the language comprehension task correctly classified 85% of the participants. Compared with the control group, a significantly greater proportion of children with FASD met the Diagnostic and Statistical Manual of Mental Disorders-fourth edition (DSM-IV) criteria of ADD, inattentive type, as reported by teachers. In contrast, hyperactive symptoms among children with FASD were comparable with the control group. Teachers rated children with FASD as having more inattentive behaviors and as performing lower in academic skills than controls. The association between reported hyperactivity symptoms and achievement scores was nonsignificant for both language and math scores, suggesting that it is not the hyperactivity causing problems, but the child's inattention. CONCLUSIONS: This research indicates that a nonclinic-referred sample of Italian children with FASD display a profile of neurobehavioral functioning consistent with that reported by other researchers. Furthermore, the neurobehavioral characteristic most identified with children diagnosed with FASD was inattention followed by hyperactivity.     

Impaired delay and trace eyeblink conditioning in school-age children with fetal alcohol syndrome

Background: Classical eyeblink conditioning (EBC) involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Impairment of EBC has been demonstrated in studies of alcohol‐exposed animals and in children exposed prenatally at heavy levels. Methods: Fetal alcohol syndrome (FAS) was diagnosed by expert dysmorphologists in a large sample of Cape Coloured, South African children. Delay EBC was examined in a new sample of 63 children at 11.3 years, and trace conditioning in 32 of the same children at 12.8 years. At each age, 2 sessions of 50 trials each were administered on the same day; 2 more sessions the next day, for children not meeting criterion for conditioning. Results: Six of 34 (17.6%) children born to heavy drinkers were diagnosed with FAS, 28 were heavily exposed nonsyndromal (HE), and 29 were nonexposed controls. Only 33.3% with FAS and 42.9% of HE met criterion for delay conditioning, compared with 79.3% of controls. The more difficult trace conditioning task was also highly sensitive to fetal alcohol exposure. Only 16.7% of the FAS and 21.4% of HE met criterion for trace conditioning, compared with 66.7% of controls. The magnitude of the effect of diagnostic group on trace conditioning was not greater than the effect on short delay conditioning, findings consistent with recent rat studies. Longer latency to onset and peak eyeblink CR in exposed children indicated poor timing and failure to blink in anticipation of the puff. Extended training resulted in some but not all of the children reaching criterion. Conclusions: These data showing alcohol‐related delay and trace conditioning deficits extend our earlier findings of impaired EBC in 5‐year‐olds to school‐age. Alcohol‐related impairment in the cerebellar circuitry required for both forms of conditioning may be sufficient to account for the deficit in both tasks. Extended training was beneficial for some exposed children. EBC provides a well‐characterized model system for assessment of degree of cerebellar‐related learning and memory dysfunction in fetal alcohol exposed children.     

Callosal thickness reductions relate to facial dysmorphology in fetal alcohol spectrum disorders

Background: Structural abnormalities of the corpus callosum (CC), such as reduced size and increased shape variability, have been documented in individuals with fetal alcohol spectrum disorders (FASD). However, the regional specificity of altered CC structure, which may point to the timing of neurodevelopmental disturbances and/or relate to specific functional impairments, remains unclear. Furthermore, associations between facial dysmorphology and callosal structure remain undetermined. Methods: One hundred and fifty‐three participants (age range 8 to 16) including 82 subjects with FASD and 71 nonexposed controls were included in this study. The structural magnetic resonance imaging data of these subjects was collected at 3 sites (Los Angeles and San Diego, California, and Cape Town, South Africa) and analyzed using classical parcellation schemes, as well as more refined surface‐based geometrical modeling methods, to identify callosal morphological alterations in FASD at high spatial resolution. Results: Reductions in callosal thickness and area, specifically in the anterior third and the splenium, were observed in FASD compared with nonexposed controls. In addition, reduced CC thickness and area significantly correlated with reduced palpebral fissure length. Conclusions: Consistent with previous reports, findings suggest an adverse effect of prenatal alcohol exposure on callosal growth and further indicate that fiber pathways connecting frontal and parieto‐occipital regions in each hemisphere may be particularly affected. Significant associations between callosal and facial dysmorphology provide evidence for a concurrent insult to midline facial and brain structural development in FASD.     

