Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Adaptive, Externalizing, and Internalizing Behavior of Children with Prenatal Alcohol Exposure: A Comparison of Three Parent-Report Questionnaires.

This study compared the Behavior Assessment System for Children-Third Edition (BASC-3) to the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales-Third Edition (VABS-3) in children with and without histories of prenatal alcohol exposure. Data were collected from Collaborative Initiative on Fetal Alcohol Spectrum Disorders Phase 4 sites. Caregivers rated their child's behavior using three questionnaires: BASC-3, CBCL, and VABS-3. BASC-3 Adaptive Skills, Externalizing Problems, and Internalizing Problems scores were correlated with comparable scores from the CBCL (Externalizing and Internalizing Problems) and VABS-3 (Adaptive Skills) both within and across groups. Sensitivity, specificity, and positive and negative predictive values were calculated for the BASC-3. BASC-3 sensitivity rates were 78.1%, 80.5%, and 47.0% and specificity rates were 79.4%, 80.4%, and 81.5% for Adaptive Skills, Externalizing Problems, and Internalizing Problems, respectively. Positive predictive values were 87.1%, 88.0%, and 81.9% and negative predictive values were 67.0%, 69.8%, and 46.3% for Adaptive Skills, Externalizing Problems, and Internalizing Problems, respectively. Results replicated previous reports of behavioral and adaptive difficulties in children with prenatal alcohol exposure. These findings provide support for using the BASC-3 in this population.

Characteristics of sleep in children with heavy prenatal alcohol exposure.

BACKGROUND: Sleep plays an important role in neurodevelopment. However, the effects of prenatal alcohol exposure on sleep quality have been understudied, despite reports of sleep disturbance in infants prenatally exposed to alcohol and elevated levels of sleep problems reported by caregivers of children with fetal alcohol spectrum disorders. The current study characterizes sleep in children with prenatal alcohol exposure using both objective (actigraphy) and subjective (questionnaires, sleep diaries) methods. METHODS: Participants aged 6-10 years, with and without prenatal alcohol exposure, were included in the study (alcohol-exposed [AE]: n = 35; control [CON]: n = 39). Objective sleep was measured via 24-h actigraphy for 2 weeks. Parents completed sleep diaries and sleep questionnaires (Children's Sleep Habits Questionnaire, Pediatric Sleep Questionnaire). Multivariate analysis of variance was used to characterize the sleep profile (objective, subjective) and examine group differences. RESULTS: There were no group differences on actigraphy metrics averaged across 2 weeks. However, the AE group showed significantly greater intraindividual variability on most actigraphy measures, particularly total sleep time, percent sleep, wake after sleep onset, and number of wake bouts. Parents reported significantly more sleep problems in the AE group than in the CON group, primarily driven by night wakings, parasomnias (e.g., sleepwalking), snoring, and daytime sleepiness. These effects were more severe in children >8.5 years of age. CONCLUSIONS: Despite similar 2-week average sleep outcomes, children with prenatal alcohol exposure showed greater intraindividual sleep variability and parents reported more sleep problems related to sleep behavior and snoring. These difficulties with sleep may be related to other cognitive and behavioral outcomes. Importantly, sleep is a modifiable behavior, and interventions that focus on variability in sleep, particularly in sleep duration, can impact the quality of life in children with prenatal alcohol exposure and their families.

Validation of the ND-PAE Diagnosis in Children with Heavy Prenatal Alcohol Exposure.

This study evaluated criteria for Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE). Kable et al. (2022) assessed the validity of this diagnosis in a sample with low exposure to alcohol. The current study expanded this assessment to a sample with a wider age range and heavier alcohol exposure. Data were collected from participants (5-17y) with prenatal alcohol exposure (PAE) and typically developing controls at six Collaborative Initiative on Fetal Alcohol Spectrum Disorders sites using neuropsychological assessment and caregiver reports. Impairment was tested at 1SD, 1.5SD, and 2SD below the normative average and a modification of the adaptive functioning requirement was tested. Testing impairment at 1SD resulted in the highest endorsement rates in both groups. Our findings replicated the study by Kable et al. and show that current criteria captured a high rate of those with PAE and that requiring fewer adaptive functioning criteria resulted in higher sensitivity to PAE.

