Chronic fatigue syndrome from vagus nerve infection: psychoneuroimmunological hypothesis

Ecoclimber

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Available online 18 June 2013
Chronic fatigue syndrome from vagus nerve infection: A psychoneuroimmunological hypothesis
Michael B. VanElzakker
Tufts University Psychology, Massachusetts General Hospital Psychiatric Neuroscience, 490 Boston Avenue, Medford, MA 02155, USA

http://dx.doi.org/10.1016/j.mehy.2013.05.034, How to Cite or Link Using DOI
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Abstract

Chronic fatigue syndrome (CFS) is an often-debilitating condition of unknown origin. There is a general consensus among CFS researchers that the symptoms seem to reflect an ongoing immune response, perhaps due to viral infection. Thus, most CFS research has focused upon trying to uncover that putative immune system dysfunction or specific pathogenic agent. However, no single causative agent has been found.

In this speculative article, I describe a new hypothesis for the etiology of CFS: infection of the vagus nerve.

When immune cells of otherwise healthy individuals detect any peripheral infection, they release proinflammatory cytokines. Chemoreceptors of the sensory vagus nerve detect these localized proinflammatory cytokines, and send a signal to the brain to initiate sickness behavior. Sickness behavior is an involuntary response that includes fatigue, fever, myalgia, depression, and other symptoms that overlap with CFS. The vagus nerve infection hypothesis of CFS contends that CFS symptoms are a pathologically exaggerated version of normal sickness behavior that can occur when sensory vagal ganglia or paraganglia are themselves infected with any virus or bacteria.

Drawing upon relevant findings from the neuropathic pain literature, I explain how pathogen-activated glial cells can bombard the sensory vagus nerve with proinflammatory cytokines and other neuroexcitatory substances, initiating an exaggerated and intractable sickness behavior signal. According to this hypothesis, any pathogenic infection of the vagus nerve can cause CFS, which resolves the ongoing controversy about finding a single pathogen. The vagus nerve infection hypothesis offers testable hypotheses for researchers, animal models, and specific treatment strategies.


Fig. 1. A highly simplified schematic of vagus nerve anatomy. Circles represent ganglia and paraganglia, which contain both glial cells and sensory vagus nerve chemoreceptors. A viral or bacterial infection within any ganglia or paraganglia causes glial activation, leading to the release of proinflammatory cytokines and other neuroexcitatory mediators. The resulting afferent signal enters the brain at the nucleus tractus solitarius (NTS), and triggers sickness behaviors. When normal glial cell activation becomes pathological as it does in neuropathic pain conditions, the signal is intensified and intractable, leading to CFS.
Link out above links to other tables and charts

Eco
 
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Interesting. always have thought there be a neuro-immune connection to these things. glad someone is researching in this area. interesting a psych department is allowing research into physiological pathologies. Thanks for the post.
 

Tito

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I have never heard fever being called a behavior before! o_O
Don't speak too loud MeSci... Because your comment (and more specifically your use of the exclamation mark) will be considered as a death threat against these "scientists". ;-)
Naughty you!
 

alex3619

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Interesting. always have thought there be a neuro-immune connection to these things. glad someone is researching in this area. interesting a psych department is allowing research into physiological pathologies. Thanks for the post.
This is the only way psychiatry will survive, too many are waking up to the entire discipline being unscientific. However this is from a psychiatric neuroscience department. I am not sure what they really mean by that though.

I expect to see more and more psychiatric research looking at the pathophysiology, especially brain pathophysiology. As this happens psychiatric disorders will move to immunology, neurology, neuroimmunology and other branches of science and medicine. So it seems that much of psychiatry is doomed anyway.
 

Valentijn

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and why is he talking about 'behavior' when he is really citing symptoms? In order for psychs to be paid to continue working on it?

I have never heard fever being called a behavior before! o_O
It's a standard term for biologically triggered changes in "behavior" when sick, due to elevated cytokines. I don't much care for it being labelled as a behavior, however, partially due to the BPS school abusing the concept, and it really being an automated biological response (more like sneezing), not a voluntary behavior.
 
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Hip

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In terms of what pathogen might actually be infecting the vagus nerve, note that Dr John Chia has pointed out that if you have an enterovirus infection of the stomach (the stomach is a major viral reservoir for enterovirus infections), then this enterovirus infection can actually get into the vagus nerve, where this nerve links to the stomach, and then the virus can travel along the entire length of the vagus nerve until it reaches the point where this nerve enters the brain. (And presumably the enterovirus may then enter and infect the brain too, where it likely precipitates more ME/CFS symptoms).

