Neonatal intensive care unit stress is associated with brain development in preterm infants.
TL;DR: The impact on brain development of 1 potential factor, exposure to stressors in the neonatal intensive care unit, has not yet been studied in a systematic, prospective manner.
Abstract: Objective: Although many perinatal factors have been linked to adverse neurodevelopmental outcomes in very premature infants, much of the variation in outcome remains unexplained. The impact on brain development of 1 potential factor, exposure to stressors in the neonatal intensive care unit, has not yet been studied in a systematic, prospective manner. Methods: In this prospective cohort study of infants born at <30 weeks gestation, nurses were trained in recording procedures and cares. These recordings were used to derive Neonatal Infant Stressor Scale scores, which were employed to measure exposure to stressors. Magnetic resonance imaging (brain metrics, diffusion, and functional magnetic resonance imaging) and neurobehavioral examinations at term equivalent postmenstrual age were used to assess cerebral structure and function. Simple and partial correlations corrected for confounders, including immaturity and severity of illness, were used to explore these relations. Results: Exposure to stressors was highly variable, both between infants and throughout a single infant’s hospital course. Exposure to a greater number of stressors was associated with decreased frontal and parietal brain width, altered diffusion measures and functional connectivity in the temporal lobes, and abnormalities in motor behavior on neurobehavioral examination. Interpretation: Exposure to stressors in the Neonatal Intensive Care Unit is associated with regional alterations in brain structure and function. Further research into interventions that may decrease or mitigate exposure to stressors in the neonatal intensive care unit is warranted. ANN NEUROL 2011;70:541–549
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TL;DR: Every health care facility caring for neonates should implement a pain-prevention program that includes strategies for minimizing the number of painful procedures performed and a pain assessment and management plan.
Abstract: The prevention of pain in neonates should be the goal of all pediatricians and health care professionals who work with neonates, not only because it is ethical but also because repeated painful exposures have the potential for deleterious consequences. Neonates at greatest risk of neurodevelopmental impairment as a result of preterm birth (ie, the smallest and sickest) are also those most likely to be exposed to the greatest number of painful stimuli in the NICU. Although there are major gaps in knowledge regarding the most effective way to prevent and relieve pain in neonates, proven and safe therapies are currently underused for routine minor, yet painful procedures. Therefore, every health care facility caring for neonates should implement (1) a pain-prevention program that includes strategies for minimizing the number of painful procedures performed and (2) a pain assessment and management plan that includes routine assessment of pain, pharmacologic and nonpharmacologic therapies for the prevention of pain associated with routine minor procedures, and measures for minimizing pain associated with surgery and other major procedures.
345 citations
TL;DR: A new MR imaging scoring system provides a more comprehensive and objective classification of the nature and extent of abnormalities than existing measures and demonstrates a high prevalence of injury and growth impairment in both the WM and gray matter.
Abstract: BACKGROUND AND PURPOSE: WM injury is the dominant form of injury in preterm infants. However, other cerebral structures, including the deep gray matter and the cerebellum, can also be affected by injury and/or impaired growth. Current MR imaging injury assessment scales are subjective and are challenging to apply. Thus, we developed a new assessment tool and applied it to MR imaging studies obtained from very preterm infants at term age.
MATERIALS AND METHODS: MR imaging scans from 97 very preterm infants (< 30 weeks' gestation) and 22 healthy term-born infants were evaluated retrospectively. The severity of brain injury (defined by signal abnormalities) and impaired brain growth (defined with biometrics) was scored in the WM, cortical gray matter, deep gray matter, and cerebellum. Perinatal variables for clinical risks were collected.
RESULTS: In very preterm infants, brain injury was observed in the WM ( n =23), deep GM ( n =5), and cerebellum ( n =23). Combining measures of injury and impaired growth showed moderate to severe abnormalities most commonly in the WM ( n =38) and cerebellum ( n =32) but still notable in the cortical gray matter ( n =16) and deep gray matter ( n =11). WM signal abnormalities were associated with a reduced deep gray matter area but not with cerebellar abnormality. Intraventricular and/or parenchymal hemorrhage was associated with cerebellar signal abnormality and volume reduction. Multiple clinical risk factors, including prolonged intubation, prolonged parenteral nutrition, postnatal corticosteroid use, and postnatal sepsis, were associated with increased global abnormality on MR imaging.
