All posts tagged vagus nerve

The Brainstem, Vagus Nerve, Neuroinflammation and Chronic Fatigue Syndrome: The VanElzakker Way

In 2013, Michael VanElzakker produced one of the most intriguing hypotheses to date in ME/CFS. His Vagus Nerve Hypothesis proposed that an infection/inflammation near the vagus nerve was causing it to send an unending stream of messages to the brain, telling it to essentially shut the body down by producing fatigue, pain and other symptoms. Since then, he’s been particularly interested in the connection between the vagus nerve, the brainstem and the ME/CFS.

He’s not the only one interested in the brainstem. In 2019 once his brainstem compression was alleviated, Jeff completely recovered from his severe ME/CFS, POTS and MCAS. Since he published his story over a dozen people have been diagnosed with craniocervical instability – a condition which compresses the brainstem.

In this critical review paper, VanElzakker et. al. pick apart some of the research done and provide a guide to successfully getting at the brainstem and other regions of the brain. It’s called a “Critical Review” and is critical, indeed. It finds many past ME/CFS studies wanting, but then points a way to a better possible future. If brainstem problems play a role in ME/CFS these researchers demonstrate how to get at them.

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.  Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia. Front. Neurol., 10 January 2019 https://doi.org/10.3389/fneur.2018.01033 https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full

First, VanElzakker et. al. examines one of the sacred cows in the chronic fatigue syndrome (ME/CFS) community – the preferred term for so many: myalgic encephalomyelitis (ME), which refers to muscle pain (myalgia) related to central nervous system inflammation (encephalomyelitis).

While muscle pain is common, it’s not universal. Even people with severe ME may not report pain.

Still, the core part of the definition deals with central nervous system inflammation – a description that, with the emergence of the 2015 Yakatomi and the 2019 Younger studies, seems more and more likely to stick. (A 2018 PET scan study also found neuroinflammation in fibromyalgia as well.)

The idea that inflammation plays a key role in this illness makes sense, given the infectious trigger so commonly (but not universally) found. The authors are just a few among many (Avindra Nath, Jarred Younger, Andrew Lloyd and others) who believe that an infectious event has triggered changes in the brain that are producing fatigue, pain and other problems in ME/CFS.

They point to three ways an infectious trigger could produce central nervous system inflammation in ME/CFS:

A) immune factors (e.g. cytokines) triggered by the infection could get transported across the blood-brain barrier (BBB) that protects the brain. The normally taut blood–brain barrier makes blood-borne infections of the brain rare, but it can, like the gut, become leaky in inflammatory states, allowing immune factors and pathogens entry. Once in the central nervous system, they could trigger a large inflammatory response, or

B) High concentrations of immune factors could allow pathogens to passively diffuse across the BBB, or

C) Immune factors in the blood could trigger the vagus nerve to send signals to the brainstem and brain, which then sparks an inflammatory response.

It’s the last option that primarily concerns these authors. VanElzakker is the author of the Vagus Nerve Hypothesis, which proposes that an infection/inflammation near the vagus nerve is causing it to send an unrelenting stream of signals to the brain, telling it to produce the flu-like symptoms that constitute “sickness behavior” (withdrawal to bed), which isolates infected people from the community and keeps them from spreading an infection.

The largest nerve in the body, the vagus nerve transmits sensory, autonomic, immune and other signals to the brainstem – making it potentially a key player in a possible neuroinflammatory disease like ME/CFS.

Studies indicate that inflammation in the periphery tends to produce a mirror inflammatory response from the immune cells (the glia) in the brain. Even small levels of cytokines in the periphery or body have the potential to activate the chemoreceptors in the vagus nerve, which then activate the immune system in the brain.

That brain activation, interestingly, tends to occur in regions (basal ganglia, limbic system organs (amygdala, hippocampus and hypothalamus), anterior cingulate cortex, prefrontal cortex, and thalamus), which studies suggest are also involved in ME/CFS.

The Brainstem

brainstem

The brainstem regulates many vital functions in the body

The authors believe the brainstem (which, as it name implies, is found at the very base of the brain, above the termination of the spinal cord), could play a key role in chronic fatigue syndrome (ME/CFS) for four reasons:

  1. Immune signals from the vagus nerve to the brain travel through the brainstem.
  2. The brainstem is dense with mast cells, and mast cell activation syndrome (MCAS) appears to be common in ME/CFS.
  3. The brainstem regulates autonomic nervous system functioning – a common trouble area for ME/CFS and related disorders.
  4. The brainstem also regulates immune functioning; in particular, it triggers an anti-inflammatory response that should limit the inflammatory response.

Whether caused by a structural problem (as in Jeff’s case), inflammation or an infection, the brainstem is a centrally placed brain component that produces many of the issues in ME/CFS.

Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Brainstem Series

Seeing the Brainstem in Chronic Fatigue Syndrome (ME/CFS)

Consistent inflammation of the brainstem has not, however, been found in ME/CFS. The authors argue, though, that researchers have rarely used the right kind of imaging needed to investigate this.

The most commonly used method for measuring inflammation in the brain involves measuring the 18kD translocator protein (TSPO) with a PET scan. This protein is produced when the immune cells of the brain – the microglia – become activated. Because the microglia are the chief producers of inflammation in the brain, the TSPO provides a reliable way to indirectly measure neuroinflammation and its effects.

The Nakatomi Study

Nakotomi’s small ME/CFS study using TSPO made a big splash in 2014.   Tony Komaroff called the finding of central nervous system inflammation the most important study in decades. Five years later, Van Elzakker et. al. called it “important” and potentially “groundbreaking”. The study used TSPO imaging to find widespread neuroinflammation, particularly in the areas leading from the brainstem to the thalamus.

While the authors regard Nakatomi’s study as potentially groundbreaking, the study is not without significant issues. The authors, in fact, seemed a bit shocked that Nakatomi found as many effects as he did, given the techniques used.

The neuroimaging techniques Nakatomi used (and which most researchers use) were not designed to address brainstem inflammation. Nakatomi used a spatial “registration” technique that aligns the image on the neocortex or upper part of the brain. This kind of alignment is typically done because researchers tend to focus on the upper, “higher” functioning areas of the brain. It can, however, impair the sensitivity of imaging done on the lower, more densely packed, primitive areas of the brain, such as the brainstem, and lead to false negatives.

The PK-1195 tracer

Nakatomi also used an older tracer (PK-11195) which does not penetrate deeply into the brain and can bind to unintended elements in the brain. Differences in blood-brain barrier permeability between the ME/CFS patients and healthy controls – a distinct possibility – could have confounded the results, as well. Nakatomi’s use of the cerebellum as a kind of baseline measure could have introduced further issues if problems with the cerebellum (another possibility) exist in ME/CFS.

Plus, the hypometabolism believed present in ME/CFS could have resulted in lower amounts of the tracer being metabolized than usual – causing higher amounts of the tracer to reach the brain – and producing a false positive. Because exercise may affect how much of the tracer is taken up into the cells, Nakatomi’s use of healthy, non-sedentary controls instead of sedentary controls introduced another issue.

Finally, because the brainstem actually pulses with every heartbeat, that movement needs to be accounted for – and usually isn’t in ME/CFS studies.  The very small but important nuclei in the brainstem are also often not picked up with the standard imaging techniques used in ME/CFS research.

Nakatomi’s study results make sense given what we know, and were given a sort of validation by Jarred Younger’s recent results using thermal mapping – a new technology – but we need more validation.

The takeaway is that the brainstem – because of the role it plays in autonomic nervous system functioning, immune regulation and the transmission of motor signals – could play a major role in ME/CFS, but is essentially, according to these authors, still something of a black box.

Barnden’s Brainstem – the Australian Study

It’s not completely a black box, though. Researchers using other techniques have found evidence of brainstem problems in ME/CFS. Barndem in Australia, in particular, has done a series of MRI studies which have found striking brainstem issues in ME/CFS.

(During his talk at the 2019 Emerge conference, Barnden noted how he had to shift his MRI to avoid the alignment problem (that VanElzakker mentioned) which prevented him from getting a good image of the brainstem. )

One study found that reduced brainstem grey matter volume – suggesting that damage to the neurons in the brainstem had occurred – was correlated with autonomic nervous system problems in ME/CFS.

Barnden brainstem damage ME_CFS

Using the right imaging approach Barnden found extensive evidence of damage to the neurons (myelin) in the brainstem. (From the 2019 Emerge Conference Livestream)

Another study finding of impaired communication from the brainstem nuclei to other nuclei in the brain suggested the same, and found increased signs of myelination in the sensorimotor cortex of the brain.  Barnden proposed that decreased signaling from a damaged brainstem provoked a compensatory increase in myelination in the sensorimotor region as it bulked up to try to understand the limited signaling coming from the brainstem. The impaired brainstem-sensorimotor connection might be, Barnden thought, impacting motor functioning in ME; i.e. the ability to carry out physical activity.

Signals to move muscles pass from the motor cortex to the sensorimotor cortex down to the thalamus and then through the brainstem to the muscles. (Signals from the muscles to the brain pass up through the same pathways.) Barnden proposed that the movement problems in ME/CFS could start with the brainstem’s inability to properly relay signals to the motor cortex to activate the muscles.

Barnden’s most recent brainstem study validated the idea that inadequate communication between the brainstem nuclei and other nuclei in the brain, including the vasomotor region, hypothalamus and prefrontal cortex, was affecting autonomic nervous system functioning in ME/CFS.

Other Kinds of Brain Scans

Other kinds of brain scans, such as magnetic resonance spectroscopy (MRS), can pick up signs of neuroinflammation. Although almost 10 MRS studies of the brain in ME/CFS have been done, VanElzakker et. al. report that a clear and consistent picture of metabolite alterations in the brain has yet to emerge.

They believe that’s due largely to a common theme in medical research, found in this disease in particular – lack of standardization. Different diagnostic criteria, different types of healthy controls, different brain regions examined, and different metabolites targeted make it difficult to present a clear picture of the metabolic alterations in the brains of people with ME/CFS.

The Japanese Take

The Japanese probably couldn’t agree with Barnden more. Their studies indicate that, as the healthy controls became more fatigued, two core regions – both of which communicate with the brainstem ( the prefrontal cortex and the anterior cingulate cortex) – shut down.

As these regions begin to shut down, control of autonomic functioning becomes lost.  In particular, the ability to activate the parasympathetic nervous system (i.e. the vagus nerve) and tone down the sympathetic nervous system activity, is lost.

The Japanese believe a breakdown in what they call the facilitation system in the brain has occurred.  As we become fatigued, the facilitation system jumps in to increase the signals coming from the primary motor cortex to the muscles. This increased “drive” from the motor cortex prompts the muscles to work harder and activates more and more of them so that activity can proceed.

Fatigue – the Japanese Way: A Chronic Fatigue Syndrome Perspective

So long as new, fresh muscle fibers remain to be recruited, the activity can continue.  If no muscle fibers are left to be recruited or if the brain has a problem recruiting new muscle fibers, fatigue sets in.

A 2003 study suggested that reduced muscle recruitment due to reduced motor cortex output was indeed occurring in ME/CFS. That study suggested that, “… changing motor deficits in CFS has a neurophysiological basis [which] … supports the notion of a deficit in motor preparatory areas of the brain”.  That study titled, “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“, to my knowledge was never followed up on.

Fatigue Explained? Japanese Assert Brain Damage Causes Fatigue in Chronic Fatigue Syndrome

Conclusion

Several studies suggest significant brainstem issues may be present in ME/CFS. Problems with the brainstem could produce everything from autonomic nervous system problems to immune issues to problems with movement.

The authors critique past brain imaging studies and provide a “how to” guide to assess the brainstem in ME/CFS. Barnden’s Australian brainstem studies suggest that when done correctly, MRI imaging studies may indeed find extensive damage is present in ME/CFS including evidence of brainstem neuron demyelination, a compensatory remyelination in parts of the brain the brainstem connects with, and lastly, a reduced connectivity between these regions.

VanELzakker et. al.  assert that future imaging studies that focus on the specific functional connectivity pathways in the brain which are activated by inflammatory processes should be able to capture the neuroinflammatory processes occurring in ME/CFS.  (Two of the three pathways they cite include the brainstem.) The thalamus’s role in sensory stimuli activity presents another fruitful pathway to assess.  Lastly, the authors suggest that researchers target the nucleus of the solitary tract (NTS) where the vagus nerve enters the brainstem.

With help from an ME/CFS donor, VanElzakker has been employing brain imagining techniques to assess the brainstem in chronic fatigue syndrome (ME/CFS). He will be speaking at the NIH ME/CFS Conference in Baltimore in April.

Michael VanElzakker Ph.d Talks – About the Vagus Nerve Infection Hypothesis and Chronic Fatigue Syndrome (ME/CFS)

 An Interview with Michael VanElzakker Ph.d

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Van Elzakker’s hypothesis could explain several of the mysteries associated with chronic fatigue syndrome

Michael VanElzakker’s Vagus Nerve Infection Hypothesis (VNIH) for Chronic Fatigue Syndrome may be the most intriguing hypothesis to come along in the last twenty years.  If it’s correct it could explain several mysteries including how a virus might trigger the disease and then seemingly disappear, why the Lipkin study failed to find an active infection, why cytokine studies have trouble finding evidence of the ‘never-ending cold’, why when antivirals work they often take so long to do so.

It’s raised a lot of interest. Now Michael VanElzakker ‘sits down’ and answers some questions about it.

Background

What is your background? When did you get interested in this subject and start  developing this hypothesis? 

I am a neuroscientist. I mostly focus on posttraumatic stress disorder (PTSD), which I consider to be very different from CFS and a separate arm of my research interests (although there are many interesting overlaps between the views of CFS and PTSD within our culture).

sick person

A sick friend prompted his interest in this disorder

However,  I got my bachelor’s and master’s at the University of Colorado – Boulder, at a time when the Psychology & Neuroscience department there was very focused on psychoneuroimmunology-related phenomena. Some of the many research programs there related to neuropathic pain, cytokines, and the vagus nerve. All it took was for someone who was thinking about CFS to be exposed to these different literatures and to start fitting them together.

I started thinking about CFS because I have a sick friend. She got sick back when CFS was viewed even more skeptically than it is today – I remember one MD referring to it as “yuppie flu.” I knew that my friend was not malingering – why would she be? She had to put her life on hold. It was pretty devastating.

The focus on the vagus nerve is simply because that organ is responsible for symptoms during “normal illness” that strongly overlap with CFS symptoms.

Testing the Theory

Apparently imaging techniques are not able yet to find localized infections in the vagus nerve. How far are they from being able to that? Is there interest in developing those kinds of techniques?

You reported that  PET scans have shown ‘promise’ in identifying activation of the microglia – a prominent part of your theory. (The VNIT proposes chronic microglial activation causes the vagus nerve to send signals to the brain that result in flu-like symptoms.)  It seems that we could settle the VNIH theory right now if PET scans showed clusters of infected areas around the vagus nerve. How effective are PET scans at doing something like this now?

I’ll answer these two questions together. As far as the effectiveness of PET scans finding local vagus infection: We don’t know. That’s part of what my group is trying to work on. There are a lot of technical problems that will require pilot testing.

PET Scan

Most PET scans are done of the brain. VE would like to do one further down in the vagus nerve area

One of the big problems is that PET scans cost thousands of dollars per hour. It’s difficult to convince funding agencies to give us money to pilot test a method so that we can even begin to ask questions about a hypothesis that may or may not be accurate. But I’ve got some really good people on my team and we’re working on it.

There’s interest because of this hypothesis, but most imaging of the vagus nerve thus far has been at the level of the brain, trying to understand the mechanism of vagus nerve stimulation for epilepsy or depression. We’re trying to image it farther down.

If someone made an animal model of the hypothesis, that would help raise interest. I laid out a protocol in the paper for creating an animal model; I hope somebody with a rat lab takes the idea and runs with it. I’m not jealously guarding these ideas, I put them in the paper in the hopes that other groups would work on them too.

You suggested that future CFS research  use radiolabeled antibodies to localize clusters of specific virus types. This is done to find tumors. Is it possible to radiolabel antibodies so that they pick up clusters of infection in the body?

Yes, it is. But there are several problems to this with regards to the VNIH of CFS. One is that antibodies are specific, but CFS could be caused by a number of different pathogens. So, we could flood someone’s body with radiolabeled antibodies against HHV-6, but maybe in that specific case, their symptoms are caused by HHV-4 (Epstein–Barr).

Another problem is that some of the pathogens that might be most likely to cause CFS are found in the vast majority of humans. So, radiolableled antibodies against HHV-1 would find a signal in most people, but only cause CFS if the viruses are in a vagus (para)ganglion. And the vagus nerve is so highly branched, that could be all over the trunk. Another problem is that antibodies cannot always get inside ganglia, which are immunoprivileged. But despite all of that, I still think it’s a research program that is worth pursuing.

Treatment

Herpesviruses apparently love to set up house in the sensory ganglia, but you suggest that antiviral drugs might have trouble getting to them and destroying them there. Why is that?

drugs

Antivirals may take much longer to work in ME/CFS because they have difficulty accessing the vagus nerve where the viruses are present

Similarly to how the central nervous system has a blood-brain barrier (BBB), peripheral nervous system ganglia are immunoprivileged. According to the hypothesis, the frequent failure of drug therapy and also one’s own immune system to eliminate infections within vagal ganglia and paraganglia is just like how some drug doses and antibodies do not penetrate the BBB.

You noted that behavioral/stress management therapies such as CBT are moderately effective in about 30% of people with chronic fatigue syndrome, and that CBT resulted in lower viral loads and improved immune functioning in HIV. Why would this be?

Stress causes a cytokine response. So, if someone who doesn’t like public speaking is giving a presentation, their immune system is generating a cytokine response. If such a person even thinks about giving a presentation, they are likely to generate a cytokine response.

People with CFS have an authentic reason to be concerned about any activity that requires physical exertion, and it’s called post-exertional malaise: worsened symptoms after exertion.

According to the vagus nerve infection hypothesis (VNIH), there is a physiological reason behind post-exertional malaise: Exercise provokes muscle tissue to produce the proinflammatory cytokine IL-6, which would then exacerbate the ongoing  local cytokine response within vagus nerve ganglia or paraganglia. That’s the hypothesized mechanism behind post-exertional malaise.