Polymorphisms in the choline transporter SLC44A1 are associated with reduced cognitive performance in normotypic but not prenatal alcohol-exposed children.

BACKGROUND: Choline is essential for healthy cognitive development. Single nucleotide polymorphisms (SNPs; rs3199966(G), rs2771040(G)) within the choline transporter SLC44A1 increase risk for choline deficiency. In a choline intervention trial of children who experienced prenatal alcohol exposure (PAE), these alleles are associated with improved cognition. OBJECTIVE: This study aimed to determine if SNPs within SLC44A1 are differentially associated with cognition in children with PAE compared with normotypic controls (genotype × exposure). A secondary objective tested for an association of these SNPs and cognition in controls (genotype-only). DESIGN: This is a secondary analysis of data from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Participants (163 normotypic controls, 162 PAE) underwent psychological assessments and were genotyped within SLC44A1. Choline status was not assessed. Association analysis between genotype × exposure was performed using an additive genetic model and linear regression to identify the allelic effect. The primary outcome was the interaction between SLC44A1 genotype × exposure status with respect to cognition. The secondary outcome was the cognitive-genotype association in normotypic controls. RESULTS: Genotype × exposure analysis identified 7 SNPs in SLC44A1, including rs3199966(G) and rs2771040(G), and in strong linkage (D' ≥ 0.87), that were associated (adjusted P ≤ 0.05) with reduced performance in measures of general cognition, nonverbal and quantitative reasoning, memory, and executive function (ß, 1.92-3.91). In controls, carriers of rs3199966(GT or GG) had worsened cognitive performance than rs3199966(TT) carriers (ß, 0.46-0.83; P < 0.0001), whereas cognitive performance did not differ by rs3199966 genotype in those with PAE. CONCLUSIONS: Two functional alleles that increase vulnerability to choline deficiency, rs3199966(G) (Ser644Ala) and rs2771040(G) (3' untranslated region), are associated with worsened cognition in otherwise normotypic children. These alleles were previously associated with greater cognitive improvement in children with PAE who received supplemental choline. The findings endorse that choline benefits cognitive development in normotypic children and those with PAE.

Results of a screening tool for fetal alcohol spectrum disorders are associated with neuropsychological and behavioral measures.

PURPOSE: This study assessed whether the outcome of a screening tool for fetal alcohol spectrum disorders (FASD), the FASD-Tree, was associated with neuropsychological and behavioral outcomes. METHODS: Data for this study were collected as part of the fourth phase of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD-4). Participants (N = 175, 5 to 16 years) with or without histories of prenatal alcohol exposure were recruited from San Diego and Minneapolis. Each participant was screened using the FASD-Tree and administered a neuropsychological test battery; parents or guardians completed behavioral questionnaires. The FASD-Tree incorporates physical and behavioral measures and provides an outcome regarding the presence of FASD (FASD-Positive or FASD-Negative). Logistic regression was used to test whether the FASD-Tree outcome was associated with general cognitive ability, executive function, academic achievement, and behavior. Associations were tested in two groups: the whole sample and only correctly classified participants. RESULTS: Results of the FASD-Tree were associated with neuropsychological and behavioral measures. Participants classified as FASD-Positive were more likely than those classified as FASD-Negative to have a lower IQ score and exhibit poorer performance on measures of executive and academic functions. Behaviorally, participants classified as FASD-Positive were rated as having more behavior problems and adaptive difficulties. Similar relationships were found for all measures when including only participants correctly classified by the FASD-Tree screening tool. CONCLUSION: Results from the FASD-Tree screening tool were associated with neuropsychological and behavioral measures. Participants classified as FASD-Positive were more likely to have impairment in all domains tested. The results support the effectiveness of the FASD-Tree as a screening tool for use in clinical settings, providing an efficient and accurate way to identify patients in need of additional evaluation.

Atypical developmental trajectories of white matter microstructure in prenatal alcohol exposure: Preliminary evidence from neurite orientation dispersion and density imaging.

