Vagus nerve stimulation changes brain chemistry, hinting at therapeutic potential

A recent study published in Psychophysiology provides new insights into how stimulating the vagus nerve through the ear might influence brain function. Researchers found that a single 30-minute session of transcutaneous auricular vagus nerve stimulation (taVNS) led to notable reductions in a specific protein associated with synaptic activity in rats. This change was observed in key brain areas linked to cognition, motor control, and mood regulation.

However, the study did not find changes in glucose metabolism, a marker of overall brain activity. These findings contribute to the growing body of research suggesting that non-invasive vagus nerve stimulation could have therapeutic potential for neurological and psychiatric disorders.

The vagus nerve is a critical part of the nervous system that connects the brain to various organs, including the heart, lungs, and digestive tract. It plays an essential role in regulating bodily functions such as heart rate, digestion, and inflammation. Because of its widespread influence, researchers have been investigating how electrical stimulation of this nerve might help treat conditions such as epilepsy, depression, and chronic pain. Traditional vagus nerve stimulation (VNS) involves implanting a device that delivers electrical impulses directly to the nerve. While effective, this method requires surgery and carries risks of complications.

More recently, scientists have been exploring a less invasive alternative: transcutaneous auricular vagus nerve stimulation (taVNS). This method uses electrodes placed on the skin of the ear, an area connected to a branch of the vagus nerve. Early studies suggest that taVNS may provide similar benefits to implanted VNS but without the need for surgery. However, the mechanisms behind taVNS remain unclear. To better understand its effects on the brain, the researchers in this study used a combination of advanced imaging techniques and animal models.

“We have studied brain stimulation modalities in animal models in our lab for several years and have looked at the effects on brain neurotransmission using PET imaging in an attempt to unravel the therapeutic mechanisms relevant to diseases like depression and Parkinson’s disease,” explained postdoctoral researcher Karina Binda and Associate Professor Anne Landau of the Translational Neuropsychiatry Unit at Aarhus University.

“Transcutaneous auricular vagus nerve stimulation (taVNS), which has shown some potential as a treatment for neurological disorders, became particularly interesting to us since the current is administered via an ear clip, making it non-invasive with no requirement for surgery or electrode implant.”

The researchers worked with 24 female Sprague–Dawley rats, a commonly used laboratory species. They divided the rats into two groups: one received real taVNS, while the other underwent a sham treatment where electrical stimulation was applied to a different part of the body (the foot) as a control measure. The stimulation lasted 30 minutes, targeting the left ear in the taVNS group.

To measure changes in brain activity, the researchers used two types of positron emission tomography (PET) imaging. One technique used a tracer called [11C]UCB-J to assess levels of synaptic vesicle glycoprotein 2A (SV2A), a protein found in presynaptic nerve terminals that plays a role in neurotransmitter release. Higher SV2A levels typically indicate more active synaptic connections. The other technique used [18F]fluorodeoxyglucose ([18F]FDG) to measure glucose metabolism, a standard marker of overall brain activity.

Each rat underwent imaging twice—once before stimulation (baseline) and once after. By comparing the two sets of images, the researchers were able to assess the impact of taVNS on brain function.

“Given the potential therapeutic utility of taVNS, we conducted a small brain imaging study in healthy rats where we aimed to determine the short-term effects of a single taVNS,” the researchers explained. “We used microPET, an approach that relies on the administration of radioactive-labeled molecules to study specific changes in the living brain and investigated brain glucose metabolism and how synaptic connections change in response to taVNS.”

The main finding was that taVNS led to significant reductions in SV2A levels in several brain regions, including the frontal cortex, striatum, and midbrain. These reductions ranged from 36% to 59%, suggesting that taVNS affects synaptic function in multiple areas of the brain. Importantly, the decrease in SV2A was observed on both sides of the brain, even though stimulation was applied only to the left ear. This suggests that taVNS has widespread effects on neural activity rather than being limited to the directly stimulated area.

“The bilateral reduction in our measure of synaptic density binding was surprising, despite the stimulation being unilateral, which suggests a more widespread initial effect than had been originally anticipated,” Binda and Landau told PsyPost.

In contrast, the study found no significant changes in glucose metabolism. This result suggests that while taVNS may influence synaptic activity, it does not cause broad shifts in overall energy use in the brain—at least not in the short term.

“It was also intriguing that these changes in our synaptic marker occurred without significant alterations in brain glucose metabolism, suggesting that taVNS may acutely influence neurotransmitter systems rather than overall metabolic activity,” the researchers said. “However, it is possible that the effects of chronic taVNS will induce different effects, and this needs to be explored in future studies.”

These findings provide new insights into how taVNS might work at the molecular level. The observed reduction in SV2A levels could indicate that taVNS influences neurotransmitter release, potentially altering communication between brain cells. Given that synaptic dysfunction is implicated in various neurological and psychiatric disorders, these changes could be relevant for understanding how taVNS might exert therapeutic effects.

“Our preliminary findings suggest that even a single administration of taVNS can modulate brain function at the synaptic level, which could have implications for treating neurological and psychiatric disorders,” Binda and Landau explained. “This should be seen as a starting point for future studies, where the mechanisms of taVNS are explored in the living brain.”

One important limitation is the small sample size, which means the findings need to be confirmed in larger studies. Additionally, the study only included female rats, so it is unclear whether the results would be the same in males. Future research should explore whether sex differences influence the effects of taVNS.

Another limitation is that the study only looked at the immediate effects of a single session of taVNS. It is possible that repeated or long-term stimulation could lead to different or more pronounced effects on brain function. Future studies could investigate whether chronic taVNS produces lasting changes in synaptic activity and whether these changes translate into behavioral or cognitive improvements.

Finally, while the study focused on synaptic density and glucose metabolism, other biological markers may also be relevant. Future research could examine whether taVNS influences inflammation, neurotransmitter levels, or other aspects of brain function.

“In the field of brain stimulation and neuroimaging, we are currently studying changes in the binding of our synaptic density PET marker in a minipig model of Parkinson’s disease in response to acute and chronic deep brain stimulation,” Binda and Landau said.

“In the context of non-invasive brain stimulation, our goal is to investigate the effects of both acute and chronic taVNS in preclinical disease models, particularly for conditions like Parkinson’s disease and depression where modulation of synaptic density could be beneficial. We aim to provide more robust preclinical data on the mechanisms of taVNS that can pave the way for its use as a therapeutic intervention for central nervous system disorders.”

The study, “Acute transcutaneous auricular vagus nerve stimulation modulates presynaptic SV2A density in healthy rat brain: An in vivo microPET study,” was authored by Karina H. Binda, Caroline C. Real, Mette T. Simonsen, Ebbe K. Grove, Dirk Bender, Albert Gjedde, David J. Brooks, Anne M. Landau.