Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality in industrialized nations today. Typically it occurs during a sleep period ? unwitnessed, it is presumed to occur during sleep itself, or during one of the many transitions between sleep and waking that occur during normal infant sleep. A leading hypothesis today is the arousal deficit hypothesis: SIDS, or a subset of SIDS, is due to a failure in the ascending arousal network (AAN) to a life-threatening stressor during sleep in a critical developmental period. Arousal is considered an essential element of consciousness, as well as essential for restoration of homeostasis during respiratory and cardiovascular challenges by providing excitatory drive to vital processes from sleep. The AAN is interconnected with cortical and subcortical networks that regulate the integration of homeostatic responses, the latter known as the central homeostatic network (CHN), comprised of connectivity with brainstem and limbic nodes. In this R21 application, we propose to map the neuroanatomic connectivity of the AAN-CHN postmortem in the human fetus and infant brain by performing ex vivo MRI with diffusion tractography at unprecedented spatial resolution from mid-gestation to the end of the first year of life. Our goal is to map the structural connectome of the AAN-CHN in developing ex vivo human fetal and infant brains in preparation for a subsequent R01 in which we will map these networks in the brains of SIDS infants compared to autopsy controls adjusted for postconceptional age. This work is expected to have a significant positive impact because mapping the connectivity of the human AAN-CHN during development will enable elucidation of how arousal systems fail in SIDS, leading in turn to potential clinical biomarkers, prevention, and intervention.
We propose to map the neuroanatomic connectivity of the ascending arousal network (AAN) postmortem in the human fetus and infant brain by performing ex vivo diffusion tractography at unprecedented spatial resolution. We propose to define the ontogeny of human AAN connectivity from midgestation to the end of the first year of life. The successful completion of this project will provide tools for a subsequent R01 in which we will map these networks in the brains of SIDS infants compared to autopsy controls adjusted for postconceptional age.
