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BACKGROUND AND OBJECTIVE: Children who experienced intrauterine growth restriction [IUGR] may be at increased risk for adverse developmental outcomes in early childhood. The objective of this study was to carry out a systematic review of neurodevelopmental outcomes from 6 months to 3 years after IUGR. METHODS: PubMed, Embase, PsycINFO, Maternity and Infant Care, and CINAHL databases were searched by using the search terms intrauterine, fetal, growth restriction, child development, neurodevelopment, early childhood, cognitive, motor, speech, language. Studies were eligible for inclusion if participants met specified criteria for growth restriction, follow-up was conducted within 6 months to 3 years, methods were adequately described, non-IUGR comparison groups were included, and full English text of the article was available. A specifically designed data extraction form was used. The methodological quality of included studies was assessed using well-documented quality-appraisal guidelines. RESULTS: Of 731 studies reviewed, 16 were included. Poorer neurodevelopmental outcomes after IUGR were described in 11. Ten found motor, 8 cognitive, and 7 language delays. Other delays included social development, attention, and adaptive behavior. Only 8 included abnormal Doppler parameters in their definitions of IUGR. CONCLUSIONS: Evidence suggests that children are at risk for poorer neurodevelopmental outcomes following IUGR from 6 months to 3 years of age. The heterogeneity of primary outcomes, assessment measures, adjustment for confounding variables, and definitions of IUGR limits synthesis and interpretation. Sample sizes in most studies were small, and some examined preterm IUGR children without including term IUGR or AGA comparison groups, limiting the value of extant studies. [ABSTRACT FROM AUTHOR]

Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm. [ABSTRACT FROM AUTHOR]

Objective: Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants. Methods: Infants born very preterm (N = 86; 24-32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery. Results: After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (β = −0.0002, p = 0.028) and reduced subcortical gray matter NAA/choline (β = −0.0006, p = 0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes. Interpretation: Early procedural pain in very preterm infants may contribute to impaired brain development. ANN NEUROL 2012; [ABSTRACT FROM AUTHOR]

Abstract: Background: Higher parenting stress in mothers of children born very preterm may be in part a response to poorer neurobehavioral development, reflecting realistic concerns in addition to adaptation to the trauma of preterm delivery. To our knowledge, there are few longitudinal studies of parenting stress that have addressed child cognitive competence. Aims: To examine parenting stress in preterm and full-term children at 8 and 18months corrected chronological age (CCA), in relation to child cognitive development and behavior. Subjects: Participants were N=152 children (98 preterm born ≤32weeks gestation, and 54 full-term) seen at 8 and 18months CCA, and the primary caregiver parent. Study design/Outcome measures: The Parenting Stress Index questionnaire was completed by a parent, child interactive behavior was videotaped, and the Bayley Scales of Infant Development (BSID II, Mental Development Index; MDI) were administered at both ages. Results: Total Parenting Stress was higher in preterm than full-term children at 8 and 18months CCA (p<.02), accounted for primarily by the Child domain. Hierarchical regression showed (after controlling for neonatal risk, number of children in the home, child interactive behavior and maternal education) that decreasing Bayley MDI scores from 8 to 18months CCA predicted higher parenting stress for preterm children. For full-term children, number of children in the home and child interactive behavior predicted parental stress at 18months. Conclusion: Higher parenting stress persisting to 18months CCA in preterm children may partly reflect realistic parental concerns with their child''s development. [Copyright &y& Elsevier]

Preterm and critically ill newborns admitted to a NICU undergo repeated skin-breaking procedures that are necessary for their survival. Sucrose is rapidly becoming the accepted clinical standard nonpharmacologic intervention for managing acute procedural pain for these infants. Although shown to be safe in single doses, only 4 studies have evaluated the effects of repeated doses of sucrose over relatively short periods of time. None has examined the use of sucrose throughout the NICU stay, and only 1 study evaluated the neurodevelopmental outcomes after repeated doses of sucrose. In that study, infants born at <31 weeks' gestational age and exposed to >10 doses per day in the first week of life were more likely to show poorer attention and motor development in the early months after discharge from the NICU. Results of studies in animal models have suggested that the mechanism of action of sucrose is through opioid pathways; however, in human infants, little has been done to examine the physiologic mechanisms involved, and the findings reported thus far have been ambiguous. Drawing from the growing animal literature of research that has examined the effects of chronic sugar exposure, we describe alternative amine and hormone pathways that are common to the processing of sucrose, attention, and motor development. In addition, a review of the latest research to examine the effects of repeated sucrose on pain processing is presented. These 2 literatures each can inform the other and can provide an impetus to initiate research to examine not only the mechanisms involved in the calming mechanisms of sucrose but also in the long-term neurodevelopmental effects of repeated sucrose in those infants born extremely preterm or critically ill. [ABSTRACT FROM AUTHOR]

