Similar cortical morphometry trajectories from 5 to 9 years in children with perinatal HIV who started treatment before age 2 years and uninfected controls.

BACKGROUND: Life-long early ART (started before age 2 years), often with periods of treatment interruption, is now the standard of care in pediatric HIV infection. Although cross-sectional studies have investigated HIV-related differences in cortical morphology in the setting of early ART and ART interruption, the long-term impact on cortical developmental trajectories is unclear. This study compares the longitudinal trajectories of cortical thickness and folding (gyrification) from age 5 to 9 years in a subset of children perinatally infected with HIV (CPHIV) from the Children with HIV Early antiRetroviral therapy (CHER) trial to age-matched children without HIV infection. METHODS: 75 CHER participants in follow-up care at FAMCRU (Family Centre for Research with Ubuntu), as well as 66 age-matched controls, received magnetic resonance imaging (MRI) on a 3 T Siemens Allegra at ages 5, 7 and/or 9 years. MR images were processed, and cortical surfaces reconstructed using the FreeSurfer longitudinal processing stream. Vertex-wise linear mixed effects (LME) analyses were performed across the whole brain to compare the means and linear rates of change of cortical thickness and gyrification from 5 to 9 years between CPHIV and controls, as well as to examine effects of ART interruption. RESULTS: Children without HIV demonstrated generalized cortical thinning from 5 to 9 years, with the rate of thinning varying by region, as well as regional age-related gyrification increases. Overall, the means and developmental trajectories of cortical thickness and gyrification were similar in CPHIV. However, at an uncorrected p < 0.005, 6 regions were identified where the cortex of CPHIV was thicker than in uninfected children, namely bilateral insula, left supramarginal, lateral orbitofrontal and superior temporal, and right medial superior frontal regions. Planned ART interruption did not affect development of cortical morphometry. CONCLUSIONS: Although our results suggest that normal development of cortical morphometry between the ages of 5 and 9 years is preserved in CPHIV who started ART early, these findings require further confirmation with longitudinal follow-up through the vulnerable adolescent period.

Multimodal magnetic resonance neuroimaging measures characteristic of early cART-treated pediatric HIV: A feature selection approach.

Children with perinatally acquired HIV (CPHIV) have poor cognitive outcomes despite early combination antiretroviral therapy (cART). While CPHIV-related brain alterations can be investigated separately using proton magnetic resonance spectroscopy (1 H-MRS), structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and functional MRI (fMRI), a set of multimodal MRI measures characteristic of children on cART has not been previously identified. We used the embedded feature selection of a logistic elastic-net (EN) regularization to select neuroimaging measures that distinguish CPHIV from controls and measured their classification performance via the area under the receiver operating characteristic curve (AUC) using repeated cross validation. We also wished to establish whether combining MRI modalities improved the models. In single modality analysis, sMRI volumes performed best followed by DTI, whereas individual EN models on spectroscopic, gyrification, and cortical thickness measures showed no class discrimination capability. Adding DTI and 1 H-MRS in basal measures to sMRI volumes produced the highest classification performance validation accuracy = 85 % AUC = 0.80 . The best multimodal MRI set consisted of 22 DTI and sMRI volume features, which included reduced volumes of the bilateral globus pallidus and amygdala, as well as increased mean diffusivity (MD) and radial diffusivity (RD) in the right corticospinal tract in cART-treated CPHIV. Consistent with previous studies of CPHIV, select subcortical volumes obtained from sMRI provide reasonable discrimination between CPHIV and controls. This may give insight into neuroimaging measures that are relevant in understanding the effects of HIV on the brain, thereby providing a starting point for evaluating their link with cognitive performance in CPHIV.

Self-navigated prospective motion correction for 3D-EPI acquisition.

