Neurobehavioral outcomes of neonatal asymptomatic congenital cytomegalovirus infection at 12-months.

BACKGROUND: Congenital cytomegalovirus (cCMV) is the most common congenital viral infection in the United States. Symptomatic infections can cause severe hearing loss and neurological disability, although ~ 90% of cCMV infections are asymptomatic at birth. Despite its prevalence, the long-term neurobehavioral risks of asymptomatic cCMV infections are not fully understood. The objective of this work was to evaluate for potential long-term neurobehavioral sequelae in infants with asymptomatic cCMV. METHODS: Infants with cCMV were identified from a universal newborn cCMV screening study in a metropolitan area in the midwestern United States. Asymptomatic infants with cCMV were enrolled in a longitudinal neurodevelopmental study (N = 29). Age- and sex-matched healthy control infants (N = 193) were identified from the Baby Connectome Project (BCP), a longitudinal study of brain and behavioral development. The BCP sample supplemented an additional group of healthy control infants (N = 30), recruited from the same participant registry as the BCP specifically for comparison with infants with asymptomatic cCMV. Neurobehavioral assessments and parent questionnaires, including the Mullen Scales of Early Learning, the Repetitive Behavior Scales for Early Childhood (RBS-EC), and the Infant Toddler Social Emotional Assessment (ITSEA) were administered at 12 months of age. Neurobehavioral scores were compared between infants with asymptomatic cCMV and all identified healthy control infants. RESULTS: Infants with asymptomatic cCMV performed equivalently compared to healthy control infants on the neurobehavioral measures tested at 12 months of age. CONCLUSIONS: These results indicate that at 12 months of age, infants with asymptomatic cCMV are not statistically different from controls in a number of neurobehavioral domains. Although follow-up is ongoing, these observations provide reassurance about neurobehavioral outcomes for infants with asymptomatic cCMV and inform the ongoing discussion around universal screening. Additional follow-up will be necessary to understand the longer-term outcomes of these children.

Preterm infant body composition, working memory, and temperament.

Altered body composition in preterm infants is associated with risks to cognitive development, but the effect specific to prefrontal cortex (PFC) development is unknown. We were interested in the impact of fat mass (FM) and fat free mass (FFM) gains out to 4 months corrected gestational age (CGA) on PFC development, as indexed by working memory and temperament. This is a prospective observational pilot study recruiting 100 preterm (<33 weeks gestation), appropriate for gestational age, and very low birth weight infants, of which 49 infants met inclusion criteria. Body composition was measured using air displacement plethysmography at hospital discharge and 4 months CGA. Questionnaire based temperament assessments were completed at 12 and 24 months CGA and a working memory assessment was completed at 24 months CGA. Associations between developmental tests and body composition obtained at term and 4 months were analyzed. Increased FM at discharge was associated with increased fear and decreased soothability at 12 months. Increased FM at 4 months was associated with increased activity level, increased distress from limitations at 12 months and decreased attentional shifting, decreased frustration, and decreased inhibitory control at 24 months. Increased FFM at 4 months was associated with increased activity level at 12 months and increased impulsivity and decreased low intensity pleasure at 24 months. In this exploratory pilot study, increased FM out to 4 months and increased FFM after discharge are associated with negative markers of infant temperament. Infant temperament may be sensitive to body composition status at least to 4 months CGA.

Randomized Trial of Early Enhanced Parenteral Nutrition and Later Neurodevelopment in Preterm Infants.

Retrospective studies indicate that the parenteral provision of calories, proteins, and lipids in the first week of life is associated with improved later neurodevelopment. We aimed to determine whether infants randomized to an enhanced parenteral nutrition protocol had improved developmental outcomes at 4, 12, or 24 months corrected age (CA). In total, 90 preterm infants (<32 weeks gestational age and <1500 g) were randomized to receive enhanced parenteral nutrition (PN) or standard PN during the first week of life. The enhanced group received a higher glucose infusion rate and intralipids. Neurodevelopmental outcomes included pattern-reversal visually evoked potentials (VEP) at 4 months CA (n = 33) and the Bayley Scales of Infant Development (BSID) at 12 (n = 46) and 24 (n = 29) months CA. P100 latency was longer in the intervention group, indicating slower processing speed (145 vs. 178 ms, p = 0.01). This association did not hold in multivariable analysis adjusting for potentially confounding variables. BSID scores were not associated with enhanced PN. Higher enteral energy and protein intake regardless of randomization group were associated with faster processing speed at 4 months CA (p ≤ 0.02 for both). Enhanced early PN was not associated with improved neurodevelopment; however, first-week enteral caloric and protein intake were associated with improved speed of processing.

