Major Depressive Disorder From a Brain-Body Perspective: Reproducible Central Cardiac Interoception Deficits and Peripheral Autonomic Dysfunctions Dissociate.

Abstract

Introduction: Brain-heart interaction (BHI) offers a systems-level framework for understanding major depressive disorder (MDD), but reproducible cross-system markers remain unclear. We aimed to identify reproducible BHI impairments in MDD and clarify their physiological and clinical correlates.

Methods: In this cross-sectional electroencephalography-electrocardiography study, we analyzed 3 independent resting-state datasets (total N = 693) and an acute stress dataset (n = 140) under strict medication control. BHI was assessed across cardiac (heart rate [HR], RR intervals), autonomic (heart rate variability [HRV]: root mean square of successive differences [RMSSD], pNN50, SD1, low-to-high frequency power ratio, etc.), and cortical (heartbeat-evoked potential [HEP]) domains.

Results: MDD cases consistently showed elevated HR, reduced vagal HRV, and attenuated HEP amplitude at the left centroparietal region (pooled Cohen's d [95% CI] for HEP = -0.35 [-0.51 to -0.20], p = 4.3 × 10^-6, I² = 0%). Under acute stress, peripheral indices were responsive whereas the central HEP marker remained stable. Only pNN50 exhibited a significant group × condition interaction, indicating blunted vagal reactivity in MDD. The central BHI marker (HEP) was linked to fatigue, hopelessness, and concentration deficits across somatic, affective, and cognitive domains, whereas peripheral indices showed domain-specific associations with sleep disturbance and psychomotor retardation. Antidepressant dose correlated with RMSSD.

Conclusions: We identified a reproducible central-peripheral BHI impairment model in MDD, suggesting partially distinct pathophysiological contributions of central and peripheral features. This model challenges the view that BHI abnormalities in MDD reflect a unitary hierarchical mechanism and provides a stratified framework that supports conceptualizing MDD as a brain-body disorder.