With an enormous potential therapeutic gain and a high safety profile, further development and application of VNS is encouraging. Yuan et. Al
Vagus nerve stimulation is one of the most promising chronic pain interventions under development today. An earlier blog on Health Rising featured an astonishing story of a woman whose very severe fibromyalgia was largely ameliorated by a vagus nerve stimulator implant.
She was part of a small 2011 study which suggested that VNS may be very effective in fibromyalgia. The study was small but the success rate was high. Dr. Natelson, a neurologist who’s been treating and researching FM and ME/CFS for decades said:
“The results blew me away. I have never seen an effect as powerful as this.”
Many of the participants in that study no longer met the criteria for FM after it: that’s a criteria for success that few FM studies are willing to even contemplate using.
The study also required the surgical implantation of a vagus nerve stimulator. That’s an option – running somewhere around 30-40K – that’s available to few. Thankfully non-invasive vagus nerve stimulators worn on the ear have and are being developed.
When a recent three part review did an overview of our understanding of what the vagus nerve does, how vagus nerve stimulation works and how it effective it is, I jumped on it. This blog took the following papers as a foundation.
- Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I. Yuan H, Silberstein SD. Headache. 2015 Sep 14. doi: 10.1111/head.12647. [Epub ahead of print] Review.
- Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II. Yuan H, Silberstein SD. Headache. 2015 Sep 18. doi: 10.1111/head.12650. [Epub ahead of print] Review.
- Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III. Yuan H, Silberstein SD. Headache. 2015 Sep 14. doi: 10.1111/head.12649. [Epub ahead of print] Review.
Besides the fibromyalgia study, the vagus nerve is of particular interest in both fibromyalgia and chronic fatigue syndrome (ME/CFS) because of the role it plays in
- regulating the autonomic nervous and immune systems
- providing sensory and other information to the brain and
- Michael Van Elzakker’s Vagus Nerve Hypothesis – Van Elzakker suspects small infections in or around the vagus nerve could be triggering it to tell the brain to produce flu-like symptoms in people with chronic fatigue syndrome (ME/CFS). A pilot study to assess that possibility is underway now.
Called the wanderer, the vagus nerve is the longest “cranial nerve” (a nerve that emanates from the head) in the body. Attaching at the medulla at the bottom of the brainstem, the many fingers of the vagus nerve reach down our torso to infiltrate most of our organs. The extensive network it forms – it’s the largest neural network in the body – provides a pathway through which information is sent to the brain regarding the status of our organs.
Vagus nerves densely innervate every ‘sensing area’ of the body with a particular focus on the walls of the blood vessels throughout the body and the digestive system. The vagus nerve regulates our heart and breathing rates, blood pressure and blood flow via receptors in the blood vessels that monitor O2, CO2, and pH levels in the blood and blood pressure.
In the gut the vagus nerve controls gut movements (motility), secretions, inflammatory responses, the integrity of the gut lining and even appetite. Reflexive movements like coughing, gagging and vomiting are all controlled by the vagus nerve.
If a pathogen is present the vagus nerve will let your brain know that. If you’ve cut your finger, are feeling hot or cold, or have just eaten something – the vagus nerve will let your brain know that.
Ultimately information on touch, heat/cold, pain and chemical, metabolic, and hormonal operations of the organs is all transmitted via the vagus nerve to the brain. It effects the functioning of every system – from the immune to endocrine to the hormonal system – in our body.
The last ten or twenty years have revealed that the vagus nerve (VN) is a significant immune system regulator. The cholinergic anti-inflammatory immune response it regulates mostly takes place in the spleen.
Think of the spleen as an enormous lymph node which dictates much of the innate or early immune response. Besides filtering blood the spleen synthesizes antibodies, removes bacteria and plays host to half the monocytes found in the body. These monocytes – which turn into dendritic cells and macrophages play a key role in the innate or early immune response, which plays a key role in producing many inflammatory states.
The cholinergic anti-inflammatory response has been shown to reduce the levels of a wide variety of inflammatory cytokines. Studies are underway to assess the ability of VNS to reduce inflammation in diseases such as rheumatoid arthritis and inflammatory bowel disease.
Autonomic Nervous System Regulator
The vagus nerve’s effects on autonomic nervous system functioning could easily account for the benefits thus far seen in fibromyalgia and other pain disorders. The vagus nerve boosts the activity of the parasympathetic nervous system (rest and digest) and reduces sympathetic nervous system (fight or flight) system.
Reduced heart rate variability findings suggest that reduced parasympthetic nervous system functioning is present in both ME/CFS and FM. Reduced HRV has been associated with increased sympathetic nervous system activity, pain and sleep and cognitive problems in ME/CFS and/or FM.
Because VNS increases heart rate variability it’s possible that besides reducing pain it could also improve sleep and cognition.
Vagus Nerve Stimulation
Vagus nerve stimulators use electrical pulses to increase vagus nerve functioning. The vagus nerve runs up and down the neck. The stimulators contact the vagus nerve either by being surgically implanted in the neck or by non-invasive devices worn on the ear or neck.
The first vagus nerve stimulators attempted to interrupt epileptic seizures in the late 1890’s. Those attempts largely failed, and it was not until the 1990’s that the researchers felt confident enough to attempt it again in humans. In 1997 the FDA approved a surgically implanted device in the neck for people with treatment resistant epilepsy. In 2005 treatment resistant depression joined the list. Since then more than 70,000 people have received surgically implanted vagus nerve stimulators.
VNS stimulation is currently being assessed in a wide variety of diseases and conditions including heart disease, inflammation. Crohn’s disease, depression, stroke, tinnitus, diabetes, migraine, irritable bowel syndrome and others.
