Jiangxi Puzhuo Medical Equipment Co., Ltd

However, for a long time, there has been a lack of direct comparative studies on the differences in regulatory effects on cerebral and cardiac physiological activities between the two, and their mechanisms of action have not yet been fully clarified. A latest study published in Brain Stimulation in 2025, for the first time, used a rat model to systematically compare the immediate effects of cVNS and aVNS on electrocardiogram (ECG) and electroencephalogram (EEG), providing critical experimental evidence for the safe clinical application and device development of VNS technology.

I. Research Background: The Urgent Need to Fill the Gap in VNS Regulatory Differences

The brain-regulatory effects of VNS have long been confirmed by research — for example, VNS can induce changes in cortical EEG oscillations and activate widespread brain region activity — but these studies have mostly focused on cVNS and have not systematically analyzed the response characteristics of different brain regions.

Meanwhile, the invasiveness of cVNS in clinical practice is accompanied by potential cardiac electrical risks. Although the non-invasive nature of aVNS offers greater advantages, whether its EEG activation effects differ from those of cVNS, and whether it possesses unique brain regulatory characteristics, has yet to be supported by direct experimental data.

Based on this, the core objective of this study was to: clarify the immediate regulatory effects of cVNS (invasive) and aVNS (non-invasive) on rat brain electrical activity, and monitor the cardiac electrical effects of both, laying the foundation for the safe application and mechanism research of VNS.

II. Experimental Design: Standardized Animal Model, Focused Dual-Indicator Brain-Heart Monitoring

This study used 8-week-old male Sprague-Dawley rats as experimental subjects, conducted with approval from the Animal Ethics Committee. All stimulation targeted the left vagus nerve of the rats, with core monitoring of two dimensions — ECG and EEG — and sample sizes and detected brain regions were clearly defined:

1. ECG detection: aVNS group n=3, cVNS group n=4, analyzing heart rate and atrioventricular conduction changes under different frequencies and intensities of stimulation;

2. EEG detection: aVNS group n=11, cVNS group n=5, recording EEG signals from the rat medial prefrontal cortex (mPFC), somatosensory cortex (S1), and parietal association cortex (PtA), analyzing changes in EEG power across different frequency bands.

III. Core Results: cVNS and aVNS Show Significant Differences in Brain-Heart Regulation

The study clearly revealed the differences in regulatory characteristics between cVNS and aVNS from both cardiac and cerebral electrical perspectives, with the safety differences in cardiac electrical effects and the specific cerebral regulatory effects becoming the core findings.

01 Cardiac Electrical Level: cVNS Has Significant Heart Rate Effects, aVNS Is Safer for Cardiac Electrical Activity

◼ cVNS: At stimulation frequencies of 20, 30, and 60 Hz, heart rate decreased significantly; and the regulatory effect of stimulation frequency on heart rate was significantly greater than that of stimulation intensity, with heart rate decreasing more markedly as frequency and intensity increased; when the stimulation frequency exceeded 20 Hz, rats exhibited atrioventricular block (disappearance of QRS waves), indicating a clear cardiac electrical risk.

◼ aVNS: At all tested frequencies, no significant changes in heart rate were observed, with no cardiac electrical abnormalities. The study confirmed that the essence of this difference is that the auricular vagus nerve consists only of afferent sensory fibers and cannot directly activate the parasympathetic nervous system that regulates the heart, whereas cVNS directly stimulates the cervical vagus nerve containing efferent fibers.

Additionally, the study mapped the heart rate change profiles of cVNS at different frequencies and intensities, providing clear experimental guidance for safe stimulation parameters of cervical vagus nerve stimulation.

02 EEG Level: Both Activate Cortical Brain Regions, aVNS Shows Gamma Band-Specific Regulation

cVNS and aVNS share common features in EEG regulation, while aVNS demonstrates unique frequency band regulatory advantages, overturning the preconceived expectation that "invasive cVNS produces stronger brain activation effects."

◼ Common features: Both significantly increased EEG power in the mPFC, S1, and PtA brain regions, with the somatosensory cortex (S1) showing the most significant activation effect, followed by the medial prefrontal cortex (mPFC) and parietal association cortex (PtA); no significant differences in EEG responses were observed between the left and right hemispheres of the rat brain.

