Nazakat Merchant

Emergence of resting state networks in the preterm human brain

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.

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.

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.

Development of BOLD signal hemodynamic responses in the human brain

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.

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.

Somatosensory cortical activation identified by functional MRI in preterm and term infants

Functional MRI (fMRI) has not previously been used systematically to investigate brain function in preterm infants. We here describe statistically robust and reproducible fMRI results in this challenging subject group using a programmable somatosensory stimulus synchronized with MR image acquisition which induced well-localized positive blood oxygen level dependent (BOLD) responses contralateral to the side of the stimulation in: 11 preterm infants (median post menstrual age 33 weeks and 4 days, range 29+1 to 35+3); 6 control infants born at term gestational age; and 18 infants born preterm (median gestational age at birth 30 weeks and 5 days, range 25+4 to 36+0) but studied at term corrected gestational age. Bilateral signals were identified in 8 of the ex-preterm infants at term age. Anatomical confirmation of appropriate activations was provided with diffusion tensor imaging (DTI) based tractography which identified connecting pathways from the regions of activation through the ipsilateral corticospinal tracts and posterior limb of the internal capsule. These results demonstrate that it is possible to reliably identify positive BOLD signals in the infant brain and that fMRI techniques can also be applied in the study of preterm infants.

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.

A method for rapid in vivo measurement of blood T1

We present a technique to measure the longitudinal relaxation time constant of venous blood (T1b) in vivo in a few seconds. The MRI sequence consists of a thick‐slab adiabatic inversion, followed by a series of slice‐selective excitations and single‐shot echo planar imaging readouts. The time intervals between excitations were chosen so that blood in macroscopic vessels is fully refreshed between excitations, making the blood signal follow an unperturbed inversion recovery curve. Static tissue, which experiences the inversion and all excitation pulses, quickly reaches a steady state at a low signal as a result of partial saturation. This allows blood‐filled voxels to be discriminated from those containing static tissue, and to be fitted voxel‐by‐voxel to a simple inversion recovery model. The sequence was tested on a flow phantom with the proposed method, yielding T1 values consistent to within 3% of those obtained using a conventional inversion recovery sequence with a spin‐echo readout. The method was applied to seven adult volunteers and 18 neonates. The blood T1 of the neonates (1799 ± 206 ms; range, 1393–2035 ms) was found to be more variable than that of adults (1717 ± 39 ms; range, 1662–1779 ms). A linear correlation between the inverse of T1b and the haematocrit was established in 12 neonates (R2 = 0.90). Copyright