Rationale: Dyspnea is the impairing cardinal symptom of asthma but its accurate perception is also crucial for timely initiation of treatment. However, the underlying brain mechanisms of perceived dyspnea in patients with asthma are unknown. Objectives: By using functional magnetic resonance imaging we compared the neuronal responses to experimentally induced dyspnea in asthma patients and healthy controls. These brain activations were compared with neuronal responses evoked by pain to study neuronal generalisation processes to another, similarly unpleasant physiological sensation. Measurements and Main Results: While lying in the scanner, fourteen patients with mild-to-moderate asthma and fourteen matched healthy controls repeatedly underwent conditions of mild dyspnea, severe dyspnea, mild pain and severe pain. Dyspnea was induced by resistive loaded breathing. Heat pain of similar intensity was induced by a contact thermode. Whereas the sensory intensity of both sensations was rated similar by patients and controls, ratings of the affective unpleasantness of dyspnea and pain were reduced in patients. This perceptual difference was mirrored by reduced insular cortex activity, but increased activity in the periaqueductal grey (PAG) in patients during both increased dyspnea and pain. Connectivity analyses showed that asthma-specific down-regulation of the insular cortex during dyspnea and pain was moderated by increased PAG activity. Conclusions: The results suggest a down-regulation of affect-related insular cortex activity by the PAG during perceived dyspnea and pain in patients with asthma. This might represent a neuronal habituation mechanism reducing the affective unpleasantness of dyspnea in asthma, which generalizes to other unpleasant physiological sensations such as pain.