The Role of Negative Effort Dependence as a Targetable Mechanism of Upper Airway Collapse in Sleep Disordered Breathing

Va San Diego Healthcare System, San Diego CA

Investigators

Linked publications, trials & patents

Abstract

This proposal outlines a 5-year research and career development plan for Dr. Brandon Nokes, director of Hypoglossal Nerve Stimulation at VA San Diego and a pulmonary/critical care physician at UCSD. The major objective of his research is deriving mechanistic understanding of within and across-breath negative effort dependence, common and important subtypes of flow limitation in obstructive sleep apnea (OSA). This CDA-2 proposal outlines and provides support for his career development plan, specifically focusing on Training Aim (TA)1, upper airway physiology and control of breathing, TA2, physiological signal processing, TA3, clinical trial design and appropriate statistics. Dr. Nokes has assembled a diverse team of collaborative experts to support his career development and mentor him consisting of Dr. Atul Malhotra, an internationally recognized expert in upper airway physiology with Dr. Owens, Chair-Elect of the Sleep and Respiratory Neurobiology (SRN) Assembly at ATS, as well as Dr. Crotty-Alexander, Section head of Pulmonary/Critical Care of VA San Diego and recipient of CDA-2 and MERIT funding pertaining to respiratory science. Additionally, his training team includes experts in upper respiratory physiology (Dr. Powell and Dr. Spragg), fluid mechanics and signal processing in the upper airway (Dr. Butler), and upper airway electrical stimulation (Dr. Strollo), as well as an expert in clinical trial design and biostatistics (Dr. Sonia Jain). Despite the significant clinical burden of obstructive sleep apnea in Veterans (the most common service-connected respiratory condition), continuous positive airway pressure (CPAP) use is historically poor. Current approaches to OSA care emphasize “one- size fits all” approach with CPAP being the gold-standard. However, it is now understood that there are multiple physiologic traits (endotypes) which may be amenable to tailored therapies beyond CPAP alone. The PI will evaluate the role of negative pressure reflexes in within-breath negative effort dependence in Aim 1. Prior investigations assessing negative pressure reflexes are well-validated and the PI is well-trained to identify NED as well as conduct physiology-based polysomnography (including genioglossus electromyography and epiglottic pressure catheter placement). However, whether reflex attenuation creates a risk for within-breath NED has yet to be established. Aim 2 will assess the role of an imbalance in respiratory drive between the upper airway and thoracic pump mechanistically underly across-breath NED. Both of these modes are flow limitation are especially important as the only way to terminate these breathing events is through arousal, leading to sleep fragmentation and potentially adverse neurocognitive and cardiac outcomes. This work will lay the groundwork for future MERIT studies focused on individualizing OSA treatments. This work will also help to build the San Diego VA Sleep lab into a world class physiology-tailored sleep lab. The research and career development plan affords Dr. Nokes an impressive foundation to develop into a prominent clinician-scientist working to improve care by developing and implementing novel approaches to Veteran sleep care. Dr. Nokes is fully committed to improving the care of Veterans with OSA by providing individualized sleep care based on individual physiology.