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OBJECTIVE: Breast milk exposure is associated with improved neurocognitive outcomes following preterm birth but the neural substrates linking breast milk with outcome are uncertain. We tested the hypothesis that high versus low breast milk exposure in preterm infants results in cortical morphology that more closely resembles that of term-born infants.METHODS: We studied 135 preterm (RESULTS: In preterm infants, high breast milk exposure was associated with reduced cortical gray matter volume (d = 0.47, 95% confidence interval [CI] = 0.14 to 0.94, p = 0.014), thickness (d = 0.42, 95% CI = 0.08 to 0.84, p = 0.039), and RD (d = 0.38, 95% CI = 0.002 to 0.77, p = 0.039), and increased FA (d = -0.38, 95% CI = -0.74 to -0.01, p = 0.037) after adjustment for age at MRI, which was similar to the cortical phenotype observed in term-born controls. Breast milk exposure quartile was associated with cortical volume (ß = -0.192, 95% CI = -0.342 to -0.042, p = 0.017), FA (ß = 0.223, 95% CI = 0.075 to 0.372, p = 0.007), and RD (ß = -0.225, 95% CI = -0.373 to -0.076, p = 0.007) following adjustment for age at birth, age at MRI, and weighted by propensity scores, suggesting a dose effect.INTERPRETATION: High breast milk exposure following preterm birth is associated with a cortical imaging phenotype that more closely resembles the brain morphology of term-born infants and effects appear to be dose-dependent. ANN NEUROL 2022.

ImportancePreterm birth and socioeconomic status (SES) are associated with brain structure in childhood, but the relative contributions of each during the neonatal period are unknown.ObjectiveTo investigate associations of birth gestational age (GA) and SES with neonatal brain morphology by testing 3 hypotheses: GA and SES are associated with brain morphology; associations between SES and brain morphology vary with GA; and associations between SES and brain structure and morphology depend on how SES is operationalized.Design, Setting, and ParticipantsThis cohort study recruited participants from November 2016 to September 2021 at a single center in the United Kingdom. Participants were 170 extremely and very preterm infants and 91 full-term or near-term infants. Exclusion criteria were major congenital malformation, chromosomal abnormality, congenital infection, cystic periventricular leukomalacia, hemorrhagic parenchymal infarction, and posthemorrhagic ventricular dilatation.ExposuresBirth GA and SES, operationalized at the neighborhood level (using the Scottish Index of Multiple Deprivation), the family level (using parental education and occupation), and subjectively (World Health Organization Quality of Life measure).Main Outcomes and MeasuresBrain volume (85 parcels) and 5 whole-brain cortical morphology measures (gyrification index, thickness, sulcal depth, curvature, surface area) at term-equivalent age (median [range] age, 40 weeks, 5 days [36 weeks, 2 days to 45 weeks, 6 days] and 42 weeks [38 weeks, 2 days to 46 weeks, 1 day] for preterm and full-term infants, respectively).ResultsParticipants were 170 extremely and very preterm infants (95 [55.9%] male; 4 of 166 [2.4%] Asian, 145 of 166 [87.3%] White) and 91 full-term or near-term infants (50 [54.9%] male; 3 of 86 [3.5%] Asian, 78 of 86 [90.7%] White infants) with median (range) birth GAs of 30 weeks, 0 days (22 weeks, 1 day, to 32 weeks, 6 days) and 39 weeks, 4 days (36 weeks, 3 days, to 42 weeks, 1 day), respectively. In fully adjusted models, birth GA was associated with a higher proportion of brain volumes (27 of 85 parcels [31.8%]; β range, −0.20 to 0.24) than neighborhood-level SES (1 of 85 parcels [1.2%]; β = 0.17 [95% CI, −0.16 to 0.50]) or family-level SES (maternal education: 4 of 85 parcels [4.7%]; β range, 0.09 to 0.15; maternal occupation: 1 of 85 parcels [1.2%]; β = 0.06 [95% CI, 0.02 to 0.11] respectively). There were interactions between GA and both family-level and subjective SES measures on regional brain volumes. Birth GA was associated with cortical surface area (β = 0.10 [95% CI, 0.02 to 0.18]) and gyrification index (β = 0.16 [95% CI, 0.07 to 0.25]); no SES measure was associated with cortical measures.Conclusions and RelevanceIn this cohort study of UK infants, birth GA and SES were associated with neonatal brain morphology, but low GA had more widely distributed associations with neonatal brain structure than SES. Further work is warranted to elucidate the mechanisms underlying the association of both GA and SES with early brain development.

