Early Heart Rate Slowing Predicts Magnetic Brain Stimulation Response in MDD

A new study discovered that patients whose heart rates slowed within 45 seconds of starting magnetic brain stimulation therapy showed significantly greater improvement in depressive symptoms 6 weeks later.1

Intermittent theta burst stimulation (iTBS), an advanced form of transcranial magnetic stimulation, shows promise for treating major depressive disorder (MDD) but elicits variable patient responses. To explore factors influencing treatment outcomes, investigators conducted a quadruple-blind, sham-controlled crossover randomized clinical trial to determine whether early cardiac rhythm changes or spatial selection of stimulation sites affected iTBS efficacy.

“As the largest prospective study to date to address these aspects, our findings show that clinical improvement driven by iTBS was associated with modulations of HR and HR variability—but not with personalized stimulation sites based on individual resting-state connectivity,” study investigator Jonas Wilkening, MD candidate, from the department of psychiatry and psychotherapy at University Medical Center Göttingen in Germany, and colleagues wrote.1

The team observed 75 patients (56% male) with MDD undergoing accelerated iTBS and tracked beat-to-beat heart rate changes from the onset of stimulation using continuous electrocardiogram (ECG). Participants were randomized to either personalized stimulation sites—selected based on the strongest negative connection between the left dorsolateral prefrontal cortex and the brain’s default mode network—or a fixed stimulation at the F3 position of the 10–20 EEG system. ECG metrics included heartbeat deceleration, heart rate slope, and changes in the root mean square of successive differences (RMSSD) between heartbeats.1

The study showed that heart rate slowing within the first 45 seconds of stimulation predicted greater improvement in depressive symptoms at 6 weeks, as reflected by steeper heart rate slopes. Investigators only observed this relationship with active stimulation, not sham treatment. Smaller changes in RMSSD during the first 270 seconds correlated with symptom improvement at week 1 (P = .013) but were not predictive of longer-term outcomes.1

Overall, early heart rhythm changes were significantly associated with antidepressant response to accelerated iTBS in MDD (P = .021), whereas RMSSD changes did not predict six-week outcomes (P = .15).1

“That was unexpected! This counterintuitive finding challenges prevailing assumptions about autonomic flexibility in depression,” noted Julio Licinio, PHD, editor-in-chief of Genomic Press and professor at State University of New York Upstate Medical University, and Helen Mayberg, MD, from Icahn School of Medicine at Mount Sinai, in an accompanying editorial.2 “It is particularly striking, as it highlights the significant gaps in our understanding of the temporal dynamics of brain–heart interactions during neuromodulation. The authors suggest that effective frontal-vagal engagement may initially reduce variability during stimulation, followed by compensatory increases that align with clinical improvement. However, this explanation remains speculative, highlighting gaps in understanding the temporal dynamics of brain-heart interactions during neuromodulation.”

Moreover, investigators observed no significant difference in MADRS score improvement between patients randomized to personalized versus fixed stimulation sites (P =.490).1

Although personalized targeting of stimulation sites did not enhance efficacy, the findings suggest that early heart rate changes may serve as a valuable biomarker for treatment response. Investigators noted that combining neuronavigation with ECG monitoring could help identify patients most likely to benefit from iTBS, supporting a precision medicine approach in MDD.1

“If validated, cardiac biomarkers could enable real-time optimization during treatment sessions," Licinio and Mayberg wrote.2 “Clinicians can adjust coil positioning, stimulation intensity, or other parameters based on immediate physiological feedback, potentially improving response rates, which currently hover around 30-50% for standard protocols. This approach sidesteps the limitations of motor threshold determination, which relies on anatomical assumptions that may not translate to prefrontal targets. Instead, cardiac monitoring provides direct evidence of relevant circuit engagement.”

References

1. Wilkening J, Jungeblut H, Adamovic I, et al. Heart rate modulation and clinical improvement in major depression: A randomized clinical trial with accelerated intermittent theta burst stimulation. Genomic Press. October 14, 2025. doi:10.61373/bm025a.0113

2. Licino J and Mayberg H. Cardiac rhythms as windows into brain stimulation response: Promise and pitfalls in precision psychiatry. Genomic Press. October 14, 2025. 10.61373/bm025d.0119