Let’s talk about nerves, baby! Vagus Nerve Stimulation opens new frontiers in medicine

In the last 200 years, medicine has achieved great advances. However, some conditions – e.g. Alzheimer’s and certain cardiovascular diseases – still lack adequate treatment, while others – like epilepsy, depression, and chronic pain – can be treatment resistant. This is where electrical nerve stimulation comes in.

Electrical stimulation can be applied to different nerves[1], [2] but is most widely used to modulate functioning of the vagus nerve. Vagus nerve stimulation is a relatively new therapeutic method, therefore extensive understanding of its action mechanisms is still missing,[3] and a comprehensive literature database on the subject is only being developed. Nevertheless, modern medicine has already recognized the potential of this treatment to remedy a growing number of physiological and psychological disorders. Its effectiveness for a multitude of conditions is currently being tested.

Whereas invasive vagus nerve stimulation (VNS) has been used to treat refractory conditions for nearly 20 years, its non-invasive counterpart (tVNS) was approved for medical use only some 5 years ago.[4] Both techniques provide promising results for a variety of diseases, but transcutaneous vagus nerve stimulation (tVNS) is associated with considerably less side effects. tVNS seems to be an effective and well tolerated method, which can make the benefits of the vagus nerve stimulation widely available to those seeking medical help.

Vagus: your “most multifunctional” nerve.

Vagus is your cranial nerve no. X (yes, cranial nerves are denoted with Roman numerals). Vagus is special because – unlike other cranial nerves that are concerned with head and neck functions – it carries information from and to internal organs, such as lungs, heart, liver, and intestines.[5] Its ascending pathways transmit a number of interoceptive signals to the brain, e.g. temperature, pain, inflammation, stretch, and pressure. On the other hand, the descending pathways regulate functioning of the inner organs. Vagus is involved in cardiovascular, respiratory, gastrointestinal, endocrine, and immune processes; it plays a prominent role in the autonomic nervous system.[6]

With all of these wonderful functional properties, no wonder vagus has become a major research focus when it comes to electrical stimulation.

internal_organs_cropped
Vagus nerve regulates many internal organs, among them the heart, lungs, liver, spleen, kidneys, stomach, pancreas, and larynx. Image retrieved from Wikipedia under CCO Public Domain licence.

Some history.

The first attempts at vagus nerve stimulation were done in the treatment of epilepsy at the end of the 19th century. They aimed at reducing cerebral blood flow, which was believed to cause epilepsy at that time. Hence, the patient experienced no improvement, but the technical foundations for VNS were laid. The method was picked up again in the 1950s and, at the turn of the century, was approved by the American Food and Drug Administration for treatment resistant epilepsy and treatment resistant depression.[4] Since then, the VNS technique has continuously been refined and improved, but the year 2010 saw a breakthrough – first transcutaneous vagus nerve stimulation device received CE certification.[7]

How vagus nerve stimulation works.

Generally, there are two types of electrical nerve stimulation: direct and transcutaneous.

Direct vagus nerve stimulation (VNS) is an invasive procedure performed under general anesthesia. Three coil-formed electrodes (cathode, anode, and tether) are attached to the nerve at the neck level. The leads connect them to the electrical stimulator, which is placed in the chest area or under the collar bone. Various parameters, such as stimulation frequency and intensity, as well as the ON- and OFF-time, are programmed externally with the help of a computer. This method allows to change the stimulation parameters in the course of the treatment, or to temporary switch off the device completely.[4], [8], [9]

On the other hand, transcutaneous vagus nerve stimulation (tVNS) is applied over the skin. Two types of devices are currently in use, targeting either auricular or cervical branch of the vagus nerve. In the former case, electrical pulse generator is placed on the pinna of the ear, where the auricular branch of the vagus nerve runs very close to the skin. In the latter case, the device targets the cervical branch of vagus in the neck area.[4]

What is vagus nerve stimulation good for?

