Jiangxi Puzhuo Medical Equipment Co., Ltd

For a long time, many studies and clinical assumptions have held that stimulating the right vagus nerve may increase cardiovascular risks such as bradycardia, leading right-ear transcutaneous auricular vagus nerve stimulation (taVNS) to be labeled as "use with caution." However, a randomized crossover study published in Psychophysiology has overturned this conventional understanding — taVNS stimulation of either the left or right ear is equally safe and effective for cardiovascular regulation, and the core effect is a reduction in heart rate variability (HRV), independent of stimulation side and metabolic state.

Study Objective: Resolving the Long-Standing Debate on "Right-Ear Stimulation Risk"

The vagus nerve is a key pathway regulating the cardiovascular system, and non-invasive taVNS has become a research hotspot in the field of neuromodulation due to its ease of use. However, two major controversies have long limited its application:

The lateral risk myth: The right vagus nerve innervates the sinoatrial node more directly, and many studies have speculated that right-side taVNS may induce bradycardia, leading most research to prefer left-side stimulation;

The consistency challenge: Previous findings on the effects of taVNS on HRV have been inconsistent — some studies reported increased HRV, while others found no significant effect, and whether metabolic state (e.g., before vs. after eating) influences the outcome remained unclear.

To clarify these questions, a team of German researchers designed a rigorous randomized crossover trial incorporating both stimulation side and metabolic state as two key variables, systematically validating for the first time the regulatory patterns of taVNS on the cardiovascular system.

[Physiological Origins of Multiple Cardiovascular Indicators (Heart Rate and Heart Rate Variability)]

☑ Heart Rate (HR): Generated by the sinoatrial node, regulated by both branches of the autonomic nervous system, and influenced by circulating hormones (e.g., adrenaline). It is also affected by metabolic and intrinsic factors (e.g., blood pressure and oxygen demand)

☑ Root Mean Square of Successive Differences (RMSSD): Quantifies the time differences between successive heartbeats in the time domain, influenced by cardiac vagal modulation. Although RMSSD is correlated with high-frequency power, it is less affected by respiratory rate

☑ High-Frequency Power (HF-HRV): Quantifies the short-term periodic dynamics of heart rate in the frequency domain (high-frequency power, 0.15–0.40 Hz), influenced by cardiac vagal modulation through efferent fibers. High-frequency heart rate variability (HF-HRV): Varies with respiratory rate

☑ Low-Frequency Power (LF-HRV): Quantifies rhythms with periods of 7 to 25 seconds in the frequency domain (0.04–0.15 Hz). Low-frequency power is regulated by baroreflexes as well as cardiac sympathetic and vagal origins

☑ Low-Frequency/High-Frequency Ratio (LF/HF ratio): Reflects a mixture of sympathetic and parasympathetic activity, but is influenced by many other factors. Its physiological origin is debated. The standard deviation of all R-R intervals (SDRR) quantifies all cyclic components of heart rate, reflecting overall autonomic cardiac regulation (depending on the length of the recording period)

Study Design: Triple Crossover, Comprehensive Validation of Safety and Efficacy

01 Core Protocol

The study enrolled 36 healthy participants (18 female, mean age 24 years), each completing 4 experimental sessions, using a triple crossover design of "stimulation type × stimulation side × metabolic state":

Stimulation type: Active taVNS (cymba conchae, an area with dense vagus nerve innervation) vs. sham stimulation (earlobe, where vagus nerve distribution is sparse);

Stimulation side: Left ear vs. right ear, directly comparing the cardiovascular effects of bilateral stimulation;

Metabolic state: Fasting state (before stimulation) vs. post high-calorie milkshake intake (approximately 400 kcal, during stimulation), simulating regulatory effects under different physiological conditions.  

