Dyspnea is the highly threatening experience of breathlessness experienced by patients with diverse pathologies, including respiratory, cardiovascular, and neuromuscular diseases, cancer and panic disorder. This debilitating symptom is especially prominent in the elderly and the obese, two growing populations in the Western world. It has further been found that women suffer more strongly from dyspnea than men. Despite optimization of disease-specific treatments, dyspnea is often inadequately treated. The immense burden faced by patients, families and the healthcare system makes improving management of chronic dyspnea a priority. Dyspnea is a multidimensional sensation that encompasses an array of unpleasant respiratory sensations that vary according to underlying cause and patient characteristics. Biopsychological factors beyond disease pathology exacerbate the perception of dyspnea, increase symptom severity and reduce quality of life. Psychological state (especially comorbid anxiety and depression), hormone status, gender, body weight (obesity) and general fitness level are particularly important. Neuroimaging has started to uncover the neural mechanisms involved in the processing of sensory and affective components of dyspnea. Awareness of biopsychological factors beyond pathology is essential for diagnosis and treatment of dyspnea. Increasing understanding the interactions between biopsychological factors and dyspnea perception will enhance the development of symptomatic treatments that specifically address each patient's most pressing needs at a specific stage in life. Future neuroimaging research can provide objective markers to fully understand the role of biopsychological factors in the perception of dyspnea in the hope of uncovering target areas for pharmacologic and non-pharmacologic therapy.

Breathlessness in chronic obstructive pulmonary disease (COPD) is often discordant with airway pathophysiology (“over-perception”). Pulmonary rehabilitation profoundly affects breathlessness, without influencing lung function. Learned associations influence brain mechanisms of sensory perception. We hypothesised that improvements in breathlessness with pulmonary rehabilitation may be explained by changing neural representations of learned associations.In 31 patients with COPD, we tested how pulmonary rehabilitation altered the relationship between brain activity during a breathlessness-related word-cue task (using functional magnetic resonance imaging), and clinical and psychological measures of breathlessness.Changes in ratings of breathlessness word cues positively correlated with changes in activity in the insula and anterior cingulate cortex. Changes in ratings of breathlessness-anxiety negatively correlated with activations in attention regulation and motor networks. Baseline activity in the insula, anterior cingulate cortex and prefrontal cortex correlated with improvements in breathlessness and breathlessness-anxiety.Pulmonary rehabilitation is associated with altered neural responses related to learned breathlessness associations, which can ultimately influence breathlessness perception. These findings highlight the importance of targeting learned associations within treatments for COPD, demonstrating how neuroimaging may contribute to patient stratification and more successful personalised therapy.

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus.Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7 ng/ml target-controlled infusion) or saline (randomised).During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices.Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli.These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.