The early development of brain white matter: A review of imaging studies in fetuses, newborns and infants

Highlights

• Review of post-mortem descriptions and in vivo MRI studies of brain development.

• Early establishment of white matter connections during human gestation.

• Maturation (myelination) of connections during infancy and impact of prematurity.

• Functional correlates (behavior, functional imaging) of structural MRI parameters.

• Outline on complementary MRI techniques and multi-parametric approaches.

Abstract

Studying how the healthy human brain develops is important to understand early pathological mechanisms and to assess the influence of fetal or perinatal events on later life. Brain development relies on complex and intermingled mechanisms especially during gestation and first post-natal months, with intense interactions between genetic, epigenetic and environmental factors. Although the baby’s brain is organized early on, it is not a miniature adult brain: regional brain changes are asynchronous and protracted, i.e. sensory-motor regions develop early and quickly, whereas associative regions develop later and slowly over decades. Concurrently, the infant/child gradually achieves new performances, but how brain maturation relates to changes in behavior is poorly understood, requiring non-invasive in vivo imaging studies such as magnetic resonance imaging (MRI).

Two main processes of early white matter development are reviewed: (1) establishment of connections between brain regions within functional networks, leading to adult-like organization during the last trimester of gestation, (2) maturation (myelination) of these connections during infancy to provide efficient transfers of information. Current knowledge from post-mortem descriptions and in vivo MRI studies is summed up, focusing on T1- and T2-weighted imaging, diffusion tensor imaging, and quantitative mapping of T1/T2 relaxation times, myelin water fraction and magnetization transfer ratio.

Introduction

Brain development relies on several complex and intermingled mechanisms, such as the maturation and functional specialization of gray matter (GM) regions (cerebral cortex and central gray nuclei) and the establishment and myelination of white matter (WM) connections between the different neural regions. Typical development is the global consequence of interactions between genetic programming, epigenetic and environmental factors (e.g. external stimulations, maternal, nutritional or medical factors). Cerebral changes are particularly intense during the last weeks of gestation and the first post-natal months, as indirectly highlighted by the non-linear increase of the cranial perimeter (by about 14 cm during the two first post-natal years, followed by only 7 cm until adulthood). Although the baby’s brain is organized early on into functional networks, it is not an adult brain in miniature: growth and maturation are asynchronous, some regions, like the sensory ones, develop early on and quickly, whereas associative regions, like frontal ones, develop later on and slowly until the end of adolescence (Paus et al., 2001).

Concurrently with this anatomical evolution of the brain, the infant gradually achieves new psycho-motor and cognitive skills, but how brain maturation explains the often abrupt changes of behavior observed during development is poorly understood. Before the development of non-invasive brain imaging methods, our knowledge on human brain development was relying on (fortunately) rare post-mortem investigations, which are intrinsically limited by the lack of anatomo-functional correlations and by the uncertainty on brain normality. Using myelin staining, most of these studies described whether myelin is present or not in a given WM region at a given age: this information is however not bundle-specific and thus might be misleading at bundles crossings. Advanced post-mortem dissection techniques now enable to follow the trajectory of long-distance bundles (Martino et al., 2010, Maldonado et al., 2013). But absolute measurements of myelin amount are still missing, which prevents the quantitative comparison across WM regions.

Another approach to understand brain development is to study animals, but if such studies enable to test particular hypotheses, they remain largely inadequate because of the specificity of human cognitive functioning and brain development. Mammals are generally classified according to their developmental stage at birth, belonging either to species with early development or to species with immature development. Humans have a special position since brain responses are already observed in utero (Draganova et al., 2007), while some high-level functions have a protracted development over two decades. For instance, the fiber myelination in the somatosensory, motor, frontopolar and visual neocortices is delayed in humans compared with chimpanzees, with slower myelination during childhood extending beyond late adolescence (Miller et al., 2012).

The recent development of non-invasive techniques (magnetic resonance imaging (MRI), electroencephalography (EEG), magnetoencephalography (MEG)) has further enabled to relate maturation of cerebral structures to infants’ neurodevelopment and behavior. In particular, several MRI techniques available on clinical scanners (section ‘Structural MRI techniques and developmental specificities’) enable to investigate and follow longitudinally the brain development and plasticity of healthy and at-risk children (Barkovich, 2000, Paus et al., 2001, Neil et al., 2002, Prayer and Prayer, 2003, Huppi and Dubois, 2006, Yoshida et al., 2013). But when these imaging techniques are applied to babies, many difficulties arise and require adapting data acquisition and post-processing to different developmental periods (fetus, preterm or at-term newborn, infant, toddler, etc.).

With these constraints in mind, we here review the main insights revealed by recent MRI studies on the early development of WM, which is a complex and long-lasting process that plays a crucial role during the human motor and cognitive development (section ‘The basic concepts of white matter development’). Two main stages can be delineated: (1) the establishment of long and short connections between brain regions during the last trimester of human gestation, leading to an early adult-like organization of neural networks, (2) the maturation of these fibers during infancy and toddlerhood to provide an efficient transfer of information between functional regions. These two processes are consecutively described in the healthy brain by summarizing current knowledge obtained from post-mortem and in vivo imaging studies (sections ‘Imaging the early organization of white matter’ and ‘Imaging the maturation of white matter’). Finally, the functional significance of early structural biomarkers of the developing WM is discussed based on studies with behavioral and neurophysiologic evaluations of infants, with a specific focus on preterms without overt brain lesions (section ‘Functional correlates of MRI biomarkers of WM maturation’).