2024

Publications

A. F. Bonthrone, M. Blesa Cabez, A. D. Edwards, J. V. Hajnal, S. J. Counsell and J. P. Boardman  Harmonizing multisite neonatal diffusion-weighted brain MRI data for developmental neuroscience DOI: 10.1016/j.dcn.2024.101488 

Abstract

Large diffusion-weighted brain MRI (dMRI) studies in neonates are crucial for developmental neuroscience. Our aim was to investigate the utility of ComBat, an empirical Bayes tool for multisite harmonization, in removing site effects from white matter (WM) dMRI measures in healthy infants born at 37 gestational weeks+ 0 days-42 weeks+ 6 days from the Theirworld Edinburgh Birth Cohort (n = 86) and Developing Human Connectome Project (n = 287). Skeletonized fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, RD) maps were harmonized. Differences between voxel-wise metrics, skeleton means and histogram widths (5th-95th percentile) were assessed before and after harmonization, as well as variance associated with gestational age at birth and scan. Before harmonization, large cohort differences were observed. Harmonization removed all voxel-wise differences from MD maps and all metric means and histogram widths, however small voxel-wise differences (<1.5 % of voxels) remained in FA, AD and RD. We detected significant relationships between GA at birth and all metrics. When comparing single site and multisite harmonized datasets of equal sample sizes, harmonized data resulted in smaller standardized regression coefficients. ComBat could enable unprecedented sample sizes in developmental neuroscience, offering new horizons for biomarker discovery and validation, understanding typical and atypical brain development, and assessing neuroprotective therapies.


 

K. Vaher, M. B. Cabez, P. L. Parga, J. Binkowska, G. J. van Beveren, M. L. Odendaal, G Sullivan, D Stoye, A Corrigan, A Quigley, M Thrippleton, M Bastin, D Bogaert, J Boardman. The neonatal gut microbiota: A role in the encephalopathy of prematurity DOI: 10.1016/j.xcrm.2024.101845

Background Information

After being born, trillions of microorganisms colonise our body of which the majority reside in our gut – this is called the gut microbiota and it is important for many physiological functions such as metabolism and immunity. The gut microbiota and the brain both develop rapidly in the first few years of life and there is accumulating evidence that the gut microbiota impacts neurodevelopment. For example, researchers have found links between gut microbiota composition and language and motor skills as well as temperament (Vaher et al. 2022 Dev Review). Preterm babies are exposed to microbes much earlier than their term-born peers, and during their first few months of life they are exposed to many factors that can influence their gut microbiota composition such as the hospital environment, antibiotic treatments, and combination of different milk types. However, very little is known about the relationships between the gut microbiota and brain development in this vulnerable group.

Research Question 

In this work we had three questions. First, how does preterm infant gut microbiota look like shortly after birth and shortly before discharge from the neonatal unit? Second, what are the clinical factors influencing gut microbiota composition? Third, how does the gut microbiota correlate with neurodevelopmental markers measured using brain MRI scans?

Findings

Shortly after birth, preterm infant guts had very low microbial diversity and most infants’ microbiotas were dominated by single microbes, mainly Staphylococcus. Birth mode was the strongest influencer of the microbiota at this time. By the time of hospital discharge, the infant gut microbiotas had diversified and babies had varying microbiota compositions: some babies had high levels of Bifidobacterium while others had high abundances of bacteria belonging to the Enterobacteriaceae family such as Klebsiella and Escherichia. The main factors impacting microbiota composition were low birth gestational age, antibiotics and infant sex. We then found that gut microbiota composition at the time of hospital discharge, particularly abundances of Escherichia and different Klebsiella bacteria, correlated with brain microstructure in the deep grey matter and the cortex.

Conclusions and Implications

This was the first study showing that preterm infant gut microbiota correlates with important brain MRI markers known to be affected by preterm birth. As the gut microbiota can be modified, for example by supplementing with pro- and prebiotics, it is an exciting avenue to promote brain health in preterm infants, but more research is needed to fully understand the linking mechanisms, design effective microbiota interventions, and find out who and when are most likely to benefit from these interventions.


