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The fifth and final article in a series attempting to explain the science behind fairly common topics and exploring how they relate to ME/CFS. This time the topic is the nervous system – by Andrew Gladman.
The nervous system, specifically the autonomic nervous system, is frequently discussed in relation to ME/CFS, with quite a plethora of research being targeted in this area.
Many of the symptoms that ME/CFS patients suffer with, such as crushing fatigue, tremor sensations and headaches, could come as a direct consequence of abnormalities in the nervous system.
In this article, I aim to explore the organization and general function of the nervous system as well as considering the research, both historic and ongoing, as it relates to ME/CFS.
What is the Nervous System?
The nervous system is the system which allows for coordination between the different organs and tissues within the body, hence controlling the voluntary and involuntary actions of animals through the transmission of signals. The vast majority of cells involved in the nervous system are known as neurons. Neurons are highly specialized cells that process and relay signals, known as nerve impulses or action potentials, between the different tissues and organs within the body. Like other cells they contain many membrane bound organelles such as the nucleus, mitochondria, endoplasmic reticulum among others - these carry out the basic cellular functions of protein-synthesis and ATP production.
Annotated diagram of a neuron
The adjacent diagram labels all of the parts of a neuron which play an active role in the transmission of action potentials. The following is a very brief overview of the role each of these plays:
- Dendrite and Axon terminal: The axon terminal of one neuron lies very close to the dendrites of another. Chemicals are released by the axon terminal when stimulated, which in turn stimulates the dendrite of the next, allowing for the action potential to be transferred from one cell to the next.
- Cell body and nucleus: All standard cellular processes occur within the cell body. The nucleus is important as it provides the genetic material required for the construction of the vital proteins required for nerve impulses.
- Axon: A long tail-like projection of the cell which transmits the action potential a long distance. This is achieved through the channel proteins in the cell membrane of the axon allowing for the flow of charged molecules in and out of the axon. This creates an electro-chemical gradient wave which flows down the axon - fundamentally a nerve impulse is simply an electro-chemical wave.
- Schwann cells, myelin sheath and nodes of ranvier: Cells known as schwann cells are tightly coiled around the axon of a neuron and secret a fat (lipid) known as myelin. This myelin forms the myelin sheath. The function of this myelin is to insulate the axon and allow for faster transmission of action potentials. This is achieved by a process known as saltatory conduction. Simply put, the gaps between schwann cells - known as nodes of ranvier - are the only places where the charged molecules can flow in and out of the cell. When an influx of these chemicals occurs at one node of ranvier, the sudden influx stimulates the proteins at the next, allowing an influx there. This process continues all down the axon and effectively allows the action potential to jump from one node of ranvier to the next, hence allowing for faster transmission. Not all neurons have schwann cells - these are known as non-myelinated neurons.
How are action potentials transmitted?
The following is an outline of the cellular and molecular processes at work which allow for the transmission of a nerve impulse. The following video provides a good overview of this process.
For an action potential to take place, the cell first has to be stimulated. This process of stimulation occurs when an adjacent neuron which is carrying an action potential releases neurotransmitters, such as acetyl choline, at its axon terminal which bind to one of the dendrites of the neuron. The site at which the axon terminal of one neuron meets the dendrite of the next is known as the synapse. This video explains further the process of how an action potential is transmitted from one neuron to the next. Once this has occurred several times on different dendrites, the action potential begins.
Most neurons, barring those contained within the central nervous system, are very elongated with a long thin tail-like projection known as an axon. Within this axon there are no organelles, therefore no complex cellular processes occur within this. These processes are all carried out within the cell body. The diagrams above depict motor neurons with the cell body at one end. Interestingly, this is not always the case, as within sensory neurons the cell body is often a small offshoot within the center of the cell. However, all neurons within the autonomic nervous system are motor neurons. This will be discussed later in this article when we explore the organization of the nervous system.
It is the axon which allows for the transmission of action potentials. Within the neuron there is also something known as a resting potential. To understand this concept, it is important for me to stress that nerve impulses are best thought of as waves. Imagine, if you will, a tank of water. If you create a wave at one end, the wave then travels along the tank until it reaches the other side. (Ignore the return wave as this is where the analogy falls down!) Now conceptually, the wave increases the height of the water in that one location as it travels down the tank and lowers back to normal once the wave has passed. In a nerve cell this is also true, however, instead of the height of the water increasing as the wave travels, it is the electric potential within the neuron that increases and then returns to normal. This 'normal' is what is known as the resting potential. It can be simply described as a negative electric potential within the neuron. Within the axon there exist lots of positively charged potassium molecules (K+), however, outside of the axon there exist positively charged sodium molecules (Na+) which greatly outnumber the potassium molecules. Therefore, the inside is negatively charged relative to outside of the axon.
