2023

Background information. 

Preterm birth is closely associated with alterations in brain development and challenges during childhood and beyond, such as cerebral palsy (movement problems), learning difficulties, vision or hearing problems, and mental health problems. 

Socioeconomic status (SES) refers to an individual's social standing, which is affected by their access to financial, educational, social, and health resources. In babies, SES may be measured at three levels:  1.    Neighbourhood deprivation - how deprived or rich a neighbourhood is. In Scotland, this is captured using the Scottish Index of Multiple Deprivation (SIMD): a postcode-based score that includes neighbourhood-level information about income, employment, health, education, housing, crime, and access to services. 2.    Family SES - parental education level and occupation. 3.    Subjective SES - a measure of how someone perceives their social standing and quality of life. Lower, compared to higher, SES is associated with differences in child brain structure and an increased chance of developing learning difficulties and mental health problems.

Research question.

We wanted to know whether SES influences the brain development of preterm babies during NICU or whether preterm birth outweighs the effects of social factors. This question is important because if low SES affects brain development during NICU, efforts to support families by reducing social inequality could promote healthier brain development in preterm babies. To answer this question, we combined SES data with brain MRI scans from babies in Theirworld Edinburgh Birth Cohort.

Findings.

Preterm birth and low socioeconomic status were associated with differences in brain structure, but preterm birth has more widely distributed effects across the brain. Family SES has a greater impact than neighbourhood deprivation in determining brain development in very early life

Conclusion.

Taking measures to reduce family-level social inequalities during NICU care could help to improve brain development after premature birth. In future work, we plan to study the biological basis by which low gestational age and social factors affect the brain because this could lead to new treatment strategies.

Background information. 

Compared to term infants, preterm infants are more susceptible to systemic inflammation, which has been linked to brain dysmaturation and neurocognitive impairment. Epigenetic modifications (the bridge between genes and environment that gives rise to phenotype) linked to inflammation have emerged as a new way to investigate this relationship. 

Think of epigenetic modifications as being like punctuation in a sentence. Similar to how commas alter the meaning of a sentence (without altering the words or letters themselves), epigenetic modifications are slight additions to our genetic code that affect how our genes are expressed or "read aloud" (without changing the underlying DNA sequence). Environmental factors, disease, and life experiences can all contribute to changes in DNA methylation (DNAm), a type of epigenetic modification, and by measuring these changes, we can develop a DNAm biomarker that serves as a molecular record of past exposures.

We previously developed a DNAm signature to index chronic inflammation, which showed stronger associations with brain and cognitive ageing than protein signatures in adult populations (Conole et al., 2021; Green et al., 2021; Stevenson et al., 2020). In this study, we applied this approach to a neonatal cohort to investigate the impact of chronic inflammation in the perinatal period.

 Research question.

Our main hypothesis was that that variance in the neonatal methylome could reflect a convergence of amassed inflammatory burden in the perinatal period – distinguishing term infants from preterm infants, and capturing downstream consequences on brain structure. We therefore set out to investigate the association between a DNA methylation signature of CRP in relation to a). maternal health / lifestyle factors linked to inflammation c). fetal inflammatory episodes c). postnatal inflammatory conditions and d). neuroimaging phenotypes.

Findings.

Our headline findings were that an epigenetic signature of inflammation was higher in preterm infants than term infants, was related to the number of inflammatory episodes experienced by these infants, and showed significant associations with aspects of brain structure. In preterm infants, this epigenetic signature was associated with widespread differences in brain structure including deep grey matter volume, hippocampal volume and white matter dysmaturation both globally and at the level of individual white matter tract microstructure. Our findings are consistent with previous work and demarcate the pervasive and widespread impact of inflammation on the development of white matter, indicating that sustained inflammation may be a key driver of neurodevelopmental disruption in preterm birth.

Conclusion.

This work suggests that using DNAm taken from saliva could offer a non-invasive way to predict and monitor susceptibility to inflammation and its consequences, which could ultimately optimise approaches in neonatal care. Additionally, identifying and validating further methylation markers could provide insight into developmental pathways that affect inflammation risk, and provide clarity on the relationship between inflammation, exposures in the perinatal period, and neurodevelopment.

More research, in larger sample sizes, and longitudinal investigations, are required to evaluate these potential clinical applications. As a first point of investigation, there is a need for further validation studies to confirm the robustness and reproducibility of DNA methylation-based biomarkers of chronic inflammation. As there are multiple other inflammatory biomarkers implicated in initiating and sustaining inflammation, the next point of investigation is to build more of these epigenetic signatures (of circulating inflammatory protein levels) across surrogate tissue types and evaluate their associations with various health outcomes. Further large-scale longitudinal studies, which encompass a diverse range of time points, tissue types, and DNAm sampling form both mothers and infants (to tease apart contributions to inflammation in the perinatal period) are needed.

Preterm birth affects around 15 million births each year and is a leading cause of developmental and learning problems in childhood. Breast milk feeding is associated with improved health outcomes and better learning outcomes in children born early, but how and when breast milk influences the developing brain is not well understood.

In this study of 212 infants, we used advanced brain scans (MRI) to investigate the effect of early breast milk feeding on the development of the cerebral cortex, a brain region important for learning and thinking, in preterm infants and healthy term-born controls. We found that preterm babies who received more breast milk during their stay in Neonatal Intensive Care had a more mature cortex when compared to babies who received less breast milk. Their brains resembled more closely the brains of healthy babies who were not premature. These findings suggest that early breast milk feeding helps to restore brain health after preterm birth through improvements in the development of the cerebral cortex.

Background information 

Myelin is a fatty insulating layer around nerve cells that allows quick and efficient signal transmission so different brain regions can better communicate with one another. Preterm infants are born during a period when myelination starts in the brain and they subsequently have poorer myelin development than their term-born peers. This could contribute to impairments some preterm children experience later in childhood. 

Many brain scan methods have been used to characterise brain differences between term and preterm infants. Yet, the most commonly used techniques are sensitive to a number of different biological properties of the brain and they are not specific to measuring myelin. 

Magnetisation transfer saturation (MTsat) is an advanced brain scan method that is more sensitive to different molecules present in the myelin layer. However, this method has not yet been used in babies. 

Research question 

We wanted to know if this advanced brain scan method allows to detect the progress of myelin development around the time of birth and whether term and preterm infants have different levels of myelin in their white matter as measured using this technique. These questions are important for understanding the biological processes underpinning brain differences between term and preterm babies. 

Findings 

We found that MTsat was positively correlated with age at scan across the white matter: babies scanned when they were older had more myelin. This means that MTsat captures the development of myelin in early life. We also found that some, but not all, white matter regions had lower MTsat in preterm compared to term-born babies. The same regions had lower MTsat, meaning that myelin in those white matter regions that myelinate later, may be more affected by preterm birth. 

Conclusion 

This study demonstrated that MTsat could be used to study myelin development in early life. As the participants in the Theirworld Edinburgh Birth Cohort come back for behavioural assessments, in future work, we plan to study whether these differences in myelin levels between term and preterm infants underly some of the difficulties preterm children have.