Dynamic changes in subplate and cortical plate microstructure precede the onset of cortical folding in utero

Abstract The structural scaffolding of the human brain is assembled during the fetal period through a series of rapid, dynamic, and intersecting processes. The third trimester of gestation is characterised by the emergence of complex patterns of cortical folding, the development of white matter connections, lamination of the cortex and formation of neural circuits. Multiple hypotheses have been proposed to explain how these processes interact to drive the formation of cortical convolutions, however there are no data-driven analyses during the fetal period to address them empirically. To explore this gap in understanding, we quantify microstructural changes in the transient fetal compartments undergoing significant developmental change at the onset of gyrification in utero, the subplate (SP) and cortical plate (CP). Using high angular resolution multi-shell diffusion-weighted imaging (HARDI) as part of the Developing Human Connectome Project (dHCP), our analysis reveals that the anisotropic, tissue component of the diffusion signal in the SP and CP decreases immediately prior to the formation of sulcal fundi in the fetal brain. By back-projecting a map of folded brain regions onto the unfolded brain, we provide evidence for cytoarchitectural differences between gyral and sulcal areas at the end of the second trimester, suggesting that regional variation in the density and complexity of neuropil in transient fetal compartments plays a mechanistic function in the onset of folding across the brain.