Characterizing the Sensory and Affective Neural Components of Persistent Dyspnea

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Abstract: The neuronal circuitry underlying respiration has been investigated thoroughly within the brainstem. In recent years, mounting evidence in animals and humans has revealed that ‘higher-level’ brain structures above the brainstem modulate key aspects of respiration, a finding that has important implications to design effective treatments for patients suffering from certain types of respiratory disease. This is especially relevant for cases where lung disease is not reversible and where neural or psychogenic influences are suspected, as in some forms of COPD, asthma, interstitial lung disease, cardiac and neuromuscular diseases, as well as palliative care and COVID-19. The overall aim of this proposal is to determine how higher-level brain regions interfere with automatic brainstem respiratory circuits to give rise to the complex pathology underlying respiratory disease in humans. To answer this question, we use a model of dyspnea (breathing discomfort) which is one of the leading symptoms (rivaling chronic pain) that cause approximately 10% of the general population to seek medical care. Patients suffering from persistent dyspnea choose descriptors such as “feeling suffocated” and “feeling like air is more precious than water”. Dyspnea is the result of an imbalance between the neural drive to breathe and the corresponding respiratory-related afferents. Current treatments that target the brain (rather than the lungs) to alleviate dyspnea are limited to opioids and/or benzodiazepines, but these drugs can suppress ventilatory drive, produce dependence and contribute to hypercapnic respiratory failure. We work towards meeting the clinical need of finding a treatment that reduces dyspnea without reducing ventilatory drive, by providing a better understanding of the cortical mechanisms that modulate respiratory-related afferents and ultimately shape the subjective sensations of dyspnea. Available evidence on the neural substrates of dyspnea in humans comes from noninvasive EEG and fMRI studies which do not afford the level of resolution required to access the deep sources involved in dyspnea nor disentangle the temporal dynamics of its different components (sensory and affective). We will utilize intracranial recordings (iEEG) from multiple cortical and subcortical regions in patients with chronically implanted electrodes for reasons unrelated to the present study (undergoing epilepsy treatment) and leverage on our recent finding that neural oscillations in these regions, recorded using iEEG, track the respiratory cycle, the so called Respiratory-Related Brain Oscillations (RRBO). The proposed experiments aim to: Aim 1: Further characterize RRBO: Determining causality between brain oscillations and the breathing cycle. Aim 2: Validate RRBO as neural marker of dyspnea: Detecting neural features of dyspnea in RRBO recorded in the primary (sensory dyspnea dimension) and secondary (affective dyspnea dimension) interoceptive cortex. Aim 3: Using direct electrical stimulation (DES) to probe cortical sites involved in dyspnea: Reducing dyspnea induced by the respiratory constrains by applying DES to key regions in the secondary interoceptive cortex.