Abstract: We examined the role of physiological regulation (heart rate, vagal tone, and salivary cortisol) in short-term memory in preterm and full-term 6-month-old infants. Using a deferred imitation task to evaluate social learning and memory recall, an experimenter modeled three novel behaviors (removing, shaking, and replacing a glove) on a puppet. Infants were tested immediately after being shown the behaviors as well as following a 10-min delay. We found that greater suppression of vagal tone was related to better memory recall in full-term infants tested immediately after the demonstration as well as in preterm infants tested later after a 10-min delay. We also found that preterm infants showed greater coordination of physiology (i.e., tighter coupling of vagal tone, heart rate, and cortisol) at rest and during retrieval than full-term infants. These findings provide new evidence of the important links between changes in autonomic activity and memory recall in infancy. They also raise the intriguing possibility that social learning, imitation behavior, and the formation of new memories are modulated by autonomic activity that is coordinated differently in preterm and full-term infants. [Copyright &y& Elsevier]

Abstract: Procedural pain in the neonatal intensive care unit triggers a cascade of physiological, behavioral and hormonal disruptions which may contribute to altered neurodevelopment in infants born very preterm, who undergo prolonged hospitalization at a time of physiological immaturity and rapid brain development. The aim of this study was to examine relationships between cumulative procedural pain (number of skin-breaking procedures from birth to term, adjusted for early illness severity and overall intravenous morphine exposure), and later cognitive, motor abilities and behavior in very preterm infants at 8 and 18months corrected chronological age (CCA), and further, to evaluate the extent to which parenting factors modulate these relationships over time. Participants were N =211 infants (n =137 born preterm ⩽32weeks gestational age [GA] and n =74 full-term controls) followed prospectively since birth. Infants with significant neonatal brain injury (periventricular leucomalacia, grade 3 or 4 intraventricular hemorrhage) and/or major sensori-neural impairments, were excluded. Poorer cognition and motor function were associated with higher number of skin-breaking procedures, independent of early illness severity, overall intravenous morphine, and exposure to postnatal steroids. The number of skin-breaking procedures as a marker of neonatal pain was closely related to days on mechanical ventilation. In general, greater overall exposure to intravenous morphine was associated with poorer motor development at 8months, but not at 18months CCA, however, specific protocols for morphine administration were not evaluated. Lower parenting stress modulated effects of neonatal pain, only on cognitive outcome at 18months. [Copyright &y& Elsevier]

Learning difficulties in preterm infants are thought to reflect impairment in arousal regulation. We examined relationships among gestational age, learning speed, and behavioral and physiological reactivity in 55 preterm and 49 full-term infants during baseline, contingency, and nonreinforcement phases of a conjugate mobile paradigm at 3 months corrected age. For all infants, negative affect, looking duration, and heart rate levels increased during contingency and nonreinforcement phases, whereas respiratory sinus arrhythmia (RSA, an index of parasympathetic activity) decreased and cortisol did not change. Learners showed greater RSA suppression and less negative affect than nonlearners. This pattern was particularly evident in the preterm group. Overall, preterm infants showed less learning, spent less time looking at the mobile, and had lower cortisol levels than full-term infants. Preterm infants also showed greater heart rate responses to contingency and dampened heart rate responses to nonreinforcement compared to full-term infants. Findings underscore differences in basal and reactivity measures in preterm compared to full-term infants and suggest that the capacity to regulate parasympathetic activity during a challenge enhances learning in preterm infants. [ABSTRACT FROM AUTHOR]

Abstract: Accurate pain assessment in preterm infants in the neonatal intensive care unit (NICU) is complex. Infants who are born at early gestational ages (GA), and who have had greater early pain exposure, have dampened facial responses which may lead to under-treatment. Since behavioral and physiological responses to pain in infants are often dissociated, using multidimensional scales which combine these indicators into a single score may limit our ability to determine the effects of interventions on each system. Our aim was to design a unidimensional scale which would combine the relatively most specific, individual, behavioral indicators for assessing acute pain in this population. The Behavioral Indicators of Infant Pain (BIIP) combines sleep/wake states, 5 facial actions and 2 hand actions. Ninety-two infants born between 23 and 32 weeks GA were assessed during 3, 1min Phases of blood collection. Outcome measures included changes in BIIP and in Neonatal Infant Pain Scale (NIPS) scores coded in real time from continuous bedside video recordings; changes in heart rate (HR) were obtained using custom physiological processing software. Scores on the BIIP changed significantly across Phases of blood collection (p <0.01). Internal consistency (0.82) and inter-rater reliability (0.80–0.92) were high. Correlations between the BIIP and NIPS were modest (r =0.64, p <0.01) as were correlations between the BIIP and mean heart rate (r =0.45, p <0.01). In this initial study, the BIIP has been shown to be a reliable, valid scale for assessing acute pain in preterm infants in the NICU. [Copyright &y& Elsevier]

Abstract: Background: Acute pain is a significant stressor for preterm infants in neonatal intensive care units (NICU); however, little is known about the effects of acute pain on subsequent motor responses during clusters of tactile handling. Aims: (1) To compare facial, body and heart rate reactivity in preterm infants at 32 weeks gestational age (GA) during routine care-giving tasks following a rest period (RCC: diapering, measuring abdominal girth and axillary temperature, mouth care) with their responses to Clustered Care following blood collection (PCC). (2) To examine how GA at birth affects patterns of stress and self-regulatory behaviors during RCC and PCC. Study Design: Within-group crossover design (random order). Subjects: Preterm infants, N=54 (mean GA at birth 29.3 ± 2.2 weeks; mean birth weight 1257 ± 423 g) were assessed at 32 weeks GA in the NICU. Outcome measures: The Newborn Developmental Care and Assessment Program (NIDCAP®) and Neonatal Facial Coding System (NFCS) were coded from continuous bedside video recordings. Changes in mean heart rate (HR) were computed using custom physiologic software. Results: All infants had heightened facial, body and HR responses when CC followed a painful procedure compared to when they had not been handled prior to CC. Infants born at earlier GA (&#60;30 weeks) had equal numbers of stress cues during RCC and PCC, but dampened self-regulatory behaviors during PCC. Conclusion: Prior pain induces heightened biobehavioral reactivity in preterm infants during subsequent tactile procedures. In addition, clustering care is particularly stressful for infants born at earlier GA. [Copyright &y& Elsevier]