 

G. Sullivan, A. J. Quigley, S. Choi, R. Teed, M. Blesa Cabez, K. Vaher, A Corrigan, D Stoye, M Thrippleton, M Bastin, J Boardman Brain 3T magnetic resonance imaging in neonates: features and incidental findings from a research cohort enriched for preterm birth DOI: 10.1136/archdischild-2024-326960

Background and objectives The survival rate and patterns of brain injury after very preterm birth are evolving with changes in clinical practices. Additionally, incidental findings can present legal, ethical and practical considerations. Here, we report MRI features and incidental findings from a large, contemporary research cohort of very preterm infants and term controls.

Methods 288 infants had 3T MRI at term-equivalent age: 187 infants born <32 weeks without major parenchymal lesions, and 101 term-born controls. T1-weighted, T2-weighted and susceptibility-weighted imaging were used to classify white and grey matter injury according to a structured system, and incidental findings described.

Results Preterm infants: 34 (18%) had white matter injury and 4 (2%) had grey matter injury. 51 (27%) infants had evidence of intracranial haemorrhage and 34 (18%) had punctate white matter lesions (PWMLs). Incidental findings were detected in 12 (6%) preterm infants. Term infants: no term infants had white or grey matter injury. Incidental findings were detected in 35 (35%); these included intracranial haemorrhage in 22 (22%), periventricular pseudocysts in 5 (5%) and PWMLs in 4 (4%) infants. From the whole cohort, 10 (3%) infants required referral to specialist services.

Conclusions One-fifth of very preterm infants without major parenchymal lesions have white or grey matter abnormalities at term-equivalent age. Incidental findings are seen in 6% of preterm and 35% of term infants. Overall, 3% of infants undergoing MRI for research require follow-up due to incidental findings. These data should help inform consent procedures for research and assist service planning for centres using 3T neonatal brain MRI for clinical purposes.


 

S. Sintoris, J. M. Binkowska, J. L. Gillan, R. P. Zuurbier, J. Twynam-Perkins, M. Kristensen, L Melrose, P Lusaretta Parga, A Ruiz Rodriguez, M Ling Chu, S van Boeckel, J Wildenbeest, D Bowdish, A Currie, R Thwaites, J Schwarze, M van Houten, J Boardman, S Cunningham, D Bogaert, D Davidson. Nasal cathelicidin is expressed in early life and is increased during mild, but not severe respiratory syncytial virus infection https://doi.org/10.1038/s41598-024-64446-1

Abstract

Respiratory syncytial virus is the major cause of acute lower respiratory tract infections in young children, causing extensive mortality and morbidity globally, with limited therapeutic or preventative options. Cathelicidins are innate immune antimicrobial host defence peptides and have antiviral activity against RSV. However, upper respiratory tract cathelicidin expression and the relationship with host and environment factors in early life, are unknown. Infant cohorts were analysed to characterise early life nasal cathelicidin levels, revealing low expression levels in the first week of life, with increased levels at 9 months which are comparable to 2-year-olds and healthy adults. No impact of prematurity on nasal cathelicidin expression was observed, nor were there effects of sex or birth mode, however, nasal cathelicidin expression was lower in the first week-of-life in winter births. Nasal cathelicidin levels were positively associated with specific inflammatory markers and demonstrated to be associated with microbial community composition. Importantly, levels of nasal cathelicidin expression were elevated in infants with mild RSV infection, but, in contrast, were not upregulated in infants hospitalised with severe RSV infection. These data suggest important relationships between nasal cathelicidin, upper airway microbiota, inflammation, and immunity against RSV infection, with interventional potential.


 

A. F. Bonthrone, M. Blesa Cabez, A. D. Edwards, J. V. Hajnal, S. J. Counsell and J. P. Boardman  Harmonizing multisite neonatal diffusion-weighted brain MRI data for developmental neuroscience DOI: 10.1016/j.dcn.2024.101488 

