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MIND-BODY HEALTH AND STRESS TOLERANCE

Copyright (c) 2003 David Jameson All Rights Reserved

http://www.mind-body-health.net

Converted to pdf using gobcl.com

Contents
1. Introduction 2. What is Stress? 3. Circadian Rhythms 4. Introducing a New Theory 5. Stress, Mental Attitude, Illness and the Immune System 6. Chronic Fatigue Syndrome 7. Irritable Bowel Syndrome 8. Relation to Other Disorders 9. Avoiding Burnout 10. Summary Glossary References Bibliography Websites Index 2 9 17 25 38 67 103 117 124 132 138 148 170 171 172

1. Introduction

1. Introduction
Why do some people cope better with stress than others? What is Chronic Fatigue Syndrome (CFS, also known as ME), how is it related to stress, and why can it be cured by seemingly quack treatments that rely on the placebo effect? What are the interactions between mind and body that cause the placebo effect and miracle cures to work? How do the mind and body interact to influence the immune system, health and stress tolerance? Mind-body-health interactions are mostly ignored by medical science and cases of miracle cures are usually relegated to the fringes of the scientific establishment. The immune system is thought of as running on auto-pilot, with nothing apart from excessive stress affecting its functioning. Stress tolerance is also thought of as being a constant; that there is a set amount of physical and mental stress that each person can handle and that nothing can be done to change this. This book shows how both of these assumptions are wrong, and the placebo effect is only one example of how the mind can positively affect the immune system and physical health. The mind can also affect physical health in a negative way, even in the absence of stress. CFS is a state of low immune function and a lack of tolerance to physical and mental stress, which persists even in the absence of any external stress or infection. Caused by a complex interaction of environmental, physical and psychological factors, CFS is a state of persistent ill health in which mind-body interactions play a crucial part in perpetuating the illness. While CFS is a severe condition that only affects a small number of people, the same mind-body interactions affect the health of everyone, and minor imbalances can cause disorders such as irritable bowel syndrome, burnout and persistent minor infections. The same factors that result in good physical health also act to increase the ability to handle physical and mental stress. Living in the modern world with increasing levels of 2

1. Introduction

stress, having a high stress tolerance is almost a necessity for survival. Illnesses such as CFS and burnout are becoming ever more prevalent and appear to some extent to be reactions to living in the modern world. The only hope for recovery from these illnesses (and preventing them from occurring in the first place) is to understand how the mind-body-stress relationship works, and to make changes to lifestyle and mental attitude which will result in a greater stress tolerance as well as improved physical and mental wellbeing. This book is the result of my own experiences of chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS) and burnout, and my research into the causes of these and other, related disorders, how they are linked by common underlying factors, and how to cure them. As well as being based on my own experiences and the accounts of many other people with these conditions, this book also draws on the results of over one hundred scientific research papers in order to build a comprehensive, cohesive theory which explains the common underlying cause of these apparently disparate conditions.

Chronic Fatigue Syndrome


CFS appears to be triggered either by a period of chronic stress or by a severe viral illness (and in many cases, a viral illness which occurs during a period of high stress). Many hypotheses have been put forward to explain the illness, such as a psychiatric disorder, an imbalance in the immune system, or a viral infection. However no satisfactory evidence has ever been produced which definitively explains the etiology of the illness. What all of the various CFS triggers have in common is that they activate the body's stress system, and it seems that it is this stress reaction (whether the cause is physical, psychological or due to illness) that is the important factor in causing CFS. There are also a number of similar conditions such as Gulf War syndrome, which appear to be triggered by stress and have similar symptoms to CFS, but which do not follow the pattern of post-traumatic stress disorder, the supposed cause of these disorders. 3

1. Introduction

In the course of this book, I will present a new theory of stress, showing how the ability to handle stress is not a constant, but is influenced by a complex combination of mental, physiological and physical factors. A lack of stress tolerance can result in burnout or CFS, but excessive stress does not necessarily lead automatically to burnout. I aim to show how the various factors contribute to stress tolerance, how this is affected by stress itself, and how this can lead to the various mental, physical and physiological symptoms suffered during burnout and CFS.

The Placebo Effect


I will also describe the placebo effect, which, although mostly ridiculed or ignored, is actually a very potent healing force. Many people have had miraculous recoveries from cancer and other incurable conditions through fake treatments that rely on the placebo effect. What this shows is that the mind has a very powerful influence over the immune system, and physical health in general. The placebo effect seems to be particularly effective at treating CFS, with many people recovering due to treatments that rely purely on the placebo effect. I aim to show that the placebo effect is in fact the body's own healing force, and that sufficient activation of this system is necessary to maintain normal health and immunity to infection. CFS, rather than being either a psychiatric disorder or an infection, is caused by a general breakdown in this health-maintaining system, which then results in an inability of the body to cope with external stressors such as infection or emotional stress. This built-in healing system is controlled by the same part of the brain which is involved in stress tolerance, the hypothalamic-pituitary-adrenal axis (or HPA axis), and I aim to show that the same factors which control stress tolerance also act to produce the placebo effect and maintain health and immunity to infection. The HPA axis operates at the interface between mind and body, and is crucial for maintaining both mental and physical health.

1. Introduction

Stress
Stress is one of the most misunderstood aspects of human life, and yet it causes severe mental, emotional and physical distress in a large percentage of the human population, and can even result in death. The Japanese even have a word karoshi, which means death from over-work. Stress is also implicated in various physical and mental illnesses such as depression and heart disease, and is thought to result in more workplace sick days than any other illness. The currently accepted theory of stress has not changed significantly since Hans Selye developed it in 1936. Selye's theory states that any kind of external stressor, such as heat, cold, illness or emotional upset, will push the body outside homeostasis (its normal resting state), into a state of allostasis. When it is in this state, the body releases large amounts of stress hormones such as cortisol and adrenaline in an attempt to conquer the threat. Selye noticed that rats placed under prolonged stress were able to cope very well initially, but eventually the stress-coping system broke down and the animals died. Selye proposed that the body only has a finite reserve for coping with stress, and that prolonged chronic stress will eventually result in physical or mental illness, or even death. Although Selye's theory has undergone minor modification over the subsequent years due to new experimental results, it is still generally accepted by the scientific community and the general public. While Selye's theory is correct as far as it goes, it does not explain why different people have different tolerances for stress, or indeed, why some people can handle high amounts of stress for a long period and then suddenly burn out. The people who tend to be able to cope with stress have high levels of cortisol (sometimes called the stress hormone, as its main purpose seems to be to protect the body from the effects of stress). On the other hand, people suffering from illnesses such as CFS and burnout tend to have lower levels of cortisol, and one of the hallmarks of these illnesses is the inability to handle even moderate levels of stress. 5

1. Introduction

Burnout
The burnout syndrome is a set of physical and mental symptoms including exhaustion, fatigue, headaches, depression, anxiety, sleep problems, non-specific pain and digestive problems, although many other symptoms can also occur. The symptoms of burnout and CFS are identical except in their severity, with the dividing line between the two diagnoses being set at the point where the symptoms become highly disabling. According to Selye, the reason for burnout is simply too much stress. However, this does not explain why some people seem to be able to avoid burnout and still maintain high stress levels. It is known that people suffering from job-related burnout tend to be those who have lost motivation in their work and have low job satisfaction, so factors such as mental attitude seem to be important in determining stress tolerance. Similar psychological factors have been shown to be important in CFS as well, even though CFS patients are generally under little or no stress. People suffering from CFS appear to be in a state of persistent, chronic burnout in the absence of any stress.

Functional Disorders
There are a number of illnesses whose symptoms are not associated with any actual disease process. These so-called functional disorders are thought to be caused by some interaction between the mind and the body that results in the illness symptoms. Irritable bowel syndrome (IBS) is generally accepted by the medical profession as being a functional gut disorder (although some people still believe that it is caused by food intolerance or parasites). The situation is not as simple for CFS, with the medical profession divided among those who think it is a functional disorder and those who think it is caused by an as-yet unidentified disease process. The arguments for CFS being a functional disorder centre on the research showing that personality, lifestyle and mental attitude play a significant role in the illness. The arguments against point out that there are many studies showing physical and physiological abnormalities 6

1. Introduction

in CFS patients, such as shrunken adrenal glands and low blood volume. Functional disorders are usually explained in very simplistic terms by doctors as being caused by either stress or neurosis, and this probably has a lot to do with the antipathy that CFS patients have towards this explanation of their illness. In the course of this book, I aim to provide a better understanding of the nature of functional disorders such as IBS, as well as showing how this can be applied to CFS.

HPA Axis
The HPA axis, which has traditionally been seen as the body's stress system, and which ultimately controls levels of cortisol and other important stress related hormones, is generally underactive in people suffering from CFS and burnout. New research is beginning to show that the HPA axis should instead be thought of as the body's energy regulator, as it is ultimately responsible for controlling virtually all of the hormones, nervous system activity and energy expenditure in the human body, as well as modulating the immune system. In CFS and burnout the HPA axis becomes suppressed, resulting in the various physical and mental symptoms associated with these conditions.

Summary of Theory
I aim to show that stress and burnout are two separate states, and that stress does not necessarily lead to burnout (and perhaps more importantly, burnout can exist even when there is no stress). Burnout is the inability of the body to handle stress, and CFS is a state of long-term, chronic burnout that is not cured by the removal of stress. Stress tolerance is determined by the hypothalamus, and the HPA axis hormones in particular. In most people, these hormones follow a regular circadian pattern throughout the day, controlled by the body clock. Abnormal levels of these hormones can lead to burnout, chronic fatigue syndrome, irritable bowel syndrome and depression.

1. Introduction

As well as presenting the research into these disorders, I also discuss the psychological factors that act to influence the stress tolerance hormones, and show the steps that can be taken to increase the body's tolerance to both physical and mental stress. In doing so I aim to show how it is possible to recover from illnesses such as chronic fatigue syndrome, and how to prevent them from occurring in the first place.

Disclaimer
The information in this book should not be used as the sole source of information or diagnosis for CFS, IBS or any of the other disorders discussed. The advice of a medical doctor should always be sought in the first instance, and the appropriate tests should be done in order to rule out other conditions. Any change in treatment plan should always be discussed with a doctor beforehand. This is especially important for drugs such as antidepressants, where a sudden cessation of medication can result in dangerous side effects.

2. What is Stress?

2. What is Stress?
At its most basic, stress is the response of the body to any significant internal or external event that threatens homeostasis. This can be due to a physical cause, such as excess heat or cold, a viral or bacterial infection, or it can be psychological in nature. The body's response is similar no matter what type of stress is involved. Originally, it was believed that this response simply involved the release of catecholamines (adrenaline and noradrenaline) from the adrenal glands. However, pioneering research by Hans Selye and others in the first half of the twentieth century showed that the main stress hormone released by the adrenal glands is actually cortisol. Catecholamines can be thought of as the immediate response of the body to stress. They are released from the adrenal medulla, which is the small central part of the adrenal gland. Adrenaline has a number of effects on the body such as increasing the heart rate, contracting blood vessels to increase blood pressure and slowing down digestion. Noradrenaline has similar functions, but has less of an effect on the digestive system, and has slightly different effects on blood pressure and heart rate. Adrenaline increases systolic but decreases diastolic pressure, resulting in little change in mean pressure. Noradrenaline increases both systolic and diastolic pressure, resulting in an overall increase in mean blood pressure. Adrenaline has a half-life of about two minutes in the blood, so it is only a very short-term response. If the stress lasts longer than a few minutes, the outer adrenal cortex (which makes up most of the adrenal gland) releases cortisol, which can remain in the bloodstream for up to a few hours. Cortisol is a catabolic hormone, which means that it promotes the breakdown of muscle and fat. The main effect of cortisol is to increase levels of amino acids, fat and glucose in the blood, resulting in a higher availability of energy. In high concentrations (such as during a period of acute stress), cortisol 9

2. What is Stress?

sympathetic nerve fibres

medulla cortex

cortisol

adrenaline

Figure 1 The adrenal gland

can also increase blood pressure and suppress the immune system. A certain amount of cortisol is required in order for the adrenal medulla to produce adrenaline from noradrenaline. Normally the adrenal medulla releases 20 percent of its catecholamine output as noradrenaline, the rest being converted to adrenaline. Noradrenaline is one of the main excitatory neurotransmitters in the body, and is also released by sympathetic nerves throughout the body. Normally most of this noradrenaline is taken back up by the nerves, but the high levels of sympathetic nervous activation during times of stress can result in excess noradrenaline being released into the blood supply, where it adds to the effects of the adrenaline released from the adrenal medulla.

Autonomic Nervous System Response to Stress


The autonomic nervous system, or ANS, is the part of the nervous system that is controlled via the brain stem, spinal cord and hypothalamus, and is mainly concerned with the automatic functions of the body. The only part of the ANS over which there is any conscious control is breathing. The sympathetic branch of the ANS controls aspects of the body that are related to activity such as increasing heart rate, breathing and muscle tone, and decreasing digestion. The 10

2. What is Stress?

parasympathetic branch controls functions related to relaxation and recovery such as promoting digestion and lowering heart rate. Normally both branches of the ANS function simultaneously at a similar level, but during times of stress the balance is shifted to the sympathetic branch in order to give the body more energy to deal with the threat. Sympathetic nerves leading to the adrenal medulla cause the release of adrenaline and noradrenaline, which results in increased heart rate and blood pressure. Sympathetic nerves leading to the digestive system cause gut motility and digestive secretions to reduce, in order to divert energy to the muscles. Once the threat has gone, the sympathetic ANS then reduces its activity and the parasympathetic branch takes over, allowing the body to recover from the effects of the stress.

Endocrine Response to Stress


Any stress lasting longer than a few minutes results in increased levels of cortisol being released from the adrenal cortex. The release of cortisol is controlled by the hypothalamus, where corticotropin-releasing hormone (CRH) is released in response to the stress. CRH then acts on the pituitary gland, causing it to release adrenocorticotrophic hormone (ACTH), which in turn causes the adrenal cortex to release cortisol. CRH and ACTH are released in short pulses, each of which causes a (roughly) 15-minute sustained release of cortisol from the adrenal cortex, which then has a half-life of 100 minutes in the blood. Prolonged release of ACTH causes the adrenal cortex to increase in size (presumably to cope with a greater need for cortisol production), whereas long-term ACTH deficiency causes it to shrink. The combined system of CRH-ACTH-cortisol release is referred to as the hypothalamicpituitary-adrenal axis (or HPA axis). Positive and negative feedback occurs at various sites in the brain to ensure that cortisol production stays within certain bounds, depending on current requirements and stress levels. Another important hormone released by the pituitary along with ACTH is beta-endorphin, a morphine-like hormone. 11

2. What is Stress?

Both ACTH and beta-endorphin are similar in structure, and are released together in response to CRH stimulation by the hypothalamus. Endorphins are thought to be important in reducing pain during times of stress. In addition to cortisol, the adrenal cortex also releases DHEA, a precursor to the sex hormones testosterone and oestrogen, and aldosterone, a mineralocorticoid that maintains blood volume and pressure by controlling the sodium/potassium balance of the blood. Both DHEA and cortisol are released in response to ACTH stimulation, but aldosterone is relatively independent of HPA axis stimulation. The ratio of cortisol to DHEA depends on a number of factors. During acute stress and illness, the balance shifts towards cortisol and away from DHEA. Interestingly, mental attitude has been shown to influence the DHEA/cortisol ratio, with high DHEA-to-cortisol ratios corresponding to feelings of warm-heartedness, and low ratios corresponding to feelings of being stressed. Studies show that when people are trained to eliminate negative emotions and thought processes, their DHEA-to-cortisol ratio also increases. During normal, non-stress situations, a certain level of cortisol is maintained in the bloodstream. There is a circadian rhythm of ACTH and cortisol release, with the highest levels occurring around 8- 10am in the morning and the lowest levels around midnight. Other hormones released by the

06:00

12:00

18:00

00:00

06:00

Figure 2 Typical variation in cortisol levels throughout the day

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2. What is Stress?
brain SCN PVN

CRH N pituitary

ACTH adrenal gland

cortisol

Figure 3 Overview of the HPA axis

hypothalamus also follow a circadian rhythm, although not necessarily peaking at the same time. For example, growth hormone release peaks during sleep, and melatonin is released at night. The circadian pattern of cortisol release is controlled by the suprachiasmatic nucleus (SCN) of the hypothalamus, also known as the body clock. Nerve signals from the SCN cause the paraventricular nucleus (PVN) of the hypothalamus to release pulses of CRH roughly once per hour, resulting in HPA axis activation and cortisol release. There are also direct links between the SCN and the adrenal gland itself (bypassing the HPA axis) through sympathetic nerve fibres, causing the adrenal gland to become more sensitive to ACTH stimulation during the morning, further adding to the circadian pattern of cortisol release throughout the day. Both the amplitude and frequency of CRH pulses can vary to change the overall pattern of HPA axis activation.

Combined Response
The autonomic and endocrine (hormonal) responses to stress normally occur simultaneously, due to interconnections between the locus coeruleus (LC), which controls the sympathetic nervous system response to stress, and the PVN, which controls the HPA axis response. Activation of either of

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2. What is Stress?

these centres in the brain will result in the simultaneous activation of the other centre.

Feeding
During prolonged stress, cortisol released through activation of the HPA axis causes increased food consumption due to its stimulation of neuropeptide-Y (NPY) from the hypothalamus. NPY has a number of functions within the hypothalamus including increased appetite, stimulation of the parasympathetic nervous system (which is necessary for digestion), and a corresponding inhibition of the sympathetic nervous system. NPY release is inhibited by CRH (and vice-versa), so that during periods of acute stress the high CRH secretion causes lowered appetite and weight loss, whereas sustained activation of the HPA axis causes weight gain due to high levels of cortisol and NPY. This means that digestion and feeding are suppressed during periods of acute stress, but are enhanced afterwards in order to recover the energy expended during the stressful situation.

Long-term Consequences of Stress


It is well established that high levels of stress over a long duration have negative health consequences such as increased risk of gastric ulcers, high blood pressure and heart disease, and lowered immunity to infection. This is before we even consider the mental and emotional consequences of stress, which in many ways can be more debilitating than the physical symptoms. Cortisol has two main effects in the body. The main role is in facilitating the metabolisation of glucose and fat, and the breakdown of muscle tissue to produce energy. Cortisol is necessary for life, and a complete loss of cortisol results in death. The secondary role of cortisol is its effect in suppressing the immune system. In the short-term, this immunosuppression is a useful way of diverting the body's energy to the muscles in order to overcome a stressful situation. In the long-term, 14

2. What is Stress?

however, it makes the body more prone to viral and bacterial infections. High blood pressure is another consequence of high levels of stress, partly due to increased cortisol, but more importantly due to higher levels of catecholamines and sympathetic nervous activation. Sustained high blood pressure is a health risk because it increases the probability of having a heart attack or stroke.

General Adaptation Syndrome


As part of his stress theory, Hans Selye proposed that there were three stages in the body's response to stress, which he termed the general adaptation syndrome (GAS): [1] The alarm phase at the onset of the stress which causes the adrenal cortex to discharge all of its supply of stored hormones into the blood. [2] The stage of resistance, where the adrenal cortex enlarges due to continued stimulation by ACTH, which results in an enhanced ability to manufacture and secrete higher levels of cortisol. [3] The stage of exhaustion, which eventually comes after continued stress, and results in symptoms similar to the alarm phase. During this phase, the adrenal glands shrink and levels of cortisol fall, resulting in an inability to cope with stress. These results were observed in rats which were injected with noxious agents, and the same response was also observed for psychological stressors (such as being immobilised), as well as during chronic illness. Other symptoms that occurred during the alarm phase included bleeding and ulceration in the stomach and gastrointestinal tract. From his results, Selye proposed that many illnesses in humans that are not obviously caused by an external pathogen, such as liver disease and heart disease, might be due to the psychological stresses of modern life. He proposed that the 15

2. What is Stress?

continual stresses of modern life result in the exhaustion phase of the GAS, which then leads to one of any number of physical illnesses. This notion has been mostly rejected today due to advances in understanding about how the body works, with a greater concentration on the underlying mechanism of diseases. In fact, most of Selye's work seems to have been forgotten today, and his GAS has largely been rejected. While it could be said that he tried to apply his theories too broadly, one very important fact that he discovered and which is largely ignored today is the exhaustion phase of the GAS, which appears to be the same state as burnout and is a major cause of ill health. Today there is a pervasive dogma that stress equates to high HPA axis activation and high levels of cortisol, and there has been very little research into the causes and effects of low cortisol, even though low cortisol and reduced HPA axis activation have been demonstrated to be present in people suffering from CFS and burnout. Recent research shows that there are a number of factors that can lead to this reduced HPA axis activation, with long-term stress being just one factor (and possibly not even the most important). This will be discussed in detail in later chapters, along with evidence showing exactly how this burnout can result in the physical illness symptoms of CFS and IBS.

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3. Circadian Rhythms

3. Circadian Rhythms
The human body maintains a roughly 24-hour rhythm of activity and sleep, even in the absence of external light and darkness cues. This circadian rhythm is controlled by the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN controls the activity of the body through hormonal and nerve signals, which are directed to other parts of the hypothalamus, as well as to the rest of the body via the autonomic nervous system. Experiments on rats have shown that a number of the body's organs, such as the heart, lungs and liver, have their own internal circadian rhythms which are resynchronised periodically by the SCN. It has been shown that the SCN in rats can maintain its rhythm for up to 32 days after being removed. The circadian rhythms of the peripheral tissues, however, only last for a few days. The exact method of synchronisation between the main body clock in the SCN and the peripheral oscillators around the body is not known, but there is evidence suggesting that the daily cortisol rhythm provides the synchronising signal.

Hypothalamus
The hypothalamus consists of a number of different regions which receive inputs from many locations throughout the brain. The hypothalamus controls many systems throughout the body via the autonomic nervous system and the endocrine (hormone) system, and can be thought of as a master controller in the body. The region of the hypothalamus that is mainly responsible for the long-term stress response is the paraventricular nucleus (PVN). The PVN receives inputs from the SCN as well as other brain areas, and these inputs are combined to produce the appropriate level of HPA axis activation depending on the time of day, energy requirements, reproductive status and stress levels. 17

3. Circadian Rhythms

Although the PVN has inputs from the main body clock located in the SCN, it also has its own circadian oscillator which is periodically synchronised by the SCN. Stress affects the PVN by increasing the density of CRH-releasing neurons, as well as increasing the amount of CRH released by each neuron, both of which result in a higher circadian activation of the HPA axis. Although CRH is the main neurotransmitter responsible for activating the HPA axis, vasopressin is also released by neurons within the PVN and acts in a similar manner. Longterm stress has been shown to change the ratio of CRH- and vasopressin-releasing neurons in the PVN, causing a shift towards vasopressin-producing neurons. The reason for this is not known, but it is likely that vasopressin has a role in maintaining the high levels of HPA axis activation required during periods of long-term stress.

Hormone Rhythms
Many body systems and behaviours, such as alertness, sleep, immune function and feeding, follow a 24-hour circadian pattern. All of these cycles are thought to originate in the master body clock in the SCN, which then imposes its rhythm on various neurotransmitters and hormones throughout the body, as well as maintaining synchronisation of the peripheral circadian oscillators in the body's organs. Hormones and neurotransmitters related to waking activity such as serotonin, noradrenaline, cortisol and acetylcholine show a peak during the day, while others such as melatonin peak during the night. Melatonin is an important sleep-regulating hormone, and is released by the pineal gland in the hypothalamus. It is now known that the retina has special receptors, separate from the normal rods and cones used for sight, which feed into the pineal gland (via the SCN) allowing it to keep track of the length of day and night. The pineal stores serotonin during the day, which is then converted into melatonin and released during darkness. Melatonin has a number of different effects on

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3. Circadian Rhythms

the body such as reducing core body temperature, modulating the immune system and promoting sleep.

Resetting the Body Block


As has already been noted, the SCN can maintain its output for at least a couple of weeks without having to be resynchronised. The actual synchronisation can happen in a number of different ways, the most effective being sunlight received through the retina. Strong sunlight early in the day results in the phase of the circadian rhythm being advanced (so the peak occurs earlier in the day), while sunlight late in the day results in the rhythm being retarded. The amount of the phase shift depends on the time of day and the strength of the sunlight. Other factors that can phase shift the SCN include the neurotransmitters serotonin and neuropeptide-Y (NPY), the latter of which causes activation of the ANS and feeding when released into the hypothalamus. This may explain why jetlag can be cured (or at least eased) by having sufficient activity during the day, and by changing eating times to that of the destination. There are in fact many inputs to the SCN from different regions of the brain, so it is likely that synchronisation of the main body clock can occur by a number of different mechanisms. The common factor seems to be that activity, sunlight and the need to be awake force the SCN into its daytime mode, whereas lack of activity and darkness tend to either engage the night part of the cycle or else have no effect at all. While the SCN itself can easily be phase shifted by up to five or six hours in a single day, the peripheral circadian oscillators in other parts of the body (such as the liver and lungs) take longer to be resynchronised. In experiments done on rats, it has been shown that after a phase shift of 6 hours, it takes about 6 days for the peripheral tissues to become fully synchronised to the new rhythm. In some cases the resulting circadian rhythms are severely disrupted for a few days. This research shows that the body is well able to cope with small changes in circadian rhythm, such as the changing seasons, but 19

3. Circadian Rhythms

is much less able to deal with the very large changes that occur with long-haul travel and during shift work. It has also been shown that melatonin itself, taken in tablet form, can be used to phase shift the SCN and reset the body clock, as it is able to cross the blood-brain barrier (unlike serotonin). Melatonin is sold over the counter as a remedy for jetlag in the USA and many other countries, but cannot be sold in the UK without a prescription. In many mammals the SCN and pineal gland are thought to be responsible for keeping track of seasonal variations in sunlight, and for controlling behaviours such as hibernation and reproduction. It is likely that in humans the strength and amount of sunlight has at least some effect on behaviour and mood. The most notable example of this is seasonal affective disorder (SAD), a condition that causes some people to suffer from symptoms such as depression and reduced energy during the dark winter months.

Relationship to Stress
Chronic stress is known to affect various circadian rhythms such as body temperature, heart rate and the sleep cycle. There is no evidence that stress directly affects the SCN, so it is likely that these effects are due to stress affecting the peripheral circadian oscillators in other parts of the body, such as the PVN, as a result of the large changes in neurotransmitter and hormone levels that occur during times of stress. In some cases this results in a reduced need for sleep and a longer daytime cycle, but at other times the result can be one or more of the hormone rhythms becoming desynchronised or flattened. This appears to be more likely during periods of long-term stress, or during a period of rest after the stress.

Abnormal and Desynchronised Circadian Rhythms


It is possible for stress to affect circadian rhythms (and the sleep/wake cycle in particular), and it can even cause a kind of jetlag or desynchronised body clock. This can also occur in the 20

3. Circadian Rhythms

absence of stress, as is seen in many patients suffering from CFS and SAD. Although daylight is the main factor responsible for setting the SCN rhythm, inputs from other parts of the brain via serotonin and NPY are equally effective. This can be seen in shift workers and blind people, who are not normally exposed to sunlight during the day but who are able to maintain a normal circadian cycle. The important factor here is likely to be the activity performed during the daytime phase, which has the same effect as sunlight in maintaining synchronisation of the body clock. Some people suffer from a desynchronised body clock during the winter, due to a lack of sufficient sunlight to keep the normal rhythm. This is related to SAD, which is thought to be caused by there not being enough sunlight during the day to shut off the conversion of serotonin to melatonin in the pineal gland. Different people have different levels of sensitivity to melatonin suppression by sunlight. In most people the amount of melatonin suppression depends on the total amount of sunlight entering the eyes over the previous few days or weeks. During times of high brightness levels, quite a high level of light is required in order to produce a significant amount of suppression. When there is a generally lower level of light entering the eyes, lower amounts of light are required for the same amount of melatonin suppression. This sensitivity is different in different people, and it is likely that this difference is a factor in causing disorders such as SAD. The result can be either an abnormally high level of melatonin during the day, causing depression, sleepiness and lack of energy, or else a completely desynchronised body clock. There is also some evidence that people suffering from bipolar disorder (manic depression) have an abnormal response to light, in that they show melatonin suppression when exposed to very dim light. Why this occurs and whether it is related to SAD is not known. The difference between the light levels inside a home or office and natural light (even on a dull day) is quite large. Natural sunlight varies from about 10,000 lux on a cloudy day to over 100,000 lux on a bright summer's day. In contrast, light levels inside the home or office tend to be between 300 and 21

3. Circadian Rhythms

1000 lux. Most researchers recommend levels of at least 2,500 lux for a few hours a day to cure SAD, with 10,000 lux recommended. Apart from the direct synchronising effect of sunlight on the SCN, there is evidence that the strength of sunlight during the day is related to the amount of melatonin released by the pineal gland at night. A lack of sufficient light during the day could result in insufficient melatonin at night to maintain synchronisation of the body clock and promote normal sleep, or even a flattening of the melatonin rhythm. Many people suffering from insomnia show an abnormally low or flattened melatonin rhythm, and this is thought to be a significant factor in the condition. As both sunlight as well as physical and mental activity can act to synchronise the body clock, one possible reason for the spontaneous jetlag suffered by some people, as well as possible cause of SAD, could be a combination of lack of sufficient sunlight as well as a lack of activity. During the dark winter months, with less sunlight and reduced scope for physical activities, it is easy to see how some people who are genetically predisposed to having a more easily shifted body clock might suffer more easily from the effects of this spontaneous jetlag. It is well known that melatonin is effective at resynchronising the body clock through its action on the SCN, which can be useful for people who suffer from a desynchronised body block, whatever the cause. Unfortunately, melatonin is not prescribed very often, as the medical profession is generally unaware of the condition, simply putting down any symptoms of insomnia at night and tiredness during the day to stress. Even if the initial cause of the symptoms is stress (which is not always the case), using melatonin in tablet form can be a fast and effective way of resynchronising the body clock rather than having to wait for the body to do this naturally (which may take some time if there is a lack of sufficient external synchronising cues), and can also act to normalise other hormone rhythms in the body through its action on the SCN.

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Light boxes provide another way of resynchronising the body clock for patients who do not want to use melatonin. Although this provides a more natural alternative to melatonin, the prices of these products tend to be quite high.

Hormone Rhythms in CFS Patients


People suffering from CFS tend to suffer quite often from a desynchronised sleep cycle, and in some cases there is a complete lack of melatonin rhythm at all. Having a desynchronised melatonin rhythm can also reduce the peak melatonin amplitude, causing further problems. As melatonin is so important in regulating many body functions (such as the temperature cycle and immune system function), any desynchronisation or reduction in amplitude is likely to exacerbate any illness symptoms. Melatonin in tablet form can be useful for CFS sufferers in alleviating sleep problems, but it is not effective in all cases. Indeed, it should be noted that melatonin only needs to be taken once in order to resynchronise the body clock. At least one study has shown that giving CFS patients melatonin every night over a period of weeks has no effect on their symptoms. It is only the patients who are suffering from a desynchronised body clock who are likely to benefit from melatonin treatment, and in those cases a single dose is normally all that is required. When levels of hormones such as cortisol are measured in people with CFS, the results are contradictory. Some studies show elevated levels of a certain hormone while other studies show the opposite. What does seem to be agreed upon, however, is that there is less of a circadian rhythm of hormones (and cortisol in particular) in patients with CFS, and sometimes a complete flattening of the rhythm. It is known that long-term stress can lead to a flattening of the cortisol rhythm, and in many ways the effects of long-term stress resemble CFS. The main difference is that people suffering from CFS tend not to be under any great stress (and many are in fact too ill to work). The CFS patients who show the greatest signs of recovery from the illness also tend to be

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3. Circadian Rhythms

those who show the most increase in the circadian variation of their cortisol rhythm. Abnormal hormone rhythms are clearly a major factor in the etiology of CFS, and as we shall see later, it is possible that these abnormal circadian rhythms cause all of the other symptoms of CFS.

Burnout
Research by Dr. Charles A. Morgan into the effects of burnout on soldiers enrolled in a combat diver qualification course showed that those soldiers suffering from burnout had a lower circadian variation in cortisol levels, with lower-than-normal cortisol in the morning and higher-than-normal in the evening, similar to that found in CFS patients. The soldiers suffering from burnout also had the poorest swimming times and navigation rankings on the course.

Sex Hormones and HPA Axis Activity


It is known that in women, HPA axis activity is modulated by the menstrual cycle, and that women's reaction to physical and emotional stress, in terms of HPA axis activation, depends on which phase of the menstrual cycle they are on. This effect is most likely mediated by estradiol, the main oestrogen released by the ovaries, which follows a monthly pattern of release along with progesterone. Estradiol is known to activate the HPA axis due to its stimulating action on the CRH-releasing neurons in the hypothalamus, and it thus alters both the sensitivity of the HPA axis in response to stress and its basal activation in the absence of stress. Men tend to have a higher hypothalamic drive than women, in that they produce greater HPA axis activation from the hypothalamus in response to stress. Although men do not have the same monthly variation in HPA axis activity seen in women, there is some evidence that men have shorter cycles, of a few days to a few weeks, in testosterone levels. Some of the testosterone in the body is converted (or aromatised) into estradiol, after which it has the same stimulating effect on the HPA axis. 24

4. Introducing a New Theory

4. Introducing a New Theory


The existing theories about stress are useful as far as they go, but they do not adequately explain burnout and CFS, which appear to be caused by an inability to handle stress (or reduced stress tolerance), rather than simply being caused by excessive stress. Additionally, most explanations of stress-related illness symptoms are very simplistic, simply putting the symptoms down to excessive stress or the wrong attitude to stress, without going any further. In addition many explanations of stress are plain wrong for example putting the symptoms of long-term stress down to the fight or flight sympathetic nervous system response, even though the longterm stress response is mainly governed by the HPA axis. The condition of burnout is usually associated with a high stress job. The general pattern is that after working at the job for some period of time (perhaps a number of years) without any problems, at some point the person begins to lose interest and motivation in the work, and starts experiencing physical and/or mental symptoms such as depression, fatigue, headaches, insomnia or recurring infections. There may be contributing psychological factors such as increasing loss of control over the work, changes in working practices that are not wanted, or emotional stresses outside the workplace. Usually the person decides that they wish to change jobs, or even move to a different line of work entirely. In most cases the symptoms ease when the person takes time off work, leaves their job or changes to a different career. CFS has similar symptoms to burnout, but is different in a number of ways. First of all, it is usually triggered by a viral flu-like illness that the patient never seems to fully recover from. For a period of months or even years the patient suffers from extreme fatigue, sometimes having to spend whole days in bed, as well as other symptoms such as depression, insomnia and digestive problems. The range of symptoms suffered by

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4. Introducing a New Theory

CFS patients is different in each person, which makes it difficult to achieve a diagnosis. While burnout and CFS may initially appear to have different causes, further investigation reveals that they are in fact quite similar. A lower HPA axis activation is seen in both, with a range of similar symptoms that are only different in their degree of severity and duration. In many cases CFS begins during a period of emotional or work stress, beginning as burnout and then developing into CFS, the symptoms of which persist long after the initial stressor has been removed. In fact, research shows that fever-inducing illnesses have a very similar effect on the HPA axis as other types of physical and mental stressors, and this will be discussed in more detail in later chapters. While it is easy to simply say that both burnout and CFS are simply due to depression and/or psychological problems, this in itself does not adequately explain the physical and physiological symptoms suffered by CFS patients. Many CFS patients have shrunken adrenal glands and abnormalities in their immune and endocrine systems that are not present in patients suffering from depression. In terms of HPA axis activation, people suffering from major depression generally have abnormally high HPA axis activation, whereas CFS patients tend to have the opposite. In addition, many CFS patients tend to see depression as a symptom of their illness rather than a cause. Patients with CFS feel that rather than being over-stressed, they instead have a reduced stress tolerance, resulting in stress symptoms such as fatigue, sweating or excessive heart rate when performing mental or physical tasks that are only mildly stressful. Such a distinction between stress and stress tolerance is not generally recognised by medical science, which would rather put such symptoms down to an excessive stress response instead.

Low Cortisol
There is a widespread myth that stress equates to high levels of cortisol and HPA axis activation, and that stress levels can be 26

4. Introducing a New Theory

assessed by simply measuring the amount of cortisol in the blood. This is a great over-simplification of the actual response of the body to stress. Initially, during a period of acute stress, large amounts of cortisol are released into the blood due to the high activation of the HPA axis, but during the long-term things aren't quite so simple. A study done on teachers to assess how feelings of burnout related to hormone levels showed that those teachers who scored highest on the Maslach Burnout Inventory, a questionnaire that assesses symptoms of job burnout, had the lowest levels of cortisol during the day, whether or not they were under stress. Studies on CFS patients have also found lower levels of cortisol, a reduced HPA axis response to stress, as well as a tendency to have shrunken adrenal glands (presumably due to a long-term under-activation of the HPA axis). The symptoms of acute adrenal insufficiency include hypotension, weight loss, tiredness, weakness, nausea, vomiting, loss of appetite and diarrhea. These symptoms also tend to be quite common in burnout and CFS, especially during the acute stages. In his book The Stress of Life, Selye notes that experiments on squirrel monkeys show that the dominant animals tend to have higher cortisol and lower adrenaline levels than their subordinates. More recent experiments performed on socially stressed male rats showed another interesting result. These rats were housed in the visible burrow system, which is a model of chronic social stress. All of the rats showed increased HPA axis activation in response to the stress, but there was a subgroup of rats which, after 14 days, displayed a reduced level of HPA axis activity that was below that of either the dominant or the submissive rats. These non-responder subordinate rats were also the most severely stressed by the experiment, as determined by the amount of weight loss experienced. The reason for the blunted HPA axis response in the nonresponder subordinates is not known, but it is thought that a dysregulation at some point in the HPA axis itself is to blame, possibly due to the genetic make-up of these rats. These nonresponder rats show a similar response to the stressed rats in 27

4. Introducing a New Theory

Selye's experiments, which eventually went into the exhaustion phase of the GAS, showing reduced adrenal response after prolonged stress. Very little other research has been done in this area to determine whether it is the length of the stress, the type of stress, or the genetic make-up of the subject which determines whether chronic long-term stress leads to exhaustion and burnout, or whether it is a combination of all three. There are obviously ethical issues regarding experiments involving putting animals under stressful situations for periods of months at a time, but considering that humans voluntarily put themselves into highly stressful situations on a regular basis there should be no lack of suitable subjects.

Stress Tolerance
Under similar stressful conditions, some people will handle the experience better than others. Mental outlook and personality seem to be the key factors, and in particular motivation and the sense of being in control of the situation. This is particularly relevant for work-related stress. People who tend to enjoy their jobs and are well motivated tend not to suffer from burnout. The usual reason given for this is that these people do not perceive their job as stressful, and therefore do not produce the high HPA axis and sympathetic nervous system response that the stressed out people have. However, many people in high stress jobs do suffer from the effects of high stress hormones, such as high blood pressure and stomach ulcers, but do not go on to suffer from exhaustion and burnout. The study on burnout among teachers showed that the ones who felt they were under stress but not suffering from burnout had high levels of cortisol, whereas those who were suffering from burnout tended to have low levels of cortisol whether or not they were under stress. The factors associated with high levels of burnout were low job satisfaction, low perceived levels of support, low perceived levels of being able to cope with stress and high levels of emotional exhaustion (although this could be a symptom rather than a cause). The study also showed that the teachers scoring highest on the burnout scales had the highest level of physical complaints, 28

4. Introducing a New Theory

and teachers who were both high on the burnout scale and under stress had the highest level of physical complaints among the whole group. The stress level did not seem to alter the number of physical complains suffered by the teachers who scored low on the burnout scale. This seems to suggest that mental attitude, in determining whether or not a person suffers from burnout, is critical in determining whether or not stress leads to physical illness symptoms. The effects of motivation on combat troops are well known to the military. A very high importance is given to keeping soldiers well motivated, whether this means allowing them to receive letters from home or ensuring they have fresh food whenever possible. Well-motivated soldiers tend to last longer before succumbing to fatigue, fight better, and are more likely to succeed in achieving their objectives when under great stress. It would seem that in long-term stressful situations, having a higher than normal HPA axis response is beneficial, whereas having a low HPA response will tend to result in the symptoms of burnout. High motivation is one of the psychological factors that allow a high HPA axis response to stress to be sustained over the long-term. In fact, it may be more accurate to think of the HPA axis as the body's response to the need for activity and energy expenditure, whether stressful or not. It is known that the HPA axis is activated during feeding, and experiments on rats have shown that the amount of HPA axis activation while eating a meal is similar to that produced by the stress of being restrained for 20 minutes. Both feeding and restraint produced a similar response in the CRH-releasing neurons of the amygdala, a part of the temporal lobe that is activated by feelings of fear and anxiety. Although feeding does not cause feelings of fear, they both appear to cause similar levels of HPA axis activation in the amygdala. While one interpretation of this experiment is that feeding is a dangerous time when the possibility of infection by parasites or poisons is high, a more likely explanation is that HPA activation is necessary for the process of digestion itself. It is known that cortisol, the end-product of HPA axis 29

4. Introducing a New Theory

activation, has a protective effect on the gut. Under acute stress, the blood supply is diverted away from the gut towards the muscles and vital organs, which can cause the gastric acid in the stomach and duodenum to damage the gut lining, resulting in ulceration. Cortisol can prevent this ulceration by maintaining the blood supply to the blood vessels in the gut, thereby maintaining the protective mucous lining. Cortisol also causes increased absorption of water and sodium in the colon and rectum, which is important for the normal functioning of the bowel. As well as the protective effects of cortisol on the intestinal tract, HPA activation is necessary for the process of digestion itself. Digestion requires activation of the vagus nerve and the parasympathetic nervous system, and this is dependent upon activation of the HPA axis. Digestion also requires increased blood flow and energy metabolisation, as well as increased activation of the immune cells in the intestinal wall, all of which requires HPA axis activation. It would seem that the HPA axis is important for all parts of the digestive process, and any under-activation is likely to lead to problems such as irritable bowel syndrome, as we shall see later.

New Theory
It appears that some people cope with stress better than others. This is due to many factors, such as some people simply being more anxious about events that other people perceive as minor. However even where different people all perceive an event as stressful, some people seem to be able to cope well with the stress, or even thrive on it, while others end up suffering from one or more of the symptoms of burnout. The key seems to be the HPA axis, in that people who tend to cope well with long-term stress tend to have a different pattern of activation of the HPA axis. People suffering from burnout and CFS tend towards a reduction in HPA axis drive, which, when combined with having to deal with a stressful situation, results in negative mental and/or physical symptoms.

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4. Introducing a New Theory

There may be a genetic factor that predisposes some people to reduced HPA axis activation under chronic stress. However it seems that psychological factors are important in avoiding this state of HPA axis under-activation in response to stress, whether or not genetic factors come into play.

Causes of Burnout
There appear to be three factors that increase the risk of suffering from burnout. The first of these is a genetic predisposition, with some people being inherently more likely to suffer from burnout than others. Second, going from a period of long-term stress, illness or high workload to a period of relaxation can trigger burnout. The third and possibly most important factor is mental attitude. A positive mental attitude towards stressful events can result in a greater activation of the HPA axis and therefore a greater ability to handle that stress. A negative mental attitude towards the stress can have the opposite effect, resulting in reduced HPA axis function, less circadian variation in the HPA axis hormones over the day, and a lower stress tolerance as a consequence. It is also not simply the case that perceiving the situation as less stressful reduces burnout. People suffering from CFS have the same symptoms of burnout, even though in most cases they are under very little stress. The study of teachers suffering from burnout shows that burnout and stress are really two different states, and that it is possible to suffer from burnout without being under any significant stress (and vice-versa). CFS appears to be a state of persistent, chronic burnout, where the symptoms remain after the initial HPA axis stressor has been removed. The existing research shows that psychological factors are important in determining whether or not burnout occurs, but does not really go much further. The study on teachers suffering from burnout shows that losing the enthusiasm, interest and motivation in work can lead to burnout. In reading the accounts of people suffering from both burnout and CFS, a common trigger for recovery in a number of cases is moving to a different job that is more fulfilling. Of course, such a simple 31

4. Introducing a New Theory

solution as changing jobs does not work in all cases. Many people who have CFS say that before contracting the illness they were very happy in their jobs. From reading the accounts of people suffering from burnout and CFS, what seems to be important is the existence of short- and long-term goals, and having an interesting and fulfilling job is only one aspect of this. In the case of CFS in particular, it is very common for people to think that they have to reduce their activity and stress levels in order to recover from the illness. However in many cases this enforced rest and relaxation simply leads to continued persistent illness. Unlike a viral or bacterial infection, where rest is likely to aid recovery, with CFS too much rest appears to lead to continued HPA axis suppression and prolonged illness. Having a positive mental attitude is another aspect of this. In fact, research shows that having a pessimistic, negative or hostile attitude to life is a predisposing factor to contracting many types of illnesses, such as coronary heart disease, rheumatoid arthritis and various other conditions. There is growing evidence that there is a disease prone personality that leads to more illness than in the general population. Mental attitude and personality have also been shown to be factors in determining which patients recover from CFS and which do not, although this will be discussed in more detail in later chapters. A common trigger for both burnout and CFS is chronic stress followed by a period of relaxation. In many cases the body appears to develop a tolerance to high stress levels, and when the stress is removed, the result is abnormally low energy levels and the symptoms of burnout. Some people appear to be predisposed to suffering from illness during periods of rest following high workloads, as a study from Tilburg University in the Netherlands recently showed, and this relaxation sickness appears to be due to the same mechanism that causes burnout following stress. This study is discussed in more detail in chapter 5.

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Purpose of Burnout
There appears to be a similar personality trait among sufferers of burnout and CFS, namely a tendency towards being a high achiever and/or a perfectionist. In the right circumstances, this personality type when combined with other factors seems to result in the symptoms of burnout. It could be that some people simply need high levels of activity, in terms of motivating short- and long-term goals, in order to function normally. A lack of sufficient goals, possibly in addition to other factors, will then result in some kind of burnout. Another possibility is that some people have a genetic trait that gives them a more variable HPA axis response, which can change depending on perceived goals and motivation. Whereas most people have a relatively uniform pattern of circadian HPA axis activation except in times of stress, these high achiever/burnout-prone people may have the ability to push themselves further than normal, in terms of mental or physical activity, when it appears that such activity is beneficial. This could have had an evolutionary benefit in pushing people to explore and colonise new territories, or in allowing them to come up with new ideas and inventions. The other side of the coin is that these people may also be more prone to disorders such as depression, burnout and CFS during the times when the outlook is more negative. Burnout itself could be a protection mechanism that protects the body from the effects of long-term stress. It is well known that chronic stress over a long period of time increases the risk of death due to heart disease. In fact a recent study showed that people in stressful jobs have twice the risk of dying from heart disease than people working in less stressful jobs. A reduction of the stress response is clearly a very important survival tool, and it is possible that burnout is the body's response to prolonged stress when it appears that continuing with the stressful activity is not in the persons best interests. The burnout experienced by some people during a period of rest after undergoing long-term stress, as well as the HPA 33

4. Introducing a New Theory

axis suppression sometimes seen after a period of chronic illness, could be a built-in mechanism to force the body to rest and recover. The human body is designed to cope very well with periods of short-term stress, provided there is sufficient time afterwards to recover. Burnout may therefore be a way in which the body aims to prevent the person from performing long-term stressful activities that are perceived as not being essential for survival. In the absence of such a forced rest mechanism, people would be more likely to push their bodies too far past the normal limit, for too long a period of time, possibly resulting in death. While this may not be as important for psychological stress which, apart from the heightened risk of heart-attack, is not particularly dangerous it would be a significant risk in the case of physical stress, which is the main type of stress that the body has evolved to cope with.

Circadian Rhythm of HPA Axis Activation


The normal activation of the HPA axis results in a circadian rhythm of cortisol and other hormones over the course of the day. This rhythm is ultimately controlled by the SCN, which then imposes its rhythm on other, peripheral oscillators throughout the body. The PVN within the hypothalamus has its own circadian oscillator which is responsible for controlling the circadian activation pattern of the HPA axis and ultimately the cortisol rhythm. All the research so far has shown that stress does not affect the output of the SCN directly. It is known, however, that stress does directly modulate the activity of the circadian oscillator genes in the PVN, resulting in greater secretion of both CRH and vasopressin, and therefore a higher activation of the HPA axis following the circadian pattern. The reduced HPA axis function seen during CFS and burnout is therefore likely to be due to suppression of the CRH and/or vasopressin neurons within the PVN, which then leads to a reduction and flattening of the normal circadian pattern of hormone release. Having a circadian rhythm rather than a constant level of certain hormones, such as cortisol and melatonin, is important to many systems in the body, and the abolition of the normal 34

4. Introducing a New Theory

rhythm is likely to cause many of the symptoms associated with CFS and burnout. Sleep, in particular, is governed by a number of circadian hormone rhythms, the main one being melatonin, which is necessary for normal sleep. During sleep itself, suppression of the HPA axis is required for the deepest slow-wave sleep to occur. This is controlled by the hippocampus, a site in the brain which has a high concentration of cortisol receptors, and which is also involved in learning. If the normal nocturnal HPA axis suppression does not occur, the hippocampus is not able to do its normal process of long-term memory storage. The daily cortisol peak is used as a signal by the hippocampus in order to control the overall level of HPA axis activation through negative feedback. Interestingly, the very high levels of cortisol released during periods of acute stress cause a breakdown in this negative feedback control system, resulting in continued high levels of HPA axis activation. If the acute stress lasts for a long time (as in the case of a trauma which results in post-traumatic stress disorder), the neurons in the hippocampus start to die off, and the size of hippocampus can be seen to be visibly reduced. This serves to cause longterm hyper-activation of the HPA axis, due to the removal of the negative feedback mechanism, resulting in the symptoms of PTSD. This reduction in hippocampus volume is not seen in CFS patients, evidence that PTSD and CFS are two separate illnesses. Overall there are a number of factors that combine to influence the circadian pattern of activation of the HPA axis. These include: Stress. Illness. Workload and physical activity. Mental attitude. Current state of the various parts of the HPA axis network, due to changes in hormone receptor density and secretory neuron density. Sex hormones, menstrual cycle and oral contraceptive use. 35

4. Introducing a New Theory

Desynchronisation of hormone rhythms due to lack of sunlight or abnormal melatonin rhythm. Stimulant use such as caffeine, nicotine, cocaine, etc. These factors combine to determine the state of the HPA axis, the amplitude and shape of the cortisol graph throughout the day, and the ability to handle stress. Some of these factors change on a daily basis, while others are due to long-term changes in HPA axis function and therefore take a long time to reverse.

The Role of NPY, the Anti-stress Neurotransmitter


As we have already seen, NPY is an important neurotransmitter that regulates feeding, digestion and ANS activation within the hypothalamus. However NPY has a much wider role than this, and is found in many other regions of the brain. In the prefrontal cortex, increased levels of NPY are associated with a greater tolerance for stress and reduced anxiety. Research by Dr. Charles Morgan at the National Center for Post-Traumatic Stress Disorder demonstrates just how powerful this effect can be. Army recruits undergoing survival training at Fort Bragg were tested for levels of NPY both before and after the training session, which included a mock POW camp where trainees were held for a few days. They found that the increase in cortisol and reduction in testosterone during these training sessions were some of the most dramatic they had ever seen, showing just how stressful the training session actually was. They found that the recruits who coped best were those who had the highest levels of NPY during the session, and the special forces trainees had the highest levels of NPY of all the recruits. After 24 hours NPY levels in the special forces trainees were back at baseline levels, but in the other trainees NPY was significantly depleted. Lower levels of NPY were associated with feelings of anxiety and being worn out, while those with high NPY stayed mentally focussed during and after the stress. It was also noted that the subjects with the highest

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levels of NPY had fewer health complaints after the stressful military training. Other research has shown that patients suffering from bipolar disorder have reduced levels of NPY in the prefrontal cortex, and imbalances in NPY have also been implicated in depression. Overall, the research seems to suggest that NPY has a protective effect during times of stress, and that a lack of NPY, especially during non-stress periods, can result in the symptoms of low stress tolerance that are associated with burnout and CFS. It is likely that some combination of NPY and HPA axis imbalance results in an inability to deal with stress, and ultimately leads to burnout and CFS. The prefrontal cortex is an important regulator of the HPA axis, and is therefore a prime candidate for the role of stress regulator within the brain. This will be discussed in more detail in the next chapter.

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5. Stress, Mental Attitude, Illness and the Immune System

5. Stress, Mental Attitude, Illness and the Immune System


It has long been known that when given the opportunity, the human body will generally heal itself. There are obviously cases where the body simply has not evolved the defences to cope with certain viruses or bacteria, and medical intervention can mean the difference between life and death. However in the case of the most common viruses such as the common cold and influenza, the human body will eventually rid itself of the infection without requiring any outside intervention. All remedies for colds, influenza and respiratory infections simply treat the symptoms, and in many cases work by blocking the body's normal immune response. Research shows that these remedies do not reduce the duration of symptoms, and it is possible that in some cases using such remedies could actually prolong the illness due to their interference with the normal functioning of the immune system. Caffeine is a common ingredient in many remedies for both colds and headaches, as it increases the ability of painkillers such as paracetamol and aspirin to reduce headache pain. Caffeine also has the effect of increasing levels of various neurotransmitters in the brain, as well as stimulating the release of adrenaline from the adrenal glands. Research shows that caffeine partially suppresses the T and B cell responses of the immune system, so it is possible that remedies containing caffeine could actually prolong the symptoms of a cold or influenza infection rather than reducing them in some cases. The actual effect may depend on whether or not the person is a regular caffeine user, as most of the stimulant effects of caffeine are reduced by regular use because of tolerance. No research has yet been done on the relationship between use of caffeine-containing remedies and the duration of illness symptoms. 38

5. Stress, Mental Attitude, Illness and the Immune System

Many people use fever-reducing drugs such as aspirin to reduce the painful symptoms of an infection. While such medications will bring about a relief of symptoms, their feverreducing effect counteracts the body's natural healing process. The higher body temperature during a fever results in a less beneficial environment for many microorganisms to grow in, and also speeds up the enzyme reactions used by the immune system to combat the infection. While an excessively high fever can cause damage to the body, a mild fever is generally beneficial to healing. It used to be the case that doctors would hand out antibiotics at the first sign of illness, even for a cold or influenza infection, but now it is recognised that this has little or no effect, and simply causes bacteria to become resistant. However there is still a general preoccupation with treating all minor infections with drugs, even though most of the time those drugs simply block the body's natural healing process and just bring about a reduction in symptoms. These illness symptoms, such as fever, inflammation, tiredness and increased mucous secretion, are never in fact caused by a pathogen, but are part of the body's natural healing process. The danger of this preoccupation with using pills to treat every illness is that for certain illnesses, such as CFS, these approaches simply do not work, and treatments which take into account the mind-body nature of the illness are required.

Overview of the Immune System


The immune system can be split into two parts: innate immunity, which is not specific to any particular pathogen, and specific immunity, which can recognise and eliminate specific pathogens such as bacteria, viruses, parasites and toxins (collectively termed antigen). Specific immunity can be further split into humoral immunity and cell-mediated immunity. Humoral immunity is mediated by B cells (so called because they mature in the bone marrow), which are a type of white blood cell that release antibodies which then bind to antigen. Antibodies are small molecules composed of a number of amino-acid chains and do 39

5. Stress, Mental Attitude, Illness and the Immune System

not directly destroy antigen themselves. Instead, they bind to antigen that they are programmed to recognise, and they then signal to other parts of the immune system which then destroy the antigen. Humoral immunity was so called because antibodies are present in the blood serum (or humor), which is the liquid part of the blood that remains once the red and white blood cells have been removed. Each B cell makes a single type of antibody, which is determined by random rearrangements in certain parts of the B cell gene coding that occur while the B cell is maturing in the bone marrow. Cell-mediated immunity is performed by T-cells, which are a type of white blood cell that matures in the thymus. Like B-cells, T-cells are programmed to recognise and bind to specific antigen. The main difference is that T-cells can only bind to self cells, i.e. cells that are part of the human body. The humoral response is normally used against extracellular bacteria (bacteria which live outside the bodys cells), while the cell-mediated response is used to defend against altered or infected body cells such as cancers and virusinfected cells. Other white blood cells such as macrophages and natural killer (NK) cells can participate in both the humoral and cellmediated immune responses, and are activated by cytokines, which are signalling molecules similar to hormones. Cytokines help to regulate the overall immune response, resulting in the activation and suppression of different parts of the immune system. Cytokines also affect the central nervous system, resulting in sickness behaviour such as sleepiness, lethargy and lack of appetite, which is thought to be a protection mechanism to force the person to rest and conserve energy while the infection is being fought by the immune system.

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5. Stress, Mental Attitude, Illness and the Immune System


HUMORAL RESPONSE CELL-MEDIATED RESPONSE

B cell

T cell

antibodysecreting B cell

TH cell

TC cell

antibodies

cytokines bacteria

altered self cell

Figure 4 Overview of the immune system

A certain class of T cells, called T-helper (or TH) cells are important in controlling the overall activation of the immune system, by releasing cytokines that alter the responses of various immune system cells. TH1 cells result in activation of the cell-mediated immune response, whereas TH2 cells activate the humoral response. Normally the activation of TH1 or TH2 cells is determined by the type of infection, but sometimes the body can get it wrong. Certain viruses can fool the immune system into producing a TH2 response when a TH1 response would be more appropriate, due to the virus mimicking proteins normally present on cytokines, or by infecting immune cells themselves. This can result in an inappropriate immune response to the virus, leading to a longer period of infection.

TH1/ TH2 Balance


An overactive TH1 immune response can increase the risk of autoimmune disorders, as the body is more likely to attack healthy cells. An overactive TH2 response on the other hand can lead to allergies, as the TH2 cells are more likely to detect antibodies bound to environmental toxins. Certain autoimmune disorders are also associated with a TH2 immune response, such 41

5. Stress, Mental Attitude, Illness and the Immune System

as Grave's disease, where antibodies bind to the thyroidstimulating-hormone (TSH) receptor causing hyperthyroidism and systemic lupus erythematosus (SLE, or sometimes just called lupus), where auto-antibodies bind to a large variety of healthy body tissues causing widespread damage. There are systems in the body that normally act to prevent these inappropriate and dangerous responses. When T and B cells are created, the types of molecules that they can bind to are chosen by random variation. It is therefore very likely that they could bind to self cells. This is prevented by a mechanism that ensures that those T and B cells that bind to self cells are destroyed before being released into the body. However certain proteins, such as those found in the nerve protein myelin and in pancreatic cells, are not present in the bone marrow and thymus, and there is a chance that T or B cell receptors could be generated which bind to these proteins. Self-cell receptors for myelin and pancreatic proteins are thought to cause multiple sclerosis and insulin-dependent diabetes respectively. Various factors are thought to increase the risk of an autoimmune response occurring, such as a virus mimicking these autoimmune-prone proteins, as well as genetic factors that predispose certain people towards a TH1 or TH2 immune response. Women are more prone to many autoimmune diseases than men as they tend to have a TH1-predominant immune response, which is thought to be due to the sex hormones. This TH1 predominance in women disappears during pregnancy, as it could cause the mother's immune system to attack the unborn child. Sunlight is also known to significantly reduce the incidence of autoimmune disorders, through the action of vitamin D on the immune system. The incidence of multiple sclerosis is significantly reduced in people living in sunnier climates as well as in populations that eat a lot of fish (both of which result in higher vitamin D intake). Experiments on mice have shown that vitamin D completely prevents experimental autoimmune encephalomyelitis, an artificially induced illness similar to multiple sclerosis, suggesting that vitamin D is a very powerful protector against autoimmune diseases. 42

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An imbalance in TH1/TH2 cells alone is not enough to trigger an allergic reaction or autoimmune disorder, but it can significantly alter the risk of developing one of these conditions. Although in most cases the TH1/TH2 balance is determined by genes and by the type of infection, personality, mental attitude and stress can influence the balance, sometimes resulting in a shift towards TH2 predominance. It is known that CFS patients, who tend to have low HPA axis activation and lower than normal levels of cortisol, generally have reduced immune function. Studies on CFS patients also tend to show a shift in the immune system away from the TH1 immune response, and towards the TH2 response, resulting in a tendency towards allergic reactions and long-term viral infections. Although many researchers believe that CFS is caused by a viral infection, there is no evidence that this is the case. Although viral infections are common triggers for CFS, there is no single virus that has been found to infect all CFS patients. There are also many cases of CFS that did not begin with any viral infection at all. In fact there is reason to believe that the immune system irregularities seen in CFS patients are simply symptoms of the illness rather than being the result of an ongoing active infection. This will be discussed in more detail in chapter 6.

Effect of Stress on the Immune System


In the normal course of things the body will be able to heal itself of all but the most serious infections and injuries. This, however, may not be the case when there are additional physical or mental stresses present. It is known that cortisol and adrenaline, the main stress hormones, will suppress the immune system when released in excess. However there are other factors that can influence the immune system either positively or negatively, some of them reversing the immunosuppressant effects of cortisol. Some people try to take as little time off work as possible when sick, relying on medications to relieve the symptoms so that they can return to work as soon as possible. This can 43

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potentially backfire, especially if the nature of the work is stressful, as the stress can result in the illness taking longer to be cleared from the body than would otherwise have been the case. There is speculation that in some cases CFS is the result of people going back to work too soon after a severe viral infection, although no concrete evidence to back this up.

Can Relaxation make you Sick?


Research done at Tilburg University in the Netherlands shows that some people become sick when they go on holiday or take time off work, suffering from headaches, colds and flu-like symptoms. The studies show that roughly 3 percent of people suffer from this condition, which they call relaxation sickness, and that it mainly affects people who are in high levels of responsibility, have high workloads, and who are typically perfectionists who are not very assertive. The researchers found that the people who tend to suffer from relaxation sickness also tended to worry a lot about their work while they were on holiday. These personality traits also seem to be present in people who suffer from CFS, suggesting that the same mechanism is at work in both cases. The authors of the study seem to think that it is the stress of the holiday that is causing the symptoms, and that these people are worrying so much about work during their holidays that it causes ill health. However another explanation seems more likely. Rather than stress during the holiday being the cause of the illness, it could be the stress (or intensity) of the work followed by the cessation of that activity during the holiday that causes the problems. The high HPA axis activation during the period of high workload, followed by a cessation of that high workload, is likely to cause alterations in HPA axis functioning, possibly resulting in a suppressed HPA axis drive from the hypothalamus during the holiday rest period. This effect has been studied by other researchers such as Marc Schoen, Assistant Clinical Professor at UCLAs School of Medicine, who calls it the let down effect.

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Many CFS patients find that their illness follows a period of high stress or intense workload. A viral illness caught during this period of high workload would cause the patient to rest afterwards, which is likely to have a similar effect on the HPA axis as the rest period following a high workload that results in relaxation sickness.

Personality, Mental Attitude and Health


A compilation of research by Professor George Freeman Solomon showed that personality has a significant effect on the susceptibility to certain diseases. The most significant effect was found for rheumatoid arthritis, where it was shown that the people who contract this autoimmune disorder tend to be people who are more nervous, worried, highly strung, and have poorer psychological coping mechanisms for dealing with stress. The research also showed that personality type has an effect on the immune system response while under stress. In a stressful situation, people who tended to worry more had lower levels of natural killer (NK) cells. NK cells are an important part of the immune response to viral infections and cancer tumours, especially in the early stages. Other studies have shown that mental attitude has a large effect on mortality from various illnesses such as heart disease and cancer. Having a positive, optimistic attitude seems to lead to a greater life expectancy than being aggressive, worried or pessimistic. This effect is not insignificant either. A recent study from Yale University showed that having a positive attitude towards aging in individuals aged 50 years and over resulted in an increased life expectancy of 7.5 years. This should be viewed in relation to other factors such as blood pressure and exercise, which only tend to affect life expectancy by about one year! This particular study interviewed 660 people 23 years ago and asked them various questions about their attitudes to aging, and then matched this to mortality data 23 years later. Other factors such as socio-economic status, age and gender were accounted for. What this study and others show is that mental attitude has a more important bearing on physical health than most people 45

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imagine. Even though this study was done on older people, other research shows that this effect is important in all people, and can alter the chances of survival from a large number of illnesses such as cancer and heart disease. There is a widespread myth that expressing anger is a good way of dealing with stress and is beneficial for health. A study from the psychology department of the University of Finland shows that this is not the case, and that outwardly expressed anger correlates with insulin resistance syndrome, the main cause of type 2 diabetes. This study also found that outwardly expressed anger correlated with a high responsiveness of the adrenal cortex to ACTH stimulation (i.e. a large secretion of cortisol for the same amount of ACTH stimulation). Other psychological factors, such as hostility and type A behaviour, were investigated in this study and were also found to alter the balance of ACTH and cortisol in different ways, but only outwardly expressed anger was associated with insulin resistance syndrome. Overall it appears that personality and mental attitude have a large effect over the immune system and health in general. The actual mechanisms underlying these interactions between mind and body are likely to involve the HPA axis hormones and catecholamines, all of which are known to significantly modulate immune function. The relative levels of these hormones are significantly influenced by psychological factors such as emotions and mental attitude. The extent of this interaction between mind and body is most apparent in the placebo effect.

The Placebo Effect


There is a vast array of alternative remedies, many of which purport to treat a wide range of different illnesses. Some of these treatments are based on relaxation or meditation and only claim to reduce stress, while others make wild claims, unsubstantiated by any sort of scientific tests, that they can cure illnesses such as CFS. Even though many of these remedies have very questionable theories behind them, and could not possibly work for the reasons given by their practitioners, the 46

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fact remains that many of these remedies do in fact lead to miraculous recoveries, due to the placebo effect. It is well known that if patients are given a pill which does not have any active ingredients, such as a sugar or chalk pill, a significant percentage of patients will sometimes improve in health over those patients not given any treatment at all, depending on the health condition being treated. In many studies the amount of improvement due to placebo alone is 50 percent or higher. Sometimes this placebo improvement is due to the normal resolution of symptoms that would have happened even in the absence of the placebo. However in many cases the placebo itself gives a significant improvement over no treatment at all. The placebo effect is more effective in treating certain symptoms and illnesses than others. The greatest effect tends to be for symptoms related to abnormalities in central nervous system functioning (and symptoms over which the CNS has an influence), such as depression, anxiety, headaches, fatigue and gastrointestinal symptoms. It is also remarkably effective as a painkiller, and numerous anecdotal accounts suggest that it can positively influence the immune system to produce miracle cures for cancer and other illnesses. For this reason, there is a requirement in most countries that all new drugs go through at least one double-blind placebo-controlled trial before they can be approved. One set of patients is given the drug being tested, and a second group is given a dummy pill. Both pills look and taste exactly the same (as far as is possible), and neither the patient nor the physician administering the treatment know which pill the patient has been given. The fact that the doctor does not know whether the patient is given the active treatment is important, as his body language could potentially give a clue to the patient as to which treatment is being administered. If the real drug is not significantly better than the placebo then the drug is not allowed to be sold as a treatment. This is the case even if the drug did cause an improvement in a significant number of patients (over those not given any treatment) due to the placebo effect.

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The difference between scientifically tested drugs and what might be called quack treatments is that, in the latter, although the treatment may work in some (or even many) cases, it is no better than a placebo. While it might be tempting to think that the placebo effect is relatively minor, or that it only affects weak-minded or suggestible people, this is far from the truth. The published research studies on antidepressants show that placebos generally give an improvement of about 30 percent, whereas the figure for active treatments is usually only about 40 percent, not much better than placebo. So the question arises what is wrong with prescribing a quack treatment that relies completely on the placebo effect if it works in some cases? The most obvious problem is the fact that it may or may not work it is mostly down to the psychology of the patient. If the treatment does not work, then the patient has spent time and money on something that is essentially a waste of time. Relying on a treatment that's only benefit comes from the placebo effect can also be potentially dangerous, as it prevents the patient from using more effective treatments. In the case of something minor like hay fever this is not an issue, but for more serious illnesses such as cancer, it could mean the difference between life and death. There is also a negative placebo effect (or nocebo), which is the opposite of a placebo. If someone is taking a medicine and they expect to have side effects, this can sometimes be enough to cause phantom side effects such as headaches, pain and nausea. The nocebo effect is also thought to be the reason why things such as witch doctor and voodoo curses work.

Power of the Placebo Effect


The placebo effect is largely ignored or ridiculed by both the medical profession and the general public, who think that it only happens to weak-minded individuals or that it is simply due to relaxation and the reduction in stress. However research clearly shows that the placebo effect has a major effect on

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many types of illnesses, and has the power to enable the body to heal itself from cancer and other incurable diseases. One of the most remarkable accounts of the placebo effect is that of Dr. Bruno Klopfer and Mr. Wright, a cancer patient who had only a few weeks to live. Dr. Klopfer treated Mr. Wright with an experimental cancer drug called Krebiozen. Shortly after being injected with the drug, the patient's tumour masses melted like snowballs on a hot stove. A few months later, however, when the newspapers published the results showing that the drug was worthless, Mr. Wright's tumours appeared again. Suspecting that Mr. Wright's belief in the drug had caused his previous recovery, Dr. Klopfer told Mr. Wright that he was going to give him a double strength of a more active form of the drug, but in reality the injections simply contained distilled water. Again the tumours disappeared and Mr. Wright was healthy for two more months. Then the newspapers published a story about the worthlessness of the drug, this time without any doubt. After reading this story, Mr. Wright's tumours reappeared and he died within two days.

What Causes the Placebo Effect?


The placebo effect is clearly psychological in nature, and it somehow involves the thought processes of the patient causing the body to heal itself. Contrary to popular opinion, it is not necessary to believe in the placebo effect for it to work. What seems to be most important is the purpose and motivation that the placebo treatment gives the patient. It is likely that there are a number of factors that can compromise normal health and immune function. The most often cited culprit is excessive stress, which results in high levels of catecholamines and cortisol, which then act to suppress the immune system. Cortisol in high levels will suppress all parts of the immune system, while catecholamines mainly affect NK cells. In the short-term, high levels of catecholamines actually result in increased levels of NK cells (by a factor of up to 600 percent). However in the long-term 49

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this effect is reversed after seven days, the same levels of increased catecholamines result in reduced NK cells. Catecholamines also appear to favour the TH2 immune response, resulting in a shift from TH1 to TH2, similar to that seen in CFS patients. It is likely that the reason why certain personality types tend to have lower NK cells is due to them having increased levels of blood-borne catecholamines (which itself is due to greater sympathetic nervous system activity). This could explain why relaxation techniques which reduce stress (and therefore sympathetic nervous system activity) can boost the immune system and result in cures from certain illnesses. While this may explain some instances of the placebo effect, there are many other cases of the placebo effect operating where stress is not an issue. Recent research seems to show that the HPA axis itself can have a positive influence on immune function. Although cortisol (the end product of HPA axis activation) has a suppressing effect on immunity, that is not the whole story. It is well known that during severe illness the HPA axis is chronically activated, and the adrenal cortex shifts away from DHEA and aldosterone and towards cortisol production. Clearly there must be other mechanisms operating to counteract the immunosuppressive effect of cortisol. An experiment by the Laboratory for Experimental Internal Medicine in Amsterdam showed that food intake could modulate the immune system, resulting in a shift towards the TH1 response. They do not know the reason for this response, but they suspect that it might be because the body requires large amounts of energy in order to fight off viral infections. The actual mechanism by which this effect occurs is not known, but it is possible that it is caused by the HPA axis activation that occurs during food intake. Another experiment that shows a clear link between HPA axis activation and immune response comes from the University of Turin. They showed that ACTH and betaendorphin (both of which are released from the pituitary as part of the HPA axis response) reduced the inhibition of NK cell activity by cortisol. Beta-endorphin was shown to have an 50

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additional effect on the immune system in that it increased the cytotoxicity (killing ability) of NK cells. What this research shows is that different parts of the HPA axis have different effects in terms of stimulating and suppressing the immune system, and it is the combination of these different hormones that is important in determining the overall immune response. We know that the normal functioning of the HPA axis is required for normal immune function. We also know that psychological factors can have a very profound influence over the status of the HPA axis, and in particular the response of the HPA axis to stress. It is therefore not unreasonable to postulate that the placebo response could be due to an increase or normalisation of HPA axis function, caused by a change in the patient's state of mind. The placebo effect could then be thought of as the removal of burnout, as it reverses the HPA axis abnormalities associated with burnout (and also cures the symptoms). The release of beta-endorphin by HPA axis activation could explain the pain-reducing effect brought about by the placebo effect. Many alternative therapies claim that they increase beta-endorphin release, and this is thought to produce the healing effect. The practitioners of therapies such as acupuncture, which are known to increase levels of betaendorphin, usually say that the therapy itself causes this increase, due to interactions with the nervous system. However there is experimental evidence showing that the placebo effect itself can result in the same increase in beta-endorphin. The placebo effect may therefore be a combination of a number of different effects that have the overall result of normalising the HPA axis and sympathetic nervous system, and therefore reversing a suppressed or abnormal immune system response that was caused by an imbalance in these hormones. It is not clear whether the short-term pain relieving placebo effect operates through the same mechanism as the long-term effects that can result in curing illnesses such as CFS. All that we can say for certain at the present time is that the placebo effect is the result of the mind interacting with the body and the immune system in order to positively influence health.

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The placebo effect can be thought of as the normal functioning of the body's built-in healing power, and is almost certainly the same as the Chinese chi, or energy, which is thought to be present throughout the body and provide health and vitality. Many alternative remedies such as acupuncture are thought to normalise the body's energy and restore the natural balance. However, rather than being some mystical force, it is likely that chi is actually the body's HPA axis, and the vitality and immunity to illness provided by these remedies are the result of the normalisation of the HPA axis. As to the actual mechanism by which the placebo effect operates, a study by the UCLA Neuropsychiatric Institute and Hospital provides some clues. They measured brain activity in patients undergoing antidepressant medication and placebo in order to see what actually happens in the brain when the placebo effect is operating. They discovered that the placebo responders had increased activity in the prefrontal cortex of the brain, in contrast to the subjects who responded to the antidepressants who tended to have reduced activity in the prefrontal cortex. The changes in brain activity in the medication responders showed up within 48 hours, but the placebo responders took two weeks to show any significant changes. The prefrontal cortex has a number of functions such as providing selective attention and filtering out irrelevant stimulus, as well as being responsible for motivation, rewards and planning for long-term goals. It is likely that it is this longterm goal planning function that is responsible for the placebo effect, and that burnout is due to an under-activity (or imbalance) in the prefrontal cortex. As the prefrontal cortex is an important modulator of the HPA axis, an imbalance in its activity could potentially result in either a suppression of the HPA axis or an abolition of its normal circadian pattern of activation. There have been shown to be abnormalities in prefrontal cortex function in patients with autism, schizophrenia and bipolar disorder, although it is not known whether the prefrontal cortex is the cause of these disorders or if they are

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the result of an underlying genetic defect that affects many parts of the brain in addition to the prefrontal cortex. As noted earlier, higher levels of NPY in the prefrontal cortex are associated with greater stress tolerance and lower anxiety. Considering all the evidence, it therefore seems likely that the prefrontal cortex plays an important role in mind-body health, as well as in the etiology of disorders such as CFS which appear to be the result of a breakdown in this system.

Mind-Body Relationship
In primitive societies that have no knowledge of modern medicine, all illnesses are assumed to be caused by outside influences such as witches or evil spirits. The patient is treated by a shaman or witch doctor who administers various rituals, potions or prayers to rid the patient of the illness. It should be obvious that the purpose of these rituals (whether the practitioner knows it or not) is to heal the patient by using his or her own mind to effect the cure. In some cases, such as with a severe infection, these treatments are not likely to have much of an effect. However in other cases these treatments will have similar value to treatment with modern medicines. It can be compared to today's alternative remedies, many of which do not have any value over and above the placebo effect. It should be remembered that the placebo effect does in many cases have a very significant healing effect, and this is almost certainly the reason why these remedies (ancient and modern) are used generation after generation, even if they do seem completely senseless to outsiders.

Physician-Patient Relationship
In today's world we rely too much on drugs to cure all illnesses, even when it might be more appropriate to use other methods. Even in cases where there is a clear psychological element to the illness, the doctor may simply tell the patient that he or she is under stress, or might suggest psychotherapy. In many cases psychological factors are either completely ignored, or are taken to be the entire explanation with the patient being told, it's all in your head. Neither of these 53

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approaches is appropriate or helpful in complex illnesses such as CFS where psychological, physical and physiological factors all interact to produce the illness. Often patients are forced to try alternative remedies that may or may not work, depending on their mindset. These remedies are not regulated in the same way as conventional medicine, and trying an untested therapy will at best simply rely on the placebo effect, and at worst could cause further harm. The problem is partly down to the limited amount of time that doctors can spend with each patient. Many patients suffering from depression tend to be given antidepressants as the only treatment, even though a majority of patients say they would like to have greater access to psychological support such as counselling or psychotherapy. The studies on the effectiveness of antidepressants over placebo show that the patient's own mind plays a much greater part in the recovery process than the drugs themselves, at least in the case of depression. It is known that patients suffering from schizophrenia in developing countries tend to have a much better outcome and quality of life than sufferers in developed countries. This is even though the incidence of the illness per head of population is the same throughout the world. It is thought that this difference is due to social factors such as stronger family ties and support and less modern-day stresses and demands. As with depression, most schizophrenia patients in the developed world are given drugs as the only treatment option, with little or no effort being put into psychotherapy, presumably due to the cost. More effort needs to be put into determining the relationships between mind and body during illness, and using the most appropriate treatment method for that particular illness. The placebo effect needs to be thoroughly investigated and understood, and treatments developed which harness its healing power without relying on quack treatments. This is likely to involve some combination of counselling and lifestyle advice. Instead of focussing solely on emotional or psychological problems like traditional psychotherapy, it

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should also attempt to help the patient understand how his or her lifestyle may be adversely affecting their health.

Psychological Factors Causing the Placebo Effect


Stories of patients recovering from chronic illnesses using various quack remedies abound, and they all follow a similar pattern. The typical account goes as follows. The person begins to get a number of different symptoms such as fatigue, depression, digestive problems, pain, weight gain and headaches. They may have been going through a stressful period at work recently, or may have recently had a bad infection, or there may be no known trigger. After being sent away from the doctor's surgery with a diagnosis of there's nothing wrong, the person turns to one or other alternative remedies. In many cases the first few therapies don't bring any benefit, and the person continues trying different remedies. Eventually they hit upon the miracle cure, the treatment that manages to relieve all of their symptoms and enables them to live a normal life again. Sometimes the initial therapy is simply a trigger that allows the person to regain normal health without having to continue with the treatment. In other cases there is a continuation of the treatment after recovery, such as following a certain diet, which is part of a health regime that the person uses in order to maintain their health. The psychological factors underlying the placebo effect are more complex than simple motivation or positive thinking. It is something more akin to religious faith, and is likely to encompass factors such as the purpose and meaning of life. Factors such as motivation, goals and having a positive outlook certainly come into this, but these phrases do not really adequately describe what is a very deep-seated, unconscious psychological effect. It is worth noting that faith healing appears to work in the same way as the placebo effect, in that it can sometimes produce miracle cures for no apparent reason (unless you believe that some divine power is the source of the healing

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power). It is likely that the same psychological factors are at work during faith healing as for the placebo effect.

Quack Medicine
There are many pseudo-scientific alternative health testing procedures that have no scientific validation, but which are widely used by the general public due to plausible (but false) scientific explanations of the techniques. There are a number of variations on the theme such as bioresonance, kinesiology and homeopathy. Some of these techniques involve testing the patient for food intolerances, and even vitamin and mineral deficiencies, simply by the patient holding on to metal cylinder. The machine then determines what is wrong with the patient by scanning the body's electromagnetic energy. In some cases, it is claimed that the test can be done on a strand of the patient's hair, without them having to be present at all. It should be noted that there are proper scientific tests which do analyse hair samples for mineral deficiencies however these tests do not claim to diagnose medical problems in various body organs or to be able to diagnose food intolerances or mineral deficiencies by simply holding a metal cylinder, as with bioresonance. Kinesiology is a similar treatment that involves the patient holding a vial of a supposed allergen while the practitioner tests the response of the patient's arm muscles. The response determines whether or not the patient is allergic to the substance in the vial (which is not in contact with any part of the patient's body). Even to someone with the most limited scientific knowledge, it should be obvious that the claims made by treatments such as these are complete nonsense. There is usually enough scientific theory in the explanations of these techniques to make them sound plausible, but a closer inspection usually reveals that the procedure relies on some magical-sounding pseudoscience which the inventor of the technique happened to think up one day. Usually there are no scientific studies showing the effectiveness of the treatments, and where independent studies are carried out, they always show that the treatment is no better than placebo. The clinics 56

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that carry out these procedures are generally run by people who have no medical training whatsoever (and in most cases not even a university degree). If they have any qualification, it is generally a diploma from an alternative therapy course. All of the scientific research on bioresonance shows that it is no better than placebo. The evidence for homeopathy isn't so clear-cut. Two recent studies in the British Medical Journal give different results one shows that homeopathy is no better than placebo, but another study does show a positive improvement over and above the placebo. Another even more recent study also gives a negative result, showing no difference between homeopathy and placebo for treating childhood asthma. The picture for acupuncture is even less clear-cut than with homeopathy. While a number of clinical trials do show an effect over and above placebo, an equal number of studies show no benefit. In addition, many of the studies that show a significant benefit are poorly designed, either having very small sample sizes or not having adequate placebo controls, not to mention the impossibility of blinding the acupuncturist. The problem with homeopathy (and many other alternative therapies) is that the theory relies on magical science. For example, the premise of homeopathy is that like cure like. A very small amount of the substance causing the illness (such as pollen in the case of hay fever) is diluted in water to such a low concentration that there should not be a single molecule of the active ingredient left, only pure water. The healing effect is supposedly due to the imprint of the substance left in the diluted water. Such a theory is completely against all current scientific knowledge, so it either relies on magic, or it involves some mechanism which is as yet undiscovered. It is, of course, possible that such a mechanism does exist, and that homeopathy does in fact work better than placebo. However for such an extraordinary theory to be proved true would require extraordinary evidence, in the form of numerous clinical trials showing positive results (as opposed to the current situation, where most of the evidence seems to point to homeopathy not working, with only one or two studies 57

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showing positive results). In the absence of such evidence it is more prudent to believe that homeopathy simply owes its benefit entirely to the placebo effect. This is not to say that these treatments don't work they almost certainly do. However, any benefit is wholly derived from the placebo effect, and there is a danger that spurious advice to patients, or the prescription of untested herbal remedies, may have negative health consequences. If a doctor tried to cure people with an amazing new treatment that, unknown to the patients, consisted solely of distilled water or sugar pills, he would be taken to court and prevented from practising medicine. However, modern alternative therapies that rely completely on the placebo effect are tolerated and require no licensing whatsoever. While we do need to get rid of the bogus therapies that rely on the placebo effect (or at the very least, educate people to understand how they work so that they can make up their own minds), it is equally important that more effort is put into understanding the placebo effect itself, and harnessing its power. Obviously it is unethical to deceive a patient into believing that he is receiving a revolutionary treatment that is actually bogus. However this deception is not necessary for the placebo effect to work. What is likely to be more effective is to actually discuss with the patient the steps that he or she can take in order to bring about the body's own healing effect. It also should be said that there are a number of alternative therapies that do have a benefit over and above a placebo. Many herbal remedies have proven effects on the mind and body, and many modern medicines are based on the active ingredients from these herbs. Aspirin, for example, is based on a substance found in willow bark, and had been used for centuries to treat pain before being discovered by science. The problem is that many herbal remedies have not been tested, either for their efficacy or for side effects. Recently, for example, kava-kava had to be withdrawn from many herbal medicines due to the finding that it can cause liver damage. Other herbs such as liquorice and ginseng are commonly used to boost energy levels, due to their effect on the HPA axis liquorice prevents the breakdown of cortisol by the liver, and 58

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ginseng is thought to stimulate either the pituitary or the hypothalamus (or both). The long-term effects of these unnatural HPA axis modulators are not known, but the danger is that artificially boosting cortisol levels by a large amount over a long time using these herbs could result in the HPA axis becoming suppressed after treatment is stopped.

Food Intolerance Testing


An integral part of many alternative therapies is the idea that various diverse illnesses such as CFS, IBS and depression are caused by food intolerances, where the body builds up an immune reaction to certain foods, and that these illnesses can be cured simply by avoiding eating these foods. These food intolerances are not the same as true allergic reactions, which are mediated by the IgE antibody, but are thought to be caused by some other type of immune reaction. Some of these tests use homeopathy or some other technique to try to treat the food intolerances, while others advocate simply avoiding the foods that come up positive in the test. There are proper scientific tests for these non-IgE immune reactions, such as the ALCAT test. This test measures the size and number of white blood cells in a sample of the patient's blood, both before and after samples of various foods are introduced to the blood sample. Any increase in cell size or number of cells indicates an immune reaction to the food. Although the ALCAT and other similar tests which measure immune system activity in the patient's blood are more likely to be detecting a real immune response than the quack tests such as bioresonance, this does not necessarily mean that avoiding the foods which are flagged in the results will necessarily give an improvement in health. The foods that do show up as causing an immune response in these tests tend to be foods that the patient has recently eaten. What is likely to be happening is that imperfect digestion is causing particles of undigested food to enter the bloodstream, and these are then cleared up by the immune system. What is known is that avoiding these foods does not generally give any benefit to the patient over and above the placebo effect, so whatever immune 59

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response is being measured is likely to be a small effect that is part of the normal functioning of the immune system. It should also be noted that placing a foodstuff directly into a blood sample is not going to produce the same results as if the food was digested and entered the bloodstream through the gut. Digestion causes the proteins in food to be broken down into smaller peptide chains and amino acids, which means that they are far less likely to activate the immune system. The ALCAT test simply measures the effect that the undigested proteins themselves have on the immune system, which is not an accurate model of reality. One of the most popular symptoms that food intolerance treatments claim to cure is weight loss. Now, thinking about it, if your body is either having a major immune response or is having difficulty digesting particular foods, you would think that this would cause weight loss rather than weight gain. Avoiding these foods should then lead to a gain in weight. If there is any loss in weight after avoiding certain foods, it is likely that it is caused by the placebo effect, due to an increase in HPA axis activity, which, in the absence of any change in food intake, will cause weight loss due to increased metabolism. The only useful piece of advice given by the proponents of food intolerance testing is the rotation diet. This basically means that you change the types of food that you eat in order to avoid building up an immune reaction to any one type of food. Practicing such a diet need not involve cutting out certain foods completely, just making sure that they arent eaten every day. As well as the possibility of reducing any immune reaction (which may or may not happen), such a diet is likely to bring about health benefits due to the increased range of food intake resulting in a more balanced intake of nutrients.

Candidiasis
Another supposed cause of various illnesses such as CFS and IBS is chronic candidiasis, also known as candidiasis hypersensitivity syndrome. This condition is said to be caused

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by the candida albicans yeast turning into its fungal form and causing widespread infection throughout the body. Candida normally lives in the intestinal tract, on the skin, the mouth and the genital areas. Although it can frequently cause vaginal infections (resulting in thrush), candida does not normally cause widespread infection except in people with highly suppressed immune systems, such as HIV patients. The proponents of the candidiasis hypersensitivity syndrome think that in some cases candida can cross from the gut into the bloodstream and multiply to produce many different symptoms such as fatigue, headaches and immune problems in fact, all of the symptoms of CFS. Candida infection is blamed for CFS by the proponents of this theory. The cause of this candida overgrowth inside the body is blamed on diet namely eating too much food containing refined sugars and yeasts. The cure involves avoiding yeastand fungus-containing foods such as wine, beer and mushrooms, as well as any food containing sugar (including fruit and milk). Many candida exclusion diets advocate removing wheat from the diet not because wheat is thought to feed the candida, but because it is thought to be a common food sensitivity. Such a diet is likely to be costly, difficult to maintain, and may be harmful unless advice is taken from a nutritionist. Other cures for candidiasis include anti-fungal medications which are normally only prescribed for vaginal candidiasis. The problem with the candidiasis hypersensitivity theory is that it has never been demonstrated either that candida can infect the body like this, or that candida actually causes these symptoms. As with many dubious medical theories, the proponents tend to say that the fact that people get cured must mean that they were suffering from chronic candidiasis, and that the diet or anti-fungal medication must have cured them. Clinical trials, however, show that these treatments are no better than placebo at curing the symptoms of fatigue, depression and gastrointestinal symptoms that are thought to be the result of candidiasis hypersensitivity. One study performed on people who were presumed to have candidiasis hypersensitivity involved a 32-week nystatin (an anti-fungal 61

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agent) or placebo treatment. The results showed that the placebo group improved by 23 percent, and the nystatin group improved by 25 percent, showing that the treatment had no significant benefit over the placebo. What this study does show, however, is that the placebo effect does actually have a significant effect in curing these symptoms. In fact, many people have had miraculous cures from CFS by performing either the candida diet, or other quack remedies such as kinesiology. This demonstrates the need for proper scientific trials on all medicines, especially those that are targeted at CFS symptoms, as the placebo effect seems to have such a large effect on the treatment of CFS.

Exclusion Diets
There are many fashionable theories that certain foods such as gluten (found in wheat and oats), casein (found in milk) or monosodium glutamate (MSG) can cause various health symptoms. As with candidiasis, these theories are not based on any kind of scientific fact, and studies show that any benefit from such an exclusion diet is no better than placebo. It should be said that there are certain people who cannot eat gluten, due to coeliac disease. For these people, an immune reaction to part of the gluten protein causes damage to the small intestine resulting in malabsorption of nutrients, diarrhea, fatigue and anaemia. This condition can easily be tested for by using antibody tests and gut biopsies. There are also many people who are allergic to milk, and again this is a condition that can be easily tested for. In contrast, the notion that gluten and casein can cause negative symptoms is based on an unproven theory that these proteins break down into peptides that resemble opiates, and these cross the blood-brain barrier and cause a kind of addiction. There is no good evidence that avoiding gluten or casein reduces the symptoms of CFS, IBS, autism or any of the other illnesses that these proteins are blamed on. Additionally, some of the books advocating special diets based on these theories are inconsistent. One book giving a diet for ADHD children based on avoiding casein, gluten and MSG has recipes 62

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that use tomatoes, cheese and other ingredients containing free glutamate, which is exactly the same substance that MSG breaks down to when it is digested. It is known that inside the body, MSG has exactly the same effect as the free glutamate that occurs naturally in certain foods such as cheese and tomatoes, and it is these glutamates that give these foods their appealing taste. If the theory that the glutamate in MSG causes hyperactivity is correct, then these other foods should cause the same symptoms. However the book in question says that eating even a little of MSG-containing foods can cause the symptoms, while at the same time giving recipes containing free glutamate. The only reason for this can be that MSG has acquired a reputation as a food that can cause problems such as headaches and hyperactivity, and people therefore link their symptoms to suspect foods that they were eating at the time such as casein, gluten and MSG.

Melatonin and the Immune System


There is a large body of evidence showing that melatonin has a modulating effect on the immune system, in that it increases levels of NK cells and alters the levels of various cytokines. Melatonin levels are normally high during the night and are suppressed during the day in response to sunlight, but in many CFS patients, as well as in people suffering from insomnia, there is a flattening of various hormone rhythms, including melatonin, with a reduction in the amplitude of melatonin released during the night. As both the melatonin and HPA axis rhythms affect the immune system, and as abnormalities in both of these are seen in CFS patients, it is likely that the combined effects of abnormal melatonin and HPA axis rhythms result in the abnormalities in immune system function seen in CFS patients. The fact that sunlight affects both HPA axis activation and melatonin secretion could explain why most cases of CFS develop during the winter months. The usual explanation for this finding is that CFS is caused by a virus, and there are more viral infections around at this time of year. However it is equally possible that the lack of sunlight during winter results 63

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in abnormal hormone rhythms in susceptible people, and this, in combination with other factors, is the trigger that initiates CFS.

Summary of Factors Influencing MindBody Health


It should be clear that the mind has a large influence over the body's ability to heal illness, as well as playing an important role in regulating immune function to provide protection from illness in the first place. While it is likely that the mechanisms behind this mind-body interaction involve the hypothalamus and prefrontal cortex (and the HPA axis in particular), the exact relationship between the mind and the immune system is not known. Current theories focus solely on the stress factor, citing the research which shows that prolonged high levels of stress hormones results in suppression of the immune system. While this is clearly one aspect of the relationship between mind and immunity, it does not explain the placebo effect and does not satisfactorily explain why CFS patients suffering from no stress show a similar immunosuppression. What seems to be important is the circadian activation pattern of hormones and their influence over the immune system. Various psychological factors other than stress and emotions appear to have a significant influence over these hormones, and ultimately over physical health. There may be some sort of energy conservation mechanism built into the HPA axis, which puts a limit on the amount of stress that can be tolerated. This mechanism would limit the amount of energy expenditure available for physical and mental activity, as well as amount of activation of the immune system. It should be noted that activating the immune system requires a lot of energy, and the body has to make a decision as to how much energy to devote to the immune system as opposed to other requirements. This decision depends on many factors such as physical activity and stress levels, availability of food, time of year and reproductive status. Clearly once an illness has developed certain mechanisms come into play to 64

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ensure that the immune system is activated in order to clear the infection. However, during times of good health, it is equally important for the body to maintain high enough levels of immunity to prevent infections developing. Important in this respect are antibodies and NK cells, both of which are important in the early stages of a viral infection. It is this immunity to infection that is most at risk of being downregulated during times of stress or burnout. Normally the body is able to maintain adequate levels of immune system activation in order to provide reasonable immunity to infection. However during burnout or CFS the energy limit appears to be set to a lower level, resulting in a reduced ability of the body to maintain adequate immunity, especially during times of stress when the body's energy resources are diverted elsewhere. During certain chronic illnesses such as cancer which require high levels of immune system activation (and NK cells in particular), mental attitude can be critical in maintaining health, and in some cases can be the difference between death on the one hand and complete recovery on the other. Factors such as motivation and the presence of long-term goals seem to be able to increase the HPA axis energy limit, resulting in a higher tolerance to physical and mental stress, as well as raising the upper limit for immune system activation. This hypothalamic energy limit may have evolved during times of unpredictable food supply, when it was important to regulate energy expenditure. In certain circumstances, when availability of resources seemed low, it would have been better for the body to conserve energy rather than engaging in a possibly futile attempt to find food. Reducing the ability (and motivation) of the body for handling stress would be one way of achieving this. Current medical advice concentrates on factors that have a negative effect on health by virtue of the damage they do to the body, such as smoking, alcohol, stress, poor diet and lack of exercise. However there is little recognition of the importance of hormones in regulating immune response, and the effect of lifestyle and mental attitude on these hormones. Lifestyle factors such as exercise and sunlight appear to significantly improve immune function, increasing the immune response to 65

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cancer and viral infections, while at the same time reducing autoimmune reactions. Both of these effects appear to be mediated through hormones vitamin D in the case of sunlight and the HPA axis in the case of exercise. Melatonin is important in regulating the immune response, and an absence of the normal melatonin secretion during the night may lead to impaired immunity. Sex hormones also appear to play a large part in modulating the immune response, resulting in different immune responses to the same illnesses between men and women. Psychological factors and mental attitude also play a large part in modulating the immune system, and again this appears to be mediated by the HPA axis, and the pituitary hormones such as ACTH and beta-endorphin in particular. Although the adrenal hormones such as cortisol and adrenaline act to suppress the immune system, the pituitary HPA axis hormones act to reverse this suppression. The HPA axis can become suppressed as a result of stress, burnout or CFS, altering the balance of these hormones and thus causing changes to the immune system. These changes can be reversed either by the placebo effect or by psychological (or lifestyle) treatments that act in the same way.

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6. Chronic Fatigue Syndrome

6. Chronic Fatigue Syndrome


Chronic Fatigue Syndrome (CFS, also known as ME), is a severe, debilitating condition consisting of a number of different physical, physiological, neurological and psychiatric symptoms including: Severe fatigue, especially after exercise, and a greatly reduced ability to perform any type of physical exertion. Sleeping problems such as insomnia, feeling sleepy all the time or having a desynchronised body clock. Depression. Anxiety attacks. Reduced immune function and susceptibility to illness, particularly viral infections. Constant sore throat. Swollen lymph nodes. Problems regulating heart rate, blood pressure and blood volume, as well as arrhythmias such as atrial fibrillation. Digestive problems, lack of appetite and nausea. Memory and cognition problems. Hypersensitivity to light and sound. Problems regulating body temperature. Tinnitus. Vertigo. Headaches. Unexplained weight gain. Emotional lability (suddenly changing emotions). Not all patients suffer from all of the symptoms, and there are many other symptoms that are also present in some patients. The only symptom that must be present for a diagnosis of CFS to be made is severe, disabling fatigue for a period of over six months. Other symptoms will occur in most cases, but are not required for a diagnosis under the Oxford criteria (although the 67

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CDC criteria does require at least four other symptoms out of a list to be present). There is no definitive test for CFS, so it is essentially an exclusion diagnosis that is reached when all other causes of illness have been ruled out. Sometimes muscle pain is listed as a symptom, however this usually results in a diagnosis of fibromyalgia rather than CFS. The symptoms of fibromyalgia are very similar to CFS, the only difference being that with fibromyalgia there is widespread chronic muscle pain over almost the entire body rather than fatigue. There is, however, a broad overlap between CFS and fibromyalgia with many patients suffering from symptoms of both conditions, and it is possible that both CFS and fibromyalgia are caused by the same underlying illness mechanism. There is also a spectrum in severity of symptoms, with many patients suffering from what could best be described as mild burnout, without being ill enough to be classified as having CFS. Many people suffer from symptoms such as being tired all the time, unexplained weight gain or susceptibility to infections. While some people would like to classify these patients as having a different (and less important) illness than CFS, this does not reduce the impact that these symptoms have on the lives of the people suffering from them. In the UK CFS used to be known as myalgic encephalomyelitis (ME), as it was originally thought to be caused by inflammation of the brain and spinal cord due to a viral infection. Encephalomyelitis can occur after infection by a number of viruses and bacteria such as measles, herpes simplex, human herpesvirus 6 (HHV-6) and Epstein-Barr virus. However it is now known that encephalomyelitis only occurs in a subset of ME patients, and is likely to be another symptom of the illness rather than a cause. For this reason the term ME has largely been abandoned in favour of CFS. There is much debate about whether CFS is a real illness, whether it is caused by a virus, and whether it is just psychological (or all in the head). Anyone who takes even the most cursory glance at the recent scientific evidence can clearly see that CFS is most definitely a real condition, and not purely a psychological illness. This evidence includes CAT 68

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scans of patients showing that they have highly shrunken adrenal glands, as well as various physiological abnormalities. As for the symptoms of CFS, there is a wide overlap with a number of other conditions such as burnout, clinical depression, panic-anxiety disorder, irritable bowel syndrome and dysthymia. Dysthymia is a form of long-term depression lasting more than two years, which also includes symptoms such as poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or indecisiveness, and feelings of hopelessness. Many CFS patients suffer from most or all of the symptoms of dysthymia, suggesting that there is a common underlying cause for both illnesses.

Differential Diagnosis of CFS


As there is no definitive diagnosis for CFS, it is important to rule out other illnesses that may be causing the symptoms. These include: Lyme disease (however beware of health practitioners who would like to explain all CFS cases as being caused by Lyme disease). Endocrine disorders (hypothyroidism, hyperthyroidism, Addisons disease). Diabetes. Lupus. Multiple sclerosis. Psychiatric disorders (bipolar disorder, major depression, anxiety disorder, dysthymia). It should be noted, however, that there is a broad overlap between many of these conditions and CFS, so CFS should not be ruled out. Long-term viral infection such as glandular fever (EBV). It should be noted, however, that one of the symptoms of CFS is a susceptibility to viral infections, so this should not rule out a diagnosis of CFS. There are also potentially many other illnesses that can cause similar symptoms to CFS, so a diagnosis is not always 69

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straightforward. Many alternative diagnoses can be ruled out by a simple blood and urine test. Once sufficient tests have been done to rule out other conditions, a diagnosis is made by looking at the symptoms and patient history. A good indicator towards CFS is if there is a range of unexplained physical, physiological and psychiatric symptoms. The symptoms of CFS also tend to vary in severity over the course of the illness, and many patients find that they feel perfectly okay some days while being acutely ill a few days afterwards.

Prevalence of CFS
Different studies give different rates of prevalence for CFS, presumably due to the difficulty in deciding exactly which patients to include. The figures range from 10 up to 300 per 100,000 persons. This means that CFS is as common as multiple sclerosis and Parkinsons disease, but the number of research papers published, as well as the amount of research funding spent, is much lower for CFS than for these other illnesses.

CFS and the HPA Axis


When individual hormones such as cortisol and growth hormone are measured, some studies find abnormally low levels of these hormones in CFS patients compared to control subjects, while other studies show normal or elevated levels of the same hormones. There are, however, two hormonal abnormalities that are almost always seen in CFS. The first is a reduction in the circadian pattern of release of various hormones such as cortisol. Rather than having high levels of cortisol in the morning and reducing levels at night, CFS patients tend to have a more flat response, showing more constant levels of cortisol throughout the day. Additionally, there appears to be an overall reduced HPA axis activation in CFS patients, both in response to stress as well as during rest. A recent study in Germany showed that CFS patients produced lower levels of ACTH in response to physical, physiological and psychological stresses than 70

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controls, as well as lower ACTH levels during rest. There were no differences in cortisol levels between CFS patients and controls, suggesting that the body is compensating for the lack of HPA axis drive by increasing the amount of cortisol released in response to ACTH stimulation. Another study has shown that CFS patients tend to have shrunken adrenal glands compared to controls. Using computer tomography (CT) scans, a team at Trinity College Medical School in Dublin found that in those CFS patients who had an underactive HPA axis, the adrenal glands were less than half the size of those of healthy subjects. This suggests a long-term under-activation of the HPA axis, resulting in a lack of ACTH (which, as well as causing the adrenal glands to release cortisol, also causes them to grow in size, hence the trophic part of the name). Any reduction in adrenal gland size will result in a reduced ability to produce cortisol during periods of stress, and could potentially be the cause of many CFS symptoms. CFS therefore appears to be the result of a reduction in the normal circadian HPA axis activation, as well as a reduced ability to activate the HPA axis during times of stress, resulting in an impaired ability to handle stress. In severe cases this results in an inability to perform tasks that are regarded as normal rather than stressful, such as doing mild exercise and having a normal immunity to illness. Although many of the symptoms of CFS are very similar to the symptoms of excessive stress, they are in fact caused by a reduced ability to handle stress, which is an important distinction.

History of CFS
It is a myth that CFS is an illness of the 20th century. The name neurasthenia was coined by George Beard in the 1860s for an illness that had symptoms of fatigue, insomnia, headaches, nervous exhaustion and depression (as well as many others). Although the illness was defined differently from CFS and was thought to be psychosomatic in nature, when the accounts of people suffering from the illness are read it is clear that there is

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a very large overlap with patients suffering from CFS today, and that they are almost certainly the same illness. Neurasthenia was thought to be caused by the stresses of modern, urban life. It mainly affected young women, although men were also susceptible. The majority of patients came from the educated middle classes, among businessmen and intellectuals, and it was thought that overwork, ambition and the pressure to succeed caused the illness. Since the 1860s, the illness has been called many different names such as irritable heart, total allergy syndrome, sick building syndrome, 20th century syndrome, chronic mononucleosis, chronic EBV, multiple chemical sensitivity and functional hypoadrenalism (to name but a few!) Although at first sight it may seem that these are all different illnesses, on closer investigation they all refer to the same set of symptoms, with the same set of disturbances to the immune, endocrine and digestive systems, and the name of the illness referring to what at the time was thought to be the cause of the illness or what were thought to be the main symptoms. Although the illness seems to much more prevalent today than in earlier times, it seems likely that it has existed since the dawn of human evolution. The ancient Chinese used ginseng to cure fatigue, exhaustion and what they thought of as imbalances in physical and mental energy, symptoms which are likely to be related to CFS. Today the term neurasthenia is not generally used, but a number of researchers would like to resurrect the neurasthenia diagnosis and apply it to CFS patients. The main argument against doing this is that neurasthenia is a psychiatric diagnosis, and many CFS researchers (and patients) reject any implication that there is a psychiatric component to their illness. Part of the problem is due to the fact that neurasthenia patients were sometimes seen as hypochondriacs who were making up their illnesses, or were thought to be suffering from a neurosis that resulted in their illness symptoms. This is even though many neurasthenia patients suffered from recurring fevers and other ailments such as muscle pain and extreme weakness, similar to today's CFS patients. Today there is much less tolerance for psychiatric or psychological explanations for 72

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illnesses which have clear physical symptoms such as the recurring infections seen in CFS patients. This results in a dichotomy of opinion as to whether CFS is an organic or psychiatric illness. Florence Nightingale famously suffered from neurasthenia after she returned from the Crimea. Her symptoms included weakness, headaches, palpitations, insomnia, tachycardia, depression and pain. At the time it was thought that her illness was due to the stress caused by her intense work during the war and her difficult campaign for medical reform after her return. There was even speculation at the time that she might have been using her illness as a means to further her cause for medical reform. Recently some commentators have speculated that her illness may have been due to Brucellosis bacteria infection as the symptoms are similar but there is no real evidence that this was the case. Florence was ill for twenty years in total, and was bedridden for six of those years. What is interesting is that her personality after returning from the Crimea was cold, cruel, gloomy and obsessive. However, after her recovery her personality changed, and she became benevolent and goodhumoured again. It seems more reasonable to think that her change in personality was one of the triggers that caused her illness in the first place, and her subsequent personality change twenty years later resulted in its remission. Another point of interest is that during her six-year period of being bed-ridden, Florence was following the advice of her doctor, who said that the cure for her illness was rest. This is similar to the case with many CFS patients today, who are told that if they simply rest and don't do anything too stressful, they will be cured. Unfortunately this is often not the case, with enforced rest simply tending to prolong the illness. CFS and burnout appear to be illnesses caused by the inability to handle stress, rather than being due to excessive stress. Although stress may play some role in the initial stages, long-term CFS patients suffer from the same symptoms even in the absence of stress.

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Chronic Fatigue Syndrome versus Chronic Fatigue


Many people mistakenly refer to CFS as chronic fatigue, which is a different condition. Chronic fatigue simply means that a person is tired all the time, but they do not have any of the other symptoms associated with CFS. People who have chronic fatigue are generally able to continue working, whereas CFS is a very disabling condition where the fatigue and other symptoms prevent the person from living a normal life, and in severe cases the person may be confined to bed for long periods of time. Stress is a major cause of chronic fatigue. There may sometimes be other symptoms as well as fatigue, but not to the extent or severity as is the case with CFS. Chronic fatigue can lead to CFS, but this is not generally the case. Most of the time, the symptoms of chronic fatigue will pass soon after the stress is removed. Having said that, it is possible that chronic fatigue and CFS are two points on the same illness spectrum, and many of the same factors are likely to cause both conditions.

CFS Triggers
Virtually all cases of CFS are preceded by a severe viral illness. In addition, many patients say that work-related stress or some other stressful life event was influential in triggering their illness. In a number of cases the illness is triggered by a car accident or similar traumatic event. Severe illnesses are known to cause activation of the HPA axis in a similar way to physical and psychological stresses. This is caused by the effect of certain cytokines, which stimulate the release of CRH in the hypothalamus and thereby activate the HPA axis. This HPA axis activation is part of the acute-phase illness response that is produced when levels of cytokines such as interleukin-6 reach high levels due to severe infection or injury. As well as activating the HPA axis, the acute-phase response also causes an increase in the set-point for body temperature resulting in fever and modulates the overall immune response in order to best fight the infection. 74

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The HPA axis activation during the acute-phase response results in high levels of circulating cortisol, which in turn suppresses the release of cytokines, reduces the immune response and inflammation in particular, and prevents damage to tissue that would otherwise be caused by an excessive immune response. A secondary result of the HPA axis activation during illness is that it provides extra energy for the immune reactions taking place and supports the fever response, which itself requires a higher metabolism in order to maintain the increased body temperature. In some cases during long-term illnesses, this initial activation of the HPA axis can reverse, resulting in reduced HPA axis activation and adrenal insufficiency. The reason for this is not known, but it is likely to be due to an imbalance at some part of the HPA axis, possibly due to genetic factors. It can be seen then that all of the known triggers for CFS acute viral infection, stress, mental attitude and rest following stress are also known to be factors that can cause HPA axis suppression. This is further evidence that an abnormality in HPA axis function is central to the etiology of CFS.

CFS Diagnosis
One of the most damaging aspects of CFS is the diagnosis itself. As there is no definitive test for CFS, the only way to get a diagnosis is through analysing the patient's symptoms and ruling out any other diseases that might be causing the symptoms. Because a CFS diagnosis requires that the patient has been ill for longer than six months, this means that the person has to suffer from the condition for a full six months before having any idea what is wrong with him or her, and those first six months are a critical time after which recovery becomes less likely. Part of the problem is the wide scope of many of the diagnostic criteria. The CDC criteria, while listing many of the additional symptoms suffered by patients, does not require the patient to have any of these additional symptoms in order to make a diagnosis (simply requiring highly disabling fatigue for

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a period of 6 months). This results in a diagnosis that could potentially cover virtually any long-term chronic illness! Research into the symptoms suffered by CFS patients shows that there is a subset of symptoms that is experienced by most patients. One study shows the following figures: fatigue: 95-100% nausea: 60-90% irritable bowel syndrome: 50-90% low blood pressure: 86% sleep disorders: 65-100% photosensitivity: 65-90% anxiety: 70-90% This is only a small sample of a list of more than 40 symptoms, each of which were present in over 50 percent of patients in the study. While no patients will share exactly the same set of symptoms, it is likely that any patient who suffers from a large proportion of these symptoms does in fact have the same illness. Rather than having a set criteria such as has the patient had x and y for z months, a better diagnosis would be to give the patient a score based on the number of CFS symptoms observed, and their severity. Such a system would clearly distinguish CFS patients from those who simply have depression, and from those who have a persistent infection but do not have CFS. However, this approach may result in ruling out some patients who do in fact have CFS. Diagnostic tests are clearly a better way of identifying CFS than relying on symptoms alone, but currently there are no universally accepted tests. This is partly because there is no agreement on what causes CFS, and partly because many of these tests only show abnormal results in certain subgroups of patients. This situation is unlikely to change until the underlying cause of CFS is unambiguously determined.

CFS Caused by Viral Infection?


A lot of research has gone into determining whether CFS is simply caused by a long-term viral infection that the body 76

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never manages to clear. Initially it was thought that EpsteinBarr virus (EBV), which causes glandular fever, or Human Herpesvirus 6 (HHV-6) caused CFS, as many cases of CFS seemed to be triggered by one of these viruses. Recent research on this has been ambiguous. On the one hand recent studies show no difference, either in the incidence of live viruses or in the number of antibodies to HHV-6 and EBV, between CFS sufferers and the general population. Other studies, however, show that certain variants of these viruses are found more often in CFS patients. These variants tend to produce a TH2 response by the body rather than a TH1. It is known that when the body produces a TH2 response to one of these viruses that the infection is likely to take longer to clear. What is known is that there is no single virus that is present in all cases of CFS, and many patients do not suffer from any persistent viral infection at all. What seems more likely is that the viral infection is simply the trigger for CFS, and that the subsequent abnormalities seen in the immune system in CFS patients such as reduced immunity and a shift towards the TH2 response are simply CFS symptoms, caused by the suppression of the HPA axis. Of course it is very difficult to completely rule out a viral cause for the illness. How is it possible to prove that there is not a latent virus hiding out in some part of the nervous system that has somehow evaded detection? The nature of science means that it is impossible to prove any theory; all that can be done is to see if it stands up to subsequent experiments designed to test its predictions. If the theory fails to explain some observation then it is either rejected in favour of a better theory, or is modified to explain the new finding. Otherwise, if the majority of scientists agree that it is a good explanation of the observed facts, then the theory stands. However it is always possible that at some point in the future someone will come up with an experiment which will either completely disprove the theory, or refine it to explain the newly observed results. Any theory that cannot be disproved by scientific experiment is therefore virtually worthless, and the virus hiding out undetected explanation for CFS certainly falls into this category. 77

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Hormonal Trigger
A number of female patients have noted that the onset of their CFS coincided with either the menopause or a hysterectomy. Some patients find that their symptoms improve after taking hormone replacement, but this is not always the case. In addition, many female CFS patients report that their symptoms vary depending on their menstrual cycle. This is also seen in irritable bowel syndrome (covered in chapter 7). Pregnancy results in a resolution of CFS symptoms in many female patients, but the symptoms normally return soon after the birth. It is likely that the high levels of estradiol and progesterone that are released during pregnancy have something to do with this estradiol in particular is a potent activator of the HPA axis, as discussed earlier. This of course does not explain CFS in all patients. There are many women who go through menopause or hysterectomy and do not suffer from CFS. In women, estradiol follows a monthly cycle, as it is the main oestrogen released by the ovaries. As estradiol has such a large effect on HPA axis functioning, and as CFS appears to be a severe dysregulation in the HPA axis, it is not unusual that major changes in estradiol levels could either cause or cure CFS in some cases.

Personality and Mental Outlook in CFS


As discussed previously, a negative mental attitude to stress seems to be one of the factors that can cause suppression of the HPA axis. One study of CFS patients shows that those patients who have a greater psychosocial explanation for their symptoms tend to recover more quickly. Anecdotal accounts from people who have recovered from CFS also seem to suggest that those patients who feel that it is within their own power to cure their illness tend to recover, whereas those who tend to think of their illness as being caused by something outside their control tend to be the people who have had CFS for the longest period of time. Other studies show that CFS patients differ significantly from the general population in certain personality traits. One study showed that a greater number of CFS patients than 78

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controls were classified as defensive high anxious. A second study showed that negative coping strategies differentiated Gulf War veterans with CFS from healthy veterans. It could of course be argued that the illness itself has a negative impact on personality and mental outlook. However one study shows that CFS sufferers tend to score higher in total perfectionism, doubts over actions and concern over mistakes scales, and it seems less likely that these personality traits could have been produced by the illness itself. Other anecdotal evidence seems to suggest that the people who contract CFS tend to be high achievers. While there is little published research showing that CFS sufferers tend to be high achievers, there is quite a lot of anecdotal evidence that this is the case. In my own discussions with CFS sufferers, virtually all of them either described themselves as high achievers, or said that their job was very stressful in the months before they contracted CFS. In most cases, the stress was not perceived as negative most said that they enjoyed their work, and in many cases they said they thrived on the stress of a high pressure job, and therefore did not think that stress was the cause of their illness. Put together, these findings may point to a possible reason why some people are more prone to developing CFS than others. There may be a personality type that I call high achiever/burnout-prone which is more likely to suffer from CFS. These people may have the ability to sustain high levels of physical and/or mental activity for long periods of time when the need arises, with long-term high levels of HPA axis activation being a consequence of this (or perhaps the mechanism allowing this to occur in the first place). The negative consequence of this ability to maintain high levels of HPA axis activation is that the opposite can occur when conditions are right, resulting in either burnout of CFS.

CFS as Negative Placebo


The placebo effect appears to play a significant part in the recovery of many patients from CFS. This appears to happen by what can best be described as a gradual change in mental attitude or lifestyle. As described earlier, a placebo treatment 79

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appears to alter the function of certain areas in the brain such as the prefrontal cortex and the HPA axis, reversing the abnormalities that cause illnesses such as CFS. Although it is difficult to pinpoint exactly what aspects of mental attitude cause this negative placebo effect, they may involve factors such as lack of long-term goals, lack of motivation, and a lack of a focus for life. These all appear to be factors which the placebo effect can reverse, and also appear to be important in the recovery of CFS patients, whether their treatment involves the placebo effect or some sort of management programme. CFS can therefore be thought of as a negative placebo effect. Although the initial trigger for the illness may be a virus or other HPA axis stressor, in the long-term, when these initial stressors are no longer present, it appears that factors such as mental attitude and lifestyle are important in perpetuating the abnormal HPA axis activation that results in CFS. These are the factors that the placebo effect can reverse.

CFS, Burnout and Dysthymia


As well as sharing similar symptoms, CFS, burnout and dysthymia are all associated with similar alterations in HPA axis function. Major depression is generally associated with an elevated HPA axis, which is secondary to the psychological factors that result in the depression. With CFS and burnout, however, the HPA axis appears to be more central to the condition, and there is generally a reduction in HPA axis function rather than an increase. Dysthymia, which shares many symptoms with CFS, is also correlated with abnormal HPA axis function. Although some studies show that dysthymic patients have similar HPA axis responses to depressed patients, other studies show a reduced HPA axis function, similar to CFS. It is difficult to separate depression from dysthymia, as there is a broad overlap in symptoms between the two. However it is possible that there are two distinct types of dysthymia one, associated with an elevated HPA axis, which is similar to major depression, and a

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second, associated with reduced HPA axis function, which is similar to burnout and CFS. The difference in diagnosis between CFS and dysthymia is mainly down to difference in severity between the psychiatric symptoms, such as depression and insomnia, and the physical symptoms, such as fatigue and pain. It is possible that CFS, burnout and certain forms of dysthymia are simply different aspects of the same underlying condition, namely a suppression of the HPA axis due to various factors. The only real distinguishing factor between CFS and burnout is the duration and severity. If the symptoms last for more than six months and the fatigue is highly disabling and not cured by sleep, then CFS is diagnosed. The actual symptoms, as well as the disturbances in the immune, endocrine and autonomic nervous systems which most likely cause the symptoms, appear to be the same for both burnout and for CFS. There are a number of cases of people with CFS who initially suffered from burnout while working in a high stress job that they either didn't enjoy or that they had lost motivation in. For these people, the symptoms of burnout continued to get worse after trying to remain in their job during the initial period of illness. Eventually, when the illness got too severe, they had to give up the job and the illness symptoms remained. In the UK, CFS used to be called yuppie flu, as at the time it was thought to mainly affect the young executives and finance industry workers living in London. Although it is now recognised that the illness is not just limited to one particular social group, there may have been some truth in the perception, as the yuppies in question would have been working in very stressful environments and certainly would have been at risk of developing burnout. The yuppie flu label also had negative connotations, and the popular feeling was that it was not a real illness, but was simply caused by laziness or some form of neurosis or hypochondria. This may in part be responsible for the dichotomy of opinion on the nature of CFS between researchers in the UK, who tend towards a psychiatric 81

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explanation, and those in the USA who tend towards a viral or other organic explanation.

Similarity to Bipolar Disorder


There are a number of similarities between CFS and bipolar disorder. In both illnesses patients show abnormalities in HPA axis function, as well as going through periods of severe depression. The evidence also points to the prefrontal cortex being implicated in both illnesses. Many CFS patients tend to be either high achievers or working in high pressure jobs before their illness, working at a very high productivity level, which could be seen as being similar to a mild form of mania. Bipolar patients go through alternating periods of depression and mania, while CFS patients seem to be stuck in something similar to the depression phase of bipolar disorder. In its mild state, bipolar disorder allows people to produce very high levels of intense creative output. There is a large body of evidence showing that creative people have a much higher likelihood of developing various mental illnesses, such as depression, bipolar disorder and schizophrenia, than the general population. The actual numbers vary depending on the study, but for the most creative professions, such as poets, the likelihood of being diagnosed with a serious mood disorder is about 10 times the figure for the general population. Although full-blown schizophrenia and bipolar disorder are clearly highly disabling, mild forms of these disorders seem to be linked with higher levels of creativity and imagination in the case of schizophrenia, and higher overall levels of work output in the case of bipolar disorder. There is a large overlap in symptoms between bipolar depression, unipolar depression and schizophrenia, and close relatives of patients with one of these disorders are more likely to be diagnosed with any of the illnesses. These disorders are thought to be caused by the combination of a number of genes, and it is likely that having some of the genes responsible for these disorders results in the advantageous traits, whereas having all of them results in mental illness. A susceptibility to 82

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CFS could be caused by some of the same genes that are responsible for bipolar disorder and other mood disorders. However, at the present time there is no research showing whether the relatives of patients with mood disorders are more likely to have CFS, so at the moment this is just speculation. Both bipolar disorder and schizophrenia are known to be triggered by stress, although there must also be a genetic predisposition to the illness. Similarly with burnout and CFS, chronic long-term stress can be the trigger that results in the illness, and again a genetic predisposition is probably important in determining whether or not stress results in burnout (or CFS).

Psychological versus Organic Debate


There is no consensus among researchers as to whether CFS is in fact a psychological or organic illness. Years of research have failed to find any disease process that would indicate an organic cause. Although many symptoms of the illness are physical or physiological in nature (such as pain, low blood volume, swollen glands, etc.), these do not necessarily indicate an organic cause. A research study by the Westmead children's hospital in Australia looked at the outcome of adolescents who were diagnosed with either CFS or a somatoform disorder (which is essentially a psychosomatic illness), and the outcome after treatment. The two groups had similar symptoms, with the diagnosis of either CFS or somatoform disorder reflecting whether the illness was thought to be organic or psychological in nature when the patient was diagnosed. Both groups underwent the same treatment programme, which was essentially psychological in nature. The study found that there was no difference in the outcome of the two groups who went through the treatment programme. Probably the most compelling evidence that psychological factors are important in the underlying etiology of CFS are the accounts of people who have recovered. Apart from cases of spontaneous remission, recovery is usually due to either some sort of therapy, a change in lifestyle, or the placebo effect. 83

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Many CFS researchers who are convinced that there is no psychological component to CFS say that these people did not have true CFS. However, looking at the accounts of these patients, it is clear that they did have a debilitating illness with real physical symptoms, with many being confined to bed due to the severity of the illness. These severely disabled patients managed to recover to full health due to essentially psychological treatments.

Is CFS All in the Head?


In talking about psychological factors acting to prolong CFS, it should be made clear that CFS is not a purely psychological illness, and is not all in the head of sufferers. Studies on CFS patients show quite clear physical abnormalities such as shrunken adrenal glands, as well as impaired ACTH secretion in response to an insulin injection. These results, and the insulin response test in particular, show that there is a clear imbalance in the HPA axis, and that the patient is not imagining the symptoms. However it is also quite clear that psychological mechanisms play a very important part in the development and perpetuation of CFS. It is dangerous and wrong to try to pigeonhole CFS as either a physical or psychological illness (as the vast majority of researchers try to do), as it appears to be an abnormality at the interface where the psychological, hormonal and immune systems interact. The prevailing opinion among psychiatrists is that CFS is a psychosomatic illness caused by neurosis. Most CFS sufferers are not suffering from any type of neurosis, and suggestions such as this are the main reason why CFS patients tend to be very hostile to any notion of a psychological cause for the illness. The psychological factors that appear to be important in perpetuating CFS are quite subtle in many cases, which makes it easy for them to be dismissed completely. Rather than being due to neurosis, it appears that factors such as a negative longterm outlook and a lack of achievable long-term goals result in the perpetuation of the symptoms. These psychological factors 84

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may be due to the illness itself, or may be due to other things happening in the person's life, or possibly a combination of the two. It may seem difficult to see how such subtle psychological factors can cause such diverse and severe physical and physiological symptoms seen in CFS patients. The reason would appear to be down to the HPA axis and related systems in the hypothalamus, which ultimately control all aspects of the immune, endocrine and autonomic nervous systems. Although there is no direct conscious control over the HPA axis, a wide body of research shows that mental attitude and lifestyle can and do play a large part in determining HPA axis function, and consequently have a significant effect over both mental and physical health.

CFS as Prolonged Burnout


The reason why CFS can last so long could be due to negative feedback from the symptoms themselves. The initial HPA axis suppression (due to long-term infection or stress) results in a reduced HPA axis drive from the hypothalamus, and possibly shrunken adrenal glands causing reduced adrenal capacity. The disturbance to the HPA axis and related systems (such as the immune system and ANS) then results in the various symptoms suffered by CFS patients. This then results in a negative mental outlook and a reduction in physical and mental activity, which then serve to cause further HPA axis suppression. There is a vicious circle of symptoms, mental feedback, HPA axis suppression and further symptoms, resulting in prolonged illness. Essentially the HPA axis has been pushed into an abnormal state of under-activation, from which it is difficult to break out of. It should be emphasised that CFS is not necessarily caused by emotional stress, but rather the inability to handle stress, which is a different thing. In some cases CFS may be triggered by stress, but this is not always the case. Many long-term CFS sufferers say that initially they were treated by their doctor as if they had a stress related disorder, and they were prescribed rest, relaxation, and in some cases 85

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tranquillisers. In general, this course of action seems to simply prolong the illness, resulting in continued symptoms. It seems that enforced long-term rest is not beneficial to CFS sufferers, and that it simply prolongs the HPA axis suppression associated with the illness. Similarly, many CFS sufferers give up work and become unemployed due to their illness. This again tends to lead to a situation where there is less and less activity performed, which leads to a perpetuation of the illness. This is not to say that CFS sufferers should be forced back into work, which is likely to lead to a worsening of the illness. What is more important is pacing activities doing as much or as little as the patient can do at that time which many patients recommend as the most effective technique in recovering from the illness. The nature of work is equally important, with motivating, fulfilling activities being more likely to lead to improvement than working in a stressful, dead-end job simply to make money. Many people who have recovered from CFS say that they got into a pattern of not working, and then thinking that they couldn't work. However, once they realised that they could do small amounts of work during the times when their illness was not so severe, that then resulted in further improvement and a greater ability to do more work, ultimately leading to a complete recovery.

Symptoms of CFS
There is a wide range of different symptoms suffered by CFS patients, and many people suffer from only a small subset of these. It is tempting for the patient to believe that he or she has many different illnesses, or for the doctor to simply label the patient as a hypochondriac. However, the similarities in the triggering events, underlying endocrine and immune abnormalities, and similar treatments, all point to there being a single illness that has different effects on different people. The symptoms of CFS can be divided into two distinct categories. First, there are the symptoms of reduced immune function such as susceptibility to illness, swollen lymph nodes, as well as increased risk of allergies due to a shift in immune function towards the TH2 response. 86

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The other main group of symptoms can be described as the inability to handle stress. This lack of stress tolerance is both physical, in terms of the ability to perform physical exercise, as well as mental and emotional. It is easy to see how a reduced HPA axis function, and the resulting reduced cortisol, adrenal capacity and blood volume could cause the physical symptoms of CFS. A reduced adrenal mass may not automatically lead to a deficiency of cortisol, as the pituitary and hippocampus will adjust their output to compensate for a lack of hypothalamic drive. However, when under stress or when performing prolonged exercise, the reduced adrenal mass may not be able to sustain the required high levels of cortisol, resulting in a fall in cortisol levels and consequent fatigue.

Psychiatric Symptoms of CFS


The mental symptoms of the illness such as depression and anxiety also appear to be an inability to handle stress, this time mental or emotional stress. Events that would not normally be perceived as very stressful can then cause symptoms of anxiety and subsequent depression, due to a reduced ability to handle stress. Under normal circumstances, the person would be able to cope well with these minor stresses, but the illness appears to reduce the ability to handle these stresses, resulting in such symptoms from minor stressors. It should be noted that not all CFS patients suffer from depression or anxiety, but it is very common, affecting somewhere between 50 percent and 90 percent of patients. Most CFS sufferers feel that the anxiety and depression they suffer from is not due to any psychological worries, but is rather a symptom of the illness. It is possible that this is due to an imbalance or a reduced production of neurotransmitters such as serotonin and noradrenaline. Whether this is a consequence of reduced HPA axis activation, or whether it is a consequence of the underlying factors which cause the reduced HPA axis activation seen in CFS is not clear. What does seem clear is that there is a difference from major depression, which tends to be associated with an overactive HPA axis, whereas CFS is associated with an underactive HPA axis. Major depression can 87

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be pictured as being caused by excessive brain activity and turnover of neurotransmitters, due to factors such as stress, worry or neurosis, whereas the depression associated with CFS is more likely to be due to an undersupply of the same neurotransmitters, resulting in a reduced ability to deal with emotional stresses.

Cardiac Symptoms of CFS


Many CFS patients complain of having a high heart rate or palpitations. While it is easy to put this down to stress (as many doctors do when presented with this and other CFS symptoms), many CFS sufferers have high heart rates even during resting, or under minor stress or mild exercise. This is related to orthostatic intolerance, another common symptom of CFS patients, which causes light-headedness and palpitations when standing up or changing posture and is thought to be caused by abnormal regulation of blood pressure. Studies have shown that CFS patients tend to have an over-activity of the sympathetic branch of the ANS, with a corresponding decrease in parasympathetic activity, even at rest. It is likely that this shift towards the sympathetic nervous system (and therefore increased heart rate) is itself a symptom of an underactive HPA axis. The hypothalamus, and HPA axis in particular, are important in regulating the overall activation of the ANS, so any dysregulation in the hypothalamus is likely to cause abnormalities in the balance of sympathetic versus parasympathetic activation. It is also possible that low levels of cortisol as are seen in some CFS patients could prompt the body to compensate by increasing heart rate. Studies on patients suffering from adrenal insufficiency have shown that they tend to have elevated levels of noradrenaline and lower levels of adrenaline than controls. This is due to the fact that a certain level of cortisol is required in order for the adrenal medulla to convert noradrenaline into adrenaline. In patients suffering from adrenal insufficiency, the body compensates for the lack of cortisol and resulting lack of adrenaline by increasing

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noradrenaline output. This results in a number of symptoms, one of which is a higher than normal heart rate. Adrenal insufficiency could also cause reduced blood volume, another common symptom of both CFS patients and patients with orthostatic intolerance. Blood volume is regulated by the aldosterone-renin-angiotensin system, which maintains blood volume by controlling the balance of sodium and water in the body. Aldosterone released from the adrenal cortex is an important part of this system, and a complete loss of aldosterone results in severe hypotension and death. In cases of severe illness or stress, where there is a greater requirement for cortisol, the adrenal gland reduces the amount of aldosterone produced. This is partly counteracted by the effect of ACTH, which causes the adrenal cortex to grow in size and thus maintain sufficient levels of all hormones. In the case of CFS, however, patients can have very shrunken adrenal glands, which may result in levels of aldosterone becoming depleted during periods of stress. It is not clear whether low blood volume, low cortisol or an imbalance in the ANS are central to the cardiac symptoms of CFS, or whether they all contribute to the condition. However, all of these systems are ultimately controlled from the hypothalamus, and the HPA axis in particular, so it is likely that an imbalance in the HPA axis is central to many, if not all, of these symptoms.

Digestive Symptoms of CFS


Another set of symptoms common to many CFS patients are reduced appetite and a reduced digestive capacity, which may manifest as symptoms such as feeling full after eating a small meal, slow stomach emptying, or having symptoms such as feeling very tired or having a high heart rate after eating a large meal. All of these symptoms are consistent with a suppression of hypothalamic NPY and the parasympathetic nervous system, as a result of reduced HPA axis activity. It is a myth that digestion is automatic, and that after eating a meal the digestive system will go into autopilot and do all that is required to digest the meal. Although the digestive system does have its 89

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own nervous system (the enteric nervous system), it requires inputs from the ANS in order to function properly. The vagus nerve of the parasympathetic nervous system is the primary pathway of this interaction between the ANS and the digestive system. HPA axis hormones such as cortisol are also important in providing energy for the digestive processes, as well as protecting the gut from damage. The HPA axis therefore has a large influence over the digestive system, and it is easy to see how imbalances such as those seen in CFS patients could disrupt its normal operation. This will be discussed in more detail in the chapter on irritable bowel syndrome.

Depression as a Symptom or Cause of CFS?


When CFS patients go to a doctor with symptoms of depression, the depression is usually thought of as the cause of their illness. Patients, however, tend to think of their depression as either a symptom of the illness itself, or as a normal psychological reaction to having such an illness. From reading the accounts of people with CFS and speaking to them, there is anecdotal evidence to suggest that depression is actually a symptom of the illness itself, and the following examples demonstrate this point. A number of CFS patients have described experiencing something along the lines of rapid cycling bipolar episodes with a (roughly) one-hour period. The actual symptoms consist of feelings of intense anxiety, followed by similarly intense depression, with a period of one or two hours between successive episodes. In all of these reports, there was no psychological trigger or explanation for the feelings. In one case, the episode was triggered by going through an entire night without sleep due to a combination of being in the middle of a particularly bad burnout phase and (presumably) having desynchronised hormone rhythms. In another case, the episode followed after the patient was given a very high dose of an anti-viral drug. During these episodes, it felt as if some natural one-hour body rhythm was causing the symptoms, due to the 90

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brain being in an abnormal state (such as being severely depleted of some essential neurotransmitter). It is interesting that in both cases the period between successive anxiety and depression episodes was about one hour, which is roughly the period between successive hypothalamic CRH pulses that result in activation of the HPA axis these symptoms could therefore be caused by the HPA axis being in an abnormal state. A lot of the time it is difficult for CFS patients themselves to really know whether their depression is a symptom of the illness or simply their psychological reaction to being unable to live a normal life due to the illness. However, in a number of cases there is a clear link between depression and known triggers. In one case, eating a large meal at night resulted in impaired sleep, followed the next morning by diarrhea, anxiety and depression. There was no psychological trigger for the depression, and the meals eaten the night before were not large in the normal sense just larger than the person could handle at that particular time, due to reduced digestive capacity because of CFS. In another case, stress during the day at work resulted in severe depression for a number of hours after returning home. The work was not particularly stressful in the normal sense, but caused symptoms such as tachycardia and mild anxiety due to impaired stress tolerance caused by CFS. On returning home and relaxing, the patient felt feelings of intense depression and uncontrollable crying for a number of hours. This was not triggered by worry or any negative feelings about the day, but was felt to have been triggered by being worn out or drained, due to the effect of the stress during the day. In all of these cases the depression appears to be a result of minor stresses causing an abnormal reaction in the brain, due to imbalances in hormones or neurotransmitters, as a result of suffering from CFS. Although it may seem a trivial point, the fact that depression is a symptom of CFS rather than a cause is very important when trying to develop effective treatments for the illness. Many CFS patients are simply given antidepressants in the mistaken belief that their symptoms are all caused by 91

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depression, but in virtually all cases this simply cures the depression and not the other CFS symptoms. Of concern is the number of CFS patients who report feeling suicidally depressed, usually during their crashes, the times when their fatigue and illness is at its worst. There are also many reports of CFS patients having taken their own lives, presumably during such periods of depression. While depression is a common reaction of the body to excessive stress, in the case of CFS it appears that the depression is a result of reduced stress tolerance rather than simply too much stress. This distinction is important for understanding the illness and developing suitable treatments.

Sympathetic Over-activity
Higher than normal sympathetic nervous system activity is a common symptom in CFS, especially in response to stress. As has already been discussed, it is likely that this is caused by the body compensating for an underactive HPA axis. It is possible that this shift in ANS activity (from parasympathetic to sympathetic) could cause the symptoms of depression and anxiety that many CFS patients suffer from. Sympathetic nervous system activity is associated with noradrenaline neurotransmitter release in the brain (this is distinct from the noradrenaline released from the adrenal medulla and from nerve endings, which does not cross the blood-brain barrier). Anxiety in particular is thought to be caused by excessive noradrenaline activity in the brain, and in CFS patients this could be caused by a depressed HPA axis leading to a compensatory increase in the sympathetic nervous system. The locus coeruleus (LC) in the brain stem is a major source of noradrenaline within the brain. The neurons in the LC extend to many parts of the brain including the cerebral cortex, the limbic system and the spinal cord. Noradrenaline activity in the LC increases during the day and reduces during sleep, and is important in controlling arousal and alertness. If an event is perceived as a threat, activation of the LC increases, resulting in increased output of noradrenaline and acute activation of the 92

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sympathetic nervous system. This results in the fight or flight reflex of increased heart rate and alertness, and suppression of the digestive system. People with generalised anxiety disorder tend to have increased levels of noradrenaline activity in the LC. In patients with CFS, it is likely that an over-activity in the LC in response to stress results in the symptoms of anxiety and sympathetic nervous system arousal. This over-activity may then result in a compensatory reduction in noradrenaline afterwards, resulting in depression. Sympathetic over-activity could also help explain the shift in immune response from TH1 to TH2 seen in CFS patients, as well as the general suppression of the immune system that is also typical of CFS. The increased release of catecholamines from the adrenal medulla caused by the sympathetic overactivity would result in both of these changes in immune function.

Mechanism for CFS


The symptoms of CFS seem to be the result of an imbalance in the hypothalamus, and the HPA axis in particular, but it is unlikely that there is any actual damage to the hypothalamus. Rather, it is likely to be an imbalance in the levels of CRH neurons and/or receptors in the hypothalamus or in the brain structures controlling these neurons, in the same way that major depression is an imbalance of serotonin and noradrenaline neurons and receptors. The changes that occur in the hypothalamus during CFS may be protection mechanisms that prevent the body from undertaking stressful activities that appear not to be beneficial. With CFS, the initial trigger is usually a viral infection, environmental toxin or emotional stress, all of which are known to activate the HPA axis. Due to factors such as personality and mental attitude, this initial trigger then leads to a prolonged imbalance in HPA axis function in some patients, resulting in CFS. This is summarised below: Initial stressor causes acute HPA axis activation. 93

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During the rest period after recovery from the stress, the HPA axis is pushed into a state of under-activation. Due to mental attitude and other factors, this abnormal state of HPA axis activation persists long afterwards. The suppressed HPA axis results in various symptoms such as fatigue, suppressed immune system, depression, anxiety, tachycardia, etc. These symptoms cause further negative mental attitude. This results in a vicious circle of continued illness. This is in contrast to the current psychiatric model for CFS, which goes something along the following lines: Neurosis causes depression psychosomatic symptoms. along with other

Although there is no direct conscious control over the hypothalamus or the HPA axis, there are many pathways from the cerebral cortex to the hypothalamus that could cause the disturbance in HPA axis function seen in CFS patients. Excitatory and inhibitory inputs to the paraventricular nucleus of the hypothalamus project from the suprachiasmatic nucleus, prefrontal cortex, amygdala and other areas of the brain, which then result in modulation of HPA axis activation. The most likely candidate for the HPA axis suppression seen in CFS is the prefrontal cortex, which, as we have already seen, is important in determining stress tolerance, and is also known to be activated when the placebo effect is occurring. A study from Japan showed that patients suffering from CFS had lower than normal synthesis of glutamate in a number of areas in the brain, including the prefrontal cortex. Glutamate neurotransmitter transmission in the prefrontal cortex is important for HPA axis activation, and abnormalities in the synthesis and uptake of glutamate have been correlated with both fatigue and pain. It is possible, therefore, that an imbalance in the prefrontal cortex, in response to psychological factors, is what causes CFS to develop and persist after the initial triggering event. 94

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Recovery from CFS


In terms of recovery, there is very little research to suggest what actually cures CFS, or that there are any effective cures at all. In most cases the illness simply goes away by itself after a period of time, which can be anywhere from a few months to over 10 years. There is not much research on the exact percentage of patients who recover from CFS. The main problem is the definition of what recovery actually is. Many patients do recover somewhat, but most of them continue to have some symptoms. One study gives a figure of 12 percent for total recovery, while others give figures of between 30 percent and 60 percent for improvement and 2 percent for complete resolution of symptoms. Anecdotal evidence suggests that the majority of patients do recover fully (although exactly what percentage is unclear). Research shows that an important factor in recovery is the duration of symptoms, with patients who have had the illness for a shorter period of time being more likely to recover at some point in the future. A number of studies have shown that the chances of recovery are greatly reduced if the symptoms have persisted for longer than two years. Some patients recover within six months to a year, while others have had the illness for over 10 years with no sign of a resolution, although the severity of the illness tends to vary over time. One study reports that 46 percent of CFS patients showed spontaneous improvement after a period of one year, even though no treatment was used during that one-year period. This study found that complete recovery only occurred when the symptoms had lasted for less than 15 months. Other factors that have been shown to reduce the chances of recovery include older age, as well as current and lifetime history of dysthymia. Recovery from CFS, when it does occur, is generally long-term and gradual. Currently the only treatments for CFS that have been proven to work are cognitive behavioural therapy (CBT), which addresses psychological attitudes to the 95

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illness, and graded exercise therapy, which aims to gradually increase physical activity. However, even these treatments do not help everyone who has CFS, and they tend to be not much better than simply doing nothing at all. As already discussed, both anecdotal reports of people who have recovered as well as scientific studies show that mental attitude is a very important factor in recovery. Simply acknowledging the fact that psychological factors may play a role in the illness is usually enough to initiate recovery, whereas a negative outlook and an attitude that nothing can be done tends to result in prolonged illness.

Reports of Recovery from CFS


There are regular reports of people recovering from CFS published in newspapers and health magazines. The reports of patients themselves are a valuable source of information about the illness, and give the best indication of exactly what factors are important in recovery. The "treatments" generally fall into two categories: either an alternative therapy (relying on the placebo effect), or a change in lifestyle. As already discussed, it is likely that both of these treatments work in the same way, in that they both correct the same underlying imbalance in mind-body health. It should be noted that I do not recommend any of the alternative therapies discussed in these reports (and that includes any change in diet, or the use of vitamin, mineral or herb supplements). Such treatments are likely to be expensive and potentially dangerous, and owe their benefit purely to the placebo effect. "Karen", from an article published in issue 27 of "Healthy Way" magazine: "Karen was diagnosed with ME and for three years it was particularly severe, which left her feeling totally exhausted physically and mentally. Karen was so ill that for two years she was largely confined to bed. However, since having Kinesiology sessions, she has made a good recovery". 96

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The article goes on to say that she is now able to go out of the house on a daily basis, whereas previously she had been confined to bed. She used to feel totally exhausted after walking 5 minutes, but can now walk for 1.5 hours. Her head used to feel "fuzzy", and she had difficulty concentrating, but now she can focus much better. Karen says that during her Kinesiology sessions it became apparent that she had multiple sensitivities to everyday things such as dust, wheat, etc., and that she had high levels of mercury in her system. She also thinks that she was sensitive to electromagnetic radiation from household appliances. Kate Lock, from an article published in the Times Saturday Magazine She also has an online version of her story at:
http://www.klockworks.co.uk/cuttings/candida.htm

Two years ago Kate Lock, an author, suffered from intense fatigue, and didn't have the energy to take her daughter to school. She was so tired that she slept all afternoon. She had a succession of illnesses, and her glands were swollen for months. She also had a "fuzzy" brain, and couldn't write more than a paragraph. Her other symptoms included digestive problems, bloating, depression and PMS. This was the latest in a cycle of health problems that had begun in her twenties. After learning about candida, Kate thought that her health problems might be due to candida infection. After starting an anti-candida diet, Kate noticed a significant improvement in her health within one or two weeks. After being on the diet for six months she felt that she was 70 percent better, and her symptoms such as thrush, migraines, PMT, joint pains, fatigue and concentration problems had all disappeared. Anna Selby, from an article published in the Times Saturday Magazine:

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Anna began to have the symptoms of ME when she was in science college at 16. Her symptoms included weight gain, low energy levels (she was sleeping most of the day and going to college for an hour a day), and intense sweating. One day she came out in a rash, and her symptoms became so severe that she was confined to bed for eight months. Eventually her family found a doctor who knew about ME, and he suggested that she should go somewhere that meant a lot to her. The family decided to go on holiday to Cardigan Bay, where she had seen her first dolphin when she was four years old. The article discusses how Anna began to recover from ME, and how she went back to see the dolphins when she had a relapse. She has now fully recovered, and works for the Biscay Dolphin Research Program. The article talks about the therapeutic effects of dolphins, and about cases of people being cured from anorexia, depression and other illnesses through contact with them. Clare Kerr, from an article published in the Sunday Times: Clare's symptoms began when she was 17, after a bout of glandular fever. After spending three months recovering from the illness, she was glad to get back to school. As she had been away for so long, she had to catch up on the previous term's work, which meant staying up late to write essays and not getting much sleep. Six weeks into the term, one morning she woke up and could barely move. The article doesn't give much detail about her symptoms, but they included severe exhaustion, tunnel vision, pounding headache and auditory hypersensitivity. Her doctor didn't believe in post-viral fatigue, and eventually she was taken to St Bart's hospital where she was referred to a psychiatrist. She didn't understand what was happening, as she was sure that there was nothing wrong with her mentally. For the next five years she tried a number of alternative therapies, but nothing seemed to work. Eventually she was referred to the Breakspear hospital, which has a history of treating patients with ME using various alternative therapies. 98

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She was diagnosed with a number of vitamin and mineral deficiencies, and was told she had allergies to a number of foods and chemicals. She was also told that her EBV infection (causing the glandular fever) was due to her having a low immune response. She has now changed her diet in order to avoid the foods that she is "allergic" to, and also takes a number of vitamin and mineral supplements to correct the supposed deficiencies. She also practises yoga and meditation, doesn't smoke or drink, and generally tries to have a healthy lifestyle. Since starting this regime, her health has improved immensely. The article doesn't give too much detail, but the impression given is that her health is now pretty much normal, and she can now live a normal life.

Treatment of CFS
There is a tendency for both patients and doctors to concentrate on treating the symptoms of CFS rather than trying to cure the illness itself. Many patients take various herbs and supplements in order to cure their symptoms. In most cases these supplements have been shown to have no effect whatsoever, and at best they only give a mild improvement. CFS researchers sometimes give patients treatments to boost the TH1 anti-viral branch of the immune system that is deficient in many CFS patients. This treatment, while it may help in combating any viral infections, has not been shown to actually cure CFS itself. When hormone tests are performed on CFS patients by some doctors, there is a tendency to treat the illness by replacing deficient hormones such as testosterone, growth hormone or the thyroid hormones. Again, this only cures some of the symptoms and does not provide a cure for CFS. Many CFS patients use sleeping pills to cure insomnia, but in many cases this simply leads to a dependence on the medication and only offers a partial or temporary cure for the actual insomnia. This is also the case for treatments for other symptoms of CFS such as depression, anxiety and tachycardia. In some cases the patient ends up taking a large number of

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different drugs, and may end up feeling just as bad or worse than if they were taking nothing! Studies have shown that providing cortisol replacement therapy in CFS patients gives a small improvement in symptoms, but again does not cure the illness. The problem with cortisol replacement is that it tends to suppress the HPA axis responsiveness of the patient, resulting in adrenal insufficiency after the treatment has ceased. In addition, as it only replaces one hormone it is not surprising that it does not cure all of the symptoms. Restoring HPA axis function artificially would require CRH pulses to be injected directly into the hypothalamus. This would then activate the immune system, ANS and all of the other hormones that rely on HPA axis activation. The existing CFS treatments really just seem to be skirting about the main issue of trying to restore the normal circadian rhythm of HPA axis activation. What is likely to be more effective is to develop a treatment which combines certain aspects of existing treatments such as CBT and graded exercise, and which also attempts to make patients aware of the steps that they can take in order to cure themselves. CBT, although useful, is based on the misguided notion that patients' negative beliefs about their illness serve to perpetuate the illness, due to some sort of neurosis. While CBT does work in a small number of cases, it is likely that it is due to something along the lines of the placebo effect, and not for the reasons given by the practitioners. If their theory of CFS was correct then CBT should be able to cure all patients. Many CFS patients will not have anything to do with CBT because it implies that they are subconsciously prolonging their illness. The treatments that tend to work best for curing CFS can be divided into three categories: psychological, changes in lifestyle and the placebo effect. All three types of treatment ultimately work in the same way, with the psychology of the patient determining the effectiveness of any particular treatment. In many cases it is probably the act of doing the treatment that results in recovery, rather than any actual benefit from the treatment itself. Purely psychological treatments such as CBT and counselling, tend not be very effective, as they 100

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tend to focus on areas such as emotional problems which are not necessarily a significant factor in many cases. In the lifestyle category, many patients find that getting a new job or changing their career to something that they really enjoy results in curing their CFS symptoms. In terms of the placebo effect, many dubious alternative therapies that rely on it for their effectiveness have resulted in people completely recovering from CFS. Treatments that have worked include anti-candida diets, kinesiology, food intolerance diets, as well as many others. It should be pointed out that these were not patients who had mild symptoms; many of these people were bedridden and had highly debilitating physical and mental symptoms, all of which were completely cured by apparently trivial treatments. Perhaps the most beneficial way of treating CFS would be a combination of psychological/lifestyle and pharmacological treatments. Initially, the patient could be treated with drugs to help cure symptoms such as adrenal insufficiency, depression, anxiety and insomnia. This would provide a temporary cure for some of the symptoms, which would then allow the patient to work on the long-term recovery process. Factors that are likely to be important in this healing process might include: Reducing any excessive negative emotional or workrelated stress. Getting rid of any negative mental attitudes to the illness, and concentrating on improving rather than thinking that the illness is going to be permanent. Increasing short- and long-term goals and motivating tasks and having sufficient physical and mental stimulation, while at the same time not doing so much that they suffer from a crash. People who have recovered from CFS say that an important factor in improving health is to learn how to pace themselves, and to only do as much as their body can handle. Making significant lifestyle changes in order to align their goals and beliefs with how they live their life.

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What is important is to make changes in mental attitude and/or lifestyle that break the vicious circle of HPA axis suppression leading to illness, which then leads to further suppression of the HPA axis. Patient support groups are not always useful for CFS patients. In many cases these groups foster the myth that recovery is not possible, which may in itself be detrimental to the chances of recovery. In summary, the only real way to treat CFS is to get to the heart of the illness and treat the underlying factors that cause the various mental, physical, endocrine and immune system symptoms associated with the illness. Concentrating on just one single group of symptoms will only bring partial relief, and will simply serve to prolong the illness. Recovery is not instant, and may take many months or even years due to long-term changes that have occurred in the HPA axis and associated areas which may take a long time to reverse. However, recovery is possible in all cases, even for the most severely disabled patients, and in many cases this can be achieved by a relatively simple change in lifestyle.

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7. Irritable Bowel Syndrome


Irritable bowel syndrome (IBS) is as much a mystery to the medical profession as CFS, as there is no generally accepted theory as to the cause (and as with CFS, there is much speculation). The main theories are that it is an abnormality in the nerves which signal the colon, or that it is caused by stress and only happens to people who worry too much. Both of these theories are very simplistic and do not reflect either the results of the scientific research into the condition, or the experiences of the patients themselves. Stress is known to make IBS symptoms worse, due to the effect that acute stress has on the digestive system. However, many people with IBS have little or no stress in their lives and still suffer from the symptoms. There has also been much debate over the role of personality and IBS. Many studies show that IBS patients tend to have neurotic personality traits, or have negative coping strategies for dealing with stress. However, as with CFS, such personality traits are not agreed on by all researchers, and many (if not most) IBS patients could not be described as being neurotic (not to mention the fact that many genuinely neurotic people do not suffer from IBS). What has been demonstrated is that IBS patients tend to have abnormal patterns of HPA axis hormones, as well as abnormal autonomic nervous system activation. These abnormalities appear in response to eating as well as when under psychological stress. There is no test for IBS; the diagnosis is simply given when tests have ruled out any other diagnosis that could be causing the symptoms (which again is similar to the situation with CFS). IBS is a functional disorder, in that there is nothing physically wrong with the gut itself. The symptoms only manifest as an abnormality in the functioning of the gut, and the colon in particular. Specifically, a diagnosis of IBS means that there are abnormal bowel movements, resulting in either 103

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constipation or diarrhea, or an alternation between the two. In some cases there may also be pain in the abdomen. In a significant number of cases, people with IBS also have symptoms that overlap with burnout or CFS such as depression, anxiety and sleep disturbances. It is not only the symptoms that overlap with CFS; research also shows that there is an imbalance in the HPA axis function of IBS patients, although the nature of this imbalance tends to be different from that seen in CFS patients. Studies have shown that IBS patients tend to have higher cortisol levels in the morning and lower levels in the evening than controls. This corresponds to a more pronounced circadian rhythm of cortisol, in contrast to CFS where there usually tends to be a reduced or flattened circadian activation pattern. IBS patients also tend to have higher levels of ACTH and cortisol after eating a meal (a physiological response), as well as higher levels of cortisol when under stress, suggesting hyperactivity at some point in the HPA axis. Many CFS patients also suffer from IBS symptoms, although there is a tendency towards symptoms such as lack of appetite and poor digestion rather than constipation or diarrhea (although these also occur in many cases). The reason may be that CFS patients tend to suffer from an underactive HPA axis whereas in IBS patients it tends to be overactive, and this will have a correspondingly different effect on the digestive system. It should be noted that these studies showing increased HPA axis activation and greater variation in hormone rhythms are for patients with diarrhea predominant IBS (IBS-D). Many studies do not differentiate between different types of IBS patients, so it is sometimes difficult to draw conclusions. One study that did separate IBS-D and IBS-C patients (where constipation is predominant) found that IBS-C patients showed no difference in cortisol release after a meal from controls (whereas IBS-D patients had a significantly higher increase in cortisol than either). The overall picture presented by this research seems to be that IBS patients (or at least, those suffering from diarrhea) tend to have an increased stress response, or stress tolerance. This is not the same as saying that they are suffering from more

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stress; many IBS patients are told that their symptoms are due to stress when the only stress in their lives is their IBS. While burnout and CFS appear to be the result of an abnormally low stress tolerance (whether or not there is any actual stress), IBS-D appears to be the opposite. The same factors that cause burnout and CFS such as lifestyle and mental attitude, also appear to be significant in causing IBS, except that in this case it appears to be due to an over-activation of the part of the brain that is causing the abnormal HPA axis activation. Genetic factors are clearly involved, as only some people are predisposed to IBS symptoms. The same genetic factors that predispose some people to burnout and CFS may also cause IBS. A subset of IBS patients alternate between constipation and diarrhea, suggesting an alternating pattern of overactive and underactive HPA axis activity. As with CFS, there may be a high achiever/burnout-prone personality type which is more likely to be associated with IBS. Certain people may simply have a greater influence over HPA axis activation depending on factors such as mental outlook and lifestyle, resulting in both over-activation and under-activation of the HPA axis at different times, which then results in various symptoms such as IBS, burnout and CFS.

Differential Diagnosis of IBS


As IBS is a diagnosis of exclusion, certain other conditions that have similar symptoms to IBS must be ruled out before a diagnosis can be made. These include: Inflammatory bowel disease (Crohns or ulcerative colitis). Medications such as laxatives or constipating drugs that the patient is taking. Infections (parasitic, bacterial or viral). Malabsorption syndromes (coeliac disease, pancreatic insufficiency). Endocrine disorders (hypothyroidism, hyperthyroidism, diabetes, Addisons disease).

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Endocrine tumours (carcinoid tumours, gastrinoma, pancreatic islet cell tumours). Intestinal pseudo-obstruction (due to scleroderma, diabetes, etc.). Lactose intolerance. Psychiatric disorders (depression, anxiety, somatisation disorder). Note, however, that there is a large overlap between IBS and these psychiatric symptoms anyway. Many of these illnesses are quite rare, and some of the tests would only be performed where other symptoms indicate a possible alternative diagnosis to IBS. Parasitic infections, for example, are very rare in most developed countries, and tests would not normally be done unless the patients symptoms began after travelling to a country where such infections are common. Blood in the stool is one indicator of inflammatory bowel disease (IBD), but it is not always visible to the naked eye so blood stool tests are usually done. A colonoscopy will provide a definitive diagnosis of IBD. If the symptoms are primarily triggered by stress or lifestyle (for example diarrhea or constipation at the beginning of the week or at weekends, or diarrhea on the morning of important events) then IBS is likely to be diagnosed.

Effect of HPA Axis Hormones on Digestion


CRH, the hormone which initiates HPA axis activation, is also known to modulate colon motility, regulating the speed of passage of waste matter through the colon. IBS-D patients tend to have the majority of their symptoms either in the morning or after eating a meal, when colon transit is greatly increased. This is most likely due to the higher activation of the HPA axis that occurs at these times. Cortisol, the end product of HPA axis activation, also has an effect on the colon. It has been shown that glucocorticoids such as cortisol cause an increase in the amount of water and sodium absorbed by the colon and rectum. An underactive 106

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HPA axis, and the resulting low levels of cortisol, could result in diarrhea due to not enough absorption in the colon, which could be one cause of diarrhea in IBS patients. Similarly, an excess of cortisol could have the opposite effect, and could result in constipation due to too much water being absorbed from the stool. Cortisol also has a protective effect on the colon, preventing ulceration and inflammation. Corticosteroids are prescribed to patients suffering from ulcerative colitis, in order to reduce ulceration. But their action in preventing diarrhea could be mainly due to their effect on absorption, rather than because of their anti-inflammatory action. There is also evidence of ANS dysregulation in IBS patients, with abnormalities in parasympathetic vagus nerve activation having been noted. Vagal activation is necessary in order to digest food properly. The release of digestive enzymes, as well as the normal movement of food through the gut, depends on the appropriate activation of the vagus nerve. Lack of vagal stimulation would explain why many IBS (and CFS) patients report having problems digesting food, as well as the more typical IBS-type symptoms. As these symptoms are not generally recognised as being part of the IBS illness definition, they tend to be ignored by doctors, with the result that the patient becomes worried that they may have a more serious illness. Activation of the digestive system is controlled from the hypothalamus through the action of NPY and the HPA axis, which are normally activated together except in cases of extreme stress. Having a higher than normal circadian activation of the HPA axis would cause an overactive HPA axis and NPY response in the morning, resulting in high gut motility and possibly diarrhea, followed by a lower than normal response in the evening, resulting in reduced digestive capacity. This pattern of highly variable colon transit speed, as well as varying levels of digestion, could result in partially digested food entering the colon, which could cause further diarrhea. Three possible scenarios are given below: 107

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Low Cortisol, High CRH When the HPA axis is in a state of increasing activity, or if the pituitary is suppressed, it is likely that levels of cortisol will be relatively low, and CRH will be high. This could be due to a change in lifestyle or stress levels, or because of the effect of mental attitude or emotions on the ratios of the HPA axis hormones. Low cortisol will lead to lack of water absorption in the colon, and the high CRH will lead to increased transit speed through the colon. The combination of these factors will then lead to diarrhea. It is also possible that the presence of too much water in the colon (as well as undigested food, if it is moving through the gut too fast to be fully digested) will feed the bacteria in the colon, leading to an imbalance of bacteria and further symptoms. High Cortisol, Low CRH When the HPA axis is in a state of reducing or low activity, cortisol will be elevated and CRH will be reduced. Emotions such as hostility and anger can also alter the ratio of HPA axis hormones, resulting in high levels of cortisol without a corresponding increase in ACTH or CRH. In this situation the high cortisol will lead to increased absorption in the colon, while the low CRH will cause reduced motility. The combination of these factors will result in constipation. Low NPY A low overall HPA axis activation, as is seen during burnout and CFS, will result in lower levels of NPY, the neurotransmitter which is responsible for promoting feeding and activating the parasympathetic nervous system when present in the hypothalamus. The result of reduced NPY will be a reduced appetite and, if too much food is eaten, it may not be properly digested, resulting in diarrhea. 108

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Symptoms such as reduced appetite, bloating, sluggish digestion and weight loss occur in a subset of CFS patients, as well as in some IBS sufferers. It is likely that these symptoms are the result of reduced NPY activity, caused by an overall reduced level of HPA axis activation.

Gut flora
The colon is home to a variety of bacteria that are beneficial to digestion. These good bacteria break down undigested food and fibre without causing unpleasant smelling gas or irritating the colon. The action of these bacteria is also important in generating vitamins as a by-product of the breakdown of indigestible fibre. Although the immune system tries to keep a balance of good bacteria in the gut, sometimes other, more harmful types of bacteria can take up residence, giving rise to symptoms such as diarrhea, bloating and flatulence. Some factors that are known to upset the balance of bacteria in the gut include the use of broad-spectrum antibiotics, excessive alcohol consumption, stress and poor diet. An upset balance in gut bacteria is sometimes postulated as a cause of IBS-D. However, it is more likely that any bacterial imbalance is caused by the underlying HPA axis abnormality. This results in an excessively short or long transit time of food through the gut and colon, either causing the bacteria to be flushed out of the colon too quickly or else letting them build up to excessively high levels. In addition, if undigested food is pushed too quickly into the colon, this can promote the growth of undesirable bacteria that thrive on undigested protein and fat. These bacteria tend to cause problems such as diarrhea and foul smelling gas when they become too prolific.

Mental State, HPA Axis and IBS


The HPA axis is known to modulate colon activity, in particular motility and absorption. Most experiments on people suffering from IBS symptoms have shown some sort of

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imbalance in the HPA axis, and this is likely to be a cause of most, if not all, of the symptoms. Many people suffering from IBS are simply told that it is due to stress, or that they worry too much. Although stress can worsen the symptoms, many people with IBS also get symptoms when they are not under any stress. There is very little research on the actual causes of IBS. Although it is generally thought to be caused by an abnormal HPA axis, and that psychological factors can affect this, there is no research at all on exactly what these factors are, or how it can be cured. The only treatment options usually given involve relaxation techniques. However, these types of treatments are only useful where the symptoms are caused by excessive stress. What is more likely to be causing the symptoms in the majority of IBS sufferers is a variable HPA axis. Unlike in burnout or CFS, where there is usually a suppression of HPA axis activity, IBS sufferers appear to have either an overactive HPA axis, or a variable state of activation, going from excessively high to excessively low. It is likely that a high variability in HPA axis activation results in the alternating symptoms of constipation and diarrhea suffered by many people with IBS. In women, HPA axis activation tends to vary over the course of the menstrual cycle, whereas men tend to have larger variations when under stress, due to having a higher hypothalamic drive than women. Women tend to suffer from IBS (and CFS) more than men, and their symptoms sometimes follow their menstrual cycle. It is likely that the monthly cycle of estradiol, and its resulting modulation of HPA axis function, causes this monthly variation in IBS symptoms. As with CFS, lifestyle and mental attitude appear to play a large role in causing IBS symptoms, due to their effect on the HPA axis. Working life tends to be a significant factor in this respect, with high-pressure jobs more likely to cause the increased HPA axis stress response that results in IBS symptoms. Large changes in workload or activity can also result in changing patterns of bowel function, with many IBS patients experiencing diarrhea during the week and constipation at the weekend when they relax. 110

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IBS Treatments
In many people, the digestive system seems to be the first part of the body to suffer from the effects of abnormal hormone rhythms. Digestive problems are commonly seen during mild cases of burnout and other stress related disorders. In the case of short-term stress, these symptoms may disappear within a few days or weeks, but if they occur during CFS they tend to remain for the duration of the illness. With IBS patients these digestive symptoms tend to occur more frequently, and it is usually more difficult to pin down a specific cause, especially when there are no obvious stresses present. Dealing with the underlying causes of stress and burnout can be useful in reducing the severity of IBS symptoms where this is an issue. Factors such as motivation and goals, control over stressful events and mental attitude all play a part in determining HPA axis activation and response to stress, and these in turn affect the digestive system. However, in the majority of cases it is likely that lifestyle plays the major part in producing the symptoms of IBS, and the solution is likely to involve changes such as: creating a better work-life balance, not rushing to finish tasks sooner than necessary, and generally balancing out the workload so that there is less of a boom-bust cycle. Many IBS patients also find that certain foods can aggravate the condition, and that simple changes in diet can greatly reduce the symptoms. Common advice includes: Eat live bio yogurt regularly (at least twice a week) to replenish the good bacteria in the gut. There are also many pro-biotic supplements that can be bought, but these tend to be very expensive and are not necessarily any more effective than bio yogurt. Don't eat too much food late at night, when the digestive system is preparing to shut down. Eat wholemeal bread rather than white bread. Having a natural level of fibre is important to the functioning of the gut too much fibre can cause diarrhea and too little can cause constipation. The blanket advice that IBS can be 111

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cured by eating more fibre is a myth for some people it does help, but for others adding extra fibre simply causes diarrhea. People with constipation predominant IBS find it useful to eat more fibre. However this doesn't mean that if you suffer from diarrhea that you should cut out fibre entirely many people find that they require a certain amount of fibre in their diet for their colon to function normally, and too little can cause diarrhea. The best advice is to see what works for you, but if you are unsure it is probably best to eat whole foods, which have fibre neither removed nor added. Different foods can cause problems for different people with IBS. Learn to notice which foods tend to cause problems and avoid them. Bear in mind that there may be occasions when you can eat any food without a problem, but other times the same food causes symptoms. If you do not feel very hungry, or seem to have sluggish digestion, it may be better simply to not eat very much food at all, rather than forcing your digestive system to process a large meal. During these occasions it may also be useful to reduce the frequency of meals (only eating three meals a day without any snacks in-between). Avoid alcohol and caffeine. Many CFS as well as IBS sufferers cannot tolerate large amounts of alcohol or caffeine. Caffeine in particular is a very powerful stimulant and has a large effect on the balance of hormones in the blood and within the brain. The benefits of caffeine, in terms of heightened alertness and increased feel good neurotransmitter release, are balanced by increased adrenaline and HPA axis activation. Caffeine appears to accentuate the body's response to stress, resulting in higher blood pressure, adrenaline and HPA axis activation in response to any type of stressor. Caffeine also causes anxiety and diarrhea in most people if ingested in large quantities, and this effect is usually magnified in people suffering from CFS and IBS, resulting in the same symptoms at a lower dose. Caffeine also stimulates the small intestine as it passes through, causing it to secrete water rather than absorb. Interestingly, however, research 112

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done by Wagner et al in 1978 showed that while caffeinated water caused marked secretion in the small intestine, coffee containing the same amount of caffeine did not produce this effect. There could be other compounds in coffee that reduce the secretion effect of caffeine, which may mean that it is less likely to cause diarrhea than other caffeinated drinks. It could also mean that different types of coffee have different effects on the small intestine. In addition to increasing the amount of water entering the colon, caffeine also stimulates motor activity in the colon itself, and the combination of these two effects is likely to be the reason why caffeine induces diarrhea in some people. Take regular exercise. Walking in particular seems to be beneficial to the digestive system, promoting normal motility and absorption, as well as being a good way of handling any mental stress. Certain herbs such as peppermint and ginger can be useful in soothing the stomach and digestive system. Many people report that calcium supplements help to reduce diarrhea. Some people recommend calcium with magnesium, zinc and vitamin D, whereas others find that the magnesium makes diarrhea worse. The best solution is to experiment with different supplements even if you find that they don't help the diarrhea, they will not do any harm (except in excessive doses!) Many people with IBS find that foods containing high amounts of lactose, sorbitol or fructose can cause gas and diarrhea, so avoiding these foods may be helpful. Studies show that about a quarter of people diagnosed with IBS have lactose intolerance, and that a lactose-reduced diet helps to relieve the symptoms of diarrhea. Lactose is a sugar found in milk, and it requires a special enzyme, lactase, to break it down into simpler sugars that can be absorbed by the gut. This enzyme is normally only present in babies and young children, but humans have evolved the ability to prevent this gene from switching off during childhood, resulting in the ability to digest milk even into adulthood. Lactose intolerance is most common in South 113

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East Asian and sub-Saharan African populations, and least common in Europeans and Indians (but even in these populations some people can still be lactose intolerant). Sorbitol is not absorbed by the human gut, which is why it is frequently added to sugar free foods. However, this means that the sorbitol remains in the gut and can feed the bacteria in the colon, causing diarrhea. Sorbitol also reduces the ability of the gut to absorb fructose, causing further problems. Fruit juices contain varying amounts of fructose, glucose, sucrose and sorbitol. Prune juice has relatively high levels of sorbitol, explaining its laxative action. Fructose is most readily absorbed when glucose is also present, and diarrhea can result from eating foods that contain high levels of fructose in the absence of glucose. Sucrose (table sugar) is broken down into glucose and fructose by enzymes in the gut, so it is readily absorbed. Many processed foods contain high fructose corn syrup (particularly soft drinks manufactured in the USA, where corn syrup is cheaper than sucrose), which can cause diarrhea in some people. Try to ensure that your diet includes sufficient fresh fruit and vegetables. Many people find that fatty, fried foods, especially those containing large amounts of saturated fats, can cause problems. It might be helpful to avoid eating gas-producing foods such as beans, cabbage and cauliflower, as these can cause diarrhea for some IBS sufferers.

Is IBS Harmful?
Most medical professionals agree that IBS is not dangerous. Although the symptoms may be distressing, generally there is no risk of serious illness or any complications. Diarrhea, for example, even if it occurs most days, will not affect the body to a significant degree. The colon absorbs water, sodium, potassium and some vitamins from undigested food. During the type of diarrhea normally associated with IBS, a significant 114

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amount of absorption still takes place in the colon. The general pattern in IBS-D is to have one or more normal bowel movements, followed by one or more loose (or watery) bowel movements, the latter usually occurring in the morning or after meals. Alternatively, symptoms may fluctuate, with normal bowel movements occurring for a few days, alternating with diarrhea during other days. Enough nutrients are absorbed from the colon during the times when it is working properly to make up for the times when absorption is reduced. Looking at sodium absorption alone, most people eat over ten times the daily requirement, so the body does not generally have much difficulty replacing it. Eating sufficient fruit and vegetables will provide sufficient quantities of the other vitamins and minerals required. If the diarrhea is associated with lack of appetite and reduced digestive capacity, there can be associated weight loss due to carbohydrates and fat passing through the digestive tract unabsorbed. Although this could potentially lead to serious consequences if it occurred over the long-term, such episodes generally tend to last for short periods of time. Although the official position is that IBS does not cause weight loss, this is not always the case. Many IBS patients go through periods of reduced digestive capacity, and it is also a common symptom of CFS. Simply worrying about IBS can be enough to make the symptoms worse, and can lead to a vicious circle of illness. While it may not always be possible to be completely free of symptoms, it is certainly possible to reduce the frequency and severity of attacks to a manageable level, and in many cases the symptoms are reduced to such an extent that they are barely noticeable.

Interaction of Factors
It is not clear how the psychological factors such as stress, burnout, mental attitude and lifestyle, are linked to physical factors such as lactose intolerance in causing IBS symptoms. It could be that these are two separate issues, and that people with lactose intolerance have a different type of IBS to those who 115

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have abnormal HPA axis responses. More research clearly needs to be done in order to determine exactly what is happening in the different groups of IBS patients, what is causing their symptoms, and whether it is one condition or a number of different conditions. Most IBS patients find that their symptoms are exacerbated both by lifestyle (or psychological) factors, as well as by diet. It is likely that certain foods cause problems due to them either being more difficult to digest, or because they are more likely to cause the bad bacteria to proliferate in the gut when they are not fully digested. It may be the combination of these foods with an abnormal HPA axis rhythm that causes the symptoms of IBS.

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8. Relation to Other Disorders

8. Relation to Other Disorders

Overtraining Syndrome
Studies suggest that the majority of athletes suffer from overtraining syndrome at some point during their careers. This is a condition of prolonged fatigue that is thought to be caused by training too hard with too little rest. The fatigue is not the same as normal post-exercise fatigue, and remains even after a number of days of rest. The symptoms of overtraining syndrome are similar to CFS, and include autonomic dysfunction, abnormally high or low resting pulse, abnormalities of various hormones including testosterone and cortisol, reduced immune system function, sleep problems, muscle pain, depression, as well as many others. In mild cases all that is required is 3 or 4 days of rest in order to recover from the symptoms of overtraining. In more severe cases it might take weeks or months to fully recover. There are also a number of people who have been suffering from overtraining syndrome for a number of years and have never recovered, which again is similar to the situation with CFS. The causes of overtraining syndrome are not clear. What actually determines overtraining is different for different people. Many athletes measure their resting heart rate in the morning and if it differs by more than 5bpm from normal then they reduce their training schedule for that day. There is evidence that non-training stresses play a role in the development of overtraining syndrome. Factors such as lifestyle and emotional stress appear in many cases to either trigger or perpetuate the symptoms of overtraining syndrome. Research is quite limited and most of the research so far has

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been done on single cases, but again there does seem to be a broad overlap with burnout and CFS. Burnout due to life stresses or a loss of motivation might be the initial trigger that reduces the athlete's ability to handle the physical stresses of training. In some cases this initial burnout may lead to a prolonged illness similar to CFS, with factors such as loss of income, inability to compete and subsequent loss of goals and motivation all serving to perpetuate the vicious circle of illness, burnout and HPA axis suppression.

Cancer
Although cancer is very different from CFS and burnout, there is a lot of evidence to suggest that the same factors that reduce burnout, such as having a normal circadian HPA axis rhythm, also act to enhance the part of the immune system that fights cancer. A study was published recently which seems to refute this. The review from the MRC at Glasgow University looked at 26 studies that investigated the association between psychological coping style and cancer survival, as well as 11 studies that investigated recurrence of the disease. They found that there were no significant associations between psychological outlook (such as fighting spirit or helplessness/hopelessness) and the chances of dying of cancer. They concluded that any positive results were due to the study samples being too small. The results of this study are interesting, and go against the popular belief that a fighting spirit is important in fighting cancer. However, it falsely gives the impression that nothing can be done by the patient to improve their chances of survival. There is very clear-cut evidence showing that lifestyle and mental outlook can vastly alter the chances of both contracting cancer and of recovery from the disease. Simply looking at the biochemical evidence, it is known that most of the adrenal and pituitary hormones modulate the immune system by a large extent, and that mental attitude can have a large effect on the relative concentrations of these hormones. The parts of the immune system that are important 118

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in fighting cancer, such as NK cells, are very sensitive to suppression by these hormones. It would therefore be very unusual if psychological factors were not found to alter the chances of cancer survival! As has been shown previously, there is also a great deal of evidence suggesting that personality, and having good psychological coping strategies in particular, has a significant effect on the immune system and levels of NK cells in particular. People who have poor strategies for coping with stress, and people who worry more, tend to have lower levels of NK cells. Another factor which appears to reduce the risk of cancer mortality is exercise, with higher levels of physical activity corresponding to a lower risk of cancer. A number of studies have shown a reduced risk of colon, breast and smoking related cancers being associated with increasing physical activity. There appears to be a large reduction in cancer risk from even low levels of activity, with gradually reducing risk for increasing levels of exercise. It is possible that this is due to the effect that exercise has on the HPA axis. Melatonin also appears to have a normalising effect on the immune system, by increasing levels of NK cells and altering the levels of various cytokines that control the immune response. It is therefore likely that cancer patients who are suffering from insomnia due to insufficient melatonin will be at increased risk. Stress and burnout are not the only factors that can disrupt the melatonin rhythm, either by desynchronising it from the normal 24-hour sleep-wake cycle, or by reducing the amplitude of melatonin secreted. Drinking caffeine at night has also been shown to greatly reduce levels of melatonin many hours later, and cause insomnia. This is likely to be due to caffeine acting to prevent the production of melatonin in the first place. Presumably during times of acute stress it is advantageous to have a greater concentration of serotonin than melatonin, so it is likely that during periods of high stimulation the conversion of serotonin to melatonin will be reduced. In fact, studies have shown that CRH, the neurotransmitter that initiates HPA axis activation, acts to inhibit the secretion of melatonin by the 119

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pineal gland, so this may be the route through which acute stress suppresses melatonin production. What all of these studies show is that having a normal circadian rhythm of hormones such as cortisol and melatonin is very important in providing protection from cancer (as well as many other illnesses). While environmental and genetic factors are the most important determinants of cancer growth, other factors such as lifestyle and mental attitude still play an important role in ensuring that the immune system is able to fight the disease, and in some cases could make the difference between survival and death.

Post-viral Fatigue Syndrome


Many cases of CFS begin with a viral infection, after which there is a period of fatigue and malaise that persists for many months. In some cases this post-viral fatigue syndrome (PVFS) simply goes away by itself in anywhere between one and six months. In other cases the symptoms persist beyond this period, resulting in a diagnosis of CFS. The only real distinction between PVFS and CFS is that in the latter case the illness has persisted for over six months. As we have seen, severe illness can sometimes result in adrenal insufficiency and suppression of the HPA axis, leading to a state of mild burnout. This is probably more likely to occur if the person has been under stress at the time of the illness, or if there are any psychological burnout factors present such as a lack of goals and motivation. The reason why some people go on to suffer from CFS while others recover from PVFS is most likely due to these psychological or lifestyle factors. While the initial trigger may be a viral illness, the perpetuating factors appear to be psychological variables such as lack of motivation and goals. In some cases these may have been present before the illness, and in other cases may be a result of the illness itself. It is likely that simply recognising the psychological factors involved is enough for the patient to prevent PVFS turning into full-blown CFS.

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Gulf War Syndrome


There is as much controversy over the nature of Gulf War syndrome (GWS) as there is for CFS. Many studies have been done since the end of the 1991 Gulf War, but with no definite conclusions. Many researchers put the symptoms down to posttraumatic stress disorder (PTSD) or hypochondria, while many simply say that the syndrome does not exist. This is the view taken by the UK government, who seem to produce a new study every few months concluding that GWS doesnt exist. The actual symptoms suffered by GWS patients are similar to CFS, and include fatigue, depression, pain and cognitive problems among others. Studies also show similarities in hormonal and autonomic nervous system abnormalities between CFS and GWS patients. A study by the US Institute of Medicine concluded that there was no strong link between exposure to sarin, depleted uranium, or vaccinations, and the symptoms reported by veterans. The study looked at 20,000 troops within 50 miles of destroyed stockpiles of Iraqi munitions that may have contained sarin nerve gas. In 99 percent of cases the soldiers reported no serious nerve illnesses. The authors of the study did point out that while high doses of sarin are known to be harmful, there is not enough information on the effects of low doses. A study by other researchers showed that low doses of sarin suppressed T cell responses in rats, and interestingly this study also showed that the rats treated with low doses of sarin had an impaired HPA axis response, which is also seen in GWS and CFS patients. A study in the UK looking at the effects of multiple vaccines in Gulf War veterans found that the majority of the illness symptoms were associated with multiple vaccines taken during the war (whereas vaccinations before the war had no effect). This study concluded that the combination of vaccinations and the stress of the war might be a factor in producing the illness. This is very similar to the case with CFS, where many patients become ill during a viral infection that occurs at a time of stress. In both cases it appears to be the combination of stress and illness (or vaccination) that triggers 121

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the syndrome. The effect of a vaccination on the body can be very similar to an actual infection. In a small number of cases, vaccinations can produce complications that are similar to those produced by the live pathogen (but there is always much less risk of dying from a vaccination than there is of dying from contracting the disease which the vaccination protects against). In the case of GWS, if the vaccination has any bearing on the resulting illness, it is likely to be due to interactions between the immune system and the HPA axis rather than any direct infection by the vaccine itself. There is also evidence that GWS is a result of attitudes to the war itself, with stress during the war, other life stresses and personality factors being significant. The argument against the stress explanation is that GWS patients are no more likely to suffer from PTSD than non-GWS veterans. PTSD is a condition caused by a traumatic event that results in symptoms such as flashbacks, hyperarousal, insomnia and emotional problems long after the initial trauma. The symptoms of GWS patients, as well as the results of tests showing abnormalities in HPA axis and ANS function similar to CFS patients, would indicate that PTSD is not the cause of GWS. PTSD patients tend to have an overactive HPA axis in contrast to CFS and GWS patients. Fatigue is also not generally a significant symptom of PTSD (at least, not to the same degree as with CFS). The most likely explanation for GWS is that, rather than being caused by PTSD, it is a state of persistent burnout similar to CFS. The factors causing the illness also appear to be similar, including: High levels of stress during the war, followed by a lack of activity after return. Multiple vaccinations during a time of stress. Negative mental attitudes to the war itself. As with CFS, it is likely that the illness itself causes a vicious circle of negative mental attitude, suppressed HPA axis and continued illness, which causes the state of burnout to continue long after the initial trigger. As with CFS, there appears to be 122

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no known cure, although patients do tend to recover gradually over time.

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9. Avoiding Burnout
Burnout is the lack of ability to cope with physical or mental stress. Although burnout can be caused by excessive stress, this is not always the case it is possible to be under chronic stress for a long period of time without suffering from burnout, and it is also possible to suffer from burnout in the absence or stress. Factors such as mental attitude and lifestyle seem to be important in determining whether or not someone suffers from burnout. Burnout may in fact be a built-in protection mechanism that prevents the human body from undergoing stresses that are not perceived as being beneficial in the longterm. Rather than stress itself being the trigger for burnout, in many cases burnout manifests during a period of relaxation following a prolonged stressful period. This may be during a holiday after a stressful time at work, or during the recovery period after a severe illness. It should be remembered that when we talk about stress, it is not simply psychological stress, but rather anything that chronically activates the HPA axis. The main factors that appear to reduce the likelihood of burnout include: Having a sense of control and involvement over stressful situations. Having high levels of motivation. Having achievable goals to work towards. Having a focus or purpose in life. Having an optimistic attitude to life. Maintaining a healthy balance of physical activity, mental activity and relaxation. It should by noted that the motivation being described here is not as simple as getting out of bed and thinking I want to do x today. Many people suffering from CFS or burnout do have 124

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high levels of this conscious type of motivation. What seems to cause burnout is a lack of a more deep-seated motivation which is not controlled by conscious thought, but is more related to the mind's perception of whether or not it is useful to devote energy to pursuing the tasks that need to be done. The motivation that is important in avoiding burnout appears to be more along the lines of religious faith or having a purpose in life, and cannot be brought about simply by positive thinking. Part of the reason for burnout may lie in the abstract nature of many modern-day jobs. Whereas in the past the tasks which needed to be performed, such as hunting, gathering, building shelters and making clothing, were directly and very closely related to basic human survival needs, today people work for money and career progression. These motivations are not hard-wired into the brain in the same way that the basic needs are, and require input from the higher brain areas in order to produce the necessary drive. Burnout may occur when this high-level, abstract motivation is lacking.

Coping with stress


Many books have been written on the subject of dealing with stress, so I will just cover a few important points here. It is not always possible to avoid stressful situations, but you can certainly change the way in which you deal with them. Being in control of the situation, rather than it controlling you, is very important in this respect. Don't worry about what you cannot control. If a problem has already occurred then deal with it as best you can as soon as possible. If there is nothing that you can do about a future event, accept the fact. Once you have dealt with any problems, try not to worry any more. Don't worry about things which might happen in the future. If possible, plan contingencies for possible problems ahead of time. Once you have done as much planning as you can and thought through any potential worries, accept the fact that there is nothing more you can do at present. 125

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Coping with work


The workplace is one of the greatest sources of stress in many people's lives. If you are at the bottom of the food chain, there is pressure on you from your managers to perform well. If you are at the top of the company or self-employed, there is pressure to increase sales and make a profit, and possibly the risk of going bust to worry about. However, the people who are most likely to suffer from stress are the middle management. Not only do they have the responsibility for managing the staff under them, but they also have the pressure put on them by their management to achieve results. Unlike the people at the top, middle managers tend to have less say about how the business is run, and this lack of control can be a significant stressor. If you are in a management position, learn to delegate work to your subordinates rather than trying to do everything yourself. Implement procedures that allow the business to run when you are not around, so that you don't feel that you must be in the office all the time. Take days off on a regular basis rather than just having a holiday once or twice a year. When you do go on holiday, make sure you are not worrying about work the whole time. If you must, phone in once or twice to put your mind at rest and make sure no disasters have occurred, but do not spend your time doing work that can wait for your return. Take regular breaks during work, especially if you are under a high workload. Going for a walk or simply chatting to colleagues is a good way of relaxing. Prioritise your tasks and keep a to do list. Learn to leave the less important tasks on the list rather than feeling that you must complete everything as soon as possible. Don't accept unrealistic deadlines. Many customers (and managers) will impose artificial deadlines with no idea of how long the task will actually take. If you are not happy with the deadline given then make that clear to your customer. Most customers will prefer to be told beforehand if a task will over-run or is simply impossible, rather than 126

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finding out on the day of the deadline. If there is a good reason for the deadline (such as a launch date which has previously been fixed), then it may be necessary to launch with a reduced product or service that meets most of the requirements, rather than releasing a rushed product that tries to fulfil all the criteria and ends up not working at all. What this all boils down to is having the backbone to say no when you feel that you are being asked to do something that is unrealistic or impossible. Being in a boring job or a job without very much work to do can be draining. If you are in this position, it might be worth either getting a new job, or seeing if you can take time off when things are not so busy. You are then more likely to be motivated to work hard during the times when there is more work to do. Some workplaces have a long-hours culture, where people are expected to work late nights and weekends. In certain industries such as highly paid investment banking jobs, this may just be the nature of the job, and you are expected to deal with the stress and long hours in return for being paid extremely well. However there are other times that employees work long hours when it is not necessary, simply to look good to management. In these situations, it is difficult to be the one person who goes home early, with the possibility of losing a pay rise or even your job. If you are a junior employee with little prior work experience, there is probably not much that you can do apart from perhaps looking for a different job. If you have more experience, however, you will have more leeway in deciding your own working hours. If you can get the work done by not working long hours, you should not have to stay in work late just to look good. Most studies show that long hours do not in fact increase productivity (in fact, in many cases they can actually reduce it). There are times when it is necessary to put in overtime, such as when an immovable deadline is looming or when a major problem comes up, but if these situations are happening on a daily basis it usually means that there are not enough people on the team. If you feel that you are under pressure to put in 127

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extra hours when it is not necessary and you have proved that you can do the work in fewer hours, make your feelings clear. If your company is reasonable, they will respect your opinion and might actually do something to change the workplace culture. Working from home may be less stressful and more productive, and may allow you to spend more time with your family. In these days of cheap, high bandwidth internet access, many jobs can be performed just as well at home as at the office. However, make sure that you maintain a good balance between work and personal life. For example, decide a time in the evening when you will switch off the phone and email, and don't do any work after that time. Working from home requires a certain amount of self-motivation and does not suit everyone. If you are stuck in a stressful or unmotivating job and there is no alternative, it might be worth considering getting a new job. If you really do not enjoy the type of work you are doing, it may even be worth changing to a completely different career, or setting up your own business. Many people working in high pressure jobs eventually realise that there is more to life than more money and another step up the career ladder. Staying in a stressful job that you do not really want to do will eventually lead to burnout.

Lifestyle
Always have future goals in mind and strive to achieve these. If you are suffering from a chronic illness such as CFS, base your goals within the restraints imposed by your illness so that they are attainable. Ensure that your life has some meaningful purpose, such as a rewarding career or religious faith, and that you have a reason to get out of bed every day. If you are not working or are retired, it may be worthwhile taking up a hobby, doing voluntary work, or joining a social group or club. If you do have a long-term illness, don't let the illness control your life. Always have a positive attitude towards the illness, fighting it rather than letting it defeat you. 128

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Have regular contact with friends and family, and make sure there is always someone close at hand who you can contact during difficult times. If you are alone, it might be worth trying to meet new people by going to events or evening classes in your area, or through the internet. If you have a long-term illness, the internet is a good place to find support groups where you can talk to other people who have gone through similar experiences. Learn to understand how your body reacts to various types of situations and stresses, and see if you can see any causal relationships between how you are living your life and how your body is reacting. Bear in mind that the effect could be immediate or it could be days, weeks or months afterwards in the case of burnout following long-term stress. Also bear in mind that perceived benefits due to drugs, diet or supplements could be due to the placebo effect or just coincidence. Try to get some regular exercise. This can be something as simple as walking part of the way to work in the morning. Don't let exercise be an additional stress in your life; rushing to get to the gym after work and pushing your body to its limit is not a good way of dealing with stress. Sunlight has a normalising effect on various hormone rhythms, such as melatonin, and can act to resynchronise circadian rhythms. Try to lead a balanced life, rather than having periods of high stress and activity followed by periods of boredom with nothing to do. The human body can adapt to different situations and the HPA axis is one of the ways in which this is done, but it takes time for this adaptation to take place. Of course, if you are in a long-term stressful situation it is better to take days off regularly, if possible, in order to minimise the overall effect of the stress. Dont get into the habit of using stress or anger to boost your energy levels. While this may provide a short-term boost, in the long-term it will simply prolong the burnout.

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Mental Attitude
Always maintain a positive attitude to life and try to see solutions and opportunities rather than problems. If you have a long-term illness, always think that you will eventually recover, and make plans for the things that you will do when that time comes. Try not to let negative emotions build up, especially anger. It is better to deal with problems by talking or having an argument rather than letting things build up. There are also situations where it is better to simply let things drop rather than starting an argument, especially over inconsequential matters.

Diet
Try to cut down on stimulants such as caffeine and alcohol, as well as smoking. Try to eat plenty of fresh fruit and vegetables every day. Reduce the amount of saturated fat, but do not cut fat out altogether. Apart from water, the human brain consists mostly of essential fatty acids. Fat is also important for transporting certain hormones and vitamins through the body. Do not cut out certain types of food (such as wheat or dairy) based on current fads, unless you have good reason to believe that you are allergic or intolerant to them. Above all, eat a balanced diet and you are less likely to suffer from a deficiency in any of the essential vitamins, minerals or fats. If possible try to eat more natural food and less that is highly processed. Processed food is likely to have less vitamins and minerals than the natural product. White flour, for example, is made by removing the bran and wheat germ before milling. This removes the fibre, oils and vitamins, and just leaves the protein and starch of the endosperm. Wholemeal flour, however, is made from all parts of the wheat, and contains all of the essential vitamins and oils that are removed from white bread. 130

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Recovery from Burnout


Although rest is important during stressful periods, enforced long-term rest is not the cure for burnout, and in many cases simply acts to prolong it, as is seen in CFS. What is more important is to have a balanced life without either excessive stress or too little activity. Mental attitude to stress (and life in general) is critical in allowing the body to provide sufficient resources, in terms of HPA axis activation, for dealing with stressful situations and maintaining both mental and physical health. As with CFS, there is no single method of dealing with burnout that works for everyone. The only solution is to look closely at your life and try to figure out what aspects of your lifestyle or mental attitude may be causing the problem.

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10. Summary
Current thinking is that the HPA axis is simply involved in responding to stress, and that its activation is generally bad. However, research now clearly shows that HPA axis activation is important in other aspects of normal, non-stressed life, such as digestion and the normal day-to-day functioning of the immune system. Rather than suppressing the immune system, it appears that a certain level of HPA axis activation is necessary for normal immune function, and NK cell activity in particular, which is an important part of the immune response to cancer tumours and viral infections. The reason that the HPA axis plays a large part in activating and modulating the immune system is likely to be because of the energy required to mount an immune response. The HPA axis is the main regulator of energy expenditure in the body, and ultimately controls all aspects of energy usage, balancing the needs of short-term stresses against the long-term dangers of excessive HPA axis activation. A high activation of the HPA axis is needed during times of stress in order to provide the body with sufficient resources to deal with the threat. Under non-stress conditions, the body generally maintains a level of circadian HPA axis activation that is sufficient to meet the normal needs of the body. However in some cases, such as with CFS and burnout, and after periods of severe illness, the HPA axis can get into an abnormal state of under-activation. This is likely to be due to negative feedback mechanisms that reduce the hypothalamic HPA axis drive after a period of stress, in order to promote recovery and prevent unnecessary or potentially dangerous activities that may not be beneficial. Certain factors reduce the likelihood of burnout, resulting in a greater ability to cope with stress without having as many physical, mental or emotional symptoms. Lifestyle and mental attitude play a large role in determining stress tolerance. The

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placebo effect most likely works in a similar way, by providing a new focus for life. The mechanism that causes burnout and CFS is not known, but may involve the prefrontal cortex. This area of the brain has been shown to change its activation as a result of the placebo effect, and is also thought to be involved in CFS. The prefrontal cortex is an important modulator of the HPA axis, and reductions in the levels of NPY in this part of the brain are associated with fatigue and anxiety when under stress. The prefrontal cortex and the hypothalamus are clearly important interfaces between the mind and body, and through their control of the autonomic nervous system and the HPA axis they are able to control many aspects of both physical and mental health.

Significance of HPA Axis Dysregulation in Illness


It is tempting to attribute many illnesses to a disturbance in the HPA axis. While an underactive or overactive HPA axis will certainly influence the immune system and could lead to infection, it would be wrong to say that it is the cause of all illnesses. In some cases, disturbances in the HPA axis may lead to a loss of immunity to infection, making it more likely that an external pathogen will infect the body. In other cases, the HPA axis dysfunction is the underlying cause of the illness, and reversing this irregularity will cure the illness itself. And there are illnesses such as genetic disorders that will occur no matter what the patient does, and upon which HPA axis function has no bearing whatsoever. I have so far limited the discussion to illnesses which can be either completely cured or at least controlled to a significant degree by the patient themselves either by a change of mental attitude or lifestyle. Short-term burnout is one example that fits into this category. IBS is slightly more physical in nature, in that although it is initially triggered by psychological or lifestyle events, this then appears to put the digestive system into an unbalanced state that can then cause further symptoms, even in the absence 133

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of the psychological factors. In this case the long-term solution is again down to mental attitude and lifestyle, but certain medications or changes in diet can also help. In the case of CFS, there is an even greater physical (or physiological) component to the illness, due to the long-term HPA axis suppression, atrophy of the adrenal glands and possibly changes in neurotransmitter and hormone receptors in the brain. The endocrine, autonomic and immune systems get stuck in an abnormal state that causes the various physical, mental and physiological symptoms of the condition. However, again, the only real cure is down to the patient changing his or her lifestyle and mental outlook. There is certainly scope for using drugs to cure some of the symptoms, but this will never in itself cure the illness. Going to the other end of the scale, for illnesses such as cancer or HIV the role of the patient's mental state in curing the illness is quite small. These and similar conditions can only ever be cured by outside medical intervention. However, it should still be borne in mind that mental state can influence the immune system to a large degree, and in some cases this could mean the difference between cure and relapse. Rather than simply relying completely on medical treatment to cure all illnesses, in some cases it would be better to help the patients to cure themselves. Trying to find a medical cure to a problem for which the only cure is down to a change in mental outlook or lifestyle will only ever lead to the patient not feeling in control of their illness, resulting in further problems. In some cases, using drugs to cure the symptoms of a primarily psychological illness will simply result in the patient becoming dependent on the drugs without providing any benefit. In the case of burnout and CFS, all that may be required is for the patient to realise exactly what is causing the illness in order for them to effect their own full recovery. Each patient must look at his or her life in order to determine what factors are causing ill health. This is usually not a simple or obvious task, and may involve a long period of careful thinking, experimentation with lifestyle changes, discussion or therapy.

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Getting to the Truth


It would be unwise and arrogant to suggest that I have completely explained CFS and related illnesses. In the future, we may be able to say that we understand CFS as well as we currently understand illnesses such as cancer, but much research still needs to be done before that can happen. In the course of writing this book, I have tried to show the ways in which the mind can significantly influence physical health both positively and negatively. I have also described research and put forward my own theories to explain the various physical and mental symptoms of CFS, some of which may prove to be incorrect. What I have tried to show is that seemingly subtle changes in mental attitude and lifestyle can have a significant effect on mental and physical health. For me, the key to maintaining good health is to always have an interesting, motivating, and preferably unstressful project to work on. Having a religious faith or using an alternative therapy appears to work for others. Some people appear to need this purpose in order to live a healthy life, while others appear to be able to be able to live a perfectly healthy life without requiring this ingredient. In susceptible people, when their life is out of balance, or perhaps when their HPA axis is upset by a particular combination of stress, illness and mental attitude, there results a period of physical and/or mental illness. This may manifest itself as depression, headaches or lack of immunity to infection. In severe cases this could lead to CFS.

Further Research
Although the theory presented in this book explains many (if not all) of the aspects of CFS, it is still only a theory, and further work will need to be done in order to see if it is valid. Many of the results discussed here, such as the effect of ACTH on the immune system and the activation of the prefrontal cortex during the placebo effect, have only been demonstrated by single studies. An interesting experiment would be to study the placebo effect on CFS patients. Similar to the experiment on patients 135

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suffering from depression, brain scans could be used to pinpoint changes in activity in the prefrontal (and other) areas of the brain, and correlate these with changes in HPA axis activity and subjective improvement in health. Patients could be split up into different groups: one receiving no treatment, one receiving a placebo, another receiving an active treatment (such as an anti-viral drug), and other groups receiving various forms of psychological therapies or management programmes. Such an experiment would show how all of the various mental, endocrine and physical factors tie together, and would hopefully demonstrate the effect of the various psychological factors in aiding recovery and show which treatments are the most effective.

Conclusion
Much of what I have said about the placebo effect and alternative treatments may appear to be negative, in that I am saying that treatments which appear to work for illnesses such as CFS are actually no better than a dummy pill. My own view is that the knowledge presented in this book that the mind has such a powerful influence over physical and mental wellbeing will empower people to have more control over their own health. Rather than pursuing expensive quack treatments which may or may not work, it is possible to achieve the same or better results for no cost at all, simply by recognising the psychological and lifestyle factors that cause burnout and ill health, and then putting into place an action plan to positively change whatever is causing ill health. While this book has not set out a list of steps that need to be taken to achieve this (which I don't think is possible anyway), it has hopefully given enough information for people to be able to develop their own regime for achieving this.

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Contact the Author


If you have any comments or questions about this book, feel free to contact the author at: davidj@mind-body-health.net

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Glossary

Glossary
acute-phase response The initial response of the body to a severe infection. Consists of fever, activation of the HPA axis, production of acute-phase proteins in the liver, as well as other effects.
adrenal gland An important regulator of energy expenditure and stress tolerance. The central medulla releases adrenaline in response to short-term stress, while the outer cortex releases cortisol in response to longer-term stress. adrenaline The main hormone released from the central adrenal medulla when it is stimulated by sympathetic nerves. Adrenaline increases the availability of glucose, increases blood pressure and heart rate, and suppresses digestion. adrenocorticotrophic hormone (ACTH) Released from the pituitary in response to CRH or VP stimulation; causes the adrenal cortex to increase in size and to release cortisol and DHEA.

aldosterone The main mineralocorticoid released by the adrenal gland. It is responsible for maintaining blood volume (and therefore blood pressure), and for regulating the sodium/potassium balance in the body. allergy An abnormal, hypersensitive immune reaction to a substance that is normally harmless. allostasis The state of being in a very stressful situation, where the body is expending large amounts of stress hormones and energy in order to counter the threat and regain homeostasis. antibody A protein that can recognise and bind to a particular antigen in order to facilitate its clearance by other parts of the immune system. Antibodies are bound to the surface of B cells, and can also be secreted into the bloodstream from plasma B cells.

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antigen A foreign substance that is recognised by the immune system and can be bound to by T cells and antibodies. autoimmunity An abnormal immune reaction to self cells. autonomic nervous system The part of the nervous system that controls mainly automatic functions such as digestion, breathing and heart rate, over which there is little or no conscious control. It can be split into the sympathetic nervous system and parasympathetic nervous system. B cell A type of immune cell produced in the bone marrow that is mainly involved in the humoral response. beta-endorphin A hormone released from the pituitary along with ACTH. Its effects include reducing pain and boosting the immune system. bipolar disorder A mood disorder characterised by alternating periods of mania and depression. Also known as manic depression. body clock See suprachiasmatic nucleus. bowel See large intestine. burnout A state of low stress tolerance, characterised by various physical and psychiatric symptoms such as headaches, depression, fatigue and persistent infections. candida albicans The yeast that causes thrush infections, which is wrongly blamed for many other health problems such as IBS and CFS by certain health gurus. casein A protein found in milk. catecholamines A group of molecules derived from the amino acid tyrosine, which includes adrenaline, noradrenaline and dopamine. Adrenaline and noradrenaline are released from the 139

Glossary

adrenal medulla where they circulate in the blood and act as hormones. Noradrenaline and dopamine are produced in the brain where they act as neurotransmitters. The blood-brain barrier prevents blood-borne catecholamines from entering the brain and acting as neurotransmitters. cell-mediated response The immune response to viruses, cancer tumours and intracellular bacteria, mediated mainly by cytotoxic T cells. central nervous system (CNS) The core part of the nervous system consisting of the brain, spinal cord and spinal nerves. chronic fatigue A mild form of chronic fatigue syndrome characterised by constant tiredness or fatigue. chronic fatigue syndrome (CFS) An illness characterised by highly disabling fatigue and other symptoms such as depression, sleep disturbances and gastrointestinal symptoms, lasting longer than six months. circadian rhythm Any body rhythm that tends to have a cyclical pattern with a period of 24 hours. cognitive behavioural therapy (CBT) A treatment for illnesses such as depression and CFS that aims to change the patients beliefs about his or her illness, in the assumption that these beliefs are perpetuating the illness. corticosteroids Adrenal hormones such as cortisol. corticotropin See ACTH. corticotropin-releasing hormone (CRH) Released from the hypothalamus in response to stress, causing the pituitary to release ACTH and activate the HPA axis. CRH is also released in a circadian pattern even in the absence of stress, giving rise to the normal circadian activation of the HPA axis.

140

Glossary

cortisol The main stress hormone released from the outer adrenal cortex. It causes increased availability of glucose, fats and amino acids in the blood. When present in large quantities it causes suppression of the immune system and increased blood pressure. It also has effects on the gut such as increasing the absorption of water and sodium in the large intestine, and preventing ulceration of the duodenum. cytokines Hormone-like signalling molecules that regulate the immune response. dehydroepiandrosterone (DHEA) The precursor to the sex hormones testosterone and estradiol, released from the adrenal cortex in response to ACTH stimulation. duodenum The first part of the small intestine, starting at the lower end of the stomach. dysthymia A type of long-term depression where there are additional symptoms such as increased or reduced need for sleep and an excessively high or low appetite. endocrine system Another term for the hormonal system, which regulates body processes by releasing hormones into the bloodstream. epinephrine See adrenaline. Epstein-Barr virus (EBV) One of the herpes family of viruses. It infects human immune cells and is the cause of glandular fever (also known as infectious mononucleosis). estradiol The main female oestrogen sex hormone. As well as having a number of effects on the body, estradiol can cross the blood-brain barrier into the brain where it activates the HPA axis. fever An increase in body temperature due to infection. The hypothalamus maintains a temperature set point. During an 141

Glossary

acute infection this set point is increased, resulting in a higher body temperature. This provides a less beneficial environment for certain microorganisms to grow in and also speeds up the enzyme reactions used by the immune system to combat the infection. fibromyalgia An illness similar to CFS where the main symptom is widespread muscle pain. functional illness An illness where there is no organic disease process, and the illness is caused purely by the inappropriate functioning of a particular system in the body. general adaptation syndrome (GAS) The effect of long-term stress on the body, as observed by Hans Selye, a pioneer in stress research. The GAS consists of three stages: the initial alarm reaction, stage of resistance, and the stage of exhaustion. glucocorticoids Adrenal hormones, such as cortisol, which have a significant effect on glucose metabolism. gluten A protein found in cereal grains, mainly wheat and oats. graded exercise therapy A treatment for CFS that attempts to gradually increase the exercise tolerance of the patient, based on the theory that CFS is caused by physical deconditioning. Gulf War syndrome An illness similar to CFS suffered by many veterans of the 1991 Gulf War. hippocampus An area of the brain associated with memory and learning. The hippocampus is also an important regulator of the HPA axis, providing negative feedback to the CRH neurons in the hypothalamus. homeostasis The ability of the body to maintain a normal, healthy state despite outside perturbations (such as heat, cold, infection, etc.) 142

Glossary

hormone A chemical messenger that is released into the bloodstream and causes effects at distant parts of the body. human herpesvirus (HHV) There are at least eight types of herpes viruses that can infect humans. After infection, the virus remains in the body for life in a latent state, but can be reactivated when the immune system is compromised. HHV infections are common triggers for CFS, although this may simply be because CFS patients tend to have suppressed immune systems. humoral response The immune response to extracellular bacteria, parasites and fungi, mediated by antibodies secreted into the bloodstream. hypothalamic-pituitary-adrenal axis (HPA axis) The system that is responsible for controlling cortisol levels in the body. CRH is released from the paraventricular nucleus of the hypothalamus, which then causes ACTH to be released from the pituitary, which in turn causes the adrenal gland to release cortisol. Negative feedback at both the pituitary and the hypothalamus ensures that cortisol levels are kept within an acceptable range. hypothalamus A part of the brain that is involved in regulating the autonomic nervous system and hormone release (including the HPA axis). The hypothalamus also regulates many body functions such as immune system activation, body temperature, feeding and reproduction. irritable bowel syndrome (IBS) A functional gut disorder, characterised by symptoms such as pain, diarrhea and/or constipation, where there is no obvious disease-causing mechanism. large intestine The part of the gut that stretches from the end of the small intestine to the rectum, and is mainly involved in extracting water and sodium from the stool. 143

Glossary

locus coeruleus (LC) Part of the limbic system that is involved in activating the sympathetic nervous system and maintaining alertness. melatonin A hormone produced in the pineal gland (as well as a number of other sites throughout the body) that has a number of functions, including modulating the immune system and promoting sleep. mineralocorticoids Steroid hormones, such as aldosterone, which are responsible for maintaining blood volume and regulating the sodium/potassium balance in the body. natural killer (NK) cell An immune cell that is important in the initial stages of a viral infection or cancer tumour. neuropeptide-Y (NPY) A peptide neurotransmitter consisting of a number of variants, which is found throughout the brain. In the prefrontal cortex it is associated with reduced anxiety and greater stress tolerance, while in the hypothalamus it is associated with feeding and activation of the parasympathetic nervous system. noradrenaline An important neurotransmitter that causes altertness when released in the brain. Noradrenaline also acts as a hormone when released in sufficient quantities from sympathetic nerve endings and from the adrenal medulla. Noradrenaline is the precursor to the adrenaline that is produced in the adrenal medulla, and has similar effects to adrenaline when released as a hormone. norepinephrine See noradrenaline. orthostatic intolerance A condition where there is an abnormal reduction in blood pressure when moving from a sitting position to standing.

144

Glossary

overtraining syndrome An illness similar to CFS, that is suffered by athletes who train too intensively. palpitations An uncomfortable sensation of the heart beating. parasympathetic nervous system The part of the autonomic nervous system related to rest, recovery and digestion. See also sympathetic nervous system. paraventricular nucleus (PVN) The part of the hypothalamus that is responsible for controlling activation of the HPA axis and the autonomic nervous system. pineal A gland in brain that converts serotonin to melatonin, which it releases during darkness. pituitary An endocrine gland at the base of the brain, responsible for producing a number of important hormones such as ACTH and growth hormone. placebo Any treatment that results in an improvement in health primarily through psychological factors rather than due to the treatment itself. post-traumatic stress disorder (PTSD) A disorder caused by a period of acute psychological stress, characterised by sleep disturbances, problems with memory and concentration, nightmares, flashbacks, anxiety, depression and abnormal emotions. post-viral fatigue syndrome (PVFS) A period of fatigue following a bacterial or (more usually) viral infection, which is similar to CFS. prefrontal cortex An area of the frontal lobe that is associated with behaviour and planning, and is also an important modulator of HPA axis activity.

145

Glossary

psychosomatic Any physical illness that is thought to have a psychological origin. relaxation sickness An illness that is primarily caused by going from a period of high workload or stress to a period of relaxation. rheumatoid arthritis A disease characterised by inflammation of the joints, caused by an abnormal immune reaction. seasonal affective disorder (SAD) Any mood disorder that is primarily caused by the time of year (usually winter). self cells Cells that are part of the body itself. stress Any significant physical or psychological event that causes the body to mount a defence response. The general stress response consists of activation of the sympathetic nervous system and the HPA axis. suprachiasmatic nucleus (SCN) A small group of cells within the hypothalamus that is responsible for generating the circadian activation of the HPA axis and other hormones. Also known as the body clock. sympathetic nervous system (SNS) The part of the autonomic nervous system related to activity. During a highly stressful situation, the balance shifts away from the parasympathetic nervous system toward the sympathetic nervous system, resulting in increased heart rate and blood pressure, and reduced digestion. T cell A type of immune cell generated in the thymus that is mainly involved in the cell-mediated immune response. The two main types of T cell are the cytotoxic T cells (TC or CTL), which actively destroy altered self cells, and T helper cells (TH), which release cytokines that regulate the overall immune response. TH cells can be further divided into TH1cells, which 146

Glossary

activate the cell-mediated response, and TH2 cells, which activate the humoral response. tachycardia A heart rate of over 100 beats per minute. testosterone The main male sex hormone, which is produced from DHEA in the testes. Testosterone has a number of effects in the body as well as within the brain. Some of the testosterone in the body is aromatised into estradiol, which can then activate the HPA axis. TH1 A type of T helper (TH) cell involved in the cell-mediated immune response. TH2 A type of T helper (TH) cell involved in the humoral immune response. thyroid A gland in the neck responsible for controlling the rate of metabolism. vasopressin (VP) In the hypothalamus, VP acts as a neurotransmitter causing the pituitary to release ACTH. Within the body it acts as a hormone, regulating blood volume by limiting urine flow.

147

References

References
Digestive system:
Filaretova L, Maltcev N, Bogdanov A, Levkovich Y, Role of gastric microcirculation in the gastroprotection by glucocorticoids released during water-restraint stress in rats., Chin J Physiol 1999 Sep 30;42(3):145-52 Kokot F, Ficek R, Effects of neuropeptide Y on appetite, Miner Electrolyte Metab 1999 Jul-Dec;25(4-6):303-5 van Dijk G, Bottone AE, Strubbe JH, Steggens AB, Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding, Brain Res 1994 Oct 10; 660(1):96-103 Straub RH, Herfarth H, Falk W, Andus T, Scholmerich J, Uncoupling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in inflammatory bowel disease?, J Neuroimmunol 2002 May;126(1-2):116-25 Elsenbruch S, Orr WC, Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses, Am J Gastroenterol 2001 Feb;96(2):460-6 Lindgren S, Stewenius J, Sjolund K, Lilja B, Sundkvist G, Autonomic vagal nerve dysfunction in patients with ulcerative colitis, Scand J Gastroenterol 1993 Jul;28(7):638-42 148

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Derelanko MJ, Long JF, Effect of corticosteroids on indomethacin-induced intestinal ulceration in the rat, Dig Dis Sci 1980 Nov;25(11):823-9 Patacchioli FR, Angelucci L, Dellerba G, Monnazzi P, Leri O, Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS), J Endocrinol Invest 2001 Mar;24(3): 173-7 Sandle GI, Hayslett JP, Binder HJ, Effect of glucocorticoids on rectal transport in normal subjects and patients with ulcerative colitis, Gut 1986 Mar;27(3):309-16 Fukudo S, Nomura T, Hongo M, Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome, Gut 1998 Jun;42(6):845-9 Million M, Maillot C, Saunders P, Rivier J, Vale W, Tache Y, Human urocortin II, a new CRF-related peptide, displays selective CRF(2)-mediated action on gastric transit in rats, Am J Physiol Gastrointest Liver Physiol 2002 Jan;282(1):G3440 Tache Y, Monnikes H, Bonaz B, Rivier J, Role of CRF in stress-related alterations of gastric and colonic motor function, Ann N Y Acad Sci 1993 Oct 29;697:233-43 Wagner SM, Mekhjian HS, Caldwell JH, Thomas FB, Effects of caffeine and coffee on fluid transport in the small intestine, Gastroenterology 1978 Sep;75(3):379-81 Rao SS, Welcher K, Zimmerman B, Stumbo P, Is coffee a colonic stimulant?, 149

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Eur J Gastroenterol Hepatol 1998 Feb;10(2):113-8 Bohmer CJ, Tuynman HA, The effect of a lactose-restricted diet in patients with a positive lactose intolerance test, earlier diagnosed as irritable bowel syndrome: a 5-year follow-up study, Eur J Gastroenterol Hepatol 2001 Aug;13(8):941-4

Immune system/Illness/Mental Attitude/Placebo Effect:


Parker LN, Levin ER, Lifrak ET, Evidence for adrenocortical adaptation to severe illness, J Clin Endocrinol Metab 1985 May;60(5):947-52 Vermes I, Beishuizen A, The hypothalamic-pituitary-adrenal response to critical illness, Best Pract Res Clin Endocrinol Metab 2001 Dec;15(4):495-511 Lavery GG, Gover P, The metabolic and nutritional response to critical illness, Curr Opin Crit Care 2000 Aug;6(4):233-238 van den Brink GR, van den Boogaardt DE, van Deventer SJ, Peppelenbosch MP, Feed a cold, starve a fever?, Clin Diagn Lab Immunol 2002 Jan;9(1):182-3 Levy SM, Herberman RB, Simons A, Whiteside T, Lee J, McDonald R, Beadle M, Persistently low natural killer cell activity in normal adults: immunological, hormonal and mood correlates, Nat Immun Cell Growth Regul 1989;8(3):173-86 Solomon, GF, Immune and nervous system interactions, 150

References

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Lewith GT, Watkins AD, Hyland ME, Shaw S, Broomfield JA, Dolan G, Holgate T, Use of ultramolecular potencies of allergen to treat asthmatic people allergic to house dust mite: double blind randomised controlled clinical trial, BMJ 2002 Mar 2;324(7336):520 Rime B, Ucros CG, Bestgen Y, Jeanjean M, Type A behaviour pattern: specific coronary risk factor or general disease-prone condition?, Br J Psychol 1989 Sep;62 (Pt 3):229-40 Gatti G, Masera RG, Pallavicini L, Sartori ML, Staurenghi A, Orlandi F, Angeli A, Interplay in vitro between ACTH, beta-endorphin, and glucocorticoids in the modulation of spontaneous and lymphokine-inducible human natural killer (NK) cell activity., Brain Behav Immun 1993 Mar;7(1):16-28 Maruta T, Colligan RC, Malinchoc M, Offord KP, Optimism-pessimism assessed in the 1960s and self-reported health status 30 years later, Mayo Clin Proc 2002 Aug;77(8):748-53 Klopfer B, Psychological variables in human cancer, Journal of Projective Techniques, 1957;21:331-340 Dodes JE, The Mysterious Placebo, Skeptical Inquirer, 1997 Jan Petticrew M, Bell R, Hunter D, Influence of psychological coping on survival and recurrence in people with cancer: systematic review, BMJ 2002;325:1066 (9 November) Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC,

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The in vivo and in vitro effects of caffeine on rat immune cells activities: B, T and NK cells, Asian Pac J Immunol 1990 Dec;8(2):77-82 Melamed I, Kark JD, Spirer Z, Coffee and the immune system, Int J Immunopharmacol 1990;12(1):129-34 Tremlett HL, Evans J, Wiles CM, Luscombe DK, Asthma and multiple sclerosis: an inverse association in a case-control general practice population, QJM 2002 Nov;95(11):753-6 Hsueh CM, Chen SF, Ghanta VK, Hiramoto RN, Expression of the conditioned NK cell activity is betaendorphin dependent, Brain Res 1995 Apr 24;678(1-2):76-82 ter Riet G, de Craen AJ, de Boer A, Kessels AG, Is placebo analgesia mediated by endogenous opioids? A systematic review, Pain 1998 Jun;76(3):273-5 Weihraunch TR, Gauler TC, Placebo efficacy and adverse effects in controlled clinical trials, Arzneimittelforschung 1999 May;49(5):385-93 Ponsonby AL, McMichael A, van der Mei I, Ultraviolet radiation and autoimmune disease: insights from epidemiological research, Toxicology 2002 Dec 27;181-182:71-8 Heyes CE, Vitamin D: a natural inhibitor of multiple sclerosis, Proc Nutr Soc 2000 Nov;59(4):531-5 Kang J, Ahn M, Kim Y, Moon C, Lee Y, Wie M, Lee Y, Shin T, 154

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Melatonin ameliorates autoimmune encephalomyelitis through suppression of intracellular adhesion molecule-1, J Vet Sci 2001;2(2):85-89

CFS/GWS/Overtraining:
Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, Peterson DL, Pearson GR, Whitman JE, Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients, J Clin Virol 2000 May;16(3);179-91 Racciatti D, Vecchiet J, Ceccomancini A, Ricci F, Pizzigallo E, Chronic fatigue syndrome following a toxic exposure, Sci Total Environ 2001 Apr 10;270(1-3):27-31 Brunello N, Akiskal H, Boyer P, Gessa GL, Howland RH, Langer SZ, Mendlewicz J, Paes de Souza M, Placidi GF, Racagni G, Wessely S, Dysthymia: clinical picture, extent of overlap with chronic fatigue syndrome, neuropharmacological considerations, and new therapeutic vistas, J Affect Disord 1999 Jan-Mar;52(1-3):275-90 Fiedler N, Lange G, Tiersky L, DeLuca J, Policastro T, KellyMcNeil K, McWilliams R, Korn L, Natelson B, Stressors, personality traits, and coping of Gulf War veterans with chronic fatigue, J Psychosom Res 2000 Jun;48(6):525-35 Creswell C, Chalder T, Defensive coping styles in chronic fatigue syndrome, J Psychosom Res 2001 Oct;51(4):607-10 Rook GA, Zumla A, Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a TH2 profile?, 155

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Stress/Depression/Burnout:
Aubry JM, Bartanusz V, Jezova D, Belin D, Kiss JZ, Single stress induces long-lasting elevations in vasopressin mRNA levels in CRF hypophysiotrophic neurones, but repeated stress in required to modify AVP immunoreactivity, Journal of Neuroendocrinology 1999, Vol II:377-384 Makino S, Shibasaki T, Yamauchi N, Nishioka T, Mimoto T, Wakabayashi I, Gold PW, Hashimoto K, Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat, Brain Res 1999 Dec 11;850(1-2):136-43 Khan A, Warner HA, Brown WA, Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials, Arch Gen Psychiatry 2000;57:311-317 McCraty R, Barrios-Choplin B, Rozman D, Atkinson M, Watkins AD, The impact of a new emotional self-management program on stress, emotions, heart rate variability, DHEA and cortisol, Integr Physiol Behav Sci 1998 Apr-Jun;33(2):151-70 Schlebusch L, Bosch BA, Polglase G, Kleinschmidt I, Pillay DJ, Cassimjee MH, A double-blind, placebo-controlled, double-centre study of the effects of an oral multivitamin-mineral combination on stress, S Afr Med J 2000 Dec;90(12):1216-23 Carroll D, Ring C, Suter M, Willemsen G, The effects of an oral multivitamin combination with calcium, magnesium, and zinc on psychological well-being in healthy young male volunteers: a double-blind placebo-controlled trial, 160

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Albeck DS, McKittrick CR, Blanchard DC, Blanchard RJ, Nikulina J, McEwen B, Sakai RR, Chronic social stress alters levels of corticotropin-releasing factor and arginine vasopressin mRNA in rat brain, The Journal of Neuroscience, Jun 15 1997;17(12):4895-4903 Kivimaki M, Leino-Arjas P, Luukkonon R, Ruhimaki H, Vahtera J, Kirjonen J, Work stress and risk of cardiovascular mortality: prospective cohort study of industrial employees, BMJ 2002;325:857 Morgan CA 3rd, Cho T, Hazlett G, Coric V, Morgan J, "The impact of burnout on human physiology and on operational performance: a prospective study of soldiers enrolled in the combat diver qualification course", Yale J Biol Med. 2002 Jul-Aug;75(4):199-205

HPA Axis:
Zuckerman-Levin N, Tiosano D, Eisenhofer G, Bornstein S, Hochberg Z, The importance of adrenocortical glucocorticoids for adrenomedullary and physiological response to stress: a study in isolated glucocorticoid deficiency, J Clin Endocrinol Metab 2001 Dec;86:5920-4 Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH, Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitaryadrenal axis, Psychosomatic Medicine 1999;61:154-162 Cavagnini F, Croci M, Putignano P, Petroni ML, Invitti C, Glucocorticoids and neuroendocrine function, Int J Obes Relat Metab Disord 2000 Jun;24 Suppl 2:S77-9 162

References

Habib KE, Weld KP, Rice KC, Pushkas J, etc. Oral administration of a corticotropin-releasing-hormone antagonist significantly attenuates behavioral, neuroendocrine and autonomic responses to stress in primates, Proc Natl Acad Sci USA, May 23 2000;97(11):6079-6084 Merali Z, McIntosh J, Kent P, Michaud D, Anisman H, Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala, The Journal of Neuroscience, June 15 1998, 18(12):4758-4766 Gunnar MR, Vazquez DM, Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in human development, Dev Psychopathol 2001 Summer;13(3):515-38 Schmidt-Reinwald A, Pruessner JC, Hellhammer DH, Federenko I, Rohleder N, Schurmeyer TH, Kirschbaum C, The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm, Life Sci 1999;64(18):1653-60 Tsigos C, Chrousos G, Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress, J Psychosom Res 2002 Oct;53(4):865 Kellnew M, Yassouridis A, Manz B, Steiger A, Holsboer F, Wiedemann K, Corticotropin-releasing hormone inhibits melatonin secretion in healthy volunteers--a potential link to low-melatonin syndrome in depression?, Neuroendocrinology 1997 Apr;65(4):284-90 al'Absi M, Lovallo WR, McKey B, Sung BH, Whitsett TL, Wilson MF,

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Circadian Rhythms:
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Other Research:
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Influence of climate on the prevalence of mania, Br J Psychiatry 1998 Jun;152:820-3 Nathan PJ, Burrows GD, Norman TR, Melatonin sensitivity to dim white light in affective disorder, Neuropsychopharmacology 1999 Sep;21(3):408-13 Volk DW, Lewis DA, Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction, Physiol Behav 2002 Dec;77(4-5):501-5 Murphy DG, Critchley HD, Schmitz N, McAlonan G, Van Amelsvoort T, Robertson D, Daly E, Rowe A, Russell A, Simmons A, Murphy KC, Howlin P, Asperger syndrome: a proton magnetic resonance spectroscopy study of brain, Arch Gen Psychiatry 2002 Oct;59(10):885-91 Lopez-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM, Regional prefrontal gray and white matter abnormalities in bipolar disorder, Biol Psychiatry 2002 Jul 15;52(2):93-100 Caberlotto L, Hurd YL, Reduced neuropeptide Y mRNA expression in the prefrontal cortex of subjects with bipolar disorder, Neuroreport 1999 Jun 3;10(8):1747-50 Maier W, Rietschel M, Lichtermann D, Wildenauer DB, Family and genetic studies on the relationship of schizophrenia to affective disorders, Eur Arch Psychiatry Clin Neurosci 1999;249 Suppl 4:57-61

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Nettle D, Strong Imagination, Oxford University Press, 2001 Selye H, The Stress of Life, McGraw-Hill, 1978 Brook CGD, Marshall NJ, Essential Endocrinology, Blackwell Science, 2001 Goldsby RA, Kindt TJ, Osborne BA, Kuby Immunology, W.H. Freemand and Company, 2000 Diagnostic and Statistical Manual of Mental Disorders: DSMIV-TR: Fourth Edition Text Revision, American Psychiatric Publishing, 2000

170

Websites

Websites
http://www.mind-body-health.net further information to that contained within this book, including new research and author contact information http://www.quackwatch.org information on various dubious medical techniques http://www.med.umich.edu/mhri/researchfacu lty/young.htm stress, depression and hormonal regulation http://www.cdc.gov/ncidod/diseases/cfs/ US Center for Disease Control information about CFS http://www.doh.gov.uk/cmo/cfsmereport/ UK Chief Medical Officer CFS/ME Working Group Report http://www.ncptsd.org National Center for PostTraumatic Stress Disorder: includes research by Dr. Charles A Morgan into the anti-stress effects of NPY http://wwcoco.com/cfids/bernesx.html Gives a list of CFS symptoms, together with percentages of patients who suffer from them http://www.cssainc.org/Articles/CFS_names.htm The names that have been given to CFS over the years http://marcschoen.com Research into the let down effect by Marc Schoen, Assistant Clinical Professor at UCLAs School of Medicine

171

Index

Index
ACTH, 1113, 15, 46, 50, 66, 7071, 84, 89, 104, 108, 135 acute-phase illness response, 74 adrenal cortex, 9, 1112, 15, 46, 50, 89 adrenal glands, 9, 13, 15, 2627, 38, 6871, 84, 85, 89, 134 shrunken, 7, 2627, 68 71, 84, 85, 89 adrenal insufficiency, 27, 75, 88, 100101, 120 adrenal medulla, 911, 88, 92 adrenaline, 911, 27, 38, 43, 66, 88, 112 adrenocorticotrophic hormone. See ACTH alcohol, 65, 109, 112, 130 aldosterone, 12, 50, 89 allergies, 4143, 59, 62, 86 alternative therapies, 51, 5659, 101 amygdala, 29, 94 anaemia, 62 ANS, 1011, 17, 19, 36, 85, 8890, 92, 100, 103, 107, 122 antibodies, 3942, 59, 62, 65, 77 antidepressants, 48, 52, 54, 91 172 anxiety, 29, 36, 47, 53, 69, 76, 8788, 9094, 99, 101, 104, 112, 133 army. See military autism, 52, 62 autoimmune disorders, 41 42 autonomic nervous system. See ANS beta-endorphin, 11, 5051, 66 bioresonance, 57, 59 bipolar disorder, 21, 37, 52, 8283 blood pressure, 911, 14, 15, 28, 45, 67, 76, 88, 112 blood volume, 12, 67, 83, 8789 body clock, 13, 1723 and melatonin, 22 and stress, 20 and sunlight, 22 desynchronised, 2024, 67 resetting, 19 bowel movements, 103, 115 burnout, 6, 16, 24, 2535, 37, 5152, 65, 66, 68 70, 7376, 7983, 90, 1045, 108, 11011, 115, 11720, 122, 132 37

Index

avoiding, 12431 causes, 3132 purpose, 3334 teachers, 2729, 31 caffeine, 36, 38, 112, 119, 130 calcium, 113 cancer, 4549, 6566, 118 20, 132, 13435 candida, 6062, 101 candidiasis, 6062 casein, 6263 catecholamines, 9, 15, 46, 4950 CBT, 95, 100101 CFS and burnout, 25, 31, 80, 85 and depression, 90 and hormone rhythms, 21, 23, 35, 63, 70 and HPA axis, 16, 27, 30, 34, 70, 87 and immune system, 43, 50 and personality, 33, 78 and placebo, 62, 80 and viral infection, 25, 43, 63, 74, 76 diagnosis, 26, 67, 75, 83 differential diagnosis, 69 history, 71 mechanism, 65, 93 overlapping conditions, 69 prevalence, 70 psychological versus organic, 68, 73, 83 recovery, 95 173

reports of recovery, 96 symptoms, 6768, 86 treatments, 39, 54, 84, 91, 95, 99 triggers, 32, 64, 74 chronic fatigue, 74 chronic fatigue syndrome. See CFS circadian rhythms, 1213, 1724, 31, 3336, 52, 64, 7071, 100, 104, 107, 118, 120, 129, 132 coeliac, 62 coffee, 113 cognitive behavioural therapy. See CBT colon, 30, 1034, 10610, 11214, 119 constipation, 1038, 110 11 corticotropin-releasing hormone. See CRH cortisol, 918, 30, 36, 43, 46, 4951, 58, 66, 70 71, 75, 87, 8990, 100, 108, 117, 120 and CFS, 23 and digestion, 29, 104, 106, 108 circadian pattern of release, 12, 23, 3436, 104 effects, 9, 14 low levels of, 16, 2628, 43, 8889, 1068 release, 11 creativity, 82

Index

CRH, 1114, 18, 24, 29, 34, 74, 91, 93, 100, 106 8, 119 cytokines, 4041, 63, 74 75, 119 depression, 20, 2526, 33, 37, 47, 5455, 59, 61, 69, 7173, 9699, 80 83, 87, 9094, 101, 104, 117, 121, 13536 desynchronised body clock, 2024, 23, 67 DHEA, 12, 50 diarrhea, 27, 62, 91, 103 15 digestion, 9, 10, 14, 29, 30, 36, 59, 89, 93, 104, 106 9, 112, 132 dysthymia, 69, 8081, 95 EBV, 72, 77 Epstein-Barr virus. See EBV estradiol, 24, 78, 110 exclusion diets, 6163 feeding, 14, 1819, 29, 36, 108 fever, 26, 39, 48, 57, 7475 fibre, 109, 111, 130 fibromyalgia, 68 flatulence, 109 food intolerance, 60, 101 fructose, 11314 functional disorders, 6, 103 GAS, 1516 general adaptation syndrome. See GAS ginger, 113 ginseng, 58, 72 glandular fever, 77 174

glutamate, 63, 94 gluten, 6263 goals, 3233, 52, 55, 65, 80, 84, 101, 111, 118, 120, 124, 128 graded exercise therapy, 96, 100 growth hormone, 13, 70, 99 Gulf War syndrome. See GWS gut absorption, 30, 10610, 11315 motility, 11, 10610, 113 gut flora, 109 GWS, 79, 12123 heart disease, 1415, 32 33, 4546 heart rate, 9, 10, 20, 26, 67, 8889, 93, 117 HHV, 68, 77 high achievers, 33, 79, 82, 105 hippocampus, 35, 87 homeopathy, 5659 hormones, 5, 913, 15, 18, 23, 28, 31, 3436, 40, 4243, 46, 51, 6366, 70, 8991, 99100, 103, 108, 112, 11720, 130 HPA axis, 4, 7, 1118, 24 37, 43, 46, 5052, 58 60, 6366, 7071, 74 82, 8494, 100110, 112, 11524, 129, 131 36

Index

human herpesvirus. See HHV hyperactivity, 63, 104 hypothalamic-pituitaryadrenal axis. See HPA axis hypothalamus, 1014, 17 19, 24, 34, 36, 59, 64, 74, 85, 8889, 9394, 100, 107, 133 IBS, 67, 16, 5960, 62, 10316, 133 and HPA axis, 1049 and stress, 1035, 110 diagnosis, 103 differential diagnosis, 105 overlapping conditions, 104 treatments, 11114 immune system and HPA axis, 50 and melatonin, 63 and mental attitude, 45 46 and stress, 10, 43 overview, 39 TH1/TH2 balance, 4043, 50, 77, 86, 93, 99 insomnia, 2223, 2526, 63, 67, 69, 7173, 81, 99, 101, 11920, 122 irritable bowel syndrome. See IBS jetlag, 1922 karoshi, 5 kinesiology, 56, 62, 101 lactose, 113, 115 LC, 13, 92 175

let down effect, 44 lifestyle, 3, 6, 54, 66, 79, 80, 83, 85, 100102, 105, 11011, 11620, 131, 13236 limbic system, 92 liquorice, 58 locus coeruleus. See LC Maslach Burnout Inventory, 27 ME, 6768 melatonin, 13, 1824, 34 36, 6364, 66, 11920, 129 mental attitude, 12, 29, 31 32, 4346, 45, 6566, 78, 79, 80, 85, 9394, 96, 102, 105, 11011, 115, 11820, 12224, 13035 military, 29, 36 milk, 6162, 113 mood disorders, 83 motivation, 25, 2829, 31, 33, 49, 52, 55, 65, 80, 81, 111, 118, 120, 124 25, 128 MSG, 6263 myalgic encephalomyelitis. See ME natural killer cells. See NK neurasthenia, 7173 neuropeptide-Y. See NPY neurosis, 72, 8082, 84, 88, 100, 103 neurotransmitters, 10, 18 20, 36, 38, 87, 9092, 94, 108, 112, 119, 134 Nightingale, Florence, 73

Index

NK, 40, 45, 4951, 63, 65, 11819, 132 noradrenaline, 911, 18, 8789, 9293 NPY, 14, 19, 21, 3637, 53, 89, 1079, 133 orthostatic intolerance, 88 89 overtraining syndrome, 117 pain, 12, 38, 48, 51, 55, 58, 68, 7273, 81, 83, 94, 104, 117, 121 palpitations, 73, 88 paraventricular nucleus. See PVN peppermint, 113 perfectionists, 33, 44 personality, 6, 28, 3233, 4346, 50, 73, 7879, 93, 103, 105, 119, 122 pineal, 1822, 120 pituitary, 1112, 50, 59, 66, 87, 118 placebo, 4663, 66, 7980, 83, 94, 100, 129, 133, 13536 post-traumatic stress disorder. See PTSD post-viral fatigue syndrome. See PVFS prefrontal cortex, 3637, 5253, 64, 80, 82, 94, 133, 13536 primitive societies, 53 psychiatric, 67, 72, 8182, 94 psychological factors, 46, 51, 53, 5556, 64, 83

85, 94, 96, 11920, 134, 136 psychosomatic, 7173, 84, 94 PTSD, 35, 12122 PVFS, 120 PVN, 13, 1718, 20, 34, 94 quack, 48, 5456, 59, 62, 136 relaxation sickness, 32, 44 reproduction, 20 rheumatoid arthritis, 32, 45 rituals, 53 SAD, 2022 schizophrenia, 52, 54, 82 83 SCN, 13, 1723, 34, 94 seasonal affective disorder. See SAD Selye, Hans, 56, 9, 1516, 2728 serotonin, 1821, 87, 93, 119 sleep, 13, 1723, 35, 76, 81, 9092, 104, 117, 119 sorbitol, 11314 special forces. See military stimulants, 130 stress and burnout, 25, 2729 and circadian rhythms, 2024 and feeding, 14 and NPY, 36 ANS response, 11 definition, 9 endocrine response, 11 long-term consequences, 14 176

Index

stress tolerance, 2526, 28, 31, 3637, 53, 87, 91, 92, 94, 1045, 132 sucrose, 114 sunlight, 1922, 36, 63, 65 suprachiasmatic nucleus. See SCN tachycardia, 73, 91, 94, 99 T-cells, 4043, 121 testosterone, 12, 24, 36, 99, 117 TH1/TH2 balance. See immune system

thyroid, 42, 99 vasopressin, 18, 34 viruses, 3841, 63, 68, 77, 80 visible burrow experiment, 27 wheat, 6162, 130 workload, 31, 35, 4445, 11011, 126 yogurt, 111 yuppie flu, 81

177