White Blood Cell Count Shape Heart-Brain Coupling and rTMS Benefit in Depression

Low-grade inflammation affects approximately 30% of individuals with major depressive disorder (MDD) and has been associated with poorer treatment outcomes, reduced antidepressant response, autonomic dysregulation, and increased cardiometabolic risk. This inflammatory state may contribute to variability in response to intermittent theta burst stimulation (iTBS) over the left dorsolateral prefrontal cortex. In this study, inflammation was indexed by clinical routine markers white blood cell count (WBC) and C-reactive protein (CRP), while heart-brain coupling (HBC), a physiological marker of frontal-vagal engagement, was derived from electrocardiographic data during the first iTBS sessions. Higher HBC was associated with symptom improvement only in individuals with lower WBC. Diffusion MRI revealed elevated free-water in the fornix and corpus callosum in patients with higher WBC, suggesting a neuroimmune profile linked to reduced clinical benefit. These findings indicate that baseline inflammation shapes the clinical relevance of HBC and may help explain variability in iTBS efficacy.