Abstract: Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty-seven preterm infants were studied at 32 (±1 weeks) postconceptional age (PCA). Infants who received analgesia or sedation in the 72h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born ≤28 weeks gestational age (GA), but not 29–32 weeks GA, higher cumulative neonatal procedural pain exposure was related to lower cortisol response to stress and to lower facial (but not autonomic) reactivity to pain, at 32 weeks PCA, independent of early illness severity and morphine exposure since birth. Repeated neonatal procedural pain exposure among neurodevelopmentally immature preterm infants was associated with down-regulation of the hypothalamic–pituitary–adrenal axis, which was not counteracted with morphine. Differential effects of early pain on development of behavioral, physiologic and hormonal systems warrant further investigation. [Copyright &y& Elsevier]

Objective. To compare academic and cognitive ability, attention, attitudes, and behavior of extremely low birth weight (ELBW) adolescents who are free of major impairments at 17 years of age with term-born control subjects. Methods. Between January 31, 1981, and February 9, 1986, 250 infants of ≤800 g were admitted for intensive care in British Columbia, 98 (39%) of whom survived to late adolescence. Teens with major sensorimotor handicaps and/or IQ < 70 were excluded (n = 19). Of the 79 eligible ELBW teens, 53 (67%) were assessed at 17.3 (16.3-19.7) years (birth weight: 720 [520 - 800g]; gestation: 26 [23-29] weeks). The test battery screened the following areas: cognitive (Wechsler Intelligence Scale for Adults Third Edition, 3 subtests), academic (Wide Range Achievement Test-3), attention (Connors' Continuous Performance Task), self-report (Harter Self-Perception Profile for Adolescents; Job Search Attitude Inventory), and parent report (Child Behavior Check List). A comparison group of term born control subjects (n = 31) were also assessed (birth weight: 3506 [3068-4196] g; gestation: 40 [39-42] weeks) at age 17.8 (16.5-19.0) years. Multivariate analysis of variance (group x gender) was conducted for each domain (cognitive, academic, self-report, and parent report). Results. The ELBW group showed lower cognitive scores (vocabulary, block design, and digit symbol) and academic skills (reading and arithmetic) compared with control subjects, with no gender differences. There were no differences in attention between the 2 groups using a repetitive computer task. ELBW teens reported lower scholastic, athletic, job competence, and romantic confidence and viewed themselves as more likely to need help from others in finding a job. In the behavioral domain, parents reported their ELBW teens to display more internalizing, more externalizing, and more total problems than the control teens, with ELBW boys showing more problems. ELBW teens showed a higher... [ABSTRACT FROM AUTHOR]

Objective. The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) is widely used in neonatal intensive care units and comprises 85 discrete infant behaviors, some of which may communicate infant distress. The objective of this study was to identify developmentally relevant movements indicative of pain in preterm infants. Methods. Forty-four preterm infants were assessed at 32 weeks' gestational age (GA) during 3 phases (baseline, lance/squeeze, and recovery) of routine blood collection in the neonatal intensive care unit. The NIDCAP and Neonatal Facial Coding System (NFCS) were coded from separate continuous bedside video recordings; mean heart rate (mHR) was derived from digitally sampled continuous electrographic recordings. Analysis of variance (phase = gender) with Bonferroni corrections was used to compare differences in NIDCAP, NFCS, and mHR. Pearson correlations were used to examine relationships between the NIDCAP and infant background characteristics. Results. NFCS and mHR increased significantly to lance/squeeze. Eight NIDCAP behaviors also increased significantly to lance/squeeze. Another 5 NIDCAP behaviors decreased significantly to lance/squeeze. Infants who had lower GA at birth, had been sicker, had experienced more painful procedures, or had greater morphine exposure showed increased hand movements indicative of increased distress. Conclusions. Of the 85 NIDCAP behaviors, a subset of 8 NIDCAP movements were associated with pain. Particularly for infants who are born at early GAs, addition of these movements to commonly used measures may improve the accuracy of pain assessment. [ABSTRACT FROM AUTHOR]

Objectives. Stress systems may be altered in the long term in preterm infants for multiple reasons, including early exposure to procedural pain in neonatal intensive care. This question has received little attention beyond hospital discharge. Stress responses (cortisol) to visual novelty in preterm infants who were born at extremely low gestational age (ELGA; ≤28 weeks), very low gestational age (VLGA; 29-32 weeks), and term were compared at 8 months of age corrected for prematurity (corrected chronological age [CCA]). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit. Methods. Seventy-six infants, 54 preterm (≤ 32 weeks' GA at birth) and 22 term-born infants who were seen at 8 months CCA composed the study sample, after excluding those with major sensory, motor, or cognitive impairment. Salivary cortisol was measured before (basal) and 20 minutes after introduction of novel toys (post 1) and after developmental assessment (post 2). Results. Salivary cortisol was significantly higher in ELGA infants at 8 months, compared with the VLGA and term groups before and after introduction of visual novelty. Term-born and VLGA infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher basal cortisol levels in preterm infants at 8 months' CCA were associated with higher number of neonatal skin-breaking procedures. In contrast, cortisol responses to novelty were predicted equally well by neonatal pain or GA at birth. No relationship between morphine dosing and cortisol response was demonstrated in these infants. Conclusions. ELGA preterm infants show a different pattern of cortisol levels before and after positive stimulation of visual novelty than... [ABSTRACT FROM AUTHOR]

ABSTRACT. Objective. Children with neurologic impairments have shown diminished pain response compared with control subjects; however, it remains unclear what mechanisms underlie this response or when it develops. If this were also true with premature infants who undergo neonatal intensive care, then infants with parenchymal brain injury (PBI) would be at increased risk of underrecognition and undertreatment of procedural pain. The purpose of this study was to determine whether infants with PBI display altered responses to acute procedural pain at 32 weeks' postconceptional age (PCA), compared with control subjects. Methods. We compared responses to blood collection by heel lance at 32 weeks' PCA in 12 very low birth weight infants (mean [range] birth weight: 876 g [630-1240 g]; gestational age: 26.3 weeks (24-28 weeks) who had sustained PBI in the neonatal period, with 12 control subjects matched for gestational age at birth and gender (838 g [625-990 g]; 26.3 weeks [24-28 weeks[) who had normal neonatal brain imaging. PBI was defined as cerebral parenchymal infarction (grade 4 intraventricular hemorrhage) or cystic periventricular leukomalacia on serial cranial ultrasound scans conducted in the neonatal period. Biobehavioral responses to pain were measured using facial activity (Neonatal Facial Coding System) and measures of heart rate (HR) variability (low-frequency [LF] power [0.04-0.15], high-frequency [HF] power [0.15-0.8 Hz], and LF/HF ratio) as a measure of cardiac autonomic modulation. Neurodevelopmental follow-up was undertaken at 18 months. Results. The infants with PBI had significantly higher illness severity scores at day 1 compared with day 3 (Score of Neonatal Acute Physiology II: 32.1 vs 19.8) but similar previous pain experiences (109 vs 115) and total morphine exposure (0.29 vs 0.30 mg/kg). Both groups of children mounted similar responses to heel lance at 32 weeks' PCA with no difference in facial response or HR variability. Mean HR and... [ABSTRACT FROM AUTHOR]

Background: Cardiac complications after premature birth are associated with negative long-term consequences to health. The Family Nurture Intervention (FNI) has been designed to support mother-infant parasympathetic calming sessions in the neonatal intensive care unit (NICU). FNI has shown neurodevelopmental and autonomic benefit across infant development.Aims: We tested the hypothesis that heart rate (HR) will decrease after FNI over the course of the NICU stay, compared to matched controls.Study Design: We used a case-matched design. The intervention included on average four ~1-hour facilitated mother-infant 'calming' sessions per week. We collected 24/7 real time heart rate data from a central monitoring system and analyzed data from two time-periods.Subjects: The intervention group comprised 37 infants born ~30 weeks gestational age (GA) in a level IV NICU, treated with FNI. From the same NICU and time-period, we created a contemporaneous comparison group of 32 infants who were case-matched to each intervention infant for sex, age-at-birth, singleton or twin status, month of admission and length of stay.Outcome Measures: Using generalized estimating equation (GEE) modeling, we analyzed 24/7 HR data during a 1-hour period between 4:30 and 5:30 am each day in the NICU, when all infants were least disturbed. Using repeated measures ANOVA, we analyzed 24/7 HR data during a 6-week period starting 1 week prior to the start of FNI and ending 5 weeks after start.Results: GEE modeling of the 1-hour data from all subjects showed significant lower HR in the FNI group, compared with controls. ANOVA modeling on a subset of subjects over the five-week period showed that FNI infant HR decreased in a dose-response manner relative to SC HR.Conclusion: This study suggests FNI may condition lower infant HR in a dose-response manner during the NICU stay. [ABSTRACT FROM AUTHOR]

The article refers to a technique called functional magnetic resonance imaging that detects changes in blood oxygenation level and suggests how new born babies feel pain like adults.It talks about the network of brain activity that underlies pain, called the pain matrix.