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.

Infants exposed to antibiotics after birth have altered recognition memory responses at one month of age.

BACKGROUND: Neonatal exposure to antibiotics, in the absence of infection, results in abnormal learning and memory in animals and is linked to changes in gut microbes. The relevance of early-life antibiotic exposure to brain function in humans is not known. METHODS: Recognition memory was assessed at 1 month of age in 15 term-born infants exposed to antibiotics (with negative cultures) and 57 unexposed infants using event-related potentials (ERPs). Linear regression analysis, adjusting for covariates, was employed to compare groups with respect to ERP features representing early stimulus processing (P2 amplitude) and discrimination between mother and stranger voices. RESULTS: Infants exposed to antibiotics exhibited smaller P2 amplitudes for both voice conditions (p = 0.001), with greatest reductions observed for mother's voice in frontal and central scalp regions (p < 0.04). Infants exposed to antibiotics showed larger P2 amplitudes to stranger's as compared to mother's voice, a reversal of the typical response exhibited by unexposed infants. Abnormal ERP responses did not consistently correlate with increased inflammatory cytokines within the antibiotic-exposed group. CONCLUSIONS: Otherwise healthy infants exposed to antibiotics soon after birth demonstrated altered auditory processing and recognition memory responses, supporting the possibility of a microbiota-gut-brain axis in humans during early life. IMPACT: Infants exposed to antibiotics after birth demonstrate altered auditory processing and recognition memory responses at 1 month of age. Preclinical models support a role for gut microbiomes in modulating brain function and behavior, particularly in developing brains. This study is one of the first to explore the relevance of these findings for human infants. The findings of this study have implications for the management and follow-up of at-risk infants with exposure to gut-microbiome disrupting factors and lay foundation for future studies to further characterize the short- and long-term effects of gut microbiome perturbation on brain development.

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.

Toenail manganese as a potential biomarker for in utero and early childhood exposure studies.

Elevated in utero and early childhood exposure to manganese may have adverse effects on neurodevelopment. We conducted preliminary analyses to evaluate toenails as a matrix for investigating manganese exposure in infants. Infant and maternal toenail and hair samples were collected from 25 infants (7 months old) and their mothers. A subset of mothers was recruited in the third trimester of pregnancy and some also provided pre-natal toenail, hair, and blood samples, cord blood, and additional post-natal samples. Collected samples were analyzed by inductively coupled plasma mass-spectrometry. Toenail manganese levels in infants ranged from below the limit of detection (LOD) to 2.80 µg/g. Only 1 toenail sample and 4 hair samples contained levels of manganese below LOD. Associations between infant and maternal biomarkers were not statistically significant. Analysis of multiple post-natal toenail samples from a single infant-mother pair showed an increase in the infant's toenail manganese and a decrease in maternal toenail manganese over the first year of the infant's life. Overall, our findings suggest that toenails may serve as a valuable biological matrix for measuring manganese exposure in newborns and infants; however, additional studies are needed to determine the impact of the timing of toenail sample collection on its utility in assessing early life exposure and health outcomes.

Early body composition changes are associated with neurodevelopmental and metabolic outcomes at 4 years of age in very preterm infants.

BACKGROUND: Very preterm (VPT) infants are at-risk for altered growth, slower speed of processing (SOP), and hypertension. This study assesses the relationship between postnatal body composition (BC), neurodevelopment (indexed by SOP), and blood pressure (BP) in VPT infants. METHODS: Thirty-four VPT infants underwent weekly measurements and BC testing until discharge and post-discharge at 4 mos CGA and 4 yrs. At post-discharge visits, SOP was assessed using visual evoked potentials and the NIH Toolbox; BP was also measured. RESULTS: In-hospital rate of weight, length and fat-free mass (FFM) gains were associated with faster SOP at 4 yrs. Higher rate of gains in weight and FFM from discharge to 4 mos CGA were associated with faster SOP at 4 mos CGA, while higher fat mass (FM) gains during the same time were positively associated with BP at 4 yrs. BC at 4 yrs nor gains beyond 4 mos CGA were associated with outcomes. CONCLUSIONS: In VPT infants, early FFM gains are associated with faster SOP, whereas post-discharge FM gains are associated with higher BPs at 4 yrs. This shows birth to 4 mos CGA is a sensitive period for growth and its relation to neurodevelopmental and metabolic outcomes. Close monitoring and early nutritional adjustments to optimize quality of gains may improve outcomes.

