Sleepiness and sleep drunkenness: narcolepsy versus GABA-related hypersomnia

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DESCRIPTION (provided by applicant): This application details the career development plan and research project designed to develop Lynn Marie Trotti, M.D., M.Sc., into an independent clinical researcher specializing in the evaluation and treatment of sleepiness, in particular that experienced in the central nervous system hypersomnia's. This proposal builds upon the exciting recent discovery that she helped to realize of an endogenous, positive allosteric modulator of the GABA-A receptor in the cerebrospinal fluid of hypersomnia patients. The proposal makes use of her education in Clinical Research and early scientific efforts in the field of sleep medicine, and is the next step in gaining the necessary training and experience to establish her successful career as an independent clinician- scientist. Her mentoring team will consist of David Rye, M.D., Ph.D. (Sleep Neurology), Carolyn Meltzer, M.D. (Radiology), Xiaoping Hu, Ph.D. (Biomedical Engineering), Bruce Crosson, Ph.D. (Neurology), and Helen Mayberg, M.D., Ph.D. (Neurology/Psychiatry/Radiology). These outstanding scientists bring complementary experience and expertise to this project. All mentors have long histories of successful mentoring of trainees and junior faculty. This work will take place at Emory University, which features an unrivaled environment for the short- and long-term career development of Dr. Trotti and for the performance of this research project. Dr. Trotti's ultimate goal is to translate discoveries regarding the pathophysiology of sleepiness into more effective treatments for this disabling symptom. As the next step in reaching this long-term goal, she has three immediate plans for this grant period: 1) to become proficient in the design, collection, and analysis of functional neuroimaging studies; 2) to develop and foster collaborative relationships with her mentors and other experts in the fields of neurology and functional neuroimaging; and 3) to gain hands-on experience in clinical research and valuable research data to allow her to transition to an independent research career. To reach these goals, Dr. Trotti will receive formal coursework in functional neuroimaging modalities, interpretation of PET and MRI data, and applied linear models. She will receive hands-on training and experience in imaging processing, analysis, and interpretation. She will have frequent, formal meetings with her team of experienced, accomplished mentors to learn from their wealth of experience in clinical research. Dr. Trotti's research protocol translates the recent discovery of excess GABA-A receptor potentiation in the majority of CNS hypersomnia patients into important questions regarding the symptomatology of sleepiness, namely: 1) does functional neuroimaging confirm a role of GABA-ergic networks in sleepiness in patients with this form of hypersomnia, distinct from that seen in other hypersomnia patients (i.e., those with hypocretin-deficient narcolepsy); 2) does altered connectivity within the brain's default mode network correlate with sleepiness in hypersomnia patients; and 3) does sleep drunkenness, the symptom of severe difficulty in transitioning from sleep to wake, reflect altered functional connectivity persisting into wakefulness? Answering these questions will be an important advance for those with GABA-related hypersomnia, but will also provide insights into the broader and common problem of pathological daytime sleepiness. The successful completion of this research and training plan will also serve as the scientific groundwork for Dr. Trotti's independent clinical research career, applying neuroimaging techniques to advance the understanding and treatment of sleepiness.