In-vivo evaluation of brain structure in preterm neonates at term-equivalent time: contribution of diffusion tensor imaging and probabilistic tractography

The preterm delivery (The most widely used imaging technique for studying neonatal brain is cranial ultrasound that can be performed at bedside and detects major brain abnormalities (hemorrhage, infarctions, cysts, dilatation of the lateral ventricles). However, it has a poor sensitivity for non-cystic or diffuse white matter abnormalities (WMA), the most common form of white matter injury in preterm infants. In comparison to ultrasound, MR (magnetic resonance) imaging has been reported to be superior in detecting WMA and is considered as an essential modality for imaging the neonatal brain. The standard sequences (e.g. T1-, T2-weighted imaging) are routinely performed for assessing not only brain anatomy, but also for evaluating brain lesions. Nevertheless, ¡§conventional MR imaging¡¨ has been criticized because it is limited in qualitative assessment and it does not provide information on the extent of specific white matter pathways injuries. Currently, diffusion tensor imaging (DTI) enables more detailed exploration of white matter microstructure. Furthermore, DTI is now the best in vivo technique capable of delineating white matter pathways and quantifying microstructural changes not visible on conventional MR imaging. Diffusion tensor tractography allows the reconstruction of the principal white matter fibers. Moreover, it also provides diffusion indices like fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (£f//), transverse diffusivity (£f¢r) that help assess the changes in fiber tracts, even before myelination becomes histologically evident. Structural MR imaging studies performed in neonates are scarce. A number of essential questions are still under debate, concerning the normal white matter structure, as well as premature brain injury. First, left language lateralization and right handedness are complex phenomena incompletely understood and the question rises whether structural lateralization already exist in healthy preterm neonates at term-equivalent age. Second, it is of interest to know whether gender-related structural differences exist in healthy preterm neonates. Finally, in the assessment of preterm brain injury, the relationship between WMA on conventional imaging and altered diffusion indices in fiber tracts is still unclear. Therefore, the aims of the thesis were to investigate the brain structure in a population of preterm neonates at term-equivalent age by DTI and probabilistic tractography.The first part of this thesis (Study I and Study II) was devoted to the study of white matter structural characteristics in healthy preterm neonates. Previous studies have shown that structural asymmetries in language and motor related fibers are present in adults and in infants (Dubois et al. 2009; Westerhausen et al. 2007). Our hypothesis was that these structural asymmetries are already present in preterm neonates at term-equivalent age. In Study I, DTI and probabilistic tractography were performed and we found volume and microstructural asymmetries in the language related parieto-temporal superior longitudinal fasciculi (SLF), in the motor related corticospinal tract (CST) and in the motor part of the superior thalamic radiation (STR) as well. In Study II, we found that compared to boys, girls have larger relative tract volumes and an advanced maturation in language and motor related fiber tracts. The second part of this thesis (Study III) investigated whether WMA on conventional MR imaging are related to abnormalities within the fiber tract microstructures. WMA were classified as normal, mild, moderate and severe according to Woodward¡¦s classification (Woodward et al. 2006). Woodward and colleagues studied a large population (167 infants) of preterm infants at term equivalent age with MRI. They demonstrated that WMA were important predictors of neurological outcomes by comparing their results with the neurological outcomes of those infants at corrected age of two. We found that compared to neonates with no abnormalities, infants with mild abnormalities have significantly higher ƒÜ¢r in the right CST, the left anterior thalamic radiation (ATR), the left sensory STR and bilateral motor STR. Those findings might be related to injuries of premyelinating oligodendrocytes resulting in subsequent failure of both development and ensheathment of axons. Considering that those fiber tracts connect important cortical zones, microstructural changes in those fiber tracts might be responsible for the later neurodevelopment deficits in motor and cognitive functions. We concluded that structural asymmetries and gender differences in motor and language related fibers are present in healthy preterm neonates at term-equivalent age well before the development of speech and hand preference. Structural asymmetries and gender differences have to be considered in neonatal white matter assessment. Finally, altered DTI indices are associated with WMA on conventional MR imaging in preterm neonates. Our results suggest that disrupted premyelination is the major correlate with WMA rather than axonal pathology. Non-invasive DTI and tractography constitute an additional tool for the assessment of white matter injuries, as it could provide more adequate diagnostic information on brain microstructure in preterm neonates at term-equivalent age.Doctorat en Sciences médicales