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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 5–17 yrs.) 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 (χ(2)) determined classification accuracy and an ROC was produced to assess the predictive accuracy. Correlations between risk scores and IQ and executive function (EF) scores were calculated. RESULTS: Subjects were accurately classified in the DC (χ(2)= 78.61, p

Background The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function. Objective Choline supplements confer cognitive improvement for those diagnosed with fetal alcohol spectrum disorder (FASD), a common set of neurodevelopmental impairments; however, the effect sizes have been modest. In this retrospective analysis, we report that genetic polymorphisms affecting choline utilization are associated with cognitive improvement following choline intervention. Methods Fifty-two children from the upper midwestern United States and diagnosed with FASD, ages 2-5 y, were randomly assigned to receive choline (500 mg/d; n = 26) or placebo (n = 26) for 9 mo, and were genotyped for 384 choline-related single nucleotide polymorphisms (SNPs). Memory and cognition were assessed at enrollment, study terminus, and at 4-y follow-up for a subset. Results When stratified by intervention (choline vs. placebo), 14-16 SNPs within the cellular choline transporter gene solute carrier family 44 member 1 (SLC44A1) were significantly associated with performance in an elicited imitation sequential memory task, wherein the effect alleles were associated with the greatest pre-/postintervention improvement. Of these, rs3199966 is a structural variant (S644A) and rs2771040 is a single-nucleotide variant within the 3' untranslated region of the plasma membrane isoform. An additive genetic model best explained the genotype associations. Lesser associations were observed for cognitive outcome and polymorphisms in flavin monooxygenase-3 (FMO3), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1), fatty acid desaturase-2 (FADS2), and adiponectin receptor 1 (ADIPOR1). Conclusions These SLC44A1 variants were previously associated with greater vulnerability to choline deficiency. Our data potentially support the use of choline supplements to improve cognitive function in individuals diagnosed with FASD who carry these effect alleles. Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population. This trial was registered at www.clinicaltrials.gov as NCT01149538.

Fetal Alcohol Spectrum Disorder (FASD) affects 2–5% of children in the United States. In the preschool age-range, inhibitory deficits frequently manifest as impaired ability to delay gratification, which is associated with deficits in cognitive flexibility in these children. The goal of this longitudinal study was to determine whether the ability to delay gratification in preschool children with FASD is: 1) associated with broader manifestations in temperament and behavior; 2) predictive of later inhibitory control, cognitive flexibility and working memory in middle childhood; and 3) predictive of later parent-reported behavioral problems and school functioning in middle childhood. Forty-seven children with FASD, ages 2.5 to 5 were administered a delay of gratification task in which they chose between receiving two snacks immediately or ten snacks after waiting for ten minutes. Two groups were defined based on a median split of waiting time. Four years later, twenty-nine children completed measures of inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort Test), and working memory (Stanford-Binet Intelligence Scales), and their parents completed the Child Behavior Checklist as a measure of the child’s behavioral problems and school functioning. Children with longer wait times on the delay of gratification task in preschool showed better inhibitory control on the Flanker task in middle childhood and better parent-reported school functioning in English. These findings indicate that early inhibitory capacity persists into middle childhood in those with FASD, and may be a promising target for early intervention to improve later cognitive outcomes in these children.

The outbreak of the coronavirus disease 2019 (COVID-19) and its rapid global spread have created unprecedented challenges to health care systems. Significant and sustained efforts have focused on mobilization of personal protective equipment, intensive care beds, and medical equipment, while substantially less attention has focused on preserving the psychological health of the medical workforce tasked with addressing the challenges of the pandemic. And yet, similar to battlefield conditions, health care workers are being confronted with ongoing uncertainty about resources, capacities, and risks; as well as exposure to suffering, death, and threats to their own safety. These conditions are engendering high levels of fear and anxiety in the short term, and place individuals at risk for persistent stress exposure syndromes, subclinical mental health symptoms, and professional burnout in the long term. Given the potentially wide-ranging mental health impact of COVID-19, protecting health care workers from adverse psychological effects of the pandemic is critical. Therefore, we present an overview of the potential psychological stress responses to the COVID-19 crisis in medical providers and describe preemptive resilience-promoting strategies at the organizational and personal level. We then describe a rapidly deployable Psychological Resilience Intervention founded on a peer support model (Battle Buddies) developed by the United States Army. This intervention-the product of a multidisciplinary collaboration between the Departments of Anesthesiology and Psychiatry & Behavioral Sciences at the University of Minnesota Medical Center-also incorporates evidence-informed "stress inoculation" methods developed for managing psychological stress exposure in providers deployed to disasters. Our multilevel, resource-efficient, and scalable approach places 2 key tools directly in the hands of providers: (1) a peer support Battle Buddy; and (2) a designated mental health consultant who can facilitate training in stress inoculation methods, provide additional support, or coordinate referral for external professional consultation. In parallel, we have instituted a voluntary research data-collection component that will enable us to evaluate the intervention's effectiveness while also identifying the most salient resilience factors for future iterations. It is our hope that these elements will provide guidance to other organizations seeking to protect the well-being of their medical workforce during the pandemic. Given the remarkable adaptability of human beings, we believe that, by promoting resilience, our diverse health care workforce can emerge from this monumental challenge with new skills, closer relationships, and greater confidence in the power of community.

