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

> **NIH VA IK2** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · —

## 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 r...

## Key facts

- **NIH application ID:** 10806050
- **Project number:** 1IK2CX002524-01A2
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Brandon Thomas Nokes
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806050

## Citation

> US National Institutes of Health, RePORTER application 10806050, The Role of Negative Effort Dependence as a Targetable Mechanism of Upper Airway Collapse in Sleep Disordered Breathing (1IK2CX002524-01A2). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10806050. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*