Restoring Brain–Heart Coupling via mPFC tFUS in Depression: A Pilot fMRI–PPG Study

Background: Major depressive disorder (MDD) has been linked to altered coupling between respiratory sinus arrhythmia (RSA) and regional BOLD signal within medial visceromotor/interoceptive networks. SSRI treatment strengthens this coupling without changing mean RSA (Shafer et al., 2015). Whether noninvasive neuromodulation of anterior medial prefrontal cortex (mPFC) can modulate this brain–heart linkage is unknown. Objective: Test whether repeated transcranial focused ultrasound (tFUS) targeting anterior mPFC enhances RSA–BOLD coupling in MDD and whether coupling relates to symptom change. Methods: Fourteen adults with MDD completed up to 11 tFUS sessions over ~3 weeks. Resting-state fMRI with simultaneous photoplethysmography (PPG) was acquired PRE and POST. A first-level RSA regressor (non-Hilbert; no HRF convolution) estimated per-TR RSA–BOLD covariation. Ten a-priori CAN/MVN ROIs (sgACC, rACC, dACC, vmPFC, rmPFC, left insula, left amygdala, left putamen, PAG, hypothalamus) were tested. Primary endpoint: across-ROI composite change in positive RSA–BOLD coupling (POST–PRE). Secondary ROI-wise and whole-brain parametric and non-parametric tests were performed; sensitivity analyses used an HRF-convolved Hilbert HRV regressor. Associations with HRSD, MADRS, BDI, PTQ, and VAS were explored. Results: The composite increased numerically but not significantly (Δ=+0.19 SD; 95% CI [−0.28, 0.66]; t(13)=0.88, p=.40; d=0.24); 9/14 participants showed higher POST values. No ROI-wise or whole-brain POST>PRE effects survived FWE correction. Baseline small-volume–corrected effects replicated canonical coupling (left anterior insula positive; sgACC negative) but did not change with treatment. Mean RSA, RMSSD, and Hilbert HRV amplitude showed no significant session effects. Symptom-coupling correlations were uniformly non-significant after correction. Conclusions: In this uncontrolled pilot, anterior mPFC tFUS did not reliably increase RSA-BOLD coupling at the group level, despite replication of baseline neurovisceral patterns. Any tFUS-related modulation appears small and variable at this sample size. Larger, controlled studies with individualized targeting and parameter optimization are warranted.