Studying the brain mechanisms of dyspnoea with functional magnetic resonance imaging

Dyspnoea (breathlessness) is a debilitating, often poorly controlled, symptom of cardiopulmonary, neurovascular and psychological disorders. This thesis develops the necessary methodology to dissociate aspects of the acute dyspnoea experience using functional magnetic resonance imaging (FMRI) in healthy volunteers. The neuronal mechanisms underlying dyspnoea anticipation, its perceived intensity and unpleasantness and the modulation of these mechanisms by the opioid remifentanil were explored. We investigated the subjective perception of respiratory loading, a commonly used dyspnoea stimulus, and its potential systematic confounds on FMRI due to cerebral blood flow changes. Investigation of the perception of respiratory loading at different levels of hypercapnia (increased end-tidal CO2) showed that hypercapnia should be kept to a minimum to avoid increased baseline respiratory unpleasantness whilst maintaining the stable arterial CO2 (isocapnia) beneficial for FMRI analysis. Investigation of the effects of respiratory loading (± 9 cmH2O) on cerebral blood flow showed that systematic confounds of respiratory loading on perfusion-based neuroimaging data were small (~5%) and did not significantly alter neural activation in response to visual stimulation. Isocapnic respiratory loading during a classical fear-conditioning paradigm during FMRI was used to investigate dyspnoea anticipation, and dissociate the intensity and unpleasantness of acute dyspnoea by modulating unpleasantness with remifentanil. Differential neural networks were found to be involved in perceived intensity (thalamus, insula, somatosensory cortex) and unpleasantness (hippocampus, medial prefrontal cortex). Remifentanil reduced respiratory unpleasantness without affecting the perceived intensity and differentially reduced brain activity during both dyspnoea anticipation and perception. This thesis showed the potential of isocapnic respiratory loading for the study of dyspnoea with FMRI. This stimulus revealed, for the first time, brain activation for dyspnoea anticipation, perceived intensity and unpleasantness. The opioid-sensitive nature of the anticipation and unpleasantness of dyspnoea provides brain targets for future research and might facilitate more effective dyspnoea palliation.This thesis is not currently available in ORA