ERP evidence of preserved early memory function in term infants with neonatal encephalopathy following therapeutic hypothermia.

BACKGROUND: Neonatal encephalopathy (NE) carries high risk for neurodevelopmental impairments. Therapeutic hypothermia (TH) reduces this risk, particularly for moderate encephalopathy (ME). Nevertheless, these infants often have subtle functional deficits, including abnormal memory function. Detection of deficits at the earliest possible time-point would allow for intervention during a period of maximal brain plasticity. METHODS: Recognition memory function in 22 infants with NE treated with TH was compared to 23 healthy controls using event-related potentials (ERPs) at 2 wk of age. ERPs were recorded to mother's voice alternating with a stranger's voice to assess attentional responses (P2), novelty detection (slow wave), and discrimination between familiar and novel (difference wave). Development was tested at 12 mo using the Bayley Scales of Infant Development, Third Edition (BSID-III). RESULTS: The NE group showed similar ERP components and BSID-III scores to controls. However, infants with NE showed discrimination at midline leads (P = 0.01), whereas controls showed discrimination in the left hemisphere (P = 0.05). Normal MRI (P = 0.05) and seizure-free electroencephalogram (EEG) (P = 0.04) correlated positively with outcomes. CONCLUSION: Infants with NE have preserved recognition memory function after TH. The spatially different recognition memory processing after early brain injury may represent compensatory changes in the brain circuitry and reflect a benefit of TH.

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.

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.

Exploratory study of the relationship of fat-free mass to speed of brain processing in preterm infants.

BACKGROUND: Preterm infants are at risk for long-term neurodevelopmental impairment as a function of postnatal nutritional status. Despite adequate neonatal weight gain, preterm infants have altered body composition, with lower fat-free mass (FFM) and higher adiposity at term corrected gestational age (CGA) than their term counterparts. The relationship between postnatal body composition and speed of brain processing in preterm infants is unknown. METHODS: Anthropometric measurements and body composition testing via air displacement plethysmography were performed on 16 appropriate-for-gestational age (GA) preterm (mean GA: 30.4 ± 2.8 wk) infants at term and 4 mo CGA. Infant visual pathway development was assessed at 4 mo CGA using pattern-reversal visual evoked potential (VEP); P100 (positive peak) latency was used to index neuronal speed of processing. RESULTS: Increased FFM at discharge (P = 0.02) and 4 mo CGA (P = 0.006) was associated with shorter latencies to the P100 peak. P100 latency was not related to total body weight, fat mass, or body fat percentage. CONCLUSION: FFM reflects protein accretion and indexes growth of organs, including the brain. The association of shorter VEP latency (i.e., faster neuronal processing) with higher FFM (i.e., better protein status) may be attributed to the positive effects of protein status on neuronal growth and differentiation.

Electrophysiological indices of memory for temporal order in early childhood: implications for the development of recollection.

The ability to recall contextual details associated with an event begins to develop in the first year of life, yet adult levels of recall are not reached until early adolescence. Dual-process models of memory suggest that the distinct retrieval process that supports the recall of such contextual information is recollection. In the present investigation, we used both behavioral and electrophysiological measures to assess the development of memory for contextual details, as indexed by memory for temporal order, in early childhood. Results revealed age-related improvements in memory for temporal order despite similar levels of memory for the individual items themselves. Furthermore, this pattern of recall was associated with specific components in the electrophysiological response. Consistent with electrophysiological research in adults, distributed, positive-going activity late in the waveform was associated with increases in recall of contextual details and the development of recollective processes.

Consequences of low neonatal iron status due to maternal diabetes mellitus on explicit memory performance in childhood.

Diabetic pregnancies are characterized by chronic metabolic insults, including iron deficiency, that place the developing brain at risk for memory impairment later in life. A behavioral recall paradigm coupled with electrophysiological measures was used to assess the longevity of these effects in 40 3(1/2)-year-old children. When memory demands were high, recall was significantly impaired in the at-risk group and correlated with perinatal measures of iron. Electrophysiological results suggested both encoding and retrieval processes were compromised. These findings support the hypothesis that prenatal iron deficiency leads to alterations in neural development that have a lasting impact on memory ability.