Recent advances in diffusion neuroimaging: applications in the developing preterm brain

Measures obtained from diffusion-weighted imaging provide objective indices of white matter development and injury in the developing preterm brain. To date, diffusion tensor imaging (DTI) has been used widely, highlighting differences in fractional anisotropy (FA) and mean diffusivity (MD) between preterm infants at term and healthy term controls; altered white matter development associated with a number of perinatal risk factors; and correlations between FA values in the white matter in the neonatal period and subsequent neurodevelopmental outcome. Recent developments, including neurite orientation dispersion and density imaging (NODDI) and fixel-based analysis (FBA), enable white matter microstructure to be assessed in detail. Constrained spherical deconvolution (CSD) enables multiple fibre populations in an imaging voxel to be resolved and allows delineation of fibres that traverse regions of fibre-crossings, such as the arcuate fasciculus and cerebellar-cortical pathways. This review summarises DTI findings in the preterm brain and discusses initial findings in this population using CSD, NODDI, and FBA

Diffusion magnetic resonance imaging assessment of regional white matter maturation in preterm neonates

PURPOSE: Diffusion magnetic resonance imaging (dMRI) studies report altered white matter (WM) development in preterm infants. Neurite orientation dispersion and density imaging (NODDI) metrics provide more realistic estimations of neurite architecture in vivo compared with standard diffusion tensor imaging (DTI) metrics. This study investigated microstructural maturation of WM in preterm neonates scanned between 25 and 45 weeks postmenstrual age (PMA) with normal neurodevelopmental outcomes at 2 years using DTI and NODDI metrics. METHODS: Thirty-one neonates (n = 17 male) with median (range) gestational age (GA) 32+1 weeks (24+2-36+4) underwent 3 T brain MRI at median (range) post menstrual age (PMA) 35+2 weeks (25+3-43+1). WM tracts (cingulum, fornix, corticospinal tract (CST), inferior longitudinal fasciculus (ILF), optic radiations) were delineated using constrained spherical deconvolution and probabilistic tractography in MRtrix3. DTI and NODDI metrics were extracted for the whole tract and cross-sections along each tract to assess regional development. RESULTS: PMA at scan positively correlated with fractional anisotropy (FA) in the CST, fornix and optic radiations and neurite density index (NDI) in the cingulum, CST and fornix and negatively correlated with mean diffusivity (MD) in all tracts. A multilinear regression model demonstrated PMA at scan influenced all diffusion measures, GA and GAxPMA at scan influenced FA, MD and NDI and gender affected NDI. Cross-sectional analyses revealed asynchronous WM maturation within and between WM tracts.). CONCLUSION: We describe normal WM maturation in preterm neonates with normal neurodevelopmental outcomes. NODDI can enhance our understanding of WM maturation compared with standard DTI metrics alone

Fetal body MRI and its application to fetal and neonatal treatment: an illustrative review

This Review depicts the evolving role of MRI in the diagnosis and prognostication of anomalies of the fetal body, here including head and neck, thorax, abdomen and spine. A review of the current literature on the latest developments in antenatal imaging for diagnosis and prognostication of congenital anomalies is coupled with illustrative cases in true radiological planes with viewable three-dimensional video models that show the potential of post-acquisition reconstruction protocols. We discuss the benefits and limitations of fetal MRI, from anomaly detection, to classification and prognostication, and defines the role of imaging in the decision to proceed to fetal intervention, across the breadth of included conditions. We also consider the current capabilities of ultrasound and explore how MRI and ultrasound can complement each other in the future of fetal imaging

Brain development in fetal ventriculomegaly

Introduction Fetal ventriculomegaly is the most common detectable central nervous system abnormality affecting 1% of fetuses and is associated with abnormal neurodevelopment in childhood. Neurodevelopmental outcome is partially predictable by the 2D size of the ventricles in the absence of other abnormalities while the aetiology of the dilatation remains unknown. The main aim of this study was to investigate brain development in the presence of isolated ventriculomegaly during fetal and neonatal life. Methods Fetal brain MRI (1.5T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly from 22-38 gestational weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3D reconstructed datasets while cortical maturation was assessed using a detailed cortical scoring system. The metabolic profile of the fetal brain was assessed using magnetic resonance spectroscopy. During neonatal life, volumetric analysis of ventricular and supratentorial brain tissue was performed while white matter microstructure was assessed using Diffusion Tensor Imaging. The neurodevelopmental outcome of these children was evaluated at 1 and 2 years of age. Results Fetuses with isolated ventriculomegaly had significantly increased cortical volumes when compared to controls while cortical maturation of the calcarine sulcus and parieto-occipital fissure was delayed. NAA:Cho, MI:Cho and MI:Cr ratios were lower whilst Cho:Cr ratios were higher in fetuses with ventriculomegaly. Neonates with prenatally diagnosed ventriculomegaly had increased ventricular and supratentorial brain tissue volumes and reduced FA values in the splenium of the corpus callosum, sagittal striatum and corona radiata. At year 2 of age, only 37.5% of the children assessed had a normal neurodevelopment. Conclusions The presence of relative cortical overgrowth, delayed cortical maturation and aberrant white matter development in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language and behavioural deficits in these children

