D-cycloserine modulates breathlessness related brain activity over pulmonary rehabilitation

Rationale: For people with Chronic Obstructive Pulmonary Disease (COPD), improvements in breathlessness from pulmonary rehabilitation are neither long lasting nor guaranteed. Previously, we showed that pulmonary rehabilitation induced brain activity changes akin to those seen in exposure based cognitive behavioural therapies (CBT) in other conditions. D-cycloserine is a partial NMDA-receptor agonist which has been shown to enhance CBT. Objectives: Here, we tested whether D-cycloserine would augment the effects of pulmonary rehabilitation on activity in brain areas that process breathlessness expectation. Methods: 72 participants with mild-to-moderate COPD were recruited to a double-blind experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or matched placebo, administered 15-30 minutes prior to the first four sessions of pulmonary rehabilitation. Brain functional magnetic resonance imaging, self-report questionnaires and clinical measures of respiratory function were collected at three time points: before, during (2-3 weeks) and after pulmonary rehabilitation (6-8 weeks). Measurements: Primary and secondary outcome measures were difference in mean and voxel-wise brain activity across key brain regions of interest. An exploratory analysis determined the interaction with breathlessness-anxiety. Main results: No difference was observed in either primary or secondary outcome measures. However, in the exploratory analysis, D-cycloserine attenuated the relationship between brain activity and breathlessness-anxiety within prefrontal cortex, superior frontal gyrus and precuneus. Conclusions: The observed effects suggest that D-cycloserine augments pulmonary rehabilitation by dampening reactivity to breathlessness cues in brain areas associated with breathlessness expectation and anxiety. This work highlights the opportunity to test brain-active drugs in the context of augmenting behavioural interventions.