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Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic–pituitary–adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress‐inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI‐exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG/S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age. [ABSTRACT FROM AUTHOR]

Exposure to pain‐related stress from frequent invasive procedures in the neonatal intensive care unit (NICU) has been associated with altered physiological stress regulation, neurodevelopment, and behavior in children born very preterm (≤32 weeks gestation). Previously, in a cohort born 2003–2006 (Cohort 1), we found that, at 18 months corrected age (CA), children born extremely low gestational age (ELGA; 24–28 weeks) and very low gestational age (VLGA; 29–32 weeks), had higher pre‐test cortisol levels and a different pattern of cortisol output across a developmental assessment involving cognitive challenge compared to children born full‐term (FT; 39–41 weeks). Also, greater neonatal pain‐related stress exposure among the preterm children was related to higher pre‐test cortisol levels. Given the adverse long‐term effects of neonatal pain in preterm infants and the ensuing rise in clinical concerns to appropriately manage pain in the NICU in recent years, we aimed to examine whether our findings from Cohort 1 would still be evident in an independent cohort (Cohort 2) born 2006–2011 and recruited from the same tertiary NICU in Vancouver, Canada. We also compared the cortisol patterns, clinical and socio‐demographic factors, and their interrelationships between the two cohorts. In Cohort 2, our findings using multi‐level modeling support and extend our earlier findings in Cohort 1, demonstrating that children born ELGA display higher pre‐test cortisol levels than FT. As well, greater cortisol output across assessment was related to more anxiety/depressive behaviors in children born VLGA. Importantly, children born ELGA were exposed to less neonatal pain/stress, mechanical ventilation, and morphine in Cohort 2 than Cohort 1. In both cohorts, however, cortisol levels and patterns were related to neonatal pain/stress and clinical factors (days on mechanical ventilation, overall morphine exposure). Despite less exposure to pain/stress and adverse clinical factors in Cohort 2 compared to Cohort 1, cortisol levels and patterns across cognitive challenge in preterm children at 18‐month CA were consistent across the two independent cohorts. These findings highlight that, despite improvements to neonatal care, children born extremely preterm continue to display altered HPA axis activity, which is associated with their poorer neurodevelopmental and behavioral outcomes. [ABSTRACT FROM AUTHOR]

To predict adverse neurodevelopmental outcome of very preterm neonates. A total of 166 preterm neonates born between 24–32 weeks' gestation underwent brain MRI early in life. Radiomics features were extracted from T1- and T2- weighted images. Motor, cognitive, and language outcomes were assessed at a corrected age of 18 and 33 months and 4.5 years. Elastic Net was implemented to select the clinical and radiomic features that best predicted outcome. The area under the receiver operating characteristic (AUROC) curve was used to determine the predictive ability of each feature set. Clinical variables predicted cognitive outcome at 18 months with AUROC 0.76 and motor outcome at 4.5 years with AUROC 0.78. T1-radiomics features showed better prediction than T2-radiomics on the total motor outcome at 18 months and gross motor outcome at 33 months (AUROC: 0.81 vs 0.66 and 0.77 vs 0.7). T2-radiomics features were superior in two 4.5-year motor outcomes (AUROC: 0.78 vs 0.64 and 0.8 vs 0.57). Combining clinical parameters and radiomics features improved model performance in motor outcome at 4.5 years (AUROC: 0.84 vs 0.8). Radiomic features outperformed clinical variables for the prediction of adverse motor outcomes. Adding clinical variables to the radiomics model enhanced predictive performance. [ABSTRACT FROM AUTHOR]

Preterm infants are at risk for adverse neurodevelopmental outcomes, especially language delay. Preterm infants < 29 weeks' gestational age, cared for in Canadian Neonatal Follow-Up Network affiliated hospitals, were assessed between 18 to 21 months corrected age using the Bayley-III. Bayley-III Language Composite Scores were compared using univariate and multivariate analyses for children in three primary language groups: English, French and other. 6146 children were included. The primary language at home was English, French or another language for 3708 children (60%), 1312 children (21%) and 1126 children (18%), respectively, and overall, 44% were exposed to two or more languages at home. Univariate analysis showed that primary language was associated with lower Bayley-III Language scores; however, multivariate analyses demonstrated that neither primary language nor language of administration were significantly associated with lower language scores when adjusted for gestational age, other developmental delays and sociodemographic factors, but multiple language exposure was. Sociodemographic and other factors are more important in determining language development than primary language at home. Further studies are needed to examine the association between exposure to multiple languages and lower Bayley-III language scores in preterm infants. [ABSTRACT FROM AUTHOR]

