Smile (sickle cell disease microbiologic and immunologic links to health) - respiratory control has long been linked to brainstem circuits, but growing evidence in animals and humans shows that…

SMILE (Sickle Cell Disease Microbiologic and Immunologic Links to Health) - Respiratory Control Research Project Grant

Emory University received a $794,661 Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under the Cardiovascular Diseases Research program (CFDA 93.837), with an award date of September 19, 2025, and a completion date of June 30, 2030. This research initiative investigates how higher-order brain regions interact with brainstem circuits to produce disordered breathing, with a specific focus on dyspnea—a persistent sensation of breathing discomfort affecting approximately 10% of the population. The research utilizes intracranial electroencephalography (iEEG) recordings from epilepsy patients with implanted electrodes to identify respiratory-related brain oscillations (RRBO) and their relationship to dyspnea perception. The project encompasses three primary aims: establishing causality between RRBO and the breathing cycle, validating RRBO as a neural marker of dyspnea by identifying sensory and affective signatures in interoceptive cortex, and using direct electrical stimulation to reduce dyspnea without impairing ventilation—ultimately supporting safer treatment alternatives to current opioid and benzodiazepine therapies that carry risks of ventilatory suppression and respiratory failure.

The award includes sub-awards to five research institutions: Children's Healthcare of Atlanta, Inc. (awarded March 30, 2026); St. Jude Children's Research Hospital Graduate School of Biomedical Sciences, LLC (January 12, 2026); Research Institute at Nationwide Children's Hospital (December 9, 2025); University of Wisconsin System/University of Wisconsin-Madison (November 25, 2025); The Ohio State University (November 18, 2025); and Georgia Tech Research Corp (November 12, 2025). These sub-awardees provide specialized research expertise in biomedical sciences, pediatric research, neuroscience, infectious disease investigation, and advanced research capabilities that support the primary investigator's work in elucidating the neurobiological mechanisms underlying dyspnea and developing safer therapeutic interventions.

Smile (sickle cell disease microbiologic and immunologic links to health) - respiratory control has long been linked to brainstem circuits, but growing evidence in animals and humans shows that higher-order brain regions actively shape breathing. This shift has major implications for treating respiratory diseases where lung pathology is irreversible and central mechanisms are suspected-such as in copd, asthma, interstitial lung disease, neuromuscular and cardiac conditions, aging, and palliative care. This project aims to define how higher brain regions interact with brainstem circuits to produce disordered breathing. We focus on dyspnea, a persistent sensation of breathing discomfort that drives ~10% of the population to seek care and rivals chronic pain in prevalence. Patients describe IT as "feeling suffocated" or "like air is more precious than water." dyspnea arises when the brain's drive to breathe is out of sync with incoming sensory feedback. Current brain-targeted treatments-opioids and benzodiazepines-carry serious risks: ventilatory suppression, dependence, and respiratory failure. Our goal is to guide safer treatments by identifying cortical mechanisms that shape the perception of dyspnea without impairing ventilation. Existing human studies (EEG, fmri) lack the spatial and temporal resolution to access deep sources or resolve the sensory and affective components of dyspnea. We overcome this using intracranial EEG (IEEG) from patients with implanted electrodes (for epilepsy treatment), and leverage on our recent work showing that brain oscillations in these regions track the breathing cycle-so-called respiratory-related brain oscillations (RRBO). We propose three aims: aim 1: determine causality between RRBO and the breathing cycle. Aim 2: validate RRBO as a neural marker of dyspnea by identifying sensory and affective signatures in interoceptive cortex. Aim 3: use direct electrical stimulation (DES) to reduce dyspnea by targeting key regions in secondary interoceptive cortex.