Early life factors and white matter microstructure in children with overweight and obesity: The ActiveBrains project

This study was supported by the Spanish Ministry of Economy and Competitiveness (DEP2013-47540, DEP2016-79512-R, and DEP2017-91544-EXP), the European Regional Development Fund, the European Commission (No 667302) and the Alicia Koplowitz Foundation. This study was partially funded by the UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme. Units of Scientific Excellence; Scientific Unit of Excellence on Exercise and Health (UCEES) and by the Regional Government of Andalusia, Regional Ministry of Economy, Knowledge, Entreprises and University and European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR. In addition, this study was further supported by the SAMID III network, RETICS, funded by the PN IthornDthornI 2017-2021 (Spain). Additional funding was obtained from the Andalusian Operational Programme supported with European Regional Development Funds (ERDF in English, FEDER in Spanish, project ref: B-CTS-355-UGR18). PS-U is supported by a grant from ANID/BECAS Chile/72180543. IE-C is supported by the Spanish Ministries of Economy and Competitiveness (RTI2018-095284-J-100), and Science and Innovation (RYC2019-027287-I). JV-R is supported by a grant from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33396). Funding for open access charge: Universidad de Granada/CBUA. We would like to thank all the families participating in the ActiveBrains. We are grateful to Ms. Ana Yara Postigo-Fuentes for her assistance with the English language. We also acknowledge everyone who helped with the data collection and all of the members involved in the fieldwork for their effort, enthusiasm, and support. This work is part of Ph.D. Thesis conducted in the Biomedicine Doctoral Studies of the University of Granada, Spain.Background & aims: Exposure to a suboptimal environment during the fetal and early infancy period's results in long-term consequences for brain morphology and function. We investigated the associations of early life factors such as anthropometric neonatal data (i.e., birth length, birth weight and birth head circumference) and breastfeeding practices (i.e., exclusive and any breastfeeding) with white matter (WM) microstructure, and ii) we tested whether WM tracts related to early life factors are associated with academic performance in children with overweight/obesity. Methods: 96 overweight/obese children (10.03 +/- 1.16 years; 38.7% girls) were included from the ActiveBrains Project. WM microstructure indicators used were fractional anisotropy (FA) and mean diffusivity (MD), derived from Diffusion Tensor Imaging. Academic performance was evaluated with the Battery III Woodcock-Munoz Tests of Achievement. Regression models were used to examine the associations of the early life factors with tract-specific FA and MD, as well as its association with academic performance. Results: Head circumference at birth was positively associated with FA of the inferior fronto-occipital fasciculus tract (0.441; p = 0.005), as well as negatively associated with MD of the cingulate gyrus part of cingulum (-0.470; p = 0.006), corticospinal (-0.457; p = 0.005) and superior thalamic radiation tract (-0.476; p = 0.001). Association of birth weight, birth length and exclusive breastfeeding with WM microstructure did not remain significant after false discovery rate correction. None tract related to birth head circumference was associated with academic performance (all p > 0.05). Conclusions: Our results highlighted the importance of the perinatal growth in WM microstructure later in life, although its possible academic implications remain inconclusive.Spanish Government DEP2013-47540 DEP2016-79512-R DEP2017-91544-EXPEuropean Commission European Commission European Commission Joint Research Centre 667302Alicia Koplowitz FoundationUGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions ProgrammeEuropean Commission SOMM17/6107/UGRSAMID III network, RETICS - PN I+D+I 2017-2021 (Spain)Andalusian Operational Programme - European Regional Development Funds B-CTS-355-UGR18ANID/BECAS Chile 72180543Spanish Government RTI2018-095284-J-100 FJCI-2017-33396 RYC2019-027287-

Mesenchymal Stem Cells Induce T-Cell Tolerance and Protect the Preterm Brain after Global Hypoxia-Ischemia

Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 106MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE

Examining the development of brain structure in utero with fetal MRI, acquired as part of the Developing Human Connectome Project

The human brain is an incredibly complex organ, and the study of it traverses many scales across space and time. The development of the brain is a protracted process that begins embryonically but continues into adulthood. Although neural circuits have the capacity to adapt and are modulated throughout life, the major structural foundations are laid in utero during the fetal period, through a series of rapid but precisely timed, dynamic processes. These include neuronal proliferation, migration, differentiation, axonal pathfinding, and myelination, to name a few. The fetal origins of disease hypothesis proposed that a variety of non-communicable diseases emerging in childhood and adulthood could be traced back to a series of risk factors effecting neurodevelopment in utero (Barker 1995). Since this publication, many studies have shown that the structural scaffolding of the brain is vulnerable to external environmental influences and the perinatal developmental window is a crucial determinant of neurological health later in life. However, there remain many fundamental gaps in our understanding of it. The study of human brain development is riddled with biophysical, ethical, and technical challenges. The Developing Human Connectome Project (dHCP) was designed to tackle these specific challenges and produce high quality open-access perinatal MRI data, to enable researchers to investigate normal and abnormal neurodevelopment (Edwards et al., 2022). This thesis will focus on investigating the diffusion-weighted and anatomical (T2) imaging data acquired in the fetal period, between the second to third trimester (22 – 37 gestational weeks). The limitations of fetal MR data are ill-defined due to a lack of literature and therefore this thesis aims to explore the data through a series of critical and strategic analysis approaches that are mindful of the biophysical challenges associated with fetal imaging. A variety of analysis approaches are optimised to quantify structural brain development in utero, exploring avenues to relate the changes in MR signal to possible neurobiological correlates. In doing so, the work in this thesis aims to improve mechanistic understanding about how the human brain develops in utero, providing the clinical and medical imaging community with a normative reference point. To this aim, this thesis investigates fetal neurodevelopment with advanced in utero MRI methods, with a particular emphasis on diffusion MRI. Initially, the first chapter outlines a descriptive, average trajectory of diffusion metrics in different white matter fiber bundles across the second to third trimester. This work identified unique polynomial trajectories in diffusion metrics that characterise white matter development (Wilson et al., 2021). Guided by previous literature on the sensitivity of DWI to cellular processes, I formulated a hypothesis about the biophysical correlates of diffusion signal components that might underpin this trend in transitioning microstructure. This hypothesis accounted for the high sensitivity of the diffusion signal to a multitude of simultaneously occurring processes, such as the dissipating radial glial scaffold, commencement of pre-myelination and arborization of dendritic trees. In the next chapter, the methods were adapted to address this hypothesis by introducing another dimension, and charting changes in diffusion properties along developing fiber pathways. With this approach it was possible to identify compartment-specific microstructural maturation, refining the spatial and temporal specificity (Wilson et al., 2023). The results reveal that the dynamic fluctuations in the components of the diffusion signal correlate with observations from previous histological work. Overall, this work allowed me to consolidate my interpretation of the changing diffusion signal from the first chapter. It also serves to improve understanding about how diffusion signal properties are affected by processes in transient compartments of the fetal brain. The third chapter of this thesis addresses the hypothesis that cortical gyrification is influenced by both underlying fiber connectivity and cytoarchitecture. Using the same fetal imaging dataset, I analyse the tissue microstructural change underlying the formation of cortical folds. I investigate correlations between macrostructural surface features (curvature, sulcal depth) and tissue microstructural measures (diffusion tensor metrics, and multi-shell multi-tissue decomposition) in the subplate and cortical plate across gestational age, exploring this relationship both at the population level and within subjects. This study provides empirical evidence to support the hypotheses that microstructural properties in the subplate and cortical plate are altered with the development of sulci. The final chapter explores the data without anatomical priors, using a data-driven method to extract components that represent coordinated structural maturation. This analysis aims to examine if brain regions with coherent patterns of growth over the fetal period converge on neonatal functional networks. I extract spatially independent features from the anatomical imaging data and quantify the spatial overlap with pre-defined neonatal resting state networks. I hypothesised that coherent spatial patterns of anatomical development over the fetal period would map onto the functional networks observed in the neonatal period. Overall, this thesis provides new insight about the developmental contrast over the second to third trimester of human development, and the biophysical correlates affecting T2 and diffusion MR signal. The results highlight the utility of fetal MRI to research critical mechanisms of structural brain maturation in utero, including white matter development and cortical gyrification, bridging scales from neurobiological processes to whole brain macrostructure. their gendered constructions relating to women