Gareth Ball

The Effect of Preterm Birth on Thalamic and Cortical Development

Preterm birth is a leading cause of cognitive impairment in childhood and is associated with cerebral gray and white matter abnormalities. Using multimodal image analysis, we tested the hypothesis that altered thalamic development is an important component of preterm brain injury and is associated with other macro- and microstructural alterations. T1- and T2-weighted magnetic resonance images and 15-direction diffusion tensor images were acquired from 71 preterm infants at term-equivalent age. Deformation-based morphometry, Tract-Based Spatial Statistics, and tissue segmentation were combined for a nonsubjective whole-brain survey of the effect of prematurity on regional tissue volume and microstructure. Increasing prematurity was related to volume reduction in the thalamus, hippocampus, orbitofrontal lobe, posterior cingulate cortex, and centrum semiovale. After controlling for prematurity, reduced thalamic volume predicted: lower cortical volume; decreased volume in frontal and temporal lobes, including hippocampus, and to a lesser extent, parietal and occipital lobes; and reduced fractional anisotropy in the corticospinal tracts and corpus callosum. In the thalamus, reduced volume was associated with increased diffusivity. This demonstrates a significant effect of prematurity on thalamic development that is related to abnormalities in allied brain structures. This suggests that preterm delivery disrupts specific aspects of cerebral development, such as the thalamocortical system.

Rich-club organization of the newborn human brain

Significance To investigate the organizational principles of human brain development, we analyzed cerebral structural connectivity in the period leading up to the time of normal birth. We found that a “rich club” of interconnected cortical hubs previously reported in adults is present by 30 wk gestation. From mid to late gestation, connections between core hubs and the rest of the brain increased significantly. To determine the influence of environmental factors on network development, we also compared term-born infants to those born prematurely. Alterations in cortical–subcortical connectivity and short-distance connections outside the core network were associated with prematurity. Rich-club organization in the human brain precedes the emergence of complex neurological function, and alterations during this time may impact negatively on subsequent neurodevelopment. Combining diffusion magnetic resonance imaging and network analysis in the adult human brain has identified a set of highly connected cortical hubs that form a “rich club”—a high-cost, high-capacity backbone thought to enable efficient network communication. Rich-club architecture appears to be a persistent feature of the mature mammalian brain, but it is not known when this structure emerges during human development. In this longitudinal study we chart the emergence of structural organization in mid to late gestation. We demonstrate that a rich club of interconnected cortical hubs is already present by 30 wk gestation. Subsequently, until the time of normal birth, the principal development is a proliferation of connections between core hubs and the rest of the brain. We also consider the impact of environmental factors on early network development, and compare term-born neonates to preterm infants at term-equivalent age. Though rich-club organization remains intact following premature birth, we reveal significant disruptions in both in cortical–subcortical connectivity and short-distance corticocortical connections. Rich club organization is present well before the normal time of birth and may provide the fundamental structural architecture for the subsequent emergence of complex neurological functions. Premature exposure to the extrauterine environment is associated with altered network architecture and reduced network capacity, which may in part account for the high prevalence of cognitive problems in preterm infants.

Construction of a consistent high-definition spatio-temporal atlas of the developing brain using adaptive kernel regression

Medical imaging has shown that, during early development, the brain undergoes more changes in size, shape and appearance than at any other time in life. A better understanding of brain development requires a spatio-temporal atlas that characterizes the dynamic changes during this period. In this paper we present an approach for constructing a 4D atlas of the developing brain, between 28 and 44 weeks post-menstrual age at time of scan, using T1 and T2 weighted MR images from 204 premature neonates. The method used for the creation of the average 4D atlas utilizes non-rigid registration between all pairs of images to eliminate bias in the atlas toward any of the original images. In addition, kernel regression is used to produce age-dependent anatomical templates. A novelty in our approach is the use of a time-varying kernel width, to overcome the variations in the distribution of subjects at different ages. This leads to an atlas that retains a consistent level of detail at every time-point. Comparisons between the resulting atlas and atlases constructed using affine and non-rigid registration are presented. The resulting 4D atlas has greater anatomic definition than currently available 4D atlases created using various affine and non-rigid registration approaches, an important factor in improving registrations between the atlas and individual subjects. Also, the resulting 4D atlas can serve as a good representative of the population of interest as it reflects both global and local changes. The atlas is publicly available at www.brain-development.org.

