Brainstem Arousal Network in Human Consciousness: Healthy development vs SIDS

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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, comprised of connectivity with brainstem and limbic nodes. Our laboratory has provided evidence over the last two decades that serotonin (5-HT) defects are concentrated mainly in a cytologically defined region of the rostral medullary reticular formation in the AAN of the brainstem which we call the putative "core lesions of SIDS" (CLS). In this R01 application, we propose to test the two-fold hypothesis that the core nuclei in the CLS have fiber interconnections with each other and with one or more known nuclei of the AAN within and above the brainstem, thereby demonstrating they are anatomically part of the AAN; and that there are structural anatomic abnormalities in the serotonergic CLS in the SIDS cases compared to the age-matched autopsy controls. We will perform ex vivo MRI with diffusion tractography and optical coherence tomography at unprecedented spatial resolution along with 5-HT immunocytochemistry in postmortem infant brains from birth to the end of the first year of life, the period of risk for SIDS. This work is expected to have a significant positive impact. By establishing the putative core CLS as an integral part of the AAN involving medullary 5-HT neurons, it will provide the foundation for targeted future brain research in SIDS, bringing us closer to the ultimate cause(s) of SIDS and specific preventive strategies.