Heart Rate Variability Biofeedback Alleviates Subthreshold Depression by Reconstructing the Brain-Heart Axis via Habenular Network Functional Connectivity Modulation

To investigate the role of the habenula (Hb)-centered brain network in regulating the cardiac autonomic nervous system (ANS) in subthreshold depression (StD), and to explore the brain-heart axis mechanisms underlying the antidepressant effects of heart rate variability biofeedback (HRV-BF) as a non-pharmacological intervention.

Thirty four StD participants and 32 healthy controls (HC) completed scale assessments (HAMD-17, PHQ-9, and PSQI) and cardiovascular measurements. StD participants received a 4-week HRV-BF with pre- and post-rs-BOLD fMRI. Bilateral Hb was used as the seed for ROI- and voxel-wise functional connectivity (FC) analyses. To minimize potential confounding effects of sex imbalance, only female participants were included in voxel-wise FC analysis (StD group, n = 8; HC group, n = 11) and pre-post intervention comparisons in ROI-wise FC analysis(StD group, n = 8).

StD participants exhibited elevated heart rate, reduced HRV indices (lnRMSSD, HF power, lnSDNN), and increased LF power. ROI-wise FC analysis revealed that with increasing depression scores, z-transformed functional connectivity (zFC) value between the Hb and the nucleus accumbens (NAc), ventral pallidum (VeP), amygdala, globus pallidus internus (GPi), and substantia nigra (SN) shifted from positive to negative, indicating a transition from functional connectivity coupling to anti-coupling. Among these, Hb-NAc and Hb-VeP showed high discriminatory power (AUC = 0.876, p < 0.001). Voxel-wise FC analysis demonstrated weakened Hb functional connectivity with several key regions within the default mode network, salience network, central executive network, visual network, and sensorimotor network, including precuneus, right posterior cingulate cortex, left middle cingulate cortex, right superior parietal lobule, cuneus, right calcarine cortex, left superior occipital gyrus, right paracentral lobule, and right postcentral gyrus. A 4-week HRV-BF intervention improved HRV indices and partially restored the functional connectivity of Hb-centered networks, accompanied by significant improvements in depressive symptoms and sleep quality.

Aberrant Hb-centered functional connectivity may contribute to cardiac autonomic dysfunction in StD. Specifically, Hb-NAc and Hb-VeP functional connectivity may serve as neuroimaging biomarkers for StD. HRV-BF enhances vagal tone, rebalances cardiac ANS function, and partly restores Hb-centered brain network functional connectivity, thereby alleviating depressive symptoms and improving sleep quality. These findings highlight that Hb may be a key hub within the brain-heart axis and suggest this pathway as a promising early non-pharmacological intervention target.