Sex-Biased Trajectories of Amygdalo-Hippocampal Morphology Change Over Human Development

The amygdala and hippocampus are two adjacent allocortical structures implicated in sex-biased and developmentally-emergent psychopathology. However, the spatiotemporal dynamics of amygdalo-hippocampal development remain poorly understood in healthy humans. The current study defined trajectories of volume and shape change for the amygdala and hippocampus by applying a multi-atlas segmentation pipeline (MAGeT-Brain) and semi-parametric mixed-effects spline modeling to 1,529 longitudinally-acquired structural MRI brain scans from a large, single-center cohort of 792 youth (403 males, 389 females) between the ages of 5 and 25 years old. We found that amygdala and hippocampus volumes both follow curvilinear and sexually dimorphic growth trajectories. These sex-biases were particularly striking in the amygdala: males showed a significantly later and slower adolescent deceleration in volume expansion (at age 20 years) than females (age 13 years). Shape analysis localized significant hot-spots of sex-biased anatomical development in sub-regional territories overlying rostral and caudal extremes of the CA1/2 in the hippocampus, and the centromedial nuclear group of the amygdala. In both sexes, principal components analysis revealed close integration of amygdala and hippocampus shape change along two main topographically-organized axes – low vs. high areal expansion, and early vs. late growth deceleration. These results bring greater resolution to our spatiotemporal understanding of amygdalo-hippocampal development in healthy males and females and discover focal sex-differences in the structural maturation of the brain components that may contribute to differences in behavior and psychopathology that emerge during adolescence. SIGNIFICANCE STATEMENT The amygdala and hippocampus are implicated in several developmentally-dynamic and sex-biased psychiatric disorders, but the spatiotemporal organization and sex-biased patterning of amygdalo-hippocampal maturation remains unclear in humans. Here, by integrating new methods for analysis of longitudinal neuroimaging data, we resolve the developmental milestones and spatial gradients that organize human amygdalo-hippocampal maturation. Each structure’s volume follows a tri-phasic, curvilinear growth trajectory which - for the amygdala - shows rapid male-female size divergence in mid-adolescence through delayed growth deceleration in males. Spatially fine-grained shape analyses localize these sex differences, and further reveal highly orchestrated shape changes across the amygdala and hippocampus that are organized by two topographical gradients. These data provide a new framework for understanding amygdalo-hippocampal organization in human development.