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Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation

Background: Chronic breathlessness in COPD is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness, helping to individualise therapy. Increasing evidence supports the role of expectation (i.e. placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulates any predictive model. Methods: Data from 72 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation was analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the dyspnoea-12 score. Findings: Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). Interpretation: Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain's expectation pathways (either pharmacological or non-pharmacological) merits further testing in the treatment of chronic breathlessness.