Aim: To quantify regional subcortical brain volume anomalies in youth with fetal alcohol spectrum disorder (FASD), assess the relative sensitivity and specificity of abnormal volumes in FASD vs. a comparison group, and examine associations with cognitive function. Method: Participants: 47 children with FASD and 39 typically-developing comparison participants, ages 8-17 years, who completed physical evaluations, cognitive and behavioral testing, and an MRI brain scan. A large normative MRI dataset that controlled for sex, age, and intracranial volume was used to quantify the developmental status of 7 bilateral subcortical regional volumes. Z-scores were calculated based on volumetric differences from the normative sample. T-tests compared subcortical volumes across groups. Percentages of atypical volumes are reported as are sensitivity and specificity in discriminating groups. Lastly, Pearson correlations examined the relationships between subcortical volumes and neurocognitive performance. Results: Participants with FASD demonstrated lower mean volumes across a majority of subcortical regions relative to the comparison group with prominent group differences in the bilateral hippocampi and bilateral caudate. More individuals with FASD (89%) had one or more abnormally small volume compared to 72% of the comparison group. The bilateral hippocampi, bilateral putamen, and right pallidum were most sensitive in discriminating those with FASD from the comparison group. Exploratory analyses revealed associations between subcortical volumes and cognitive functioning that differed across groups. Conclusion: In this sample, youth with FASD had a greater number of atypically small subcortical volumes than individuals without FASD. Findings suggest MRI may have utility in identifying individuals with structural brain anomalies resulting from PAE.

BackgroundPrenatal alcohol exposure (PAE) impacts hippocampal structure and function, contributing to deficits in memory and decision-making in affected individuals. Here, we evaluate hippocampal anomalies in children with PAE and an unexposed comparison group using advanced MRI methods that characterize hippocampal curvature and thickness.MethodsParticipants, ages 8 to 16 years, included children with PAE (n = 48) and an unexposed comparison group (n = 46) who underwent a dysmorphology exam, neuropsychological assessment, and an MRI scan. Height, weight, head circumference, and dysmorphic facial features were evaluated. Of those with PAE, 4.2% had fetal alcohol syndrome (FAS), 22.9% had partial FAS, and 72.9% had alcohol-related neurodevelopmental disorder. Neuropsychological testing included measures of intelligence and memory functioning. T1-weighted anatomical data were processed with the Hippunfold pipeline, which "unfolds" the complex hippocampal structure onto a template surface and provides measures of thickness and gyrification/curvature at each vertex. Permutation Analysis of Linear Models (PALM) was used to test for group differences (PAE vs. comparison) in hippocampal thickness and gyrification at each vertex and also to assess correlations with cognitive functioning.ResultsThere were significant regional differences in thickness and gyrification across bilateral hippocampi, with the PAE group showing substantially thinner tissue and less curvature than the comparison group, especially in CA1 and subiculum regions. For those with PAE, thinner subicular tissue (bilateral) was associated with lower IQ. Also in the PAE group, lower episodic memory performance was associated with thinness in the right hippocampus, especially in the subiculum region. There were no significant regional hippocampal patterns that were associated with cognitive functioning for individuals in the unexposed comparison group.ConclusionsWe used a novel MRI method to evaluate hippocampal structure in children with PAE and an unexposed comparison group. The data suggest that PAE disrupts hippocampal development, impacting both the early-stage folding of the structure and its ultimate thickness. The data also demonstrate that these developmental anomalies have functional consequences in terms of core memory functions as well as global intellectual functioning in children with PAE.

BACKGROUND:Fetal alcohol spectrum disorders (FASDs) are associated with neurocognitive deficits for which there are no biological treatments. Choline supplementation may attenuate these deficits. OBJECTIVES:This study was aimed to evaluate choline as a neurodevelopmental intervention for preschool-aged children with FASD. METHODS:We present combined data from 104 participants with FASD (aged 2.5-5.9 y) from 3 placebo randomized controlled trials (RCTs). Participants in RCT1 and RCT2 were randomly assigned to 9 mo choline (500 mg daily) or placebo. Participants in RCT3 were randomly assigned to 9 mo choline (19 mg/kg daily) or placebo. The primary outcome measure was an elicited imitation (EI) memory task. RESULTS:Adherence was high (78% doses received). Adverse effects were similar across groups except fishy body odor: choline group, 36%; placebo group, 8%. We observed a trend-level choline advantage; participants receiving choline performed 25% better on EI short-delay adjacent pairs (sequential memory) than those on placebo, with a steeper increase in scores between 6 and 9 mo (ŷ = -10.06; P = 0.03; 95% CI: -19.13, -0.99). No sex difference in response was seen, nor did we observe a dose-response relationship. Age-moderated response to choline between baseline and 9 mo (ŷ = 10.02; P = 0.01; 95% CI: 2.47, 17.57), with greater response in younger (≤4.2 y) than that in older (>4.2 y) participants. Overall, choline showed a beneficial effect on memory but no impact on executive functioning or intelligent quotient. CONCLUSIONS:The results support choline as a neurodevelopmental intervention for improvement of memory in young children exposed to alcohol prenatally. Specifically, the use of choline bitartrate as a supplement in the range of 260-500 mg/d in children between 2.5 and 5.9 y of age is supported. Future studies are needed to further define appropriate dosage as well as optimal lengths and developmental windows for supplementation. This trial was registered at clinicaltrials.gov as NCT01149538 and NCT02735473.