PURPOSE: Although 3D EPI is more susceptible to motion artifacts than 2D EPI, it presents some benefits for functional MRI, including the absence of spin-history artifacts, greater potential for parallel imaging acceleration, and better functional sensitivity in high-resolution imaging. Here we present a self-navigated 3D-EPI sequence suitable for prospective motion-corrected functional MRI without additional hardware or pulses. METHODS: For each volume acquisition, the first 24 of the 52 partitions being acquired are accumulated to a new feedback block that was added to the image reconstruction pipeline. After zero-filling the remaining partitions, the feedback block constructs a volumetric self-navigator (vSNav), co-registers it to the reference vSNav acquired during the first volume acquisition, and sends motion estimates to the sequence. The sequence then updates its FOV and acquires subsequent partitions with the adjusted FOV, until the next update is received. The sequence was validated without and with intentional motion in phantom and in vivo on a 3T Skyra. RESULTS: For phantom scans, the FOV was updated 0.704 s after acquisition of the vSNav partitions, and for in vivo scans after 0.768 s. Both phantom and in vivo data demonstrated stable motion estimates in the absence of motion. For in vivo acquisitions, prospective head-pose estimates using the vSNav's and retrospective estimates with FLIRT (FMRIB's Linear Image Registration Tool) agreed to within 0.23 mm (< 10% of the slice thickness) and 0.14° in all directions. CONCLUSION: Depending when motion occurs during a volume acquisition, the proposed method fully corrects the FOV and recovers image quality within one volume acquisition.

Stability and change in the interpretation of facial emotions in fetal alcohol spectrum disorders from childhood to adolescence.

BACKGROUND: The ability to identify and interpret facial emotions plays a critical role in effective social functioning, which may be impaired in individuals with fetal alcohol spectrum disorders (FASD). We previously reported deficits in children with fetal alcohol syndrome (FAS) and partial FAS (PFAS) on the "Reading the Mind in the Eyes" (RME) test, which assesses the interpretation of facial emotion. This follow-up study in adolescents was designed to determine whether this impairment persists or represents a developmental delay; to classify the RME stimuli by valence (positive, negative, or neutral) and determine whether RME deficits differ by affective valence; and to explore how components of executive function mediate these associations. METHODS: The RME stimuli were rated and grouped according to valence. Sixty-two participants who had been administered the RME in late childhood (mean ± SD = 11.0 ± 0.4 years) were re-administered this test during adolescence (17.2 ± 0.6 years). Overall and valence-specific RME accuracy was examined in relation to prenatal alcohol exposure (PAE) and FASD diagnosis. RESULTS: Children with FAS (n = 8) and PFAS (n = 15) performed more poorly on the RME than non-syndromal heavily exposed (HE; n = 19) and control individuals (n = 20). By adolescence, the PFAS group performed similarly to HE and controls, whereas the FAS group continued to perform more poorly. No deficits were seen for positively valenced items in any of the groups. For negative and neutral items, in late childhood individuals with FAS and PFAS performed more poorly than HE and controls, but by adolescence only the FAS group continued to perform more poorly. Test-retest reliability was moderate across the two ages. At both timepoints, the effects in the FAS group were partially mediated by Verbal Fluency but not by other aspects of executive function. CONCLUSIONS: Individuals with full FAS have greater difficulty interpreting facial emotions than those with non-syndromal HE and healthy controls in both childhood and adolescence. By contrast, RME deficits in individuals with PFAS in childhood represent developmental delay.

Compromised interhemispheric transfer of information partially mediates cognitive function deficits in adolescents with fetal alcohol syndrome.