For the 'wave' to be triggered within the neuron, multiple signals need to be received by the dendrites. There exists a threshold level which the stimulation must reach before an action potential is triggered, to prevent over-stimulation. Once this threshold is reached, sodium channel proteins open at the start of the axon and allow Na+ molecules to flood into the axon. This flooding in of positive sodium molecules raises the electric potential at the start of the axon. This in turn triggers the next sodium channel proteins along the axon to open, allowing more positive molecules to flood in. Once the electric potential gets very high at the start of the axon, potassium channel proteins open here and K+ floods out of the cell. This lowers the electric potential at the start of the axon to below the threshold value, therefore stopping the action potential at the start. It is for this reason that the action potential travels as a wave. This process of sodium flooding in and potassium flooding out continues along the axon until the wave reaches the end of the axon. At this point, the increase of electric potential triggers processes at the synapse which ultimately ends with the release of neurotransmitters, hence starting the action potential in the next neuron. Within the neuron there also exist other proteins known as sodium/potassium pumps. These pump sodium out of the cell and potassium in, setting up optimal resting potential conditions to prime the cell for another action potential. There is a slight delay between an action potential being transmitted and restoration of the resting potential. This ensures the neuron does not become overstimulated as it could cause damage to the neuron.
From this very brief and quite simplified outline, it is clear that the process of nerve impulse transmissions on a cellular level is very complex. It is therefore easy to see why small problems in any of the multiple stages or any damage to any of the involved cells can have quite drastic consequences on a macro-molecular level.
How is the Nervous System Organized?
Diagram explaining how the nervous system is organized.
Read any credible research into physiological pathology and possible disease mechanisms of ME/CFS and you're certain to come across the phrase 'autonomic nervous system'. Unfortunately, it isn't always easy to understand what this tangibly relates to without further understanding the sub-divisions of the nervous system as a whole.
Fundamentally, the nervous system is initially split into two: the central nervous system and the peripheral nervous system. The central nervous system consists of all the neurons and associated cells within the brain and spinal cord. This receives information from every organ and tissue within the body, analyzes the information and transmits appropriate responses back to the organ.
As an aside, there do exist processes within the body that do not require any analysis. In these, the information is often transmitted to the spinal cord and a preset response is instantly transmitted back. This is often known as a reflex arc. A common example would be when you burn you hand - in response to this you instantly move your hand away from the heat source without conscious thought. These arcs exist to protect the body from danger in situations where hesitation would likely lead to further damage to the body.
The peripheral nervous system accounts for all the neurons that bring information into and out of the central nervous system. This is sub-divided into the motor and sensory nervous systems. The sensory nervous system is comprised of sensory neurons which monitor and process sensory information, including information from all sensory organs such as the eyes and ears. The motor nervous system is comprised of motor neurons. This system carries all the information coming from the brain in response to sensory input. To clarify this process in order: A sensory input such as seeing a vicious dog is detected by the eyes. This creates a nerve impulse (action potential) within the sensory neuron attached to the eyes - this being known as the optic nerve. This action potential travels into the central nervous system, specifically the brain, where brain processes the information. It recognizes the dog as a threat - and in response, generates an action potential which travels via a motor neuron to many different parts of the body. This stimulates the release of adrenalin from the adrenal glands, part of a process known as a fight or flight response, and makes the person step back from the danger.
The motor nervous system is then further subdivided into the autonomic and somatic nervous systems. The somatic nervous system is often described as the voluntary nervous system, which eloquently describes it. It is this part of the nervous system which we as beings have conscious control over, via skeletal muscles which are stimulated by efferent nerves.
The autonomic nervous system is the most relevant of all these divisions to ME/CFS, given the substantial research attention it now receives. It is also known as the involuntary nervous system, which makes clear what the function this crucial component of the nervous system is. It acts as a control system within the body, maintaining and carrying out all tasks that fall below the level of consciousness. This includes tasks such as the beating of the heart, the process of digestion and the respiratory rate - although this can be consciously controlled, under most circumstances it is an automated and non-conscious process. This system has a further, and final, subdivision into the sympathetic and parasympathetic nervous systems.
This division is not as clear-cut as previous ones, however, it can be described as such: The sympathetic system often speeds up functions while the parasympathetic often has the opposite, relaxing, effect. Examples of sympathetic division: dilates pupils, increases heart rate and blood flow, dilates bronchioles to increase oxygen in blood, constricts blood vessels, increases blood pressure, slows digestion. These often occur as part of the previously mentioned 'fight or flight' response, which is controlled purely through the sympathetic element of the autonomic nervous system. The parasympathetic nervous system therefore has the opposite effect to the sympathetic system, resulting in constriction of pupils, returning vision to normal, slowing the heart rate and blood flow, constricting bronchioles and returning digestion to normal.
Why is the Nervous System Important in ME/CFS?
Given the previously discussed information regarding how the nervous system works on a cellular level, it is quite easy to understand why any problems occurring on this cellular level can have far reaching consequences on the entire body. For quite a number of years, it has been clear that there is autonomic dysfunction occurring within ME/CFS patients. Symptoms such as orthostatic intolerance, vertigo and mental exhaustion all imply such. Yet it has been quite difficult for researchers to discover the reason for this dysfunction, and in many cases, to find it consistently in ME/CFS patients between studies - likely in no small part due to the non-homogeneous nature of the ME/CFS diagnosis. However, as time advances, the evidence and data continues to mount pointing towards autonomic dysfunction as a central pillar within ME/CFS.
