Neurophysiological correlates of memory change in children with fetal alcohol spectrum disorders treated with choline.

Background: Prenatal and early postnatal choline supplementation reduces cognitive and behavioral deficits in animal models of Fetal Alcohol Spectrum Disorder (FASD). In a previously published 9-month clinical trial of choline supplementation in children with FASD, we reported that postnatal choline was associated with improved performance on a hippocampal-dependent recognition memory task. The current paper describes the neurophysiological correlates of that memory performance for trial completers. Methods: Children with FASD (N = 24) who were enrolled in a clinical trial of choline supplementation were followed for 9 months. Delayed recall on a 9-step elicited imitation task (EI) served as the behavioral measure of recognition memory. Neurophysiological correlates of memory were assessed via event-related potentials (ERP). Results: Delayed recall on EI was correlated with two ERP components commonly associated with recognition memory in young children: middle latency negative component (Nc amplitude; range: r = -0.41 to r = -0.44) and positive slow wave (PSW area under the curve; range: r = -0.45 to r = -0.63). No significant ERP differences were observed between the choline and placebo groups at the conclusion of the trial. Conclusion: Although the small sample size limits the ability to draw clear conclusions about the treatment effect of choline on ERP, the results suggest a relationship between memory performance and underlying neurophysiological status in FASD. This trial was registered.

Early delay of gratification predicts later inhibitory control and academic performance in children with prenatal alcohol exposure.

Fetal alcohol spectrum disorder (FASD) affects 2-5% of the 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 2.5-5 years were administered a delay of gratification task in which they chose between receiving 2 snacks immediately or 10 snacks after waiting for 10 min. Two groups were defined based on a median split of waiting time. Four years later, 29 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.

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.

Four-year follow-up of a randomized controlled trial of choline for neurodevelopment in fetal alcohol spectrum disorder.

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.

Individual Traits, Personal Values, and Conflict Resolution in an Isolated, Confined, Extreme Environment.

BACKGROUND: The study of personality traits, personal values, and the emergence of conflicts within groups performing in an isolated, confined, and extreme environment (ICE) may provide insights helpful for the composition and support of space crews for long duration missions. METHODS: Studied pre/post and over the 2-yr period of the investigation were 10 Danish military personnel deployed to stations in Greenland on a 26-mo staggered rotation. Subjects completed the NEO PI-R, Triarchic Psychopathy Measure, and Portrait Values Questionnaire, and participated in structured interviews. During deployment, questionnaires were completed biweekly and a cognitive function test once a month. RESULTS: Personality findings indicated a generally well-adjusted group, above average in positive personality traits [Conscientiousness T-score = 59.4 (11.41); Agreeableness T-score = 54.4 (9.36)] and boldness. Personal values of benevolence and self-direction were highly rated. The decision when to "pick sides" and intervene during disagreements between group members was viewed as an important component of conflict resolution. There were no changes in positive/negative affect or cognitive function over the annual light/dark cycle. DISCUSSION: The personal values of group members appear highly compatible for living in a small group ICE environment for an extended period. Disagreements between group members impact the functioning of the entire group, particularly in regard to decisions whether to support one of the individuals or let the argument run its course. Extended training in strategies for conflict resolution are needed in planning for future long duration missions to avoid fault lines forming within the group.Corneliussen JG, Leon GR, Kjærgaard A, Fink BA, Venables NC. Individual traits, personal values, and conflict resolution in an isolated, confined, extreme environment. Aerosp Med Hum Perform. 2017; 88(6):535-543.

Abnormal Eating Behaviors Are Common in Children with Fetal Alcohol Spectrum Disorder.

