Diliana Pecheva1, Hui Zhang2, Gareth Ball1, Mary Rutherford1, Nigel Kennea 3, Joseph V. Hajnal1, Daniel Alexander2, A. David Edwards1, and Serena J. Counsell1
1Centre for the Developing Brain, King's College London, London, United Kingdom, 2Department of Computer Science & Centre for Medical Image Computing, University College London, London, United Kingdom, 3Neonatal Unit, St Georges Hospital NHS Trust, London, United Kingdom
Synopsis
Preterm birth adversely affects brain development and diffuse white matter (WM) injury is often observed in preterm infants. Diffusion tensor imaging (DTI) allows us to study these effects in vivo. In this study tract-specific analysis, a novel method for large infant cohort analyses, was used to study the effects of age at scan and prematurity at birth on major WM tracts in 384 preterm infants. Our results show that age at scan is associated with widespread changes in DTI metrics across WM tracts, while the impact of prematurity at birth is more localized. Purpose
Cerebral white matter (WM) injury is often
observed in infants born preterm1 and may be related to impaired neurological outcome observed in this population. Analysis of diffusion tensor imaging (DTI) data allows us to
quantitatively assess microstructural changes in cerebral WM in preterm infants. Tract-specific analysis2 (TSA) is a novel method for anatomically specific analysis of individual WM tracts in large infant cohorts. In this work we apply TSA for the first time to a large cohort of preterm infants to assess the effects of age at scan and prematurity at birth on WM tracts in the preterm brain.
Methods
We studied 384 infants (192 female)
born between 23.6-32.9 (median 30.4) weeks gestational age (GA) and imaged at
37.9-45 (median 42.5) weeks postmenstrual age (PMA). Infants were recruited as
part of the E-Prime study of preterm brain development, written parental consent was obtained prior to imaging. Infants with focal lesions visible on T1- and T2- weighted MRI scans were not included in the analysis.
MR imaging was performed on a 3T MR system on the neonatal intensive care unit. Single shot echo planar diffusion-weighted MRI was acquired in 32 non-collinear directions with parameters; TR=8000 ms, TE=49 ms, slice thickness 2mm,
voxel size: 2mm3 isotropic, b-value=750s/mm2, SENSE factor of 2. T1- and T2-weighted MR imaging were also acquired.
The standard TSA framework was used to
represent major fasciculi and analyse subjects’ DTI data. Subjects’ diffusion
tensor images were registered to an unbiased study-specific neonatal template
using a tensor-based algorithm3. WM tracts were delineated
in the template using deterministic tractography based on the FACT algorithm4, using manually drawn regions of interest based on a widely accepted protocol5. The tracts delineated included the corpus callosum
(CC), corticospinal tract (CST), inferior fronto-occipital fasciculus (IFOF),
inferior longitudinal fasciculus (ILF) and uncinate fasciculus (UNC). Each tract was modeled as a medial surface – the tract skeleton, with
a tract boundary6. Diffusion data from every subject was projected onto the skeleton
by searching within the tract boundary along the unit normal from the skeleton
to the boundary, and statistical analysis was carried out on each tract
skeleton.
Regression analysis was carried out at each vertex on the skeleton between fractional
anisotropy (FA), axial and radial diffusivity (AD, RD) and PMA (GA as covariate)
and between FA, AD, RD and GA (PMA as a covariate) for every tract. To correct
for family-wise errors, non-parametric permutation-based suprathreshold cluster
analysis was performed with primary threshold of p=0.05.
Results
All subjects were successfully registered
to the template, with good alignment between subjects. TSA showed a strong positive
correlation between FA and PMA at scan (figure 1a), and strong negative
correlation between AD and RD and PMA at scan (figures 2a and 3a respectively) in
all tracts. GA at birth correlated positively with FA (figure 1b) and
negatively with AD and RD (figures 2b and 3b respectively) in body of the CC and
posterior areas of the ILF and IFOF bilaterally (p<0.05). A small region in
the CST showed negative correlation between GA and RD
bilaterally (figure 3b).
Discussion
TSA allows the study of many WM tracts in large cohorts that would be impractical using labour-intensive methods like individual subject tractography. TSA maintains anatomical specificity as it only allows data projection from within the tract boundary, and by preserving the structure of each tract it is possible to identify regions of statistical significance within tracts.
Our results show FA increases and AD and RD decrease with increasing PMA, which is consistent with previous studies7,8. Changes related to PMA are likely to reflect myelination and premyelination events such as increases in axon diameter and decreased membrane permeability9, oligodendrocyte proliferation and maturation10, resulting in more coherent axonal organization and overall reduction in free water.
Within this cohort of preterm infants, GA was positively correlated with FA and negatively correlated with AD and RD in specific regions suggesting oligodendrocyte and axonal injury in those infants who were most premature at birth.
Conclusions
TSA enables the relationship between perinatal factors and development of specific fasciculi to be assessed in large infant cohorts. We demonstrate that the effects of PMA at scan are
widespread across all nine of the WM tracts studied here, whereas prematurity at birth shows localized correlation with diffusion characteristics at term equivalent age.
Acknowledgements
This study was funded in part by the National Institute for Health Research and the Medical Research Council. References
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