Title: Persistent burnout theory of chronic fatigue syndrome
Author: David Jameson
Copyright (c) 2004 David Jameson.
Chronic fatigue syndrome (CFS, also known as myalgic encephalomyelitis or ME) is a severe illness of unknown etiology that has numerous physical, neurological, physiological and psychiatric symptoms. Many theories have been put forward to explain the illness, but none has been universally agreed on. This is mainly due to a failure of existing theories to explain all aspects of the illness, and the confusing array of symptoms and abnormal findings associated with the illness, many of which are only seen in a subset of patients.
Certain findings, however, do seem to be central to the illness:
Hypothalamic-pituitary-adrenal (HPA) axis disturbances, including a central under-activation of the HPA axis and a loss of circadian rhythm.
Abnormalities in the physical structure and activation of the prefrontal cortex (PFC).
Psychosocial treatments, the placebo effect, and rehabilitation programmes have been shown to be effective in curing the illness.
Taken together, these findings point to a possible etiology of the illness. It is known that the PFC is an important modulator of the HPA axis. The PFC is also the main brain region involved in the placebo effect and has functions relating to long-term goals and motivation.
This hypothesis suggests that CFS is a functional illness caused by structural changes in the PFC due to long-term morbid stress (or burnout), reinforced by the illness itself, which can be reversed by psycho-social rehabilitation treatments.
An outline of an experiment is presented to examine the correlation between CFS symptoms, prefrontal cortex activity and morphology, and HPA axis state for patients at different stages of treatment.
MeSH Keywords: “Fatigue Syndrome, Chronic”, “Burnout, Professional”, “Stress”, “Hypothalamo-Hypophyseal System”, “Placebo Effect”, “Prefrontal Cortex”.
Chronic fatigue syndrome (CFS, also known as ME) is a severe illness of unknown etiology that has numerous physical, physiological and psychiatric symptoms. Common triggers for the illness include viral infections – and herpesvirus family infections in particular – as well as stress (1,2).
Different studies give widely varying values for the incidence of the illness, but the general consensus is that it affects between 100 and 300 people per 100,000 population (3). This suggests that CFS is as prevalent as conditions such as autism, multiple sclerosis or Parkinson's disease, yet the research funding for CFS is much lower than for any of these other conditions (4).
The main hypotheses which attempt to explain CFS are:  the cognitive behavioural theory, which proposes that CFS is due to abnormal illness beliefs (5); and  various viral theories, which propose that CFS is caused by a persistent but as-yet unidentified viral infection. These two theories also represent the differing viewpoints about the illness: namely, whether it is psychiatric or organic in origin.
The problem with  is that it does not adequately explain the physical and physiological symptoms of the illness, such as abnormal immune and HPA axis function.
With , the problem is that no single virus has been shown to infect all CFS patients. It is more likely that the persistent herpesvirus and other infections seen in CFS patients are simply a symptom of the suppressed immune function seen in CFS, rather than being the cause of CFS itself. Also, the viral theories do not adequately explain why personality and mental attitude have been shown to be important in determining which patients contract CFS and which recover the most quickly, and why stress is a significant trigger in initiating the illness (2,6,7,8).
Psychosocial treatments do result in recovery from CFS (8,9,10), but the nature of the treatment itself is important. Cognitive behavioural therapy (CBT) has been shown by some studies to be effective and by others to be ineffective, and this has been taken by some researchers as evidence that psychosocial treatments in general do not work for CFS (11). However, it should be borne in mind that the patient’s motivation and belief in the treatment are likely to be important to recovery, and the fact that many CFS patients have a lack of confidence and motivation in CBT probably has a lot to do with CBT’s lack of effectiveness (12).
The HPA axis controls the release of cortisol from the outer cortex of the adrenal glands, via the hypothalamus and the pituitary. Plasma cortisol levels follow a circadian pattern, with high levels in the morning and lower levels in the evening. Under conditions of stress the activation of the HPA axis increases, resulting in a higher cortisol peak.
CFS patients tend to have a reduced HPA axis response to stress (13), a less pronounced circadian activation pattern of the HPA axis (14), an overall lower HPA axis activation (15), and a subset of patients have significantly low cortisol and shrunken adrenal glands (15,16). Research shows that the patients who recover most tend to be those who show the greatest improvement in circadian HPA axis activation (14).
The HPA axis is commonly thought of as the body’s response to stress, but research over recent years has shown that it is more accurate to think of it as the body’s energy expenditure regulator. As well as being involved in the stress response, the HPA axis also plays a central role in many normal non-stress functions such as digestion and the activation of the immune system and the autonomic nervous system (ANS).
The prefrontal cortex is the most evolved part of the brain, and is involved (among other tasks) in goal-directed activity, long-term planning and motivation. The prefrontal cortex is also known to be an important modulator of the HPA axis and is thought to be central to depression – a common CFS symptom – due to its regulation of neurotransmitters such as serotonin.
Studies have shown that CFS patients have reduced grey matter and an abnormal distribution of acetyl-L-carnitine in the bilateral prefrontal cortex (17,18).
A quantitative electroencephalography (EEG) study of depressed patients has shown that those patients who respond to a placebo treatment show a significant increase in prefrontal activity, with no significant change in any other brain region (19).
Burnout is a syndrome characterised by symptoms such as fatigue, depression, anxiety, headaches, disturbed sleep and susceptibility to illness. Research has shown that a physiological indicator of burnout is reduced HPA axis function and consequent low plasma cortisol (20,21). As both burnout and CFS show the same symptoms and physiological profile, as well as the same psychosocial causes, it is likely that they are in fact the same state, and that CFS is simply a more severe form of burnout.
While the various symptoms and triggers of CFS may appear confusing, the reports of patients who have recovered from the illness all share a common factor. Whether the patient recovers due to an alternative therapy, a change in lifestyle, or due to the placebo effect, in each case the common factor is the motivation and focus provided by treatment.
The most effective treatments appear to be rehabilitation programmes which fit in with the patient’s mindset and which encourage the patient to re-integrate back into normal life while reducing negative stressors and increasing motivating, enjoyable activities. Anti-depressants can also be useful, especially where depression and anxiety are present.
CFS shares many features with burnout: the symptoms are identical except in severity, the triggers are the same, and the same abnormalities in HPA axis function are observed in both. The main reason why burnout has not been considered as a cause of CFS is twofold:  the incorrect notion that burnout is a purely psychological state of not enjoying one's job; and  the fact that CFS persists even in the absence of stress, when the popular misconception is that burnout equates to excessive stress.
I postulate that CFS is caused by a persistent, chronic functional suppression of the HPA axis, which is essentially the same state as "burnout". This burnout persists long after the triggering HPA axis stressors have been removed, due to factors such as negative mental attitude and loss of motivation and perceived goals, either due to the illness itself or due to other factors.
The prefrontal cortex is likely to be central to the etiology of CFS, as it has been shown to be abnormal in CFS patients. Also, its function as a modulator of the HPA axis and its control over serotonin would explain most, if not all, of the physiological and psychiatric symptoms of CFS. The prefrontal cortex is also the area of the brain involved in the placebo effect, which is relevant because many reports of recovery from CFS involve treatments that are essentially placebos (homeopathy, kinesiology, anti-candida diets, etc.)
The prefrontal cortex may have a stress protection function, reducing HPA axis activation and serotonin production during periods of long-term morbid stress. This results in burnout and depression (or to put it another way, a reduction in both physical and mental energy and motivation), aiming to force the person to change the situation. If the situation is not changed, or if the burnout itself becomes a negative stressor, then the burnout will persist and lead to CFS.
In order to further elucidate the etiology of CFS, an experiment is proposed which will investigate the correlation of prefrontal cortex activity and morphology, HPA axis function, symptoms and treatment. Such an experiment would give us a clearer understanding of the nature of CFS, bridging the gap between the physical and psychiatric debate about the illness.
The participants would be divided into three groups:  a control group of non-patients;  a control group of CFS patients receiving no treatment; and  a group of CFS patients undergoing a rehabilitation programme.
If funding permits, the following extra groups could be added:
· A placebo group of CFS patients receiving a sham drug treatment.
· An active treatment group of CFS patients receiving an antidepressant medication.
· A group of CFS patients receiving homeopathy treatment.
· A group of patients suffering from burnout syndrome, for comparison with CFS.
Prior to the experiment, participants would be assessed by the Maslach Burnout Inventory to determine the degree to which the psychological burnout factors are present.
The participants would be monitored for brain activation (using either QEEG cordance or MRI scans), brain morphology (using voxel based MRI) and HPA axis activation (measuring cortisol after awakening and circadian variation in cortisol). At various stages of the experiment the patients would be assessed on visual analogue scales to determine subjective recovery from CFS symptoms, with follow-ups afterwards.
If the predictions of this theory are correct then patients receiving all treatments should show changes in the prefrontal cortex and in HPA axis function. Those patients on the rehabilitation programme should show the most significant improvement in symptoms as well as changes in prefrontal cortex and HPA axis activity, and this improvement is more likely to be permanent that in the placebo group. CFS symptoms are likely to be correlated with the state of the prefrontal cortex and HPA axis.
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