Latha Srinivasan

Diffusion tensor imaging with tract-based spatial statistics reveals local white matter abnormalities in preterm infants

Infants born preterm have a high incidence of neurodevelopmental impairment in later childhood, often associated with poorly defined cerebral white matter abnormalities. Diffusion tensor imaging quantifies the diffusion of water within tissues and can assess microstructural abnormalities in the developing preterm brain. Tract-based spatial statistics (TBSS) is an automated observer-independent method of aligning fractional anisotropy (FA) images from multiple subjects to allow groupwise comparisons of diffusion tensor imaging data. We applied TBSS to test the hypothesis that preterm infants have reduced fractional anisotropy in specific regions of white matter compared to term-born controls. We studied 26 preterm infants with no evidence of focal lesions on conventional magnetic resonance imaging (MRI) at term equivalent age and 6 healthy term-born control infants. We found that the centrum semiovale, frontal white matter and the genu of the corpus callosum showed significantly lower FA in the preterm group. Infants born at less than or equal to 28 weeks gestational age (n=11) displayed additional reductions in FA in the external capsule, the posterior aspect of the posterior limb of the internal capsule and the isthmus and middle portion of the body of the corpus callosum. This study demonstrates that TBSS provides an observer-independent method of identifying white matter abnormalities in the preterm brain at term equivalent age in the absence of focal lesions.

Specific relations between neurodevelopmental abilities and white matter microstructure in children born preterm

Survivors of preterm birth have a high incidence of neurodevelopmental impairment which is not explained by currently understood brain abnormalities. The aim of this study was to test the hypothesis that the neurodevelopmental abilities of 2-year-old children who were born preterm and who had no evidence of focal abnormality on conventional MR imaging were consistently linearly related to specific local changes in white matter microstructure. We studied 33 children, born at a median (range) gestational age of 28(+5) (24(+4)-32(+1)) weeks. The children were recruited as infants from the Neonatal Intensive Care Unit at Queen Charlottes and Hammersmith Hospital in the early neonatal period and imaged at a median corrected age of 25.5 (24-27) months. The children underwent diffusion tensor imaging to measure fractional anisotropy (FA) as a measure of tissue microstructure, and neurodevelopmental assessment using the Griffiths Mental Development Scales [giving an overall developmental quotient (DQ) and sub-quotients scores for motor, personal-social, hearing-language, eye-hand coordination and performance scales] at 2 years corrected age. Tract-based spatial statistics with linear regression analysis of voxel-wise cross-subject statistics were used to assess the relationship between FA and DQ/sub-quotient scores and results confirmed by reduced major axis regression of regions with significant correlations. We found that DQ was linearly related to FA values in parts of the corpus callosum; performance sub-scores to FA values in the corpus callosum and right cingulum; and eye-hand coordination sub-scores to FA values in the cingulum, fornix, anterior commissure, corpus callosum and right uncinate fasciculus. This study shows that specific neurodevelopmental impairments in infants born preterm are precisely related to microstructural abnormalities in particular regions of cerebral white matter which are consistent between individuals. FA may aid prognostication and provide a biomarker for therapeutic or mechanistic studies of preterm brain injury.

A dynamic 4D probabilistic atlas of the developing brain

Probabilistic atlases are widely used in the neuroscience community as a tool for providing a standard space for comparison of subjects and as tissue priors used to enhance the intensity-based classification of brain MRI. Most efforts so far have focused on static brain atlases either for adult or pediatric cohorts. In contrast to the adult brain the rapid growth of the neonatal brain requires an age-specific spatial probabilistic atlas to provide suitable anatomical and structural information. In this paper we describe a 4D probabilistic atlas that allows dynamic generation of prior tissue probability maps for any chosen stage of neonatal brain development between 29 and 44 gestational weeks. The atlas is created from the segmentations of 142 neonatal subjects at different ages using a kernel-based regression method and provides prior tissue probability maps for six structures - cortex, white matter, subcortical grey matter, brainstem, cerebellum and cerebro-spinal fluid. The atlas is publicly available at www.brain-development.org.