One researcher undertaking ground-breaking and still ongoing research, funded by ME Research UK, into autonomic dysfunction within ME/CFS patients is Prof. Julia Newton and her team at the University of Newcastle. Prof. Newton's past research has indicated abnormalities in both muscle function, with excess lactate produced upon stimulation, and cardiac function which also shows considerable abnormalities as discussed at greater length in the previous article of this series. Her ongoing study has the following:
The investigation has two broad aims. The first is to examine fully the people attending the Newcastle CFS/ME Clinical Service, and develop a database of patients who can be followed up over the long term. The second is to begin to answer the question, Does the autonomic dysfunction in people with ME/CFS arise in association with abnormalities of brain, muscle and liver, as has already been shown in other patients with other illnesses?
A novel hypothesis relating to the nervous system was recently proposed by Michael B. VanElzakker. His hypothesis proposes that ME/CFS may stem from an infection of the vagus nerve. The vagus nerve is a long cranial nerve that stretches from the brain down to the lower abdomen. This nerve is highly branched with offshoots stretching to numerous organs and tissues within the body. The vagus nerve primarily conveys sensory information to the brain with 80-90% of it being comprised of sensory neurons. However, there are also a smaller number of motor neurons forming a small motor division of the nerve. The function of this nerve is to convey information about the current state of organs within the body - functions include regulation of the gastrointestinal tract via interaction with the enteric nervous system (nervous system of the gut).
In the instance of a vagus nerve infection as hypothesized, the vagus nerve is likely to suffer a degree of inflammation. This would disrupt the normal transmission of action potentials and would likely result in times of over-stimulation and, perhaps, under-stimulation. Over time, such dysfunction would likely cause further damage to the nerve, causing further dysfunction, and so the process would continue indefinitely. It must be stressed, however, that while this hypothesis is certainly an interesting idea, there is little in the way of evidence to support it. Further research must be completed before it can gain any merit.
There is a general consensus among ME/CFS researchers that the symptoms seem to reflect an ongoing immune response, perhaps due to viral infection. Thus, most ME/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 ME/CFS: infection of the vagus nerve. When immune cells of otherwise healthy individuals detect any peripheral infection, they release pro-inflammatory cytokines. Chemoreceptors of the sensory vagus nerve detect these localized pro-inflammatory cytokines, and send a signal to the brain to initiate sickness behavior.
Quite recently, there have also been a number of articles appearing discussing the similarities between ME/CFS and Multiple Sclerosis (MS), although this is no recent occurrence, as the similarities have been noted many times previously to this. As the majority likely know, MS is caused through an autoimmune response targeted towards the myelin sheath secreting schwann cells, that wrap around some neurons. This allows for the previously discussed saltatory conduction, hence allowing for faster nerve impulse transmission. The destruction of these schwann cells, therefore, has far reaching consequences within the nervous system, causing the distressing symptoms that MS patients suffer. The relative morbidity between ME/CFS and MS is clear to see, given that both have profound adverse effects upon the quality of life. However unlike MS, ME/CFS has yet to receive irrefutable evidence regarding the pathophysiology of the ongoing disease process. For this reason, it is helpful in some respects to compare the two diseases. However it is also important to contrast the two, highlighting the differences between the diseases.
For instance, in MS, there is clear evidence of ongoing inflammatory mechanisms within the nervous system. However, despite this being reported in several ME/CFS studies, it is in no way conclusive. It appears that if an autoimmune mechanism truly lies at the heart of ME/CFS, that it functions in a more complex, subtle and devious way than MS appears to. Although it is of note that despite MS being recognized as an autoimmune disease, the actual understanding of the complex ongoing process still eludes researchers. One important difference that I as a personal observer have come to, is that while MS typically adversely affects the central nervous system, ME/CFS appears to have consequences in both the sensory nervous system (with sensory overload being a common complaint) and autonomic nervous system. Unfortunately, dysfunction of the central system appears somewhat easier to casually observe, whereas autonomic and sensory dysfunction appear somewhat more convoluted. Perhaps this is why ME/CFS is only now losing the incorrect label of a psychological condition.
There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue, a worsening of symptoms following exercise, and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living.
Given the research discussed here and the plethora of historical research into autonomic dysfunction within ME/CFS, it is clear that dysfunction and perhaps even mechanical damage to the nervous system, specifically the autonomic and sensory systems, plays a central role within the ongoing disease process within ME/CFS patients. An interesting point to make is that many of the previous articles center on areas that have direct interaction with these neurological systems. Any abnormality in one can have profound effects upon another - with the cardiovascular, nervous and immune systems all being closely intertwined and interdependent upon one another. Of all the areas within biology and medicine, the nervous system is likely the most complex and is therefore a fast advancing field. Hopefully, as time progresses and ME/CFS research continues, it won't take too long to discover that one key piece of evidence that points us towards the cause of ME/CFS, and hopefully leads to treatments in the future.
And so concludes the final article in this series. I sincerely hope those reading have enjoyed this series as much as I have writing it. Be sure to let us know what you thought of this series. Keep a look out for the series conclusion coming soon, which will discuss and summarize everything we've explored in the last five articles.
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