Fetal alcohol spectrum disorders (FASD) are among the most common neurodevelopmental disorders and substantially impact public health. FASD can affect people of all races and ethnicities; however, there are important racial and ethnic disparities in alcohol-exposed pregnancy prevention, assessment and diagnosis of FASD, and interventions to support individuals with FASD and their families. In this article we use the Dis/Ability Studies and Critical Race Theory (Dis/Crit) framework to structure the exploration of disparities and possible solutions within these three areas (prevention, diagnosis, intervention). Dis/Crit provides a guide to understanding the intersection of dis/ability and race, while framing both as social constructs. Following the Dis/Crit framework, the systemic, historical, and contemporary racism and ableism present in psychological care is further discussed. We aim to elucidate these racial and ethnic disparities within the fields of psychology and neuropsychology through the Dis/Crit framework and provide potential points of action to reduce these disparities.

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.

OBJECTIVE:To evaluate the use of a large magnetic resonance imaging (MRI) normative dataset to quantify structural brain anomalies that may improve diagnostic sensitivity for atypical brain volume in youth with fetal alcohol spectrum disorder (FASD). STUDY DESIGN:Participants included 48 children with prenatal alcohol exposure (PAE) and 43 controls, ages 8-17 years, from the longitudinal Collaborative Initiative on FASD s. Recently published lifespan brain charts were used to quantify participants' (per)centile for brain volumes (cortical and subcortical gray matter and cortical white matter), providing an index of (dis)similarity to typically developing individuals of the same age and sex. RESULTS:Participants with PAE demonstrated lower mean centile scores compared with controls. Participants with PAE and scores ≤ 10th centile on at least 1 brain volume metric demonstrated significantly lower performance on measures of intellectual function and aspects of executive functioning compared with participants with PAE and "typical" volumes (>10th centile). Brain volume centiles explained a greater amount of variance in IQ and improved sensitivity to brain volume anomalies in FASD compared with the most commonly used diagnostic criterion of occipitofrontal circumference (OFC) ≤ 10th. CONCLUSION:Age- and sex-adjusted brain volumes based on a large normative dataset may be useful predictors of functional outcomes and may identify a greater number of individuals with FASD than the currently used criterion of OFC.

Objective:Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental condition associated with deficits in cognitive functioning (executive functioning [EF], attention, working memory, etc.), behavioral impairments, and abnormalities in brain structure including cortical and subcortical volumes. Rates of comorbid attention-deficit/hyperactivity disorder (ADHD) are high in children with FASD and contribute to significant functional impairments. Sluggish cognitive tempo (SCT) includes a cluster of symptoms (e.g. underactive/slow-moving, confusion, fogginess, daydreaming) found to be related to but distinct from ADHD, and previous research suggests that it may be common in FASD. We explored SCT by examining the relationship between SCT and both brain volumes (corpus callosum, caudate, and hippocampus) and objective EF measures in children with FASD vs. typically developing controls.Participants and Methods:This is a secondary analysis of a larger longitudinal CIFASD study that consisted of 35 children with prenatal alcohol exposure (PAE) and 30 controls between the ages of 9 to 18 at follow-up. Children completed a set of cognitive assessments (WISC-IV, DKEFS, & NIH Toolbox) and an MRI scan, while parents completed the Child Behavior Checklist (CBCL), which includes a SCT scale. We examined group differences between PAE and controls in relation to SCT symptoms, EF scores, and subcortical volumes. Then, we performed within-and between-group comparisons with and without controlling for total intracranial volume, age, attention problems, and ADHD problems between SCT and subcortical brain volumes. Finally, we performed correlations between SCT and EF measures for both groups.Results:Compared to controls, participants with PAE showed significantly more SCT symptoms on the CBCL (t [57] = 3.66, p = 0.0006), more parent-rated attention problems and ADHD symptoms, lower scores across several EF measures (DKEFS Trail-Making and Verbal Fluency; WISC-IV Digit Span, Symbol Search, and Coding; effect sizes ranging from 0.44 to 1.16), and smaller regional volumes in the caudate, hippocampus, and posterior areas of the corpus callosum. In the PAE group, a smaller hippocampus was associated with more SCT symptoms (controlling for parent-rated attention problems and ADHD problems, age, and intracranial volume). However, in the control group, a larger mid posterior and posterior corpus callosum were significantly associated with more SCT symptoms (controlling for parent-rated attention problems, intracranial volume, and age; r [24] = 0.499, p = 0.009; r [24] = 0.517, p = 0.007). In terms of executive functioning, children in the PAE group with more SCT symptoms performed worse on letter sequencing of the Trail-Making subtest (controlling attention problems & ADHD symptoms). In comparison, those in the control group with more SCT symptoms performed better on letter sequencing and combined number letter sequencing of the Trail-Making subtest (controlling attention problems).Conclusions:Findings suggest that children with FASD experience elevated SCT symptoms compared to typically developing controls, which may be associated with worse performance on EF tasks and smaller subcortical volumes (hippocampus) when taking attention difficulties and ADHD symptoms into account. Additional research into the underlying causes and correlates of SCT in FASD could result in improved tailoring of interventions for this population.