CONCLUSIONS: Very preterm infants demonstrate a high prevalence of injury and growth impairment in both the WM and gray matter. This MR imaging scoring system provides a more comprehensive and objective classification of the nature and extent of abnormalities than existing measures.
GM
: gray matter
VPT
: very preterm
336 citations
TL;DR: Bronchopulmonary dysplasia was found to be a crucial factor for cognitive outcome and lowering the high incidence of BPD may be key to improving long-term outcomes after EP/VP birth.
Abstract: Importance Despite apparent progress in perinatal care, children born extremely or very preterm (EP/VP) remain at high risk for cognitive deficits. Insight into factors contributing to cognitive outcome is key to improve outcomes after EP/VP birth. Objective To examine the cognitive abilities of children of EP/VP birth (EP/VP children) and the role of perinatal and demographic risk factors. Data Sources PubMed, Web of Science, and PsycINFO were searched without language restriction (last search March 2, 2017). Key search terms included preterm , low birth weight , and intelligence . Study Selection Peer-reviewed studies reporting intelligence scores of EP/VP children ( Data Extraction and Synthesis MOOSE guidelines were followed. Data were independently extracted by 2 researchers. Standardized mean differences in intelligence per study were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using multivariate, random-effects meta-regression analysis. Main Outcomes and Measures Primary outcome was intelligence. Covariates included gestational age, birth weight, birth year, age at assessment, sex, race/ethnicity, socioeconomic status, small for gestational age, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, sepsis, and postnatal corticosteroid use. Results The 71 included studies comprised 7752 EP/VP children and 5155 controls. Median gestational age was 28.5 weeks (interquartile range [IQR], 2.4 weeks) and the mean age at assessment ranged from 5.0 to 20.1 years. The median proportion of males was 50.0% (IQR, 8.7%). Preterm children had a 0.86-SD lower IQ compared with controls (95% CI, −0.94 to −0.78, P I 2 = 74.13; P P Conclusions and Relevance Extremely or very preterm children born in the antenatal corticosteroids and surfactant era show large deficits in intelligence. No improvement in cognitive outcome was observed between 1990 and 2008. These findings emphasize that improving outcomes after EP/VP birth remains a major challenge. Bronchopulmonary dysplasia was found to be a crucial factor for cognitive outcome. Lowering the high incidence of BPD may be key to improving long-term outcomes after EP/VP birth.
314 citations
TL;DR: Though rich-club organization remains intact following premature birth, significant disruptions in both in cortical–subcortical connectivity and short-distance corticocortical connections are revealed.
Abstract: Combining diffusion magnetic resonance imaging and network analysis in the adult human brain has identified a set of highly connected cortical hubs that form a “rich club”—a high-cost, high-capacity backbone thought to enable efficient network communication. Rich-club architecture appears to be a persistent feature of the mature mammalian brain, but it is not known when this structure emerges during human development. In this longitudinal study we chart the emergence of structural organization in mid to late gestation. We demonstrate that a rich club of interconnected cortical hubs is already present by 30 wk gestation. Subsequently, until the time of normal birth, the principal development is a proliferation of connections between core hubs and the rest of the brain. We also consider the impact of environmental factors on early network development, and compare term-born neonates to preterm infants at term-equivalent age. Though rich-club organization remains intact following premature birth, we reveal significant disruptions in both in cortical–subcortical connectivity and short-distance corticocortical connections. Rich club organization is present well before the normal time of birth and may provide the fundamental structural architecture for the subsequent emergence of complex neurological functions. Premature exposure to the extrauterine environment is associated with altered network architecture and reduced network capacity, which may in part account for the high prevalence of cognitive problems in preterm infants.
306 citations
TL;DR: Severe brain injury and impaired brain growth patterns were independently associated with perinatal risk factors and delayed cognitive development and cerebral palsy at term-equivalent age.
Abstract: BACKGROUND: To define the nature and frequency of brain injury and brain growth impairment in very preterm (VPT) infants by using MRI at term-equivalent age and to relate these findings to perinatal risk factors and 2-year neurodevelopmental outcomes.
