Genetic Control and Environmental Effects

Genes play a significant role in the variability of global and local brain gray/white matter volumes, cortical thickness, and surface area.²³'²⁴²⁵²⁶ Brain functions and functional brain networks are also genetically modulated.^{27 28} Therefore, quantitative measures of diffusion properties of the major WM tracts during early brain development should also reflect the modulation of genetic factors. Geng et al²⁹ studied the genetic and environmental effects on the spatiotemporal growth of different major WM fiber tracts using a model of additive genetic and common and specific environmental variance components. Genetic and environmental contributions to both global and local diffusion parameters were estimated, including FA, RD, and AD. Their results indicate that the individual differences in the global WM microstructure characterized by all three metrics (i.e., FA, RD, and AD) are heritable

Fig. 4.5 Heritability of white matter diffusivity in the neonatal brain. Heritability values of fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) over each region of interest (top row) and their corresponding p-values (bottom row, normalized using - log(p), - log(0.05) = 1.3, and - log(0.0001) = 4). (Reproduced from Geng et al., with permission²⁹)

(? Fig. 4.5). Specifically, global FA had the highest heritability of 60%, followed by AD (57%), and RD (53%). There was significant heritability in both hemispheres of FA and RD, but AD heritability appeared to be lateralized to the right hemisphere only. There is a significant positive correlation between RD heritability and mean RD, and similarly between AD heritability and mean AD. Combined with the decreasing trend of both RD and AD during development, these findings seem to suggest that the more mature the region is, the less genetic variation it shows. This conclusion is also consistent with the lower heritability estimates reported in adults than in pediatric subjects.

For the environmental effects, the bilateral ante- rior/posterior limb of internal capsule, external capsule, uncinate fasciculus, and left middle cerebellar peduncle show high shared environmental effects in RD (57-82%). Similarly, the bilateral external capsule, middle cerebellar peduncle, and inferior frontal occipital fasciculus also have a large proportion of shared environmental effects in AD (47-71%). Particularly, shared environmental effects are substantial for the RD of the bilateral external capsule (left/right: 73%/82%). Together with the anterior-posterior limb of the internal capsule, the external capsule may have started myelination earlier prenatally than other association fibers³⁰ and demonstrated a lower RD. The authors postulated that prenatal neurohormonal and uterine environment may affect the maturation process of the external capsule, which might lead to the observed shared environmental variation. In general, the authors observed substantial heritability of diffusion properties during infancy, which is higher than that reported in adults. However, genetic effects are heterogeneous over different WM regions (see ? Fig. 4.5). The significant positive correlation between heritability and diffusion measures suggests that regional genetic effects may be modulated by maturation status—the more mature the region, the less heritable its variation. Common environmental effects are present in fewer regions that tend to be characterized by a low RD.