So conceivably, as the virus travels along the vagus nerve, it may also remain within this nerve as a permanent, chronic nerve infection, thereby leading to the autonomic nervous system symptom of ME/CFS.

The mechanism by which viruses like enterovirus travel along the vagus nerve is known as retrograde axonal transport. Studies have shown that enterovirus 71 travels along nerves by this mechanism (ref: 1). Poliovirus also travels along nerves by retrograde axonal transport (ref: 1)

THE VAGUS NERVE (THE 10TH CRANIAL NERVE)​
vagus nerve.jpg
 

Hip

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alex3619 A.B. These are the type of discussions I used to love having!

The body-mind duality is deeply rooted in psychology and psychiatry.
The mind-body duality is also profoundly discussed by philosophers: see Philosophy of mind.
The purpose of ascribing symptoms to the mind is to promote the idea of psychogenic illness. There is no other reason to create this distinction between body and mind.
Do I understand you correctly that you are suggesting the only reason we have the mind-body distinction is to promote the idea of psychogenic illnesses! There are numerous far more important reasons for assuming a distinction between body and mind that have nothing to do with illnesses at all. For example, the knotty philosophical problem of explaining why qualia exist. Don't get me wrong, I am dead set against the idea of psychosomatic illnesses. I doubt if any really exist. But that has nothing to do with whether mind itself exists as a real and distinct entity.
It just means rejecting the notion and theories that say this depression is caused by this mysterious and invisible entity called the mind
I think depression can be caused both by psychological reasons (problems in your life) and by biochemical reason (problems with your brain chemistry). I know from experience, as I have had both types. Though I think something severe like schizophrenia can only arise from problems with your brain chemistry. Likewise with ME/CFS, which probably can only arise from problems with your brain chemistry.
However as we move to a non-dualist view I think we will find that mind will become synomymous as a function of brain. The mind does not really exist, its just a convenient label.
In case there is any doubt on theory of mind I am a monist, but I do understand that dualist descriptions of brain function can simplify things.
I favor the view that mind/consciousness is actually a separate entity in its own right, and in its essence is fundamentally different to matter and the physical world.

I also think that science will soon demonstrate that mind and matter are fundamentally different entities. If you read about the concepts of quantum mind, which proposes that mind is a quantum level phenomenon, you can begin to appreciate how mind and matter might be vastly different and incomparable entities — simply because the quantum world and the physical world of matter are vastly different and incomparable. The quantum world and the physical world are really like two different universes: there are actually different laws of physics in each of these two universes.
 

alex3619

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The quantum mind concept (Penrose?) is old, I was looking into it in the early 90s. So far its not proven. Its also unnecessary at this point. Brain function itself can potentially explain it all, and requires no additional hypotheses. So its the simpler view. Further any quantum issue, if proven, might simply be another layer of physical brain mechanism.

Don't take me the wrong way, I would be overjoyed if someone could prove mind exists. It would open up a whole new field of research into the mysteries of the universe. Its just neither proven nor necessary. It is however claimed by many. Its part of popular culture and language.

The ancient Greeks speculated about mind, but I forget almost everything about that. This was followed by many philosophers up to recent times, the most famous of whom is probably Descartes.

Psychogenic claims are based on speculation about mind. Its right up there with modern mysticism. Most of the early speculation has been debunked, but of course that was Charcot and Freud. Maybe the modern version could be right even if they were wrong? Thats what keeps happening: debunked, disproved, discredited, then hang on a minute, this new version has not been disproved! Fair enough it hasn't (often, anyway) yet that does not make it right, and the history of failure should make accepting any such hypotheses a matter of objective evidence, testing and reason, and not speculation.

I think its pretty clear that with current knowledge the concept of mind is unnecessary, but that doesn't prove its wrong. I would be happy to be surprised. However getting into mind/body discussions typically confuses things, and will lose most readers fairly fast.

I put this all down to mysticism, superstition, modern day magic, and all the dogma that goes with these things. Could there be something to it? Of course. Is there credible objective evidence there is something to mind? No. I will be expounding on magical thinking in discussing psychogenic medicine in the future, as well as the nature of dogma, the problem of nonscience, promotion by emotional and empty (and often fallacious) rhetoric, pseudoscience, zombie science, bias, and then (hopefully) tackle a big one: quackery. Hmmm, that reminds me I may have to reread the Golden Bough, a classic on the theory of pagan magic and religion.

