Long-term follow-up of a randomized controlled trial of choline for neurodevelopment in fetal alcohol spectrum disorder: corpus callosum white matter microstructure and neurocognitive outcomes.

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.

Prenatal and Postnatal Choline Supplementation in Fetal Alcohol Spectrum Disorder.

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.

Prenatal metal mixture concentrations and reward motivation in children.

Reward motivation is a complex umbrella term encompassing the cognitions, emotions, and behaviors involved in the activation, execution, and persistence of goal-directed behavior. Altered reward motivation in children is characteristic of many neurodevelopmental and psychiatric disorders. Previously difficult to operationalize, the Progressive Ratio (PR) task has been widely used to assess reward motivation in animal and human studies, including children. Because the neural circuitry supporting reward motivation starts developing during pregnancy, and is sensitive to disruption by environmental toxicants, including metals, the goal of this study was to examine the association between prenatal concentrations of a mixture of neurotoxic metals and reward motivation in children. We measured reward motivation by administering a PR test to 373 children ages 6-8 years enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) Study in Mexico City. Children were asked to press a response lever for a token reward; one press on the response lever was required to earn the first token and each subsequent token required an additional 10 lever presses. Maternal blood concentrations of lead, manganese, zinc, arsenic, cadmium, and selenium were measured using inductively-coupled plasma mass spectrometry during the 2nd and 3rd trimesters of pregnancy. We performed generalized Weighted Quantile Sum (gWQS) regression analyses to examine associations between the prenatal metal mixture and reward motivation; adjusting for child sex, birthweight and age; and maternal IQ, education, and socioeconomic status. The prenatal metal mixture was significantly associated with higher motivation as indicated by more lever presses (ß = 0.02, p < 0.001) and a shorter time between receiving the reinforcer and the first press (ß = 0.23, p = 0.01), and between subsequent presses (ß = 0.07, p = 0.005). Contributions of different metals to this association differed by trimester and child sex. These findings suggest that children with increased exposure to metal during the 2nd and 3rd trimesters of gestation demonstrate increased reward motivation, which may reflect a tendency to perseverate or hypersensitivity to positive reinforcement.

Prenatal PM2.5 exposure in the second and third trimesters predicts neurocognitive performance at age 9-10 years: A cohort study of Mexico City children.

INTRODUCTION: Prenatal exposure to fine particulate matter air pollution (PM2.5) is an important, under-studied risk factor for neurodevelopmental dysfunction. We describe the relationships between prenatal PM2.5 exposure and vigilance and inhibitory control, executive functions related to multiple health outcomes in Mexico City children. METHODS: We studied 320 children enrolled in Programming Research in Obesity, GRowth, Environment and Social Stressors, a longitudinal birth cohort study in Mexico City. We used a spatio-temporal model to estimate daily prenatal PM2.5 exposure at each participant's residential address. At age 9-10 years, children performed three Go/No-Go tasks, which measure vigilance and inhibitory control ability. We used Latent class analysis (LCA) to classify performance into subgroups that reflected neurocognitive performance and applied multivariate regression and distributed lag regression modeling (DLM) to test overall and time-dependent associations between prenatal PM2.5 exposure and Go/No-Go performance. RESULTS: LCA detected two Go/No-Go phenotypes: high performers (Class 1) and low performers (Class 2). Predicting odds of Class 1 vs Class 2 membership based on prenatal PM2.5 exposure timing, logistic regression modeling showed that average prenatal PM2.5 exposure in the second and third trimesters correlated with increased odds of membership in low-performance Class 2 (OR = 1.59 (1.16, 2.17), p = 0.004). Additionally, DLM analysis identified a critical window consisting of gestational days 103-268 (second and third trimesters) in which prenatal PM2.5 exposure predicted poorer Go/No-Go performance. DISCUSSION: Increased prenatal PM2.5 exposure predicted decreased vigilance and inhibitory control at age 9-10 years. These findings highlight the second and third trimesters of gestation as critical windows of PM2.5 exposure for the development of vigilance and inhibitory control in preadolescent children. Because childhood development of vigilance and inhibitory control informs behavior, academic performance, and self-regulation into adulthood, these results may help to describe the relationship of prenatal PM2.5 exposure to long-term health and psychosocial outcomes. The integrative methodology of this study also contributes to a shift towards more holistic analysis.

Behavioral trainings and manipulations to reduce delay discounting: A systematic review.

In everyday decision-making, individuals make trade-offs between short-term and long-term benefits or costs. Depending on many factors, individuals may choose to wait for larger delayed reward, yet in other situations they may prefer the smaller, immediate reward. In addition to within-subject variation in the short-term versus long-term reward trade-off, there are also interindividual differences in delay discounting (DD), which have been shown to be quite stable. The extent to which individuals discount the value of delayed rewards turns out to be associated with important health and disorder-related outcomes: the more discounting, the more unhealthy or problematic choices. This has led to the hypothesis that DD can be conceptualized as trans-disease process. The current systematic review presents an overview of behavioral trainings and manipulations that have been developed to reduce DD in human participants aged 12 years or older. Manipulation studies mostly contain one session and measure DD directly after the manipulation. Training studies add a multiple session training component that is not per se related to DD, in between two DD task measurements. Ninety-eight studies (151 experiments) were identified that tested behavioral trainings and manipulations to decrease DD. Overall, results indicated that DD can be decreased, showing that DD is profoundly context dependent and changeable. Most promising avenues to pursue in future research seem to be acceptance-based/mindfulness-based trainings, and even more so manipulations involving a future orientation. Limitations and recommendations are discussed to identify the mechanistic processes that allow for changes in discount rate and behavior accordingly.