Ashok Gupta MA (Cantab), MSc
Web: Updated versions of this paper, and other information for doctors and patients are available at www.cfsrecovery.com
ABSTRACT: Hypothesis: Chronic Fatigue Syndrome is a neurophysiological disorder focusing on the amygdala. During a "traumatic" neurological event often involving acute psychological stress combined with a viral infection or other physical stressor, a conditioned network or "cell assembly" is created in the amygdala, analogous to conditioning episodes seen in severe phobias and anxiety states. This cell assembly is particularly resistant to extinction. The unconscious amygdala has become conditioned to be chronically sensitised to negative symptoms arising from the body, given that "fear" tends to generalise unconsciously during periods of severe emotional arousal. Negative signals from the viscera, or psychological and physical stress, become conditioned stimuli, and the conditioned response is a chronic sympathetic outpouring from the amygdala via various brain pathways including the hypothalamus. There may also be a reactivation of the immune system in some patients as a conditioned response, given that this was the response that was initiated during the learning episode. Pavlovian conditioning of the immune system has been demonstrated in rats.
This cell assembly then produces the CFS vicious circle, where an unconscious negative reaction to symptoms causes immune reactivation/dysfunction, chronic sympathetic stimulation leading to sympathetic dysfunction, severe continuous muscle tension, mental and physical exhaustion, and a host of other distressing symptoms and secondary complications individual to each patient. And these are exactly the symptoms that the amygdala and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle. A patient also becomes hyper-reactive to external psychological, physiological or chemical stressors due to the excited state of the amygdala, and the limbic brain’s "arresting" of areas of the cortex. Recovery from CFS may involve projections from the medial prefrontal cortex to the amygdala, to control the amygdala’s expressions.
CFS is not a psychological illness, and patients are "in the grip of" a predominantly unconscious process which they are not in control of or even aware of. Existing cognitive approaches will only have very modest effects.
I suffered from CFS around 4 years ago while I was studying at Cambridge University. After conducting extensive research into the illness and making some interesting discoveries, I developed a theory about the cause of CFS, and then developed a programme of recovery for myself. I am now fully recovered and have since been researching CFS in-depth for over two years.
As someone who has suffered from it and subsequently recovered, I feel that, like many patients, I can bring useful insights to the psychological and physiological processes at work. I certainly know the frustration that many CFS patient experience in terms of the lack of a medical explanation, and the prevalence of "psychosocial" explanations, which make patients feel that their real suffering is going unacknowledged.
Whether you are a patient or a doctor, I hope you will find the theory interesting even if you are highly sceptical. I have deliberately written this paper so that it is accessible to practitioners of all disciplines. I have also started developing a unique programme of recovery which, as far as I am aware, has not been tried until now. I want to make it clear that I am not claiming that this is the complete answer for all patients as "CFS" may be made up of a heterogeneous population of patients, but I do believe that it is worthy of further investigation. The hypothesis is a combination of my own experience and subsequent recovery from CFS, work with other patients, and the latest thought and research in the areas of emotion and neuroscience.
Before you read on, I want to make it clear from the outset that I believe that CFS is a very real illness with real symptoms, but that there is a unique unconscious neurological process which patients are currently not aware of or in control of. This unconscious process has previously only been applied to psychiatric disorders, but the neurological process is also applicable to physiological processes. Patients are in no way responsible for their symptoms, and to control these unconscious processes requires a complete programme of recovery, not simply different beliefs or perceptions about the illness.
I am looking for research partners and research funding for a study based on the therapies I am developing, as well as other research related to the hypothesis. I can be contacted by e-mail, and would value any comments and criticisms on the paper, as well as any suggestions for next steps.
DISCLAIMER: ADVICE TO PATIENTS
No one should assume that they have Chronic Fatigue Syndrome. If you have not already done so, you should see your doctor and make sure that your symptoms are not due to any other cause. There are many other serious illnesses which can mimic the symptoms of CFS, and these have to be discounted.
Even then, the following text is only theoretical at this stage, and you should approach it with a healthy scepticism. No responsibility is accepted for its particular application to any individual. Again, if you are in any doubt about the following information, please consult your doctor and discuss it with her/him.
WHICH PATIENTS MAY THIS THEORY APPLY TO?
There are currently many names and definitions for this illness. I want to emphasise that the hypothesis I outline in this paper may apply to a significant subgroup of CFS patients with unexplained fatigue and other symptoms. The sub-set relevant to the hypothesis may exhibit some or most of the following characteristics:
Medium to high levels of stress immediately preceding the onset of the illness, with or without a viral or environmental trigger.
General mental and physical exhaustion, not appreciably helped by rest
Muscular fatigue, aches or pains
Sore throat and/or lymph glands, and slight fever
Emotional lability and vulnerability
Psychological or physical stress increases symptoms
Difficulties in concentrating, and memory problems
Autonomic dysfunction and/or gastrointestinal disorder
Sleep disturbances (too little or too much)
Some patients may be assessed according to a stricter definition, and this may point to the existence of different etiologies to that described in this paper. Alternatively, these disorders may represent an extreme morbidity of the illness I describe in this paper.
EMOTION RESEARCH IN NEUROSCIENCE
The hypothesis expressed in this paper is hardly conventional, but I do believe that the solution to CFS may well involve a reappraisal of the way illnesses such as these are envisioned. Many of the core ideas expressed in this paper involve the work of neuroscientists involved in research on emotion. Much of their work is particularly pertinent to anxiety disorders, and has relevance for treatments. Although I would not class CFS as an anxiety disorder in the traditional sense, many researchers have commented on the psychological aspects involved in CFS. By researching the basis of cognitive emotional experience in CFS, a unique insight can be gained in to how these emotions relate to the devastating physical illness which these patients endure. I believe that only once the complex mind-body link has been solved in CFS, will the solutions to its long-term treatment present themselves. The literature and ideas which I regularly refer to can be obscure. For a good general introduction, see
Joseph Ledoux (1998), The Emotional Brain (Weidenfeld & Nicolson), chapters 6-9
R.D. Lane and L. Nadel (eds) (2000), "Cognitive Neuroscience of Emotion", (Oxford University Press), especially the chapter by Joseph Ledoux.
Although the ideas expressed in this paper are solely my own, I would like to thank the following doctors, patients and friends for their thoughts, criticisms and feedback: Professor Joseph Ledoux, Dr. Ellen Goudsmit, Professor Laurence A. Bradley, Dr. A. Chaudhuri, Sophia Collins, Dr. Simon Merritt, Dr. Neal Navani, Dr. Nitesh Bindal, Dr. David Seddon, Miriam Mulcahy, Julia Haddon, Carolyn Mole, Dr. Daksha Patel, Dr. Devika Khanna, John Heptonstall, and Dr. Philip Stowell.
SYNOPSIS Page 5
1. Conditioning Page 16
Conditioned Responses – The "Stress Signature" Hypothesis
Conditioned Stimuli and Responses, and Unconditioned Stimuli
Neuroendocrinological Aspects – Downgraded CRF Response
2. Explanation Of CFS Symptoms Page 20
3. Is This Really How The Patient Feels About The Illness? Page 27
4. The Path To Recovery From CFS Page 29
5. Why Do Therapies Like CBT Seem To Help Some Patients? Page 30
6. Hypothesis: An Explanation For The Vague Concept Of
"Functional Somatic Syndromes". Page 31
7. Next Steps Page 39
8. Appendices Page 40
Fear Pathways as Mediated by the Amygdala
References Page 44
Bibliography Page 50
I shall firstly discuss predisposing, precipitating, and perpetuating factors involved in the etiology of CFS, followed by the patient’s experience of the illness. Finally, I shall look at a suggested explanation for the symptoms of CFS. The sections after this synopsis provide more detailed information on specific concepts discussed in this section.
Much of the literature identifies personality characteristics pertinent to CFS. From personal observations, I would argue that whilst anyone can develop CFS, there is a tendency for patients to be more prone to stress and anxiety. More specifically, patients tend to be naturally more introspective before the illness, and this may drive certain perfectionist tendencies in some, but not all patients. These personality types can be prone to overworking, and may spend little time relaxing. Over long periods of time, higher plasma levels of catecholamines are present. The person is likely to go through periods of higher perceived stress because:
they may take on more than they can handle
they perceive tasks as more stressful and more of a challenge than they actually are
There may also be some genetic factors to consider, and panic disorder has been identified as the having the highest rate of familial comorbidity in CFS(1). The combination of personality, long term elevated stress levels, and genetics are risk factors for CFS, but the development of CFS tends to require a combination of precipitating factors.
Many CFS patients generally recall a time of psychological stress (or "life event") which seemed to accompany the onset of the illness, combined with a viral infection. Etiological studies on viral illnesses have shown that they have widespread neurological and physiological effects on the body, and can act as an added bodily stressor. The effectiveness of the immune system is generally lowered during stress, and therefore the viral illness is likely to be more severe and prolonged, and patients do report the viral illness being of longer duration than usual.
About a quarter of patients develop CFS without recalling a specific viral trigger. In fact, for some the onset is related to inoculations, exposure to pesticides, toxins, etc. However, CFS does not necessarily require a virus to trigger the illness. Any physical stressor on the body which occurs while the mind is under acute psychological stress, can potentially trigger CFS. (For some patients, the psychological stress may be partly due to their reaction to the illness itself).
Recent research into the neuroscience of emotion by Professor Joseph Ledoux (2) has implicated the amygdala in fear responses, stress and anxiety disorders. The amygdala operates at an unconscious level and has two roles. Firstly it determines whether immediately present stimuli pose a threat to well-being. Secondly, if the stimuli are negative, the amygdala must "orchestrate behavioural responses and associated autonomic and endocrine reactions that increase the likelihood of surviving that danger"(3)(see appendices for more detail). During the period of stress during the onset of the illness therefore, I hypothesise that the amygdala is activated (in association with many other limbic brain structures), and the amygdala mediates this emotional response, stimulating the "freeze, fight or flight" response via the hypothalamus and other brain pathways.
Whilst the psychological stress is being experienced, there are physical symptoms which are being endured simultaneously. The physical symptoms may derive from the following sources:
The symptoms of an overactive sympathetic nervous system in response to external psychological stress, and the internal psychological stress of the viral infection.
The effects of a viral infection acting on a weakened immune system
The effects of an active immune system (which itself produces symptoms of general weakness)
Potentially also a prolonged period of post-viral fatigue
(Patients who do not recall a specific viral or other environmental/pharmacological trigger may experience 1. as the main source of negative bodily symptoms).
From this point onwards, there may be other etiologies for different types of CFS which proceed. However, I believe that there is a significant subset of CFS patients for which the following etiology unfolds.
The amygdala plays an important role in assigning affective significance to any cognitive or sensory input, and this includes negative somatic signals from the viscera. For instance, Ketterer et. al.(1996) (4) found increased blood flow in the amygdala in response to pharmacological elicitors of negative effect, and this underlines that the amygdala operates at an unconscious level. The amygdala can detect any psychological, pharmacological, or visceral stimulus of negative effect which may pose even minor danger to a person. Recent work has implicated the basal ganglia (of which the amygdala is a part) in the processing of noxious (and non-noxious) somatosensory processing, including nociception and pain (Chudler and Dong 1995(5)).
According to Ledoux, subcortical thalamo-amygdala pathways are often used to decide what is of affective significance, and these pathways are "quick and dirty", i.e. they are not accurate in describing what is actually the source of danger. Therefore, fear and anxiety can generalise unconsciously. This explains how being stressed about one particular stimulus can make us generally more stressed about other things. As Ledoux comments(6),
"…a neutral stimulus…that occurs in the presence of a "trauma" will acquire the capacity to elicit fear reactions, and that phobias are nothing more than fear (anxiety) that has been conditioned to some otherwise meaningless event"
When the amygdala is at a heightened state of awareness during anxiety, it may be prone to learning new sensitivities and fears. The limbic structures gradually attributes the source of the danger to the physical symptoms the body is experiencing, as well as the external source of the psychological stress, and this is reinforced by conscious thought processes described below. The amygdala is being conditioned to implicitly fear any negative physical symptoms arising from the body. The immune system is less effective during stress, and hence the episode of "Pavlovian fear conditioning" occurs over a prolonged period of time. The amygdala has been strongly implicated in fear conditioning which can occur in phobias and other anxiety disorders(7). However, fear is an extreme word in the context of CFS, and whilst the unconscious amygdala believes the symptoms are to be feared, the conscious mind may simply be naturally concerned or mildly anxious about the symptoms.