VNS is currently widely used for refractory epilepsy and depression.[4] Since vagus is implicated in the immune function, it can reduce inflammatory responses. This makes VNS potentially very useful for treating conditions which involve inflammation, such as rheumatoid arthritis, stroke, inflammatory bowel diseases, and cardiovascular diseases.[10], [11], [12], [13] Extensive research is currently conducted on VNS as a treatment for such diseases as bipolar disorder, obesity, Alzheimer’s disease, cerebellar tremor, involuntary movement disorders, traumatic brain injury, asthma, and gastrointestinal disorders.[4]

VNS is a potentially powerful but invasive technique, so its use is limited to disorders which cannot be treated with any other currently available method. In contrast, a great advantage of tVNS is its non-invasiveness. tVNS can be self-administered, which makes its use more flexible. In addition, if the device malfunctions or the therapy is not well tolerated, no surgery is required to fix this. Research shows that tVNS produces similar brain activity patterns to those generated by VNS, which indicates that these techniques could have comparable effects[4]

tVNS was approved in Europe for treatment of epilepsy, depression, and chronic pain. A growing body of research indicates that effectiveness of tVNS in treating epilepsy is similar to that of VNS.[14], [15], [16] VNS has already been shown to influence cortical plasticity and memory.[17], [18] However, tVNS could be useful in this area, too. Just one session of tVNS was demonstrated to boost associative memory in older adults.[19]

depression-free
VNS has been used to treat depression for some 20 years. But because it’s an invasive procedure only a relatively small number of patients could be subjected to it. tVNS could make this method available to a much broader audience. Retrieved from https://pixabay.com under CCO Public Domain licence

tVNS produces very promising results in treating chronic pain conditions, such as allodynia (perception of pain from non-painful stimuli, e.g. touch), chronic headaches (migraines, cluster headaches, hemicrania continua, and medication overuse headache), pelvic pain, and fibromyalgia. This technique can decrease hyperalgesia and central sensitization, common to many of pain disorders, as well as increase thresholds for mechanical and pressure pain. Interestingly, tVNS only decreases pain perception at higher stimulation intensities. If stimulation intensity is low, responses to painful stimuli will be potentiated instead.[20]

Furthermore, tVNS shows great potential to remedy gastrointestinal disorders, asthma and other respiratory diseases, and a number of psychological conditions, such as panic disorder, posttraumatic stress disorder, major depression, and obsessive compulsive disorder.[4]

tVNS vs. Depression – 1:0. [21]

Major depression is one of the greatest health problems leading to disability worldwide. The relapse rates are high and this disorder is often nonresponsive to currently available treatments. VNS has already been approved for the intractable form of depression, but a study by Fang et al. (2016) is taking this approach further by looking at the effects of tVNS on mild and moderate depression.

Depression is associated with abnormalities in functional connectivity of areas typically associated with reaction to stress, reward, self-representation, and emotional processing. Hence, the question for Fang and colleagues was whether tVNS is able to reduce depressive symptoms on the behavioral as well as on the neural level.

To investigate this, 34 participants with mild to moderate depressive disorder were divided into two groups: tVNS-group and sham-group. Both groups received training and had to self-administer tVNS/sham at home for an hour a day during the 4-week period. The process was identical for all participants. However, the tVNS-group was told to attach the electrodes to the inner part of the pinna where many vagus branches are located, whereas the sham-group was instructed to apply the device to the outer part of the ear, with no vagus distribution in that area.

Assessment of depressive symptoms and fMRI scanning sessions were conducted before the intervention (as baseline) and after the 4-week period. After the treatment, the tVNS-group demonstrated significantly reduced depression and anxiety symptoms in comparison to the sham-group. Moreover, functional connectivity of areas associated with depression was also modulated by the tVNS, and these changes were associated with the decrease in clinical symptoms.

As it is often the case, further research is needed, especially given that this study was neither randomized nor double-blind. Nevertheless, current results indicate that tVNS could be a well-tolerated, effective treatment providing relief for people suffering from major depression by regulating the brain function and influencing the neural signature of this disorder. [21]

af3
Though VNS is generally considered well tolerated, it is still associated with quite a few possible adverse effects. Contrary, the non-invasive tVNS is a much safer method. Retrieved from https://pixabay.com under CCO Public Domain licence

The other side of the coin: adverse effects of VNS.