Development of cortical microstructure in the preterm human brain

Cortical maturation was studied in 65 infants between 27 and 46 wk postconception using structural and diffusion magnetic resonance imaging. Alterations in neural structure and complexity were inferred from changes in mean diffusivity and fractional anisotropy, analyzed by sampling regions of interest and also by a unique whole-cortex mapping approach. Mean diffusivity was higher in gyri than sulci and in frontal compared with occipital lobes, decreasing consistently throughout the study period. Fractional anisotropy declined until 38 wk, with initial values and rates of change higher in gyri, frontal and temporal poles, and parietal cortex; and lower in sulcal, perirolandic, and medial occipital cortex. Neuroanatomical studies and experimental diffusion–anatomic correlations strongly suggested the interpretation that cellular and synaptic complexity and density increased steadily throughout the period, whereas elongation and branching of dendrites orthogonal to cortical columns was later and faster in higher-order association cortex, proceeding rapidly before becoming undetectable after 38 wk. The rate of microstructural maturation correlated locally with cortical growth, and predicted higher neurodevelopmental test scores at 2 y of age. Cortical microstructural development was reduced in a dose-dependent fashion by longer premature exposure to the extrauterine environment, and preterm infants at term-corrected age possessed less mature cortex than term-born infants. The results are compatible with predictions of the tension theory of cortical growth and show that rapidly developing cortical microstructure is vulnerable to the effects of premature birth, suggesting a mechanism for the adverse effects of preterm delivery on cognitive function.

An optimised tract-based spatial statistics protocol for neonates: applications to prematurity and chronic lung disease

Preterm birth is associated with altered white matter microstructure, defined by metrics derived from diffusion tensor imaging (DTI). Tract-based spatial statistics (TBSS) is a useful tool for investigating developing white matter using DTI, but standard TBSS protocols have limitations for neonatal studies. We describe an optimised TBSS protocol for neonatal DTI data, in which registration errors are reduced. As chronic lung disease (CLD) is an independent risk factor for abnormal white matter development, we investigate the effect of this condition on white matter anisotropy and diffusivity using the optimised protocol in a proof of principle experiment. DTI data were acquired from 93 preterm infants (48 male) with a median gestational age at birth of 28(+5) (23(+4)-35(+2))weeks at a median postmenstrual age at scan of 41(+4) (38(+1)-46(+6))weeks. Nineteen infants developed CLD, defined as requiring supplemental oxygen at 36weeks postmenstrual age. TBSS was modified to include an initial low degrees-of-freedom linear registration step and a second registration to a population-average FA map. The additional registration steps reduced global misalignment between neonatal fractional anisotropy (FA) maps. Infants with CLD had significantly increased radial diffusivity (RD) and significantly reduced FA within the centrum semiovale, corpus callosum and inferior longitudinal fasciculus (p<0.05) compared to their peers, controlling for degree of prematurity and age at scan. The optimised TBSS protocol improved reliability for neonatal DTI analysis. These data suggest that potentially modifiable respiratory morbidity is associated with widespread altered white matter microstructure in preterm infants at term-equivalent age.

The influence of preterm birth on the developing thalamocortical connectome

INTRODUCTION Defining connectivity in the human brain signifies a major neuroscientific goal. Advanced imaging techniques have enabled the non-invasive tracing of brain networks to define the human connectome on a millimetre-scale. During early development, the brain undergoes significant changes that are likely represented in the developing connectome, and preterm birth represents a significant environmental risk factor that impacts negatively on early cerebral development. Using tractography to comprehensively map the connections of the thalamocortical unit, we aim to demonstrate that premature extrauterine life due to preterm delivery results in significantly decreased thalamocortical connectivity in the developing human neonate. METHODS T1- and T2-weighted magnetic resonance images and 32-direction diffusion tensor images were acquired from 18 healthy term-born neonates (median gestational age: 41(+3)) and 47 preterm infants (median gestational age: 28(+3)) scanned at term-equivalent age. Using a novel processing pipeline for tracing connections in the neonatal brain we map and compare the thalamocortical macro-connectome between groups. RESULTS We demonstrate that connections between the thalamus and the frontal cortices, supplementary motor areas, occipital lobe and temporal gyri are significantly diminished in preterm infants (FDR-corrected, p < .001). CONCLUSIONS This supports the hypothesis that the thalamocortical system is vulnerable following preterm birth and the tractographic framework presented represents a method for analysing system connectivity that can be readily applied to other populations and neural systems.

Neonatal tract-based spatial statistics findings and outcome in preterm infants.