BACKGROUND: Prenatal alcohol exposure (PAE) has been associated with compromised interhemispheric transfer of tactile stimuli in childhood and structural changes to the corpus callosum (CC). In this study, we used a finger localization task (FLT) to investigate whether interhemispheric transfer deficits persist in adolescence; whether effects of PAE on perceptual reasoning, working memory, and executive function are mediated by deficits in interhemispheric transfer of information; and whether CC size in childhood predicts FLT performance in adolescence. METHODS: Participants, aged 16 to 17 years, were from the Cape Town Longitudinal Cohort, whose mothers were recruited during pregnancy and interviewed regarding their alcohol use using the timeline follow-back method. Diagnoses of fetal alcohol syndrome (FAS) and partial FAS (PFAS) were determined by two expert dysmorphologists; nonsyndromal exposed children were designated as heavily exposed (HE); those born to abstainers or light drinkers, as controls. The FLT was administered to 74 participants (12 FAS, 16 PFAS, 14 HE and 32 controls). CC size at age 9 to 12 years was available for 35 participants (7 FAS, 13 PFAS, 5 HE and 10 control). RESULTS: Although the degree of PAE was similar in the FAS, PFAS, and HE groups, only the adolescents with FAS showed more transfer-related errors than controls in conditions in which one finger was stimulated. FLT performance mediated the effects of FAS on perceptual reasoning and executive function. In the subsample for which neuroimaging data from childhood were available, there was an association among adolescents with PAE of smaller CC volumes with more transfer-related errors on the one-finger/hand hidden condition, suggesting that CC damage previously seen in childhood continues to impact function through adolescence. CONCLUSIONS: This study provides evidence of compromised interhemispheric transfer of information in adolescents with FAS, while those with PFAS or heavy exposed nonsyndromal individuals are apparently spared. It is the first to show that PAE effects on important aspects of cognitive function are partially mediated by deficits in the interhemispheric transfer of information.

Magnitude comparison and automaticity in number processing in adolescents with prenatal alcohol exposure: An event-related potentials study.

BACKGROUND: Individuals with fetal alcohol spectrum disorders may exhibit a distinct pattern of dysmorphic facial features, growth restriction, and cognitive deficits, particularly in arithmetic. Magnitude comparison, a fundamental element of numerical cognition, is modulated by the numerical distance effect, with numbers closer in value more difficult to compare than those further apart, and by the automaticity of the association of numerical values with their symbolic representations (Arabic numerals). METHODS: We examined event-related potentials acquired during the Numerical Stroop numerical and physical tasks administered to 24 alcohol-exposed adolescents (eight fetal alcohol syndrome (FAS), eight partial FAS (PFAS), eight heavily exposed (HE) nonsyndromal) and 23 typically developing (TD), same- age controls. The distance effect was assessed on the numerical task to examine differences in reaction time (RT) and accuracy when two numbers are close in value (e.g., 1 vs. 2) compared to when the numbers are less close (e.g., 1 vs. 6). Automaticity was assessed in the physical task by examining the degree to which RT and accuracy are reduced when the relative physical size of two numerals is incongruent with their numerical values (e.g., 1 vs. 6). RESULTS: Adolescents in all four groups performed behaviorally as expected on these relatively simple magnitude comparison tasks, but accuracy was poorer and RT was slower on both tasks in the FAS and PFAS than the HE and TD groups. At the neurophysiological level, in the numerical task, a higher level of prenatal alcohol exposure was associated with smaller P2p amplitude. In the physical task, only the TD and nonsyndromal HE groups exhibited the expected smaller P300 amplitude in the incongruent than the congruent condition. CONCLUSIONS: These findings suggest that magnitude comparison in alcohol-exposed individuals may be mediated by recruitment of alternative neural pathways that are likely to be inefficient when number processing becomes more challenging.

Reading impairment in adolescents with fetal alcohol spectrum disorders.

Purpose: To date, research on effects of prenatal alcohol exposure (PAE) has focused on a broad range of cognitive impairments, but relatively few studies have examined effects of PAE on development of reading skills. Although PAE has been linked to poorer reading comprehension, it remains unclear whether this impairment is attributable to deficits in phonological processing, word reading, oral language skills, and/or executive functioning. Methods: A comprehensive reading battery was administered to 10 adolescents with fetal alcohol syndrome (FAS); 16 with partial FAS; 30 nonsyndromal heavily-exposed; 49 controls. Results: PAE was related to poorer reading comprehension but not to single word reading or phonological processing, suggesting that the mechanics of reading are intact in adolescents with fetal alcohol spectrum disorders at this age. PAE-related impairment in reading comprehension was mediated, in part, by deficits in mastery of oral language skills, including vocabulary, language structure, and verbal fluency. Conclusions: These results are consistent with research showing that reading comprehension in adolescence relies increasingly on linguistic comprehension abilities, especially once word reading becomes automatic and text complexity increases. Our findings suggest that reading-impaired adolescents with PAE will benefit from intervention programs targeting vocabulary knowledge, language structure, verbal fluency, and reading comprehension skills.