The above effects tend to occur mainly at an unconscious level. The following process operating consciously may also contribute to fear conditioning. Acute psychological stress brings on feelings of anxiety and vulnerability, and this makes the person feel increasingly vulnerable to negative bodily symptoms, which seem more noxious and troublesome given the intense emotional arousal. Certain personality characteristics may contribute to this bodily introspection. The person may begin to monitor the body for the symptoms of stress and the virus in anticipatory concern, especially given the prolonged nature of the illness, and the person’s urgency to return to dealing with the source of the psychological stress. Areas of the prefrontal cortex, orbital cortex and the anterior cingulate are involved in attention to dangerous or negative stimuli(8). There may be associated anxieties about the prolonged length of the period of post-viral fatigue, and anticipatory concern about long-term illness. These concerns contribute to fear conditioning in the amygdala. It is important to bear in mind that fear conditioning can occur whilst the person still has the viral illness (or other physical stressor), and/or even once the viral illness has passed during a period of post-viral fatigue.
The release of noradrenaline and adrenaline via the stress response affects the formation of memories in various parts of the brain including the amygdala and the hippocampus. Adrenaline indirectly "stamps" and strengthens memories in the amygdala, meaning that if the same stimuli present themselves again, the amygdala can recognise them and react to them – an emotional memory(9). It is thought that learning through association of co-occurring events may be due to "long-term potentiation" (LTP), where synaptic strength between co-firing neurones increases after brief but repetitive stimulation. NMDA receptors are thought to be involved in the mechanism of this process of forming associations between stimuli.
During neurological learning, conditioning increases the functional interaction between neurones so that the likelihood that two cells will fire at the same time in the future dramatically increases. This can create "cell assemblies" or conditioned networks in the lateral nucleus of the amygdala, which means that a given input will produce a larger output(10,11,12). (As Ledoux notes, the concept of "cell assemblies" is still hypothetical, although it fits very closely to laboratory observations and is a likely process). In the future, a detection of negative bodily symptoms by the amygdala via the thalamus will elicit a stress response which is out of keeping with the danger the symptoms actually present. The diagram below shows the formation of a cell assembly:
This cell assembly represents the neurological activities which were occurring during the "traumatic" learning period, and it is the intense emotional arousal which facilitates such strong plasticity encouraging neurological learning. In the future, any inputs as described on the left which occurred during conditioning, trigger the cell assembly, which produces a conditioned output or response that was also associated with the learning period. After even a few stimulations, the output will be much stronger for a given input. This cell assembly is particularly resistant to "extinction", which is the process involved in reprogramming the amygdala. This means that once conditioning occurs, the "hard-wiring" may stay with a person for life, and for some if not all patients, the amygdala’s expressions can only be regulated rather than fully extinguished(13).
Patients differ in the length and severity of their illness, and there may be many factors for this as discussed later in section 2. One factor may be in the level of plasticity in the cell assembly, where full extinction resistant plasticity may represent extreme long-term morbidity.
On the right, I have labelled a potential output as the "stress signature". Given that during the fear conditioning period, the immune response may have been activated (with or without conscious awareness of an external pathogen), the neurones involved in immune activation may be re-triggered in the future as part of the conditioned response, causing a unique response in each patient – the stress signature. This effect may occur to differing intensities in each patient dependent on a number of other factors to be identified. The amygdala has strong interconnections with the hypothalamus, which itself is implicated in activation of the immune system in association with the pituitary gland.
Pavlovian immune system conditioning in association with stress pathways is not a new concept (Ader)(14). Psychologists Robert Ader and Nicholas Cohen were the first to demonstrate this effect in rats in 1974. They injected rats with sweetened water at the same time as cyclophosphamide, which suppresses the immune system and causes sickness. The rats learned to associate the sweet water with getting sick, so they stopped drinking the water. The researchers then stopped injecting the immune suppressant when rats drank the water, and eventually rats lost their fear and began drinking the water again. However, 6 weeks later, an unusual number of rats began dying, and Ader and Cohen realised that the immune response was being lowered by the sweet water alone. Therefore, although the rats had extinguished their fear response to the water, they had not yet lost their learned immune response. This shows that the sweet water had become a conditioned stimulus, and the conditioned response is a lowering of the immune system. In CFS, the conditioned response to stress or any negative physical symptoms may be to reactivate certain aspects of the immune response, which in itself increases symptoms.
Recently there has been much controversy over whether CFS occurs in local epidemics. I can only hypothesise that if these epidemics are proven, one of the following processes is occurring:
Epidemics represent a completely separate etiology to the one described in this paper
There may be a particular virus/bacteria which encourages the neurological learning outlined above, causing CFS epidemics
In small communities under acute levels of stress, a severe virus which has struck down a number of people is seen as evidence of long term illness, and patients consciously (but unwittingly) contribute to unconscious fear conditioning.
Whilst the "conditioning" phraseology used may seem more appropriate to laboratory rats than human beings, brain systems underlying certain emotional behaviours like fear conditioning have been preserved throughout many levels of brain evolution. They are present to enable our survival in dangerous situations, and therefore operate at an unconscious level. However, given the presence of increased stress in modern lifestyles, these highly efficient fear systems may be prone to malfunction(15).
Once sensitisation or "fear conditioning" has occurred, the CFS vicious circle is produced. Negative bodily symptoms in the future act as conditioned stimuli for the unconditioned stimulus of being in the throes of a debilitating illness. The amygdala takes on the role of monitoring the body for these negative stimuli, and there is evidence of increased blood flow in the thalamus(16). The amygdala drives arousal systems which keep brain cortical networks that are processing the stimuli in a state of hypersensitivity. Dopamine has a role to play in riveting attention to the source of the danger. This explains the hyper-vigilance or "symptom monitoring" observed in some, but not all patients. Furthermore, the more the amygdala becomes stimulated into action, the more its initiated stress response stimulates and arouses itself, prolonging the entire response. This process is facilitated by glutamate-containing excitatory neurones in the amygdala, but may be moderated by GABA inhibitory neurones in the amygdala. Below is a diagram illustrating the CFS vicious circle:
Once any symptoms of stress are detected by the thalamus as on the right, information is passed directly to the amygdala, as well as the cortex. The amygdala implicitly remembers that the symptoms are of affective significance, and explicit emotionally charged memories are retrieved from the hippocampus and other memory centres to justify this conclusion. Information about symptoms is also transferred to the cortex. The cortex is "arrested" or "emotionally hijacked" by the amygdala, which can regulate the inputs which the cortex receives. Areas of the prefrontal cortex and anterior cingulate may be involved in continuous attentional processing of these stimuli, which makes it difficult for a patient to shift their attention to other stimuli. The patient simply has to consciously believe that the symptoms are negative or of concern, and this message is enough of a confirmation response for the amygdala. Given the debilitating nature of the illness, it is no surprise that patients are concerned or anxious about the symptoms. The amygdala then orchestrates a chronic stress response via the conditioned network which is out of keeping with the very minor danger which the symptoms might pose to the patient. The amygdala has strong projections to the hypothalamus to stimulate sympathetic (and parasympathetic) stimulation, as well as other brain structures normally involved in fear responses. The observed over-activity of the sympathetic nervous system leading to sympathetic dysfunction is a key marker of this process. The chronic long-term stress response becomes pathological to the body, and contributes to the myriad of different symptoms observed in patients, of which fatigue is but one.
Whilst a stress response in itself could not cause such severe symptoms, a continuous unremitting sympathetic stimulation (with immune reactivation) will eventually lead to mental and physical exhaustion with glandular depletion, as well as secondary abnormalities in bodily systems. And it is exactly these symptoms to which the patient has become sensitised to, increasing the distress associated with the entire morbid experience. A patient’s heightened perception of the symptoms, and increased symptoms in response to effort, can further contribute to avoidance behaviour and symptom distress. On an anecdotal level, continued stimulation of an exhausted mind and body to an "always-present danger" is likely to lead to various complications, and chronic suffering.
Any external stressor, based on an individual’s individual sensitivities, has the ability to trigger or reinforce the CFS vicious circle, making it more difficult to recover. On-going psychological, pharmacological, dietary or environmental stressors may now have the ability to increase chronic stress to levels out of proportion to the danger these stimuli actually present, reinforcing the vicious circle. In fact, it may be exactly these triggers which a patient attributes the illness to. Furthermore, every time the vicious circle is initiated, it further ingrains the unconscious fear of symptoms into the amygdala and associated emotional memory centres such as the hippocampus, making it far more difficult to moderate the amygdala’s expressions in the future.
There may be an added idiosyncrasy to the conditioned responses initiated. Individual patients’ conditioned response may mimic the response initiated during the "traumatic" period of learning in response to the conditioned stimuli, which may involve a reactivation of certain aspects of the immune system, or stress signature as mentioned earlier. Alternatively, there may be a host of other reasons for the observed immune abnormalities, as there is a whole literature in psychoneuroimmunology emphasising the close links between stress and immune function. Stress hormones and neurotransmitters are well known to have complex and wide-ranging effects on the immune system(17). The levels of these chemicals may in themselves be unique to each patient, depending on the level of glandular depletion and/or adaptation in stress systems to chronic stimulation.
The Patient’s Experience of the Illness
Patients are far more sophisticated in their mental approach to their illness than this theory may convey, and the role of conditioned and unconditioned stimuli may seem over-simplistic. There are a wide variety of coping strategies and belief mechanisms which operate. Patients are also heterogeneous in terms of the amount of overlapping psychiatric morbidity, with some patients suffering severe depression or anxiety, and some exhibiting no signs of this at all. However, I believe that the patient is "in the grip of" a predominantly unconscious process over which they have little control, and which they are probably not aware of. Differing cognitive approaches to dealing with the illness may have only modest effects, unless the approach is specifically involved in the reprogramming of the amygdala’s conditioned responses.
Whilst patients may question the direct causal link between concern about their symptoms and symptom perpetuation, the whole process eventually occurs automatically, and a patient is not consciously aware of it until he or she feels slight concern or anxiety about the symptoms, which may seem inconsequential in any case. The amygdala is conditioned to produce a large output to a mild input. Even a "niggling" concern over symptoms is enough of a confirmation message for the amygdala to continue the stress response, once chronic conditioning has occurred. It is almost as though the mind and body have unconsciously become "allergic" to the visceral and psychological expressions of stress, given that these expressions act as conditioned stimuli for the unconditioned stimulus of being in the throes of a debilitating illness called CFS. Even negative thoughts or memories about the symptoms can trigger the cell assembly, and the whole process is seamless, with the patient not necessarily even aware of any causal link. The stronger the conscious response to symptoms, the more the sympathetic response is reinforced in the amygdala. The diagram below shows how any level of concern about symptoms can lead to symptoms perpetuation:
Moreover, concern about symptoms is governed by previous memories of the illness. The amygdala retrieves memories mainly from the hippocampus, and the cortex also retrieves memories from other memory centres such as the temporal lobe. Cortical memory systems are reshuffled so that knowledge and memories most relevant to CFS will be recalled, taking precedence over other less relevant strands of thought. Therefore, the response from the cortex to the amygdala becomes automatic, with little conscious control once powerful unconscious emotional memory centres have been stimulated. The diagram below, based on Ledoux’s work, shows how immediate conscious experience within areas of the prefrontal cortex are affected:
Conscious experience during symptoms involves detection of symptoms from the sensory cortex, as well as arousal by the amygdala and the hippocampus(18). The amygdala arrests the cortex because of the negative salience of the symptoms. The hippocampus brings back explicit emotionally charged memories of the last time the symptoms were encountered, and how the person felt, and what emotional response was initiated. This diagram shows that it is little wonder that a patient’s concern about symptoms can occasionally turn into full-blown anxiety about symptoms, given the arousal from unconscious brain structures. However, once again I wish to underline that any negative thoughts or memories about symptoms is enough to trigger the amygdala’s chronic outpourings(19), and the more concerned a patient is about the symptoms, the stronger the response will be.