METHODS: MRI scans at term-equivalent age from 3 VPT cohorts ( n = 325) were reviewed. The severity of brain injury, including periventricular leukomalacia and intraventricular and cerebellar hemorrhage, was graded. Brain growth was assessed by using measures of biparietal width (BPW) and interhemispheric distance. Neurodevelopmental outcome at age 2 years was assessed across all cohorts ( n = 297) by using the Bayley Scales of Infant Development, Second Edition (BSID-II) or Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and evaluation for cerebral palsy.
RESULTS: Of 325 infants, 107 (33%) had some grade of brain injury and 33 (10%) had severe injury. Severe brain injury was more common in infants with lower Apgar scores, necrotizing enterocolitis, inotropic support, and patent ductus arteriosus. Severe brain injury was associated with delayed cognitive and motor development and cerebral palsy. Decreased BPW was related to lower gestational age, inotropic support, patent ductus arteriosus, necrotizing enterocolitis, prolonged parenteral nutrition, and oxygen at 36 weeks and was associated with delayed cognitive development. In contrast, increased interhemispheric distance was related to male gender, dexamethasone use, and severe brain injury. It was also associated with reduced cognitive development, independent of BPW.
CONCLUSIONS: At term-equivalent age, VPT infants showed both brain injury and impaired brain growth on MRI. Severe brain injury and impaired brain growth patterns were independently associated with perinatal risk factors and delayed cognitive development.
278 citations
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...001 Inotropic support, n (%) 127 (39) 26 (44) 75 (41) 26 (32) ....
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References
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TL;DR: Moderate-to-severe white-matter abnormalities on MRI were significant predictors of severe motor delay and cerebral palsy after adjustment for other measures during the neonatal period, including findings on cranial ultrasonography.
Abstract: Background Very preterm infants are at high risk for adverse neurodevelopmental outcomes. Magnetic resonance imaging (MRI) has been proposed as a means of predicting neurodevelopmental outcomes in this population. Methods We studied 167 very preterm infants (gestational age at birth, 30 weeks or less) to assess the associations between qualitatively defined white-matter and gray-matter abnormalities on MRI at term equivalent (gestational age of 40 weeks) and the risks of severe cognitive delay, severe psychomotor delay, cerebral palsy, and neurosensory (hearing or visual) impairment at 2 years of age (corrected for prematurity). Results At two years of age, 17 percent of infants had severe cognitive delay, 10 percent had severe psychomotor delay, 10 percent had cerebral palsy, and 11 percent had neurosensory impairment. Moderate-to-severe cerebral white-matter abnormalities present in 21 percent of infants at term equivalent were predictive of the following adverse outcomes at two years of age: cognitive ...
1,162 citations
"Neonatal intensive care unit stress..." refers methods in this paper
...Brain injury was scored using 4 scales representing white matter, cortical gray matter, deep nuclear gray matter, and cerebellar injury, which were summed to produce a total MRI injury score.(16) Eight measurements were made on tissue and fluid spaces, including bifrontal, brain and bone biparietal, white matter, transverse cerebellar, and right and left lateral ventricular diameters and interhemispheric distance....
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TL;DR: The data indicate that preterm birth is associated with regionally specific, long-term reductions in brain volume and that morphological abnormalities are, in turn, associated with poorer cognitive outcome.
Abstract: ContextPreterm infants have a high prevalence of long-term cognitive and behavioral
disturbances. However, it is not known whether the stresses associated with
premature birth disrupt regionally specific brain maturation or whether abnormalities
in brain structure contribute to cognitive deficits.ObjectiveTo determine whether regional brain volumes differ between term and
preterm children and to examine the association of regional brain volumes
in prematurely born children with long-term cognitive outcomes.Design and SettingCase-control study conducted in 1998 and 1999 at 2 US university medical
schools.ParticipantsA consecutive sample of 25 eight-year-old preterm children recruited
from a longitudinal follow-up study of preterm infants and 39 term control
children who were recruited from the community and who were comparable with
the preterm children in age, sex, maternal education, and minority status.Main Outcome MeasuresVolumes of cortical subdivisions, ventricular system, cerebellum, basal
ganglia, corpus callosum, amygdala, and hippocampus, derived from structural
magnetic resonance imaging scans and compared between preterm and term children;
correlations of regional brain volumes with cognitive measures (at age 8 years)
and perinatal variables among preterm children.ResultsRegional cortical volumes were significantly smaller in the preterm
children, most prominently in sensorimotor regions (difference: left, 14.6%;
right, 14.3% [P<.001 for both]) but also in premotor
(left, 11.2%; right, 12.6% [P<.001 for both]),
midtemporal (left, 7.4% [P = .01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P = .01]; right, 7.4% [P = .005]), and subgenual
(left, 8.9% [P = .03]; right, 11.7% [P = .01]) cortices. Preterm children's brain volumes were significantly
larger (by 105.7%-271.6%) in the occipital and temporal horns of the ventricles
(P<.001 for all) and smaller in the cerebellum (6.7%; P = .02), basal ganglia (11.4%-13.8%; P≤.005),
amygdala (left, 20.2% [P = .001]; right, 30.0% [P<.001]), hippocampus (left, 16.0% [P = .001]; right, 12.0% [P = .007]), and corpus
callosum (13.1%-35.2%; P≤.01 for all). Volumes
of sensorimotor and midtemporal cortices were associated positively with full-scale,
verbal, and performance IQ scores (P<.01 for all).ConclusionsOur data indicate that preterm birth is associated with regionally specific,
long-term reductions in brain volume and that morphological abnormalities
are, in turn, associated with poorer cognitive outcome.