Motion correction methods for MRS: experts' consensus recommendations.

Long acquisition times due to intrinsically low signal-to-noise ratio and the need for highly homogeneous B0 field make MRS particularly susceptible to motion or scanner instability compared with MRI. Motion-induced changes in both localization and shimming (ie B0 homogeneity) degrade MRS data quality. To mitigate the effects of motion three approaches can be employed: (1) subject immobilization, (2) retrospective correction, and (3) prospective real-time correction using internal and/or external tracking methods. Prospective real-time correction methods can simultaneously update localization and the B0 field to improve MRS data quality. While localization errors can be corrected with both internal (navigators) and external (optical camera, NMR probes) tracking methods, the B0 field correction requires internal navigator methods to measure the B0 field inside the imaged volume and the possibility to update the scanner shim hardware in real time. Internal and external tracking can rapidly update the MRS localization with submillimeter and subdegree precision, while scanner frequency and first-order shims of scanner hardware can be updated by internal methods every sequence repetition. These approaches are most well developed for neuroimaging, for which rigid transformation is primarily applicable. Real-time correction greatly improves the stability of MRS acquisition and quantification, as shown in clinical studies on subjects prone to motion, including children and patients with movement disorders, enabling robust measurement of metabolite signals including those with low concentrations, such as gamma-aminobutyric acid and glutathione. Thus, motion correction is recommended for MRS users and calls for tighter integration and wider availability of such methods by MR scanner manufacturers.

Evolution of the Physical Phenotype of Fetal Alcohol Spectrum Disorders from Childhood through Adolescence.

BACKGROUND: This paper reports findings from the first longitudinal study on the evolution of the physical phenotypes of fetal alcohol syndrome (FAS) and partial FAS (PFAS) from early childhood through adolescence. METHODS: The sample consisted of 155 children (78 males and 77 females) born to women recruited at an antenatal clinic serving a Cape Coloured (mixed ancestry) population in Cape Town, South Africa. Two expert FASD dysmorphologists, blind regarding prenatal alcohol exposure, independently evaluated each child's growth and dysmorphology at 4 clinics conducted over an 11-year period. Case conferences were held to reach consensus regarding which children had FAS or PFAS growth and physical features using the Revised Institute of Medicine (2005) guidelines. RESULTS: The prevalence of the physical phenotype was stable across the 4 ages for about half of the children with FAS and about one-third of those with PFAS but more variable for the others. Test-retest reliability was substantial for the FAS phenotype, but poorer for PFAS. Two distinct patterns were seen: a "strong phenotype" that was consistently identified and a less consistent one in which dysmorphic features and/or anthropometric deficits fluctuated or diminished with age. The physical phenotype was most apparent during early childhood and least apparent during puberty, due to differences in timing of the growth spurt and the evolving adult face. Short palpebral features and small head circumference diminished with age, flat philtrum fluctuated, while thin vermilion and weight and height restriction were stable. CONCLUSIONS: Key facial features that characterize FASD in early childhood diminish or evolve in some individuals, making diagnostic examinations that rely on these characteristics most sensitive during early childhood and school age. Moreover, puberty poses classification problems due to variability in timing of the growth spurt. Given that several features and small head circumference diminished with age, many individuals would be misdiagnosed if only examined at a later age.

Fetal Alcohol Exposure Alters BOLD Activation Patterns in Brain Regions Mediating the Interpretation of Facial Affect.

