Article summary of Delineation of early brain development from fetuses to infants with diffusion MRI and beyond by Ouyang et al. - Chapter

What does the period of brain development until the age of 2 years old entail?

The period until the age of 2 years old is characterised by the most dynamic period of brain development. From birth to 2 years of age, the overall brain size increases dramatically, reaching close to 90% of adult volume by the age of 2 years. The gray matter volume also reaches a lifetime maximum at around 2 years of age. These structural changes in the brain are accompanied by the process of brain circuit formation, as a result of neurogenesis, neuronal migration, synapse formation, dendritic arborisation, axonal growth, pruning and myelination. These processes shape the structural and functional architecture of the human brain.

Despite the significant contribution of histological studies to understanding typical and atypical brain development, these studies are relatively labor-intensive and time-consuming and may not be suitable for surveying the entire brain. Therefore, it is extremely difficult to reveal the global maturation pattern of the white matter or the cerebral cortex with histological approaches alone. Magnetic resonance imaging (MRI) techniques, on the other hand, are able to survey the entire brain in a very time-efficient way.

How are we able to image the brain using different MRI techniques?

As a consequence of recent developments, the diffusion MRI (DTI) technique has become an effective probe to qualitatively and quantitatively characterize brain tissue microstructure, white matter tract anatomy and the structural connectivity of developing human brain. T1 weighted and T2 weighted imaging, relaxometry MRI and MTI have provided other options to image the developing brain.

We distinguish different types of MRI techniques that we can use to image the brain: diffusion MRI, diffusion tensor imaging, diffusion MRI-based tractography, T1 and T2 relaxometry and approaches based on magnetization transfer.

• In the human brain, diffusion of water molecules most of the time occurs along the axons. Diffusion MRI (dMRI) is a non-invasive imaging technique that provides a unique opportunity to measure the diffusional characteristics of the human brain. It can be particularly be interesting to use in cases where the contrast from other imaging methods is not sensitive enough to resolve the boundaries between brain tissues. The diffusion sensitised signal is calculated using the formula S = S₀exp (-bD), in which D is the diffusion coefficient with units of mm2/s and S and S₀ are the diffusion sensitized and non-diffusion signals. By solving the equation of this formula in each voxel, the apparent diffusion coefficient (ADC) in biological tissues can be obtained.
• Diffusion tensor imaging (DTI) is able to display the magnitude, anisotropy and orientation of diffusion in the human brain in a 3D ellipsoid. Fractional anisotropy provides a measurement to characterise the shape of the 3D ellipsoid. In addition, axial diffusivity (AD), which provides the primary eigenvalue (λ1) of the tensor, quantifies the water diffusion parallel to the primary eigen-vector of the diffusion tensor. AD has been thought to describe the axonal integrity of the white matter fiber bundle. Radial diffusivity (RD) quantifies the magnitude of diffusion orthogonal to the principal diffusion direction. RD has been thought to reflect the extent of white matter myelination. Although AD and RD have been used to infer these microstructural changes, we need to take caution in interpretation.
• Diffusion MRI-based tractography can be used to reconstruct white matter pathways in a 3D form. In this way, the structural connections of the human brain can be mapped. More complex methods of dMRI tractography are even able to resolve complex fiber architecture in a given voxel. 
• The longitudinal relaxation time (T1) characterises the proton interactions with its environment. On the other hand, the transverse relaxation time (T2) characterises the interactions between protons. Both T1 and T2 are sensitive to local chemical and magnetic environment. Quite recently, it was proposed that computing the ratio between T1w and T2w image intensities can be used to map myelination differences across cortical areas. Nonetheless, the best approach to measure reliable differences across individuals or across brain regions within the same individual is to map T1 and T2 relaxation time constants quantitatively. Furthermore, maps of the fraction of water related to myelin, sometimes called the myelin water fraction (MWF), can be obtained using the T1 and T2 measurements as well.
• Other MR quantitative parameters relying on myelin amount have been developed and proposed in the recent years as well. The MTR technique, for example, informs about the ratio between free water and water with restricted motion bound to macromolecules.

How does the process of maturation of white matter take place from the middle fetal stage until the age of 2 years old?

Gray matter are metaphorically also thought of as information processing hubs, and white matter acts as a long-range communication and transmission systems. For several decades, the architecture of white matter has been imaged in histological studies of postmortem brains. The recent developments within the field of MRI techniques have led to the opportunity to image how certain connections emerge at the beginning of life and how the maturational trajectories of white matter tracts in typical development look like. The major white matter tracts in the human brain can be categorised into five functional categories: limbic, commissural, projection, association and brainstem tract groups. Using DTI studies, erogeneous emergence patterns of white matter across different tracts and tract groups were observed. Significant micro-structural changes of white matter tracts take place during the fetal stage. Inhomogeneous but organized myelination processes have been found to be possibly contributing to a reshuffled inter-tract correlation pattern and strengthening of the correlation of homologous tracts from neonates to children around puberty.

A variety of advanced dMRI techniques have also been used in the study of white matter maturation. T1 and T2 decrease with developmental processes, and specifically more strongly in white matter than in gray matter because of the myelination. T1 and T2 drops are particularly rapid over the two first years of life. MTR increases during white matter maturation, following an exponential time course. To better understand the cellular processes underlying white matter maturation in terms of axonal growth, organisation and myelination, biophysical models have been proposed. These models aim to link these cellular processes to the DTI-derived measurement changes during early brain development.

How does micro-structural maturation of gray matter take place from the middle fetal stage until the age of 2 years old?

Gray matter also develops rapidly in the fetal and infant stages. It has been shown in neurological research using structural MRI that the cortical gray matter volume in the human brain increases more than 4-fold in the short period of the 3rd trimester. Furthermore, gray matter volume increases 1.5-fold in the first two years of postnatal life. During cortical development, the majority of cortical neurons are generated near the cerebral ventricles and migrate towards the cortical surface along a radially arranged scaffolding of glial cells. In the fetal and preterm stage of development, the frontal lobe of the human brain appears to be relatively immature, as it displays less dendritic arborisation, synaptic formation and cellular differentiation. The maturation pattern of cortical FA and MD  is rather heterogeneous. This finding may be used to infer the complicated but precisely organised cellular and molecular processes during cortical maturation.

Marked microstructural changes are also observed in central gray nuclei throughout a young child's development. Microstructural changes that can be observed using the DTI technique suggest that membrane proliferation and fiber myelination processes are intense in the developing deep gray matter of the baby brain.

How does the baby brain develop connectivity?

Exciting developments in defining the developmental changes of whole-brain connectivity have been achieved by applying graph theory to diffusion tractography of white matter and resting state fMRI of gray matter. In network analysis of the structural connectome, the gray matter regions represent the “nodes” and the white matter connections between different nodes represent the “edges”. It is beyond the scope of this article to comprehensively review this rapidly evolving field.

What conclusions can be drawn?

On this basis of this research, several conclusions can be drawn:

• The maturational process of major white matter fiber bundles in most of the period from mid-fetal to 2-years-old is characterised by an increased FA and a decreased MD, whereas that of cortical gray matter is characterized by a decrease in both FA and MD.
• Another conclusion is that the maturation patterns of DTI-derived measurements reflect known cellular and molecular processes.
• Lastly, the early development of white and gray matter is spatiotemporally heterogeneous.