964 citations
TL;DR: Hippocampal volume was directly correlated with combat exposure, which suggests that traumatic stress may damage the hippocampus and smaller hippocampi volume may be a pre-existing risk factor for combat exposure and/or the development of PTSD upon combat exposure.
827 citations
"Neonatal intensive care unit stress..." refers result in this paper
...to selectively reduce hippocampal volume in rats,(27) and studies on post-traumatic stress disorder in humans support this finding.(28) Although this study did not specifically examine the effects of exposure to stressors on the hippocampus, it is possible that some of the changes seen in temporal lobe microstructure and connectivity may also be reflected in altered hippocampal size and structure....
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TL;DR: This is the first in vivo evidence of enhanced brain function and structure due to the NIDCAP, and demonstrates that quality of experience before term may influence brain development significantly.
Abstract: Objective. To investigate the effects of early experience on brain function and structure. Methods. A randomized clinical trial tested the neu- rodevelopmental effectiveness of the Newborn Individ- ualized Developmental Care and Assessment Program (NIDCAP). Thirty preterm infants, 28 to 33 weeks' ges- tational age (GA) at birth and free of known develop- mental risk factors, participated in the trial. NIDCAP was initiated within 72 hours of intensive care unit admission and continued to the age of 2 weeks, corrected for pre- maturity. Control (14) and experimental (16) infants were assessed at 2 weeks' and 9 months' corrected age on health status, growth, and neurobehavior, and at 2 weeks' corrected age additionally on electroencephalogram spec- tral coherence, magnetic resonance diffusion tensor im- aging, and measurements of transverse relaxation time. Results. The groups were medically and demograph- ically comparable before as well as after the treatment. However, the experimental group showed significantly better neurobehavioral functioning, increased coherence between frontal and a broad spectrum of mainly occipital brain regions, and higher relative anisotropy in left in- ternal capsule, with a trend for right internal capsule and frontal white matter. Transverse relaxation time showed no difference. Behavioral function was improved also at 9 months' corrected age. The relationship among the 3 neurodevelopmental domains was significant. The re- sults indicated consistently better function and more ma- ture fiber structure for experimental infants compared with their controls. Conclusions. This is the first in vivo evidence of en- hanced brain function and structure due to the NIDCAP. The study demonstrates that quality of experience before term may influence brain development significantly. Pe- diatrics 2004;113:846 - 857; preterm infants, NIDCAP, neu- robehavior, spectral coherence, diffusion tensor imaging, transverse relaxation time, Bayley Scales of Infant Devel- opment, APIB.
807 citations
TL;DR: 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 of prematurely born infants.
Abstract: 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.
676 citations
"Neonatal intensive care unit stress..." refers background or methods in this paper
...Recent studies have shown differences in functional connectivity between term and preterm infants at term equivalent age, with preterm infants demonstrating decreased correlation, decreased long-range connectivity, and lack of emergence of the default mode network compared to term infants.(18) We found a specific association of high stress exposure with altered interhemispheric connections between the temporal lobes....
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...The BOLD time series for seed regions was then cross-correlated with all other voxels within the brain, generating correlation maps identifying regions with functional connection to the regions of interest.(18)...
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