BACKGROUND: Although deficits in the interpretation of affective facial expressions have been described clinically and in behavioral studies of fetal alcohol spectrum disorders (FASD), effects of prenatal alcohol exposure on the neural networks that mediate affective appraisal have not previously been examined. METHODS: We administered a nonverbal event-related fMRI affective appraisal paradigm to 64 children (mean age = 12.5 years; 18 with fetal alcohol syndrome (FAS) or partial FAS (PFAS), 18 nonsyndromal heavily exposed (HE), and 28 controls). Happy, sad, angry, fearful, and neutral faces and pixelated control images were presented sequentially in a randomized order. The child indicated whether the currently displayed face showed the same or different affect as the previous one. RESULTS: Data from whole-brain analyses showed that all groups activated the appropriate face processing neural networks. Region of interest analyses indicated that, compared to HE and control children, the FAS/PFAS group exhibited greater blood oxygenation level-dependent (BOLD) signal changes when processing neutral faces than pixelated images in 2 regions that form part of the visual sensory social brain network, which plays an important role in the initial processing of facial affect. By contrast, BOLD signal when processing angry faces was weaker for the FAS/PFAS group in a region involved in the processing of facial identity and facial expressions and in a region involved in the recognition and selection of behavioral responses to aggressive behavior. CONCLUSIONS: These findings of greater BOLD signal in the FAS/PFAS group in response to neutral faces suggest less efficient neural processing of more difficult to interpret emotions, and the weaker BOLD response to angry faces suggests altered processing of angry stimuli. Although behavioral performance did not differ in this relatively simple affective appraisal task, these data suggest that in children with FAS and PFAS, the appraisal of neutral affect and anger is likely to be more effortful in more challenging and dynamic social contexts.

Maternal choline supplementation mitigates alcohol exposure effects on neonatal brain volumes.

BACKGROUND: Prenatal alcohol exposure (PAE) is associated with smaller regional and global brain volumes. In rats, gestational choline supplementation mitigates adverse developmental effects of ethanol exposure. Our recent randomized, double-blind, placebo-controlled maternal choline supplementation trial showed improved somatic and functional outcomes in infants at 6.5 and 12 months postpartum. Here, we examined whether maternal choline supplementation protected the newborn brain from PAE-related volume reductions and, if so, whether these volume changes were associated with improved infant recognition memory. METHODS: Fifty-two infants born to heavy-drinking women who had participated in a choline supplementation trial during pregnancy underwent structural magnetic resonance imaging with a multi-echo FLASH protocol on a 3T Siemens Allegra MRI (median age = 2.8 weeks postpartum). Subcortical regions were manually segmented. Recognition memory was assessed at 12 months on the Fagan Test of Infant Intelligence (FTII). We examined the effects of choline on regional brain volumes, whether choline-related volume increases were associated with higher FTII scores, and the degree to which the regional volume increases mediated the effects of choline on the FTII. RESULTS: Usable MRI data were acquired in 50 infants (choline: n = 27; placebo: n = 23). Normalized volumes were larger in six of 12 regions in the choline than placebo arm (t ≥ 2.05, p ≤ 0.05) and were correlated with the degree of maternal choline adherence (ß ≥ 0.28, p ≤ 0.04). Larger right putamen and corpus callosum were related to higher FTII scores (r = 0.36, p = 0.02) with a trend toward partial mediation of the choline effect on recognition memory. CONCLUSIONS: High-dose choline supplementation during pregnancy mitigated PAE-related regional volume reductions, with larger volumes associated with improved 12-month recognition memory. These results provide the first evidence that choline may be neuroprotective against PAE-related brain structural deficits in humans.

Reduced Hippocampal Volumes Partially Mediate Effects of Prenatal Alcohol Exposure on Spatial Navigation on a Virtual Water Maze Task in Children.

