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.