OBJECTIVE: To assess our hypothesis that brain macrostructure is different in individuals with mucopolysaccharidosis type I (MPS I) and healthy controls (HC), we conducted a comprehensive multicenter study using a uniform quantitative magnetic resonance imaging (qMRI) protocol, with analyses that account for the effects of disease phenotype, age, and cognition. METHODS: Brain MRIs in 23 individuals with attenuated (MPS IA) and 38 with severe MPS I (MPS IH), aged 4-25 years, enrolled under the study protocol NCT01870375, were compared to 98 healthy controls. RESULTS: Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC. Thicker cortex, lower white matter and corpus callosum volumes were already present at the youngest MPS I participants aged 4-5 years. Age-related differences were observed in both MPS I groups, but most markedly in MPS IH, particularly in cortical gray matter metrics. IQ scores were inversely associated with ventricular volume in both MPS I groups and were positively associated with cortical thickness only in MPS IA. CONCLUSIONS: Quantitatively-derived MRI measures distinguished MPS I participants from HC as well as severe from attenuated forms. Age-related neurodevelopmental trajectories in both MPS I forms differed from HC. The extent to which brain structure is altered by disease, potentially spared by treatment, and how it relates to neurocognitive dysfunction needs further exploration.

Background We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (PAE). Results of the present study provided some support for this hypothesis. Methods We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from 3 separate cohorts of patients: (i) pregnant women who consumed moderate-to-high levels of alcohol or low/unexposed controls, (ii) children with PAE and non-alcohol-exposed controls, and (iii) children with PAE treated with or without choline. Results We found pregnant women who consumed moderate-to-high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone. Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. Conclusions These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.

Summary Although prenatal alcohol exposure causes craniofacial anomalies, growth retardation, neurological abnormalities, cognitive impairment, and birth defects, fetal alcohol spectrum disorder is underdiagnosed. Global prevalence of fetal alcohol spectrum disorder is 0·77%, with a higher prevalence of 2–5% in Europe and North America, highlighting the need for increased diagnosis and treatment. However, diagnosis remains challenging because of the poor reliability of self-reported maternal drinking histories, an absence of sensitive biomarkers, and the infrequency of diagnostic dysmorphic facial features among individuals with fetal alcohol spectrum disorder. Different diagnostic systems and disagreements over criteria have slowed progress in the diagnosis and management of the disorder. Neuroimaging shows abnormalities in brain structure, cortical development, white matter microstructure, and functional connectivity in individuals with fetal alcohol spectrum disorder. These abnormalities modify developmental trajectories and are associated with deficits in cognition, executive function, memory, vision, hearing, motor skills, behaviour, and social adaptation. Promising trials of nutritional interventions and cognitive rehabilitation therapies are underway, with the aim of treating cognitive deficits in fetal alcohol spectrum disorders.

ObjectivePrevious research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I.MethodsVolumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls.ResultsThe MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT.ConclusionsWe found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.

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.

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.

Myotonic dystrophies (DM) are neuromuscular conditions that cause widespread effects throughout the body. There are brain white matter changes on MRI in patients with DM that correlate with neuropsychological functional changes. How these brain alterations causally relate to the presence and severity of cognitive symptoms remains largely unknown. Deep neural networks have significantly improved the performance of image classification of huge datasets. However, its application in brain imaging is limited and not well described, due to the scarcity of labeled training data. In this work, we propose an approach for the diagnosis of DM based on a spatio-temporal deep learning paradigm. The obtained accuracy (73.71%) and sensitivities and specificities showed that the implemented approach based on 4-D convolutional neural networks leads to a compact, discriminative, and fast computing DM-based clinical medical decision support system.Clinical relevance- Many adults with DM experience cognitive and neurological effects impacting their quality of life, and ability to maintain employment. A robust and reliable DM-based clinical decision support system may help reduce the long diagnostic delay common to DM. Furthermore, it can help neurologists better understand the pathophysiology of the disease and analyze effects of new drugs that aim to address the neurological symptoms of DM.