Unique facial features distinguish fetal alcohol syndrome patients and controls in diverse ethnic populations

BACKGROUND: Effective management of fetal alcohol spectrum disorders (FASD) is dependent on the timely and reliable diagnosis of affected individuals. There are significant diagnostic difficulties because of the reduced prominence of facial features as children age to adulthood as well as potential population or ethnic differences in the most characteristic alcohol-related facial features. METHODS: A total of 276 subjects were recruited from 4 sites (Cape Town, South Africa; Helsinki, Finland; Buffalo, New York; and San Diego, California) and completed a detailed dysmorphology evaluation to classify subjects as either fetal alcohol syndrome (FAS; 43%) or control (57%). Computerized anthropometry was employed to identify facial features that could distinguish FAS patients from controls across a wide age range and across ethnically disparate study populations. RESULTS: Subjects were placed into 1 of 4 populations based on their ancestry (Cape Coloured, Finnish Caucasian, African American, or North American Caucasian). Analyses performed in each of the 4 study populations were able to identify a unique set of variables which provided excellent discrimination between the 2 groups (FAS, control). In each study group, at least one ocular-related measurement, shortened palpebral fissure, reduced outer canthal width, or reduced inner canthal width, was included in the final classification model. CONCLUSIONS: We found measurements that reflected reduced size of the eye orbit to be a consistent feature discriminating FAS and controls across each study population. However, each population had a unique, though often overlapping, set of variables which discriminated the 2 groups, suggesting important ethnic differences in the presentation of FAS. It is possible that these differences were accentuated by the wide age distribution of the study subjects.     

Comparison of motor delays in young children with fetal alcohol syndrome to those with prenatal alcohol exposure and with no prenatal alcohol exposure

BACKGROUND: Researchers are increasingly considering the importance of motor functioning of children with fetal alcohol spectrum disorder (FASD). The purpose of this study was to assess the motor development of young children with fetal alcohol syndrome (FAS) to determine the presence and degree of delay in their motor skills and to compare their motor development with that of matched children without FAS. METHODS: The motor development of 14 children ages 20 to 68 months identified with FAS was assessed using the Vineland Adaptive Behavior Scales (VABS). In addition, 2 comparison groups were utilized. Eleven of the children with FAS were matched for chronological age, gender, ethnicity, and communication age to: (1) 11 children with prenatal alcohol exposure who did not have FAS and (2) 11 matched children without any reported prenatal alcohol exposure. The motor scores on the VABS were compared among the 3 groups. RESULTS: Most of the young children with FAS in this study showed clinically important delays in their motor development as measured on the VABS Motor Domain, and their fine motor skills were significantly more delayed than their gross motor skills. In the group comparisons, the young children with FAS had significantly lower Motor Domain standard (MotorSS) scores than the children not exposed to alcohol prenatally. They also had significantly lower Fine Motor Developmental Quotients than the children in both the other groups. No significant group differences were found in gross motor scores. For MotorSS scores and Fine Motor Developmental Quotients, the means and standard errors indicated a continuum in the scores from FAS to prenatal alcohol exposure to nonexposure. CONCLUSIONS: These findings strongly suggest that all young children with FAS should receive complete developmental evaluations that include assessment of their motor functioning, to identify problem areas and provide access to developmental intervention programs that target deficit areas such as fine motor skills. Fine motor delays in children with FAS may be related to specific neurobehavioral deficits that affect fine motor skills. The findings support the concept of an FASD continuum in some areas of motor development.     

Frontal white matter and cingulum diffusion tensor imaging deficits in alcoholism

Background:  Alcoholism-related deficits in cognition and emotion point toward frontal and limbic dysfunction, particularly in the right hemisphere. Prefrontal and anterior cingulate cortices are involved in cognitive and emotional functions and play critical roles in the oversight of the limbic reward system. In the present study, we examined the integrity of white matter tracts that are critical to frontal and limbic connectivity.
Methods:  Diffusion tensor magnetic resonance imaging (DT-MRI) was used to assess functional anisotropy (FA), a measure of white matter integrity, in 15 abstinent long-term chronic alcoholic and 15 demographically equivalent control men. Voxel-based and region-based analyses of group FA differences were applied to these scans.
Results:  Alcoholic subjects had diminished frontal lobe FA in the right superior longitudinal fascicles II and III, orbitofrontal cortex white matter, and cingulum bundle, but not in corresponding left hemisphere regions. These right frontal and cingulum white matter regional FA measures provided 97% correct group discrimination. Working Memory scores positively correlated with superior longitudinal fascicle III FA measures in control subjects only.
Conclusions:  The findings demonstrate white matter microstructure deficits in abstinent alcoholic men in several right hemisphere tracts connecting prefrontal and limbic systems. These white matter deficits may contribute to underlying dysfunction in memory, emotion, and reward response in alcoholism.     

A review of social skills deficits in individuals with fetal alcohol spectrum disorders and prenatal alcohol exposure: profiles, mechanisms, and interventions

Background: Individuals gestationally exposed to alcohol experience a multitude of sociobehavioral impairments, including deficits in adaptive behaviors such as social skills. Methods: The goal of this report is to critically review research on social skills deficits in individuals with prenatal alcohol exposure, including individuals with and without fetal alcohol spectrum disorders (FASD). Results: Social deficits are found in alcohol‐exposed children, adults, and adolescents with and without a clinical presentation. These deficits tend to persist across the lifespan and may even worsen with age. Social deficits in this population appear to be independent of facial dysmorphology and IQ and are worse than can be predicted based on atypical behaviors alone. Abnormalities in neurobiology, executive function, sensory processing, and communication likely interact with contextual influences to produce the range of social deficits observed in FASD. Conclusions: Future investigations should strive to reconcile the relationship between social skills deficits in FASD and variables such as gender, age, cognitive profile, and structural and functional brain impairments to enable better characterization of the deficits observed in this population, which will enhance diagnosis and improve remediation.     