ObjectiveTo determine if preterm birth is associated with adaptation of the hypothalamic–pituitary–adrenal (HPA) axis and whether HPA axis programming relates to the degree of prematurity (defined as extremely preterm birth at DesignThis study reports findings from a prospective birth cohort. Saliva cortisol concentrations were measured prevaccination and postvaccination, and in the morning and evening, at 4 months chronological age.SettingInfants born at a single Scottish hospital.Participants45 term-born, 42 very preterm and 16 extremely preterm infants.OutcomesCortisol stress response to vaccination (postvaccination minus prevaccination cortisol concentrations), diurnal slope (log-transformed morning minus log-transformed evening cortisol values) and mean log-transformed daily cortisol.ResultsCompared with infants born at term, infants born extremely preterm had a blunted cortisol response to vaccination (5.8 nmol/L vs 13.1 nmol/L, difference in means: −7.3 nmol/L, 95% CI −14.0 to −0.6) and a flattened diurnal slope (difference in geometric means: −72.9%, 95% CI −87.1 to −42.8). In contrast, the cortisol response to vaccination (difference in means −2.7 nmol/L, 95% CI −7.4 to 2.0) and diurnal slope at 4 months (difference in geometric means: −33.6%, 95% CI −62.0 to 16.0) did not differ significantly in infants born very preterm compared with infants born at term.ConclusionsInfants born extremely preterm have blunted cortisol reactivity and a flattened diurnal slope. These patterns of HPA axis regulation are commonly seen after childhood adversity and could contribute to later metabolic and neurodevelopmental phenotypes observed in this population.

BackgroundPreterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown.MethodsUsing salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 – 34.84 weeks, n = 103 term, gestational age at birth 37.00 – 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity.ResultsHigher DNAm CRP was linked to preterm status (−0.0107 ± 0.0008, compared with - 0.0118 ± 0.0006 among term infants; p < 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p < 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippocampi and amygdalae (β range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (β range |0.206| to |0.371|), independent of other confounding exposures.ConclusionsEpigenetic biomarkers of inflammation provide an index of innate immunity in relation to neonatal health. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences.

A cardinal feature of the encephalopathy of prematurity is injury/dysmaturation of developing white matter and subsequent hypomyelination. Magnetisation transfer imaging (MTI) offers surrogate markers for myelination including magnetisation transfer ratio (MTR) and magnetisation transfer saturation (MTsat). In this work, using data from 105 neonates, we use MTR, MTsat and approximation of R1 (R1app) to characterise myelination in the developing brain by investigating how these measures are affected by gestational age at scan and preterm birth. We explore correlations of the three measures with fractional anisotropy (FA) and T1w/T2w ratio which are commonly used markers of white matter integrity in development. We used two complementary analysis methods: voxel-wise analysis across the white matter skeleton, and tract-of-interest analysis across 16 major white matter tracts. We found that MTR, MTsat and R1app positively correlate with gestational age at scan. Preterm infants at term-equivalent age had lower values of R1app across the brain and MTsat in the genu and splenium of the corpus callosum, while MTR was higher in central white matter regions, the cortico-spinal tract and the uncinate fasciculus. Correlations of MTI metrics with FA and T1w/T2w ratio revealed that there were moderate positive correlations between T1w/T2w and MTsat and MTR at voxel-level, but at tract-level FA had stronger positive correlations with these metrics. This work demonstrates that MTI captures features consistent with lower myelination and cellular/axonal density in preterm infants at term-equivalent age compared to term controls. Furthermore, correlations between MTI-derived features and conventional measures from dMRI could provide new understanding about the contribution of myelination to non-specific imaging metrics used to characterise early brain development.HighlightsWe applied magnetisation transfer imaging (MTI) in the neonatal brainMTR, MTsat and R1app positively correlate with gestational age at scanPreterm birth associated with lower values of R1app and MTsat, and higher MTRCorrelations between MTI and other white matter integrity metrics were exploredMTI captures myelin progression and suggests lower myelination in the preterm brain