Automatic segmentation and reconstruction of the cortex from neonatal MRI

Segmentation and reconstruction of cortical surfaces from magnetic resonance (MR) images are more challenging for developing neonates than adults. This is mainly due to the dynamic changes in the contrast between gray matter (GM) and white matter (WM) in both T1- and T2-weighted images (T1w and T2w) during brain maturation. In particular in neonatal T2w images WM typically has higher signal intensity than GM. This causes mislabeled voxels during cortical segmentation, especially in the cortical regions of the brain and in particular at the interface between GM and cerebrospinal fluid (CSF). We propose an automatic segmentation algorithm detecting these mislabeled voxels and correcting errors caused by partial volume effects. Our results show that the proposed algorithm corrects errors in the segmentation of both GM and WM compared to the classic expectation maximization (EM) scheme. Quantitative validation against manual segmentation demonstrates good performance (the mean Dice value: 0.758+/-0.037 for GM and 0.794+/-0.078 for WM). The inner, central and outer cortical surfaces are then reconstructed using implicit surface evolution. A landmark study is performed to verify the accuracy of the reconstructed cortex (the mean surface reconstruction error: 0.73 mm for inner surface and 0.63 mm for the outer). Both segmentation and reconstruction have been tested on 25 neonates with the gestational ages ranging from approximately 27 to 45 weeks. This preliminary analysis confirms previous findings that cortical surface area and curvature increase with age, and that surface area scales to cerebral volume according to a power law, while cortical thickness is not related to age or brain growth.

Quantification of Deep Gray Matter in Preterm Infants at Term-Equivalent Age Using Manual Volumetry of 3-Tesla Magnetic Resonance Images

OBJECTIVE. Nonhypothesis-based MRI-analysis techniques including deformation-based morphometry and automated tissue segmentation have suggested that preterm infants at term-equivalent age have reduced tissue volume in the basal ganglia and thalami, which is most apparent among infants with supratentorial lesions. The aim of our study was to test this hypothesis by direct measurement of thalamic and lentiform nuclei volumes in preterm infants at term-equivalent age and term-born controls using manual volumetry. DESIGN/METHODS. Forty preterm infants at term-equivalent age (median gestational age: 29.5 weeks; median birth weight: 1.3 kg) and 8 term-born controls were examined using a 3-T Philips (Best, Netherlands) system. T1-weighted volume images and T2-weighted fast-spin echo pseudovolumes were acquired. There was no significant difference in postmenstrual age at image acquisition between the 2 groups. ImageJ 1.34 (National Institutes of Health, Bethesda, MD) was used for manual segmentations. RESULTS. The median thalamic and lentiform nuclei volumes for preterm infants at term-equivalent age were 13.6 and 3.07 cm3, respectively, significantly smaller than term-control volumes of 16.3 and 5.6 cm3, respectively. Ten preterm infants at term-equivalent age had supratentorial lesions (intraventricular hemorrhage, periventricular leukomalacia, or hemorrhagic parenchymal infarction), and the median thalamic and lentiform volumes for this group were 10.4 and 1.7 cm3, respectively. When this group was excluded, the remaining infants who had mild or moderate diffuse excessive high signal intensity in the white matter on T2-weighted images had a smaller, yet significant, volume reduction compared with controls. Tissue volumes were not related to weight and gestational age at birth. CONCLUSIONS. Manual volumetry confirms that preterm infants at term-equivalent age have reduced thalamic and lentiform volumes compared with controls. This was most marked among infants with supratentorial lesions but was also seen among those with nonfocal white matter abnormalities.

