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

BackgroundLow-grade inflammation occurs in [~]30% of individuals with major depressive disorder (MDD) and is linked to poorer treatment outcomes, autonomic dysregulation, and elevated cardiometabolic risk. Such inflammation may contribute to variability in response to intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex. We tested whether baseline inflammation moderates the association between heart-brain coupling (HBC) during iTBS and clinical improvement, and examined neuroimaging correlates of inflammatory status. MethodsInflammation was indexed using routine clinical markers: white blood cell count (WBC) and C-reactive protein (CRP). HBC, a physiological marker of frontal-vagal engagement, was derived from electrocardiographic recordings obtained during the first iTBS sessions. Diffusion MRI free-water metrics were used to assess white-matter microstructural alterations associated with inflammation. ResultsHigher HBC was associated with symptom improvement only among individuals with lower WBC. Patients with higher WBC counts showed elevated free-water diffusion MRI signal in the fornix and corpus callosum, consistent with a neuroimmune profile associated with reduced clinical benefit. ConclusionsBaseline inflammation shapes the clinical relevance of HBC and may help explain inter-individual variability in iTBS efficacy. Routine inflammatory markers could support stratification approaches for biomarker-guided neuromodulation in MDD. HIGHLIGHTSO_LIBaseline WBC moderates HBC-iTBS response in major depression C_LIO_LIHigh HBC predicts improvement only when WBC is low ({approx}<6.44x10/L) C_LIO_LICRP does not significantly moderate HBC-response associations C_LIO_LIHigher WBC links to elevated DTI free-water in the fornix & corpus callosum C_LIO_LIWBC may be a low-cost stratifier for biomarker-guided neuromodulation C_LI