Objectives: To assess the association of head circumference (HC) <10th percentile at birth and discharge from the neonatal intensive care unit (NICU) with neurodevelopment in very preterm (24-32 weeks' gestational age) neonates, and to compare the association of HC and total cerebral volume (TCV) with neurodevelopmental outcomes.Design: In a prospective cohort, semiautomatically segmented TCV and manually segmented white matter injury (WMI) volumes were obtained. Multivariable regressions were used to study the association of HC and TCV with neurodevelopmental outcomes, accounting for birth gestational age, WMI and postnatal illness.Setting: Participants born in 2006-2013 at British Columbia Women's Hospital were recruited.Patients: 168 neonates had HC measurements at birth and discharge and MRI at term-equivalent age (TEA). 143 children were assessed at 4.5 years.Main Outcome Measures: Motor, cognitive and language outcomes at 4.5 years were assessed using the Movement Assessment Battery for Children Second Edition (M-ABC) and Wechsler Preschool and Primary Scale of Intelligence Third Edition Full Scale IQ (FSIQ) and Verbal IQ (VIQ).Results: Small birth HC was associated with lower M-ABC and FSIQ scores. In children with small birth HC, small discharge HC was associated with lower M-ABC, FSIQ and VIQ scores, while normal HC at discharge was no longer associated with adverse outcomes. HC strongly correlated with TCV at TEA. TCV did not correlate with outcomes.Conclusions: Small birth HC is associated with poorer neurodevelopment, independent of postnatal illness and WMI. Normalisation of HC during NICU care appears to moderate this risk. [ABSTRACT FROM AUTHOR]

Objective: To examine whether the family integrated care (FICare) programme, a multifaceted approach which enables parents to be engaged as primary caregivers in the neonatal intensive care unit, impacts infant neurodevelopment and growth at 18 months' corrected age.Design/methods: Prospective cohort study of infants born <29 weeks' gestational age (GA) who participated in the FICare cluster randomised control trial (cRCT) and were assessed in the Canadian Neonatal Follow-Up Network (CNFUN). The primary outcome measure, Cognitive or Language composite score <85 on the Bayley-III, was compared between FICare exposed and routine care children using logistic regression, adjusted for potential confounders and employing generalised estimation equations to account for clustering of infants within sites.Results: Of 756 infants <29 weeks' GA in the FICare cRCT, 505 were enrolled in CNFUN and 455 were assessed (238 FICare, 217 control). Compared with controls, FICare infants had significantly higher incidence of intraventricular haemorrhage (IVH) (19.5% vs 11.7%, p=0.024) and higher proportion of employed mothers (76.6% vs 73.6%, p=0.043). There was no significant difference in the odds of the primary outcome (adjusted OR: 0.92 (0.59 to 1.42) FiCare vs Control) on multivariable analyses adjusted for GA, IVH and maternal employment. However, Bayley-III Motor scores (adjusted difference in mean (95% CI) 3.87 (1.22 to 6.53) and body mass index 0.67 (0.36 to 0.99) were higher in the FICare group.Conclusions: Very preterm infants exposed to FICare had no significant difference in incidence of cognitive or language delay but had better motor development.Trial Registration Number: Participants in this cohort study were previously enrolled in a registered trial: NCT01852695. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to determine how preterm white matter injury (WMI) and long‐term thalamic growth interact to predict 8‐year neurodevelopmental outcomes. Methods: A prospective cohort of 114 children born at 24 to 32 weeksʼ gestational age (GA) underwent structural and diffusion tensor magnetic resonance imaging early in life (median 32 weeks), at term‐equivalent age and at 8 years. Manual segmentation of neonatal WMI was performed on T1‐weighted images and thalamic volumes were obtained using the MAGeT brain segmentation pipeline. Cognitive, motor, and visual‐motor outcomes were evaluated at 8 years of age. Multivariable regression was used to examine the relationship among neonatal WMI volume, school‐age thalamic volume, and neurodevelopmental outcomes. Results: School‐age thalamic volumes were predicted by neonatal thalamic growth rate, GA, sex, and neonatal WMI volume (p < 0.0001). After accounting for total cerebral volume, WMI volume remained associated with school‐age thalamic volume (β = −0.31, p = 0.005). In thalamocortical tracts, fractional anisotropy (FA) at term‐equivalent age interacted with early WMI volume to predict school‐age thalamic volumes (all p < 0.02). School‐age thalamic volumes and neonatal WMI interacted to predict full‐scale IQ (p = 0.002) and adverse motor scores among those with significant WMI (p = 0.01). Visual‐motor scores were predicted by thalamic volumes (p = 0.04). Interpretation: In very preterm‐born children, neonatal thalamic growth and WMI volume predict school‐age thalamic volumes. The emergence at term of an interaction between FA and WMI to impact school‐age thalamic volume indicates dysmaturation as a mechanism of thalamic growth failure. Cognition is predicted by the interaction of WMI and thalamic growth, highlighting the need to consider multiple dimensions of brain injury in these children. ANN NEUROL 2021;90:584–594 [ABSTRACT FROM AUTHOR]

Prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants may influence white matter (WM) development, as previous studies report widespread microstructural alterations and reduced interhemispheric connectivity in SSRI‐exposed infants. In rodents, perinatal SSRIs had sex‐specific disruptions in corpus callosum (CC) axon architecture and connectivity; yet it is unknown whether SSRI‐related brain outcomes in humans are sex specific. In this study, the neonate CC was selected as a region‐of‐interest to investigate whether prenatal SSRI exposure has sex‐specific effects on early WM microstructure. On postnatal day 7, diffusion tensor imaging was used to assess WM microstructure in SSRI‐exposed (n = 24; 12 male) and nonexposed (n = 48; 28 male) term‐born neonates. Fractional anisotropy was extracted from CC voxels and a multivariate discriminant analysis was used to identify latent patterns differing between neonates grouped by SSRI‐exposure and sex. Analysis revealed localized variations in CC fractional anisotropy that significantly discriminated neonate groups and correctly predicted group membership with an 82% accuracy. Such effects were identified across three dimensions, representing sex differences in SSRI‐exposed neonates (genu, splenium), SSRI‐related effects independent of sex (genu‐to‐rostral body), and sex differences in nonexposed neonates (isthmus‐splenium, posterior midbody). Our findings suggest that CC microstructure may have a sex‐specific, localized, developmental sensitivity to prenatal SSRI exposure. [ABSTRACT FROM AUTHOR]

Children born preterm display altered sensory processing, which may manifest as hyper‐ and/or hypo‐sensitivity to sensory information. In this vulnerable population, exposure to neonatal pain‐related stress is associated with altered stress regulation, as indexed by alterations in cortisol levels. It is unknown whether sensory processing behaviors are also affected by early life adversity, and whether dysregulated cortisol is related to sensory processing problems in preterm children. We examined relationships between neonatal pain‐related stress, sensory processing profiles and cortisol levels at age 4 years, and whether pathways were sex‐specific. In a longitudinal prospective cohort study, N = 146 infants born 24–32 weeks gestational age were recruited from BC Women's Hospital, Vancouver, BC, Canada; neonatal factors were collected from daily chart review. At age 4 years, saliva to assay cortisol was collected three times across cognitive assessment (pre‐test, during, end) and parents completed the Short Sensory Profile questionnaire. Using generalized linear modeling, independent of other neonatal factors, higher number of invasive procedures (pain/stress) was associated with more sensory processing problems (total, hypo‐ and hyper‐sensitivity) for girls only. After accounting for neonatal factors, greater cortisol output across the assessment was associated with more total sensory processing problems in girls only, and hypersensitivity to sensory input in both boys and girls. Findings suggest that in children born very preterm, how a child responds to sensory input and cortisol reactivity to stress are related but may have different precursors. Girls may be somewhat more susceptible to neonatal pain‐related stress exposure in relation to sensory processing at preschool age. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between cerebellar hemorrhage (CBH) size and location and preschool-age neurodevelopment in very preterm neonates.Methods: Preterm magnetic resonance images of 221 very preterm neonates (median gestational age = 27.9 weeks) were manually segmented for CBH quantification and location. Neurodevelopmental assessments at chronological age 4.5 years included motor (Movement Assessment Battery for Children, 2nd Edition [MABC-2]), visuomotor integration (Beery-Buktenica Developmental Test of Visual-Motor Integration, 6th Edition), cognitive (Wechsler Primary and Preschool Scale of Intelligence, 3rd Edition), and behavioral (Child Behavior Checklist) outcomes. Multivariable linear regression models examined the association between CBH size and 4.5-year outcomes accounting for sex, gestational age, and supratentorial injury. Probabilistic maps assessed CBH location and likelihood of a lesion to predict adverse outcome.Results: Thirty-six neonates had CBH: 14 (6%) with only punctate CBH and 22 (10%) with ≥1 larger CBH. CBH occurred mostly in the inferior aspect of the posterior lobes. CBH total volume was independently associated with MABC-2 motor scores at 4.5 years (β = -0.095, 95% confidence interval = -0.184 to -0.005), with a standardized β coefficient (-0.16) that was similar to that of white matter injury volume (standardized β = -0.22). CBH size was similarly associated with visuomotor integration and externalizing behavior but not cognition. Voxelwise odds ratio and lesion-symptom maps demonstrated that CBH extending more deeply into the cerebellum predicted adverse motor, visuomotor, and behavioral outcomes.Interpretation: CBH size and location on preterm magnetic resonance imaging were associated with reduced preschool motor and visuomotor function and more externalizing behavior independent of supratentorial brain injury in a dose-dependent fashion. The volumetric quantification and localization of CBH, even when punctate, may allow opportunity to improve motor and behavioral outcomes by providing targeted intervention. ANN NEUROL 2020;88:1095-1108. [ABSTRACT FROM AUTHOR]

