Objective To evaluate associations between neonatal intensive care unit (NICU) room type (open ward and private room) and medical outcomes; neurobehavior, electrophysiology, and brain structure at ...hospital discharge; and developmental outcomes at 2 years of age. Study design In this prospective longitudinal cohort study, we enrolled 136 preterm infants born <30 weeks gestation from an urban, 75-bed level III NICU from 2007-2010. Upon admission, each participant was assigned to a bedspace in an open ward or private room within the same hospital, based on space and staffing availability, where they remained for the duration of hospitalization. The primary outcome was developmental performance at 2 years of age (n = 86 infants returned for testing, which was 83% of survivors) measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition. Secondary outcomes were: (1) medical factors throughout the hospitalization; (2) neurobehavior; and (3) cerebral injury and maturation (determined by magnetic resonance imaging and electroencephalography). Results At term equivalent age, infants in private rooms were characterized by a diminution of normal hemispheric asymmetry and a trend toward having lower amplitude integrated electroencephalography cerebral maturation scores ( P = .02; β = −0.52 CI −0.95, −0.10). At age 2 years, infants from private rooms had lower language scores ( P = .006; β = −8.3 CI −14.2, −2.4) and a trend toward lower motor scores ( P = .02; β = −6.3 CI −11.7, −0.99), which persisted after adjustment for potential confounders. Conclusion These findings raise concerns that highlight the need for further research into the potential adverse effects of different amounts of sensory exposure in the NICU environment.
Recent resting-state functional MRI investigations have demonstrated that much of the large-scale functional network architecture supporting motor, sensory and cognitive functions in older pediatric ...and adult populations is present in term- and prematurely-born infants. Application of new analytical approaches can help translate the improved understanding of early functional connectivity provided through these studies into predictive models of neurodevelopmental outcome. One approach to achieving this goal is multivariate pattern analysis, a machine-learning, pattern classification approach well-suited for high-dimensional neuroimaging data. It has previously been adapted to predict brain maturity in children and adolescents using structural and resting state-functional MRI data. In this study, we evaluated resting state-functional MRI data from 50 preterm-born infants (born at 23–29weeks of gestation and without moderate–severe brain injury) scanned at term equivalent postmenstrual age compared with data from 50 term-born control infants studied within the first week of life. Using 214 regions of interest, binary support vector machines distinguished term from preterm infants with 84% accuracy (p<0.0001). Inter- and intra-hemispheric connections throughout the brain were important for group categorization, indicating that widespread changes in the brain's functional network architecture associated with preterm birth are detectable by term equivalent age. Support vector regression enabled quantitative estimation of birth gestational age in single subjects using only term equivalent resting state-functional MRI data, indicating that the present approach is sensitive to the degree of disruption of brain development associated with preterm birth (using gestational age as a surrogate for the extent of disruption). This suggests that support vector regression may provide a means for predicting neurodevelopmental outcome in individual infants.
•Multivariate pattern analysis was applied to neonatal functional MRI data.•Support vector machines accurately distinguished term- from preterm-born infants.•Differences in inter- and intrahemispheric functional connectivity were widespread.•Support vector regression estimated birth gestational age of individual infants.•Results suggest potential for presymptomatic prediction of developmental outcomes.
Alterations in the normal developmental trajectory of amygdala resting state functional connectivity (rs-FC) have been associated with atypical emotional processes and psychopathology. Little is ...known, however, regarding amygdala rs-FC at birth or its relevance to outcomes. This study examined amygdala rs-FC in healthy, full-term (FT) infants and in very preterm (VPT) infants, and tested whether variability of neonatal amygdala rs-FC predicted internalizing symptoms at age 2 years.
Resting state fMRI data were obtained shortly after birth from 65 FT infants (gestational age GA ≥36 weeks) and 57 VPT infants (GA <30 weeks) at term equivalent. Voxelwise correlation analyses were performed using individual-specific bilateral amygdala regions of interest. Total internalizing symptoms and the behavioral inhibition, depression/withdrawal, general anxiety, and separation distress subdomains were assessed in a subset (n = 44) at age 2 years using the Infant Toddler Social Emotional Assessment.
In FT and VPT infants, the amygdala demonstrated positive correlations with subcortical and limbic structures and negative correlations with cortical regions, although magnitudes were decreased in VPT infants. Neonatal amygdala rs-FC predicted internalizing symptoms at age 2 years with regional specificity consistent with known pathophysiology in older populations: connectivity with the anterior insula related to depressive symptoms, with the dorsal anterior cingulate related to generalized anxiety, and with the medial prefrontal cortex related to behavioral inhibition.
Amygdala rs-FC is well established in neonates. Variability in regional neonatal amygdala rs-FC predicted internalizing symptoms at 2 years, suggesting that risk for internalizing symptoms may be established in neonatal amygdala functional connectivity patterns.
