Search

Background: Chronic breathlessness in chronic obstructive pulmonary disease (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 and help to individualise therapy. Increasing evidence supports the role of expectation (ie, 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 asked whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulated any predictive model., Methods: Data from 71 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation were 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., Results: 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)., Conclusions: 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) therefore merits further testing in the treatment of chronic breathlessness., Competing Interests: Competing interests: CH has valueless shares in p1vital and serves on their advisory panel. She has received consultancy payments from p1vital, Zogenix, J&J, Pfizer, Servier, Eli-Lilly, Astra Zeneca, Lundbeck. KTSP is named as co-inventors on a provisional UK patent application titled Use of cerebral nitric oxide donors in the assessment of the extent of brain dysfunction following injury. NMR, has received consulting fees from Rocket Medical UK. MB has received travel expenses from Lundbeck for attending conferences, has shares in P1vtial Products and has acted as a consultant for Jansen and for CHDR. Drs Pattinson and Finnegan are named as co-inventors on a provisional U.K. patent titled "Discordant sensory stimulus in VR based exercise" UK Patent office application: 2204698.1 filing date 31/3/2022. The remaining authors have no biomedical financial interests or potential conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)