Objective Methods Results Interpretation The hippocampus plays a critical role in cognitive networks. The anterior hippocampus is vulnerable to early‐life stress and socioeconomic status (SES) with alterations persisting beyond childhood. How SES modifies the relationship between early hippocampal development and cognition remains poorly understood. This study examined associations between SES, structural and functional development of neonatal hippocampus, and 18‐month cognition in very preterm neonates.In total, 179 preterm neonates were followed prospectively. Structural and resting‐state functional MRI were obtained early‐in‐life and at term‐equivalent age (median 32.9 and 41.1 weeks post‐menstrual age) to calculate anterior and posterior hippocampal volumes and hippocampal functional connectivity strength. Eighteen‐month cognition was assessed via Bayley‐III. Longitudinal statistical analysis using generalized estimating equations, accounting for birth gestational age, post‐menstrual age at scan, sex, and motion, was performed.SES, measured as maternal education level, modified associations between anterior but not posterior hippocampal volumes and 18‐month cognition (interaction term p = 0.005), and between hippocampal connectivity and cognition (interaction term p = 0.05). Greater anterior hippocampal volumes and hippocampal connectivity were associated with higher cognitive scores only in the lowest SES group. Maternal education alone did not predict neonatal hippocampal volume from early‐in‐life and term.SES modified the relationship between neonatal hippocampal development and 18‐month cognition in very preterm neonates. The lack of direct association between maternal education and neonatal hippocampal volumes indicates that socio‐environmental factors beyond the neonatal period contribute to modifying the relationship between hippocampal development and cognition. These findings point toward opportunities to more equitably promote optimal neurodevelopmental outcomes in very preterm infants. [ABSTRACT FROM AUTHOR]

Background: Children born very preterm demonstrate behavioural challenges due to clinical factors, exposure to the high stress environment of intensive care, and separation from parents during neonatal hospitalization at a critical stage in development. Family Integrated Care (FICare) significantly reduced parent stress and anxiety, and improved neonatal outcomes.Aims: To examine the impact of FICare on behavioural outcomes at 18-21 months corrected age (CA), and assess possible mediation through parenting or infant growth.Study Design and Methods: A prospective cohort study enrolling infants under 33 weeks gestation and parents from the FICare cluster randomized controlled trial. Primary outcome was behaviour assessed by the Infant Toddler Social Emotional Assessment (ITSEA). Parent child variables were measured with the Nursing Child Assessment Satellite Training (NCAST), Parenting Stress Index (PSI) and infant growth.Results: Subjects included 123 FICare infants and 62 standard care controls evaluated at 18-21 months CA. FICare infants demonstrated lower ITSEA Dysregulation, indicating better self-regulation skills, compared with the control group (T-score 41.7 vs 46.6, p < 0.01). At 12 months CA, the NCAST Child subtotal score was higher and the PSI-Child Domain score was lower in FICare infants than non-FICare infants. The PSI-Child domain was identified as a possible mediator of FICare on child behaviour (mediation effect 1.28, -2.96-0.02, p = 0.044).Conclusion: FICare in the NICU has a sustained effect on child behaviour, improving self-regulation at 18-21 months CA. [ABSTRACT FROM AUTHOR]

Children born very low gestational age (VLGA, 29–32 weeks gestational age [GA]) display slower processing speed and altered hypothalamic pituitary adrenal (HPA) axis function, with greater effects in those born extremely low gestational age (ELGA; 24–28 weeks GA). We investigated trajectories of HPA axis activity as indexed by cortisol output and patterns across cognitive assessment at ages 1.5, 3 and 4.5 years, comparing children born ELGA and VLGA and associations with 4.5-year processing speed. In a prospective longitudinal cohort study, infants born very preterm (<33 weeks gestation) returned for developmental assessment at ages 1.5, 3, and 4.5 years. At each age, children completed standardized cognitive testing and saliva samples collected before (Pretest), during (During) and after (End) challenging cognitive tasks were assayed for cortisol. For the total group (n = 188), cortisol area under the curve with respect to ground (AUCg) decreased, while cortisol reactivity to challenge (Pre-test to During) increased from 1.5 to 3 years, remaining stable to 4.5 years. This longitudinal pattern was related to higher Processing Speed (WPPSI-IV) scores at 4.5 years. Children born ELGA displayed higher AUCg than VLGA, particularly at age 3, driven by higher Pre-test cortisol levels. Overall, relative to those born VLGA, children born ELGA displayed greater cortisol responsivity to cognitive challenge. A higher setpoint of cortisol levels at age 3-years in children born ELGA may reflect altered HPA axis regulation more broadly and may contribute to difficulties with information processing in this population, critical for academic and social success. [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]

Abstract: Premature infants are at risk for adverse motor outcomes, including cerebral palsy and developmental coordination disorder. The purpose of this study was to examine the relationship of antenatal, perinatal, and postnatal risk factors for abnormal development of the corticospinal tract, the major voluntary motor pathway, during the neonatal period. In a prospective cohort study, 126 premature neonates (24-32 weeks'' gestational age) underwent serial brain imaging near birth and at term-equivalent age. With diffusion tensor tractography, mean diffusivity and fractional anisotropy of the corticospinal tract were measured to reflect microstructural development. Generalized estimating equation models examined associations of risk factors on corticospinal tract development. The perinatal risk factor of greater early illness severity (as measured by the Score for Neonatal Acute Physiology–II [SNAP-II]) was associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.02), even after correcting for gestational age at birth and postnatal risk factors (P = 0.009). Consistent with previous findings, neonatal pain adjusted for morphine and postnatal infection were also associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.03 and 0.02, respectively). Lessening illness severity in the first hours of life might offer potential to improve motor pathway development in premature newborns. [Copyright &y& Elsevier]