Abstract

Large diffusion-weighted brain MRI (dMRI) studies in neonates are crucial for developmental neuroscience. Our aim was to investigate the utility of ComBat, an empirical Bayes tool for multisite harmonization, in removing site effects from white matter (WM) dMRI measures in healthy infants born at 37 gestational weeks+ 0 days-42 weeks+ 6 days from the Theirworld Edinburgh Birth Cohort (n = 86) and Developing Human Connectome Project (n = 287). Skeletonized fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, RD) maps were harmonized. Differences between voxel-wise metrics, skeleton means and histogram widths (5th-95th percentile) were assessed before and after harmonization, as well as variance associated with gestational age at birth and scan. Before harmonization, large cohort differences were observed. Harmonization removed all voxel-wise differences from MD maps and all metric means and histogram widths, however small voxel-wise differences (<1.5 % of voxels) remained in FA, AD and RD. We detected significant relationships between GA at birth and all metrics. When comparing single site and multisite harmonized datasets of equal sample sizes, harmonized data resulted in smaller standardized regression coefficients. ComBat could enable unprecedented sample sizes in developmental neuroscience, offering new horizons for biomarker discovery and validation, understanding typical and atypical brain development, and assessing neuroprotective therapies.


 

Katie Mckinnon, Eleanor L. S. Conole, Kadi Vaher, Robert F. Hillary, Danni A. Gadd, Justyna Binkowska, Gemma Sullivan, Anna J. Stevenson, Amy Corrigan, Lee Murphy, Heather C. Whalley, Hilary Richardson, Riccardo E. Marioni, Simon R. Cox & James P. Boardman. Infants born preterm show differences in their immune system using new epigenetic scores.  Clinical Epigenetics 16, 84 (2024). doi.org/10.1186/s13148-024-01701-2

Background information

Preterm birth, being born before your due date, can be associated with changes to brain development and challenges during childhood and beyond. A family’s socioeconomic status (SES) describes a family’s access to financial, educational, social, and health resources. Being born into a family affected by low SES can also be associated with difficulties in development.

Inflammation is the way the body’s immune system responds to infection, injuries, and other experiences that can damage the body. Inflammation might be one way that preterm birth and low SES might affect development.

Epigenetic changes are ways that the environment and experiences affect how your genes in your DNA are used, without changing the DNA itself. Scientists have created epigenetics scores, known as EpiScores, for various proteins in the blood, and these EpiScores might be better than the proteins themselves for investigating how inflammation affects the body, particularly the brain. Within the Theirworld Edinburgh Birth Cohort, we have calculated these EpiScores using saliva samples taken when babies reached their due date.

We have previously shown that one of these EpiScores was associated with preterm birth, brain changes after preterm birth, and various illnesses we see in preterm-born infants.

Research question

We investigated whether preterm birth and low SES were associated with 104 EpiScores, including inflammation-related proteins.

Findings

Preterm birth was linked to 43 EpiScores, representing proteins responsible for infection and inflammation responses, and development of the brain, blood vessels and other body systems.

Only three EpiScores were linked to low SES, and when we took into account the illnesses we see in infants born preterm, these links disappeared.

Conclusion

A range of proteins are linked to preterm birth – this helps us understand how the immune system is changed when babies are born early.

However, there are very few protein EpiScores linked to low SES, so it is unlikely that inflammation is the main reason why low SES affects the development of preterm infants in the neonatal period.


 

Jiménez-Sánchez L, Blesa Cábez M, Vaher K, Corrigan A, Thrippleton M.J, Bastin M.E, Quigley A.J, Fletcher-Watson S, Boardman J.P. Infant attachment does not depend on neonatal amygdala and hippocampal structure and connectivity, Developmental Cognitive Neuroscience, Volume 67, June 2024, 101387 doi.org/10.1016/j.dcn.2024.101387 PMID: 38692007 PMCID: PMC11070590

Babies' attachment to their caregivers at nine months is not affected by how their brains' amygdala and hippocampus are shaped and connected at birth.

Background information.

Attachment refers to one aspect of the relationship between an infant and a caregiver that is related to making the child feel safe and protected. Infants who feel secure around caregivers are better at handling emotions and getting along with others as they grow up. However, prematurity can affect how babies develop socially and emotionally.

It is possible that infants are born with traits that help them attach securely to their caregivers. Differences in attachment might come from how infants react to stress and how they interpret care from their parents. The development of some parts of the infant’s brain – like the amygdala and hippocampus – has been associated with stress during pregnancy, infants’ fear expression and parental care early in life. Prematurity might also affect how these brain regions develop.

Research question.

We wanted to determine if the development of the amygdala, hippocampus, or their whole-brain connections at birth influences attachment in term and preterm infants later on. Understanding which parts of the brain are linked to attachment and what affects them can help us find ways to support babies’ socioemotional growth. To address this, we conducted brain MRI scans at birth and observed how babies reacted when their caregiver briefly stopped interacting with them at nine months.