◼ Specific differences: aVNS significantly increased gamma wave power in the S1 region, and this effect was present at all stimulation parameters of 1, 10, 30, and 60 Hz; although cVNS could also increase gamma wave power in the S1 region, the difference was not statistically significant compared to other frequency bands.

Gamma waves are closely related to the perception and processing of sensory information in the brain, and their activation involves a complex brain network of the somatosensory cortex, prefrontal cortex, and parietal cortex, which also provides a new target direction for the mechanism of VNS in treating neurological diseases.

Figure D:Normalized increase in EEG power across different frequency bands in each brain region of the right hemisphere during VNS. Upper panel: aVNS-induced EEG power changes in the medial prefrontal cortex (mPFC), somatosensory cortex (S1), and parietal association cortex (PtA); Lower panel: cVNS-induced EEG power changes in mPFC, S1, and PtA(* indicates p < 0.0125 after α correction)

IV. Research Value: Filling the Gap, Providing Three Key Supports for VNS Technology Translation

This study, published in a neuromodulation journal, is the first to directly compare the immediate EEG effects of cVNS and aVNS across extensive cortical regions in rats. Its results provide multiple key supports for VNS basic research and clinical translation, and also have important guiding significance for the R&D of neuromodulation medical devices:

1. Defining the cVNS Safety Threshold

For the first time, the association between cVNS stimulation frequency/intensity and heart rate/atrioventricular block was quantified, providing experimental evidence for the parameter design and safe clinical application of invasive vagus nerve stimulation devices.

2. Highlighting the Clinical Potential of aVNS

It was confirmed that the cortical activation effect of non-invasive aVNS is comparable to that of invasive cVNS, with no cardiac electrical risk, laying the core experimental foundation for the application of aVNS in long-term, non-invasive neuromodulation scenarios.

3. Discovering aVNS-Specific Regulatory Targets

The specific activation of gamma waves in the S1 region by aVNS was clearly identified, providing new therapeutic targets and technology directions for neurological diseases related to abnormal sensory information processing, such as migraine, tinnitus, and traumatic brain injury.

V. Clinical and Device R&D Implications: Precise Differentiation, Leveraging Respective Strengths

The results of this study have direct guiding value for the R&D of vagus nerve stimulation medical devices and the selection of clinical application scenarios, indicating clear directions for industry development:

(1) cVNS R&D and Application

Development should focus on precise frequency/intensity modulation modules to avoid the risk of atrioventricular block above 20 Hz. Clinical applications require simultaneous real-time ECG monitoring, making it suitable for scenarios with high-intensity demand for brain regulatory effects where invasive procedures and cardiac monitoring are acceptable.

(2) aVNS R&D and Application

As a non-invasive technology, its dual advantages of cardiac electrical safety and specific EEG activation make it the preferred direction for large-scale, long-term neuromodulation. Development should focus on portable non-invasive aVNS devices targeting diseases such as migraine, tinnitus, and obesity, with parameter optimization focused on somatosensory cortex gamma wave regulation.

(3) Clinical Indication Selection

For neurological disease patients with comorbid cardiovascular disease, aVNS is the safer choice; for scenarios such as brain injury requiring rapid and potent brain region activation, cVNS can be used under strict cardiac monitoring.

Summary and Outlook

This study is the first to systematically compare the immediate regulatory effects of cVNS and aVNS on rat brain and cardiac activity, clearly revealing the core characteristic that "invasive cVNS carries cardiac electrical risk while non-invasive aVNS shows EEG specificity," filling the research gap in this field and providing critical experimental data for the basic mechanism research and clinical translation of vagus nerve stimulation technology.

For the neuromodulation medical device industry, this study provides clear experimental evidence for the parameter design and safety management of cVNS and aVNS devices; at the clinical level, it also lays the foundation for the selection of indications and the development of individualized treatment plans for VNS technology.

In the future, with the conduct of large-sample animal experiments and human clinical trials, as well as research on the long-term regulatory effects of VNS, cVNS and aVNS will further achieve precise and personalized application in the treatment of neurological diseases, and non-invasive vagus nerve stimulation is expected to become one of the mainstream technologies in the field of neuromodulation, leveraging its advantages of safety and convenience.