Temporal vulnerability of fetal cerebellar Purkinje cells to chronic binge alcohol exposure: ovine model

BACKGROUND: Human magnetic resonance imaging (MRI) and autopsy studies reveal abnormal cerebellar development in children who had been exposed to alcohol prenatally, independent of the exposure period. Animal studies conducted utilizing the rat model similarly demonstrate a broad period of vulnerability, albeit the third trimester-equivalent of human brain development is reported to be the most vulnerable period, and the first trimester-equivalent exposure produces cerebellar Purkinje cell loss only at high doses of alcohol. However, in the rat model, all 3 trimester-equivalents do not occur prenatally, requiring the assumption that intrauterine environment, placenta, maternal interactions, and parturition do not play an important role in mediating the damage. In this study, we utilized the ovine model, where all 3 trimester-equivalents occur in utero, to determine the critical window of vulnerability of fetal cerebellar Purkinje cells. METHODS: Four groups of pregnant sheep were used: first trimester-equivalent pair-fed saline control group, first trimester-equivalent alcohol group (1.75 g/kg), third trimester-equivalent pair-fed saline control group, and third trimester-equivalent alcohol group (1.75 g/kg). The alcohol exposure regimen was designed to mimic a human binge pattern. Alcohol was administered intravenously on 3 consecutive days beginning on day 4 and day 109 of gestation in the first and third trimester-equivalent groups, respectively, and the alcohol treatment was followed by a 4-day inter-treatment interval when the animals were not exposed to alcohol. Such treatment episodes were replicated until gestational day 41 and 132 in the first and third trimester-equivalent groups, respectively. All fetal brains were harvested on day 133 and processed for stereological cerebellar Purkinje cell counting. RESULTS: Significant deficits were found in the fetal cerebellar Purkinje cell number and density in the first and third trimester-equivalent alcohol exposed fetuses compared with those in the saline controls. However, there was no difference between the first and third trimester-equivalent alcohol administered groups. When comparing the present findings to those from a previous study where the duration of alcohol exposure was all 3 trimester-equivalents of gestation, we did not detect a difference in fetal cerebellar Purkinje cell number. CONCLUSIONS: We conclude that the fetal cerebellar Purkinje cells are sensitive to alcohol exposure at any time during gestation and that women who engage in binge drinking during the first trimester are at a high risk of giving birth to children with cerebellar damage even if drinking ceases after the first trimester. Our findings also support the hypothesis that only a certain population of Purkinje cells are vulnerable to alcohol-induced depletion irrespective of the timing or duration of alcohol exposure.     

Fetal alcohol spectrum disorders in children residing in Russian orphanages: a phenotypic survey

BACKGROUND: Alcohol use in Russia is among the highest in the world. Over 600,000 children reside in institutional care in Russia, most of them in baby homes and orphanages. The actual prevalence of fetal alcohol spectrum disorders (FASD) among these children is unknown. Therefore, we performed a systematic survey of phenotypic features associated with prenatal alcohol exposure among institutionalized Russian children and related these findings to their growth, development, medical, and social histories. METHODS: Phenotypic screening was conducted of all 234 baby home residents in the Murmansk region of Russia (mean age 21+12.6 months). Phenotypic expression scores were devised based on facial dysmorphology and other readily observable physical findings. Growth measurements from birth, time of placement in the baby home, and at present were analyzed. In addition, the charts of 64% of the children were randomly selected for retrospective review. Information collected included maternal, medical, developmental, and social histories. RESULTS: Thirteen percent of children had facial phenotype scores highly compatible with prenatal alcohol exposure and 45% had intermediate facial phenotype scores. These scores correlated with maternal gravidity and age. At least 40% of mothers in whom history was available ingested alcohol during pregnancy; some also used illicit drugs and tobacco. Z scores for growth measurements corresponded to phenotypic score, as did the degree of developmental delay. Children with no or mild delay had significantly lower phenotypic scores than those with moderate or severe delay (p = 0.04); more than 70% of children with high phenotypic scores were moderately or severely delayed. CONCLUSIONS: More than half of residents of the baby homes in Murmansk, Russia, have intermediate (45%) or high (13%) phenotypic expression scores suggesting prenatal exposure to alcohol. Despite good physical care, stable daily routine, availability of well-trained specialists, and access to medical care, these vulnerable children show significant growth and developmental delays compared with their institutionalized peers.