Children born very preterm (≤32 weeks gestational age) show poorer cognitive and language development compared with their term-born peers. The importance of supportive maternal responses to the child's cues for promoting neurodevelopment is well established. However, little is known about whether supportive maternal behavior can buffer the association of early brain dysmaturation with cognitive and language performance. Infants born very preterm (N = 226) were recruited from the neonatal intensive care unit for a prospective, observational cohort study. Chart review (e.g., size at birth, postnatal infection) was conducted from birth to discharge. Magnetic resonance imaging, including diffusion tensor imaging, was acquired at approximately 32 weeks postmenstrual age and again at term-equivalent age. Fractional anisotropy, a quantitative measure of brain maturation, was obtained from 11 bilateral regions of interest in the cortical gray matter. At 3 years (n = 187), neurodevelopmental testing (Bayley Scales of Infant and Toddler Development-III) was administered, and parent-child interaction was filmed. Maternal behavior was scored using the Emotional Availability Scale-IV. A total of 146 infants with neonatal brain imaging and follow-up data were included for analysis. Generalized estimating equations were used to examine whether maternal support interacted with mean fractional anisotropy values to predict Cognitive and Language scores at 3 years, accounting for confounding neonatal and maternal factors. Higher maternal support significantly moderated cortical fractional anisotropy values at term-equivalent age to predict higher Cognitive (interaction term β = 2.01, p =.05) and Language (interaction term β = 1.85, p =.04) scores. Findings suggest that supportive maternal behavior following early brain dysmaturation may provide an opportunity to promote optimal neurodevelopment in children born very preterm. [ABSTRACT FROM AUTHOR]

Adaptive minimum variance beamformers are widely used analysis tools in MEG and EEG. When the target brain activity presents in the form of spatially localized responses, the procedure usually involves two steps. First, positions and orientations of the sources of interest are determined. Second, the filter weights are calculated and source time courses reconstructed. This last step is the object of the current study. Despite different approaches utilized at the source localization stage, basic expressions for the weights have the same form, dictated by the minimum variance condition. These classic expressions involve covariance matrix of the measured field, which includes contributions from both the sources of interest and the noise background. We show analytically that the same weights can alternatively be obtained, if the full field covariance is replaced with that of the noise, provided the beamformer points to the true sources precisely. In practice, however, a certain mismatch is always inevitable. We show that such mismatch results in partial suppression of the true sources if the traditional weights are used. To avoid this effect, the “alternative” weights based on properly estimated noise covariance should be applied at the second, source time course reconstruction step. We demonstrate mathematically and using simulated and real data that in many situations the alternative weights provide significantly better time course reconstruction quality than the traditional ones. In particular, they a) improve source-level SNR and yield more accurately reconstructed waveforms; b) provide more accurate estimates of inter-source correlations; and c) reduce the adverse influence of the source correlations on the performance of single-source beamformers, which are used most often. Importantly, the alternative weights come at no additional computational cost, as the structure of the expressions remains the same. [ABSTRACT FROM AUTHOR]

Objective To determine whether the ability to predict severe motor impairment at age 5 years improves between birth and 18 months. Design Ancillary study of the Caffeine for Apnea of Prematurity Trial. Setting and Patients International cohort of very low birth weight children who were assessed sequentially from birth to 5 years. Outcome Measures Severe motor impairment was defined as a score <5th percentile on the Movement Assessment Battery of Children (MABC), or inability to complete the MABC because of cerebral palsy. Multivariable logistic regression cumulative risk models used four sets of predictor variables: early neonatal risk factors, risk factors at 36 weeks' postmenstrual age, risk factors at a corrected age of 18 months, and sociodemographic variables. A receiver operating characteristic curve (ROC) was generated for each model, and the four ROC curves were compared to determine if the addition of the new set of predictors significantly increased the area under the curve (AUC). Results Of 1469 children, 291 (19.8%) had a severe motor impairment at 5 years. The AUC increased from 0.650 soon after birth, to 0.718 (p<0.001) at 36 weeks' postmenstrual age, and to 0.797 at 18 months (p<0.001). Sociodemographic variables did not significantly improve the AUC (AUC=0.806; p=0.07). Conclusions Prediction of severe motor impairment at 5 years of age using a cumulative risk model improves significantly from birth to 18 months of age in children with birth weights between 500 g and 1250 g. [ABSTRACT FROM AUTHOR]

Background Parent ratings on questionnaires may provide valid and cost-effective tools for screening cognitive development of children at risk of developmental delay. Aims In this study, we examined the convergent validity of combining parent-based reports of non-verbal cognitive abilities (PARCA3) and verbal abilities (CDI-III) in relation to the Bayley-III cognitive scale in 3-year-olds born late pre-term. Methods Mothers of 185 late-preterm children were asked to complete the PARCA3 and the CDI-III shortly before children reached age three; children were then assessed using the Bayley-III close to their third birthday. Results The two maternal questionnaires were significantly and moderately correlated with the Bayley-III cognitive scores. Together the maternal ratings accounted for 15% of the variance in the Bayley-III cognitive scores, after controlling for other covariates in regression analysis. In particular, the PARCA3 contributed significantly to explain variance in the Bayley-III cognitive scores when controlling for the CDI-III. However, the CDI-III was also independently associated with the Bayley-III cognitive scores. Conclusions Parent ratings of child cognition and language together may provide cost-effective screening of development in “at risk” preschoolers. [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]

