Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth.

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multimodal 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 at term-equivalent age. Compared with term-born controls, 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.

Breast Milk Exposure is Associated With Cortical Maturation in Preterm Infants.

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 (<32 weeks' gestation) and 77 term infants. Feeding data were collected from birth until hospital discharge and brain magnetic resonance imaging (MRI) was performed at term-equivalent age. Cortical indices (volume, thickness, surface area, gyrification index, sulcal depth, and curvature) and diffusion parameters (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], axial diffusivity [AD], neurite density index [NDI], and orientation dispersion index [ODI]) were compared between preterm infants who received exclusive breast milk for <75% of inpatient days, preterm infants who received exclusive breast milk for ≥75% of inpatient days and term-born controls. To investigate a dose response effect, we performed linear regression using breast milk exposure quartile weighted by propensity scores. 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 2023;93:591-603.

Emotion regulation and cortisol response to the still-face procedure in preterm and full-term infants.

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

General factors of white matter microstructure from DTI and NODDI in the developing brain.

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.

DNA methylation in relation to gestational age and brain dysmaturation 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 < 3.6 × 10-8) and 1767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component that explained 23.5% of the variance in DNA methylation, and this was negatively associated with gestational age at birth. The first principal component was associated with peak width of skeletonized mean diffusivity (ß = 0.349, P = 8.37 × 10-10) and peak width skeletonized neurite density index (ß = 0.364, P = 4.15 × 10-5), but not with peak width skeletonized fraction anisotropy (ß = -0.035, P = 0.510); these relationships mirrored the imaging metrics' associations with gestational age at birth. Low gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome that is apparent at term equivalent age. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNA methylation and image markers of white matter tract microstructure suggest that variation in DNA methylation may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterizes atypical brain development in preterm infants.

Preterm birth and infant diurnal cortisol regulation.

BACKGROUND: Hypothalamic-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. METHODS: A 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. RESULTS: Compared 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. CONCLUSIONS: Extremely 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.

Saliva cortisol diurnal variation and stress responses in term and preterm infants.

OBJECTIVE: To 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 <28 weeks or very preterm birth at 28-32 weeks gestation). DESIGN: This 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. SETTING: Infants born at a single Scottish hospital. PARTICIPANTS: 45 term-born, 42 very preterm and 16 extremely preterm infants. OUTCOMES: Cortisol 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. RESULTS: Compared 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. CONCLUSIONS: Infants 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.

Retrospective evaluation of systemic hypertension in dogs with nonassociative (primary) immune-mediated hemolytic anemia (December 2016 to April 2019): 26 cases.

OBJECTIVE: To report the prevalence of arterial hypertension in a population of dogs with nonassociative immune-mediated hemolytic anemia (IMHA) on presentation and during hospitalization. To determine the relationships of systolic blood pressure (SBP) with mortality and a prognostic indicator, the canine hemolytic anemia objective score. DESIGN: Retrospective observational study (December 2016 to April 2019). SETTING: University teaching hospital. ANIMALS: Twenty-six clinical dogs presenting to the ICU with nonassociative (primary) IMHA and a control group of 23 clinical dogs with idiopathic epilepsy hospitalized in the ICU for seizure treatment or monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hypertension was defined as SBP ≥ 160 mm Hg and severe hypertension as SBP ≥ 180 mm Hg. Mean SBP was significantly increased in IMHA dogs (161 mm Hg, SD = 21) compared to ICU control dogs (138 mm Hg, SD = 14; P < 0.005). Hypertension was present in 13 of 26 (50.0%) dogs across the period of hospitalization and was severe in three of 26 (11.5%). During at least 1 day of hospitalization, 18 of 26 (69.2%) dogs were hypertensive and eight of 26 (34.6%) were severely hypertensive. Hypertension was not associated with short-term mortality or canine hemolytic anemia objective score. CONCLUSIONS: In this retrospective study, hypertension was more prevalent in dogs with nonassociative IMHA than a control population of ICU-hospitalized dogs. An association between autoimmune conditions and hypertension has been previously reported in people but not within a canine population. Hypertension in dogs may have an inflammatory or autoimmune etiology. SBP should be monitored closely in canine IMHA, in case antihypertensive treatment is required.

Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis.

Introduction: Preterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not. Population: For objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available. Methods: Placental histopathology was used to identify reaction patterns indicative of HCA, and a customized 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. Results: The umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. 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 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1ß and MMP-9) when compared to preterm infants who were not exposed. Conclusion: Preterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life.

Perinatal determinants of neonatal hair glucocorticoid concentrations.

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 < 0.001). In term born infants, neonatal hair cortisol is positively associated with maternal hair cortisol concentration (ß = 0.240, p = 0.045) and negatively associated with birthweight z-score (ß = -0.340, p = 0.006). Additionally, being born without maternal labour is associated with lower hair cortisol concentrations (ß = -0.489, p < 0.001) and a lower ratio of cortisol to cortisone (ß = -0.484, p = 0.001). In preterm infants, histological chorioamnionitis is associated with a higher cortisol to cortisone ratio in hair (ß = 0.459, p = 0.001). In samples collected 6 weeks after preterm birth, hair cortisol concentration is associated with cortisol hair concentrations measured after birth (ß = 0.523, p < 0.001), chorioamnionitis (ß = 0.250, p = 0.049) and postnatal exposures including intravenous hydrocortisone therapy (ß = 0.343, p < 0.007) and neonatal sepsis (ß = 0.290, p = 0.017). In summary, neonatal hair cortisol is associated with birth gestation, maternal hair cortisol concentration and fetal growth. Additionally, exposures at delivery are important determinants of hair cortisol, and should be considered in the design of future research investigating how neonatal hair cortisol relates to prenatal exposures or fetal development.