The positive relationship between socioeconomic status (SES) and cognitive performance is mediated, in part, by differences in brain structure in typically developing youth. Associations between brain regions that relate to SES overlap with brain regions known to be sensitive to prenatal alcohol exposure (PAE). Animal models demonstrate that PAE attenuates neural and cognitive benefits of early life enrichment. However, whether or not environmental factors related to SES are associated with brain development in youth affected by PAE remains unknown in humans. Methods. T1-weighted magnetic resonance imaging (MRI) scans were obtained in participants with PAE and compared to age- and sex- matched Controls (n=197, 48% with PAE, 44% girls, 6.5-17.7 years old). General linear modeling was utilized to examine associations between SES and subcortical brain volumes for youth with PAE compared to Controls. Results. Group by SES interactions were observed within the hippocampus (HPC), nucleus accumbens (NAc) and ventral diencephalon (vDC) (corrected p values < 0.05), where positive associations (e.g., higher SES related to larger subcortical volumes) were observed within Controls, but not youth with PAE. Post-hoc analyses examined associations between SES and brain volumes within each group independently, and revealed widespread positive associations among Controls (Amyg, HPC, NAc, Pallidum, Putamen, vDC), but not youth with PAE. Across both groups, larger subcortical volumes were related to higher cognitive performance. Conclusions. Typically developing youth exhibit increased subcortical volumes with increased SES, and surprisingly, this relationship is attenuated, and often absent, in adolescents with PAE. Findings suggest that subcortical brain volumes are neurocognitively relevant in both groups. The present results expand our understanding of the impact of PAE on the developing human brain within varying environmental contexts, and may inform novel environmental interventions that aim to improve, in part, on-going disruptions in brain development among youth with PAE. Our study highlights novel complexities in the pursuit to understand SES-brain associations, as we provide evidence that SES matters for brain outcomes among typically developing youth, and possibly not as much on an already altered brain as a result of PAE.

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.

Background This study was a randomized double-blind sham-controlled trial examining the effects of transcranial direct current stimulation (tDCS) augmented cognitive training (CT) in children with Fetal Alcohol Spectrum Disorders (FASD). Prenatal alcohol exposure has profound detrimental effects on brain development and individuals with FASD commonly present with deficits in executive functions including attention and working memory. The most commonly studied treatment for executive deficits is CT, which involves repeated drilling of exercises targeting the impaired functions. As currently implemented, CT requires many hours and the observed effect sizes are moderate. Neuromodulation via tDCS can enhance brain plasticity and prior studies demonstrate that combining tDCS with CT improves efficacy and functional outcomes. TDCS-augmented CT has not yet been tested in FASD, a condition in which there are known abnormalities in neuroplasticity and few interventions. Methods This study examined the feasibility and efficacy of this approach in 44 children with FASD. Participants were randomized to receive five sessions of CT with either active or sham tDCS targeting the dorsolateral prefrontal cortex, a region of the brain that is heavily involved in executive functioning. Results The intervention was feasible and well-tolerated in children with FASD. The tDCS group showed nominally significant improvement in attention on a continuous performance test compared to sham (p = .043). Group differences were observed at the third, fourth and fifth treatment sessions. There was no effect of tDCS on working memory (p = .911). Further, we found no group differences on a trail making task (p = .659) or on the verbal fluency test (p = .826). In the active tDCS group, a significant correlation was observed between improvement in attention scores and decrease in parent-reported attention deficits (p = .010). Conclusions These results demonstrate that tDCS-augmented CT is well tolerated in children with FASD and potentially offers benefits over and above CT alone.

Objectives: Cortical abnormalities in prenatal alcohol exposure (PAE) are known, including in gyrification (LGI), thickness (CT), volume (CV), and surface area (CS). This study provides longitudinal and developmental context to the PAE cortical development literature. Experimental design: Included: 58 children with PAE and 52 controls, ages 6–17 at enrollment, from four Collaborative Initiative on FASD (CIFASD) sites. Participants underwent a formal evaluation of physical anomalies and dysmorphic facial features associated with PAE. MRI data were collected on three platforms (Siemens, GE, and Philips) at four sites. Scans were spaced two years apart. Change in LGI, CT, CS, and CV were examined. Principal observations: Several significant regional age-by-diagnosis linear and quadratic interaction effects in LGI, CT, and CV were found, indicating atypical developmental trajectories in PAE. No significant correlations were observed between cortical measures and IQ. Conclusions: Regional differences were seen longitudinally in CT, CV, and LGI in those with PAE. The findings represent important insights into developmental trajectories and may have implications for the timing of assessments and interventions in this population. It is noteworthy that cortical metrics did not correlate with IQ, suggesting that more specific aspects of cognitive development may need to be explored to provide further context. Keywords: Cerebral cortex, Fetal alcohol spectrum disorder, Longitudinal MRI, Neuropsychology, Pediatric

The 2016 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was titled “Rehabilitation in FASD: Potential Interventions and Challenges”. During the previous decades, studies with human subjects and animal models have improved much of our understanding of the mechanisms underlying FASD, putting the scientific community in a good position to test hypotheses that can lead to potential therapeutic interventions. During the conference, two keynote speakers addressed potential interventions used in different fields and their applicability to FASD research. The conference also included updates from several government agencies, short presentations by junior and senior investigators that showcased the latest in FASD research, and award presentations. The conference was closed by a talk by Dr. Charles Goodlett, the recipient of the 2016 Henry Rosett award.

