Cortical folding: when, where, how, and why?

Why the cerebral cortex folds in some mammals but not in others has long fascinated and mystified neurobiologists. Over the past century-especially the past decade-researchers have used theory and experiment to support different folding mechanisms such as tissue buckling from mechanical stress, axon tethering, localized proliferation, and external constraints. In this review, we synthesize these mechanisms into a unifying framework and introduce a hitherto unappreciated mechanism, the radial intercalation of new neurons at the top of the cortical plate, as a likely proximate force for tangential expansion that then leads to cortical folding. The interplay between radial intercalation and various biasing factors, such as local variations in proliferation rate and connectivity, can explain the formation of both random and stereotypically positioned folds.