Background Preterm birth can lead to impaired language development. This study aimed to predict language outcomes at 2 years corrected gestational age (CGA) for children born preterm. Methods We analysed data from 89 preterm neonates (median GA 29 weeks) who underwent diffusion MRI (dMRI) at term-equivalent age and language assessment at 2 years CGA using the Bayley-III. Feature selection and a random forests classifier were used to differentiate typical versus delayed (Bayley-III language composite score Results The model achieved balanced accuracy: 91%, sensitivity: 86%, and specificity: 96%. The probability of language delay at 2 years CGA is increased with: increasing values of peak width of skeletonized fractional anisotropy (PSFA), radial diffusivity (PSRD), and axial diffusivity (PSAD) derived from dMRI; among twins; and after an incomplete course of, or no exposure to, antenatal corticosteroids. Female sex and breastfeeding during the neonatal period reduced the risk of language delay. Conclusions The combination of perinatal clinical information and MRI features leads to accurate prediction of preterm infants who are likely to develop language deficits in early childhood. This model could potentially enable stratification of preterm children at risk of language dysfunction who may benefit from targeted early interventions. Impact A combination of clinical perinatal factors and neonatal DTI measures of white matter microstructure leads to accurate prediction of language outcome at 2 years corrected gestational age following preterm birth. A model that comprises clinical and MRI features that has potential to be scalable across centres. It offers a basis for enhancing the power and generalizability of diagnostic and prognostic studies of neurodevelopmental disorders associated with language impairment. Early identification of infants who are at risk of language delay, facilitating targeted early interventions and support services, which could improve the quality of life for children born preterm.

Structured abstractImportancePreterm birth and socioeconomic status (SES) are associated with brain structure in childhood, but the relative contributions of each during the neonatal period are unknown.ObjectiveTo investigate associations of gestational age (GA) and SES with neonatal brain morphology, by testing 3 hypotheses: GA and SES are associated with brain morphology; associations between SES and brain morphology vary across the GA range, and; associations between SES and brain structure/morphology depend on how SES is operationalized.DesignCohort study, recruited 2016-2021.SettingSingle center, UK.Participants170 preterm infants and 91 term infants with median (range) birth GA 30+0(22+1-32+6) and 39+4(36+3-42+1) weeks, respectively. Exclusion criteria: major congenital malformation, chromosomal abnormality, congenital infection, cystic periventricular leukomalacia, hemorrhagic parenchymal infarction, post-hemorrhagic ventricular dilatation.ExposuresUsing linear ridge regression models, we investigated associations of GA and SES, operationalized at the neighborhood-level (Scottish Index of Multiple Deprivation), family-level (parental education and occupation) and subjectively (WHO Quality of Life), with regional brain volumes and cortical morphology.Main outcomes/measuresBrain volume (85 parcels) and 5 whole-brain cortical morphology measures (gyrification index, thickness, sulcal depth, curvature, surface area) at term-equivalent age.ResultsIn fully adjusted models, GA associated with a higher proportion of brain volumes (22/85 [26%], β range |-0.13| to |0.22|) than neighborhood SES (1/85 [1%], β=0.17). GA associated with cortical surface area (β=0.10 [95% confidence interval (CI) 0.02-0.18]) and gyrification index (β=0.16 [95% CI 0.07-0.25]); neighborhood SES did not. Family-level SES associated with the volumes of more parcels than neighborhood SES, but it did not have as extensive associations with brain structure as GA. There were interactions between GA and both family- and subjective-level SES measures on brain structure.Conclusions/relevanceIn a UK cohort, GA and SES impact neonatal brain morphology, but low GA has more widely distributed effects on neonatal brain structure than neighborhood-level, family-level and subjective measures of SES. Further work is warranted to elucidate the mechanisms embedding GA and level-specific SES in early brain development.Three key pointsQuestionWhat are the impacts of preterm birth and socioeconomic status (SES), operationalized at neighborhood, family, and subjective levels, on neonatal brain structure?FindingAfter mutual adjustment, both low gestational age (GA) and SES associate with brain structure. The nature of SES-brain structure associations varies depending how SES is operationalized; there are interactions between GA and measures of family- and subjective-level SES on brain structure.MeaningLow GA, and to a lesser extent SES, are associated with neonatal brain structure. Further work is required to elucidate the mechanisms that embed preterm birth and level-specific SES in the developing brain.