The CBT practitioners in the infamous PACE study were focused on avoidance/fear of activity because they began with the assumption that CFS is psychological. They think the fear of activity itself is the cause of CFS; I’d say that fear of activity is justified, but like all fear, it can become dysfunctional. For the vast majority of their patients, CBT did not help. The three out of ten that found some slight improvement may have used CBT to figure out exactly what level of activity they should be worried about. So, the moderate improvements they reported in a minority of patients were probably related to stress reduction.

In patients with HIV, reducing something like stress that taxes the immune system is bound to help a little bit.

I understand that this is a really charged topic among CFS advocates, and there is a lot of misinformation out there. Just to be clear, cognitive-behavioral therapy (CBT) does not get at the root cause of CFS. CBT offers coping strategies and is not a cure. But I can’t think of a single medical condition that isn’t exacerbated by stress. CFS is no different. Having a chronic illness is stressful and it makes one’s life complicated and there’s a grieving process. CBT is for those parts of the illness. It’s intended to help people solve problems and to challenge dysfunctional patterns. If you’re seeing a CBT practitioner who views CFS as a psychologically-based illness and is approaching your CBT that way, fire them. Find someone else.

While CBT can help people with serious and chronic medical problems, it should be used as an adjunct and not a primary treatment. It would be crazy, for example, for a doctor to prescribe CBT instead of chemotherapy for cancer. But chemotherapy is a known, empirically tested treatment for cancer. CFS doesn’t have such a thing yet.

stress

Behavioral practices like CBT that reduce stress can be helpful in immune mediated diseases such as HIV and ME/CFS, but are adjunct, not primary therapies

Without a cure, the next best thing is to focus on quality of life. I am very much focused on finding an explanation for CFS, which would then lead to a cure. I have hypothesized that CFS is a neurological illness triggered by a foreign pathogen infecting the vagus nerve. But the fact is that stress has profound impact on immune system function. CBT for CFS patients can reduce stress, which is one mechanism of action to improve symptoms.

I should also say – CBT sometimes gets conflated with graded exercise therapy as well. Some studies have combined these two techniques but they are not the same thing. In the paper I gave an example of a treatment regimen that included graded exercise therapy.

Again, to be clear, if the VNIH is correct and some combination of glial inhibitor, antivirals and vagus nerve stimulation can be used to quell symptoms, then and only then does it make sense to begin graded exercise therapy. At that point, the root cause of CFS symptoms has been dealt with, and the next priority is to deal with muscle deconditioning which is not an insignificant factor in ongoing symptoms.

I absolutely do not condone forcing still-sick patients to exercise if it’s making their symptoms worse. This should be obvious.

Others

The heart rate variability evidence suggests the parasympathetic nervous system (vagus nerve) is under-activated in ME/CFS while the sympathetic nervous system is over-activated.  The SNS activation, in fact, may be due to the PNS’s inability to rein it in.  The increased heart rate at rest, for instance, could be due to be due to the inability of the vagus nerve to slow it down. In your theory, though,  the vagus nerve appears to be activated by the localized infection.  I’m a bit confused.

ANS

Is an infection contributing to the autonomic nervous system problems in ME/CFS?

This has to do with the fact that the vagus nerve is a mixed cranial nerve, meaning it has both sensory (afferent, or towards the brain) and motor (efferent, or away from the brain) divisions. Its parasympathetic influence over the body results from efferent activity; its function in detecting peripheral infection and triggering sickness behavior results from afferent activity.

However, terms like over-active and under-active are a bit too simplified – what matters is that the nerve is able to respond and signal appropriately, to be able to create a functional signal-to-noise ratio.

Researchers have been looking for cytokines in ME/CFS for decades. Sometimes they find them, sometimes they don’t. When they do find them sometimes research groups find similar cytokines and sometimes they don’t. The one constant is that they keep looking. You mentioned that lung infections are also not associated with increased cytokine levels in the blood.  Are there many other infections like this?

Well, to be more accurate, it’s not necessarily that lung infections won’t show a cytokine response in the blood. It’s more that we cannot be certain to find a cytokine response from a local infection – that is, any local infection. If a lung infection were severe enough, you might find cytokines in the blood. Cytokine studies are quite prone to false negatives, and it’s a mistake to infer from a negative cytokine blood test that there is no cytokine response happening anywhere in the body.

In studies that look for cytokines in blood, there are 3 relevant questions:

  1. Is there any cytokine response in the first place?
  2. Did that cytokine response diffuse into peripheral blood?
  3. Did the method of detection work?
IL-1B

VE notes the difficulties present in finding a cytokine response in an infectious disease

The question we’re interested in is #1, however it’s a big assumption that the answers to #2 and #3 are “yes” when we infer from a negative blood test that there is no cytokine response.

Those of us who think that CFS is not psychologically-based tend to think there’s an immune dysfunction of some sort. People have been looking for cytokines because they are an obvious potential link between the immune system and CFS symptoms, but a lot of studies have ignored how cytokines work.

If a research group is unfamiliar with the cytokine literature they may have also made some easy mistakes in the cytokine assay – the actual lab methods for looking for these proteins.

For example, cytokines are relatively labile, meaning unstable. If someone who didn’t know any better stored their blood samples in a refrigerator instead of a -80° freezer, you can bet they did not find cytokines. If blood samples went through freeze-thaw cycles, the cytokines will also start to denature (break down). There are definitely a lot of really good researchers who have looked into cytokines, but the literature can get muddied pretty easily by bad studies. And because the symptoms are systemic, most people have been thinking in systemic terms (i.e., not thinking about a localized infection causing CFS).

In general, I’m skeptical of any attempts to find a “cytokine profile” for CFS or any other infectious disease. That doesn’t mean it can’t be done, but it’s difficult. Cytokine responses are very complex, they interact with each other and they change in daily and hourly rhythms. You could study one individual and not find a “cytokine profile” unless you took several samples a day for many days.

Response to the Hypothesis and the Future

This is a really intriguing theory. Kristin Loomis of the HHV-6 Foundation was excited by it.  Have you gotten much response from it? 

I’ve actually been really pleasantly surprised by the response. I’ve had the idea for quite a long time, and spent a lot of time and effort trying to set up a collaboration with a rat lab, to create an animal model. To make a very long and frustrating story short, nothing worked out.

people networking

The response to VE’s hypothesis has been very positive; he is working on putting a study together to test his hypothesis

I’ve been telling anybody who would listed about the hypothesis. It’s not like doors were getting slammed in my face, but most people simply didn’t have a background in the different literatures that the hypothesis ties together.

It wasn’t until recently that I discovered this unique journal, Medical Hypotheses, so I made some time to write up the idea. It gave me a forum to really give people the background they needed to understand the idea, and allows people to check the citations themselves. Based on past experience, I thought I’d have to keep cold-calling researchers to push the hypothesis. But it really took off right away.

I put it up online for free, and it’s been downloaded over 1000 times there; I don’t know how many people have downloaded it from the publisher through a university or hospital subscription. I’ve heard from researchers from 5 continents. Somebody translated the paper into Dutch and put it up online.

The week the paper came out, Anthony Komaroff contacted me, we’ve been in contact since. He finds the hypothesis to be “provocative and plausible” and shares my hope that functional imaging can help to shed some light on it. I’ve been in contact with a lot of other well-known CFS researchers, and I think the idea is at least changing the way that some people think about the problem.

VanElzakker

Van Elzakker will be at the IACFSME conference with a poster presentation of his hypothesis

I also know that the paper is already being taught at some universities and medical schools, so hopefully it will at least get young scientists to start thinking about CFS. I hope people start to think about new CFS findings through the lens of this hypothesis because in my experience, it explains a lot of phenomenology.

Even if the hypothesis doesn’t turn out to be accurate, or is only partially accurate, I hope that it gets us closer to effective treatments that are actually attacking the root causes of CFS symptoms and not just helping people cope with them.

Some reports suggest you’re engaged in a pilot study. Can you comment on that?

On the record, I’d just say that I’ve put together a really great team to pursue the VNIH and that Dr. Komaroff is part of it. There are a lot of technical issues but we’re hoping to use functional imaging to gain enough preliminary data that we can pursue it further.

 

 

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Big Theory

It could explain the Chronic Fatigue Initiatives pathogen study results.  It could show how an infection could cause chronic fatigue syndrome, and then seemingly disappear.  It integrates two of the biggest players in ME/CFS; the autonomic nervous system and the immune system. It focuses on the herpesviruses. It includes sensory nerves, an increasingly hot topic in ME/CFS/FM, and it follows an  established model of fibromyalgia.

light bult

If it’s correct VanElzakker’s hypothesis could explain a lot about chronic fatigue syndrome

It’s the Vagus Nerve Infection Hypothesis (VNIH) for chronic fatigue syndrome, and it could change how this disorder is viewed, researched and treated.

Created by Michael VanElzakker, a Tufts neuroscientist,  the VNIH proposes that nerve loving viruses trigger a difficult to detect  immune response which produces the fatigue and other symptoms present in chronic fatigue syndrome.

Location, Location, Location

VanElzakker proposes that an infection triggers ME/CFS, but if his theory is right the most important thing about that infection is not what it is but where it is.   That ‘where’  is the biggest nerve in the body; the vagus nerve – a ‘wandering nerve’ that stretches over much of our torso and sends its roots into most of the organs of the body.