The first hints that VNS might helpful in reducing pain came when epilepsy patients reported experiencing reduced pain.
VNS may be effective with chronic pain because it’s able to effect a wide variety of factors that contribute to it including inflammation, oxidative stress, autonomic nervous system activity, the opioid response, central sensitization, and pain perception.
Studies indicate that VNS may be able to reduce the process of “temporal summation” that plays a crucial role in the production of many chronic pain states. Temporal summation refers to the windup mechanism that causes the nervous system to become more and more sensitive to pain.
During wind-up the nervous system learns to respond more and more quickly to the slightest hint of pain signals. VNS appears to help the CNS to unlearn this process in a manner that allows VNS, unlike other therapies, to become more effective over time.
The poor response to opioid pain drugs found in a significant portion of people with fibromyalgia could have its roots in vagus nerve problems. It turns out that good responses to opioids only take place in people with healthy vagal nerve activity.
Non Invasive Ways of Stimulating the Vagus Nerve
Two non-invasive means of stimulating the vagus nerve at the ear and the neck have been produced.
The NEMOS stimulator that attaches to the ear was approved for epilepsy and depression in 2010, and pain in 2012 in Europe. Imaging studies indicate the ear device has similar effects on the brain as the invasive device.
A similar device in the U.S. called the NET 1000 is being currently marketed as a microcurrent/music therapy device by a private company named Aura Stim Medical. The company markets the device, which costs $650.00, as a music therapy device for migraines and other disorders. It has been assessed in three studies.
The company believes that the electrical frequencies and audio signals the device delivers can induce the secretion of pain reducing substances such as beta-endorphins and neurotransmitters such as serotonin and dopamine. The device, which can be hooked up to a smartphone, is marketed to people with migraine and other types of headaches, premenstrual syndrome and/or depression, anxiety, and stress related to chronic pain.
The gammaCore device produced by a New Jersey company ElecroCore LLC has been cleared in Canada and parts of Europe to treat severe headache (migraine, cluster), reactive airway diseases (asthma, COPD, exercise induced bronchospasm), epilepsy, IBS, gastric mobility disorders and panic disorder, PTSD and other mood disorders. It appears to be able to inhibit glutamate expression in the trigeminal nerve in the head in migraine.
The Gamma Core Device
Three gammaCore headache studies were published in 2013 and 2014 and the company states three more are underway.
Another device that can be placed on the skin overlying the vagus nerve on the neck and then activated several times a day has been cleared to be clinically tested in an ME/CFS-like disorder.
The vagus nerve encompasses a complex system. It carries autonomic, sensory, metabolic and other information to the brain via afferent nerve fibers. It also regulates autonomic and other activity (heart rate, blood pressure, blood vessel functioning, gut activity, secretions, immune functioning, etc.) via efferent brain fibers leading to the organs.
Given the vagus nerve’s widespread effects, altering its activity has the potential to affect many processes and diseases. The expensive and invasive nature of surgically implanted vagus nerve stimulators has undoubtedly, however, interfered with its more widespread adoption. (Even in the two diseases VNS has been approved for, it’s approved only for treatment resistant versions of them.)
As noted above non-invasive means of VNS stimulation have been and are being developed, but studies are few. The few studies that have been done suggest the invasive and non-invasive devices producing similar effects on the autonomic nervous system and brain.
Vagus nerve technology is continuing to evolve. Miniaturized devices are being tested in rheumatoid arthritis. A heart failure device able to unidirectionally activate vagus nerve fibers is being tested as well. It’s the only device, thus far, able to activate only the nerve fibers going from the brain to the body. It specifically activates the B-fibers leaving the brain that stimulate parasympathetic nerve activity.
Researchers are becoming able to identify which frequencies work best in which diseases, as well. The anti-inflammatory response of the vagus nerve, for instance, is best triggered at specific electrical frequencies (5Hz, 15-20 Hz.).
It’s clear that intensity matters as well. High voltage VNS stimulation can cause low blood pressure, low heart rates and bronchoconstriction, while low voltage stimulation can reduce bronchoconstriction without effecting the heart rate at all.
Research on the non-invasive vagus nerve stimulators that might be affordable for FM and ME/CFS patients is still in its infancy however, with most of the studies being done in the last couple of years. They appear to be mostly produced by small companies doing relatively small trials.
Natelson’s experience in this field may be instructive. His and Gudrun Lange’s ability to produce a small trial of surgically implanted stimulators in FM was remarkable given the expense and newness of the technology to FM.
It stopped there, however. It’s remarkable to me, given the excellent results of the study, that five years later no followup has occurred. It hasn’t been for the lack of trying.
The NIH turned down Natelson’s request for a followup study because the study would not reveal more about the mechanisms at work. (The NIH apparently does not fund clinical trials to determine treatment efficacy!)
No FM VNS studies are in progress that I know of either. Efficacy, as we’ve seen in ME/CFS, does not always translate into more studies.
A non-invasive VNS study, that will, however, begin soon in an ME/CFS-like disease could provide a bridge to further ME/CFS and FM studies, and gammaCore may be available in the U.S. soon.
More on the Vagus Nerve
For more on the use of vagal nerve stimulation including past blogs, and how to possibly use a TENS unit to stimulate the vagus nerve visit Health Rising’s Vagus Nerve Resource page.
Other Means of Increasing Vagus Nerve Activity
Breathing slowly in and out through the nose, some yoga practices, gentle resistance breathing and other practices may be able to stimulate the vagus nerve as well.
After years of work it’s time to attempt what we’ve never been able to do before – get Congress to force the NIH to double its funding for ME/CFS. Support the historic bill to increase research funding, add new ME/CFS research centers, require the development of a strategic plan, etc.. It will take less than 5 minutes.