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multi-modal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development. Preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.

Injury to the developing brain during the perinatal period often causes hypomyelination, leading to clinical deficits for which there is an unmet therapeutic need. Dysregulation of inflammation and microglia have been implicated, yet the molecular mechanisms linking these to hypomyelination are unclear. Using human infant cerebrospinal fluid (CSF) and postmortem tissue, we found that microglial activation of the pro‐inflammatory molecular complex the NLRP3 inflammasome is associated with pathology. By developing a novel mouse brain explant model of microglial inflammasome activation, we demonstrate that blocking the inflammasome rescues myelination. In human and mouse, we discovered a link between the inflammasome product IL1β and increased levels of follistatin, an endogenous inhibitor of activin‐A. Follistatin treatment was sufficient to reduce myelination, whereas myelination was rescued in injured explants upon follistatin neutralization or supplementation with exogenous activin‐A. Our data reveal that inflammasome activation in microglia drives hypomyelination and identifies novel therapeutic strategies to reinstate myelination following developmental injury., Main points Microglia inflammasome activation correlates with white matter injury.Inflammasome inhibition promotes myelination.IL1β increases the activin‐A inhibitor follistatin, which impedes myelination.Activin‐A enhances myelination following injury.

1AbstractBackgroundPreterm birth is associated with atypical cognitive and socioemotional outcomes in childhood. Secure infant attachment protects against adverse outcomes, but could be modified by alterations in the early caregiving environment inherent to essential neonatal intensive care or co-morbidities of preterm birth. We aimed to test the hypothesis that preterm birth is associated with differences in infant attachment, and to investigate clinical, neurodevelopmental and socioeconomic variables that are associated with infant attachment.Methods82 preterm and 75 term infants with mean (range) gestational age at birth 29.5 (22.1 – 32.9) and 39.6 (36.4 – 42.1) weeks, respectively, completed the Still-Face Paradigm (SFP) at nine months of corrected age. Attachment dimensions and categories were obtained from infant responses to the SFP during the reunion episode using a published coding scheme, and an alternative principal component (PC) and clustering strategy. Neurodevelopment was assessed using the Vineland Adaptive Behavior Scales, and socioeconomic status was operationalized as neighborhood deprivation.ResultsPreterm and term infants significantly differed in fretfulness, attentional PC scores and in their distribution between attachment clusters (p-values ≤ 0.3); with preterm infants exhibiting less fretful and more neutral responses to the SFP. Preterm and term infants did not significantly differ in distress, attentiveness to caregivers, emotional PC scores, or in their distribution between attachment styles (p-values ≥ .13). In the whole sample, fretfulness correlated with socioeconomic deprivation (rs= −0.18, p-value = .02).ConclusionsData reveal subtle attachment differences between preterm and term infants at nine months of age, which may not always be captured by traditional approaches for categorizing attachment. Findings suggests that caregiver-infant attachment relationships may not be fully resilient to the effects of prematurity on the developing infant, but this depends on how attachment is measured. Our results highlight putative links between socioeconomic deprivation and infant attachment that warrant further study.

