ABSTRACT
Background The global geometry of the human cerebrum forms in a highly conserved fashion. Existing models of radial glial cell migration explain individual gyral formation but fail to explain both the global configuration of the cerebral lobes and the unique configuration of the insular gyri.
Methods To quantify the geometric differences in the insula, we calculated morphologic data in the insula and other lobes in both adults (N=107 adult subjects) and in a fetal brain atlas constructed from in utero brain MRIs of 81 healthy human fetuses (gestational age 21-38 weeks).
Results We find that the insula is morphologically different in adults and that these differences emerge during fetal development. Specifically, the insula exhibits shallower sulci (p<0.0001), less extrinsic curvature (p<0.0001), and less complex surface (p<0.0001) in adults and progressively throughout fetal development. In utero, the insular volume demonstrates logistic growth of an order of magnitude lower than the other lobes (α=0.002 vs. 0.05/0.03/0.04/0.02) and a surface area that grows linearly, in contrast with the exponential growth of the other lobes, resulting in a significantly smaller insula in adults (p<0.0001). We demonstrate that the lenticular nuclei obstruct 60-70% of radial pathways from the ventricular zone (VZ) to the insula compared to the other lobes (p<0.01), forcing a curved or tangential migration path to the insula in contrast to the direct radial pathway from VZ to all other cortices. To validate this hypothesis, using fetal diffusion tractography, we identify streams of putative insular progenitor cells that originate from the VZ near the pallial-subpallial boundary and migrate tangentially around the lenticular nuclei to form the insula. Shape analysis confirms that these streams to the insula are quantitatively different with higher curl (p < 0.001) and elongation (p < 0.001).
Conclusions This alternative mechanism to direct radial migration can explain the altered morphology of the insula, the slow volumetric and surface area growth of the insula, and ultimately how the operculae overgrow the insula and create the global configuration of the human cerebrum.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Added Figure 4; Minor Edits to Manuscript; Edited Acknowledgements