Figure 1: Summary of the experimental schematic. (A) The timeline for each session includes a baseline phase (30 minutes, no stimulation) and a stimulation phase (30 minutes), when taVNS or sham stimulation is applied. Participants received a high-calorie load to challenge the autonomic nervous system, while we collected the post-caloric load phase (30 minutes) with simultaneous stimulation. (B) The cymba conchae electrode position for transcutaneous auricular vagus nerve stimulation (taVNS, red), with sham stimulation (blue) shown at the earlobe position. (C) Stimulation protocol schematic, bidirectional sinusoidal waveform at 25 Hz frequency, 250 microsecond pulse width, alternating 30 seconds on and 30 seconds off. The stimulation intensity (mA) for each participant was adjusted until they perceived a "slight tingling sensation."

02  Key Measurements and Blinding Control

Physiological indicators: Heart rate (HR) was continuously recorded via electrocardiogram (ECG), and 4 core HRV metrics (SDRR, RMSSD, HF-HRV, LF/HF ratio) were calculated to comprehensively reflect autonomic regulation function;

Blinding design: Participants were fully double-blinded to stimulation type, with post-experiment guessing accuracy of only 45.5%, comparable to chance level, thoroughly eliminating subjective bias;

Safety monitoring: Adverse events such as bradycardia and dizziness were recorded throughout to verify the safety of right-side stimulation.  

Core Findings: Three Conclusions That Overturn Conventional Understanding

01 No Additional Risk with Right-Side Stimulation, Bilateral Effects Are Consistent

The most critical finding of this study was that left and right taVNS showed no significant difference in their regulatory effects on HR and HRV, and no cardiovascular adverse events occurred throughout.

Bilateral stimulation did not induce bradycardia, and heart rate (HR) showed no significant change (BF₁₀=0.21);

The HRV-reducing effects of stimulation on both sides showed stronger correlation, suggesting that afferent signals from the auricular branch of the vagus nerve are integrated in the brain to regulate cardiovascular function, with no side-specific risk.

This result directly refutes the conventional belief that "right-side stimulation is more dangerous," confirming that right-side taVNS is as safe as left-side, providing more options for clinical application.

Figure 2:Vagus nerve stimulation on both sides showed no differences in heart rate and heart rate variability (SDRR, RMSSD, HF-HRV, LF/HF ratio). (A, B) Point representations of cardiovascular metrics show participants' mean scores for SDRR, RMSSD, HF-HRV, LF/HF ratio, and HR (taVNS — artifact of change from baseline), with group distributions showing no significant differences across stimulation and thermal load phases (left vs. right). (C, D) taVNS-induced changes in SDRR, RMSSD, HF-HRV, LF/HF ratio, and heart rate (red) showed stronger correlations across sides, while sham (blue) is represented by stars on the per-participant data correlation lines. (E) Correlation coefficients of cardiovascular indices across stimulation sides were higher after taVNS than after sham stimulation.

taVNS Does Not Affect Heart Rate, but Significantly Reduces HRV

Contrary to some studies concluding that "taVNS increases HRV," this study found:

Regardless of fasting or postprandial state, taVNS did not alter heart rate (HR), but significantly reduced HRV;

Specifically: time-domain SDRR (total cycle heart rate variability), RMSSD (root mean square of successive heartbeat differences), and frequency-domain HF-HRV (high-frequency heart rate variability, reflecting vagal modulation) were all significantly reduced;

The reductions in RMSSD (BF₁₀=15.11) and HF-HRV (BF₁₀=11.80) were supported by strong statistical evidence, indicating that this effect is stable and reliable.

Figure 3:Stimulation reduces heart rate (HR), while caloric load increases heart rate. (A) During stimulation, heart rate decreased across both sides (left vs. right) and both stimulation conditions (transcutaneous vagus nerve stimulation, red; sham stimulation, blue), as indicated by the p-values below the title. Through bootstrapped distributions of change relative to baseline, we observed no significant differences between stimulation conditions on each side. (B) After caloric load, heart rate increased across both sides (left and right) and stimulation conditions (transcutaneous vagus nerve stimulation and sham), as indicated by the p-values below the title. Through bootstrapped distributions of change relative to baseline, we observed no significant differences between stimulation conditions on each side. The dots depict the mean heart rate change relative to baseline for each participant during transcutaneous vagus nerve stimulation (red) and sham stimulation (blue).