Evidence indicates better cognitive and behavioral outcomes for females born very preterm (≤32 weeks gestation) compared to males, but the neurophysiology underlying this apparent resiliency of the female brain remains poorly understood. Here we test the hypothesis that very preterm males express more pronounced connectivity alterations as a reflection of higher male vulnerability. Resting state MEG recordings, neonatal and psychometric data were collected from 100 children at age 8 years: very preterm boys (n = 27), very preterm girls (n = 34), full‐term boys (n = 15) and full‐term girls (n = 24). Neuromagnetic source dynamics were reconstructed from 76 cortical brain regions. Functional connectivity was estimated using inter‐regional phase‐synchronization. We performed a series of multivariate analyses to test for differences across groups as well as to explore relationships between deviations in functional connectivity and psychometric scores and neonatal factors for very preterm children. Very preterm boys displayed significantly higher (p <.001) absolute deviation from average connectivity of same‐sex full‐term group, compared to very preterm girls versus full‐term girls. In the connectivity comparison between very preterm and full‐term groups separately for boys and girls, significant group differences (p <.05) were observed for boys, but not girls. Sex differences in connectivity (p <.01) were observed in very preterm children but not in full‐term groups. Our findings indicate that very preterm boys have greater alterations in resting neurophysiological network communication than girls. Such uneven brain communication disruption in very preterm boys and girls suggests that stronger connectivity alterations might contribute to male vulnerability in long‐term behavioral and cognitive outcome. [ABSTRACT FROM AUTHOR]

Aim: To determine concurrent validity between the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III) and the Peabody Developmental Motor Scales, 2nd edition (PDMS-2). Methods: Both assessments were administered to 184 preterm children at 18 months corrected age; standard scores for total score, gross motor, and fine motor were calculated for each child. Cross-tabulation and Pearson correlation coefficient (r) determined concurrent validity between the Bayley-III and the PDMS-2 motor domains. Results: High correlations were found between total motor (r = 0.88), gross motor (r = 0.88), and fine motor scores (r = 0.79). Both assessments had 93% agreement on classification for motor impairment; 23 children were identified by both assessments as having motor impairments, but 12 children were identified differently on each assessment (7 as impaired on PDMS-2 but average on Bayley-III; 5 as impaired on Bayley-III but average on PDMS-2). Most children with motor impairments were identified as 1SD below the mean on the PDMS-2 (27/30) and Bayley-III (18/28); however, the Bayley-III identified more children 2SD below the mean (10/28) compared to the PDMS-2 (3/30). Conclusions: Both the Bayley-III and PDMS-2 identify motor delays in children; however, clinicians should be aware of the concurrent validity as each assessment may lead to differing results. [ABSTRACT FROM AUTHOR]

Background: Children born very preterm often display selective cognitive difficulties at school age even in the absence of major brain injury. Alterations in neurophysiological activity underpinning such difficulties, as well as their relation to specific aspects of adverse neonatal experience, remain poorly understood. In the present study, we examined interregional connectivity and spectral power in very preterm children at school age, and their relationship with clinical neonatal variables and long‐term outcomes (IQ, executive functions, externalizing/internalizing behavior, visual‐motor integration). Methods: We collected resting state magnetoencephalographic (MEG) and psychometric data from a cohort at the age of 8 years followed prospectively since birth, which included three groups: Extremely Low Gestational Age (ELGA, 24–28 weeks GA n = 24, age 7.7 ± 0.38, 10 girls), Very Low Gestational Age (VLGA, 29–32 weeks GA n = 37, age 7.7 ± 0.39, 24 girls), and full‐term children (38–41 weeks GA n = 39, age 7.9 ± 1.02, 24 girls). Interregional phase synchrony and spectral power were tested for group differences, and associations with neonatal and outcome variables were examined using mean‐centered and behavioral Partial Least Squares (PLS) analyses, respectively. Results: We found greater connectivity in the theta band in the ELGA group compared to VLGA and full‐term groups, primarily involving frontal connections. Spectral power analysis demonstrated overall lower power in the ELGA and VLGA compared to full‐term group. PLS indicated strong associations between neurophysiological connectivity at school age, adverse neonatal experience and cognitive performance, and behavior. Resting spectral power was associated only with behavioral scores. Conclusions: Our findings indicate significant atypicalities of neuromagnetic brain activity and connectivity in very preterm children at school age, with alterations in connectivity mainly observed only in the ELGA group. We demonstrate a significant relationship between connectivity, adverse neonatal experience, and long‐term outcome, indicating that the disruption of developing neurophysiological networks may mediate relationships between neonatal events and cognitive and behavioral difficulties at school age. [ABSTRACT FROM AUTHOR]

Background: Prenatal maternal depression (PMD) and selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with increased developmental risk in infants. Reports suggest that PMD is associated with hyperconnectivity of the insula and the amygdala, while SSRI exposure is associated with hyperconnectivity of the auditory network in the infant brain. However, associations between functional brain organization and PMD and/or SSRI exposure are not well understood.Methods: We examined the relation between PMD or SSRI exposure and neonatal brain functional organization. Infants of control (n = 17), depressed SSRI-treated (n = 20) and depressed-only (HAM-D ≥ 8) (n = 16) women, underwent resting-state functional magnetic resonance imaging at postnatal Day 6. At 6 months, temperament was assessed using Infant Behavioral Questionnaire (IBQ). We applied GTA and partial least square regression (PLSR) to the resting-state time series to assess group differences in modularity, and connector and provincial hubs.Results: Modularity was similar across all groups. The depressed-only group showed higher connector hub values in the left anterior cingulate, insula, and caudate as well as higher provincial hub values in the amygdala compared to the control group. The SSRI group showed higher provincial hub values in Heschl's gyrus relative to the depressed-only group. PLSR showed that newborns' hub values predicted 10% of the variability in infant temperament at 6 months, suggesting different developmental patterns between groups.Conclusions: Prenatal exposures to maternal depression and SSRIs have differential impacts on neonatal functional brain organization. Hub values at 6 days predict variance in temperament between infant groups at 6 months of age. [ABSTRACT FROM AUTHOR]