IMPACT: As newborn screening is now available for X-linked adrenoleukodystrophy, there is a need to establish meaningful disease markers to detect the onset of the severe demyelinating cerebral form of this disease at the earliest possible stage, and to quantify early disease progression to evaluate the relative efficacy of therapies. OBJECTIVES/GOALS: Longitudinal testing of neurocognitive and motor function using smartphone and tablet-based applications holds promise for early detection and quantification of brain white matter changes in patients with adrenoleukodystrophy (ALD) and other rare demyelinating diseases, but this methodology requires validation in pediatric populations. METHODS/STUDY POPULATION: We developed an iPad application with a game-like interface to assess interhemispheric transfer across the corpus callosum, the brain structure where cerebral demyelinating disease typically begins in patients with ALD. Feasibility data from remote test administrations with healthy children were collected to analyze and speed and timing of finger tapping movements requiring bimanual coordination on a touchscreen. RESULTS/ANTICIPATED RESULTS: Among our pilot sample of healthy school-aged children, age-related improvements in finger tapping speed were observed in both single-hand and alternating-hand conditions. Results indicate that remote testing using iPad applications is a viable way to collect psychometric testing data rapidly in pediatric populations and is feasible during a pandemic. Next steps in this research project will be: (1) evaluating the stability of repeated test administrations (test-retest reliability), (2) assessing agreement between performance on our iPad application and validated measures of interhemispheric transfer and fine motor function, and (3) comparing performance of children with known corpus callosum white matter abnormality to performance of healthy children. DISCUSSION/SIGNIFICANCE OF FINDINGS: Brief neurocognitive tests that can be frequently administered may have the ability to capture subtle brain changes in developing children. Approaches enabling remote (virtual) testing will facilitate research during the covid-19 pandemic and are especially well-suited for data collection in rare disease populations.

Prenatal alcohol exposure can impact both brain development and neurobehavioral function, including verbal learning and recall, although the relation between verbal recall and brain structure in this population has not been examined fully. We aimed to determine the structural neural correlates of verbal learning and recall in youth with histories of heavy prenatal alcohol exposure using a region of interest (ROI) approach. As part of an ongoing multisite project, subjects (age 10-16 years) with prenatal alcohol exposure (AE, n = 81) and controls (CON, n = 81) were tested using the CVLT-C and measures of cortical volume, surface area, and thickness as well as hippocampal volume were derived from MRI. Group differences in brain and memory indices were tested with ANOVA. Multiple regression analyses tested whether brain ROIs significantly predicted memory performance. The AE group had lower scores than the CON group on all CVLT-C variables (ps ≤ .001) and volume and surface area (ps

Objectives Prenatal alcohol exposure (PAE) adversely affects early brain development. Previous studies have shown a wide range of structural and functional abnormalities in children and adolescents with PAE. The current study adds to the existing literature specifically on cortical development by examining cortical gyrification in a large sample of children with PAE compared to controls. Relationships between cortical development and intellectual functioning are also examined. Experimental design Included were 92 children with PAE and 83 controls ages 9–16 from four sites in the Collaborative Initiative on FASD (CIFASD). All PAE participants had documented heavy PAE. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Cortical gyrification was examined using a semi-automated procedure. Principal observations Whole brain group comparisons using Monte Carlo z-simulation for multiple comparisons showed significantly lower cortical gyrification across a large proportion of the cerebral cortex amongst PAE compared to controls. Whole brain comparisons and ROI based analyses showed strong positive correlations between cortical gyrification and IQ (i.e. less developed cortex was associated with lower IQ). Conclusions Abnormalities in cortical development were seen across the brain in children with PAE compared to controls. Cortical gyrification and IQ were strongly correlated, suggesting that examining mechanisms by which alcohol disrupts cortical formation may yield clinically relevant insights and potential directions for early intervention., Highlights • Children exposed to alcohol prenatally have widespread abnormalities in the development of cortical gyrification. • Abnormally smooth cortex occurs in developmental insults that interfere with cell proliferation and neuronal migration. • In FASD, we observed that abnormally smooth cortex was strongly associated with lower IQ.