Background Preterm birth is associated with dysconnectivity of structural brain networks, impaired cognition and psychiatric disease. Systemic inflammation contributes to cerebral dysconnectivity, but the immune mediators driving this association are poorly understood. We analysed information from placenta, umbilical cord and neonatal blood, and brain MRI to determine which immune mediators link perinatal systemic inflammation with dysconnectivity of structural brain networks. Methods Participants were 102 preterm infants (mean gestational age 29+1 weeks, range 23+3-32+0). Placental histopathology identified reaction patterns indicative of histologic chorioamnionitis (HCA), and a customized immunoassay of 24 inflammation-associated proteins selected to reflect the neonatal innate and adaptive immune response was performed from umbilical cord (n = 55) and postnatal day 5 blood samples (n = 71). Brain MRI scans were acquired at term-equivalent age (41+0 weeks [range 38+0-44+4 weeks]) and alterations in white matter connectivity were inferred from mean diffusivity and neurite density index across the white matter skeleton. Results HCA was associated with elevated concentrations of C5a, C9, CRP, IL-1β, IL-6, IL-8 and MCP-1 in cord blood, and IL-8 concentration predicted HCA with an area under the receiver operator curve of 0.917 (95% CI 0.841 – 0.993, p Conclusions These findings suggest that IL-8 dysregulation has a role in linking perinatal systemic inflammation and atypical white matter development in preterm infants.

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from the saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes or regions. We tested the hypothesis that variation in DNA methylation could underpin the association between low gestational age at birth and atypical brain development by linking differentially methylated probes with measures of white matter connectivity derived from diffusion MRI metrics: peak width skeletonized mean diffusivity, peak width skeletonized fractional anisotropy and peak width skeletonized neurite density index. Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8870 CpG probes (P

In infancy, stress responses and emotion regulation are often coupled. Both are impacted by prematurity, thoughtheir relationship to one another in the case of infants born preterm is not fully understood. We investigatedemotion regulation behaviours, cortisol reactivity and recovery and coupling between emotion regulation andcortisol reactivity to and recovery from a stressor in preterm infants. 53 preterm and 67 full-term infants withmean (range) gestational age at birth 29+3 (24+0-31+6) and 39+3 (36+2-42+0) weeks respectively were exposedto a socio-emotional stressor, the still-face (SF) paradigm, at 9 months of age (corrected for prematurity). Theduration of negative affect and self-comforting behaviours exhibited in response to the SF, coded from a 10-minutevideo-taped interaction, were compared between groups. Saliva was collected from a subset (20 preterm, 24term infants) at three timepoints: pre-SF and 20- and 30-minutes post SF. Cortisol concentrations at eachtimepoint were compared between groups. Associations between behavioural measures and cortisol concentrationswere explored. There was no significant difference in duration of self-comforting behaviour betweenpreterm and term infants. Preterm infants spent a significantly smaller proportion of time in a negative affectivestate compared to term infants (0.18 vs 0.25 s, p = 0.03). Salivary cortisol concentration was significantly higherin the preterm compared to the term group 30 min post SF (2.85 vs 1.77 nmol/L, p = 0.009), though findingswere no longer significant after adjusting for time of day of sampling and socioeconomic deprivation. Aftercontrolling for time of day, greater negative affect was correlated with higher cortisol concentration 30 min postSF in the full-term (r = 0.58, p = 0.004) but not the preterm group (r = 􀀀 0.01, p > 0.05). Our findings suggestaltered response to an acute stressor in preterm infants, manifesting as a muted emotional response, and a lack ofcoupling between endocrine and behavioural stress response. Replication studies in larger samples would help tofurther understand biological stress repose in preterm infants and its relationship to behaviour, time of day anddeprivation.