Yet in all this I am aware there are deep issues involved in what we call mental illness, with a lot of sick and distressed people needing help. I think that helping them, and even better curing them, requires that we have a very sound grasp of what is wrong, and not just empty speculation based on yet more empty speculation.

PS I also have my own version of monist theory of mind, which I might blog about next year.
 

Richie

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The brain mediates mental symptoms. It is influenced by biochemistry, external environment and by its own conscious and subconscious activity. The external environment and thought/emotional environment influence the biochemistry and vice versa, One can accept that the biochemistry is the immediate cause of changes in mental state without reducing all psychiatry to biochem.Thus it makes sense for those treating mental illness to consider such things as neurotransmitter levels, mitochondrial activity, vitamin levels etc alongside the external environment - from e.g. sunlight to love life, and the thought/emotional patterns of the patient.

Further the brain influences the rest of the body for good and illl and is therefore relevant to somatic health and medicine while the rest of the body also responds to the environment and changes may feed back on the brain and thus be relevant to mental health, symptomology e.g. gut brain axis, psychobiotics etc.

Would any of the above be controversial in a clinical setting - at least in principle.

IMO these matters are what medicine should deal with pragmatically, regardless of philosophy. Philosophy is important but so is common sense.
 

A.B.

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Do I understand you correctly that you are suggesting the only reason we have the mind-body distinction is to promote the idea of psychogenic illnesses! There are numerous far more important reasons for assuming a distinction between body and mind that have nothing to do with illnesses at all. For example, the knotty philosophical problem of explaining why qualia exist. Don't get me wrong, I am dead set against the idea of psychosomatic illnesses. I doubt if any really exist. But that has nothing to do with whether mind itself exists as a real and distinct entity.
I did not express myself as well as I could have. I meant that the only reason for ascribing a group of symptoms to the mind and another group of symptoms to the body is to promote the idea of psychogenic illness.

I also think that science will soon demonstrate that mind and matter are fundamentally different entities. If you read about the concepts of quantum mind, which proposes that mind is a quantum level phenomenon, you can begin to appreciate how mind and matter might be vastly different and incomparable entities — simply because the quantum world and the physical world of matter are vastly different and incomparable. The quantum world and the physical world are really like two different universes: there are actually different laws of physics in each of these two universes.
Science is discovering that more and more quantum effects occur in living organisms, for example during photosynthesis in plants. It wouldn't come as surprise that quantum effects are also taking place in the brain. It wouldn't validate the theory of psychogenic illness though.

Quantum physics are still physics. We're still dealing with measurable effects and phenomena here, and thus quantum physics is firmly rooted in reality, unlike theories about psychogenic illness which, as far as I'm aware, lack the scientific criteria of falsifiability.

That some quantum effects are baffling and unexplainable doesn't mean that the theory of psychogenic illness gets a free pass and can be accepted as real without concrete evidence.

I would argue that the idea of psychogenic illness is simply an old superstition in modern clothes. Man has always believed that some mysterious unknown force is causing disease, and has come up with various rituals to counter this unhealthy influence. In modern times, this mysterious unknown force is called the mind or psyche, and the ritual is called psychotherapy. Like any superstition, it can neither be proven nor disproven, and its purpose is to make people feel in control of the situation and to give a false sense of knowledge.

When I was younger and naive, I used to be a big believer in psychology. It made me feel insightful and knowledgable. Then I got sick and had to confront reality, and realized that only "physical" interventions actually help with any consistency, and that "physical" factors can alleviate or cause "mental" symptoms.
 
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On the testability (rat models don't really do it for me, as you can't ask the rat how they are feeling).