BACKGROUND: Prenatal alcohol exposure (PAE) has been linked to poorer performance on the Morris water maze (MWM), a test of spatial navigation in rodents that is dependent on hippocampal functioning. We recently confirmed these findings in children with PAE on a human analog of the MWM, the virtual water maze (VWM). Previous studies have shown that the hippocampus is particularly sensitive to PAE. Our aim was to determine whether hippocampal volume mediates the relation between PAE and virtual navigation. METHODS: VWM and MRI hippocampal data were collected from 50 right-handed 10-year-old children in a heavily exposed Cape Town, South African sample. PAE data had been collected from their mothers during pregnancy, and the children were examined by expert fetal alcohol spectrum disorder (FASD) dysmorphologists. In the VWM, the participant attempts to learn the location of a hidden platform in a virtual pool of water across a series of learning trials using only distal room cues. Hippocampal volumes were derived using FreeSurfer from MRI scans administered within 1 week of completing the VWM task. RESULTS: Both the fetal alcohol syndrome (FAS)/partial FAS and nonsyndromal heavy-exposed (HE) groups had smaller hippocampal volumes than controls. PAE was associated with reduced right hippocampal volumes even after control for total intracranial volume (ICV). Hippocampal volume was also positively associated with VWM performance. The relation between PAE and VWM performance was partially mediated by right hippocampal volume but not by total ICV. CONCLUSIONS: These data confirm previous reports linking PAE to poorer spatial navigation on the VWM and are the first to provide direct evidence that volume reductions in this region partially mediate the relation of FASD diagnosis to place learning, suggesting that PAE specifically impairs the ability to encode the spatial information necessary for successful location of the hidden platform on a navigation task.

Prenatal Alcohol Exposure Alters Error Detection During Simple Arithmetic Processing: An Electroencephalography Study.

BACKGROUND: Arithmetic is the domain of academic achievement most consistently related to prenatal alcohol exposure (PAE). Error detection, an important aspect of arithmetic processing, can be examined in a mathematical verification task. Electroencephalographic (EEG) studies using such tasks have shown bursts of synchronized theta-band activity in response to errors. We assessed this activity for error detection in adolescents with PAE and typically developing (TD) matched controls. We predicted that the PAE group would show smaller theta bursts during error detection and weaker responses depending on the size of the error discrepancy. METHODS: Participants' mothers were recruited during pregnancy and interviewed about their alcohol consumption using a timeline follow-back interview. Participants were followed from infancy and diagnosed for fetal alcohol syndrome (FAS) or partial FAS (PFAS) by expert dysmorphologists. EEGs were recorded for 48 adolescents during a verification task, which required differentiation between correct/incorrect solutions to simple equations; incorrect solutions had small or large deviations from correct solutions. RESULTS: Performance was good-excellent. The PAE group showed lower accuracy than the TD group: Accuracy was inversely related to diagnosis severity. The TD and heavily exposed (HE) nonsyndromal groups showed the expected differentiation in theta-burst activity between correct/incorrect equations, but the FAS/PFAS groups did not. Degree of impairment in brain response to errors reflected severity of diagnosis: The HE group showed the same differentiation between correct/incorrect solutions as TD but failed to differentiate between levels of discrepancy; PFAS showed theta reactions only in response to large error discrepancies; and FAS did not respond to small or large discrepancies. CONCLUSIONS: Arithmetical error-related theta activity is altered by PAE and can be used to distinguish between exposed and nonexposed individuals and within diagnostic groups, supporting the use of numerical and quantitative processing patterns to derive a neurocognitive profile that could facilitate diagnosis and treatment of fetal alcohol spectrum disorders.

Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments.

BACKGROUND: Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. METHODS: DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard-Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. RESULTS: 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. CONCLUSION: Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study.

Real-time simultaneous shim and motion measurement and correction in glycoCEST MRI using double volumetric navigators (DvNavs).

