Abstract
White matter undergoes rapid changes during the fetal period that are foundational for future cognitive functions. However, how these changes contribute to the brain's capacity to support its dynamic activities-its controllability -remains largely unknown. Here, we apply network control theory (NCT) to investigate the developmental trajectory of controllability from the second trimester through the first postnatal month. We analyzed structural connectivity data from fetuses and infants as part of the developing Human Connectome Project. We identified a robust, nonlinear U-shaped developmental curve of whole-brain controllability across the perinatal period, with a minimum at approximately 35 weeks of gestation. Preterm birth disrupted these trajectories, leading to greater controllability and earlier minimums compared to age-matched fetuses. Using gene expression microarray data from 18 fetal post-mortem brains, we identified genes implicated in synaptic functions that co-develop with changes in controllability during the fetal period. We then used positron emission tomography in seven pregnant rhesus macaques to quantify changes in fetal synaptic density. Increased synaptic density in non-human primates (NHPs) co-occurred with periods of reduced controllability in humans. Finally, using longitudinal scans of a pregnant woman, we mapped the trajectory of changes in maternal controllability during pregnancy. This trajectory exhibited a U-shaped pattern that inversely correlated with the fetal trajectory, reaching a maximum around 36 weeks. Together, fetal controllability follows a nonlinear trajectory that co-develops with synaptic functions and synchronizes with maternal changes in controllability during pregnancy.