For reasons reviewed above, systemic measures in human CFS patients such as peripheral blood cytokine levels may not be particularly diagnostic or informative. With no blood test for CFS forthcoming, live human studies are difficult. The current gold standard of direct evidence to support the VNIH may be CFS patient cadaver studies consisting of immunohistohemical staining for activated glia, inflammation, and active virus infection within vagus nerve, its paraganglia and ganglia, or NTS. However, the most common marker for glial activation, glial fibrillary acidic protein (GFAP), may not be present in paraganglionic satellite glial cells [74]. Furthermore, given the likely difficulty finding suitable cadavers, the fact that CFS infection could be caused by any number of neurotropic viruses (some of which the majority of humans already harbor), and the difficulty of dissecting out all possible infection locations in the long and highly branched vagus nerve, other models and approaches should also be considered.
In patients, magnetic resonance imaging (MRI) after injection of gadolinium can be used to detect viral lesions in tissue within the central nervous system [116]. This can only be accomplished within the central nervous system because gadolinium contrasting delineates a disruption of the blood–brain barrier and not a viral lesion per se. Live imaging of an infection in peripheral vagal paraganglia would be more difficult. In vivo electrophysiological recordings of vagus nerve are possible [117] but invasive. A new line of research should seek to develop novel protocols for resting-state and functional imaging of vagus nerve and brainstem NTS in CFS patients. In addition, the use of translocator protein radioligands in positron emission tomography (PET) imaging has shown promise as a method of imaging microglial activation in neurodegenerative disorder-induced neuroinflammation [118], and may prove valuable in CFS research. Such methods could provide both support for the general hypothesis and important information that could inform individual treatment strategies.
One significant ongoing barrier to human CFS research is the difficulty recruiting the most severely symptomatic patients, who are often unable to get out of bed on their own and who recognize that even the minor physical activity associated with traveling to a research facility would likely lead to a severe and sustained post-exertional malaise. Given normal individual differences in measures of vagal tone and immune physiology, studies attempting to contrast vagus function in mildly symptomatic patients versus controls may become underpowered. It is important for any CFS study to include patients with the most severe symptoms, and as such budgeting and IRB approval for home visits should be included in grant proposals when feasible.
The paper also proposes the potential treatments ibudilast - macrophage-migration inhibitory factor (MIF) and other glial inhibitors minocycline, pentoxifylline and propentofylline.
 

Gijs

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The mind consists of interaction of neurons. Neurons are chemicals. The mind is a chemical product. This nervus vagus infection is a good theory but i like to see proof. There are so many hypothesis about CFS i get little tired :)
 

Richie

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RE "sickness behaviour" I think that the psychologisers of ME/CFS like to use the term "illness behaviour" in relation to these conditions..
"sickness behaviour" as others have pointed out is an odd but "legit" term - in that it is not an attempt to deny organic aetiology, "illness behaviour" ia another matter.
 

Tito

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Do you know anyone else who has published a theory that ME/CFS is due to vagus nerve infection?
I found this document of 2000 from the U.S. Department of Health and Human Services Chronic Fatigue Syndrome Coordinating Committee (http://www.co-cure.org/SOS.pdf) where it says,
"Illness behavior is represented by a complex physiological array that includes fatigue, fever, pain, stress and neuroendocrine abnormalities, with influences by, cytokines, thus suggesting a sharing of common mechanisms across diseases. There is suggestive evidence that much of the symptomatology for diffuse pain symptoms of the type seen in CFS, FMS, and IBS may be mediated by the subdiaphragmatic portion of the vagus nerve."

There was indeed a previous study in 1995, "Vagal tone is reduced during paced breathing in patients with the chronic fatigue syndrome" (http://www.ncbi.nlm.nih.gov/pubmed/7549414), showing a vagal implication in CFS.

This study, "Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome" of 2012 (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049518) also shows an association between reduced cardiac vagal tone and cognitive impairment in CFS and confirms previous reports of diminished vagal activity.
These results were heavily published. Cort Johnson also wrote his thoughts about this (http://www.cortjohnson.org/blog/201...gnitive-problems-in-chronic-fatigue-syndrome/). He actually already had pinpointed this interesting idea in a post of 2009 (http://forums.phoenixrising.me/inde...nd-me-cfs-a-cause-of-central-sensitivity.426/).

The idea of an infectious agent travelling from the stomach/guts to the brain via the vagus nerve is not new either. In 1998, the following study, "Chronic Fatigue, Fainting and Autonomic Dysfunction: Further Similarities Between Post-Polio Fatigue and Chronic Fatigue Syndrome?" (http://www.ippso-world.org/ppsinfo/articles/bruno/rlb-stateart.html) was already setting a potential parallel between this known issue for polio to that suspicion for CFS. And if my memory serves me, I think Dr Chia has spent more than a decade showing how pathogens migrate via the vagus nerve.

In conclusion, and this is the result of a 8-minute search on Google, it seems to me that the hypothesis from this graduate student of the Department of Psychology at Tufts University is not an entirely new concept. It does not mean it is not worth it, it just means that this is not new.

Interestingly enough, I also came across a study of 2003, "Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge"
(http://jap.physiology.org/content/95/5/1873.long). It says,
"Importantly, the results of this study demonstrate that core body temperature and plasma corticosterone are elevated and that activity is suppressed before either cytokines or endotoxin are elevated in the circulation. Therefore, neither is a prerequisite for the activation of the sickness or HPA response."
It seems to suggest cytokines are not a prerequisite to a 'sickness behaviour' like fever.