Altered hippocampal morphology and reduced volumes have been found in children born preterm compared to full-term. Stress inhibits neurogenesis in the hippocampus, and neonatal stress/noxious stimulation in rodent pups are associated with long-term alterations in hippocampal volumes. We have previously shown reduced cortical thickness and cerebellar volumes in relation to more exposure to pain-related stress of neonatal invasive procedures in children born very preterm. We have reported targeted gene-by-pain environment interactions that contribute to long-term brain development and outcomes in this population. We now aim to determine whether exposure to pain-related stress (adjusted for clinical factors and genotype) differentially impacts regional structures within the limbic system and thalamus, and investigate relationships with outcomes in very preterm children. Our study included 57 children born very preterm (<32 weeks GA) followed longitudinally from birth who underwent 3-D T1 MRI neuroimaging at ∼8 years. Hippocampal subfields and white matter tracts, thalamus and amygdala were automatically segmented using the MAGeT Brain algorithm. The relationship between those subcortical brain volumes (adjusted for total brain volume) and neonatal invasive procedures, gestational age (GA), illness severity, postnatal infection, days of mechanical ventilation, number of surgeries, morphine exposure, and genotype (COMT, SLC6A4 , and BDNF) was examined using constrained principal component analysis. We found that neonatal clinical factors and genotypes accounted for 46% of the overall variance in volumes of hippocampal subregions, tracts, basal ganglia, thalamus and amygdala. After controlling for clinical risk factors and total brain volume, greater neonatal invasive procedures was associated with lower volumes in the amygdala and thalamus (p = 0.0001) and an interaction with COMT genotype predicted smaller hippocampal subregional volume (p = 0.0001). More surgeries, days of ventilation, and lower GA were also related to smaller volumes in various subcortical regions (p < 0.002). These reduced volumes were in turn differentially related to poorer cognitive, visual-motor and behavioral outcomes. Our findings highlight the complexity that interplays when examining how exposure to early-life stress may impact brain development both at the structural and functional level, and provide new insight on possible novel avenues of research to discover brain-protective treatments to improve the care of children born preterm. [ABSTRACT FROM AUTHOR]

Sucrose is recommended for the treatment of pain during minor procedures in preterm infants in the neonatal intensive care unit (NICU) and is currently used worldwide as the standard of care. We recently reported that adult mice repetitively exposed to sucrose compared to water during the first week of life, irrespective of exposure to an intervention, had significantly smaller brain volumes in large white matter, cortical and subcortical structures (e.g., hippocampus, striatum, fimbria). These structures are important for stress regulation and memory formation. Here, we report the effects of repeated neonatal exposure to pain and sucrose on adult behavior in mice. Neonatal C57BL/6J mice (N = 160, 47% male) were randomly assigned to one of two treatments (sucrose, water) and one of three interventions (needle-prick, tactile, handling). Pups received 10 interventions daily from postnatal day 1 (P1) to P6. A single dose of 24% sucrose or water was given orally 2 min before each intervention. At adulthood (P60-85) mice underwent behavioral testing to assess spatial memory, anxiety, motor function, pain sensitivity, and sugar preference. We found that mice that had received sucrose and handling only, had poorer short-term memory in adulthood compared to water/handling controls (p < 0.05). When exposed to pain, mice treated with repetitive sucrose or water did not differ on memory performance (p = 0.1). A sugar preference test showed that adult mice that received sucrose before an intervention as pups consumed less sugar solution compared to controls or those that received water before pain (p < 0.05). There were no significant group differences in anxiety, motor, or pain sensitivity. In a mouse model that closely mimics NICU care, we show for the first time that memory in adulthood was poorer for mice exposed to pain during the first week of life, irrespective of sucrose treatment, suggesting that sucrose does not protect memory performance when administered for pain. In the absence of pain, early repetitive sucrose exposure induced poorer short-term memory, highlighting the importance of accurate pain assessment. [ABSTRACT FROM AUTHOR]