Background Despite the high prevalence of fetal alcohol spectrum disorder (FASD), there are few interventions targeting its core neurocognitive and behavioral deficits. FASD is often conceptualized as static and permanent, but interventions that capitalize on brain plasticity and critical developmental windows are emerging. We present a long-term follow-up study evaluating the neurodevelopmental effects of choline supplementation in children with FASD 4 years after an initial efficacy trial. Methods The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2–5-year-olds with FASD. Participants include 31 children (16 placebo; 15 choline) seen 4 years after trial completion. The mean age at follow-up was 8.6 years. Diagnoses were 12.9% fetal alcohol syndrome (FAS), 41.9% partial FAS, and 45.1% alcohol-related neurodevelopmental disorder. The follow-up included measures of intelligence, memory, executive functioning, and behavior. Results Children who received choline had higher non-verbal intelligence, higher visual-spatial skill, higher working memory ability, better verbal memory, and fewer behavioral symptoms of attention deficit hyperactivity disorder than the placebo group. No differences were seen for verbal intelligence, visual memory, or other executive functions. Conclusions These data support choline as a potential neurodevelopmental intervention for FASD and highlight the need for long-term follow-up to capture treatment effects on neurodevelopmental trajectories. Trial registration ClinicalTrials.Gov #NCT01149538; Registered: June 23, 2010; first enrollment July 2, 2010

BACKGROUND Youth with heavy prenatal alcohol exposure have high rates of behavioral concerns and psychopathology, including increased oppositional and conduct behaviors. The relation between those concerns and executive function (EF) deficits is unknown. We investigated the association of oppositional and conduct behavior and EF in adolescents to inform targeted intervention. METHODS Subjects (N = 267) ages 10 to 17 years comprised 3 groups: alcohol-exposed with oppositional/conduct behaviors (AE+), alcohol-exposed without oppositional/conduct behaviors (AE-), and controls (CON). Group differences on direct neuropsychological (Delis-Kaplan Executive Function System [D-KEFS]) and indirect parent-report (Behavior Rating Inventory of Executive Function [BRIEF]) EF measures were tested with multivariate analysis of covariances, followed by univariate analysis of variances and pairwise comparisons. The contribution of attention-deficit/hyperactivity disorder (ADHD) within the AE groups was assessed in secondary analyses. RESULTS On the D-KEFS, there was an omnibus main effect of group, with significant main effects on 3 of 6 variables (CON>AE+, AE-). Within the AE groups, ADHD did not alter the results. On the BRIEF, there was an omnibus significant main effect of group, with significant main effects on all scales (CON

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.

Consistent with well-documented structural and microstructural abnormalities in prenatal alcohol exposure (PAE), recent studies suggest that functional connectivity (FC) may also be disrupted. We evaluated whole-brain FC in a large multi-site sample, examined its cognitive correlates, and explored its potential to objectively identify neurodevelopmental abnormality in individuals without definitive dysmorphic features. Included were 75 children with PAE and 68 controls from four sites. All participants had documented heavy prenatal alcohol exposure. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Resting-state FC was examined using whole-brain graph theory metrics to characterize each individual’s connectivity. Although whole-brain FC metrics did not discriminate prenatally-exposed from unexposed overall, atypical FC (> 1 standard deviation from the grand mean) was significantly more common (2.7 times) in the PAE group vs. controls. In a subset of 55 individuals (PAE and controls) whose dysmorphology examination could not definitively characterize them as either Fetal Alcohol Syndrome (FAS) or non-FAS, atypical FC was seen in 27 % of the PAE group, but 0 % of controls. Across participants, a 1 % difference in local network efficiency was associated with a 36 point difference in global cognitive functioning. Whole-brain FC metrics have potential to identify individuals with objective neurodevelopmental abnormalities from prenatal alcohol exposure. When applied to individuals unable to be classified as FAS or non-FAS from dysmorphology alone, these measures separate prenatally-exposed from non-exposed with high specificity.

The 2015 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was titled “Basic Mechanisms and Translational Implications”. Despite decades of basic science and clinical research, our understanding of the mechanisms by which ethanol affects fetal development is still in its infancy. The first keynote presentation focused on the role of heat shock protein pathways in the actions of ethanol in the developing brain. The second keynote presentation addressed the use of magnetoencephalography to characterize brain function in children with FASD. The conference also included talks by representatives from several government agencies, short presentations by junior and senior investigators that showcased the latest in FASD research, and award presentations. An important part of the meeting was the presentation of the 2015 Henry Rosett award to Dr. Michael Charness in honor of his achievements in research on FASD.