Findings.

We did not find any significant links between the size or connections of the amygdala and hippocampus at birth and babies’ distress, anger or attention to their caregiver during the 9-month test. Importantly, these results applied to both preterm and term babies. This suggests that the way babies form attachments might involve more parts of the brain or develop later in life rather than being determined by these specific brain structures early on.

Conclusion.

If more studies demonstrate that infants’ natural traits around birth – like brain structure – do not play a big role in how they attach to their caregivers, strategies trying to support infant socio-emotional growth could focus more on how parents care for the baby after birth. By paying attention to how parents interact with their babies, we may be able to help term and preterm infants develop socially and emotionally in a positive way.


 

Galdi P, Cabez MB, Farrugia C, Vaher K, Williams LZJ, Sullivan G, Stoye DQ, Quigley AJ, Makropoulos A, Thrippleton MJ, Bastin ME, Richardson H, Whalley H, Edwards AD, Bajada CJ, Robinson EC, Boardman JP. Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth. Hum Brain Mapp. 2024 Mar;45(4):e26660. doi: 10.1002/hbm.26660. PMID: 38488444; PMCID: PMC10941526

Studying How Being Born Early Affects Cerebral Cortex Development in Babies

Background information.

The cerebral cortex is the outer layer of the brain, playing a key role in memory, attention, perception, awareness, thought, language, and consciousness. Different parts of the cortex have specific functions: the temporal lobe handles hearing and memory, the occipital lobe processes visual information, the frontal lobe is involved in decision making and movement, and the parietal lobe integrates sensory information. In the last few months before birth and shortly after, the brain undergoes rapid development. Being born early (preterm) can interrupt this crucial period, potentially affecting lifelong brain function and development.

Research question.

We aimed to investigate how being born preterm affects the detailed structure of the brain at the time of normal birth (term-equivalent age) using a new measurement method called the Vogt-Bailey (VB) index.

Findings.

The study found that preterm babies have different microscopic details in brain structures in several areas compared to full-term babies, with more uniform structures in parts of the temporal, occipital, frontal, and parietal lobes. The VB index provided a detailed and reliable way to see these differences, offering better precision than previous methods. These findings were consistent across two different groups of babies, ensuring the reliability of the results.

Conclusion.

Understanding how preterm birth affects brain development can help identify early signs of potential cognitive or functional issues. This knowledge can guide interventions and support for preterm babies. Future studies could use the VB index to link early brain differences to long-term outcomes, leading to strategies that help preterm babies develop as healthily as possible.


 

Mckinnon K, Jardine C, Barclay G, Thrippleton MJ, Abel S, Wardlaw JM, Bastin ME, Whalley HC, Richardson H, Boardman JP. An unexpected ferromagnetic foreign body in a paediatric research participant undergoing 3T MRI. BMJ Case Rep. 2024 Jan 24;17(1):e258969. doi: 10.1136/bcr-2023-258969. PMID: 38272527; PMCID: PMC10826474.

A ball-bearing found in a child’s ear at a research MRI

Background information.

In this article, we discuss a child who attended his research MRI at five years of age and was found to have an unexpected 5mm ball bearing in his ear. It was found when he approached the MRI scanner, and the magnet dislodged the ball bearing. 

Description. ​​​

We used magnetic resonance imaging (MRI) scans regularly to study the brains development after preterm birth, and found they are generally very safe, with no radiation exposure. Metal “foreign bodies” and implants can be a safety risk when performing MRIs, because of the magnet strength involved in taking pictures of the brain. Risks are reduced by thorough safety checks, including questions about any possible metal, both intentionally put there by doctors or surgeons, and unintentionally through putting objects in ears or nostrils, or swallowing. We also use visual checks before starting a scan.  We then discuss some of the wider research about making MRI scans as safe as possible for children.

Since this child’s ball bearing, we now additionally use a magnet wand to check for any metal objects in ears or nostrils before children enter the MRI scanner.

Conclusion.

This project has shown the importance of thorough safety screening, particularly in young children or those with cognitive or behavioural problems who are more likely to have “foreign bodies”, but that there is no perfect screening method to prevent all unexpected metal. We hope that sharing our experience will contribute to MRI safety worldwide.

 


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