Expectation and dyspnea: The neurobiological basis of respiratory nocebo effects

Cues such as odours that do not per se evoke bronchoconstriction can become triggers of asthma exacerbations. Despite its clinical significance, the neural basis of this respiratory nocebo effect is unknown. We investigated this effect in a functional magnetic resonance imaging (fMRI) study involving 36 healthy volunteers. The experiment consisted of an Experience phase in which volunteers experienced dyspnea while being exposed to an odorous gas (“Histarinol”). Volunteers were told that “Histarinol” induces dyspnea by bronchoconstriction. This was compared to another odorous gas which did not evoke dyspnea. Actually, dyspnea was induced by a concealed, resistive load inserted into the breathing system. In a second, Expectation phase, Histarinol and the control gas were both followed by an identical, very mild load. Respiration parameters were continuously recorded and after each trial participants rated dyspnea intensity. Dyspnea ratings were significantly higher in Histarinol compared to control conditions, both in the Experience and in the Expectation phase, despite identical physical resistance in the Expectation phase. Insula fMRI signal matched the actual load, i.e. a significant difference between Histarinol and Control in the Experience phase, but no difference in the Expectation phase. The periaqueductal gray showed a significantly higher fMRI signal during the expectation of dyspnea. Finally, Histarinol related deactivations during the Expectation phase in the rostral anterior cingulate cortex mirror similar responses for nocebo effects in pain. These findings highlight the neural basis of expectation effects associated with dyspnea, which has important consequences for our understanding of the perception of respiratory symptoms.