Finnegan Sarah L, Harrison Olivia K, Ezra Martyn, Harmer Catherine J, Nichols Thomas E, Rahman Najib M, Reinecke Andrea, Pattinson Kyle T S
Wellcome Centre for Integrative Neuroimaging and Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Department of Psychology, University of Otago, Dunedin, New Zealand.
PLoS One. 2025 Jun 2;20(6):e0323213. doi: 10.1371/journal.pone.0323213. eCollection 2025.
Combining traditional therapies such as pulmonary rehabilitation with brain-targeted drugs may offer new therapeutic opportunities for the treatment of chronic breathlessness. Recently, we asked whether D-cycloserine, a partial NMDA-receptor agonist which may enhance behavioural therapies, modifies the relationship between breathlessness related brain activity and breathlessness anxiety over pulmonary rehabilitation. However, whether any 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 the connectivity between key brain regions associated with the processing of breathlessness anxiety. 72 participants with mild-to-moderate COPD took part in a longitudinal study in parallel to their pulmonary rehabilitation course. Diffusion tensor brain imaging 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. Following the first four sessions of pulmonary rehabilitation (visit 2), during which D-cycloserine was administered, improvements in breathlessness anxiety were linked with increased insula-hippocampal structural connectivity in the D-cycloserine group when compared to the placebo group. No differences were found between the two groups following the completion of the full pulmonary rehabilitation course 4-6 weeks later (visit 3). 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 how unpleasant an experience is may support the re-evaluation of breathlessness cues, illustrated improvements in breathlessness anxiety. Trial registration ClinicalTrials.gov (NCT01985750).
将肺康复等传统疗法与脑靶向药物相结合，可能为慢性呼吸急促的治疗提供新的治疗机会。最近，我们探讨了D-环丝氨酸（一种可能增强行为疗法的部分NMDA受体激动剂）是否会改变肺康复过程中与呼吸急促相关的大脑活动和呼吸急促焦虑之间的关系。然而，潜在脑结构的改变是否支持这些变化仍不清楚。在这里，我们研究了在肺康复过程中D-环丝氨酸对与呼吸急促焦虑处理相关的关键脑区之间连通性的影响。72名轻度至中度慢性阻塞性肺疾病（COPD）患者参与了一项与他们的肺康复疗程并行的纵向研究。在三个时间点（肺康复前、期间和之后）收集弥散张量脑成像和呼吸功能的临床测量数据。参与者被随机分配接受250毫克D-环丝氨酸或安慰剂，并以随机双盲程序分四次给药。在肺康复的前四个疗程（第2次访视）中，即给予D-环丝氨酸的期间，与安慰剂组相比，D-环丝氨酸组呼吸急促焦虑的改善与岛叶-海马结构连通性增加有关。在4-6周后的整个肺康复疗程完成后（第3次访视），两组之间未发现差异。D-环丝氨酸对脑连通性的作用似乎仅限于其给药后的短时间窗口内。这种与评估一种体验有多不愉快相关的两个关键区域脑连通性的暂时增强，可能支持对呼吸急促线索的重新评估，表现为呼吸急促焦虑的改善。试验注册ClinicalTrials.gov（NCT01985750）。