Introduction: Fetal alcohol spectrum disorder (FASD), a life-long condition resulting from prenatal alcohol exposure (PAE), is associated with structural brain anomalies and neurobehavioral differences. Evidence from longitudinal neuroimaging suggest trajectories of white matter microstructure maturation are atypical in PAE. We aimed to further characterize longitudinal trajectories of developmental white matter microstructure change in children and adolescents with PAE compared to typically-developing Controls using diffusion-weighted Neurite Orientation Dispersion and Density Imaging (NODDI). Materials and methods: Participants: Youth with PAE (n = 34) and typically-developing Controls (n = 31) ages 8-17 years at enrollment. Participants underwent formal evaluation of growth and facial dysmorphology. Participants also completed two study visits (17 months apart on average), both of which involved cognitive testing and an MRI scan (data collected on a Siemens Prisma 3 T scanner). Age-related changes in the orientation dispersion index (ODI) and the neurite density index (NDI) were examined across five corpus callosum (CC) regions defined by tractography. Results: While linear trajectories suggested similar overall microstructural integrity in PAE and Controls, analyses of symmetrized percent change (SPC) indicated group differences in the timing and magnitude of age-related increases in ODI (indexing the bending and fanning of axons) in the central region of the CC, with PAE participants demonstrating atypically steep increases in dispersion with age compared to Controls. Participants with PAE also demonstrated greater increases in ODI in the mid posterior CC (trend-level group difference). In addition, SPC in ODI and NDI was differentially correlated with executive function performance for PAE participants and Controls, suggesting an atypical relationship between white matter microstructure maturation and cognitive function in PAE. Discussion: Preliminary findings suggest subtle atypicality in the timing and magnitude of age-related white matter microstructure maturation in PAE compared to typically-developing Controls. These findings add to the existing literature on neurodevelopmental trajectories in PAE and suggest that advanced biophysical diffusion modeling (NODDI) may be sensitive to biologically-meaningful microstructural changes in the CC that are disrupted by PAE. Findings of atypical brain maturation-behavior relationships in PAE highlight the need for further study. Further longitudinal research aimed at characterizing white matter neurodevelopmental trajectories in PAE will be important.

Delayed cortical thinning in children and adolescents with prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is associated with abnormalities in cortical structure and maturation, including cortical thickness (CT), cortical volume, and surface area. This study provides a longitudinal context for the developmental trajectory and timing of abnormal cortical maturation in PAE. METHODS: We studied 35 children with PAE and 30 nonexposed typically developing children (Comparisons), aged 8-17 at enrollment, who were recruited from the University of Minnesota FASD Program. Participants were matched on age and sex. They underwent a formal evaluation of growth and dysmorphic facial features associated with PAE and completed cognitive testing. MRI data were collected on a Siemens Prisma 3T scanner. Two sessions, each including MRI scans and cognitive testing, were spaced approximately 15 months apart on average. Change in CT and performance on tests of executive function (EF) were examined. RESULTS: Significant age-by-group (PAE vs. Comparison) linear interaction effects in CT were observed in the parietal, temporal, occipital, and insular cortices suggesting altered developmental trajectories in the PAE vs. Comparison groups. Results suggest a pattern of delayed cortical thinning in PAE, with the Comparison group showing more rapid thinning at younger ages and those with PAE showing accelerated thinning at older ages. Overall, children in the PAE group showed reduced cortical thinning across time relative to the Comparison participants. Symmetrized percent change (SPC) in CT in several regions was significantly correlated with EF performance at 15-month follow-up for the Comparison group but not the group with PAE. CONCLUSIONS: Regional differences were seen longitudinally in the trajectory and timing of CT change in children with PAE, suggesting delayed cortical maturation and an atypical pattern of development compared with typically developing individuals. In addition, exploratory correlation analyses of SPC and EF performance suggest the presence of atypical brain-behavior relationships in PAE. The findings highlight the potential role of altered developmental timing of cortical maturation in contributing to long-term functional impairment in PAE.

Current considerations for fetal alcohol spectrum disorders: identification to intervention.