Metabolic State Does Not Interfere with Effects — Effective in Both Fasting and Postprandial States

After high-calorie milkshake intake, participants' heart rate significantly increased (mean increase of 3.28 bpm), and some HRV metrics showed physiological changes, but the regulatory effects of taVNS were not affected:

Regardless of fasting or postprandial state, taVNS consistently reduced SDRR, RMSSD, and HF-HRV;

Even though the milkshake itself caused a reduction in HF-HRV, taVNS still exerted additional regulatory effects, demonstrating that its efficacy is independent of metabolic state fluctuations.

Figure 4:taVNS reduces HRV as indexed by SDRR, RMSSD, and HF-HRV. (A) Changes in SDRR, RMSSD, and LF/HF ratio under both stimulation conditions (taVNS vs. sham) before caloric load (left vs. right), indicated by p-values at the top of each panel. taVNS (red distributions) reduced SDRR, RMSSD, and LF/HF ratio in a side-specific manner compared to sham distributions (blue distributions), as shown by bootstrapped distributions of bilateral differences relative to baseline. Statistical data for taVNS-induced effects on both sides are shown below the panels. (B) Caloric load altered SDRR, HF-HRV, and LF/HF ratio but not RMSSD, across both sides (left vs. right) and stimulation conditions (taVNS vs. sham), as indicated by p-values at the top of each panel. taVNS under caloric load compared to sham showed reductions in SDRR, RMSSD, and HF-HRV as displayed by bootstrapped distributions.

Mechanism Interpretation: Not "Relaxation," but "Precise Arousal Regulation"

The traditional view holds that the core effect of vagus nerve stimulation is activation of the "rest-and-digest" mode, reflected by increased HRV indicating a relaxed state. However, the findings of this study propose a new interpretation:

By activating vagal afferent fibers, taVNS may participate in arousal level regulation rather than pure relaxation, which is consistent with previous findings that VNS can increase pupil dilation and enhance motivational drive;

The acute reduction in HRV is not a sign of functional impairment, but rather an adaptive regulation in response to demands, reflecting the flexible regulatory capacity of the autonomic nervous system, rather than the traditionally assumed "suppression of vagal activity."

This also explains the contradictions in previous studies — the varying effects of taVNS on HRV across different studies may stem from differences in stimulation parameters, measurement timing, or metric selection, whereas this study, through standardized design and multi-dimensional metrics, arrived at more reliable conclusions.

Research Significance: Opening New Pathways for Clinical Application

01 Theoretical Value

THEORETICAL VALUE

✦ First to clearly demonstrate that the core effect of taVNS on the cardiovascular system in healthy individuals is a reduction in HRV rather than a change in heart rate, correcting the conventional understanding that "taVNS increases HRV";

✦ Thoroughly resolving the controversy that "right-side stimulation is more dangerous," confirming that bilateral stimulation effects are consistent and safe, providing a standardized reference for future research.

02 Application Prospects

APPLICATION PROSPECTS

✦ Safety expansion: Right-side taVNS is as safe as left-side, with no concern for bradycardia risk, expanding the options for clinical application, especially for individuals with left ear injuries or discomfort;

✦ Scenario expansion: Since it is unaffected by metabolic state, taVNS has greater potential for cardiovascular regulation across different physiological scenarios, providing new approaches for non-invasive intervention in conditions such as hypertension and arrhythmia.

Conclusion

This study, published in Psychophysiology, not only dispels the long-standing clinical myth that "right-ear taVNS carries additional cardiovascular risk," but also clarifies the core regulatory patterns of non-invasive vagus nerve stimulation on the cardiovascular system through a rigorous randomized crossover design, removing key obstacles for both basic research and clinical application of taVNS. The study confirms that bilateral taVNS produces consistent and safe cardiovascular regulation effects, and its core effect of reducing HRV provides an entirely new perspective on the mechanisms of vagus nerve stimulation, giving us a more precise understanding of the interaction between the vagus nerve and the autonomic nervous system.

Of course, the study also has certain limitations, such as not including patient populations and using standard stimulation parameters. Future research should further explore the differences in effects across different populations and stimulation protocols, enabling more precise application of the cardiovascular regulatory effects of taVNS.

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