Objectives: Caregivers of youth with heavy prenatal alcohol exposure report impaired communication, which can significantly impact quality of life. Using data collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), we examined whether cognitive variables predict communication ability of youth with histories of heavy prenatal alcohol exposure. Methods: Subjects (ages 10–16 years) comprised two groups: adolescents with heavy prenatal alcohol exposure (AE) and non-exposed controls (CON). Selected measures of executive function (NEPSY, Delis-Kaplan Executive Function System), working memory (CANTAB), and language were tested in the child, while parents completed communication ratings (Vineland Adaptive Behavior Scales – Second Edition). Separate multiple regression analyses determined which cognitive domains predicted communication ability. A final, global model of communication comprised the three cognitive models. Results: Spatial Working Memory and Inhibition significantly contributed to communication ability across groups. Twenty Questions performance related to communication ability in the CON group only while Word Generation performance related to communication ability in the AE group only. Effects remained significant in the global model, with the exception of Spatial Working Memory. Conclusions: Both groups displayed a relation between communication and Spatial Working Memory and Inhibition. Stronger communication ability related to stronger verbal fluency in the AE group and Twenty Questions performance in the CON group. These findings suggest that alcohol-exposed adolescents may rely more heavily on learned verbal storage or fluency for daily communication while non-exposed adolescents may rely more heavily on abstract thinking and verbal efficiency. Interventions aimed at aspects of executive function may be most effective at improving communication ability of these individuals. (JINS, 2018, 24, 1026–1037)

Resting-state functional magnetic resonance imaging allows one to study brain functional connectivity, partly motivated by evidence that patients with complex disorders, such as Alzheimer's disease, may have altered functional brain connectivity patterns as compared with healthy subjects. A functional connectivity network describes statistical associations of the neural activities among distinct and distant brain regions. Recently, there is a major interest in group-level functional network analysis; however, there is a relative lack of studies on statistical inference, such as significance testing for group comparisons. In particular, it is still debatable which statistic should be used to measure pairwise associations as the connectivity weights. Many functional connectivity studies have used either (full or marginal) correlations or partial correlations for pairwise associations. This article investigates the performance of using either correlations or partial correlations for testing group differences in brain connectivity, and how sparsity levels and topological structures of the connectivity would influence statistical power to detect group differences. Our results suggest that, in general, testing group differences in networks deviates from estimating networks. For example, high regularization in both covariance matrices and precision matrices may lead to higher statistical power; in particular, optimally selected regularization (e.g., by cross-validation or even at the true sparsity level) on the precision matrices with small estimation errors may have low power. Most importantly, and perhaps surprisingly, using either correlations or partial correlations may give very different testing results, depending on which of the covariance matrices and the precision matrices are sparse. Specifically, if the precision matrices are sparse, presumably and arguably a reasonable assumption, then using correlations often yields much higher powered and more stable testing results than using partial correlations; the conclusion is reversed if the covariance matrices, not the precision matrices, are sparse. These results may have useful implications to future studies on testing functional connectivity differences.

Background Our objective is to help clinicians detect the facial effects of prenatal alcohol exposure (PAE) by developing computer based tools for screening facial form. Methods All 415 individuals considered were evaluated by expert dysmorphologists and categorized as 1) healthy control (HC), 2) fetal alcohol syndrome (FAS) or 3) heavily prenatally alcohol exposed (HE) but not clinically diagnosable as FAS. 3D facial photographs were used to build models of facial form to support discrimination studies. Surface curvature based delineations of facial form were introduced. Results a. Facial growth in FAS, HE and control subgroups is similar in both cohorts. b. Cohort consistency of agreement between clinical diagnosis and HC-FAS facial form classification is lower for mid-line facial regions and higher for non-mid-line regions. c. Specific HC-FAS differences within and between the cohorts include: - for HC, a smoother philtrum in Cape Coloured individuals;/p> - for FAS, a smoother philtrum in Caucasians; - for control-FAS philtrum difference, greater homogeneity in Caucasians; - for control-FAS face difference, greater homogeneity in Cape Coloured individuals; d. Curvature changes in facial profile induced by prenatal alcohol exposure are more homogeneous and greater in Cape Coloureds than in Caucasians. The Caucasian HE subset divides into clusters with control-like and FAS-like facial dysmorphism. The Cape Coloured HE subset is similarly divided for non-mid-line facial regions but not clearly for mid-line structures. f. The Cape Coloured HE subset with control-like facial dysmorphism shows orbital hypertelorism. Conclusions Facial curvature assists the recognition of the effects of prenatal alcohol exposure and helps explain why different facial regions result in inconsistent control-FAS discrimination rates in disparate ethnic groups. Heavy prenatal alcohol exposure can give rise to orbital hypertelorism, supporting a long-standing suggestion that prenatal alcohol exposure at a particular time causes increased separation of the brain hemispheres with a concomitant increase in orbital separation.

