Role of perinatal inflammation in preterm brain injury

Perinatal inflammation is associated with an increased risk of brain injury and neurodevelopmental impairment in preterm infants but the immune mediators driving this association are not well understood. This PhD thesis seeks to further characterise the inflammatory response associated with preterm birth, describe the relationship between perinatal inflammation and white matter development and explore the effect of specific inflammation-associated proteins on the development of human cortical neurons derived from induced pluripotent stem cells (iPSCs). In the first study, I investigated the inflammatory profile at birth in 55 very preterm infants, compared to 59 term-born controls and then used this profile to predict exposure to intrauterine inflammation in the preterm group. Preterm infants had a distinct pro-inflammatory profile in umbilical cord blood at delivery when compared to term-born controls and IL-8 was found to be the strongest predictor of intrauterine inflammation. In the second study, I investigated the association between specific inflammation-associated proteins and white matter microstructure in 71 very preterm infants using structural MRI and diffusion-weighted imaging of the brain. Elevated IL-8 in the first week of life was associated with white matter dysmaturation at term-equivalent age. Following this discovery, I investigated the effect of IL-8 on the maturation and morphology of iPSC-derived cortical neurons and found that exposure was associated with impaired neurite outgrowth. This thesis provides further evidence to support the role of inflammation in the aetiology of preterm brain injury and suggests that IL-8 dysregulation may link systemic inflammation with atypical cortical development and white matter disease in preterm infants

The association between academic pressure and adolescent mental health problems: A systematic review

BACKGROUND: Academic pressure is a potential contributor to adolescent mental health problems, but international evidence on this association has never been synthesised. METHODS: We conducted the first systematic review of the association between academic pressure and adolescent depression, anxiety, self-harm, suicidality, suicide attempts and suicide. We searched MEDLINE, PsycINFO, ERIC and Web of Science (core collection) up to November 24, 2022, for studies of school-going children or adolescents, which measured academic pressure or timing within the school year as the exposure and depression, anxiety, self-harm, or suicidal ideation, attempts or suicide as outcomes. Risk of bias was assessed using the Mixed Methods Appraisal Tool. We used narrative synthesis to summarise the evidence. The review was prospectively registered with PROSPERO (CRD42021232702). RESULTS: We included 52 studies. Most studies assessed mixed anxiety and depressive symptoms (n = 20) or depressive symptoms (n = 19). Forty-eight studies found evidence of a positive association between academic pressure or timing within the school year and at least one mental health outcome. LIMITATIONS: Most studies were cross-sectional (n = 39), adjusted for a narrow range of confounders or had other limitations which limited the strength of causal inferences. CONCLUSIONS: We found evidence that academic pressure is a potential candidate for public health interventions which could prevent adolescent mental health problems. Large population-based cohort studies are needed to investigate whether academic pressure is a causal risk factor that should be targeted in school- and policy-based interventions. FUNDING: UCL Health of the Public; Wellcome Institutional Strategic Support Fund

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

Preterm birth is associated with immune dysregulation which persists in infants exposed to histologic chorioamnionitis

IntroductionPreterm 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.PopulationFor 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.MethodsPlacental 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.ResultsThe 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-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 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