BackgroundHypothalamic-pituitary-adrenal (HPA) axis adaptation is a potential mechanism linking early life exposures with later adverse health. This study tested the hypothesis that preterm birth is associated with adaptation of diurnal cortisol regulation across infancy.MethodsA secondary analysis was conducted of saliva cortisol measured morning, midday and evening, monthly, across infancy, as part of a birth cohort conducted in Linköping, Sweden. Diurnal cortisol regulation of infants born extremely preterm (n=24), very preterm (n=27) and at term (n=130) were compared across infancy through random coefficients regression models.ResultsCompared with infants born at term, infants born extremely preterm (−17.2%, 95% CI: −30.7 to −1.2), but not very preterm (1.7%, 95% CI: −14.1 to 20.4), had a flattened diurnal slope across infancy.ConclusionsExtremely preterm birth is associated with a flattened diurnal slope in infancy. This pattern of cortisol regulation could contribute to adverse metabolic and neurodevelopmental phenotypes observed in this population.

Preterm birth is closely associated with diffuse white matter dysmaturation inferred from diffusion MRI and neurocognitive impairment in childhood. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) are distinct dMRI modalities, yet metrics derived from these two methods share variance across tracts. This raises the hypothesis that dimensionality reduction approaches may provide efficient whole-brain estimates of white matter microstructure that capture (dys)maturational processes. To investigate the optimal model for accurate classification of generalised white matter dysmaturation in preterm infants we assessed variation in DTI and NODDI metrics across 16 major white matter tracts using principal component analysis and structural equation modelling, in 79 term and 141 preterm infants at term equivalent age. We used logistic regression models to evaluate performances of single-metric and multimodality general factor frameworks for efficient classification of preterm infants based on variation in white matter microstructure. Single-metric general factors from DTI and NODDI capture substantial shared variance (41.8-72.5%) across 16 white matter tracts, and two multimodality factors captured 93.9% of variance shared between DTI and NODDI metrics themselves. General factors associate with preterm birth and a single model that includes all seven DTI and NODDI metrics provides the most accurate prediction of microstructural variations associated with preterm birth. This suggests that despite global covariance of dMRI metrics in neonates, each metric represents information about specific (and additive) aspects of the underlying microstructure that differ in preterm compared to term subjects.HighlightsWe measured variation of 7 DTI and NODDI metrics across 16 major tractsGeneral factors for DTI and NODDI capture substantial shared variance across tractsGeneral factors also capture substantial shared variance between DTI and NODDISingle-metric and multimodality factors associate with gestational age at birthThe best preterm prediction model contains all 7 single-metric g-factors

ObjectiveTo characterise the umbilical cord blood immune profile in preterm infants compared to term-born controls and the postnatal immune response following exposure to histologic chorioamnionitis (HCA) in preterm infants.DesignDescriptive, observational cohort study.SettingEdinburgh, UK.Population118 preterm infants (mean gestational age 29+0 weeks, range 23+2 to 32+0) and 59 term-born controls.MethodsPlacental histopathology was used to identify reaction patterns indicative of HCA, and a customised immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group.ResultsThe umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242×10−14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 5 immune proteins on postnatal day 5 (BDNF, C3, IL-8, MIP-1β and MMP-9) when compared to preterm infants who were not exposed.ConclusionPreterm birth is associated with a distinct immune profile in umbilical cord blood and infants exposed to HCA experience specific alterations in immune function that persist to day 5 of postnatal life.