Spatial and functional gradients of development have been described for the maturation of cerebral gray and white matter using histological and radiological approaches. We evaluated these patterns in ...very preterm (VPT) infants using diffusion tensor imaging. Data were obtained from 3 groups: 1) 22 VPT infants without white matter injury (WMI), of whom all had serial MRI studies during the neonatal period, 2) 19 VPT infants with WMI, of whom 3 had serial MRI studies and 3) 12 healthy, term-born infants. Regions of interest were placed in the cortical gray and adjacent white matter in primary motor, primary visual, visual association, and prefrontal regions. From the MRI data at term-equivalent postmenstrual age, differences in mean diffusivity were found in all areas between VPT infants with WMI and the other 2 groups. In contrast, minimal differences in fractional anisotropy were found between the 3 groups. These findings suggest that cortical maturation is delayed in VPT infants with WMI when compared with term control infants and VPT infants without WMI. From the serial MRI data from VPT infants, synchronous development between gray and white matter was evident in all areas and all groups, with maturation in primary motor and sensory regions preceding that of association areas. This finding highlights the regionally varying but locally synchronous nature of the development of cortical gray matter and its adjacent white matter.
To assess the extent to which social and family factors explain variability in cognitive, language, and motor development among very preterm (<30 weeks of gestation) children from 2 to 5 years of ...age.
As part of a longitudinal study, very preterm children recruited as neonates were assessed at 2 (n = 87) and 5 (n = 83) years of age using standardized tests of cognitive, language, and motor ability alongside demographically matched full term (FT) children (n = 63). For very preterm children, developmental change scores were calculated for each domain to assess within-individual variability to 5 years of age. Multivariate regression and mixed-effect models examined social risk index, parenting stress, family functioning, and maternal intellectual ability as predictors of developmental variation among very preterm children.
Very preterm children demonstrated poorer cognitive, language, and motor abilities than FT children at 2 (P ≤ .001) and 5 (P < .002) years of age. Social adversity was associated with cognitive (P < .001) and language (P < .001) outcomes at both ages, with parenting stress also related to cognitive outcomes (P = .03). Infant medical risk was associated with motor outcome at 5 years (P=.01). Very preterm children showed considerable within-individual variation between assessments. Among very preterm children, neonatal white matter abnormalities predicted worsening cognitive (P=.04) and motor development (P = .01). Social risk index predicted worsening language development (P = .04), but this association was subsequently explained by dysfunctional maternal affective involvement (P = .01) and lower maternal intellectual ability (P = .05).
Both clinical and socioenvironmental factors are associated with cognitive, language, and motor developmental variation among very preterm children from infancy to early school age.
Application of resting state functional connectivity magnetic resonance imaging (fcMRI) to the study of prematurely born infants enables assessment of the earliest forms of cerebral connectivity and ...characterization of its early development in the human brain. We obtained 90 longitudinal fcMRI data sets from a cohort of preterm infants aged from 26 weeks postmenstrual age (PMA) through term equivalent age at PMA-specific time points. Utilizing seed-based correlation analysis, we identified resting state networks involving varied cortical regions, the thalamus, and cerebellum. Identified networks demonstrated a regionally variable age-specific pattern of development, with more mature forms consisting of localized interhemispheric connections between homotopic counterparts. Anatomical distance was found to play a critical role in the rate of connection development. Prominent differences were noted between networks identified in term control versus premature infants at term equivalent, including in the thalamocortical connections critical for neurodevelopment. Putative precursors of the default mode network were detected in term control infants but were not identified in preterm infants, including those at term equivalent. Identified patterns of network maturation reflect the intricate relationship of structural and functional processes present throughout this important developmental period and are consistent with prior investigations of neurodevelopment in this population.
Preterm infants are at high risk for brain injury during the perinatal period. Intraventricular hemorrhage and periventricular leukomalacia, the two most common patterns of brain injury in ...prematurely-born children, are associated with poor neurodevelopmental outcomes. The hippocampus is known to be critical for learning and memory; however, it remains unknown how these forms of brain injury affect hippocampal growth and how the resulting alterations in hippocampal development relate to childhood outcomes. To investigate these relationships, hippocampal segmentations were performed on term equivalent MRI scans from 55 full-term infants, 85 very preterm infants (born ≤32 weeks gestation) with no to mild brain injury and 73 very preterm infants with brain injury (e.g., grade III/IV intraventricular hemorrhage, post-hemorrhagic hydrocephalus, cystic periventricular leukomalacia). Infants then underwent standardized neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, 3rd edition at age 2 years, corrected for prematurity. To delineate the effects of brain injury on early hippocampal development, hippocampal volumes were compared across groups and associations between neonatal volumes and neurodevelopmental outcomes at age 2 years were explored. Very preterm infants with brain injury had smaller hippocampal volumes at term equivalent age compared to term and very preterm infants with no to mild injury, with the smallest hippocampi among those with grade III/IV intraventricular hemorrhage and post-hemorrhagic hydrocephalus. Further, larger ventricle size was associated with smaller hippocampal size. Smaller hippocampal volumes were related to worse motor performance at age 2 years across all groups. In addition, smaller hippocampal volumes in infants with brain injury were correlated with impaired cognitive scores at age 2 years, a relationship specific to this group. Consistent with our preclinical findings, these findings demonstrate that perinatal brain injury is associated with hippocampal size in preterm infants, with smaller volumes related to domain-specific neurodevelopmental impairments in this high-risk clinical population.
