Brain Responses during the Anticipation of Dyspnea

Abstract

Dyspnea is common in many cardiorespiratory diseases. Already the anticipation of this aversive symptom elicits fear in many patients resulting in unfavorable health behaviors such as activity avoidance and sedentary lifestyle. This study investigated brain mechanisms underlying these anticipatory processes. We induced dyspnea using resistive-load breathing in healthy subjects during functional magnetic resonance imaging. Blocks of severe and mild dyspnea alternated, each preceded by anticipation periods. Severe dyspnea activated a network of sensorimotor, cerebellar, and limbic areas. The left insular, parietal opercular, and cerebellar cortices showed increased activation already during dyspnea anticipation. Left insular and parietal opercular cortex showed increased connectivity with right insular and anterior cingulate cortex when severe dyspnea was anticipated, while the cerebellum showed increased connectivity with the amygdala. Notably, insular activation during dyspnea perception was positively correlated with midbrain activation during anticipation. Moreover, anticipatory fear was positively correlated with anticipatory activation in right insular and anterior cingulate cortex. The results demonstrate that dyspnea anticipation activates brain areas involved in dyspnea perception. The involvement of emotion-related areas such as insula, anterior cingulate cortex, and amygdala during dyspnea anticipation most likely reflects anticipatory fear and might underlie the development of unfavorable health behaviors in patients suffering from dyspnea.

Figure 1

MRI task and protocol. In alternating order, subjects were visually cued for either mild or severe dyspnea followed by the respective load. Each load was followed by two Borg rating scales, one on dyspnea intensity and one on dyspnea unpleasantness. The order of the scales was randomized. Each anticipatory cue lasted for 6 s. Then the cue, a thin cross, turned into a solid cross and the load was introduced manually for 24 s. There were ten blocks of mild and severe dyspnea, respectively. The last intensity and unpleasantness ratings were followed by ratings on the average anticipatory fear during the two different cues.

Figure 2

Mean (SEM) ratings of perceived intensity, unpleasantness, and anticipatory fear for mild (white) and severe (black) dyspnea, respectively. Increases from mild to severe dyspnea were significant at p < 0.001. ∗∗∗ indicates a significance level of p < 0.001.

Figure 3

Perception (a) and anticipation (b) of severe versus mild dyspnea activated insular, parietal opercular, and cerebellar cortex. (c) Activation during anticipation (displayed in red) and perception of dyspnea (displayed in yellow) overlapped in the left cerebellum and parietal operculum while insular activation was more anterior during anticipation as compared to perception of dyspnea. Activation patterns are displayed at a threshold of p < 0.05, corrected for the specific ROI, and superimposed on the group-specific T1-weighted mean image generated by the DARTEL-protocol. L = left.

Figure 4

Psychophysiological interactions during the anticipation period. (a) During the anticipation of severe as compared to mild dyspnea the left anterior insular cortex shows significantly increased coactivation with ACC (x = 4, y = 38, z = 0; ROI-corrected p = 0.003) and right insular cortex (x = 36, y = −18, z = 18; ROI-corrected p = 0.019). (b) The left parietal operculum shows increased coactivation with ACC (x = 8, y = 40, z = −4; ROI-corrected p = 0.029) and right insular cortex (x = 30, y = 26, z = −4; ROI-corrected p = 0.007). (c) The left cerebellar cortex shows increased coactivation with the amygdala, bilaterally (x = −24, y = −8, z = −14; ROI-corrected p = 0.011 and x = 22, y = −4, z = −24; ROI-corrected p = 0.016, resp.). The nonsignificant interactions within the rostral cingulate cortex (b) and primary sensorimotor cortex (c) were outside our ROIs and did not reach whole-brain-corrected significance. All interactions are displayed at a threshold of p < 0.05, corrected for the specific ROI, and superimposed on the group-specific T1-weighted mean image generated by the DARTEL-protocol.

Figure 5

(a) Backward model: right insular activation during dyspnea perception is significantly correlated with midbrain/PAG activation during dyspnea anticipation (x = −2, y = −30, z = −10; ROI-corrected p = 0.026). (b) Anticipatory fear is significantly correlated with increased brain activation during dyspnea anticipation in the ACC (x = −4, y = 36, z = 14; ROI-corrected p = 0.001) and right insular cortex (x = 38, y = 12, z = −4; ROI-corrected p = 0.007). The nonsignificant correlations with the putamen and medial prefrontal cortex (b) were outside our ROIs and did not reach whole-brain-corrected significance. All correlations are displayed at a threshold of p < 0.05, corrected for the specific ROI, and superimposed on the group-specific T1-weighted mean image generated by the DARTEL-protocol.