Stimulus-dependent sex differences in dyspnoea: Mechanical loading vs. hypercapnia

Dyspnoea is a multidimensional sensation of breathing discomfort that varies in sensory and affective experience. During exercise, healthy adults commonly report dyspnoea sensations of 'air hunger' and 'work/effort', with females more frequently reporting air hunger at maximal exertion. Interpreting these sex differences and their underlying mechanisms is challenging due to the complex physiological responses associated with exercise. Therefore, this study used laboratory models to target respiratory stimuli and evaluate sex-differences in perceptual and physiological responses to dyspnoea. In a randomized crossover design, 34 healthy participants (n = 17M; n = 17F) completed two breathing challenges. Work/effort was targeted using incremental inspiratory pressure threshold loading (IPTL). Air hunger was targeted by constraining ventilation while incrementally increasing the partial pressure of end-tidal carbon dioxide ( $P_{\mathrm{ETC}{O}_2}$ ). Ratings of dyspnea intensity, unpleasantness, work/effort and air hunger were assessed at the end of each increment. Electromyography of the crural diaphragm (EMG_di), sternocleidomastoid (EMG_scm) and scalene (EMG_sca) were measured throughout each trial. Mixed-effects models tested sex-by-stimulus interactions. During IPTL, males exhibited a significantly steeper increase in dyspnoea intensity and work/effort ratings than females. These perceptual differences occurred without a concomitant sex difference in EMG_di, while EMG_scm and EMG_sca were lower in males compared to females. During hypercapnia, there were no sex-by-stimulus interactions for perceptual or physiological outcomes, despite significantly greater EMG_scm in females than males. These findings highlight that sex differences in dyspnoea are stimulus-dependent, occurring during mechanical loading but not chemostimulation, and may partly reflect differences in perceptual anchoring to experience and expectation.