Some may argue that it is only natural for a patient to be mildly concerned or anxious about such debilitating symptoms. I would argue that it is precisely this point which underlies why patients can endure the illness for so many years with little change, and why the symptoms are not appreciatively helped by rest, and why this theory has not been expressed in the past. Interestingly, there is evidence in studies showing that patients may acknowledge persistent stress as a possible cause of on-going fatigue(20).
What’s New About this Theory?
Previously conditioned fear responses have mainly been thought of in terms of external stimuli, with a notable exceptions being panic disorder(21,22) and tinnitus. However, the amygdala, which mediates fear mechanisms in the brain, receives direct projections from the sensory thalamus, which monitors the entire viscera, as well as receiving information about the outside world from the senses. Therefore, it is not inconceivable that sensitised responses to bodily events can be "learned" by the amygdala. This does not mean that CFS is a psychological illness. I am applying an unconscious neurological process which normally occurs in anxiety disorders to a neurophysiological paradigm. Although I refer to the process as "fear conditioning", it is fear in terms of the amygdala’s sensitisation to symptoms, and fear in its traditional sense may be an inappropriate way of envisioning conscious cognitions. Instead the amygdala believes that negative symptoms from the viscera are of "affective significance".
The conditioned fear mechanism described is not to be confused with Hypochondriasis, which is a fear that one might be suffering from a serious disease. Patients are already aware that they probably suffer from CFS.
Somatisation disorder - "the expression of personal and social distress in an idiom of bodily complaints with medical help seeking". Although the etiology described above may have some minor links to somatisation, they are very different illnesses, and CFS in the context of fear conditioning deserves a whole new classification.
Unhelpful beliefs about the illness - Fear conditioning represents a deep-seated unconscious fear of symptoms, and unhelpful beliefs are an output rather than an input to the illness.
A fear conditioning model for tinnitus is now acknowledged in the literature as a likely etiology(23,24). Although tinnitus is a very different physiological illness to CFS, the evidence points to the ease with which conditioned sensitisation can occur in response to bodily signals.
2. Explanation of the Symptoms of CFS – It’s NOT "All in the Mind".
Several commentators have argued that a chronic stress response (which is the major feature of a chronic fear response) could act as a final common pathway for CFS. Prolonged stress is known to have pathogenic effects on the body, and the stress response affects every organ and system in the body. This leads to a wide-ranging number of chronic symptoms, which can differ, from patient to patient depending on individual sensitivities, leading to the observation that CFS may form a heterogeneous group. The neurophysiology described may then cause secondary abnormalities in other systems such as the immune system and the digestive system, which further exacerbate symptoms, and lead practitioners to observe these various abnormalities in patients. Furthermore, the continual stress response may eventually lead to glandular depletion and eventually adaptation, where the body adapts to over-stimulation. This may make it difficult to pinpoint sympathetic activity. Continual mental and physical tension with intrusive negative thoughts causes interrupted sleep patterns, which may contribute to the general exhaustion experienced, with patients not experiencing refreshing sleep. In fact, there is evidence of disturbed circardian sleep/temperature rhythms(25).
Whilst the symptomatology may exhibit some similarities to that observed in major affective disorder, physiological morbidity is far worse, given that CFS patients cannot engage in avoidance to the same extent that anxiety patients can. The stress response is continuous and unremitting, and such a chronic response may cause the secondary abnormalities which may or may not be observed in patients suffering from psychiatric disorders. The reactivation of the immune system individual to each patient will cause a variety of negative effects including general weakness. This may characterise CFS as a unique illness in terms of patient experiences, e.g. secondary allergies and sensitivities, with immune system abnormalities.
The literature on CFS and immunity is complex, and there are numerous observations of abnormalities found in patients, some of them contradictory. I hypothesise that there may be two contrasting processes occurring that may account for some of these observations, which may differ from patient to patient. Firstly, the conditioned response may re-trigger certain aspects of the immune system due to the "stress signature" hypothesis expressed earlier. For instance, there may be certain aspects of an over-active immune response which may contribute to symptoms such as fever, and sore throats and glands (effects of cytokines). Secondly, it has been known for many decades that chronic stress decreases the effectiveness of the immune system, as research within disciplines such as psychoneuroimmunology exemplifies. For instance, there is evidence of significant suppression of NK cell activity in CFS patients, but this has also been linked to a person’s reaction to emotional stress(26). These co-occurring processes unique to each patient may help to explain the immune abnormalities observed. For some patients, there may be no immune coupling during fear conditioning, and for others it may occur chronically.
The observed downgrading of the Hypothalamic-Pituitary-Adrenal (HPA) axis in response to stress (lower response to CRF and lower circulating levels of cortisol), may be due to adaptation in systems to chronic stimulation. It may be due to enhanced sensitivity of the HPA feedback mechanism with increased hippocampal inhibition, and is also seen in some patients suffering from Post-Traumatic Stress Disorder, which is another chronic stress disorder(27). This means that when a patient tries to engage in activity, the body feels too exhausted to cope with the rigours of life. HPA abnormalities themselves may have also have a function in stimulating aspects of the immune system.
Intolerance to alcohol has often been cited as a characteristic marker of CFS. Much medical research demonstrates that alcohol actually induces the stress response by stimulating hormone release via the hypothalamus(29). This is exactly the response which the amygdala is conditioned to respond to, causing further symptoms. Furthermore, in CFS this reaction may malfunction due to a downgraded HPA axis and other hormonal abnormalities as a result of the stress response, causing increased sensitivity to alcohol.
Identifying the exact nature of muscle aches and fatigue can be problematic. However, a hypothesis can be made. Actual muscular fatigue may be caused by continuous tension. Prolonged tension is initiated and maintained by the freeze, fight, or flight response, as the muscles are primed for reaction to dangerous stimuli. Adrenaline is particularly potent in maintaining muscle contraction(30), and the amygdala also projects to the reticulopontis caudalis, the fibres of the central gray, and corpus striatum, which all play a role in tightening muscle groups in response to fearful stimuli (the "freeze" response). Continuous muscle tension may cause the chemicals of fatigue such as lactic acid to temporarily accumulate and disperse, but lead researchers to find few physical abnormalities in the muscles. Continuous tension may cause secondary abnormalities in muscles, which require further definition The muscle de-conditioning which some researchers have identified may be an added factor rather than the central cause of fatigue.
The stress response causes vasoconstriction except in those vessels supplying the heart and the limbs, where vessels actually dilate. Over a prolonged period of time, this effect may cause gravitational venous pooling in the legs, which can contribute to the observed orthostatic intolerance and general weakness experienced(31).
Generalised anxiety and depression are overlapping psychiatric conditions which occur in CFS, but are a result of the actual underlying fear conditioning which causes an increase in the excitatory level of the amygdala, rather than the original cause of the illness. They may further contribute to symptoms themselves, given that fatigue is also characteristic of these illnesses. General avoidance behaviour may increase the perceived effort of tasks in the future, further ingraining fear of activity into the amygdala’s and hippocampus’ circuitry. Therefore, a routine task in the future may have the ability to elicit an ultimately exhausting sympathetic response which is out of keeping with the actual effort involved.
There may be various reasons for cognitive impairment seen in patients. The hippocampus can become damaged during a chronic stress response, and no longer is able to fulfil its role in short-term memory retrieval. Studies have shown that a brief period of stress can disrupt spatial memory in rats and interfere with long-term potentiation in the hippocampus(32).Therefore, the formation of new memories in the hippocampus may be inhibited, which means that patients may experience problems with short term memory retrieval(33). General concentration and attentional deficits may be due to mental exhaustion after short periods of continual stimulation. Concentrating on external stimuli for long periods of time may be difficult as cortical memory systems are reshuffled so that knowledge and memories most relevant to CFS will be recalled, taking precedence over other less relevant strands of thought.
Some, but not all patients are helped by various pharmacological and/or lifestyle interventions (e.g. CBT), which may be helpful in treating individual symptoms. These improvements place patients on a virtuous spiral where they begin to live with their symptoms and feel less concerned about them, contributing to the cortex mildly controlling and moderating the amygdala’s innate reactions. However, relapses occur and complete recovery is unlikely, unless the patient themselves develops a complete understanding of the processes involved in the illness.
(For more detail on CFS symptomatology, see pages 20-26)
Consequences For Patient Recovery
Recovery involves the amygdala’s expression of danger becoming regulated by the cortex, or more specifically the medial prefrontal cortex, in a process called "extinction". This process is also hypothesised to partly occur when patients engage in psychotherapy to treat severe anxieties or phobias. However, it is far more difficult to regulate ingrained fear of stimuli which are continually present (i.e. the symptoms of CFS) within the context of a neurophysiological paradigm, and patients cannot simply be told to try and not think about or worry about symptoms, because the cortex is continually arrested, and fear processing mainly occurs unconsciously. CFS is not a psychological illness, but the unconscious processes which occur in psychological illnesses still apply. The cell assemblies produced may be particularly strong in CFS. A unique new type of therapy is required, and I am currently in the process of developing and testing with patients, for which I wish to collaborate with research institutions and funding bodies, as well as patient groups. It is a "holistic" approach, which also incorporates issues about diet, exercise, sleep, and activity.
At this stage I do not in anyway advocate the use of anti-anxiety drugs to cope with CFS. Firstly, they do not change the underlying fear mechanism at work. Secondly, many of the side effects associated with these drugs actually mimic the symptoms of CFS, and can cause long term dependency, which will make it more difficult in the future to recover. New pharmaceutical interventions may be developed to treat CFS but they may only offer a short-term remedy, and only reprogramming may offer a long term solution.
For a more detailed description of the effects of conditioning, and the stress signature, please turn to page 16
For a detailed description of each symptom, please turn to page 20
For a look at the patient’s experience of the illness, and the effects of CBT, turn to page 27
The perpetuation of the process thus described relies on the CFS vicious circle. However, patients report "good days and bad days", with symptoms coming and going without warning. Therefore patients may be "in the throes" of the vicious circle to varying degrees at different points during the illness, and occasionally may actually release themselves from it. Patients often report relapses, and can sometimes link increases in physiological and/or psychological stress to an aggravation of symptoms. Below I list a number of factors which can either increase the intensity of the vicious circle, or can actually cause a relapse into the vicious circle if a person has previously made a recovery. They act as conditioned stimuli:
External Mild or Severe Stress: If a patient experiences some mild external stress in the future, the sympathetic nervous system is mildly aroused. This then causes symptoms which mildly mimic CFS. The amygdala and the hippocampus sense both the physical and emotional arousal which act as retrieval cues from emotional memory into the conditioned cell assembly, and the vicious circle begins once again. This explains patients’ inability to cope with the stresses of everyday life. (In terms of this feedback, the vagus nerve carries visceral information back to the brain from the body. It can transmit information about current emotional arousal(34).
Innocuous Symptoms Mimicking CFS: There are many external triggers which can mimic the mild symptoms of CFS. For instance, vigorous exertion can fatigue muscles, and this is a normal response to exercise. However, this is interpreted by the unconscious as evidence of CFS, and so the conditioned response occurs once again. This explains how some patients complain of relapses after they have attempted a particularly strenuous task, or why exercise seems to make symptoms much worse. It is worth noting that a strenuous task or vigorous exercise conducted whilst in the throes of the CFS vicious circle is not advised, as the body is already in a state of exhaustion from stimulation.