PURPOSE OF REVIEW: This review highlights recent findings regarding the prevalence, public health impact, clinical presentation, intervention access and conceptualization of fetal alcohol spectrum disorders (FASDs). Despite ongoing work in prevention and identification of this population, the rates of drinking during pregnancy have increased and significant gaps remain in diagnosis and intervention. RECENT FINDINGS: Prenatal alcohol exposure is the most common preventable cause of developmental disability in the world. Research has focused on improving diagnostic clarity, utilizing technology and neuroimaging to facilitate identification, engaging broader stakeholders (including self-advocates) to inform understanding and needs, and increasing access to effective interventions. There is an emerging focus on developmental trajectories and experiences in young and middle adulthood. Public policy advocacy has also made great strides in recent years. SUMMARY: Increases in public awareness, greater concordance of diagnostic schema, leveraged use of novel technology, and the development of targeted interventions within a holistic, strengths-based conceptualization are important considerations for this population.

Validation of the FASD-Tree as a screening tool for fetal alcohol spectrum disorders.

BACKGROUND: As many as 80% of individuals with fetal alcohol spectrum disorders (FASD) are misdiagnosed or not diagnosed. This study tests the accuracy and validity of a web-based screening tool (the FASD-Tree) for identifying children and adolescents with FASD. METHODS: Children with histories of prenatal alcohol exposure (PAE) and controls (N = 302, including 224 with PAE and 78 controls) were examined for physical signs of fetal alcohol syndrome (FAS), and parents completed behavioral questionnaires. Data were entered into the FASD-Tree, a web-based decision tree application. The FASD-Tree provided two outcomes: a dichotomous indicator (yes/no) and a numeric risk score (0 to 5), which have been shown separately to identify children with PAE and neurobehavioral impairment and to correlate with neurobehavioral outcomes. Overall accuracy (ACC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the decision tree, risk score, and their combination. Misclassified cases were examined for systematic bias. RESULTS: The FASD-Tree was successful in accurately identifying youth with histories of PAE and the subgroup of individuals with FASD, indicating its validity as an FASD screening tool. Overall accuracy rates for FASD-Tree components ranged from 75.0% to 84.1%, and both the decision tree outcome and risk score, and their combination, resulted in fair to good discrimination (area under the curve = 0.722 to 0.862) of youth with histories of PAE or FASD. While most participants were correctly classified, those who were misclassified differed in IQ and attention. Race, ethnicity, and sex did not affect the results. CONCLUSION: The FASD-Tree is not a biomarker of PAE and does not provide definitive evidence of prenatal alcohol exposure. Rather it is an accurate and valid screening tool for FASD and can be used by clinicians who suspect that a patient has a history of PAE, even if the exposure is unknown.

Profiles of language and communication abilities in adolescents with fetal alcohol spectrum disorders.

OBJECTIVE: Language and communication are largely understudied among youth with fetal alcohol spectrum disorders (FASD). Findings have been mixed, and have generally focused on more severely affected (i.e., children with FAS alone) or younger children. This study aimed to elucidate the profiles of language (i.e., receptive, expressive, general language) and communication (i.e., functional, social) abilities in adolescents with FASD. METHOD: Participants aged 12-17 years with (AE = 31) and without (CON = 29) prenatal alcohol exposure were included. Receptive and expressive language were measured by the Clinical Evaluation of Language Fundamentals - Fifth Edition (CELF-5). Parents or caregivers completed the Children's Communication Checklist - Second Edition as a subjective measure of general language skills. Functional communication was measured by the Student Functional Assessment of Verbal Reasoning and Executive Strategies and parents or caregivers completed the Social Skills Improvement System Rating Scales as a measure of social communication. Multivariate analysis of variance determined the overall profiles of language and communication and whether they differed between groups. RESULTS: The AE group performed significantly lower than the CON group on receptive language and parent report of general language while groups did not significantly differ on expressive language. Groups did not significantly differ on functional communication while social communication was significantly lower in the AE group. CONCLUSIONS: Results of this study provide important information regarding the overall profile of basic language abilities and higher-level communication skills of adolescents with FASD. Ultimately, improving communication skills of youth with FASD may translate to better overall functioning.

