Heterogeneous migration of neuronal progenitors to the insula shapes the human brain

The human cerebrum consists of a precise and stereotyped arrangement of lobes, gyri, and connectivity that underlies human cognition. The development of this arrangement is less clear. Current models of radial glial cell migration explain individual gyral formation but fail to explain the global configuration of the cerebral lobes. Moreover, the insula, buried in the depths of the Sylvian fissure, belies conventional models. Here, we show that the insula has unique morphology in adults, that insular morphology and slow volumetric growth emerge during fetal development, and that a novel theory of curved migration is required to explain these findings. We calculated morphologic data in the insula and other lobes in adults (N=107) and in an in utero fetal brain atlas (N=81 healthy fetuses). In utero, the insula grows an order of magnitude slower than the other lobes and demonstrates shallower sulci, less curvature, and less surface complexity both in adults and progressively throughout fetal development. Novel spherical projection analysis demonstrates that the lenticular nuclei obstruct 60-70% of radial pathways from the ventricular zone (VZ) to the insula, forcing a curved migration path to the insula in contrast to a direct radial pathway. Using fetal diffusion tractography, we identify streams of putative progenitor cells that originate from the VZ and migrate tangentially around the lenticular nuclei to form the insula. These results challenge existing models of radial migration to the cortex, provide an alternative model for insular and cerebral development, and lay the groundwork to understand cerebral malformations, insular functional connectivity, and insular pathologies.