External Conditioned Stimuli: There may be certain situations, places or events which become associated with the worse symptoms of CFS. Explicit memory projections from the hippocampus and other memory centres signal to the amygdala that symptoms tend to be worse in these situations, and the amygdala responds in fearful anticipation, making it a self-fulfilling prophecy. I have personally met patients who have complained that their symptoms become worse in certain situations. These situations tend to be those in which symptoms have been particularly acute in the past, or situations in which experiencing symptoms would be particularly debilitating.
Thoughts of CFS Symptoms Returning: Conscious cognitions or memories anticipating the return of the symptoms may be enough to trigger the response. Simply thinking about the symptoms, and the detrimental effects it is having on a patient’s life, is enough to trigger a mild response, initiating a vicious circle. This does not mean that it is "all in the mind". It means that the unconscious has such a hold on conscious thought processes, that a patient’s thoughts are continually coloured by ingrained negative beliefs which further serve to perpetuate these thought processes.
Some observers have noted that patients experience what they expect to experience, due to a model of the body that the brain has created. I would take a different tack, theorising that if patients expect a certain experience, these conscious cognitions work with memory centres to trigger a the cell assembly conditioned response most appropriate to make that experience a self-fulfilling prophecy. In summary, anticipatory expectation of a physical experience make it a self-fulfilling prophecy, via the pathways described (including the stress signature hypothesis discussed below). These concepts are particularly significant for the etiology of illnesses other than CFS, and this shall be discussed further in section 6.
Conditioned Responses – The "Stress Signature" Hypothesis
The conditioned response involves a chronic sympathetic outpouring, which leads to autonomic dysfunction and a host of other negative effects, as in the CFS vicious circle. However, it is possible that there is an added idiosyncrasy to the conditioned response which is individual to each patient.
As mentioned earlier, it has been theorised by Hebb(35) that conditioning can also create "cell assemblies", "cell plasticity", or "conditioned networks", where individual cells develop stronger interconnections so that when one cell fires the others also fire, and these cell assemblies may be particularly resistant to extinction. Therefore a particular input can elicit a particular response; if a buzzer is twinned with an electrical shock, a rat can be conditioned to jump over a bar in response to a buzzer even if the shock is no longer present; Pavlov’s dogs started salivating when the bell rung (a learned response, but not a traumatic one).
Therefore, the conditioned response reflects the response which was initiated during the learning episode. The rat learned to jump in response to the buzzer because they experience an electric shock. The dogs learned to salivate because the meat was present when the bell was rung. This means that in conditioned fear responses as in CFS, the conditioned response to conditioned stimuli may re-enact the response initiated during the traumatic learning event, i.e. the immune response. Therefore there may be some further stimulation of the immune system occurring even after the virus has disappeared. Conditioned stimuli may include psychological stress, physiological symptoms of stress, and any symptoms which mimic the effects of a virus (generally some symptoms of CFS). The conditioned response may be one which triggers certain aspects of the immune system, as this was a response which was occurring during fear conditioning, and the stress response and the immune response may have developed strong neural interconnections (leading to the stress signature). The amygdala already has strong interconnections with the hypothalamus and the pituitary gland, two glands which have been strongly implicated in controlling the immune system.
Many patients do describe symptoms such as sore throats, enlarged glands, etc. which may suggest that the immune response has not been properly "switched off" after the triggering event(36). Many researchers have identified a number of immune abnormalities which suggest a continued immune response, e.g. increased levels of alpha interferon(37), and higher levels of autoantibodies(38). However, these findings are complex and often contradictory.
Immune system "learning" is not a new concept. Psychologists Robert Ader and Nicholas Cohen were the first to demonstrate this effect in rats(39). They injected rats with sweetened water at the same time as cyclophosphamide, which suppresses the immune system and causes sickness. The rats learned to associate the sweet water with getting sick, so they stopped drinking the water. The researchers then stopped injecting the immune suppressant when rats drank the water, and eventually rats lost their fear and began drinking the water again. However, 6 weeks later, an unusual number of rats began dying, and Ader and Cohen realised that the immune response was being lowered by the sweet water alone. Therefore, although the rats had extinguished their fear response to the water, they had not yet lost their learned immune response. This shows that the sweet water had become a conditioned stimulus, and the conditioned response is a lowering of the immune system. In CFS, the conditioned response to stress or physical symptoms may be to activate the immune response, which in itself may increase symptoms.
I caution against the idea of a stress signature in CFS patients until further work is carried out, because there may be other explanations for the apparent stimulation of the immune system. Some practitioners believe that lethargy and fatigue states can occur in the context of abnormalities in HPA function outlined above, where a hyporesponsive adrenal cortex can result in increased susceptibility to disordered states of immunity, manifesting either as CFS or fibromyalgia(40). There is already a host of literature within psychoneuroimmunology emphasising the close relationship between emotions, the brain and the immune system. For instance, electron-microscope studies show that the autonomic nervous system has synapse-like connections to immune cells. Given the chronic stress response outlined, it is not inconceivable that the immune alterations seen may be a result of autonomic dysfunction or other effects of stress, rather than a direct stimulation of the immune system due to long term potentiation.
Conditioned Stimuli, Conditioned Responses, and Unconditioned Stimuli
Whilst the "conditioning" phraseology used may seem more appropriate to laboratory rats than human beings, brain systems underlying certain emotional behaviours like fear conditioning have been preserved throughout many levels of brain evolution. They are present to enable our survival in dangerous situations, and therefore operate at an unconscious level.
The diagram below explains the link between the various conditioned stimuli, and the conditioned response:
Whilst the patient is in the throes of the CFS vicious circle, the symptoms of CFS act as the main conditioned stimuli. This elicits a conditioned response, which in itself causes the symptoms of CFS, perpetuating a vicious circle. The other 4 triggering mechanisms identified above also act as conditioned stimuli, which can trigger the conditioned response, which then places a patient back in the CFS vicious circle. Given the various conditioned stimuli as well as the vicious circle, it is not surprising that patients experience high variability in symptoms from one hour or day to the next. Activity, the psychological state of mind, the environment, the current state of symptoms, all have a role to play in rapidly changing symptomatology from one time period to the next.
What is interesting about this model of fear conditioning is that the conditioned response actually causes the unconditioned stimuli to be present. This model has also been identified for panic disorder, where fear of the unconditioned stimuli (a panic attack) stimulates the conditioned response (sympathetic response), which in turn causes the unconditioned stimuli to occur(41). In the case of CFS "extinction" of the ingrained fear is much more difficult, because often extinction involves repeated exposure to the conditioned stimulus without the unconditioned stimulus being present.
Neuroendocrinological Aspects of Conditioned Fear Response – Downgraded CRH Response
Several researchers have noted a downgrading of the central drive within the HPA axis in patients. A reduced ACTH output in response to CRH has been observed. This cannot be explained by negative feedback from high glucocorticoid levels, as they tend to be slightly low. This feature has also been seen in Post-Traumatic Stress Disorder (PTSD)(42), and it has been hypothesised that fear conditioning is also involved in this illness, which is characterised by a prolonged stress response(43). This would help explain why there is some shared symptomatology in both illnesses, as I propose that a chronic stress response resulting from fear conditioning is the basis for CFS, as well as PTSD. However, the physiological symptoms are far worse in CFS compared to PTSD, given the chronicity of a continual stress response that CFS patients experience.
One hypothesis is that there is an enhanced sensitivity of the HPA feedback mechanism, potentially involving increased glucocorticoid receptor activity. This may involve increased hippocampal inhibition in response to severe levels of hormones(44). This enhanced feedback could be the body’s way of stopping particularly pathogenic levels of stress hormones and neurotransmitters.
Another possible hypothesis is that CRF is over-secreted – particularly in the amygdala, the hippocampus, and the locus ceruleus – alerting the body for an emergency. Potentially the brain, trying to lower the rate of chronic CRF secretion, may compensate by decreasing the number of receptors, because they were already overloaded with the stress hormones(45). This helps explain other processes in the body relating to the inappropriate response to exercise, where cortisol levels do not rise enough to cope with the task at hand. Lack of CRF is associated with the inability to respond to stressors, or more simply, the demands of everyday life.
Researchers had previously suspected a physiopathological malfunction in the HPA axis for years to be potentially responsible for CFS. The abnormalities found could now be accounted for by chronic stimulation as seen in PTSD. In fact, a recent paper also noted the considerable overlap between symptoms of PTSD and fibromyalgia(46). However, there is a major difference between CFS and PTSD; PTSD patients suffer some degree of trauma every time they relive previous traumatic memories, whereas CFS patients suffer anxiety whenever they experience symptoms of CFS.
EXPLANATION OF THE SYMPTOMS
It should be noted that the explanation for the symptoms below is based on the suggested effects of a chronic prolonged stress response, rather than an in-depth researched study into each symptom. There may be secondary symptomatologies not identified below which require further investigation.
CFS patients suffer symptoms arising from two sources: firstly from the direct effects of a chronic prolonged stress response, and secondly from secondary abnormalities arising in bodily systems as a result of the prolonged stress response (e.g. in the immune system). The prolonged stress response may cause:
Continual severe muscle tension and orthostatic intolerance
Difficulty sleeping (or excessive sleeping) leading to sleep deprivation and fatigue
Chronic stress hormone release
Potential adaptation by some stress hormone receptors, and/or depletion of hormone releasing glands.
Inability to deal with external stressors due to bodily exhaustion from continuous stimulation
The CFS vicious circle is particularly vicious. It is already known that a prolonged stress response can becomes toxic to the body, and so such severe symptoms resulting from a continuing stress/fear response is not surprising. There exist a myriad of different chemical and physiological changes identified in CFS. Each researcher is attempting to identify individual small abnormalities in patients, and using those differences as a potential cause of CFS. However, if a body is subjected to pathological levels of stress for prolonged periods of time, where every body organ and system is affected, there may be wide-ranging secondary complications in bodily systems which seem to go unexplained. On an anecdotal level, continued stimulation of an exhausted mind and body to an "always-present" danger is likely to lead to devastating complications, and chronic suffering.
Differing symptomatologies are based on particular symptom fears that a patient has, as well as the unique individual stress responses (stress signature) and emotions that an individual initiates. It used to be believed that the stress response was uniform, whatever the actual source of the stress was. But as Joseph Ledoux notes,
"…we now know that the autonomic nervous system, which controls the viscera, has the ability to respond selectively, so that the visceral organs can be activated in different ways in different situations. Recent studies show, for example, that different emotions (anger, fear, disgust, sadness, happiness, surprise) can be distinguished to some extent on the basis of different autonomic nervous system responses (like skin temperature and heart rate)"(47).
Furthermore, as mentioned above, individual elements of the autonomic nervous system can be controlled by the amygdala’s responses, so that each individual physical change can be tracked to a particular emotion, e.g. neck and shoulder muscles tighten in response to certain types of anxiety. Therefore, it is not inconceivable that the symptoms that the patient particularly concentrates on as indicative of the illness, actually become worse because those particular muscle groups tighten, or other autonomic changes produce negative effects in localised areas. While this notion is not required to fulfil the psychopathology described, it is an area for future research. This may have implications on where fibromyalgia fits into the equation. It could depend on which symptoms a patient particularly is anxious about, which in these patients’ case may be the muscle aches and pains resulting from severe prolonged muscle tension.
Previously, a few practitioners have attributed sympathetic dysfunction to associated overlying psychological complications. However, the continuous sympathetic response may be integral to the process, and prolonged stimulation of a body to an inescapable "danger" may lead that body to reach exhaustion. If all CFS patients had described general feelings of anxiety about life, or Generalised Anxiety Disorder (GAD), then CFS may have probably been partly attributed to somatic symptoms arising from psychological causes. It is interesting to note that similar pathways are involved for anxiety about the external environment, as well as the internal bodily environment, which emphasises why the symptoms of CFS mimic closely the symptoms of acute anxiety. CFS is much more of a chronic condition compared to anxiety as the fear is particularly potent, because the conditioned and unconditioned stimuli are permanently present (i.e. bodily symptoms of CFS), and patients cannot engage in avoidance behaviour to the same extent that anxiety patients can.