BACKGROUND AND PURPOSE: WM injury is associated with different disabilities that children born prematurely may experience during their lives. The aim of this study was to use TBSS to test the hypothesis that WM microstructure at TEA in preterm infants is correlated with cognitive and motor outcome at 2-year corrected age. MATERIALS AND METHODS: Sixty-three preterm infants, born at a mean gestational age of 28.7 weeks, underwent MR imaging and DTI at TEA. Neurodevelopmental performance was assessed by using the BSITD-III. Voxelwise analysis of the DTI data was performed by using TBSS to assess the relationship among FA, AD, and RD at TEA, and cognitive, fine-motor, and gross-motor scores at 2-year corrected age. RESULTS: Cognitive scores were correlated with FA values in the CC. Fine-motor scores were correlated with FA and RD throughout the WM. Gross-motor scores were associated with RD in the CC, fornix, and internal and external capsule. CONCLUSIONS: WM microstructure in preterm infants at TEA was associated with cognitive, fine-motor, and gross-motor performance at 2-year corrected age. This study suggests that TBSS of DTI data at TEA has the potential to be used as a biomarker for subsequent neurodevelopment.

Thalamocortical Connectivity Predicts Cognition in Children Born Preterm

Thalamocortical connections are: essential for brain function, established early in development, and significantly impaired following preterm birth. Impaired cognitive abilities in preterm infants may be related to disruptions in thalamocortical connectivity. The aim of this study was to test the hypothesis: thalamocortical connectivity in the preterm brain at term-equivalent is correlated with cognitive performance in early childhood. We examined 57 infants who were born <35 weeks gestational age (GA) and had no evidence of focal abnormality on magnetic resonance imaging (MRI). Infants underwent diffusion MRI at term and cognitive performance at 2 years was assessed using the Bayley III scales of Infant and Toddler development. Cognitive scores at 2 years were correlated with structural connectivity between the thalamus and extensive cortical regions at term. Mean thalamocortical connectivity across the whole cortex explained 11% of the variance in cognitive scores at 2 years. The inclusion of GA at birth and parental socioeconomic group in the model explained 30% of the variance in subsequent cognitive performance. Identifying impairments in thalamocortical connectivity as early as term equivalent can help identify those infants at risk of subsequent cognitive delay and may be useful to assess efficacy of potential treatments at an early age.

Diffusion tensor imaging in preterm infants with punctate white matter lesions

Our aim was to compare white matter (WM) microstructure in preterm infants with and without punctate WM lesions on MRI using tract-based spatial statistics (TBSS) and probabilistic tractography. We studied 23 preterm infants with punctate lesions, median GA at birth 30 (25–35) wk, and 23 GA- and sex-matched preterm controls. TBSS and tractography were performed to assess differences in fractional anisotropy (FA) between the two groups at term equivalent age. The impact of lesion load was assessed by performing linear regression analysis of the number of lesions on term MRI versus FA in the corticospinal tracts in the punctate lesions group. FA values were significantly lower in the posterior limb of the internal capsule, cerebral peduncles, decussation of the superior cerebellar peduncles, superior cerebellar peduncles, and pontine crossing tract in the punctate lesions group. There was a significant negative correlation between lesion load at term and FA in the corticospinal tracts (p = 0.03, adjusted r2 = 0.467). In conclusion, punctate lesions are associated with altered microstructure in the WM fibers of the corticospinal tract at term equivalent age.

Whole-Brain Mapping of Structural Connectivity in Infants Reveals Altered Connection Strength Associated with Growth and Preterm Birth

Cerebral white-matter injury is common in preterm-born infants and is associated with neurocognitive impairments. Identifying the pattern of connectivity changes in the brain following premature birth may provide a more comprehensive understanding of the neurobiology underlying these impairments. Here, we characterize whole-brain, macrostructural connectivity following preterm delivery and explore the influence of age and prematurity using a data-driven, nonsubjective analysis of diffusion magnetic resonance imaging data. T1- and T2-weighted and -diffusion MRI were obtained between 11 and 31 months postconceptional age in 49 infants, born between 25 and 35 weeks postconception. An optimized processing pipeline, combining anatomical, and tissue segmentations with probabilistic diffusion tractography, was used to map mean tract anisotropy. White-matter tracts where connection strength was related to age of delivery or imaging were identified using sparse-penalized regression and stability selection. Older children had stronger connections in tracts predominantly involving frontal lobe structures. Increasing prematurity at birth was related to widespread reductions in connection strength in tracts involving all cortical lobes and several subcortical structures. This nonsubjective approach to mapping whole-brain connectivity detected hypothesized changes in the strength of intracerebral connections during development and widespread reductions in connectivity strength associated with premature birth.