The mechanisms linking maternal stress in pregnancy with infant neurodevelopment in a sexually dimorphic manner are poorly understood. We tested the hypothesis that maternal hypothalamic-pituitary-adrenal axis activity, measured by hair cortisol concentration (HCC), is associated with microstructure, structural connectivity, and volume of the infant amygdala. In 78 mother-infant dyads, maternal hair was sampled postnatally, and infants underwent magnetic resonance imaging at term-equivalent age. We found a relationship between maternal HCC and amygdala development that differed according to infant sex. Higher HCC was associated with higher left amygdala fractional anisotropy (β = 0.677, p=0.010), lower left amygdala orientation dispersion index (β = −0.597, p=0.034), and higher fractional anisotropy in connections between the right amygdala and putamen (β = 0.475, p=0.007) in girls compared to boys. Furthermore, altered amygdala microstructure was only observed in boys, with connectivity changes restricted to girls. Maternal cortisol during pregnancy is related to newborn amygdala architecture and connectivity in a sexually dimorphic manner. Given the fundamental role of the amygdala in the emergence of emotion regulation, these findings offer new insights into mechanisms linking maternal health with neuropsychiatric outcomes of children., eLife digest Stress during pregnancy, for example because of mental or physical disorders, can have long-term effects on child development. Epidemiological studies have shown that individuals exposed to stress in the womb are at higher risk of developmental and mood conditions, such as ADHD and depression. This effect is different between the sexes, and the biological mechanisms that underpin these observations are poorly understood. One possibility is that a baby’s developing amygdala, the part of the brain that processes emotions, is affected by a signal known as cortisol. This hormone is best known for its role in coordinating the stress response, but it also directs the growth of a fetus. Tracking fetal amygdala changes as well as cortisol levels in the pregnant individual could explain how stress during pregnancy affects development. To investigate, Stoye et al. recruited nearly 80 volunteers and their newborn children. MRI scans were used to examine the structure of the amygdala, and how it is connected to other parts of the brain. In parallel, the amount of cortisol was measured in hair samples collected from the volunteers around the time of birth, which reflects stress levels during the final three months of pregnancy. Linking the brain imaging results to the volunteers’ cortisol levels showed that being exposed to higher cortisol levels in the womb affected babies in different ways based on their sex: boys showed alterations in the fine structure of their amygdala, while girls displayed changes in the way that brain region connected to other neural networks. The work by Stoye et al. potentially reveals a biological mechanism by which early exposure to stress could affect brain development differently between the sexes, potentially informing real-world interventions.

The human adult structural connectome has a rich topology composed of nodal hierarchies containing highly diverse connectivity patterns, aligned to the diverse range of functional specialisations in the brain. The emergence of this hierarchical complexity in human development is unknown. Here, we substantiate the hierarchical tiers and complexity of brain networks in the newborn period, assess correspondences with hierarchical complexity in adulthood, and investigate the effect of preterm birth, a leading cause of neu-rocognitive impairment and atypical brain development, on hierarchical complexity. We report that the neonatal and adult structural connectomes are both composed of distinct hierarchical tiers. Consistency of ROIs is found at both ends of this hierarchy during early life and in adulthood, but significant differences are evident in intermediate tiers. The neonatal connectome is hierarchically complex in term born neonates, but hierarchically complexity is altered in association with preterm birth. This is mainly due to diversity of connectivity patterns in Tier 3, which is comprised of regions that underlie sensorimotor processing and its integration with cognitive information. For neonates and adults, the highest tier (comprising hub regions) is ordered, rather than complex, with more homogeneous connectivity patterns in structural hubs. This suggests that the brain develops first a more rigid hierarchical structure in hub regions allowing for the development of greater and more diverse functional specialisation in lower level regions, while connectivity underpinning this diversity is dysmature in infants born preterm.

Highlights • Multiple MRI features are integrated in a single model to study brain maturation in newborns. • Morphometric similarity networks (MSNs) provide a whole-brain description of the structural properties of neonatal brain. • The information encoded in MSNs is predictive of chronological brain age in the perinatal period. • MSNs provide a novel data-driven method for investigating neuroanatomic variation associated with preterm birth., Graphical abstract, Multi-contrast MRI captures information about brain macro- and micro-structure which can be combined in an integrated model to obtain a detailed “fingerprint” of the anatomical properties of an individual’s brain. Inter-regional similarities between features derived from structural and diffusion MRI, including regional volumes, diffusion tensor metrics, neurite orientation dispersion and density imaging measures, can be modelled as morphometric similarity networks (MSNs). Here, individual MSNs were derived from 105 neonates (59 preterm and 46 term) who were scanned between 38 and 45 weeks postmenstrual age (PMA). Inter-regional similarities were used as predictors in a regression model of age at the time of scanning and in a classification model to discriminate between preterm and term infant brains. When tested on unseen data, the regression model predicted PMA at scan with a mean absolute error of 0.70 ± 0.56 weeks, and the classification model achieved 92% accuracy. We conclude that MSNs predict chronological brain age accurately; and they provide a data-driven approach to identify networks that characterise typical maturation and those that contribute most to neuroanatomic variation associated with preterm birth.