Spiral drawing deficits in children with prenatal alcohol exposure.

AIMS: Empirical investigations reveal that, in comparison to their typically developing peers, children with histories of prenatal alcohol exposure experience deficits in writing but not drawing skills, both of which require fine motor control. This study examines drawing skills in this clinical group by assessing simple free-form spiral drawings with indices of spectral features and structural organization. METHODS: Children with (n = 15) and without (n = 24) prenatal alcohol exposure used their dominant and nondominant hands to draw a series of spirals using a wireless pen stylus that either provided concurrent visual feedback in the form of a black ink trace or left no visible ink trace of each drawing. Spirals were drawn on a sheet of paper placed on a digitizing table, which facilitated online data acquisition. The data were assessed by power spectral density function analysis and sample entropy analysis. RESULTS: In comparison to their typically developing peers, children with prenatal alcohol exposure produced spirals with a lower mean frequency and less spectral variability. Spirals in the prenatally exposed group were also lower in complexity and structural organization than in the control group. These results occurred independently of hand dominance or the availability of visual feedback. CONCLUSIONS: The drawing skills of children with prenatal alcohol exposure have inherent signal characteristics that differ significantly from those produced by typically developing peers. Simple tasks requiring fine motor control may be useful in identifying individuals with fetal alcohol spectrum disorders.

Development and validation of a postnatal risk score that identifies children with prenatal alcohol exposure.

BACKGROUND: This study aimed to develop an efficient and easily calculable risk score that can be used to identify an individual's risk of having been exposed to alcohol prenatally. METHODS: Data for this study were collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, Phases 2 and 3. Two cohorts (ages 5 to 17 years) completed a comprehensive neurobehavioral battery and a standard dysmorphology exam: a development cohort (DC; n = 325) and a comparative cohort (CC; n = 523). Both cohorts included two groups: those with histories of heavy prenatal alcohol exposure (AE-DC, n = 121; AE-CC, n = 177) and a control group that included subjects with minimal or no prenatal alcohol exposure (CON-DC, n = 204; CON-CC, n = 346). Behavioral assessments and physical exam data were combined using regression techniques to derive a risk score indicating the likelihood of prenatal alcohol exposure. Subjects were then divided into two subgroups: (1) low risk and (2) high risk. Chi-square (χ2 ) determined classification accuracy and ROC curves were produced to assess the predictive accuracy. Correlations between risk scores and intelligence quotient and executive function scores were calculated. RESULTS: Subjects were accurately classified in the DC (χ2  = 78.61, p < 0.001) and CC (χ2  = 86.63, p < 0.001). The classification model also performed well in the DC (ROC = 0.835 [SE = 0.024, p < 0.001]) and CC (ROC = 0.786 [SE = 0.021, p < 0.001]). In the AE-CC and CON-CC, there were modest but significant associations between the risk score and executive function (AE-CC: r = -0.20, p = 0.034; CON-CC: r = -0.28, p < 0.001) and intelligence quotient (AE-CC: r = -0.20, p = 0.034; CON-CC: r = -0.28, p < 0.001). CONCLUSION(S): The risk score significantly distinguished alcohol-exposed from control subjects and correlated with important cognitive outcomes. It has significant clinical potential and could be easily deployed in clinical settings.

Social behaviors and gray matter volumes of brain areas supporting social cognition in children and adolescents with prenatal alcohol exposure.

