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.

The authors have declared no competing interest.

NCT05260086

Funding: This project received financial support from the German Federal Ministry of Education and Research (BMBF: 01 ZX 1507). The funders had no role in the study design, data collection, analysis, interpretation, or manuscript preparation.

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The study protocol (NCT05260086) was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University Medical Center Goettingen (UMG). All participants provided both verbal and written informed consent after receiving a full explanation of the study procedures.

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Ethics Approval and Consent to Participate: The study protocol (https://clinicaltrials.gov/study/NCT05260086) was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University Medical Center Göttingen (UMG). All participants provided both verbal and written informed consent after receiving a full explanation of the study procedures.

Consent for Publication: Not applicable.

Availability of Data and Materials: The data supporting the findings of this study are not publicly available due to European Union data protection regulations. However, data may be made available upon reasonable request from the corresponding author, provided appropriate legal and ethical conditions are met.

Competing Interests: The authors declare no competing interests.

Funding: This project received financial support from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF: 01 ZX 1507, “PreNeSt - e:Med”). The funders had no role in the study design, data collection, analysis, interpretation, or manuscript preparation.

Employment: None of the authors was employed or contracted by any organization that could gain or lose financially from the publication of this manuscript.

Personal Financial Interests: The authors did not receive any form of financial compensation (e.g., salaries, stocks, consulting fees) from commercial entities related to this research.

Statement: During the preparation of this manuscript, the authors used Grammarly Inc. and ChatGPT to assist with language refinement and grammar correction. Elicit was used to support the literature search. All content was critically reviewed and edited by the authors, who take full responsibility for the final version of the manuscript.

Declarations of Interest: BP-P acknowledges receiving a Seed Money for Research grant from the Central Institute of Mental Health. RG-M acknowledges receiving a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF: 01 ZX 1507, “PreNeSt - e:Med”). MA holds equity/stock in Sama Therapeutics, served as consultant to Synaeda, Sama Therapeutics, Neumarker and is named inventor on patents and intellectual property but receives no royalties.

The data supporting the findings of this study are not publicly available due to European Union data protection regulations. However, data may be made available upon reasonable request from the corresponding author, provided appropriate legal and ethical conditions are met.