Forensic taphonomy is an essential research field; however, the decomposition of human cadavers at forensic science facilities may lead to nutrient loading and the introduction of unique biological compounds to adjacent areas. The infrastructure of a water retention sys- tem may provide a mechanism for the biogeochemical processing and retention of nutrients and compounds, ensuring the control of runoff from forensic facilities. This work provides a proof of concept for a hydrologic retention system and an autonomous water quality monitoring pro- gram designed to mitigate runoff from The Southeast Texas Applied Forensic Science (STAFS) Facility. Water samples collected along a sam- ple transect were analyzed for total phosphorous, total nitrogen, NO 3 ,N O 2 ,N H4 ,F , and Cl. Preliminary water quality analyses confirm the overall effectiveness of the water retention system. These results are discussed with relation to how this infrastructure can be expanded upon to monitor additional, more novel, byproducts of forensic science research facilities.

Cerebral involvement in Myotonic Dystrophy Type 1 (DM1) is well-established but not well characterized. This study applied new Diffusion Tensor Imaging (DTI) tractography to characterize white matter disturbance in adults with DM1. Forty-five participants with DM1 and 44 control participants had MRIs on a Siemens 3T TIM Trio scanner. Data were processed with TRActs Constrained by UnderLying Anatomy (TRACULA) and 7 tracts were evaluated. Bilateral disturbances in white matter integrity were seen in all tracts in participants with DM1 compared to controls. There were no right-left hemisphere differences. The resulting DTI metrics were correlated with cognitive functioning, particularly working memory and processing speed. Motor speed was not significantly correlated with white matter microstructural integrity and, thus, was not the core explanation for the working memory and processing speed findings. White matter integrity was correlated with important clinical variables including the muscular impairment rating scale (MIRS). CTG repeat length was moderately associated with white matter status in corticospinal tract and cingulum. Sleepiness (Epworth Sleepiness Scale) was moderately associated with white matter status in the superior longitudinal fasciculus and cingulum. Overall, the results add to an emerging literature showing widespread white matter disturbances in both early-onset and adult-onset DM1. Results suggest that further investigation of white matter pathology is warranted in DM1 and that non-invasive measures such as DTI have a potentially important clinical value in characterizing the status of individuals with DM1.

The purpose of the current study was to evaluate the relationship between parent-report and objective measures of executive function in children diagnosed with Fetal Alcohol Spectrum Disorder (FASD). The participants were a clinical sample of 551 children who completed 597 evaluations, including initial and re-evaluations. Participants were 6-16 years old, with a mean age of 10. Pearson correlations were used to determine the relationship between performance-based measures and parent-report measures of executive functioning. Relationships among the same types of measures, that is, performance based or parent report, were also evaluated. The data largely demonstrate low nonsignificant correlations between performance-based measures and parental report of executive function. Parent-report measures were internally consistent as were objective measures. It is possible that a third variable, for example, parental frustration, significantly influences parent reports. It is also likely that objective measures, which are administered in a controlled environment, do not fully capture children's day-to-day functioning. That is, a child may have the executive function abilities (i.e., good performance on objective measures) but may be unable to deploy the appropriate skills in their daily lives, as evidenced by parental report. Children with FASD who have executive function abilities but not implementation skills likely require different interventions than children who lack abilities and skills.

There are no biological treatments for fetal alcohol spectrum disorders (FASDs), lifelong conditions associated with physical anomalies, brain damage, and neurocognitive abnormalities. In preclinical studies, choline partially ameliorates memory and learning deficits from prenatal alcohol exposure. This phase I pilot study evaluated the feasibility, tolerability, and potential adverse effects of choline supplementation in children with FASD. We hypothesized that choline would be well tolerated with minimal adverse events. The study design was a double-blind, randomized, placebo-controlled trial. Participants included 20 children aged 2.5 to 4.9 years with prenatal alcohol exposure and FASD diagnoses. Participants were randomly assigned to 500 mg choline or placebo daily for 9 months (10 active, 10 placebo). Primary outcome measures included feasibility, tolerability, adverse effects, and serum choline levels. Seventeen participants completed the study. Compliance was 82% to 87%, as evidenced by parent-completed log sheets and dose counts. Periodic 24-hour dietary recalls showed no evidence of dietary confounding. Adverse events were minimal and were equivalent in the active and placebo arms with the exception of fishy body odor, which occurred only in the active group. There were no serious adverse events to research participants. This phase I pilot study demonstrates that choline supplementation at 500 mg/d for 9 months in children aged 2 to 5 years is feasible and has high tolerability. Further examination of the efficacy of choline supplementation in FASD is currently underway.

