Distinct brain pathways link depressive symptoms due to respiratory dysfunction and reduced physical activity in patients with chronic obstructive pulmonary disease: A single-center observational pilot study

Mental health issues, such as depression, are increasingly recognized as critical comorbidities in chronic obstructive pulmonary disease (COPD). While analyses of individual domains or pairwise relationships among airflow obstruction severity, brain morphological features, and mental health conditions in COPD have provided valuable insights into their direct associations, a more integrative approach may offer additional mechanistic understanding. This study aimed to clarify potential mediators in multiple brain regions between airflow obstruction and depressive tendencies in patients with COPD. We analyzed 19 patients with COPD and 23 age-matched healthy controls. Path analysis was used to evaluate the relationships among respiratory indices, regional brain volumes, and depressive symptoms. The path analysis revealed two potential pathways to depressive symptoms in the COPD group. One was a pulmonary pathway, involving forced expiratory volume in one second (%FEV1) and the genu of the corpus callosum (β = 0.503, p < 0.05) leading to depressive symptoms (β = 0.532, p < 0.05). The other was a behavioral pathway, in which physical activity (β = 0.444, p < 0.05) affected the right postcentral gyrus (β = -0.286, p < 0.05) and, in turn, depressive symptoms. No significant group differences were observed in other examined regions, including the posterior cingulate, hippocampus, hypothalamus, insula, or other corpus callosum subregions, nor in depression or anxiety scores. The model demonstrated a good fit in the COPD group (GFI = 0.876), whereas in controls, the model showed poor fit and no significant relationships (GFI = 0.784). These preliminary findings suggest potential brain pathways linking airflow obstruction, physical activity, and depressive symptoms in COPD, which warrant confirmation in larger, longitudinal studies.