So, VNS sounds great, doesn’t it? But another important aspect also deserves our attention: the adverse effects. Since VNS requires a surgical procedure, it is associated with more adverse reactions than its non-invasive relative tVNS.

Intraoperative complications include bradycardia (when the heart beats too slow), vagus nerve trauma, and peritracheal hematoma – a condition that might need another surgical intervention to be resolved and increases the risk of developing other unpleasant conditions, such as vocal cord dysfunction and dyspnea (difficulty breathing). And of course, don’t forget about infection, which is always lurking in the shadows waiting for a chance to get into the incision. Nevertheless, the risk of intraoperative complications is relatively low and problems are usually resolved by removing the device.[3], [4], [20]

Some postoperative stimulation-induced complications are also possible and are usually resolved by changing stimulation parameters or within 1-2 years of treatment.[3] They include voice alterations (ca. 66% of patients are affected), cough, paresthesia, and pain. Furthermore, exposing the VNS device to a radiofrequency transmitter coil – such as those in MRI, ECT, and defibrillator – can be dangerous and should be avoided, since induced heat can damage the vagus nerve, adjacent structures, or the device itself.[4], [20]

In addition, the chances are high that one would need a revision surgery for battery replacement, lead malfunction, or poor efficacy among other issues.[22]

In contrast, tVNS seems not to cause any arrhythmic reactions.[4] tVNS could lead to skin irritation, muscle stiffness, paresthesia, dizziness, and pain. These adverse effects are, however, mild to moderate and usually resolve within a short time without special treatment. Since tVNS does not require surgery, it does not produce any intraoperative adverse reactions. In addition, stimulation related side effects are also greatly reduced because tVNS employs shorter duration of stimulation. All in all, it is considered a much safer, well tolerated option and can be administered to a broader circle of patients.[3]

In case you are horrified by such a list of possible side effects – don’t be too fast to judge! Watch this video to get the taste of what we usually disregard when taking medication.

Summing it up.  

VNS is a relatively new advancement, so a lot about this method still remains to be elucidated and proved. However, a growing body of evidence shows its ability to remedy conditions, many of which currently lack adequate treatment.

Its non-invasive relative tVNS probably follows the same action mechanisms, providing a safer option with comparable efficacy. It is likely to become the research focus in the nearest future. The use of tVNS would eliminate many side effects associated with VNS and allow electrical vagus stimulation to be performed without the risks of perioperative complications, thus making it possible for a much greater number of patients to benefit from this technique.

References

  1. Gross,T., Schneider, M. P., Bachmann, L. M., Blok, B. F., Groen, J., A‘t Hoen, L., Castro-Diaz, D., Fernández, B.P., Del Popolo, G., Musco, S., & Hamid, R. (2016). Transcutaneous Electrical Nerve Stimulation for Treating Neurogenic Lower Urinary Tract Dysfunction: A Systematic Review. European urology

  2. Trevizol, A. P., Taiar, I., Malta, R. C. R., Sato, I. A., Bonadia, B., Cordeiro, Q., & Shiozawa, P. (2016). Trigeminal nerve stimulation (TNS) for social anxiety disorder: A case study.Epilepsy & Behavior, (56), 170-171.

  3. Ben‐Menachem, E., Revesz, D., Simon, B. J., & Silberstein, S. (2015). Surgically implanted and non‐invasive vagus nerve stimulation: a review of efficacy, safety and tolerability.European Journal of Neurology,22(9), 1260-1268.

  4. Yuan, H., & Silberstein, S. D. (2015). Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II.Headache The Journal of Head and Face Pain.

  5. Breedlove, S. M., Watson, N. V., & Rosenzweig, M. R. (2010). Biological Psychology: An Introduction to Behavioral, Cogitive, and Clinical Neuroscience (6th ed.). Sunderland, Massachusetts: Sinauer Associates, Inc.

  6. Yuan, H., & Silberstein, S. D. (2015). Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I.Headache The Journal of Head and Face Pain.

