The role of heritable factors in determining the common neurologic deficits seen after preterm birth is unknown, but the characteristic phenotype of neurocognitive, neuroanatomical, and growth abnormalities allows principled selection of candidate genes to test the hypothesis that common genetic variation modulates the risk for brain injury.
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.
Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials.
Early neuroimaging may provide a surrogate marker for brain development and outcome after preterm birth. Tract-Based Spatial Statistics (TBSS) is an advanced Diffusion Tensor Image (DTI) analysis technique that is sensitive to the effects of prematurity and may provide a quantitative marker for neuroprotection following perinatal brain injury or preterm birth. Here, we test the sensitivity of TBSS to detect diffuse microstructural differences in the developing white matter of preterm infants at term-equivalent age by modelling a treatment effect as a global increase in fractional anisotropy (FA). As proof of concept we compare these simulations to a real effect of increasing age at scan. 3-Tesla, 15-direction diffusion tensor imaging (DTI) was acquired from 90 preterm infants at term-equivalent age. Datasets were randomly assigned to treated or untreated groups of increasing size and voxel-wise increases in FA were used to simulate global treatment effects of increasing magnitude in all treated maps. Treated and untreated FA maps were compared using TBSS. Predictions from simulated data were then compared to exemplar TBSS group comparisons based on increasing postmenstrual age at scan. TBSS proved sensitive to global differences in FA within a clinically relevant range, even in relatively small group sizes, and simulated data were shown to predict well a true biological effect of increasing age on white matter development. These data confirm that TBSS is a sensitive tool for detecting global group-wise differences in FA in this population.
Our aims were to (1) assess the corticospinal tracts (CSTs) in infants with focal injury and healthy term controls using probabilistic tractography and (2) to correlate the conventional magnetic resonance imaging (MRI) and tractography findings in infants with focal injury with their later motor function.
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. T(1)- and T(2)-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.
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.
The functions of the resting state networks (RSNs) revealed by functional MRI remain unclear, but it has seemed possible that networks emerge in parallel with the development of related cognitive functions. We tested the alternative hypothesis: that the full repertoire of resting state dynamics emerges during the period of rapid neural growth before the normal time of birth at term (around 40 wk of gestation). We used a series of independent analytical techniques to map in detail the development of different networks in 70 infants born between 29 and 43 wk of postmenstrual age (PMA). We characterized and charted the development of RSNs from recognizable but often fragmentary elements at 30 wk of PMA to full facsimiles of adult patterns at term. Visual, auditory, somatosensory, motor, default mode, frontoparietal, and executive control networks developed at different rates; however, by term, complete networks were present, several of which were integrated with thalamic activity. These results place the emergence of RSNs largely during the period of rapid neural growth in the third trimester of gestation, suggesting that they are formed before the acquisition of cognitive competencies in later childhood.
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.
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.
In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing populations. We aimed to characterize HRF in human infants before and after the normal time of birth using rapid sampling of the blood oxygen level dependent (BOLD) signal. A somatosensory stimulus and an event related experimental design were used to collect data from 10 healthy adults, 15 sedated infants at term corrected post menstrual age (PMA) (median 41+1 weeks), and 10 preterm infants (median PMA 34+4 weeks). A positive amplitude HRF waveform was identified across all subject groups, with a systematic maturational trend in terms of decreasing time-to-peak and increasing positive peak amplitude associated with increasing age. Application of the age-appropriate HRF models to fMRI data significantly improved the precision of the fMRI analysis. These findings support the notion of a structured development in the brains response to stimuli across the last trimester of gestation and beyond.
INTRODUCTION: Visual impairment in preterm infants at term equivalent age (TEA) is associated with impaired microstructural development in the optic radiation, measured as reduced fractional anisotropy (FA) by Diffusion Tensor Imaging (DTI). We tested the hypothesis that these abnormalities develop during the late preterm period. METHODS: DTI was performed in 53 infants born at a median (range) of 30(+1) (25(+4)-34(+6)) weeks post-menstrual age (PMA), 22 of whom were imaged twice. RESULTS: FA in the optic radiation at TEA was related to: visual function (p = .003); PMA at birth (p = .015); and PMA at scan (p = .008); while a significant interaction between PMA at birth and scan (p = .019) revealed an effect of the period of premature extra-uterine life additional to the degree of prematurity. We explored this further in a sub-group of 22 infants who were studied twice. FA increased from mean (95% CI) .174 (.164-.176) on the first image at 32(+5) (29(+5)-36) weeks PMA, to .198 (.190-.206) on the second image at 40(+6) (39(+2)-46) weeks PMA. Visual function was not predicted by FA on the images obtained in the early neonatal period, but was significantly related to the rate of increase in FA between scans (p = .027) and to FA on the second image (p = .015). CONCLUSION: Microstructural maturation during the late preterm period is thus required for normal visual function, suggesting that interventions applied after 30 weeks PMA might reduce impairment in preterm infants.
Objective biomarkers are needed to assess neuroprotective therapies after perinatal hypoxic-ischemic encephalopathy (HIE). We tested the hypothesis that, in infants who underwent therapeutic hypothermia after perinatal HIE, neurodevelopmental performance was predicted by fractional anisotropy (FA) values in the white matter (WM) on early diffusion tensor imaging (DTI) as assessed by means of tract-based spatial statistics (TBSS).
Consistent patterns of rotational intracardiac flow have been demonstrated in the healthy adult human heart. Intracardiac rotational flow patterns are hypothesized to assist in the maintenance of kinetic energy of inflowing blood, augmenting cardiac function. Newborn cardiac function is known to be suboptimal secondary to decreased receptor number and sympathetic innervation, increased afterload, and increased reliance on atrial contraction to support ventricular filling. Patterns of intracardiac flow in the newborn have not previously been examined.
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