Understanding the causes of Chronic Fatigue Syndrome​ through the Vagus Nerve

Chronic Fatigue Syndrome: examining the impact of infections.

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, or CFS, is a long-term illness that is characterised by extreme tiredness in addition to a host of other discomforts. Researchers have struggled to find an identifiable origin to this debilitating disease and as a result, it has proven difficult to treat.

Understanding the root cause of CFS for each patient is not simple, this is in part due to the difficulty in diagnosis as the symptoms which make up CFS can sometimes be attributed to depression, anxiety, insomnia or other conditions with which these symptoms overlap. This has caused debate over CFS and a tendency to attribute these symptoms to a psychological cause as opposed to a biological cause. However, a new investigational blood test has so far demonstrated 100% accuracy in distinguishing individuals with CFS[1] and there is now a consensus among research scientists that CFS is a reflection of an underlying immune response, probably a reaction towards infections.

A few years ago, a report published by the American National Academy of Medicine[1] reinforced that idea of infections triggering symptoms of CFS. The evidence presented in the report matched with an earlier hypothesis paper by Michael VanElzakker[2]. In this paper, VanElzakker theorised that CFS may arise from infection of the vagus nerve, a significant insight that helps us progress towards finding effective treatment of the disease.

The role of the vagus nerve

The vagus nerve has a primary role in regulating the immunity and inflammatory response. It is an integral part of the larger immune network (known as the inflammatory reflex) that helps the body to fight infection and stay healthy. 

Once the immune system detects an infection, signals will be sent via the vagus nerve to the brain to elicit a proper response. Part of this natural response is the generation of fatigue, flu-like symptoms or pain to slow the body down in exchange for a good rest. Historically, these reactions have helped us to recover from the infection, but when the infective source is on or in close proximity to the vagus nerve, the neural signals are thought to be transmitted constantly. This could explain why certain people feel chronically fatigued[1]. 

Aptly named as the Vagus Nerve Infection Hypothesis, VanElzakker suggested that an infection of any nature, be it viral or bacterial, would cause the vagus nerve to mistakenly  enhance the fatigue signals to the central nervous system[2][3].

Most interestingly, the infection that could trigger this cascade of inflammation does not need to be serious - it only needs to be within the proximity of the glial cells (a type of supporting cells) surrounding the vagus nerve. Upon sensing the presence of the infection, the glial cells will release proinflammatory cytokines and other compounds which function as signals to the brain.

It was this signalling pathway that could lead to a pathologically exaggerated fatigue response. As the infections may be small and localised to the vagus nerve, conventional blood tests may not be sufficiently sensitive to suggest an infection in CFS patients. Further, in animal studies when the vagus nerve is removed, there is no observable "sickness behaviour" when responding to infection[2]. This strengthens the idea that the infected vagus nerve is intimately involved in CFS.

The hypothesis proposed by VanElzakker was also partly echoed by another prominent scientist, Turhan Canli, who concurred with the role of the vagus nerve in CFS but believed that specific classes of pathogens could target the nervous system in a way that causally led to depressive symptoms commonly seen in sickness behaviour.

Depression: the twin sister of chronic fatigue syndrome

It is also important to discuss the parallels between depression and CFS as the two conditions share many key pathways that underpin their origins. There is strong empirical evidence to support the notion that the manifestation of both depression and CFS can be contributed  to by abnormalities in the inflammatory, oxidative and nitrosative (IO&NS) pathways[3]. In other words, there is an uncanny overlap between depression, inflammation and CFS that we are only just beginning to understand.

It is thought that chronic activation of the immune system drives activation of oxidative and nitrosative stress (O&NS) pathways long after the initial infection has been eliminated. The sustained activation of this pathway then causes further damage and provokes the subsequent release of pro-inflammatory compounds in a large quantity signaled via the vagus nerve. The combined actions of the immune system, the O&NS pathway and the resultant damages are responsible for the hallmark symptoms of CFS[4].

Understanding paves the way to treatment.

As CFS is complex, it's unlikely a single treatment will help all individuals, however, building on the understanding of the vagus nerve's role in the condition there is new evidence emerging that supports the idea that stimulating the vagus nerve can help to alleviate symptoms of CFS. Stimulating the vagus nerve has been shown to activate antiinflammatory pathways[5] which may counter the inflammatory and subsequent fatigue signals sent to the brain.

In a recent study published by researchers from the University of New South Wales, it was shown that patients with CFS had diminished vagal activity and significantly lower heart rate variability (HRV) compared to healthy volunteers. This lower level of HRV was correlated with patients' cognitive performance speed[6].

To address this deficiency, there is a growing body of scientific evidence that points to the beneficial effects of using transcutaneous vagus nerve stimulation (tVNS) to increase HRV, improve vagal tone and attempt to reduce the chronic immune response that leads to the symptoms of fatigue that characterise CFS.

Parasym is working with world-leading researchers in this area to understand how VNS can benefit individuals with CFS. With this new research Parasym hopes to bring better treatment to this otherwise immobilizing disorder.

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References:

1.    Clayton, EW. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an Illness. JAMA. 2015; 313(11): 1101-1102. doi: 10.1001/jama.2015.1346

2.    VanElzakker, MB. Chronic Fatigue Syndrome from Vagus Nerve Infection: A PSychoneuroimmunological Hypothesis. Med Hypotheses. 2013; 81: 414-423. doi:10.1016/j.mehy.2013.05.034

3.    Maes M. An Intriguing and Hitherto Unexplained Co-occurrence: Depression and Chronic Fatigue Syndrome Are Manifestations of Shared Inflammatory, Oxidative and Nitrosative (IO&NS) Pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 784-794. doi:10.1016/j.pnpbp.2010.06.023

4.    Morris, G & Maes, M. A Neuro-immune Model of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Metab Brain Dis. 2012; 28(4): 523-540. doi:10.1007/s11011-012-9324-8.

5.    Borovikova LV, Ivanova S, et al. Vagus Nerve Stimulation Attenuates the Systemic Inflammatory Response to Endotoxin. Nature. 2000; 405(6785): 458-462. doi: 10.1038/35013070

6.    Beumont A,Burton AR, et al. Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome. PLoS ONE. 2012; 7(11):e49518. doi:10.1371/journal.pone.0049518

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