  7. Kreuzer, P. M., Landgrebe, M., Husser, O., Resch, M., Schecklmann, M., Geisreiter, F., F., Poeppl, T.B., Prasser, S.J., Hajak, G., & Langguth, B. (2012). Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study.Frontiers in Psychiatry, Frontiers in Neuropsychiatric Imaging and Stimulation,3, 70.

  8. VNS_Informationsblatt. (n.d.). Charite: Klinik für Psychiatrie und Psychotherapie. Retrieved from http://psychiatrie.charite.de/patienten/behandlung_von_depressionen/stimulationsverfahren/

  9. Vagus Nerve Stimulation. (n.d.). Freiburg Epilepsy Center: Department of Neurosurgery. Retrieved from https://www.uniklinik-freiburg.de/epilepsy/therapy/vagus-nerve-stimulator.html

  10. Yuan, H., & Silberstein, S. D. (2015). Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III.Headache: The Journal of Head and Face Pain.

  11. Fujita, T. (2016). Therapeutic Potentials of Enteric Nerve Activation with Vagus Nerve Stimulation.Journal of the American College of Surgeons,222(1), 103-105.

  12. Olshansky, B. (2016). Vagus nerve modulation of inflammation: cardiovascular implications.Trends in cardiovascular medicine,26(1), 1-11.

  13. Li, P., Liu, H., Sun, P., Wang, X., Wang, C., Wang, L., & Wang, T. (2016). Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats.Experimental gerontology,74, 43-55.

  14. Bauer, S., Baier, H., Baumgartner, C., Bohlmann, K., Fauser, S., Graf, W., Mayer, T., Schulze-Bonhage, A., Steinhoff, B.J., Weber, Y., & Hartlep, A. (2016). Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02).Brain Stimulation.

  15. He, W., Jing, X., Wang, X., Rong, P., Li, L., Shi, H., Shang, H., Wang, Y., Zhang, J., & Zhu, B. (2013). Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial.Epilepsy & Behavior,28(3), 343-346.

  16. Stefan, H., Kreiselmeyer, G., Kerling, F., Kurzbuch, K., Rauch, C., Heers, M., M., Kasper, B.S., Hammen, T., Rzonsa, M., Pauli, E., & Ellrich, J. (2012). Transcutaneous vagus nerve stimulation (t‐VNS) in pharmacoresistant epilepsies: A proof of concept trial.Epilepsia,53(7), e115-e118.

  17. Borland, M. S., Vrana, W. A., Moreno, N. A., Fogarty, E. A., Buell, E. P., Sharma, P., Engineer, C.T., & Kilgard, M. P. (2016). Cortical map plasticity as a function of vagus nerve stimulation intensity.Brain stimulation,9(1), 117-123.

  18. Larsen, L. E., Wadman, W. J., van Mierlo, P., Delbeke, J., Grimonprez, A., Van Nieuwenhuyse, B., Portelli, J., Boon, P., Vonck, K., & Raedt, R. (2016). Modulation of Hippocampal Activity by Vagus Nerve Stimulation in Freely Moving Rats.Brain stimulation,9(1), 124-132.

  19. Jacobs, H. I., Riphagen, J. M., Razat, C. M., Wiese, S., & Sack, A. T. (2015). Transcutaneous vagus nerve stimulation boosts associative memory in older individuals.Neurobiology of aging,36(5), 1860-1867.

  20. Chakravarthy, K., Chaudhry, H., Williams, K., & Christo, P. J. (2015). Review of the uses of vagal nerve stimulation in chronic pain management.Current pain and headache reports,19(12), 1-9.

  21. Fang, J., Rong, P., Hong, Y., Fan, Y., Liu, J., Wang, H., Zhang, G., Chen, X., Shi, S., Wang, L., & Liu, R. (2016). Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder.Biological psychiatry,79(4), 266-273.

  22. Couch, J. D., Gilman, A. M., & Doyle, W. K. (2016). Long-term Expectations of Vagus Nerve Stimulation: A Look at Battery Replacement and Revision Surgery.Neurosurgery,78(1), 42-46.

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