Background: Choline is an important nutrient during development. However, there are limited data on dietary choline intake and status in toddlers and the relation to neurodevelopmental outcomes.Objective: This study assessed dietary choline intake and status in healthy toddlers at ages 1 and 2 y and determined the relation to neurodevelopmental outcomes.Methods: This is a secondary analysis of data from healthy toddlers enrolled in a double-blind, randomized controlled trial of long-chain polyunsaturated fatty acid supplementation between ages 1 and 2 y. Dietary intakes of betaine and choline were estimated by 3-d food records; plasma free choline, betaine, and dimethylglycine were quantified by liquid chromatography-tandem mass spectrometry. Developmental outcomes were assessed at age 2 y with the use of the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), Cognitive and Language composites, and the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI).Results: The mean ± SD daily intake for total choline at age 1 y was 174 ± 56.2 mg/d and increased (P < 0.001) to 205 ± 67.5 mg/d at age 2 y. At ages 1 and 2 y, 71.8% and 55.8%, respectively, of toddlers did not meet the recommended 200-mg/d Adequate Intake (AI) for dietary choline. At age 1 y, mean ± SD plasma free choline, betaine, and dimethylglycine concentrations were 10.4 ± 3.3, 41.1 ± 15.4, and 4.1 ± 1.9 µmol/L, respectively. Plasma free choline (8.5 ± 2.3 µmol/L) and dimethylglycine (3.2 ± 1.3 µmol/L) concentrations were lower (P < 0.001) at age 2 y. Plasma betaine concentrations were positively associated with the Beery-VMI (β = 0.270; 95% CI: 0.026, 0.513; P = 0.03) at age 2 y.Conclusions: These findings suggest that most toddlers are not meeting the recommended AI for dietary choline and that higher plasma betaine concentrations are associated with better visual-motor development at age 2 y. Further work is required to investigate choline metabolism and its role in neurodevelopment in toddlers. The trial is registered at clinicaltrials.gov as NCT01263912. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate how patterns of maternal depressive symptoms from mid-pregnancy to 3 years postpartum are associated with children’s behavior at age 3 years and executive functions. Maternal depressive symptoms were measured from mid-pregnancy to 3 years postpartum. Growth mixture modeling was used on standardized maternal depression scores (n = 147) to identify trajectories. Children’s behavioral problems and mental health symptomatology (internalizing, externalizing, and attention deficit hyperactivity disorder) were obtained at 3 and 6 years. EFs were assessed by a laboratory-based computerized task and maternal-report at 6 years. Multivariable linear regressions of children’s outcomes against maternal depressive symptom trajectories were conducted (n = 103). Three distinct patterns of maternal depressive symptom trajectories were identified: low (n = 105), increasing (n = 27), and decreasing (n = 15). Children of mothers whose depressive symptoms increased reported more problem behaviors at 3 years and poorer EFs at 6 years as assessed by both instruments, but no significant differences in mental health symptomatology at 6 years, relative to those whose mothers had consistently low depressive symptoms. Children whose mothers became less depressed over time had comparable levels of behavioral problems at age 3, executive functions, and internalizing and externalizing scores at age 6; and fewer reported ADHD behaviors at age 6, than those whose mothers remained less depressed over time. If mothers’ depressive symptoms improve over the first 3 years postpartum, their children’s outlook may be comparable to those whose mothers had consistently low depressive symptoms. [ABSTRACT FROM AUTHOR]

Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and A-acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development. [ABSTRACT FROM AUTHOR]

Objective: To determine whether severe retinopathy of prematurity (ROP) is associated with (1) abnormal white matter maturation and (2) neurodevelopmental outcomes at 18 months' corrected age (CA) compared with neonates without severe ROP.Design: We conducted a prospective longitudinal cohort of extremely preterm neonates born 24-28 weeks' gestational age recruited between 2006 and 2013 with brain MRIs obtained both early in life and at term-equivalent age. Severe ROP was defined as ROP treated with retinal laser photocoagulation. Using diffusion tensor imaging and tract-based spatial statistics (TBSS), white matter maturation was assessed by mean fractional anisotropy (FA) in seven predefined regions of interest. Neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development-III (Bayley-III) composite scores at 18 months' CA. Subjects were compared using Fisher's exact, Kruskal-Wallis and generalised estimating equations.Setting: Families were recruited from the neonatal intensive care unit at BC Women's Hospital.Patients: Of 98 extremely preterm neonates (median: 26.0 weeks) assessed locally for ROP, 19 (19%) had severe ROP and 83 (85%) were assessed at 18 months' CA.Results: Severe ROP was associated with lower FA in the posterior white matter, and with decreased measures of brain maturation in the optic radiations, posterior limb of the internal capsule (PLIC) and external capsule on TBSS. Bayley-III cognitive and motor scores were lower in infants with severe ROP.Conclusions: Severe ROP is associated with maturational delay in the optic radiations, PLIC, external capsule and posterior white matter, housing the primary visual and motor pathways, and is associated with poorer cognitive and motor outcomes at 18 months' CA. [ABSTRACT FROM AUTHOR]

Objectives The objective of this study was to describe survival, short-term, and longterm morbidities of neonates with birth weight < 500 g. Study Design Retrospective cohort studies to calculate survival, short-term, and long-term morbidity rates of neonates born weighing < 500 g from 1993 to 2012 and neurodevelopmental impairment rates at 4.5 years for births 1993 to 2008 in one center. Results Of 549 inborn neonates with birth weight < 500 g, 4% survived. For live births and neonatal intensive care unit (NICU) admissions, 10 and 55% survived, respectively. Of 28 NICU (inborn and outborn) survivors (median birth weight 460 g and gestation 25.9 weeks [range: 22.6-30.3 weeks]), 71 % were inborn, 50% male, and 75% were small for gestational age. One in five neonates was a twin or multiple. Shortterm morbidities noted were bronchopulmonary dysplasia (91%), culture proven sepsis (50%), retinopathy of prematurity (41%), and severe brain injury (22%); 27% had no long-term impairment, 23% one, 23% two, 18% three, and 9% four impairments in motor, cognitive, vision, and/or hearing domains. At 4.5 years, 29% had visual impairment, 10% wore hearing aids, 50% had IQ < 70, 18% cerebral palsy, and 68% had low motor scores. Conclusion Only 4% of births < 500 g survived. All survivors had short-term morbidities; 27% neonates survived without long-term major impairments. [ABSTRACT FROM AUTHOR]

