High Resolution Postmortem MRI Discovers Developing Structural Connectivity in the Human Ascending Arousal Network

Human arousal is essential to survival and mediated by the ascending arousal network (AAN) and its connections. It spans from the brainstem to the diencephalon, basal forebrain, and cerebral cortex. Despite advances in mapping the AAN in adults, it is unexplored in fetal and early infant life, especially with high-resolution magnetic resonance imaging techniques. In this study, we conducted-for the first time-high-resolution ex vivo diffusion MRI-based analysis of the AAN in seven fetal, infant, and adult brains, incorporating probabilistic tractography and quantifying connectivity using graph theory. We observed that AAN structural connectivity becomes increasingly integrated during development, progressively reaching rostrally during the first postconceptional year. We quantitatively identified the dorsal raphe (DR) nucleus and ventral tegmental area (VTA) as AAN connectivity hubs already in the fetus persisting into adulthood. The DR appears to form a local hub of short-range connectivities, while the VTA evolves as a long-range global hub. The identified connectivity maps advance our understanding of AAN architecture changes due to normative human brain development, as well as disorders of arousal, such as coma and sudden infant death syndrome.