The similarity between anxiety and CFS has been demonstrated using a number of different fields of research, and the diagnosis of GAD requires at least three symptoms from a list including fatigue, difficulty concentrating, irritability, poor sleep and muscle tension(48). These are similar to the symptoms which appear in the diagnostic criteria for CFS. Some studies also claim that 98% of CFS patients claimed to feel "emotionally liable"(49).
There are several parameters which determine the length and severity of symptoms in CFS patients:
The conditioned fear that is imprinted into the neural networks of the amygdala may vary in intensity. This depends on how traumatic the learning experience was for each patient, and how concerned each patient is consciously about CFS (the unconditioned stimulus).
The levels of on-going external psychological or environmental stressors which serve to drive the CFS vicious circle.
Some patients will be consciously concerned about their symptoms to a greater or lesser degree at different stages of the illness, which in turn will cause less or more symptoms, depending on their coping strategies.
Patients will have different "pain thresholds", i.e. if person A and person B have the same level of physical exhaustion, person A may still engage in more activity, because they are less fearful of the effects this may have on their bodies. (This aspect is the one most directly addressed by Cognitive Behavioural Therapy, challenging the benefits of prolonged rest).
Patients may become hyper-vigilant of different symptoms, depending on which symptoms they find the most disagreeable
Each individuals particular type of emotion will lead to slightly different bodily responses, given that every single part of the body can be controlled very accurately via the autonomic nervous system. Immune reactivation may differ from patient to patient, depending on the stage of the illness (the "Stress Signature").
Muscular Fatigue and Aching Joints: A CFS patient’s feeling of fatigue is dissimilar to that of normal fatigue experienced after exercise. It is hypothesised here that the muscle fatigue and pain may in part be as a result of severe muscle tension. Pinpointing the actual experience of fatigue is difficult, and general exhaustion may contribute itself to the feeling of fatigued muscles.
The stress response is sometimes known as the "fight, flight or freeze" response. The freeze response keeps the muscles tense, so that they are ready to respond to an impending threat. Relaxed muscles are in a state called tone, which is a state balanced between relaxation and contraction. Prolonged tension in muscles upsets tone and allows the chemicals of fatigue to temporarily accumulate and disperse, such as lactic acid (several studies have shown lactic acid abnormalities in response to exercise for around a third of patients, implying inefficient aerobic muscle metabolism(50)). This is why patients may suffer from aching limbs that seem to feel heavy and drag, but there seems to be no physiological abnormalities in the muscles. Patients suffering from fibromyalgia may experience more severe symptoms as a result of this process. Adrenaline and noradrenaline have a particular role in maintaining muscle tension, and even if this hormonal response is no longer elicited, the amygdala projects directly to the reticulopontis caudalis, the corpus striatum, and the "central gray", which may have a role to play in tightening skeletal muscle groups in response to fear. Fear of aching limbs also means that patients consciously tense the muscles further, making the sensations even worse. It is the effects of severe muscle tension over a continuous period of time which may contribute to the fatigue and pain, not just muscle tension per se. Immune activation may have effects on muscle yet to be identified.
Muscle de-conditioning as a result of avoidance behaviour may be a factor contributing to fatigue, but this may be an aggravator rather than the central cause. Therefore, a graduated mild exercise programme may be beneficial in dealing with any muscle de-conditioning which may have occurred as a result of the avoidance of activity, but the central mechanism that is perpetuating muscle tension should be addressed first. Some studies have shown that a few patients have found that magnesium supplements tend to help muscle fatigue. This is because magnesium can act as a muscle relaxant.
Fatigue from sleep problems: Studies have shown that anxiety can cause insomnia via two pathways: bodily arousal (somatic), and worrisome thoughts (cognitive). Studies by Borkovec(51) have shown that the main cause of insomnia may actually be intrusive thoughts, and insomniacs were chronic worriers who could not stop worrying, no matter how sleepy they were. So it is with CFS patients. The mind is constantly being bombarded with intrusive thoughts about symptoms and the general negative state of health, and so patients find it difficult to get to and stay asleep.
Alternatively, even if a patient is able to sleep, when a mind and body is tense, sleep is interrupted and fragmented during the night. Studies have shown that interrupted sleep causes further aches and fatigue the next day(52). A prolonged stress response may also have adverse reactions on the body clock, and indeed research has shown a mismatch between temperature rhythms and melatonin secretion in CFS patients. The mismatches in CFS patients have been shown to be very similar to those suffering from stress and sleep deprivation(53).
Initially falling asleep can be difficult because a tense and anxious mind and body need to be relaxed before deep refreshing sleep can take its course.
Intolerance to Alcohol: Intolerance to alcohol has often been cited as a characteristic marker of CFS. Much medical research demonstrates that alcohol actually induces the stress response by stimulating hormone release via the hypothalamus(54,55). This is exactly the response which the amygdala is conditioned to respond to, causing further chronic symptoms. Furthermore, in CFS this reaction may malfunction due to a downgraded HPA axis and other hormonal abnormalities as a result of the stress response, causing increased sensitivity to alcohol. These findings have been demonstrated in animal studies. In one study with rats, the administration of alcohol initiated the physiological stress response, measured by increased levels of corticosterone(56). In addition to stimulating the hormonal stress response, continued exposure to alcohol also results in large increases in adrenaline(57).
Adverse reaction to exercise or other stressors: Some studies have also shown that CFS patients do not respond correctly to exercise, in terms of inadequate release of cortisol and the catecholamines. Although this area requires further research, an hypothesis can be made. The chronic stress response may mean that the adrenal glands eventually get depleted, and whilst the signals still exist to release cortisol and other stress hormones, the response no longer occurs. There is some evidence of reduced size of the adrenal glands(58). This may be exacerbated by the lower bodily response of CRF due to various neurological changes in response to chronic over-release of stress hormones as seen in Post Traumatic Stress Disorder. Low levels of cortisol and the inability to stimulate cortisol mean that when a CFS patient tries to exercise, the body does not maintain blood flow and heart rate in keeping with the response required. The reactivation of the immune system may also have a part to play here.
Exercise can exacerbate the symptoms of CFS in patients, because the muscles already feel fatigued as a result of prolonged tension, and because of the downgrading of the HPA axis as described above. However, there may be benefits in engaging in a mild graduated exercise programme to deal with any associated de-conditioning, and to realise other benefits which mild exercise may bring, after a patient has started a programme of recovery based on reprogramming the amygdala.
General avoidance behaviour may increase the perceived effort of tasks in the future, further ingraining fear of activity into the amygdala’s and hippocampus’ circuitry. Therefore, a routine task in the future may have the ability to elicit an ultimately exhausting stress response which is out of keeping with the actual effort involved.
Gastro-intestinal Problems, e.g. Irritable Bowel Syndrome (IBS): When the "fight or flight" response is initiated by the sympathetic nervous system, adrenaline and noradrenaline direct the bodily energies and resources to the organs which are involved in fighting or fleeing. These are the muscles in the limbs, so that they can respond quickly, and the brain, so that the mind can think quickly and concentrate on the source of the danger. Therefore, all other non-essential bodily functions are downregulated, such as the digestive system. These means that food regularly passes through the gut but may not be digested correctly. Also, the mouth can become dry.
The digestive system is controlled by its own nervous system, called the enteric nervous system. This is further controlled by the autonomic nerves, using neurotransmitters and hormones. Given the autonomic dysfunction resulting from sympathetic overactivity, regulation of the digestive system may malfunction, just as a patient may endure temperature and blood pressure problems. Furthermore, muscles in the body become tense. The colon normally moves food by moderate contractions or spasms. Muscle tension may upset these rhythms giving either too many or too few contractions, leading to either diarrhoea or constipation, or both.
Patients may then add another secondary learned fear. The sensory neurones detect the feelings of irritable bowel syndrome, and convey these messages to the amygdala in an instant. The amygdala triggers the stress response if "fear of the IBS symptoms" has been learned as a secondary fear, and so another vicious circle can be created. Urinary adrenaline levels have also been recorded as high in patients suffering from IBS(59).
Some patients find that changing their diet seems to help, and that is because there are certain food types which are easier to digest, and to which the body is less sensitive in general. Eating foods which are difficult to digest while the digestive system is in the above state, could worsen symptoms. Some patients also talk about candida as a potential cause for CFS. Whilst I cannot comment on every theory for CFS which has been forward, there are several dietary interventions which can help patients, and may be explained by a number of different pathologies, which may actually be secondary complications.
Immune-Dysfunction: The literature on CFS and immunity is complex, and there are numerous observations of abnormalities found in patients, some of them contradictory. I hypothesise that there may be two processes occurring that may account for some of these observations, which may differ from patient to patient. Firstly, the conditioned response may re-trigger certain aspects of the immune system due to the "stress signature" hypothesis expressed earlier. For instance, there may be certain aspects of an over-active immune response which may contribute to symptoms such as fever, and sore throats and glands. Secondly, it has been known for many decades that chronic stress decreases the effectiveness of the immune system, as research within disciplines such as psychoneuroimmunology exemplifies. For instance, there is evidence of significant suppression of NK cell activity in patients, but this has also been linked to a person’s reaction to emotional stress(60). These co-occurring processes unique to each patient may help to explain the immune abnormalities observed.
Furthermore, different patients may experience varying immune abnormalities because the various levels of catecholamines and glucocorticoids may be different themselves, depending on the chronicity of the stress response and the level of adaptation to over-release, as seen in the downgrading of the HPA axis. Unfortunately, few studies seem to have been done to evaluate multiple hormones simultaneously acting on cells of the immune system(61).
Autonomic Dysfunction e.g. temperature problems, blood pressure problems, palpitations, sweating, cold hands, feeling faint, etc. The amygdala has direct projections to the autonomic nervous system (ANS), as well as via the hypothalamus, and the ANS co-ordinates many bodily responses including temperature and blood pressure. Researchers have known for years that emotional states are closely linked to the autonomic nervous system, and that individual emotions can be linked to individual autonomic responses. Therefore abnormalities in autonomic function can be directly attributable to chronic long term sympathetic stimulation by the amygdala via the hypothalamus.
Orthostatic Intolerance: Recent work on orthostatic intolerance by Dr.Bell(62) has revealed some interesting observations which may be explained by a continual stress response. Dr.Bell has hypothesised that orthostatic abnormalities may be due to excessive gravitational venous pooling. A stress response causes vasoconstriction except in the limbs where vessels actually dilate (to aid "fight or flight"). This may cause blood to pool in the legs in the long term as blood vessels are constricted in other areas of the body. This may lead to the observed orthostatic abnormalities.
Visual disturbances and Sensitivity to Light: The delicate muscles which accommodate the lens of the eye are called ciliary muscles, and these may also be affected by muscular tension and fatigue, so that vision may become blurred, especially when looking near-to-far and vice versa. Eye fatigue also occurs because, when the fight or flight system is initiated, the vision sharpens and the eyelids retract so that the eyes can focus better on the source of the danger. Hypothetically, this observation may partly explain why CFS patients are particularly sensitive to bright light.
New Symptoms: In general, the stress response affects the entire body. For instance, the autonomic nervous system affects all the organs and systems in the body, and that is why there may be many wide-ranging somatic symptoms experienced. And because the amygdala is at a heightened state of awareness of all stimuli, new fears can be "learned", even superficially. This means that even when innocuous bodily signals enter the sensory thalamus, these signals can be misinterpreted as dangerous by the amygdala, and subsequently become new conditioned stimuli. Hypothetically, this may explain added allergies and chemical sensitivities, which the excited amygdala may react to, triggering immune response which are unwarranted. Patients may monitor signals from their bodies, and signals can be perpetuated. CFS patients can develop added symptoms, which can mysteriously come and go. This is also a major source of added fear, as patients worry that they may have developed serious secondary illnesses, such as heart problems.