The goal of this study was to examine: 1) differences in parent-reported prosocial and antisocial behaviors between children and adolescents with and without prenatal alcohol exposure (PAE); 2) differences in gray matter volumes of brain areas supporting social cognition between children and adolescents with and without PAE; 3) correlations between gray matter volumes of brain areas supporting social cognition and parent-reported prosocial and antisocial behaviors. Parents of children and adolescents ages 8-16 years completed measures on their prosocial and antisocial behaviors (i.e., Behavior Assessment Scale for Children, Vineland Adaptive Behaviors Scales, and Child Behavior Checklist) (n = 84; 41 with PAE, 43 without PAE). Seventy-nine participants (40 with PAE, 39 without PAE) also completed a structural Magnetic Resonance Imaging (MRI) scan with quality data. Gray matter volumes of seven brain areas supporting social cognitive processes were computed using automated procedures (FreeSurfer 6.0): bilateral fusiform gyrus, superior temporal gyrus, medial orbitofrontal cortex, lateral orbitofrontal cortex, posterior cingulate cortex, precuneus, and temporal pole. Children and adolescents with PAE showed decreased prosocial behaviors and increased antisocial behaviors as well as smaller volumes of the precuneus and lateral orbitofrontal cortex, even when controlling for total intracranial volume. Social brain volumes were not significantly correlated with prosocial or antisocial behaviors. These findings suggest that children and adolescents with PAE show worse social functioning and smaller volumes of brain areas supporting self-awareness, perspective-taking and emotion-regulation than their same-age peers without PAE.

Validity and Reliability of Executive Function Measures in Children With Heavy Prenatal Alcohol Exposure: Correspondence Between Multiple Raters and Laboratory Measures.

BACKGROUND: Rating scales are designed to complement traditional performance-based measures, and both can provide useful information about the functioning of youth with histories of prenatal alcohol exposure. Few studies, however, have compared ratings from multiple informants or the relationship between these subjective rating scale scores and the objective results from laboratory performance-based scales. METHODS: The current study addressed both of these questions in 3 study groups: children with histories of prenatal alcohol exposure (n = 47), attention-deficit/hyperactivity disorder (ADHD; n = 41), and typically developing controls (CON; n = 73). All subjects completed a standardized neuropsychological test battery, including laboratory measures of executive functioning and a self-report measure of executive function behaviors. Parents and teachers completed corresponding rating scales of executive function behaviors for each subject. This study assessed the relationship between these behavior rating scales and corresponding neuropsychological tests, and interrater agreement among the multiple informants. RESULTS: Weak correlations were found between the rating scales and laboratory measures, indicating poor convergent validity for the behavior rating scale. Interrater reliability was found but it differed by group. Agreement was found between parent and teacher ratings for children with prenatal alcohol exposure, whereas teacher-child agreement was found for those with ADHD. CONCLUSIONS: Findings from this study indicate that behavior ratings can be used to supplement laboratory measures but may not be measuring cognitive abilities regardless of whether a clinical diagnosis is present. A multimethod approach should be used when measuring skills in this domain. This was one of the first studies to examine cross-informant agreement in a sample of children with prenatal alcohol exposure. Further research is necessary to understand why interrater agreement differed for children with prenatal alcohol exposure and those with ADHD.

Executive and Social Functioning Across Development in Children and Adolescents With Prenatal Alcohol Exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is linked to a variety of neurodevelopmental challenges, including social functioning (SF) and executive functioning (EF) deficits. These deficits present differently across developmental stages from preschool age to adolescence. METHODS: The post hoc analyses described here were conducted on data from 83 preschool-age children with PAE (early childhood group; ages 2.5 to 5.0) and 95 adolescents (49 with PAE, 46 controls; ages 8 to 16). Each child completed EF tasks as part of several prior studies. Parents completed social and communication inventories about their child's abilities. Thirty-three participants from the early childhood group returned for a 4-year follow-up and completed both SF and EF measures. RESULTS: Both the early childhood and adolescent groups with PAE showed deficits in SF and EF. There was a relationship between SF and EF within the adolescent PAE group that was not present in the adolescent control group or the early childhood PAE group. However, at the 4-year follow-up (Mage  = 8.45), participants originally in the early childhood PAE group also demonstrated this relationship. CONCLUSIONS: These findings support previous research on EF/SF deficits in adolescents with PAE while also addressing a gap in the literature concerning early childhood research on this topic. Additionally, these findings suggest that the relationship between EF and SF deficits may strengthen throughout development. This line of research highlights potential sensitive periods for SF and EF training in children with PAE and suggests that fetal alcohol spectrum disorders programs consider targeting EF training as a component of social skill interventions.

Revisiting total recognition discriminability in Huntington's and Alzheimer's disease: New insights from the CVLT-3.

