Search

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.

Myelination of neuronal axons is a critical aspect of central nervous system development and function. However, the fundamental cellular and molecular mechanisms influencing human developmental myelination and its failure are not fully understood. Here, we used digital spatial transcriptomics of a rare bank of human developing white matter to uncover that a localized dysregulated innate immune response is associated with impeded myelination. We identified that poorly myelinating areas have a distinct signature of Type II interferon signalling in microglia/macrophages, relative to adjacent myelinating areas. This is associated with a surprising increase in mature oligodendrocytes, which fail to form myelin processes appropriately. We functionally link these findings by showing that conditioned media from interferon-stimulated microglia is sufficient to dysregulate myelin process formation by oligodendrocytes in culture. We identify the Type II interferon inducer, Osteopontin (SPP1), as being upregulated in poorly myelinating brains, indicating a potential biomarker. Our results reveal the importance of microglia-mature oligodendrocyte interaction and interferon signaling in regulating myelination of the developing human brain.

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.

Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Using the prospective Avon Longitudinal Study of Children and Parents birth cohort (N = up-to 6401), we have examined longitudinal associations of early-life inflammation [exposures: interleukin-6 (IL-6), C-reactive protein (CRP) levels at age 9y; IL-6 and CRP DNA-methylation (DNAm) scores at birth and age 7y; and IL-6 and CRP polygenic risk scores (PRSs)] with the number of depressive episodes and psychotic experiences (PEs) between ages 10-28 years. Psychiatric outcomes were assessed using the Short Mood and Feelings Questionnaire and Psychotic Like Symptoms Questionnaires, respectively. Exposure-outcome associations were tested using negative binomial models, which were adjusted for metabolic and sociodemographic factors. Serum IL-6 levels at age 9y were associated with the total number of depressive episodes between 10 and 28y in the base model (n = 4835; β = 0.066; 95%CI:0.020-0.113; pFDR = 0.041) which was weaker when adjusting for metabolic and sociodemographic factors. Weak associations were observed between inflammatory markers (serum IL-6 and CRP DNAm scores) and total number of PEs. Other inflammatory markers were not associated with depression or PEs. Early-life inflammatory markers are associated with the burden of depressive episodes and of PEs subsequently from childhood to adulthood. These findings support a potential role of early-life inflammation in the aetiology of depression and psychosis and highlight inflammation as a potential target for treatment and prevention.

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.

The gut microbiota is increasingly recognized as a modulator of brain and behavior but its role in early childhood, when the microbiome and the brain are both undergoing rapid development, is poorly understood. Preclinical work suggests there are critical windows during early life when bacterial signals are required for normal neurobehavioral development, whereas gut microbial dysfunction has been observed in patients with certain neurodevelopmental disorders. Here, we review the evidence that gut bacterial diversity and community composition affect brain structure/function and behavior in typically developing pre-school children. Following narrative synthesis, we report that twenty studies suggest the microbiome-gut-brain axis may operate across three domains in infancy and early childhood: general neurocognitive development, socio-emotional behaviors, and brain structure and function inferred from neuroimaging. However, there is substantial variation in the bacteria-brain/behavior relationships reported. We identified sources of clinical and methodological heterogeneity in the studies, including participant characteristics, small sample sizes, variations in DNA extraction and sequencing, and statistical analysis approaches. We propose that harmonization of sample collection and data processing pipelines, longitudinal assessments, and mechanistic insights from whole metagenome analyses could improve understanding of the role of gut microbiome in brain development during early development. This will also promote comparability between studies and increase study power by allowing for meta-analyses. Greater knowledge of the role of gut microbiome in brain development may ultimately offer new avenues for promoting brain health in early life.

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.

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.

Highlights • 60 studies of association between DNAm and human brain MRI were identified. • Differential DNAm is associated with brain structure and function throughout life. • There is modest consistency between DNAm and image endophenotypes. • Approaches for reducing heterogeneity in DNAm-MRI analyses are proposed., MRI has enhanced our capacity to understand variations in brain structure and function conferred by the genome. We identified 60 studies that report associations between DNA methylation (DNAm) and human brain structure/function. Forty-three studies measured candidate loci DNAm; seventeen measured epigenome-wide DNAm. MRI features included region-of-interest and whole-brain structural, diffusion and functional imaging features. The studies report DNAm-MRI associations for: neurodevelopment and neurodevelopmental disorders; major depression and suicidality; alcohol use disorder; schizophrenia and psychosis; ageing, stroke, ataxia and neurodegeneration; post-traumatic stress disorder; and socio-emotional processing. Consistency between MRI features and differential DNAm is modest. Sources of bias: variable inclusion of comparator groups; different surrogate tissues used; variation in DNAm measurement methods; lack of control for genotype and cell-type composition; and variations in image processing. Knowledge of MRI features associated with differential DNAm may improve understanding of the role of DNAm in brain health and disease, but caution is required because conventions for linking DNAm and MRI data are not established, and clinical and methodological heterogeneity in existing literature is substantial.

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.