Objective:Fetal alcohol spectrum disorder (FASD) is a life-long condition, and few interventions have been developed to improve the neurodevelopmental course in this population. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. In this study, we examine treatment group differences in executive function (EF) outcomes and diffusion MRI of the corpus callosum using the Neurite Orientation Dispersion and Density Index (NODDI) biophysical model.Participants and Methods:The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5- to 5-year-olds with FASD. Participants in this long-term follow-up study included 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up evaluation included measures of executive functioning (WISC-V Picture Span and Digit Span; DKEFS subtests) and diffusion MRI (NODDI).Results:Children who received choline early in development outperformed those in the placebo group across a majority of EF tasks at long-term follow-up (effect sizes ranged from -0.09 to 1.27). Children in the choline group demonstrated significantly better performance on several tasks of lower-order executive function skills (i.e., DKEFS Color Naming [Cohen's d = 1.27], DKEFS Word Reading [Cohen's d = 1.13]) and showed potentially better white matter microstructure organization (as indicated by lower orientation dispersion; Cohen's d = -1.26) in the splenium of the corpus callosum compared to the placebo group. In addition, when collapsing across treatment groups, higher white matter microstructural organization was associated with better performance on several EF tasks (WISC-V Digit Span; DKEFS Number Sequencing and DKEFS Word Reading).Conclusions:These findings highlight long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that changes in white matter organization may represent an important target of choline in this population. Unique to this study is the use of contemporary biophysical modeling of diffusion MRI data in youth with FASD. Findings suggest this neuroimaging approach may be particularly useful for identifying subtle white matter differences in FASD as well as neurobiological responses to early intervention associated with important cognitive functions.

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.

Fetal alcohol spectrum disorder (FASD) is common and represents a significant public health burden, yet very few interventions have been tested in FASD. Cognitive deficits are core features of FASD, ranging from broad intellectual impairment to selective problems in attention, executive functioning, memory, visual–perceptual/motor skills, social cognition, and academics. One potential intervention for the cognitive impairments associated with FASD is the essential nutrient choline, which is known to have numerous direct effects on brain and cognition in both typical and atypical development. We provide a summary of the literature supporting the use of choline as a neurodevelopmental intervention in those affected by prenatal alcohol. We first discuss how alcohol interferes with normal brain development. We then provide a comprehensive overview of the nutrient choline and discuss its role in typical brain development and its application in the optimization of brain development following early insult. Next, we review the preclinical literature that provides evidence of choline’s potential as an intervention following alcohol exposure. Then, we review a handful of existing human studies of choline supplementation in FASD. Lastly, we conclude with a review of practical considerations in choline supplementation, including dose, formulation, and feasibility in children.

Background Fetal alcohol spectrum disorder (FASD) is a lifelong condition. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. Methods The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5 to 5 year olds with FASD. Participants in this long-term follow-up study include 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11.0 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up included measures of executive functioning and an MRI scan. Results Children who received choline had better performance on several tasks of lower-order executive function (e.g., processing speed) and showed higher white matter microstructure organization (i.e., greater axon coherence) in the splenium of the corpus callosum compared to the placebo group. Conclusions These preliminary findings, although exploratory at this stage, highlight potential long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that choline may affect white matter development, representing a potential target of choline in this population. Trial registration Prior to enrollment, this trial was registered with clinicaltrials.gov ( NCT01149538 ) on June 23, 2010.

Compared to their stably housed peers, homeless, and highly mobile (HHM) youth experience disproportionately greater adversity and risk leading to a wide variety of poor developmental outcomes, and targeted interventions have the potential to mitigate such outcomes. A growing literature highlights the need for accurate diagnosis in high-risk populations given the considerable overlap between posttraumatic symptomology and behaviorally based disorders such as ADHD. Objective testing inferring neurobiological and circuit-based abnormalities in posttraumatic stress disorder (PTSD) and ADHD may provide a useful clinical tool to aid accurate diagnosis and treatment recommendations. This novel, exploratory study examined the relation between executive function (EF) as measured by objective testing and parent ratings with symptoms of posttraumatic stress and ADHD in 86 children (age 9 to 11) living in emergency homeless shelters. Parent-rated EF problems suggested broad impairment associated with ADHD symptoms but specific impairment in emotional/behavioral function associated with posttraumatic stress symptoms. While measures of inhibition and shifting EF were strongly associated with symptomology in bivariate correlations, they explained minimal variance in regression models. Internalizing behavior problems were associated with posttraumatic stress symptoms, while externalizing behavior problems were associated with ADHD symptoms. Implications for clinical practice and future research are discussed.