OBJECTIVE: To compare the eating behaviors and nutrition-related concerns in children with fetal alcohol spectrum disorder (FASD) with those in typically developing children. STUDY DESIGN: A survey that assessed eating behaviors was completed between October 2013 and May 2014 by the caregivers of children screened for FASD at the University of Minnesota's Fetal Alcohol Spectrum Disorders Program, and typically developing children recruited from that clinic or from the Research Participation Core of the Waisman Center, University of Wisconsin. RESULTS: Compared with controls (N = 81), children with FASD (N = 74) had delayed acquisition of self-feeding behavior (P < .001) and solid food introduction (P < .001). Impaired satiety was common and independent of medication use: 23.0% were never full/satisfied, 31.1% snacked constantly, and 27.0% concealed food (all P ≤ .002). They consumed the equivalent of an additional meal/snack daily (P < .01). Children with FASD were more likely to have a past diagnosis of underweight (P < .001). Mean body mass index was significantly reduced for males (P = .009) but not females (P = .775) with FASD, and only 2 children with FASD were currently underweight. Children with FASD were more physically active (P < .01). CONCLUSIONS: Abnormal eating patterns are common in children with FASD and may contribute to their delayed growth and nutritional inadequacies. Their poor satiety may reflect poor impulse control. Children with FASD may benefit from diet counseling. Conversely, some children with hyperphagia may warrant referral for FASD screening.

Choline supplementation in children with fetal alcohol spectrum disorders: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fetal alcohol spectrum disorders (FASDs) are conditions characterized by physical anomalies, neurodevelopmental abnormalities, and neurocognitive deficits, including intellectual, executive, and memory deficits. There are no specific biological treatments for FASDs, but rodent models have shown that prenatal or postnatal choline supplementation reduces cognitive and behavioral deficits. Potential mechanisms include phospholipid production for axonal growth and myelination, acetylcholine enhancement, and epigenetic effects. OBJECTIVE: Our primary goal was to determine whether postnatal choline supplementation has the potential to improve neurocognitive functioning, particularly hippocampal-dependent memory, in children with FASDs. DESIGN: The study was a double-blind, randomized, placebo-controlled pilot trial in children (aged 2.5-5 y at enrollment) with FASDs (n = 60) who received 500 mg choline or a placebo daily for 9 mo. Outcome measures were Mullen Scales of Early Learning (primary) and the elicited imitation (EI) memory paradigm (secondary). RESULTS: The administration proved feasible, and choline was well tolerated. Participants received a dose on 88% of enrolled days. The only adverse event linked to choline was a fishy body odor. Choline supplementation improved the secondary outcome (EI) only after immediate recall performance was controlled for, and the outcome was moderated by age. The treatment effect on EI items recalled was significant in the younger participants (2.5- to ≤4.0-y-olds); the young choline group showed an increase of 12-14 percentage points greater than that of the young placebo group on delayed recall measures during treatment. However, there was a marginal baseline difference in delayed item recall between the young choline and placebo groups as well as a potential ceiling effect for item recall, both of which likely contributed to the observed treatment effect. We also observed a trend toward a negative effect of choline supplementation on the immediate EI recall of ordered pairs; the young placebo group showed an increase of 8-17 percentage points greater than that of the choline group during treatment. There was an inverse relation between choline dose (in mg/kg) and memory improvement (P = 0.041); the data suggest that weight-adjusted doses may be a better alternative to a fixed dose in future studies. Limitations included trend-level baseline differences in performance, the post-hoc determination of age moderation, and potential ceiling effects for the memory measure. CONCLUSIONS: This pilot study suggests that an additional evaluation of choline supplementation as an intervention for memory functioning in children with FASDs is warranted. The observed interaction between age and choline's effect on EI suggests that potential sensitive periods should be considered in future work. This trial was registered at clinicaltrials.gov as NCT01149538.

Executive functioning deficits in preschool children with Fetal Alcohol Spectrum Disorders.

Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the vast majority of available evidence comes from school-age children and adolescents. Very little is known about EF during the critical developmental period prior to 6 years of age in FASD. We evaluated EF in 39 children with FASD (3.0-5.5 years) and a comparison group of 50 age-matched, nonexposed controls. Measures included the EF Scale for Early Childhood and a Delay of Gratification task. Compared to age-matched controls, preschool children with FASD had impairments on the EF Scale and showed more impulsivity on the Delay of Gratification task. To confirm the EF Scale finding, FASD group performance was compared to a separate normative dataset (N = 1,400). Those with FASD performed below normal (M = -0.57, SD = 0.92). Within the FASD group, IQ was correlated with the EF Scale (partial r = .60, p = .001) and Delay of Gratification (partial r = .58, p = .005). EF Scale performance did not differ significantly across levels of FASD severity (fetal alcohol syndrome [FAS], partial FAS, or alcohol-related neurobehavioral disorder [ARND]). However, compared to normative data, those with FAS had the largest deficits (M = -0.91 SD from the mean, SE = 0.23), followed by partial FAS (M = -0.66 SD from the mean, SE = 0.26), then ARND (M = -0.36 SD from the mean, SE = 0.20). These novel data show that EF deficits manifest well before the age of 6 years in children with FASD, that they occur across the spectrum, and that EF may be most impaired in children with more severe forms of FASD and/or lower IQs.