The vagus nerve isn’t just any nerve; it’s the nervous system’s immune conduit to the brain. VE believes that an infection there doesn’t need to be large to cause havoc in the brain; it just needs to be present.

In some ways, vagus nerve appears, in fact, to be ripe for infection in ME/CFS. As it ‘wanders’ through the body it comes into contact with virus havens such as the esophagus, stomach, lungs and spleen, all of which have likely at one time or another harbored the herpesviruses (HHV6, HHV-5 [cytomegalovirus], HHV-4 [Epstein-Barr virus]) that have been thought to be associated with ME/CFS for decades.

Most humans carry several of these herpesviruses in latent form unless some stressor or biological event allows them to become reactivated.

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Van Elzakker suggests ME/CFS is caused by localized infections associated with the vagus nerve

VanElzakker believes that upon reactivation these viruses replicate and move outside the nerves where they run into glial cells that attempt to gobble them up.  The glial cells perk up remarkably in the presence of viruses, releasing all manner of pro-inflammatory and neuroexcitatory compounds (proinflammatory cytokines [IL-1B, IL-6, TNF-a], glutamate, prostaglandins, nitric oxide and free radicals. )

Receptors on the vagus nerve that sniff out these alarm signals tell the brain an infection is present, which then shuts the body down by sending out  signals  (fatigue, flu-like symptoms, pain, etc.) that slow the body down, tell it to stop moving, stop eating, stop thinking.

Because these infections are localized right on the main immune conduit to the brain, VanElzakker believes they don’t need to produce the outsized cytokine response researchers have been looking for.   All they need to do is tweak the vagus nerve and let it and the brain the do the rest.

You don’t need a ‘big’ infection to produce ME/CFS; all you need is a little infection  in the right place.

The Key Component – Glial Cells

The glial cells that surround and protect the vagus nerve are the key. Once thought to be mere structural scaffolding for the nerves, these cells  (e.g., astrocytes) are  now known to regulate nervous system signaling, a fact that’s been borne out in chronic fatigue syndrome’s sister disease,  fibromyalgia.

Immune system

VE believes pathogen triggered,but localized immune system activation around the vagus nerves may be causing ME/CFS

Glial cell  release of cytokines, glutamate, free radicals, etc.  in the dorsal horn of the spinal cord causes  increased pain sensitivity and allodynia in susceptible individuals. At some point the constant production of these excitatory substances  causes  a switch to get flipped sending the pain response spiraling upwards instead of shutting down.

At its most extreme (allodynia), the nervous system can interpret even the slightest touch as eliciting pain.   The pain response  system at this point, as VanElzakker, puts it,  has become, ‘pathological’.

That model of pain production has been solidly documented. VanElzakker proposes the same process  causing pain sensitization in the dorsal horn is  causing fatigue and other symptoms in chronic fatigue syndrome, except this time it’s associated with glial cells surrounding the vagus nerve.

A New Model of Fatigue

There is no  reason to suspect  that vagus-nerve associated glia would function any different than pain associated glia. VanElzakker

Nobody knows what a herpesvirus infection  of the vagus nerve would look like,  but VanElzakker doesn’t see any  reason it should look any different  from an infection in other parts of the body.

shingles

Herpesvirus infections of the trigeminal nerve cause shingles. Do herpesvirus infections of the vagus nerve cause chronic fatigue syndrome?

We know a  herpesvirus infection of your trigeminal nerve gets you shingles and chronic pain.  Researchers believe a chronic infection in the dorsal horn of your spinal cord will can  get you fibromyalgia and allodynia.  Would  an  infection of the vagus nerve get you sickness behavior and  chronic fatigue syndrome?

There’s a good chance it might.  Animal studies indicate that fatigue/flu-like symptoms go gangbusters when the vagus nerve gets infected. In fact, it’s  possible  the flu-like symptoms associated  with infections wouldn’t even exist without the vagus nerve.  Rodents with their vagus nerves cut don’t act sick even after they’ve been infected with a pathogen; the fevers, fatigue, the desire for isolation – are gone.

What if the vagus nerve receptors were…ceaselessly bombarded with these cytokines?  The symptoms of sickness behavior would be severe and intractable.

If the glial cells surrounding the vagus nerve function the same way they do in the dorsal horn, a lingering or even a ‘smoldering’ infection (aka Dr. Lerner’s theory), could trigger the similar type of hypersensitive reaction in the vagus nerve. In this ‘immune sensitization’ model, it takes only very small amounts of cytokines to trigger fatigue and flu-like behavior.

In fact, VanElzakker suggests chronic fatigue syndrome and fibromyalgia could both be ‘glial cell diseases’.