Little is known about arachidonic acid (ARA) and docosahexaenoic acid (DHA) requirements in toddlers. A longitudinal, double blind, controlled trial in toddlers (n = 133) age 13.4 ± 0.9 months (mean ± standard deviation), randomized to receive a DHA (200 mg/day) and ARA (200 mg/day) supplement (supplement) or a corn oil supplement (control) until age 24 months determined effects on neurodevelopment. We found no effect of the supplement on the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) cognitive and language composites and Beery--Buktenica Developmental Test of Visual--Motor Integration (Beery VMI) at age 24 months. Supplemented toddlers had higher RBC phosphatidylcholine (PC), phosphatidylethanolamine (PE), and plasma DHA and ARA compared to placebo toddlers at age 24 months. A positive relationship between RBC PE ARA and Bayley III Cognitive composite (4.55 (0.21-9.00), B (95% CI), p = 0.045) in supplemented boys, but not in control boys, was observed in models adjusted for baseline fatty acid, maternal non-verbal intelligence, and BMI z-score at age 24 months. A similar positive relationship between RBC PE ARA and Bayley III Language composite was observed for supplemented boys (11.52 (5.10-17.94), p < 0.001) and girls (11.19 (4.69-17.68), p = 0.001). These findings suggest that increasing the ARA status in toddlers is associated with better neurodevelopment at age 24 months. [ABSTRACT FROM AUTHOR]

Objectives To examine associations between maternal pregnancy-specific stress and umbilical (UA PI) and middle cerebral artery pulsatility indices (MCA PI), cerebroplacental ratio, absent end diastolic flow (AEDF), birthweight, prematurity, neonatal intensive care unit admission and adverse obstetric outcomes in women with small for gestational age pregnancies. It was hypothesised that maternal pregnancy-specific stress would be associated with fetoplacental haemodynamics and neonatal outcomes. Design This is a secondary analysis of data collected for a large-scale prospective observational study. Setting This study was conducted in the seven major obstetric hospitals in Ireland and Northern Ireland. Participants Participants included 331 women who participated in the Prospective Observational Trial to Optimise Paediatric Health in Intrauterine Growth Restriction. Women with singleton pregnancies between 24 and 36 weeks gestation, estimated fetal weight <10th percentile and no major structural or chromosomal abnormalities were included. Primary and secondary outcome measures Serial Doppler ultrasound examinations of the umbilical and middle cerebral arteries between 20 and 42 weeks gestation, Pregnancy Distress Questionnaire (PDQ) scores between 23 and 40 weeks gestation and neonatal outcomes. Results Concerns about physical symptoms and body image at 35–40 weeks were associated with lower odds of abnormal UAPI (OR 0.826, 95% CI 0.696 to 0.979, p=0.028). PDQ score (OR 1.073, 95% CI 1.012 to 1.137, p=0.017), concerns about birth and the baby (OR 1.143, 95% CI 1.037 to 1.260, p=0.007) and concerns about physical symptoms and body image (OR 1.283, 95% CI 1.070 to 1.538, p=0.007) at 29–34 weeks were associated with higher odds of abnormal MCA PI. Concerns about birth and the baby at 29–34 weeks (OR 1.202, 95% CI 1.018 to 1.421, p=0.030) were associated with higher odds of AEDF. Concerns about physical symptoms and body image at 35–40 weeks were associated with decreased odds of neonatal intensive care unit admission (OR 0.635, 95% CI 0.435 to 0.927, p=0.019). Conclusions These findings suggest that fetoplacental haemodynamics may be a mechanistic link between maternal prenatal stress and fetal and neonatal well-being, but additional research is required. [ABSTRACT FROM AUTHOR]

Aim: To characterize corpus callosum development in neonates born very preterm from early in life to term-equivalent age and its relationship with neurodevelopmental outcome at 18 months corrected age.Method: In a prospective cohort of 193 neonates born preterm, 24 to 32 weeks' gestation, we used magnetic resonance imaging and diffusion tensor imaging acquired early in life (n=193) and at term-equivalent age (n=159) to measure corpus callosum development: mid-sagittal area (including corpus callosum subdivisions) and length, and fractional anisotropy from the genu and splenium. We examined the association of (1) intraventricular haemorrhage (IVH) and white matter injury (WMI) severity, and (2) neurodevelopmental outcome at 18 months corrected age with corpus callosum development.Results: Severe WMI and severe IVH were strongly associated with reduced corpus callosum area (both p<0.001) and WMI with lower fractional anisotropy (p=0.002). Mild WMI predicted smaller corpus callosum area only posteriorly; mild IVH predicted smaller area throughout. Adverse motor outcome was associated with smaller corpus callosum size in the posterior subdivision (p=0.003). Abnormal cognitive outcomes were associated with lower corpus callosum fractional anisotropy (p=0.008).Interpretation: In newborn infants born very preterm, brain injury is associated with changes in simple metrics of corpus callosum development. In this population, the development of the corpus callosum, as reflected by size and microstructure, is associated with neurodevelopmental outcomes at 18 months corrected age. [ABSTRACT FROM AUTHOR]