Adult hair glucocorticoid concentrations reflect months of hypothalamic-pituitary-adrenal axis activity. However, little is known about the determinants of neonatal hair glucocorticoids. We tested associations between perinatal exposures and neonatal hair glucocorticoids. Cortisol and cortisone were measured by LC-MS/MS in paired maternal and infant hair samples collected within 10 days of birth (n = 49 term, n = 47 preterm), with neonatal samples collected at 6-weeks in n = 54 preterm infants. We demonstrate cortisol accumulation in hair increases with fetal maturity, with hair cortisol being higher in term than preterm born infants after delivery (median 401 vs 106 pg/mg; p, Highlights • Neonatal hair cortisol is higher after term compared to preterm birth. • Neonatal hair cortisol reflects fetal growth, maternal cortisol and birth exposures. • Hair sampled at 6 weeks reflects postnatal exposures in preterm infants.

Morphometric similarity networks (MSNs) have been recently proposed as a novel, robust, and biologically plausible approach to generate structural connectomes from neuroimaging data. In this work, we apply this method to multi-centre neonatal data (postmenstrual age range: 37–45 weeks) to predict brain dysmaturation in preterm infants. To achieve this goal, we combined different imaging sequences (diffusion and structural MRI) to extract a set of metrics from cortical and subcortical brain regions (e.g. regional volumes, diffusion tensor metrics, neurite orientation dispersion and density imaging features) which were used to construct a similarity network. A regression model was then trained to predict postmenstrual age at the time of scanning from inter-regional connections. Finally, to quantify brain maturation, the Relative Brain Network Maturation Index (RBNMI) was computed as the difference between predicted and actual age. The model predicted chronological age with a mean absolute error of 0.88 (±0.63) weeks, and it consistently predicted preterm infants to have a lower RBNMI than term infants. We conclude that MSNs derived from multimodal imaging predict chronological brain development accurately, and provide a data-driven approach for defining cerebral dysmaturation associated with preterm birth.

Preterm infants are at increased risk of alterations in brain structure and connectivity, and subsequent neurocognitive impairment. Breast milk may be more advantageous than formula feed for promoting brain development in infants born at term, but uncertainties remain about its effect on preterm brain development and the optimal nutritional regimen for preterm infants. We test the hypothesis that breast milk exposure is associated with improved markers of brain development and connectivity in preterm infants at term equivalent age. We collected information about neonatal breast milk exposure and brain MRI at term equivalent age from 47 preterm infants (mean postmenstrual age [PMA] 29.43 weeks, range 23.28-33.0). Network-Based Statistics (NBS), Tract-based Spatial Statistics (TBSS) and volumetric analysis were used to investigate the effect of breast milk exposure on white matter water diffusion parameters, tissue volumes, and the structural connectome. Twenty-seven infants received exclusive breast milk feeds for ≥75% of days of in-patient care and this was associated with higher connectivity in the fractional anisotropy (FA)-weighted connectome compared with the group who had 75% of days receiving exclusive breast milk feeds (NBS, p = 0.04). Within the TBSS white matter skeleton, the group that received ≥75% exclusive breast milk days exhibited higher FA within the corpus callosum, cingulum cingulate gyri, centrum semiovale, corticospinal tracts, arcuate fasciculi and posterior limbs of the internal capsule compared with the low exposure group after adjustment for PMA at birth, PMA at image acquisition, bronchopulmonary dysplasia, and chorioamnionitis (p 0.05). The effect on structural connectivity and tract water diffusion parameters was greater with ≥90% exposure, suggesting a dose effect. There were no significant groupwise differences in brain volumes. Breast milk feeding in the weeks after preterm birth is associated with improved structural connectivity of developing networks and greater FA in major white matter fasciculi.

This article provides a review of the 2017 Faculty of Medical Leadership and Management Conference in Scotland with reflections on the promotion of personal, managerial and organisational resilience.