Probabilistic diffusion tractography of the optic radiations and visual function in preterm infants at term equivalent age

Children born prematurely have a high incidence of visual disorders which cannot always be explained by focal retinal or brain lesions. The aim of this study was to test the hypothesis that visual function in preterm infants is related to the microstructural development of white matter in the optic radiations. We used diffusion tensor imaging (DTI) with probabilistic diffusion tractography to delineate the optic radiations at term equivalent age and compared the fractional anisotropy (FA) to a contemporaneous evaluation of visual function. Thirty-seven preterm infants (19 male) born at median (range) 28(+4) (24(+1)-32(+3)) weeks gestational age, were examined at a post-menstrual age of 42 (39(+6)-43) weeks. MRI and DTI were acquired on a 3 Tesla MR system with DTI obtained in 15 non-collinear directions with a b value of 750 s/mm(2). Tracts were generated from a seed mask placed in the white matter lateral to the lateral geniculate nucleus and mean FA values of these tracts were determined. Visual assessment was performed using a battery of nine items assessing different aspects of visual abilities. Ten infants had evidence of cerebral lesions on conventional MRI. Multiple regression analysis demonstrated that the visual assessment score was independently correlated with FA values, but not gestational age at birth, post-menstrual age at scan or the presence of lesions on conventional MRI. The occurrence of mild retinopathy of prematurity did not affect the FA measures or visual scores. We then performed a secondary analysis using tract-based spatial statistics to determine whether global brain white matter development was related to visual function and found that only FA in the optic radiations was correlated with visual assessment score. Our results suggest that in preterm infants at term equivalent age visual function is directly related to the development of white matter in the optic radiations.

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.

Thalamo-cortical connectivity in children born preterm mapped using probabilistic magnetic resonance tractography ☆

Our aim was to investigate the feasibility of studying white matter tracts and connections between the thalamus and the cortex in 2-year-old infants who were born preterm by probabilistic magnetic resonance (MR) tractography. Using this approach, we were able to visualize and quantify connectivity distributions in a number of white matter tracts, including the corticospinal tracts, optic radiations, fibers of the genu and splenium of the corpus callosum, superior longitudinal fasciculus and inferior fronto-occipital fasciculus, and to map the distribution within thalamus of fibers connecting to specific cortical regions. In eleven infants with no MR evidence of focal cerebral lesions and appropriate neurodevelopment as shown by general quotient (GQ) scores above 100, we mapped cortical connections to the thalamus that appeared similar to those reported in adults. However, in a proof-of-principle experiment, we examined one further child with marked white matter abnormalities and found that the volume and pattern of thalamo-cortical connections were severely disrupted. This technique promises to be a useful tool for assessing connectivity in the developing brain and in infants with lesions.

Early Growth in Brain Volume Is Preserved in the Majority of Preterm Infants

Preterm infants have reduced cerebral tissue volumes in adolescence. This study addresses the question: Is reduced global brain growth in the neonatal period inevitable after premature birth, or is it associated with specific medical risk factors?

The Association of Lung Disease With Cerebral White Matter Abnormalities in Preterm Infants

OBJECTIVE: Preterm infants have a high incidence of neurodevelopmental impairment associated with diffuse cerebral white matter abnormalities and also a high incidence of serious respiratory disease. However, it is unclear if lung disease and brain injury are related, and previous research has been impeded by confounding effects, including prematurity and infection. Using a new approach that permits multivariate statistical analysis, we tested the hypothesis that lung disease is associated with specific white matter abnormalities, detected as reduced fractional anisotropy (FA) in diffusion tensor imaging data. METHODS: Fifty-three preterm infants with no evidence of focal abnormality on conventional MRI were studied at term-equivalent age by using tract-based spatial statistics, an automated observer-independent method for voxelwise analysis of major white matter pathways. RESULTS: In several white matter tracts, FA decreased with a linear relation to the gestational age at birth. Independent of the confounding effects of prematurity and age at scan, respiratory disease was associated with specific white matter abnormalities in preterm infants; those infants receiving mechanical ventilation for >2 days in the perinatal period (n = 10) showed reduced FA in the genu of the corpus callosum, whereas subjects with chronic lung disease (n = 15) displayed a reduction in FA in the left inferior longitudinal fasciculus. CONCLUSION: Independent of the degree of prematurity, respiratory disease is associated with cerebral white matter abnormalities.