PURPOSE: CEST MRI allows for indirect detection of molecules with exchangeable protons, measured as a reduction in water signal because of continuous transfer of saturated protons. CEST requires saturation pulses on the order of a second, as well as repeated acquisitions at different offset frequencies. The resulting extended scan time makes CEST susceptible to subject motion, which introduces field inhomogeneity, shifting offset frequencies and causing distortions in CEST spectra that resemble true CEST effects. This is a particular problem for molecules that resonate close to water, such as hydroxyl group in glycogen. To address this, a technique for real-time measurement and correction of motion and field inhomogeneity is proposed. METHODS: A CEST sequence was modified to include double volumetric navigators (DvNavs) for real-time simultaneous motion and shim correction. Phantom tests were conducted to investigate the effects of motion and shim changes on CEST quantification and to validate the accuracy of DvNav motion and shim estimates. To evaluate DvNav shim and motion correction in vivo, acquisitions including 5 experimental conditions were performed in the calf muscle of 2 volunteers. RESULTS: Phantom data show that DvNav-CEST accurately estimates frequency and linear gradient changes because of motion and corrects resulting image distortions. In addition, DvNav-CEST improves CEST quantification in vivo in the presence of motion. CONCLUSION: The proposed technique allows for real-time simultaneous motion and shim correction with no additional scanning time, enabling accurate CEST quantification even in the presence of motion and field inhomogeneity.

Spatial Navigation in Children and Young Adults with Fetal Alcohol Spectrum Disorders.

BACKGROUND: Rodent studies have consistently shown that prenatal alcohol exposure (PAE) impairs performance on the Morris water maze (MWM), a test of spatial navigation. A previous study comparing boys with fetal alcohol syndrome (FAS) to controls found poorer performance on the virtual water maze (VWM), a human analogue of the MWM. We examined PAE effects on virtual navigation in both sexes using the VWM in a moderately exposed Detroit cohort (N = 104; mean = 19.4 year) and a heavily exposed Cape Town, South African cohort (N = 62; mean = 10.4 year). METHODS: The task requires the participant to learn the location of a hidden platform in a virtual pool of water. The set of acquisition trials requires the participant to learn the location of the hidden platform and to return to that location repeatedly. The single-probe trial requires the participant to return to that location without knowing that the platform has been removed. RESULTS: No effects of FASD diagnostic group or PAE were detected on virtual navigation in the Detroit moderately exposed cohort. By contrast, in the more heavily exposed Cape Town cohort, the FAS/partial FAS (PFAS) group took longer to locate the hidden platform during acquisition than nonsyndromal heavily exposed (HE) and control groups, an effect that persisted even after controlling for IQ. Among boys, both the FAS/PFAS and HE groups performed more poorly than controls during acquisition, and both boys and girls born to women who binge drank performed more poorly than those born to abstainers/light drinkers. Both amount and frequency of PAE were related to poorer performance during the probe trial at 10 years of age. CONCLUSIONS: These data demonstrate deficits in spatial navigation among heavily exposed syndromal boys and girls and in nonsyndromal exposed boys.

Alcohol-Related Alterations in Placental Imprinted Gene Expression in Humans Mediate Effects of Prenatal Alcohol Exposure on Postnatal Growth.

BACKGROUND: A growing body of evidence in animal models has implicated alcohol-induced alterations in epigenetic programming as an important mechanism in fetal alcohol spectrum disorders (FASD). Imprinted genes, a subset of epigenetically regulated genes that are sensitive to the prenatal environment, are chiefly involved in growth and neurobehavior. We tested the hypothesis that alterations in placental imprinted gene expression mediate fetal alcohol growth restriction. METHODS: Placental expression of 109 genes previously shown to be imprinted and expressed in the placenta was assessed using the NanoString™ nCounter Analysis System in flash-frozen samples from 34 heavy drinkers and 31 control women in Cape Town, South Africa, from whom prospective pregnancy alcohol consumption data had been obtained. Length/height, weight, and head circumference were measured at 6.5 and 12 months and at an FASD diagnostic clinic (at ages 1.1 to 4.6 years) that we organized. Imprinted gene expression between exposed and control placentas was compared using the limma R package. The relation of alcohol exposure to World Health Organization length-for-age z-scores was examined before and after inclusion of expression for each alcohol-related imprinted gene, using hierarchical mixed regression models with repeated measures. RESULTS: Heavy drinkers averaged 8 standard drinks on 2 to 3 days/wk (vs. 0 for controls). Prenatal alcohol exposure was associated with smaller length/height and weight during the postnatal period. Heavy exposure was related to alterations in expression of 11 of 93 expressed imprinted genes, including increased expression of 5 genes found to be negatively associated with growth and decreased expression of 3 genes positively associated with growth. Alcohol-related alterations in expression of 5 genes statistically mediated the effect of prenatal alcohol exposure on length. CONCLUSIONS: These findings identify alcohol-related alterations in placental imprinted gene expression as potential biomarkers of adverse effect in FASD and suggest that these alterations may play a mechanistic role in fetal alcohol growth restriction. Future studies are needed to determine whether alterations in imprinted gene expression also mediate FASD neurobehavioral deficits and whether such alterations are amenable to intervention.