Overweight and obesity among children and adolescents with fetal alcohol spectrum disorders.

BACKGROUND: Because prenatal alcohol exposure is associated with growth deficiency, little attention has been paid to the potential for overweight and obesity in children with fetal alcohol spectrum disorders (FASD). This study examined the prevalence of overweight/obesity (body mass index [BMI]) in a large clinical sample of children with FASD. METHODS: Children, aged 2 to 19 years, who were evaluated for FASD at University Clinics, included 445 with an FASD diagnosis and 171 with No-FASD diagnosis. Prevalence of overweight/obesity (BMI ≥ 85 percentile) was compared to national and state prevalence. BMI was examined in relation to FASD diagnosis, gender, and age. Dietary intake data were examined for a young subsample (n = 42). RESULTS: Thirty-four percent with any FASD diagnosis were overweight or obese, which did not differ from the No-FASD group or U.S. prevalence. Underweight was prevalent in those with fetal alcohol syndrome (FAS) (17%). However, increased rates of overweight/obesity were seen in those with partial FAS (40%). Among adolescents, those with any FASD diagnosis had increased overweight/obesity (42%), particularly among females (50%). The rate in adolescent females with FASD (50%) was nearly 3 times higher than state prevalence for adolescent females (17 to 18%), p < 0.001. In the young subsample, those who were overweight/obese consumed more calories, protein, and total fat per day than those who were not overweight or obese. CONCLUSIONS: Rates of overweight/obesity are increased in children with partial FAS. In adolescents, rates are increased for any FASD diagnosis (particularly in females). Results are suggestive of possible metabolic/endocrine disruption in FASD-a hypothesis for which there is evidence from animal models. These data suggest that clinicians may consider prenatal alcohol exposure as a risk factor for metabolic/endocrine disruption, should evaluate diet as a risk in this population, and may need to target interventions to females prior to puberty to effect changes in overweight-related outcomes.

Choline supplementation in children with fetal alcohol spectrum disorders has high feasibility and tolerability.

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.

Inadequate intake of nutrients essential for neurodevelopment in children with fetal alcohol spectrum disorders (FASD).

This study evaluated dietary intake in children with fetal alcohol spectrum disorders (FASD). Pre-clinical research suggests that nutrient supplementation may attenuate cognitive and behavioral deficits in FASD. Currently, the dietary adequacy of essential nutrients in children with FASD is unknown. Dietary data were collected as part of a randomized, double-blind controlled trial of choline supplementation in FASD. Participants included 31 children with FASD, ages 2.5-4.9 years at enrollment. Dietary intake data was collected three times during the nine-month study via interview-administered 24-hour recalls with the Automated Self-Administered 24-hour Recall. Dietary intake of macronutrients and 17 vitamins/minerals from food was averaged across three data collection points. Observed nutrient intakes were compared to national dietary intake data of children ages 2-5 years (What we Eat in America, NHANES 2007-2008) and to the Dietary Reference Intakes. Compared to the dietary intakes of children in the NHANES sample, children with FASD had lower intakes of saturated fat, vitamin D, and calcium. The majority (>50%) of children with FASD did not meet the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for fiber, n-3 fatty acids, vitamin D, vitamin E, vitamin K, choline, and calcium. This pattern of dietary intake in children with FASD suggests that there may be opportunities to benefit from nutritional intervention. Supplementation with several nutrients, including choline, vitamin D, and n-3 fatty acids, has been shown in animal models to attenuate the cognitive deficits of FASD. These results highlight the potential of nutritional clinical trials in FASD.