Mechanics of Brain Folding in Human Infants Evaluated Using MRI

Abstract In human brain development, the third trimester represents a critical period of cortical expansion, folding, and white matter organization. Deviations from the normal developmental trajectory have been linked to abnormal cortical morphologies and white matter organization, which in turn have been linked to disorders including

epilepsy, developmental delay, autism spectrum disorder, schizophrenia, anxiety, and depression. However, the mechanisms underlying folding, and hence the etiology of folding abnormalities, are the subject of active debate. Current evidence suggests that rapid expansion of the cortical surface is a driving force in brain folding, with

mechanical buckling or bending inducing formation of gyri (outward folds) and sulci (inward folds). However, computational simulations of this mechanism have fallen short of predicting human brain morphology, and few have addressed the spatiotemporal relationships that exist between folding and white matter organization.

Recently, our team uncovered regional gradients and temporal changes in the rates of cortical expansion over development in human and animal models. We hypothesize that these expansion patterns within the cortical plate play a crucial role in determining the timing and positioning of cortical folds in humans. Further, we

hypothesize an important role for folding-induced axon elongation in the organization of underlying white matter. These phenomena have yet to be implemented in models of human cortical expansion and folding, and model predictions have yet to be tested in the context of human data and disease. In this study, we will use two unique magnetic resonance imaging (MRI) datasets, alongside MRI-informed

computational modeling, to determine whether observed patterns and rates of cortical expansion are sufficient to drive normal and aberrant brain structure. In Aim 1, we will use multimodal, longitudinal MRI data from preterm infants to assess whether patterns of cortical expansion are aligned with gradients of cortical maturation, and

whether these gradients are sufficient to induce early emerging patterns of folding. Analysis will be supplemented with longitudinal, in-utero imaging of typically developing fetuses. In Aim 2, we will use subcortical diffusion data from the preterm cohort to determine whether simulated, folding-induced white matter organization is consistent

with the organization observed in the developing human brain. In Aim 3, we will determine the ability of cortical expansion-driven models to predict later emerging folds that are highly variable across individuals: first training models on rich longitudinal datasets from preterm individuals tracked through age 10, then extending models to

preterm and typically developing individuals with more limited longitudinal data. The proposed aims will provide unprecedented spatial and temporal detail on the relationships between cortical expansion, folding, and white matter organization during normal and abnormal brain development in human. Furthermore, it will lay the

groundwork for future studies aimed at understanding the genesis of cortical folding abnormalities and their relationship to developmental outcomes.