Headaches and "Foggy" Head: These occur as a result of prolonged tension and stress, especially due to tension in the neck muscles. The mind may be in a state of heightened arousal throughout the day, and becomes fatigued from such chronic stimulation. This can make the head sensitive and sore.
Inability to concentrate/Attentional Deficits: The mind is on edge and anxious from the excitatory state of the amygdala. Furthermore, the conscious mind is "arrested" by the amygdala, as it is bombarded with signals about the body. Therefore, the mind finds it difficult to focus on other tasks, because it is also continually trying to process signals from the fear mechanism.
When patients are experiencing symptoms, cortical memory systems are reshuffled so that knowledge and memories most relevant to CFS will be recalled, taking precedence over other less relevant strands of thought. This may make concentrating on anything for a continued period of time difficult.
Goldstein believes that these deficits may be due to low than normal levels of brain neurotransmitters such as noradrenaline. In my model, a sustained period of attention to symptoms has the ability to cause a surge and subsequent decrease in noradrenaline levels (as well as other neurotransmitters such as dopamine), which then may cause the associated cognitive deficiencies.
Problems with Memory: The prefrontal cortex has a role to play in the development of memories, and given that it is arrested by the amygdala and tends to be attentionally riveted to fearful stimuli, memories about less emotionally relevant stimuli may not occur as strongly. Also, the hippocampus fulfils two roles, in firstly providing a system for short and long term memory retrieval, and secondly as a "control knob" which tries to stop the release of the stress hormones. The hippocampus can become damaged during a chronic stress response, and no longer is able to fulfil these dual roles well. Studies have shown that a brief period of stress can disrupt spatial memory in rats and interfere with long-term potentiation in the hippocampus(63).Therefore, the formation of new memories in the hippocampus may be inhibited, which means that patients may experience problems with short term memory formation and subsequent retrieval(64).
Emotional Lability, Anxiety and Depression: Caused by the prolonged release of stress hormones and neurotransmitters, especially adrenaline, as well as the excited amygdala’s continual neuronal arresting of the prefrontal cortex, signalling the presence of fearful stimuli. This causes a wide variety of added psychiatric complaints and further learned fears, especially depression. Long term stress in itself is thought to cause depression. These mood disorders are secondary to the unconscious conditioned fear mechanism, and are often the worst aspects of the illness experience for patients.
Some researchers believe that CFS is not related to anxiety, as about a third to a half of patients do not report anxiety. However, anxiety is something traditionally associated with the external environment, and psychiatric disorders, and anxiety specifically about symptoms may not be captured in studies. If patients were to be asked if they were anxious about how they are feeling physically, and the effect it was having on their lives, then undoubtedly the response would be that they are particularly worried.
Susceptibility to Stress: External stress can act as a conditioned stimuli on the cell assembly, triggering a stress response which is out of keeping with the external threat posed. For some patients, the world seems more dangerous than it actually is, and this is exacerbated by the fear of increased symptoms to stress. Furthermore, secondary fears can be learned, as the amygdala is in a continual state of hyper-vigilance, with a lower threshold level for an anxious reponse. This explains why some patients subsequently develop added psychiatric complaints such as vertigo, agoraphobia, panic disorder and general anxiety. In fact, any psychological, pharmacological, or environmental stressors may have the ability to increase levels of stress, reinforcing the vicious circle. Patients may indeed attribute their symptoms to the particular external stressor they are facing.
This has implications for long term recovery, in that even if the unconscious ingrained fear about symptoms is moderated or extinguished, the stress response may remain poorly controlled in response to external stimuli. This is enough to bring back symptoms, as the amygdala’s conditioned fear response may simply be being controlled by the cortex, rather than be truly extinguished. The amygdala may sense the symptoms of severe stress which trigger memory retrieval in the amygdala and hippocampus, and unleash its conditioned fear response and arrest the cortex, causing a relapse.
Panic Attacks: A minority of patients become prone to panic attacks. Panic attacks can actually be seen as conditioned fear responses, where the conditioned stimuli are any bodily change which could signal the start of a panic attack. The amygdala may detect certain bodily changes such as blood pressure increasing as a result of an external stress, and it may prepare for a panic attack. This can become a self-fulfilling prophecy: the amygdala and the conscious mind fear a panic attack coming on, and this in itself initiates it. This is similar to the whole aetiology of CFS(65).
3. IS THIS REALLY HOW THE PATIENT FEELS ABOUT THE ILLNESS?
If the hypothesis in this paper proves to be correct, it may cause a large shift in the way CFS is envisaged. Some of you may feel that it does not apply to the patients you have heard about, or maybe worked with. You may feel that whilst patients are uncomfortable with their symptoms – who would not be, with such a debilitating illness – they do not fear them 100% of the time, and to such an extent that it would cause the symptoms to perpetuate. "It’s not just in their minds". In response, I would firstly say that the explanation above does not, in any way, discount the presence of symptoms. On the contrary, it describes a process which would cause severe mental and physical symptoms, which can easily perpetuate. Secondly, much of the above process occurs unconsciously, without the patient even realising the mechanism at work. Their conscious thinking mind is only aware of something once it feels "emotional", or anxious – even these conscious emotions may seem inconsequential to the patient. A negative thought or memory about CFS can drive the cell assembly. The therapies I describe in the recovery paper are designed to reverse this, so that the patient can gain control of a thus uncontrolled unconscious process.
Some of you may question the explanation of CFS I give above, because patients have been helped by various therapies. Some patients have spoken of how they believe that the "candida" yeast infection is to blame for CFS, and have benefited from taking out certain food categories from their diet. Others talk about "Enada", and the positive effects this drug has on supplying the tired cells in the body with energy. Even more talk about the benefits meditation and relaxation have had, and how they are gradually returning to a normal life. How can my model be correct if patients can be helped by various interventions? I believe that a patient can improve by treating symptoms enabling the body to cope with the illness better, and once symptoms ameliorate slightly, this puts a person on a virtuous spiral. They develop milder symptoms, so they are less fearful of the effect CFS is having on their lives, they feel they are on a positive path to recovery if they follow a certain therapy, and so they mildly start to recover. This is very positive news. However, patients do tend to find that they do not fully recover, and that relapses occur regularly. This is because the underlying cause, the unconscious learned fear of the symptoms, is only being addressed indirectly.
Furthermore, a subset of patients find that their condition may improve over time, without little explanation. I would hypothesise here that there is process of "putting up with" symptoms. Gradually patients learn about their relationship with the illness, and discover that "fighting" (as in "fighting-or-fleeing") and tensing up against the illness does not help. They maybe try an alternative therapy such as a new dietary regime, which helps with moderating symptoms. A virtuous circle ensues, where fewer symptoms mean they are less concerned about symptoms, and so on. Eventually they take on some new activities, and the distraction keeps them on the virtuous spiral. For some chronically ill patients however, the virtuous spirals are far more difficult to achieve, because the fear is far more ingrained, and the devastating illness continues unremittingly with little change.
Interestingly, many patients do recover, but find that they only recover 70-80%, and there is a continuous background "noise" which interferes with their ability to get on with life. Once again, this continuous remnant of the illness is present because the amygdala’s conditioned fear is simply subdued rather than extinguished. External stress still serves as an input into the conditioned cell assembly, and relapses can occur quite easily.
Figure 6 shows the effects of various pharmacological and lifestyle interventions:
4. THE PATH TO RECOVERY FROM CFS
There are two strategies to use to combat CFS. The first one is to aim to treat the symptoms as much as is possible; for instance, many patients have found that taking certain food products out of their diet can improve their stomach complaints. The second more important strategy involves a new type of cognitive approach. Whilst patients may be reluctant to try cognitive approaches (I certainly would have been reluctant when I was ill), with full explanation of the mechanisms at work, a patient can be gradually encouraged to realise that they are in no way to blame for their symptoms. They are at the whim of a predominantly unconscious process which they cannot currently control, and new therapies may enable them to re-establish this control.
Although I describe cognitive approaches, this does not mean that I believe CFS is psychological. Visualisation and cognitive exercises are used in cancer therapy, but no-one would say that cancer is psychological! Pharmaceutical companies may look to develop drugs which can help patients as a result of this hypothesis, but I believe that these interventions will only be temporary measures. The amygdala requires reprogramming rather than simple submission to offer a long term solution.
With learned responses, the path to recovery involves a mechanism called "extinction". This probably involves interaction between the medial prefrontal cortex and the amygdala. During a severe stress response, the amygdala arrests the cortex. The projections from the amygdala to the cortex are far stronger than the projections from the cortex to the amygdala. This makes extinction difficult, but by no means impossible.
Whilst the brain process of extinction may be similar to that seen in anxiety disorders and phobias, the tools used can be quite different to received wisdom in this area. This is because the conditioned stimuli do not occur occasionally as in many other fear responses, but are present in chronic proportions all the time (i.e. the symptoms of CFS). Furthermore, many anxieties or phobic responses are based on irrational perspectives or beliefs which perpetuate a fear. With CFS, the fear is not irrational. The symptoms are debilitating, and have a major effect on patients’ lives. Therefore, extinction is much more difficult and a less reliable process, although once again, the positive news is that I believe that it is possible.
At this stage I do not in anyway advocate the use of anti-anxiety drugs to cope with CFS. Firstly, they do not change the underlying fear mechanism at work. Secondly, many of the side effects associated with these drugs actually mimic the symptoms of CFS, and can cause long term dependency, which will make it more difficult in the future to recover.
Having a positive attitude may help with the recovery process, but is by no means the answer to CFS. Recovery involves therapies, which reprogram the unconscious into a new way of thinking about the symptoms, and is a complex gradual process – there is no miracle cure here. In the process of recovery, therefore, there is a new form of therapy which, as far as I am aware, has not been tried until now. I do not include further information on suggested therapies because they are still at an early stage of being developed and tested with patients, before being ready for publication.
5. WHY DO THERAPIES LIKE CBT SEEM TO HELP SOME PATIENTS?
Quote: "CBT, or Cognitive Behavioural Therapy, involves giving patients small tasks that gradually get harder as the treatment progresses. By slowly adapting to the increasing activity, they no longer perceive their effort as excessive. With this opportunity to gain control gradually, they learn to cope with the illness"(66).
Whilst I am not advocating the current form of CBT as the correct treatment for CFS, I can see why there may be a few benefits for some patients. By giving a patient a programme of activity, you first of all are offering the patient some distraction away from the symptoms, but more importantly, you are making the patient less focused on their symptoms. This is because he or she gradually realises that they can lead an almost normal life, and can cope with the illness, and this may moderate a patient’s fearful interpretation of the illness, and decrease avoidance behaviour only for severely ill patients. The same process is involved for a graduated programme of exercise. However, CBT in its current form is only useful in the long term to the extent that it increases the moderation of the amygdala’s fearful outpourings by increasing projections from the medial prefrontal cortex to the amygdala – and this is unlikely in the context of CBT. There are many factors which will influence whether or not this effect will occur.
One of the main reasons why patients are mildly anxious is because of the detrimental effect that the illness is having on the patient’s life. This can lead to avoidance behaviour, which makes them believe that performing those tasks in the future will be even harder. General avoidance behaviour may increase the perceived effort of tasks in the future, further ingraining fear of activity into the amygdala’s and hippocampus’ circuitry. Therefore, a routine task in the future may have the ability to elicit an ultimately exhausting stress response which is out of keeping with the actual effort involved. This consequently increases the concern about the illness even more. By gradually introducing a patient back to activity, they gradually realise that they still do most things in life. They begin to become more positive about the symptoms, and this increases their "fatigue or pain threshold", and so the sympathetic response to an activity is moderated, allowing a patient to achieve more with less resulting exhaustion. Once again this may be only beneficial in treating some aspects of the illness.
This process may decrease symptoms enough for some patients to return to a vaguely normal life, but relapse rates from these treatments can be high, and it does not work for everyone. In fact, there is a whole body of evidence challenging the effectiveness of traditional CBT in CFS. Complete extinction can only come from the patient fully understanding the pathology themselves, and then engaging in a programme of unconscious reprogramming which can be complex.
Some practitioners talk about CFS as a situation where the brain harbours a model of the body that it uses to predict the consequences of movement. If this perception is wrong, they say, then perceived effort to accomplish tasks is higher than actual effort. There is an element of truth in this, as I have mentioned that the sensory cortex magnifies the symptoms of CFS, so they are felt more acutely. This can encourage avoidance behaviour. However, it is only half the story. The symptoms are still present and are real (if amplified in the mind), and significant effort like vigorous exercise will only worsen the situation, because the mind and body are already exhausted via the exaggerated and prolonged stress response.
6. HYPOTHESIS: AN EXPLANATION FOR THE VAGUE CONCEPT OF "FUNCTIONAL SOMATIC SYNDROMES"
Recently there has been a lot of publicity and controversy over the concept of "Functional Somatic Syndromes". Dr. Peter Manu, an American internist who edited a recent book on the subject, says that the various FSS share "multiple somatic symptoms"; they lack "defining structural defects or laboratory abnormalities"; there’s a "frequent association with psychiatric disorders"; an "absence of proven pathophysiological mechanisms" and "a paucity of effective therapeutic interventions". Apart from CFS, the term is supposed to cover fibromyalgia, premenstrual syndrome (PMS), multiple chemical sensitivities (MCS), irritable bowel syndrome (IBS), non-cardiac chest pain, hyperventilation and tension headaches.
On this subject,
I do not think that CFS should be classed as FSS because of the neurophysiological process I have described, even if they may display a few characteristics of FSS
I do not believe that there is a benefit in grouping treatment for patients on the basis of FSS, as symptoms are very different in each case, enough to warrant specialists in each area
There may be some benefit in researching FSS to see if there is an underlying mechanism to some of the illnesses, but to group them together before this strong link is established is dangerous, and is likely to increase patient frustration. A lack of an adequate explanation seems to be real link here.
Having said this, I have a hypothesis for a possible common explanation for some illnesses currently being classed as FSS. However, the term FSS is misleading, because FSS’s central perpetuating mechanism seems to be "psychosocial" factors, whereas I believe that this factor has simply arisen in the literature because there is currently no explanation for these illnesses. The common factor I identify below is unconscious conditioned fear. As a side note, why should emotion feature as the universal final gateway for these conditions? I believe that bodily symptoms and illness in general can elicit conscious and unconscious emotional responses in people (especially anxious ones), and that these emotional responses can vary on a scale from mild concern to full-blown fear, all operating through the amygdala and associated structures. And as mentioned earlier, the amygdala is part of the basal ganglia, and it has been recently appreciated that the basal ganglia processes non-noxious and noxious somatosensory information, such as nociception(67).
An Hypothesis for CFS, Fibromyalgia, irritable bowel syndrome, panic disorder, hyperventilation, and potentially other FSS which may fit the hypothesis:
In the explanation of CFS, I have essentially hypothesised that patients initially suffer a traumatic learning experience involving fear conditioning, which subsequently leads to a conditioned fear response. Traditionally these mechanisms have been mainly applied to external stimuli, such as in PTSD, but I have theorised that they may also apply to the internal bodily environment, as has been frequently theorised for panic disorder and tinnitus. However, I feel that these illnesses should not be classed together with other traditional psychiatric disorders such as phobias, because the underlying mechanisms and patient treatments are sufficiently different to warrant a new class of illness. The tag of FSS may be incorrect. I prefer calling them NEUROPHYSIOLOGICAL CONDITIONED SYNDROMES (NCS) for want of a better term, and hence will refer to them like this below. Panic disorder would also come under the heading of NCS. I believe that CFS is a NCS. I suspect that Fibromyalgia, Irritable Bowel Syndrome, and tension headaches may be NCS, and I also suspect that other illnesses previously attributed to FSS may fit into this category, and will identify these after further research.
Below I outline a possible common etiology for NCS. I want to make it clear that this theory is particularly hypothetical, and has not been researched to the same extent as for the explanation for CFS. I am simply applying the CFS theory to other syndromes to stimulate debate.
It would be impossible to do justice to such a complex mechanism here, but I shall attempt to explain the main concepts.
Predisposing Factors for NCS: There are several predisposing factors for developing NCS, and these may include being prone to anxiety or stress (as in panic disorder), introspection, and being exposed to long term stress. There may be other factors as yet unidentified such as genetic factors.
Precipitating Factors for NCS: The NCS develops during a traumatic learning period. During this time, the person either has to deal with a particularly severe external stress, or is still experiencing general long-term stress. Note that the external stress does not in itself have to be seen as stressful by observers – what counts is the patient’s subjective perception of what is stressful. At the same time, the person suffers a severe internal bodily stressor, which may mimic the eventual syndrome which is developed. For instance, in CFS, a person develops a virus, in which a patient develops many of the symptoms that are fairly similar to CFS. In Irritable Bowel Syndrome, the patient may have developed a mild stomach bug or indigestion, or experienced food poisoning. In fact, with IBS, many patients recall a specific onset related either to stress, specific stomach complaints, or to both(68). Some patients may not recall a specific onset, as learning in the amygdala occurs unconsciously without the conscious mind necessarily being aware of its existence.
Wolpe (1988)(69), who has developed the most complete conditioning theory of panic disorder, argues that the "first" panic attack seems to be the result of experiencing the consequences of hyperventilation, which may be due to toxic chemicals in the workplace, recreational drugs like amphetamines, or even as a direct result of severe stress. For instance, he found that severe marital conflict occurred during the first year before the first panic attack in 84% of patients surveyed. Once the first panic attack has occurred, any stimuli which happened to be present at the time will become conditioned fear stimuli.
On a highly hypothetical basis, I propose here that tension headaches may fall under the banner of NCS. The first severe headache may have occurred during a particularly stressful event, or may be the result of an illness such as a virus (which patients may not recall). Once the first severe headache has occurred, as above, any stimuli which happened to be present at the time can or may become conditioned fear stimuli.
In summary, during the traumatic learning period, the patient experiences external stress, and internal stress, which mimics the eventual syndrome which is developed. The internal stressor during this period may be a symptom itself of the prolonged stress response. For instance, patients who suffer long term stress tend to develop stomach problems, and sometimes symptoms which mimic CFS. The internal stress could also be as a result of an external bodily stressor such as a virus, or food poisoning. The combination of severe external stress and bodily stress may be enough to ingrain the fear of the physical symptoms of the NCS into the amygdala.
The traumatic learning experience leaves its legacy on the amygdala. The amygdala is now trained to watch out for the symptoms of the particular NCS, and whenever they are detected, it is programmed to unleash its sympathetic reactions. This sympathetic outflow has the ability to produce the symptoms of each NCS. IBS may be caused by autonomic dysfunction resulting from sympathetic over-activity which affects the enteric nervous system. Also, muscle tension may cause spasms in the muscles of the gut, as well as the diversion of resources away from the digestive system as a whole. Headaches may be caused by the tightening of muscle groups in the head and neck during the stress response.
What may actually link all the NCS, is that they can be brought on by sympathetic overactivity, as well as other pathways that the amygdala uses to signal the "fight or flight" response. The particular NCS that a person has will then depend on which particular physical symptom of acute stress a person has a conditioned fear of, and focuses on. This explains why many FSS seem to share some of the same symptoms, but that the patient seems to concentrate and experience a particular type of symptom relevant to their NCS.
Patients may actually have a particular NCS because of a combination of three reasons:
"Stress Signature": When traumatic fear conditioning occurs, emotional memories of associated events are involved. In this case, there are two co-curing events, which are the psychological and physiological responses to stress, and the bodily response to a physiological stressor. In CFS for instance, the two co-curing events are the external severe stress and the body’s immune response to the viral illness. During the traumatic learning experience, the neurones responsible for these two effects are firing simultaneously for a period of time, under conditions which encourage neurological "learning" (activation of NMDA receptors). This increases the synaptic strength between these co-triggered neurones, causing "long term potentiation", so that the co-curing events become associated with each other in the future forming a "cell assembly", which is particularly resistant to extinction. An "emotional memory" of a physiological process has been produced, which is then stored in the amygdala and the hippocampus.
Therefore, the traumatic learning experience results in any feelings of psychological stress or relevant physiological stressors becoming conditioned stimuli, and the tailored autonomic response, or stress signature becomes the conditioned response. (In Ader and Cohen’s rat experiments described in section 1, immune suppression is the conditioned response, and sweet water has become a conditioned stimuli(70)). In the future, a specific autonomic response is elicited causing the NCS, and this conditioned autonomic response is triggered in response to stress. In irritable bowel syndrome, studies have shown that there are abnormalities in the electrical patterns in the gut which seem to occur when IBS patients experience even mild stress(71). IBS patients show a greater change in colonic and ileal motility in response to stress leading to the conclusion that IBS sufferers have hyper-reactive bowels which over-react to any kind of stress(72). In CFS, there is some evidence of immune activation in response to a virus which may not actually be present.
The formation of particular unique "cell assemblies" is facilitated by the fact that the amygdala has the ability to affect the workings of the autonomic nervous system very accurately via high levels of interconnectivity with the hypothalamus. Autonomic changes can be linked to individual types of emotions, and as Joseph Ledoux comments, the different organs of the viscera (and the immune system) can be controlled selectively. The amygdala also projects directly to the reticulopontis caudalis, the central gray, and the corpus striatum, which control muscle tension in all the muscles of the body. Therefore, as mentioned in the section 2 (Explanation of Symptoms), it is not inconceivable that autonomic activity and muscle tension may be concentrated in the areas of the body where the symptoms originate from, as a result of "emotional learning".
Symptom Amplification: The amygdala arouses the thalamus and the sensory cortex, and orders them to concentrate all their energies on amplifying the signals from the body which relate to the particular learned fear. So CFS patients will consciously and unconsciously body-watch for virtually all the short term and long term symptoms of a chronic stress response (which explains the severity of symptoms). IBS patients will watch for any pain in the stomach, or any signal relating to the digestive system. Tension headache sufferers will become sensitive to any negative signals arising from the head or neck.
Secondary Complications: The effect of 1 may actually cause secondary abnormalities and diseases in the particular systems that are feared. With CFS, I commented that a prolonged stress response can become toxic to the body. With any NCS, if the stress response occurs chronically, there are many secondary illnesses or bodily changes which may result, which may be interpreted as the original cause of the NCS. For instance, with CFS, patients seem to share some of the same symptoms, but there are many new symptoms which appear without warning. This sometimes give rise to the hypothesis that CFS is actually made up of a number of different syndromes, each with their own particular set of symptoms, whereas it could actually be a product of an individuals particular bodily vulnerabilities. I am therefore hypothesising that secondary physical diseases and abnormalities may occur in some patients with a NCS.
Figure 8 below shows the development and perpetuation of a NCS:
Perpetuating Factors: Once the unconscious fear is ingrained, there are four potential pathways via which the amygdala’s reaction can be triggered, as numbered 1-4 on the diagram above:
External Mild or Severe Stress: If a patient experiences some mild external stress in the future, the sympathetic nervous system is mildly aroused. I emphasise the mild, because the relapse of NCS symptoms can occur very easily. The physical and emotional symptoms arising from stress have become internal conditioned stimuli, as the "first" experience of symptoms of NCS occurred during stress. The amygdala senses the mild bodily arousal and is reminded, through explicit memories from the hippocampus and other memory centres, that this physical and emotional arousal tends to occur when the NCS is present, suggesting that the NCS may be coming on. The amygdala, fearing the onset of the NCS, sends alarm signals to the cortex, and if the patient is even mildly afraid or concerned about the NCS, then the amygdala will receive a confirmation response that the NCS is to be feared. The amygdala then begins its alarm signals all over the brain and body via numerous pathways, and elicits the specific conditioned response or "stress signature" via the autonomic nervous system.
