The effect of D-cycloserine on brain connectivity over a course of pulmonary rehabilitation

RationaleCombining traditional therapies such as pulmonary rehabilitation with brain- targeted drugs may offer new therapeutic opportunities for the treatment of chronic breathlessness. Recent work has shown that D-cycloserine, a partial NMDA-receptor agonist which has been shown to enhance cognitive behavioural therapies, modifies the relationship between breathlessness related brain activity and breathlessness anxiety over pulmonary rehabilitation. However, whether these changes are supported by alterations to underlying brain structure remains unknown. Here we examine the effect of D-cycloserine over a course of pulmonary rehabilitation on regional brain volume and connectivity. Methods72 participants with mild-to-moderate COPD took part in a longitudinal study in parallel to their pulmonary rehabilitation course. Diffusion tensor brain imaging, self-report questionnaires and clinical measures of respiratory function were collected at three time points (before, during and after pulmonary rehabilitation). Participants were assigned to 250mg of D-cycloserine or placebo, which they were administered with on four occasions in a randomised, double-blind procedure. ResultsFollowing four sessions of pulmonary rehabilitation, improvements in breathlessness anxiety were linked with increased insula-hippocampal structural connectivity in the D-cycloserine group. No group differences were found following the completion of pulmonary rehabilitation, or in the integrity of structural connectivity. ConclusionsThe action of D-cycloserine on brain connectivity appears to be restricted to within a short time-window of its administration. This temporary boost of the brain connectivity of two key regions associated with the evaluation of unpleasantness may support the re-evaluation of breathlessness cues, illustrated improvements in breathlessness anxiety. This work highlights the relevance of targeting breathlessness expectation in pulmonary rehabilitation.