Little is currently known about the brain regions involved in central processing of dyspnea. We performed a functional imaging study with positron emission tomography (PET) to assess brain activation associated with an important component of dyspnea, respiratory discomfort during loaded breathing. We induced respiratory discomfort in eight healthy volunteers by adding external resistive loads during inspiration and expiration. Brain activation was characterized by a significant increase in regional cerebral blood flow (rCBF) (Z score of peak activation > 3.09). As compared with the unloaded control condition, high loaded breathing was associated with neural activation in three distinct brain regions, the right anterior insula, the cerebellar vermis, and the medial pons (respective Z scores = 4.75, 4.44, 4.41). For these brain regions, we further identified a positive correlation between rCBF and the perceived intensity of respiratory discomfort (respective Z scores = 4.45, 4.75, 4.74) as well as between rCBF and the mean amplitude of mouth pressure swings (DeltaPm), the index of the main generating mechanism of the sensation (respective Z scores = 4.67, 4.36, 4.31), suggesting a common activation by these two parameters. Furthermore, we identified an area in the right posterior cingulate cortex where neural activation was specifically associated with perceived intensity of respiratory discomfort that is not related to DeltaPm (Z score = 4.25). Our results suggest that respiratory discomfort related to loaded breathing may be subserved by two distinct neural networks, the first being involved in the concomitant processing of the genesis and perception of respiratory discomfort and the second in the modulation of perceived intensity of the sensation by various factors other than its main generating mechanism, which may include emotional processing.