Advanced neuroimaging techniques have been increasingly applied to the study of preterm and term infants in an effort to further define the functional cerebral architecture of the developing brain. ...Despite improved understanding of the complex relationship between structure and function obtained through these investigations, significant questions remain regarding the nature, location, and timing of the maturational changes which occur during early development. Functional connectivity magnetic resonance imaging (fcMRI) utilizes spontaneous, low frequency (< 0.1Hz), coherent fluctuations in blood oxygen level dependent (BOLD) signal to identify networks of functional cerebral connections. Due to the intrinsic characteristics of its image acquisition and analysis, fcMRI offers a novel neuroimaging approach well suited to investigation of infants. Recently, this methodology has been successfully applied to examine neonatal populations, defining normative patterns of large-scale neural network development in the maturing brain. The resting-state networks (RSNs) identified in these studies reflect the evolving cerebral structural architecture, presumably driven by varied genetic and environmental influences. Principal features of these investigations and their role in characterization of the tenets of neural network development during this critical developmental period are highlighted in this review. Despite these successes, optimal methods for fcMRI data acquisition and analysis for this population have not yet been defined. Further, appropriate schemes for interpretation and translation of fcMRI results remain unknown, a matter of increasing importance as functional neuroimaging findings are progressively applied in the clinical arena. Notwithstanding these concerns, fcMRI provides insight into the earliest forms of cerebral connectivity and therefore holds great promise for future neurodevelopmental investigations.
► Resting-state fcMRI enables identification of the earliest neural networks. ► Limited fcMRI investigations of preterm and term infants have been completed. ► RSNs are identifiable in cortical and subcortical regions in infants. ► Functional and anatomical connections are interrelated, but not identical. ► fcMRI offers great promise as an investigational tool of neurodevelopment.
Health disparities are driven by underlying social disadvantage and psychosocial stressors. However, how social disadvantage and psychosocial stressors lead to adverse health outcomes is unclear, ...particularly when exposure begins prenatally. Variations in the gut microbiome and circulating proinflammatory cytokines offer potential mechanistic pathways. Here, we interrogate the gut microbiome of mother-child dyads to compare high-versus-low prenatal social disadvantage, psychosocial stressors and maternal circulating cytokine cohorts (prospective case-control study design using gut microbiomes from 121 dyads profiled with 16 S rRNA sequencing and 89 dyads with shotgun metagenomic sequencing). Gut microbiome characteristics significantly predictive of social disadvantage and psychosocial stressors in the mothers and children indicate that different discriminatory taxa and related pathways are involved, including many species of Bifidobacterium and related pathways across several comparisons. The lowest inter-individual gut microbiome similarity was observed among high-social disadvantage/high-psychosocial stressors mothers, suggesting distinct environmental exposures driving a diverging gut microbiome assembly compared to low-social disadvantage/low-psychosocial stressors controls (P = 3.5 × 10
for social disadvantage, P = 2.7 × 10
for psychosocial stressors). Children's gut metagenome profiles at 4 months also significantly predicted high/low maternal prenatal IL-6 (P = 0.029), with many bacterial species overlapping those identified by social disadvantage and psychosocial stressors. These differences, based on maternal social and psychological status during a critical developmental window early in life, offer potentially modifiable targets to mitigate health inequities.
Objective To evaluate the safety and short-term outcomes of preterm neonates born at 34-35 weeks gestation with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia. Study ...design Medical records of preterm neonates born at 34-35 weeks gestational age with HIE treated with therapeutic hypothermia were retrospectively reviewed. Short-term safety outcomes and the presence, severity (mild, moderate, severe), and patterns of brain injury on magnetic resonance imaging were reviewed using a standard scoring system, and compared with a cohort of term neonates with HIE treated with therapeutic hypothermia. Results Thirty-one preterm and 32 term neonates were identified. Therapeutic hypothermia-associated complications were seen in 90% of preterm infants and 81.3% of term infants ( P = .30). In the preterm infants, hyperglycemia (58.1% vs31.3%, P = .03) and rewarming before completion of therapeutic hypothermia (19.4% vs 0.0%, P = .009) were more likely compared with term infants. All deaths occurred in the preterm group (12.9% vs 0%, P = .04). Neuroimaging showed the presence of injury in 80.6% of preterm infants and 59.4% of term infants ( P = .07), with no differences in injury severity. Injury to the white matter was more prevalent in preterm infants compared with term infants (66.7% vs 25.0%, P = .001). Conclusions Therapeutic hypothermia in infants born at 34-35 weeks gestational age appears feasible. Risks of mortality and side effects warrant caution with use of therapeutic hypothermia in preterm infants.
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