The original and second editions of the California Verbal Learning Test (CVLT) used nonparametric and parametric methods, respectively, to assess Total Recognition Discriminability (RD). In a previous study, we found evidence that the nonparametric formula may be more sensitive than the parametric formula to high false positive (FP) rates and provide more accurate assessments of yes/no recognition in neurodegenerative populations prone to high FP rates, including Alzheimer's disease (AD). In the present study, we extended our investigation to examine the utility of CVLT-3 nonparametric and parametric Total RD indices in the assessment and comparison of yes/no recognition in individuals with Huntington's disease (HD) and AD in mild and moderate stages of dementia. Findings suggested that the CVLT-3 nonparametric Total RD index was more sensitive than the parametric index to HD and AD differences in yes/no recognition across mild and moderate stages of dementia. Additionally, group differences on total FP errors were more closely mirrored by group differences on the nonparametric Total RD index. The present results bolster our previous findings and highlight the utility of examining nonparametric (in addition to parametric) Total RD on the CVLT-3 in assessments of yes/no recognition involving clinical populations prone to high FP rates.

Hippocampal subfield abnormalities and memory functioning in children with fetal alcohol Spectrum disorders.

BACKGROUND: Prenatal alcohol exposure (PAE) affects early brain development and has been associated with hippocampal damage. Animal models of PAE have suggested that some subfields of the hippocampus may be more susceptible to damage than others. Recent advances in structural MRI processing now allow us to examine the morphology of hippocampal subfields in humans with PAE. METHOD: Structural MRI scans were collected from 40 children with PAE and 39 typically developing children (ages 8-16). The images were processed using the Human Connectome Project Minimal Preprocessing Pipeline (v4.0.1) and the Hippocampal Subfields package (v21) from FreeSurfer. Using a large dataset of typically developing children enrolled in the Human Connectome Project in Development (HCP-D) for normative standards, we computed age-specific volumetric z-scores for our two samples. Using these norm-adjusted hippocampal subfield volumes, comparisons were performed between children with PAE and typically developing children, controlling for total intracranial volume. Lastly, we investigated whether subfield volumes correlated with episodic memory (i.e., Picture Sequence Memory test of the NIH toolbox). RESULTS: Five subfields had significantly smaller adjusted volumes in children with PAE than in typically developing controls: CA1, CA4, subiculum, presubiculum, and the hippocampal tail. Subfield volumes were not significantly correlated with episodic memory. CONCLUSIONS: The results suggest that several regions of the hippocampus may be particularly affected by PAE. The finding of smaller CA1 volumes parallels previous reports in rodent models. The novel findings of decreased volume in the subicular cortex, CA4 and the hippocampal tail suggest avenues for future research.

Cross-Sectional Analysis of Spatial Working Memory Development in Children with Histories of Heavy Prenatal Alcohol Exposure.

BACKGROUND: In children with prenatal alcohol exposure, spatial working memory is affected and brain regions important for spatial working memory performance exhibit atypical neurodevelopment. We therefore hypothesized that children with prenatal alcohol exposure may also have atypical development of spatial working memory ability. METHODS: We examined the relation between spatial working memory and age using a cross-sectional developmental trajectory approach in youth with and without histories of heavy prenatal alcohol exposure. The Cambridge Neuropsychological Test Automated Battery Spatial Working Memory subtest was administered to children 5.0 to 16.9 years old. RESULTS: While the controls and children with prenatal alcohol exposure showed similar performance at younger ages, larger group differences were observed in older children. This effect was replicated in a separate sample. CONCLUSIONS: The atypical brain development that has previously been reported in children with heavy prenatal alcohol exposure may have clinically relevant implications for cognitive development; however, longitudinal cognitive analyses are needed.

Para-limbic Structural Abnormalities Are Associated With Internalizing Symptoms in Children With Prenatal Alcohol Exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para-limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies. METHODS: Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi-automated procedures (FreeSurfer) were used to derive para-limbic volumes from T1-weighted anatomical images. RESULTS: There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend-level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children. CONCLUSIONS: Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE.