See also the Persistent Burnout Theory of CFS for a concise theory of the etiology of CFS.
There is no currently accepted theory as to what causes Chronic Fatigue Syndrome (CFS). The main theories put forward are the psychiatric (cognitive behavioural) theory, which has wide acceptance in the UK, and the viral theory, which has widespread support in the USA.
The problem with the psychiatric theory is that it doesn't adequately explain all of the symptoms of CFS, such as the endocrine and immune irregularities, simply putting these down to mind-body interactions without really trying to explain them. The psychiatric theory tends to explain CFS symptoms either as neurosis or cognitive behavioural, essentially saying "it's all in your head, and you're creating your own illness", which does not really correspond with the experiences of the patients themselves. It is not surprising that there is such a vehement backlash against any psychological explanation for the illness.
The viral theory, on the other hand, doesn't explain why psychological factors are so important in the illness. Also, research has clearly shown that there is no single virus that is present in all CFS patients. It is possible that there is some as-yet-undiscovered virus hiding out in the nervous system of CFS patients, but such a theory is not credible until evidence is produced.
The problem is that there are so many different CFS symptoms, and no two patients have exactly the same set of symptoms. It is easy in such circumstances to put the entire illness down to hypochondria. However there are certain abnormalities which are present in virtually all patients. One such common feature is an underactivation of the hypothalamic-pituitary- adrenal (HPA) axis, especially in response to stress, and a lower than normal variation in the normal circadian pattern of HPA axis activation.
The HPA axis has traditionally been seen as the body's "stress system". During periods of stress, the hypothalalmus releases corticotropin-releasing hormone (CRH), which causes the pituitary to release adrenocorticotrophic hormone (ACTH, or just corticotropin). ACTH in turn circulates in the bloodstream and causes the outer cortex of the adrenal gland to increase in size and to release cortisol. Cortisol has similar properties to adrenaline, in that it causes increased metabolism of glucose and suppression of the immune system. However, unlike adrenaline it has a long half-life in the blood (circa 90 minutes compared with about 2 mintes for adrenaline), and is thought to be the body's long-term response to stress, in contrast to adrenaline which is a very immediate and short-term response (the "fight or flight" response).
Recent research seems to be showing that, rather than simply being the "stress system", the HPA axis has a more broad scope, and can be more accurately described as the body's energy metabolism system. As well as controlling the availability of blood glucose, activation of the HPA axis is critical to a number of non-stress activities, such as activation of the immune system and facilitation of digestion. It is likely that the abnormalities in these functions which are seen in CFS patients are secondary to the underactivation of the HPA axis.
In the absence of stress, the HPA axis normally has a circadian pattern of activation, with high levels of cortisol in the morning which steadily reduce until mid-afternoon, after which there is a second peak. Cortisol levels then trail off, reaching a minimum during the early hours of the morning. The circadian pattern of cortisol is controlled by a circadian pacemaker (or bodyclock) in the paraventricular nucleus (PVN) of the hypothalamus, which results in bursts of HPA axis activation roughly once per hour. This is ultimately controlled by the body's "master body clock", the suprachiasmatic nucleus, which imposes its circadian rhythm on many systems throughout the body.
A number of research studies have shown possible reasons for the underactivation of the HPA axis which is seen in CFS patients, including:
Burnout can be described as the inability to cope with physical and mental stress, and appears to be caused by (or at least, associated with) underactivation of the HPA axis. CFS can be thought of as severe burnout, as it is characterised by the same symptoms and HPA axis disturbances as people suffering from burnout, albeit to a much greater extent. All known cases of CFS begin with one or more of the triggers listed above, i.e. long-term stress, stress followed by rest, negative mental attitude to stress (or the illness itself or life in general), or a severe viral illness. In fact a large percentage of CFS patients share every single one of these triggers.
Research shows that psychological factors can significantly influence the HPA axis. Stress results in an increase in HPA axis activity, while CFS is generally associated with reduced HPA axis response which can been seen as reduced stress tolerance. Most CFS patients are under pretty low levels of stress, and yet the symptoms they suffer from are virtually identical to those suffered by people who are under too much stress. This can lead to doctors prescribing rest, relaxation and tranquilizers to CFS patients, which in most cases simply makes the illness worse.
