Amygdala modulation of volitional versus automatic breathing

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PROJECT SUMMARY Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Findings from SUDEP cases and from animal models of seizure-induced death suggest that central apnea is critical for SUDEP. The mechanisms underlying seizure-induced inhibition of breathing during SUDEP are unclear, and therefore, no known preventive strategies exist. Candidate: Dr. Brian Dlouhy, M.D. is a neurosurgeon at the University of Iowa whose clinical practice focuses on the surgical treatment of epilepsy. This proposal will be critical for his continued development as a neurosurgeon-scientist. This proposal will allow his research to build upon his established interest in how the amygdala modulates the neural control of respiration, will produce novel scientific results, and will provide critical training for Dr. Dlouhy. Dr. Dlouhy’s ultimate goal is to become an R01-funded academic neurosurgeon-scientist with an independent research program exploring neural control of respiration. Environment: The University of Iowa provides a rich training environment for Dr. Dlouhy, and he has the full support from the Carver College of Medicine and his Chair in the Department of Neurosurgery, Dr. Matthew Howard. Dr. Dlouhy has combined a unique team of mentors, each leaders of their respective fields and who possess expertise instrumental to Dr. Dlouhy’s research plan: amygdala circuitry, neural control of respiration, and human brain neurophysiology. Dr. George Richerson, is an expert in the field of respiratory neurophysiology; Dr. John Wemmie is a leader in the field of amygdala neurobiology; Dr. Matthew Howard is an expert in human electrophysiology. Research: Using intracranial recordings in epilepsy patients, Dr. Dlouhy previously found that apnea occurs when seizures propagate to the amygdala. Electrical stimulation of the amygdala can lead to apnea that is not associated with air hunger (dyspnea) or urge to breathe. Volitional control of respiration is spared during stimulation-induced apnea; subjects can speak normally and breathe when prompted. The underlying neural mechanisms by which the amygdala influences the brain’s respiratory control network to mediate these effects or regulate normal breathing are unknown. This proposal aims to identify and characterize neural activity within the amygdala and its functional connections with brain respiratory control sites. Dr. Dlouhy will also study how experimental neuromodulation of the amygdala affects volitional versus automatic breathing, and the perception of dyspnea. These aims will be accomplished using a combination of direct electrophysiological recording and stimulation techniques, electrical stimulation concurrent with fMRI, and respiratory physiology experiments. The proposed scientific research plan, the excellent mentorship team of Drs. Richerson, Wemmie, and Howard, and the enthusiastic support of the candidate’s institution and department will enable Dr. Dlouhy to launch a successful career as an independent neurosurgeon-scientist.