How to Have an Infection That Doesn’t Show Up in the Blood

“Cytokines Responding to a Local Infection Stay Local” VanElzakker

If VanElzakker is right, the  same group of viruses are wreaking  havoc in different locations in different ME/CFS patients.  The problem is it’s just darn hard to get at them.  You can’t find them in the blood and you sure as heck can’t biopsy the vagus nerve.

A series of fascinating studies exploring how central nervous system infections cause chronic nerve pain may, however, illuminate what’s happening in ME/CFS.  First, researchers mimicked a localized nervous system infection by dropping an HIV protein known to activate glial cells  into rodents’  spinal cord.

mouse

The vagus nerve is the immune conduit to the brain; mice studies suggest it plays a key role in producing ‘sickness behavior’

They found that the glial cells  reared up and starting producing pro-inflammatory cytokines to take care of the intruder. Not surprisingly,  the rodents looked and acted sick – the cytokines were doing their job to keep the animal down and isolated – but  no trace of those cytokines could be found  in their bloodstream.  Only if the animal’s spinal cord was sampled near where the ‘infection’ was  it possible to find any evidence of increased cytokine levels.

If VanElzakker is right, then blood  cytokine levels in ME/CFS are a function of where your vagus nerve is infected. If it’s infected in your  abdominal area, you might find cytokines in the blood, but it might be hard to find them in your spinal fluid. If your vagus nerve is infected near your brainstem you might find cytokines  in the spinal fluid, but you probably won’t find them in your blood.

Wherever the infection is there’s a good chance you may not find cytokines in the blood  at all.  This isn’t a  completely surprising fact or even restricted to the vagus nerve infections; cytokines in  mice with lung infections, for instance, showed up only when the lungs themselves were sampled.

Next Steps

VanElzakker suggests animal studies to better understand infections of the vagus nerve and to ultimately to build a chronic fatigue syndrome rodent model would be helpful.  Magnetic resonance imaging (MRI) may be able to detect viral lesions in central nervous system tissues. It is not yet known if  PET scans can detect the activation of a different type of glial cells; the satellite glia that are in vagus nerve ganglia and paraganglia, but special PET scans might be able to be used to assess microglial activation.

Cadaver studies of people who had ME/CFS definitely aren’t his first choice, but they could find activated glia, inflammation and viral infections of the vagus nerve and associated structures.  Finally,  novel protocols should be developed to assess the vagus nerve and brainstem functioning in ME/CFS.  The severely ill should be given a prominent place in future studies.

 

prescription drugs

If VanElzakker is correct different treatments could be in store for people with ME/CFS

A New Treatment Approach

“Glial cell inhibitors could become standard treatment for CFS (caused by CNS vagus nerve infection)” VanElzakker

Glial Cell Inhibitors

If VE’s theory is correct then glial cell inhibitors to stop the immune activation, antivirals to attack the pathogens, vagus nerve stimulation and surgical alteration of the vagus nerve might be possible treatments sometime in the future.

Glial cell inhibitors have a good safety profile, have been helpful at curbing neuropathic pain and are not used much in chronic fatigue syndrome or fibromyalgia.

ibudilast

If VanElzakker is right then Ibudilast, a drug in clinical trials now for another disorder, is a possibility.

Ibudilast (AV411/MN166), a drug used mostly in Japan, knocks down glial cell activation by inhibiting the production of a proflammatory cytokine called macrophage-migration-inhibitory factor (MIF)  and TNF-a.  Reduced levels of TNF-a could provide a bonus by increasing the breakdown of  a excitatory neurotransmitter called glutamate that may be helping to keep your central nervous system on edge.

Ibudilast is also  known to have neuroprotective and vasodilative effects and is usually used to treat asthma and stroke. It’s ability to suppress glial cell activation has made it useful in the treatment of neuropathic pain, and it’s currently undergoing clinical trials to treat neuropathic pain in Australia.  Ibudilast can also prevent viral activation of the microglia.

The NIH is funding Ibudilast trials in the US to see if it’s effective against drug addiction. If successful the drug could be available here for off-label use in ME/CFS  in three or four years.

Other general microglial inhibitors exist (minocyline, pentoxyfilline, propentfylline) but have undesirable side effects.

Antivirals

Stopping glial cell activation may be easier than getting at the viruses themselves.  Herpesviruses living in the sensory ganglia may be protected from antiviral drugs and antibodies.  (One new herpesvirus drug may be coming on the market soon, however.) Alternately, viruses other than the herpesviruses could be infecting the vagus nerve.

Behavioral Therapy

VanElzakker also notes that while behavioral therapies are not curative and may only apply to a subset of patients, they can help moderate symptoms and improve quality of life in some.

Conclusion

The VNIT may be able to explain more puzzling aspects of chronic fatigue syndrome than any other.  Next up we talk with Dr. VanElzakker about how he got interested in ME/CFS and what his theory may mean for this disorder.