Highlights: [•] Investigated impact of depression & SRI treatment on early mother–infant interactions. [•] Despite prenatal SRI treatment, depressed mothers interrupt infants more frequently. [•] SRI exposure & higher prenatal depression severity increases infant responsiveness. [•] Without SRI exposure, higher postnatal depression decreases infant responsiveness. [ • ] Infant responsiveness following prenatal SRI exposure may reflect ‘fetal programming’. [Copyright &y& Elsevier]

Summary: Cortisol plays an important role in learning and memory. An inverted-U shaped function has been proposed to account for the positive and negative effects of cortisol on cognitive performance and memory in adults, such that too little or too much impair but moderate amounts facilitate performance. Whether such relationships between cortisol and mental function apply to early infancy, when cortisol secretion, learning, and memory undergo rapid developmental changes, is unknown. We compared relationships between learning/memory and cortisol in preterm and full-term infants and examined whether a greater risk for adrenal insufficiency associated with prematurity produces differential cortisol–memory relationships. Learning in three-month old (corrected for gestational age) preterm and full-term infants was evaluated using a conjugate reinforcement mobile task. Memory was tested by repeating the same task 24h later. Salivary cortisol samples were collected before and 20min after the presentation of the mobile. We found that preterm infants had lower cortisol levels and smaller cortisol responses than full-term infants. This is consistent with relative adrenal insufficiency reported in the neonatal period. Infants who showed increased cortisol levels from 0 to 20min on Day 1 had significantly better memory, regardless of prematurity, than infants who showed decreased cortisol levels. [Copyright &y& Elsevier]

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]

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: The severity and treatment of depression/anxiety during pregnancy and postpartum has important implications for maternal and child well-being. Yet, little is known about prenatal SSRI use and early child socioemotional development. This study explores effects of prenatal SSRI exposure, and pre- and postnatal internalizing symptoms on trajectories of infant temperament, identifying potential differences for boys and girls.Methods: Using latent growth models, sex differences in infant temperament trajectories from 3- to 10-months were examined in relation to prenatal and postpartum internalizing symptoms and prenatal SSRI exposure among 185 mother-infant dyads.Results: For girls, prenatal internalizing symptoms were associated with greater initial distress to limitations, and lower duration of orienting, smiling/laughter, and soothability. Postnatal symptoms predicted slower decreases in girls' duration of orienting. SSRI exposure predicted decreases in distress to limitations and slower increases in smiling and laughter. For boys, maternal internalizing symptoms did not generally affect temperament profiles. SSRI exposure was associated with higher initial activity level and slower declines in distress to limitations.Limitations: Only parent-report indicators of infant temperament across 10 months of infancy were provided. Maternal internalizing symptoms were measured at discrete times during pregnancy and postpartum, with no analysis of changes in symptoms across time.Conclusions: Prenatal SSRI treatment, and both prenatal and postpartum internalizing symptoms, exert unique effects on infant temperament. Overall, the present study suggests sex-dependent fetal programming effects that should be further evaluated in future research. Results have implications for perinatal mental health treatment and perceived impacts on child socioemotional development. [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]

Highlights • Predictive, subnetwork-based machine learning model for connectome data. • Novel connectivity and backbone network priors regularize model. • Approach validated on 168 structural connectomes and 1013 functional connectomes. • Proposed priors outperform all other competing methods on prediction tasks. • Resulting subnetworks are well connected and anatomically plausible. Abstract We present a new method to identify anatomical subnetworks of the human connectome that are optimally predictive of targeted clinical variables, developmental outcomes or disease states. Given a training set of structural or functional brain networks, derived from diffusion MRI (dMRI) or functional MRI (fMRI) scans respectively, our sparse linear regression model extracts a weighted subnetwork. By enforcing novel backbone network and connectivity based priors along with a non-negativity constraint, the discovered subnetworks are simultaneously anatomically plausible, well connected, positively weighted and reasonably sparse. We apply our method to (1) predicting the cognitive and neuromotor developmental outcomes of a dataset of 168 structural connectomes of preterm neonates, and (2) predicting the autism spectrum category of a dataset of 1013 resting-state functional connectomes from the Autism Brain Imaging Data Exchange (ABIDE) database. We find that the addition of each of our novel priors improves prediction accuracy and together outperform other state-of-the-art prediction techniques. We then examine the structure of the learned subnetworks in terms of topological features and with respect to established function and physiology of different regions of the brain. [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500 -1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial. METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models. RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates. [ABSTRACT FROM AUTHOR]