Objective. To examine the comparative effectiveness of two topical anesthetics in controlling the pain associated with tongue-tie release (frenotomy) in young infants. Design. Randomized trial. Setting. A Pediatric Craniofacial Clinic. Subjects. Forty-two infants who were referred for frenotomy were randomly allocated to receive the topical anesthetic gel 2% tetracaine or 20% benzocaine applied prior to frenotomy. Frenotomies were videotaped. The primary outcome measure was the Neonatal Facial Coding System (NFCS) score. Secondary outcome measures included cry duration and a visual analog scale (VAS) assessed by the parents. Results. The two groups were comparable with regard to weight, age, gender, previous painful experience, and last feeding time. Median NFCS scores prior to frenotomy in the tetracaine and the benzocaine groups were 4.5 (IQR: 0.75-10.2) and 3.5 (IQR: 0-9.5), respectively (P50.89, 95% CI 23 to 4). During frenotomy, median NFCS score increased to 28 (IQR: 24.5-30.25) in the tetracaine group (P< 0.0001, median difference 222, 95% CI 224.5 to 219), and to 28 (IQR: 26-30) in the benzocaine group (P< 0.0001, median difference 223, 95% CI 227 to 217). Mean cry durations in the tetracaine and the benzocaine groups were 69.4 seconds and 63.9 seconds, respectively (P50.32, 95% CI 247 to 15), and mean VAS scores were 57.2 and 58.2, respectively (P50.89, 95% CI 215.2 to 13.4). Conclusions. These topical anesthetics seem ineffective in controlling the pain associated with frenotomy. Clinicians should continue to search for an effective treatment for this procedure. [ABSTRACT FROM AUTHOR]

Child executive functions (cognitive flexibility, inhibitory control, working memory) are key to success in school. Cortisol, the primary stress hormone, is known to affect cognition; however, there is limited information about how child cortisol levels, parenting factors and child care context relate to executive functions in young children. The aim of this study was to examine relationships between child cortisol, parenting stress, parent coping, and daycare quality in relation to executive functions in children aged 3–5 years. We hypothesized that (1) poorer executive functioning would be related to higher child cortisol and higher parenting stress, and (2) positive daycare quality and positive parent coping style would buffer the effects of child cortisol and parenting stress on executive functions. A total of 101 children (53 girls, 48 boys, mean age 4.24 years ±0.74) with complete data on all measures were included. Three saliva samples to measure cortisol were collected at the child’s daycare/preschool in one morning. Parents completed the Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P), Parenting Stress Index (PSI), and Ways of Coping Questionnaire (WCQ). The Early Childhood Environment Rating Scale – Revised (ECERS-R) was used to measure the quality of daycare. It was found that children with poorer executive functioning had higher levels of salivary cortisol, and their parents reported higher parenting stress. However, parent coping style and quality of daycare did not modulate these relationships. Identifying ways to promote child executive functioning is an important direction for improving school readiness. [ABSTRACT FROM AUTHOR]

The role of prenatal Selective Serotonin Reuptake Inhibitor (SSRI) exposure and SLC6A4 promoter methylation status in shaping soothability at 3 and 6 months of age, for infants exposed to antidepressant medication prenatally ( n = 46) and those not exposed ( n = 69) was investigated. SSRI exposure status and duration of exposure (number of days) were examined along with neonatal methylation status at mean CpG 9,10 and via factor analysis across 10 CpG sites yielding PC1 (CpGs sites: 3,4,5,7) and PC2 (CpG 1,8). Analyses revealed interactions for methylation markers and SSRI exposure variables. A significant interaction between SSRI exposure and mean SLC6A4 methylation at CpG 9,10 and separately for PC1 emerged, controlling for multiple birth/medical and background covariates (e.g., Apgar scores, maternal education). Increased neonatal methylation status was associated with increased soothability changes from 3 to 6 months among infants prenatally exposed to SSRIs. [ABSTRACT FROM AUTHOR]

Objective: Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome.Methods: A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries.Results: Total midazolam dose predicted decreased hippocampal volumes (β = -1.8, p < 0.001) and increased MD (β = 0.002, p = 0.02), whereas invasive procedures did not (β = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (β = -0.31, p = 0.003), midazolam dose (β = -0.27, p = 0.03), and surgery (β = -8.32, p = 0.04).Interpretation: Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned. [ABSTRACT FROM AUTHOR]