This triggering mechanism has an interesting consequence for the study of functional somatic syndromes, and the study of "somatisation" disorders. Somatisation disorders can be defined as the expression of personal and social distress in an idiom of bodily complaints with medical help seeking. An alternative way of viewing this process is to hypothesise that external stress increases the excitatory level of the amygdala, which re-ignites hidden unconscious fears about bodily sensations. These sensations then perpetuate via processes described such as the stress signature, whereas the practitioner may solely blame the external stress for continued symptom expression.
Innocuous Symptoms Mimicking the NCS: There are many external triggers which can mimic the mild symptoms of the NCS. Patients have become hypersensitive to all bodily sensations associated with the NCS. In IBS, there are certain food types which can be more difficult to digest, or which can agitate the gut such as spicy foods. As a precursor to headaches, slight tension in the head can occur and can be caused by a variety of factors. These normal everyday bodily sensations are conditioned stimuli detected by the amygdala and the sensory cortex, and taken as evidence as return of the NCS. The sympathetic response is initiated which aggravates those symptoms and makes them seem even more noxious and troublesome.
External Conditioned Stimuli: The amygdala’s reaction may be mediated by a third pathway. There may be certain situations, places, sensations, or events which become associated with the worse symptoms of the NCS. For instance, some patients claim that their symptoms are worse when they travel in a car or consume certain food groups. Simply being in a situation which reminds the memory centres of the illness consciously and unconsciously, is enough to arouse the system described in 1.
Thoughts, Memories or Fears of NCS Symptoms Returning: The patient may consciously think about the return of the symptoms of the NCS. Because of the detrimental effects the illness or symptoms are having on a person’s life, they may monitor the body to check if the symptoms are present. These cortical cognitions may then serve as retrieval cues for explicit memories of past experiences when the NCS symptoms occurred. The combination of neocortical thoughts, and memories from the hippocampus, may be enough in itself to trigger the amygdala, and this mechanism has been hypothesised for panic disorder by Ledoux. Many people comment that "If you think you are going to get ill, you will get ill!". In some instances, there may be some truth in this. Simply preparing for a symptom in anticipatory fear may unleash a conditioned sympathetic response (stress signature) which makes it a self-fulfilling prophecy.
In some cases, even an anticipatory belief that symptoms will occur may be enough to trigger the response, even if the fear emotion is not present. Many commentators have pointed out that patients tend to experience what they expect to experience, because of the model of the body that the mind holds. I believe that the central process is different. Conscious cognitions about a anticipated physical state (without particular fear) arouse memory systems, which subsequently stimulate conditioned responses making the physical state a self-fulfilling prophecy. Cell assemblies have a role to play in linking conditioned memories, responses and stress signatures together. The placebo effect may also work via these pathways, where a strong belief in a different physical state halts the above process.
As with the explanation for the CFS vicious circle, once the symptoms are triggered, the system perpetuates like a runaway train. The amygdala arouses itself, making it even more sensitive to internal and external stimuli. The amygdala drives cortical and thalamic networks into a state of hypersensitivity, so that even more signals enter the amygdala about the "dangerous" physical symptoms. The amygdala sometimes can arrest the cortex, so a person feels as though he or she is "getting carried along" with the illness, with little opportunity for control or relaxation. And every time this system is initiated, the fear is ingrained further into the amygdala and the hippocampus, storing up implicit and explicit memories of the emotional experience for future retrieval.
The entire system described for perpetuation can occur in a matter of seconds, and yet the patient can be utterly oblivious to it. The only cognitions which may occur include the feelings of anxiety which may accompany a NCS. I myself have experienced these cycles for years, without realising what was happening. Once the model is understood by a patient, they can set about reversing the vicious circle.
What parameters affecting the severity of the NCS experience for the patient are listed in the introduction to section 2.
Characteristics of NCS which may have categorised them as Functional Somatic Syndromes:
Below I identify some of the characteristics of NCS which are shared with Functional Somatic Syndromes, and which may have previously categorised them as FSS (in my view incorrectly):
1. Women are disproportionately affected by NCS/FSS, because a predisposing factor for NCS is being prone to anxiety. In general, women tend to be more prone to anxiety and other psychiatric disorders than men, which may be as a result of various hormonal factors.
2. There is an overlap of symptoms across the NCS/FSS, because they are all generally caused by an overactive stress response.
3. Stress seems to make the syndromes worse. This is because the stress response acts as a trigger for the memories of the syndrome as outlined above.
4. Symptom attribution to serious illness seems to worsen outcome in FSS. This is the same for NCS, because if the patient suspects that he or she has a serious illness, then the symptoms are seen as more dangerous, and so an exaggerated fear response is initiated. However, attributing the symptoms to a non-serious illness does not mean they will disappear. The amygdala is sensitised to the symptoms in all cases.
Barsky and Borus(73), who are advocates of the FSS approach, comment that FSS seem to be prevalent in healthy, non-patient populations. This is hardly surprising if some FSS are actually NCS, given that most people suffer from stress at some point in their lives. In fact, the symptoms which Barsky and Borus describe as FSS are very similar to those experienced in acute stress:
"Symptoms common to the functional somatic syndromes include fatigue; weakness; sleep difficulties; headache; muscle aches and joint pain; problems with memory, attention, and concentration; nausea and other gastrointestinal symptoms; anxiety; depression; irritability; palpitations and "racing heart"; shortness of breath; dizziness or light-headedness; sore throat; and dry mouth".
The difference between healthy populations and NCS patients is that NCS patients have developed a unconscious conditioned fear of these symptoms, so much so that the symptoms perpetuate chronically.
Borus and Barsky also comment that:
"Ambiguous sensations that were previously ignored, dismissed as innocuous, or never consciously noticed are now interpreted as further evidence of the presence of the suspected disease. A self-validating and self-perpetuating cycle of symptom amplification and disease conviction ensues: The suspicion of disease heightens bodily awareness, symptom perception, and distress, and these, in turn, reinforce the belief that the sufferer is sick".
Whilst I agree about the symptom amplification, I challenge the psycho-social process at work that Borus and Barsky describe. Their theory does not account for many physiological abnormalities which have been observed in patients, and instead they underline the belief mechanisms as central to the perpetuation process. The symptom amplification may instead be due to conditioned fear, and the perpetuation of symptoms is due to a defined pathophysiological process producing real noxious symptoms, as I describe throughout this paper.
7. Cognitive Behavioural Therapy and graded exercise has been shown to help in some of the cases of supposed FSS. As I have explained previously, CBT enables a person to learn how to cope with everyday life despite the symptoms. This inevitably reduces some fear associated with the illness, and so symptoms moderate. However, this in no way means that the symptoms are not real, or that they will completely disappear from this approach.
Finally, Barsky and Borus argue that
"Suggestion amplifies and maintains symptoms because humans tend to perceive what they expect to perceive. The cognitive processing of current bodily sensation is guided by our expectations of what we will experience next".
I hypothesise here that, as with the diagram for the NCS above, that symptoms of NCS can be brought on simply by thinking about what will happen next, as in perpetuating factor number 4 in the diagram above. Conscious cognitions about symptoms can in themselves trigger the symptoms via memories and the sympathetic response, but the patient does not necessarily have conscious control over the unconscious pathophysiological process. Symptom amplification is only part of the story, and incorrect cognitive processing may be a secondary factor in the patient’s experience of the illness.
Overall, the proponents of FSS point to studies showing that illnesses can perpetuate simply because of factors such as the sick role, symptom attribution, and suggestion. Although highly theoretical at this stage, I believe that these are secondary factors, and that they all operate through the universal gateway of conditioned fear or sensitisation of the NCS illness. FSS posits that belief in an illness perpetuates an illness. I posit that conditioned fear of an illness can perpetuate an illness, causing observable physiological changes via a conditioned sympathetic outpouring or "stress signature". Whilst FSS concentrates on psychological aspects, and opponents of FSS underline the observed physiological changes, the theory in this paper embraces both aspects into a neurophysiological explanation. I believe that some of the illnesses attributed to FSS should be researched further, to see if they fit under the heading of Neurophysiological Conditioned Syndromes (e.g. migraines, Gulf War Syndrome, multiple chemical sensitivity, IBS, PMS, etc), as the implications for treatment and recovery may well prove to be far more useful.
7. NEXT STEPS FOR CFS
Whilst I appreciate that the explanation is highly speculative in some areas, I believe that they are worthy of further research. This is difficult, given that much of the perpetuating process occurs unconsciously in the brain. I therefore propose a research study based on the programme of recovery that I am in the process of developing for patients. It involves a process of unconscious reprogramming so that conscious control via the cortex can override and control the amygdala. The approach is quite different from traditional interventions for psychiatric disorders, given the enigmatic neurophysiological nature of CFS.
If you are aware of any institutions that may be interested in conducting or funding research, or may be interested yourselves, then please contact me at firstname.lastname@example.org
Fear Pathways as Mediated by the Amygdala. The stress/fear response is mediated by an almond shaped brain structure in the limbic region called the "amygdala", and the diagrams below illustrate the wide-ranging effects on the body when it is triggered.
The amygdala has two roles. Firstly it determines whether immediately present stimuli pose a threat to well-being. Secondly, if the stimuli is negative, the amygdala must "orchestrate behaviourial responses and associated autonomic and endocrine reactions that increase the likelihood of surviving that danger"(74). The amygdala receives projections from all over the brain, and acts as the hub for the fear response based on the information it receives and collates(75):
The amygdala can initiate a stress/fear response via a number of projections to the brain and the body (76)
Below is a diagram illustrating one of the stress pathways, involving the Hypothalamic-Pituitary-Adrenal axis(77)
HPA Stress Pathway:
"Stimuli associated with danger activate the amygdala. By way of pathways from the amygdala to the paraventricular nucleus of the hypothalamus (PVN Hypo), corticotrophin-releasing factor (CRF) is sent to the pituitary gland, which, in turn, releases adrenocorticotrophic hormone (ACTH) into the bloodstream. ACTH then acts on the adrenal cortex, causing it to release stress hormones into the bloodstream. These hormones freely travel from the blood into the brain, where they bind to specialised receptors on neurones in regions of the hippocampus and amygdala, as well as other regions. Through the hippocampus, the stress hormones inhibit the further release of CRF from the PVN. However, as long as the emotional stimulus is present, the amygdala will attempt to cause PVN to release CRF. The balance between the excitatory inputs (+) from the amygdala and the inhibitory inputs (-) from the hippocampus to PVN determines how much CRF, ACTH, and ultimately cortisol will be released"(78).
Traditionally "emotional stimuli" have been interpreted as originating from the external world. However, throughout this paper I have argued that any physical symptoms that a person experiences are also emotional stimuli, given that illness has the ability to elicit a fear reaction, or at least concern. Anxiety about physical symptoms can drive the HPA axis.
The amygdala becomes "trigger happy", as it becomes used to stimulating the stress response, and monitoring the internal and external environment. The body moves into a state similar to one associated with anxiety states: SENSITISATION. Emotional stimuli, whether they be physical symptoms or external events, enter the hyper-vigilant thalamus and sensory cortex, and the events are interpreted. The stimuli are magnified due to sensitisation, and the amygdala is also sensitised due to continual arousal (represented by the "slider control" in figure 12, which predicts the level of amygdala sensitisation). The amygdala unleashes a sympathetic reaction which is not in keeping with the actual danger present, and the chronic pathophysiological effects of a psychoneurological process ensue. Recovery in the future may be held back by on-going psychological and environmental stressors.
It is worth noting here that although I have labelled the "slider control" as the amygdala, it can apply to areas of the conscious emotional brain, because the amygdala is constantly signalling and arresting the conscious mind with the emotions of anxiety.
Sensitisation is also seen in anxiety states. However there is an importance difference between an anxiety state and CFS. Anxiety state sufferers become over-fearful of their external environment or a particular external stimuli (interestingly they also tend to suffer from some chronic fatigue). CFS sufferers are concerned about internal stimuli (i.e. bodily symptoms), and their experience tends to be chronic, because it is constant; the symptoms are continually present, and patients cannot engage in avoidance to the same extent as anxiety patients.
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