Feasibility and Acceptability of Maternal Choline Supplementation in Heavy Drinking Pregnant Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Choline, an essential nutrient, serves as a methyl-group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies suggest that choline supplementation during pregnancy can mitigate adverse effects of prenatal alcohol exposure on growth and neurocognitive function. We conducted a randomized, double-blind exploratory trial to examine feasibility and acceptability of a choline supplementation intervention during pregnancy. METHODS: Seventy heavy drinkers, recruited in mid-pregnancy, were randomly assigned to receive a daily oral dose of 2 g of choline or a placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape-flavored drink. Adherence was assessed by collecting used and unused drink packets on a monthly basis and tabulating the number used. Side effects were assessed in monthly interviews. Blood samples obtained at enrollment and at 4 and 12 weeks after randomization were assayed for plasma choline concentration. RESULTS: Adherence was good-to-excellent (median doses taken = 74.0%; interquartile range = 53.9 to 88.7%) and was not related to a range of sociodemographic characteristics or to alcohol consumption ascertained using a timeline follow-back interview. By 4 weeks, plasma choline concentrations were significantly higher in the choline supplementation than the placebo arm, and this group difference continued to be evident at 12 weeks. The only side effect was a small increase in nausea/dyspepsia. No effects were seen for diarrhea, vomiting, muscle stiffness, blood pressure, or body odor changes. CONCLUSIONS: This study demonstrated that a choline supplementation program with very heavy drinkers during pregnancy is feasible even among highly disadvantaged, poorly educated women. The broad acceptability of this intervention is indicated by our finding that adherence was not related to maternal education, intellectual function, depression, nutritional status, or alcohol use.

Efficacy of Maternal Choline Supplementation During Pregnancy in Mitigating Adverse Effects of Prenatal Alcohol Exposure on Growth and Cognitive Function: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: We recently demonstrated the acceptability and feasibility of a randomized, double-blind choline supplementation intervention for heavy drinking women during pregnancy. In this study, we report our results relating to the efficacy of this intervention in mitigating adverse effects of prenatal alcohol exposure (PAE) on infant growth and cognitive function. METHODS: Sixty-nine Cape Coloured (mixed ancestry) heavy drinkers in Cape Town, South Africa, recruited in mid-pregnancy, were randomly assigned to receive a daily oral dose of either 2 g of choline or placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape-flavored drink. The primary outcome, eyeblink conditioning (EBC), was assessed at 6.5 months. Somatic growth was measured at birth, 6.5, and 12 months, recognition memory and processing speed on the Fagan Test of Infant Intelligence, at 6.5 and 12 months. RESULTS: Infants born to choline-treated mothers were more likely to meet criterion for conditioning on EBC than the placebo group. Moreover, within the choline arm, degree of maternal adherence to the supplementation protocol strongly predicted EBC performance. Both groups were small at birth, but choline-treated infants showed considerable catch-up growth in weight and head circumference at 6.5 and 12 months. At 12 months, the infants in the choline treatment arm had higher novelty preference scores, indicating better visual recognition memory. CONCLUSIONS: This exploratory study is the first to provide evidence that a high dose of choline administered early in pregnancy can mitigate adverse effects of heavy PAE on EBC, postnatal growth, and cognition in human infants. These findings are consistent with studies of alcohol-exposed animals that have demonstrated beneficial effects of choline supplementation on classical conditioning, learning, and memory.