Despite accumulating evidence from animal models demonstrating that prenatal alcohol exposure (PAE) results in life-long neuroendocrine dysregulation, very little is known on this topic among humans with fetal alcohol spectrum disorders (FASD). We expected that alterations in gonadal hormones might interfere with the typical development of white matter (WM) myelination, and in a sex-dependent manner, in human adolescents with FASD. In order to investigate this hypothesis, we used diffusion tensor imaging (DTI) to assess: 1) whether or not sex moderates the impact of PAE on WM microstructure; and 2) how gonadal hormones relate to alterations in WM microstructure in children and adolescents affected by PAE. Methods 61 youth (9 to 16 yrs.; 49% girls; 50% PAE) participated as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). DTI scans and passive drool samples were obtained to examine neurodevelopmental associations with testosterone (T) and dehydroepiandrosterone (DHEA) levels in boys and girls, and estradiol (E2) and progesterone (P) levels in girls. Tract-based spatial statistics were utilized to generate fractional anisotropy (FA) and mean diffusivity (MD) for 9 a priori WM regions of interest (ROIs). Results As predicted, alterations in FA were observed in adolescents with PAE relative to controls, and these differences varied by sex. Girls with PAE exhibited lower FA (Inferior fronto-occipital and Uncinate fasciculi) while boys with PAE exhibited higher FA (Callosal body, Cingulum, Corticospinal tract, Optic radiation, Superior longitudinal fasciculus) relative to age-matched controls. When gonadal hormone levels were examined in relation to DTI measures, additional group differences in FA were revealed, demonstrating that neuroendocrine factors are associated with PAE-related brain alterations. Conclusions These findings provide human evidence that PAE relates to sex-specific differences in WM microstructure, and underlying alterations in gonadal hormone function may, in part, contribute to these effects. Determining PAE-effects on neuroendocrine function among humans is an essential first step towards developing novel clinical (e.g., assessment or intervention) tools that target hormone systems to improve on-going brain development among children and adolescents with FASD.

Background Neurobehavioral consequences of heavy prenatal alcohol exposure are well documented; however, the role of age or sex in these effects has not been studied. The current study examined the effects of prenatal alcohol exposure, sex, and age on neurobehavioral functioning in children. Methods Subjects were 407 youth with prenatal alcohol exposure (n = 192) and controls (n = 215). Two age groups (child [5 to 7 years] or adolescent [10 to 16 years]) and both sexes were included. All subjects completed standardized neuropsychological testing, and caregivers completed parent-report measures of psychopathology and adaptive behavior. Neuropsychological functioning, psychopathology, and adaptive behavior were analyzed with separate 2 (exposure history) × 2 (sex) × 2 (age) multivariate analyses of variance (MANOVAs). Significant effects were followed by univariate analyses. Results No 3-way or 2-way interactions were significant. The main effect of group was significant in all 3 MANOVAs, with the control group performing better than the alcohol-exposed group on all measures. The main effect of age was significant for neuropsychological performance and adaptive functioning across exposure groups with younger children performing better than older children on 3 measures (language, communication, socialization). Older children performed better than younger children on a different language measure. The main effect of sex was significant for neuropsychological performance and psychopathology; across exposure groups, males had stronger language and visual spatial scores and fewer somatic complaints than females. Conclusions Prenatal alcohol exposure resulted in impaired neuropsychological and behavioral functioning. Although adolescents with prenatal alcohol exposure may perform more poorly than younger exposed children, the same was true for nonexposed children. Thus, these cross-sectional data indicate that the developmental trajectory for neuropsychological and behavioral performance is not altered by prenatal alcohol exposure, but rather, deficits are consistent across the 2 age groups tested. Similarly, observed sex differences on specific measures were consistent across the groups and do not support sexually dimorphic effects in these domains.

Diffusion tensor imaging was used to evaluate cerebral white matter in 16 patients (ages 9-18) with myotonic dystrophy type 1 compared to 15 matched controls. Patients with myotonic dystrophy showed abnormalities in mean diffusivity compared to controls in frontal, temporal, parietal, and occipital white matter and in all individual tracts examined. Whole cerebrum mean diffusivity was 8.6 % higher overall in patients with myotonic dystrophy compared to controls. Whole cerebrum fractional anisotropy was also abnormal (10.8 % low overall) in all regions and tracts except corticospinal tracts. Follow-up analysis of parallel and perpendicular diffusivity suggests possible relative preservation of myelin in corticospinal tracts. Correlations between Wechsler working memory performance and mean diffusivity were strong for all regions. Frontal and temporal fractional anisotropy were correlated with working memory as well. Results are consistent with earlier studies demonstrating that significant white matter disturbances are characteristic in young patients with myotonic dystrophy and that these abnormalities are associated with the degree of working memory impairment seen in this disease.