The reduced HPA axis activation in CFS patients is very similar to burnout, which is a condition that also shares many symptoms with CFS. Contrary to popular opinion, burnout is not caused by too much stress. Rather, it is the attitude to the stress that is important. People suffering from work related burnout tend to have lost interest and motivation in their jobs. Although people suffering from burnout tend to be in stressful jobs, the stress does not automatically lead to burnout, and many people work in stressful jobs without suffering from burnout. The critical point seems to be the perception of the stressful event, or the person's attitude towards it. Burnout is likely to be the body's protection mechanism against unnecessary and potentially dangerous long-term stress. Some mechanism acts to limit HPA axis activiation in the hypothalamus, resulting in a reduced ability to cope with stress and (more importantly), a reduced motivation and reduced energy level, causing the person to rest and conserve energy.
CFS appears to be a persistent burnout, caused by the illness itself. While the initial trigger of the illness may be purely physical (such as a viral infection), psychological factors seem to be critical in perpetuating the illness and in determining whether or not recovery occurs.
Reading cases of CFS patients gives other indications that CFS and burnout are related. Many cases of CFS begin as job related burnout, with CFS developing when the person continues to work in the stressful job.
The common factor behind all cases of recovery from CFS (except spontaneous remission) is that the patient either changes their lifestyle - whether their job, their attitude to life, or their purpose in life - or they recover after using an alternative treatment which has no benefit over and above the placebo effect. Rather than being due to belief in the treatment by weak-minded people, the placebo effect is actually a very powerful healing force built in to the body, and the mechanisms behind it operate in everyone. It is not necessarily belief in the drug which causes the placebo effect, but rather the increased motivation, goals and purpose in life. In the same way, many people recover from CFS by changing an aspect of their lifestyle - such as going to a more motivating job. In both cases (placebo cure and change in lifestyle) it is the increased drive and purpose in life which results in recovery.
The mechanism underlying the HPA axis suppression in CFS and burnout is not known, but a possibility is the prefrontal cortex. This is an area of the brain which is involved in long-term planning, and it is also a strong modulator of the HPA axis, being able to both activate and suppress HPA axis activation.
Research into the placebo effect shows that those patients who recover from depression due to a placebo drug have increasing levels of prefrontal activity over the course of the sham treatment period.
Placebos have also been shown to increase ACTH and beta-endorpin, showing that mental attitude can increase HPA axis activation without there needing to be any stressor present. It is thought that the increase in beta-endorphin during the placebo effect is what causes increased immune system function, and results in the miraculous cures that are attributed to placebos. This increase in beta-endorphin indicates an increase in HPA axis function, as beta-endorphin is released by the pituitary alongside ACTH upon stimulation with CRH.
Direct evidence showing a link between the prefrontal cortex and CFS was published recently, showing reduced synthesis of glutamate in the prefrontal cortex of CFS patients. Glutamate is an excitatory neurotransmitter which, in the prefrontal cortex, is associated with activation of the HPA axis.
In summary, I propose that CFS is caused by a reduced circadian activation of CRH-releasing neurons in the paraventricular nucleus of the hypothalamus. This HPA axis suppression is initially caused by an acute HPA axis stressor, such as a viral illness, but persists due to mental attitude to the illness itself or to other aspects of the patient's lifestyle. Certain people appear to be more predisposed to CFS and burnout, and these people also tend to be overachievers. It is likely that certain people have more control over HPA axis activation, resulting in an ability to maintain high energy levels during times when they perceive things as going well, and reduced energy levels (and "burnout") during the times when it seems that effort spent will not be justified by future returns. "Burnout thinking" in these people results in the prefrontal cortex suppressing the HPA axis. If this persists for a long period of time, changes in neurons and hormone receptors at various places in the HPA axis feedback loop result in an abnormal base state of HPA axis activation and/or abnormal circadian pattern of HPA axis activation. Due to the important position of the HPA axis in controlling hormones and autonomic nervous system activation througout the body, this then results in the various symptoms of CFS.
It should be noted that recovery from CFS is not as simple as "positive thinking". The psychological mechanisms which regulate the HPA axis are not under direct conscious control, and appear to be related to factors such as purpose in life, deeply held beliefs, motivation and long-term goals.
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