Our objectives were to determine whether procedural pain and glucose exposure are associated with altered structural and functional brain development differently in preterm males and females, and neurodevelopment at 18-month corrected age. Fifty-one very preterm neonates (22 males; median [interquartile range] gestational age 27.6 [2.0] weeks) underwent 3 serial scans including T1-weighted and resting-state functional magnetic resonance imaging (MRI) at median postmenstrual weeks: 29.4, 31.9, and 41.1. Thalamus, basal ganglia, and total brain volumes were segmented. Functional resting-state MRI data were extracted from the independent-components maps. Pain was operationalized as the total number of neonatal intensive care unit-administered invasive procedures. Neurodevelopmental outcomes at 18-month corrected age were assessed with the Bayley Scales of Infant Development, second edition. Generalized estimating equations assessed the association of pain and glucose exposure with brain structural and functional development. More invasive procedures were independently associated with slower growth of thalamic (P < 0.001), basal ganglia (P = 0.028), and total brain volumes (P = 0.001), particularly in females. Similar relationships were observed between glucose exposure and brain volumes. Functional connectivity between thalamus and sensorimotor cortices was negatively associated with number of invasive procedures. Greater procedural pain and higher glucose exposure were related to poorer neurodevelopmental outcomes. These findings suggest that structural and functional brain development is vulnerable to procedural pain. Glucose used for analgesia does not appear to mitigate the adverse impact of pain on brain development. The vulnerability of brain development in females towards early pain is distinct from other neonatal morbidities. The link between pain and glucose with neurodevelopment suggests that these factors have long-lasting impact. [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]

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]

Oral sucrose is administered routinely to reduce pain of minor procedures in premature infants and is recommended as standard care in international guidelines. No human or animal studies on effects of early repeated sucrose exposure on long-term brain development have been done in the context of pain. We evaluated the effects of repeated neonatal sucrose treatment before an intervention on long-term brain structure in mouse pups. Neonatal C57Bl/6J mice (n = 109) were randomly assigned to one of 2 treatments (vehicle vs sucrose) and one of 3 interventions (handling, touch, or needle-prick). Mice received 10 interventions daily from postnatal day 1 to 6 (P1-6). A dose of vehicle or 24% sucrose was given orally 2 minutes before each intervention. At P85-95, brains were scanned using a multichannel 7.0 T MRI. Volumes of 159 independent brain regions were obtained. Early repetitive sucrose exposure in mice (after correcting for whole brain volume and multiple comparisons) lead to smaller white matter volumes in the corpus callosum, stria terminalis, and fimbria (P < 0.0001). Cortical and subcortical gray matter was also affected by sucrose with smaller volumes of hippocampus and cerebellum (P < 0.0001). These significant changes in adult brain were found irrespective of the type of intervention in the neonatal period. This study provides the first evidence of long-term adverse effects of repetitive sucrose exposure and raises concerns for the use of this standard pain management practice during a period of rapid brain development in very preterm infants. [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]

Background Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with an enhanced risk of preterm birth. Very preterm-born neonates (<32 weeks’ gestation) antenatally-exposed to SSRIs may show altered brain development. Objective To examine whether antenatal-SSRI exposure was associated with adverse neonatal brain microstructural and metabolic development using diffusion tensor and magnetic resonance spectroscopic imaging. Design/Methods Of 177 neonates enrolled, 14 (8%) were antenatally exposed to SSRIs. Neonates were scanned twice (median week 32; interquartile range [IQR]: 30.4–33.6) and again at term-equivalent age (40.1, IQR: 38.6–42.1). Using a region-of-interest approach, N-acetylaspartate to choline ratios (NAA/Cho), lactate to choline ratios, white and gray matter fractional anisotropy (FA), mean, axial, radial diffusivity (MD, AD, RD) values were extracted from white and gray matter subcortical regions. Neurodevelopment was assessed at 18 months, corrected age. Results SSRI-exposed neonates exhibited increased FA and decreased MD, AD and RD values in the superior white matter ( p < 0.05). FA values in the basal ganglia and thalamus were significantly lower in neonates antenatally exposed to SSRIs, compared to non-exposed ( p = 0.004). Lower NAA/Cho values ( p = 0.04) and higher Lactate/Cho values ( p = 0.004) in posterior gray matter were evident in neonates exposed to SSRIs. No association with antenatal-SSRI exposure and neurodevelopment was evident. Conclusions Given the importance of treating depression in mothers at risk for preterm delivery, the impact of antenatal-SSRIs on early brain development requires further attention. Future research is directed at determining the mechanism of this relationship and the contribution of maternal mood. [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]

We propose BrainNetCNN, a convolutional neural network (CNN) framework to predict clinical neurodevelopmental outcomes from brain networks. In contrast to the spatially local convolutions done in traditional image-based CNNs, our BrainNetCNN is composed of novel edge-to-edge, edge-to-node and node-to-graph convolutional filters that leverage the topological locality of structural brain networks. We apply the BrainNetCNN framework to predict cognitive and motor developmental outcome scores from structural brain networks of infants born preterm. Diffusion tensor images (DTI) of preterm infants, acquired between 27 and 46 weeks gestational age, were used to construct a dataset of structural brain connectivity networks. We first demonstrate the predictive capabilities of BrainNetCNN on synthetic phantom networks with simulated injury patterns and added noise. BrainNetCNN outperforms a fully connected neural-network with the same number of model parameters on both phantoms with focal and diffuse injury patterns. We then apply our method to the task of joint prediction of Bayley-III cognitive and motor scores, assessed at 18 months of age, adjusted for prematurity. We show that our BrainNetCNN framework outperforms a variety of other methods on the same data. Furthermore, BrainNetCNN is able to identify an infant's postmenstrual age to within about 2 weeks. Finally, we explore the high-level features learned by BrainNetCNN by visualizing the importance of each connection in the brain with respect to predicting the outcome scores. These findings are then discussed in the context of the anatomy and function of the developing preterm infant brain. [ABSTRACT FROM AUTHOR]