Hierarchical Complexity of the Macro-Scale Neonatal Brain.

The human adult structural connectome has a rich nodal hierarchy, with highly diverse connectivity patterns aligned to the diverse range of functional specializations in the brain. The emergence of this hierarchical complexity in human development is unknown. Here, we substantiate the hierarchical tiers and hierarchical 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 atypical brain development and later neurocognitive impairment, on hierarchical complexity. We report that neonatal and adult structural connectomes are both composed of distinct hierarchical tiers and that hierarchical complexity is greater in term born neonates than in preterms. This is due to diversity of connectivity patterns of regions within the intermediate tiers, which consist of regions that underlie sensorimotor processing and its integration with cognitive information. For neonates and adults, the highest tier (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 structure in hub regions allowing for the development of greater and more diverse functional specialization in lower level regions, while connectivity underpinning this diversity is dysmature in infants born preterm.

Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner.

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 (ß = 0.677, p=0.010), lower left amygdala orientation dispersion index (ß = -0.597, p=0.034), and higher fractional anisotropy in connections between the right amygdala and putamen (ß = 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.

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.

Interleukin-8 dysregulation is implicated in brain dysmaturation following preterm birth.

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-1ß, 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 < 0.001). Fourteen analytes explained 66% of the variance in the postnatal profile (BDNF, C3, C5a, C9, CRP, IL-1ß, IL-6, IL-8, IL-18, MCP-1, MIP-1ß, MMP-9, RANTES and TNF-α). Of these, IL-8 was associated with altered neurite density index across the white matter skeleton after adjustment for gestational age at birth and at scan (ß = 0.221, p = 0.037). CONCLUSIONS: These findings suggest that IL-8 dysregulation has a role in linking perinatal systemic inflammation and atypical white matter development in preterm infants.

Peak Width of Skeletonized Water Diffusion MRI in the Neonatal Brain.

Preterm birth is closely associated with cognitive impairment and generalized dysconnectivity of neural networks inferred from water diffusion MRI (dMRI) metrics. Peak width of skeletonized mean diffusivity (PSMD) is a metric derived from histogram analysis of mean diffusivity across the white matter skeleton, and it is a useful biomarker of generalized dysconnectivity and cognition in adulthood. We calculated PSMD and five other histogram based metrics derived from diffusion tensor imaging (DTI) and neurite orientation and dispersion imaging (NODDI) in the newborn, and evaluated their accuracy as biomarkers of microstructural brain white matter alterations associated with preterm birth. One hundred and thirty five neonates (76 preterm, 59 term) underwent 3T MRI at term equivalent age. There were group differences in peak width of skeletonized mean, axial, and radial diffusivities (PSMD, PSAD, PSRD), orientation dispersion index (PSODI) and neurite dispersion index (PSNDI), all p < 10-4. PSFA did not differ between groups. PSNDI was the best classifier of gestational age at birth with an accuracy of 81±10%, followed by PSMD, which had 77±9% accuracy. Models built on both NODDI metrics, and on all dMRI metrics combined, did not outperform the model based on PSNDI alone. We conclude that histogram based analyses of DTI and NODDI parameters are promising new image markers for investigating diffuse changes in brain connectivity in early life.

DNA methylation and brain structure and function across the life course: A systematic review.

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.

Neonatal morphometric similarity mapping for predicting brain age and characterizing neuroanatomic variation associated with preterm birth.

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.

Maternal Glucocorticoid Metabolism Across Pregnancy: A Potential Mechanism Underlying Fetal Glucocorticoid Exposure.

CONTEXT: Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development. OBJECTIVES: The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of cortisol metabolism and clearance, between the second and third trimester of pregnancy. Secondary objectives were to test associations of total maternal urinary glucocorticoid excretion, with maternal serum cortisol levels and offspring birth weight z score. DESIGN, PARTICIPANTS, AND SETTING: A total of 151 women with singleton pregnancies, recruited from prenatal clinic at the Pittsburgh site of the Measurement of Maternal Stress (MOMS) study, had 24-hour urine collections during both the second and third trimesters. RESULTS: Between the second and third trimester, total urinary glucocorticoid excretion increased (ratio of geometric means [RGM] 1.37, 95% CI 1.22-1.52, P < .001), and there was an increase in calculated 5ß-reductase compared to 5α-reductase activity (RGM 3.41, 95% CI 3.04-3.83, P < .001). During the third trimester total urinary glucocorticoid excretion and serum cortisol were negatively correlated (r = -0.179, P = .029). Mean total urinary glucocorticoid excretion across both trimesters and offspring birth weight z score were positively associated (ß = 0.314, P = .001). CONCLUSIONS: The estimated activity of maternal enzymes responsible for cortisol metabolism change between the second and third trimester of pregnancy. Additionally, maternal peripheral metabolism and clearance of cortisol may serve as a novel mechanism affecting fetal cortisol exposure and growth.