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

Rationale: Combining 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. Methods: 72 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. Results: Following 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. Conclusions: The 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT0198575 ### Funding Statement This work was supported by Biomedical Research Council, the Dunhill Medical Trust (Grant R333/0214) and the National Institute for Health Research Biomedical Research Centre (Grant RCF18/002) based at Oxford University Hospitals NHS Foundation Trust and The University of Oxford. This research was funded in whole, or in part, by the Wellcome Trust 203139/Z/16/Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study approval was granted by South Central Oxford REC B (Ref: 118784, Ethics number: 12/SC/0713). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors