SUMMARY: I propose here a novel hypothesis for Chronic Fatigue Syndrome (ME/CFS). ME/CFS may be a neurophysiological disorder focusing on the amygdala. During a "traumatic" neurological event often involving acute psychological stress combined with a viral infection or other chemical or physiological stressor, a conditioned network or "cell assembly" may be created in the amygdala. The unconscious amygdala may become conditioned to be chronically sensitised to negative symptoms arising from the body. Negative signals from the viscera or physiological, chemical and dietary stressors, become conditioned stimuli, and the conditioned response is a chronic sympathetic outpouring from the amygdala via various brain pathways including the hypothalamus.

This cell assembly then produces the ME/CFS vicious circle, where an unconscious negative reaction to symptoms causes immune reactivation/dysfunction, chronic sympathetic stimulation leading to sympathetic dysfunction, mental and physical exhaustion, and a host of other distressing symptoms and secondary complications. And these are exactly the symptoms that the amygdala and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle. Recovery from ME/CFS may involve projections from the medial prefrontal cortex to the amygdala, to control the amygdala's expressions.

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I shall firstly discuss predisposing, precipitating, and perpetuating factors involved in the possible etiology of chronic fatigue syndrome (ME/CFS), followed by the patient's experience of the illness. Finally, I shall look at a suggested explanation for the symptoms of ME/CFS.

Much of the literature identifies personality characteristics pertinent to ME/CFS. I would argue that whilst anyone can develop ME/CFS, there is a tendency for patients to be more prone to stress and anxiety. Certain 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.

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 ME/CFS¹ . The combination of personality, long term elevated stress levels, and genetics are risk factors for ME/CFS, but the development of ME/CFS may tend to require a combination of precipitating factors.

Many ME/CFS patients generally recall a period of acute 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.

About a quarter of patients develop ME/CFS without recalling a specific viral trigger. In fact, for some the onset is related to inoculations, exposure to pesticides, toxins, etc. However, ME/CFS may not necessarily require a virus to trigger the illness. Any physical or chemical stressor on the body which occurs while the mind is experiencing acute psychological stress, may potentially trigger ME/CFS.

Recent research into the neuroscience of emotion by Professor Joseph Ledoux² 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 . During the period of stress before the onset of the illness therefore, I hypothesise that the amygdala is highly aroused (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:

1. The symptoms of an overactive sympathetic nervous system in response to psychological stress
2. The effects of a viral infection acting on a weakened immune system
3. The effects of an active immune system (which itself produces symptoms of general weakness)
4. 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 in heterogeneous subgroups of ME/CFS patients which proceed. However, I believe that there is a significant subset of ME/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 sub-structure) in the processing of noxious (and non-noxious) somatosensory processing, including nociception and pain (Chudler and Dong 1995⁵ ).

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 comments⁶ ,

"…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 arousal during a period of anxiety, it may be prone to "learning" new sensitivities. The limbic structures gradually attribute 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 through conscious thought processes described below. The amygdala is becoming conditioned to implicitly be highly sensitised to any negative physical symptoms arising from the body. The immune system is less effective in dealing with the virus during stress, and hence the episode of "Pavlovian fear conditioning" occurs over a prolonged period of time. The amygdala has been strongly implicated in unconscious fear conditioning which can occur in phobias and other anxiety disorders⁷ .

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 full health in order to deal 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 stimuli⁸ . 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 amygdale via the viscera, 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. Activation of NMDA receptors is 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). As above, the amygdala has become conditioned to believe that negative symptoms from the viscera are "dangerous". 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. Figure 1 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 in Figure 1 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 patients, the amygdala's expressions can only be regulated rather than fully extinguished¹³ . Complete extinction resistant plasticity may represent extreme long-term morbidity.

On the right in Figure 1, 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 immuno-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.

Once sensitisation or "fear conditioning" has occurred, a 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 thalamo-amygdala pathway takes on the role of monitoring the body for these negative stimuli, and there is consistent evidence of increased blood flow in the thalamus¹⁵ . 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 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. Figure 2 illustrates the ME/CFS vicious circle:

Once any symptoms of ME/CFS 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 sensitisation 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 and secondary illnesses 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 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 ME/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, given the excitatory state of the amygdala, 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 sensitisation to 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 system¹⁶, 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 . 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.

Patients are far more sophisticated in their mental approach to their illness than this hypothesis 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 few 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 not necessarily 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 concern or worry about the symptoms. Figure 3 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 ME/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. Figure 4, 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 hippocampus¹⁷ . 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 outpourings¹⁸ , and the more anxious a patient is about the symptoms, the stronger the response will be. Interestingly, there is evidence in studies showing that patients may acknowledge persistent stress as a possible cause of on-going fatigue¹⁹ .

Previously conditioned fear responses have mainly been thought of in terms of external stimuli, with a notable exceptions being panic disorder^20,21 , 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

The conditioned fear mechanism described is not to be confused with

A fear conditioning model for tinnitus is now acknowledged in the literature as a likely etiology^22,23 . Although tinnitus is a very different physiological illness to ME/CFS, the evidence points to the ease with which conditioned sensitisation can occur in response to bodily signals.

Several commentators have argued that a chronic stress response could act as a final common pathway for ME/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 ME/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 about a patient's state of health 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 rhythms²⁴ .

Whilst the symptomatology may exhibit some similarities to that observed in major affective disorder, physiological morbidity may be far worse, given that ME/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. This may characterise ME/CFS as a unique illness in terms of patient experiences, e.g. secondary allergies and sensitivities, with immune system abnormalities.

The literature on ME/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 (e.g. 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 natural killer cell activity in ME/CFS patients, but this has also been linked to a person's reaction to emotional stress²⁵ . These co-occurring processes unique to each patient may help to explain the immune abnormalities observed.

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 Disorder²⁶, which is another chronic stress disorder . 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 also have a function in stimulating aspects of the immune system.

Intolerance to alcohol has often been cited as a characteristic marker of ME/CFS. Much medical research demonstrates that alcohol actually induces the stress response by stimulating hormone release via the hypothalamus^27,28. This is exactly the response which the amygdala is conditioned to respond to, causing further symptoms. Furthermore, in ME/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 leading to fatigue. 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 contraction²⁹ , 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.

A 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 experienced³⁰ .

Generalised anxiety and depression may be overlapping psychiatric conditions which occur in ME/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 hippocampus³¹ .Therefore, the formation of new memories in the hippocampus may be inhibited³² . 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 ME/CFS will be recalled, taking precedence over other less relevant strands of thought.

Recovery is likely to involve two distinct processes. Firstly symptoms resulting from secondary illnesses such as digestive problems need to be addressed initially. Once symptoms have moderated, further recovery may involve the amygdala's expression of danger becoming regulated by the cortex, or more specifically the medial prefrontal cortex, in a process called "extinction". It may be particularly difficult to regulate ingrained fear of stimuli which are continually present (i.e. the symptoms of ME/CFS), and patients cannot simply be told to try and not think about or worry about symptoms at a cognitive level, because the cortex is continually arrested and fear processing mainly occurs unconsciously. New therapies may be required which may be distinct to received wisdom in this area, and further research is required to test the validity of new therapies resulting from this hypothesis.

1. Hudson J.I., Goldenberg D.L., Pope H.G., Keck P.E., Schlesinger L. (1992) Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 92(4): 363-367

2. Ledoux, J.(1998), The Emotional Brain (Pheonix), ch6-9

3. Ledoux, J. Cognitive-Emotional Interactions P139 in R.D. Lane and L. Nadel (eds) (2000), "Cognitive Neuroscience of Emotion", (Oxford University Press)

4. Ketterer, T.A. et al (1996). Anterior paralimbic meditation of procaine-induced emotional and psychosensory experiences. Archives of General Psychiatary, 53, 59-69

5. Chudler EH, Dong WK. (1995) The Role of the basal ganglia in nociception and pain. Pain 60: 3-38

6. Ledoux, J. (1998) The Emotional Brain (Weidenfeld & Nicolson) p234

7. Ledoux, J. (1998), The Emotional Brain (Pheonix) chapters 6-9

8. Ledoux, J. Cognitive Emotional Interactions P145 in R.D. Lane and L. Nadel (eds) (2000), "Cognitive Neuroscience of Emotion", (Oxford University Press)

9. McGaugh, J.L., Introini-Collision, I.B., Cahill, L.F., Castellano, C., Dalmaz, C., Parent, M.B., and Williams, C.L. (1993). Neuromodulatory systems and memory storage: Role of the Amygdala. Behavioural Brain Research 58, 81-90. See also Ledoux, J. (1998) The Emotional Brain p208

10. Ledoux, J. (1998) The Emotional Brain (Weidenfeld & Nicolson) p251-253

11. Hebb D.O. (1949) The Organisation of Behaviour (New York: Wiley)

12. Ledoux, J. (1998), The Emotional Brain (Pheonix) p251-3

13. Ledoux, J. (1998), The Emotional Brain (Pheonix) p250-3

14. See Cohen N, Moynihan JA, Ader R (1994) Pavlovian conditioning of the immune system. Int Arch Allergy Immunol 105(2):101-6. Also Ader, R., et al., (1990) Psychoneuroimmunology, 2d ed. (San Diego: Academic Press). See also Dozier, R., W., (1998), Fear Itself, (St. Martins Press) p210.

15. MacHale, SM., Lawrie, SM., Cavanagh, JTO., Glabus, MF., Murray, CL., Ebmeier, KP and Goodwin, GM. (2000) Cerebral perfusion in chronic fatigue syndrome and depression. British Journal of Psychiatry 176, 550-556.

16. Rabin, B. (1999), Stress, Immune Function and Health, (Wiley-Liss)

17. Diagram reproduced by the kind permission of Weidenfeld and Nicolson from Ledoux, J (1998) The Emotional Brain p204

18. Ledoux, J. (1998) The Emotional Brain p212-213

19. Friedberg F, Dechene L, McKenzie MJ 2nd, Fontanetta R, (2000) Symptom patterns in long-duration chronic fatigue syndrome. J Psychosom Res 48(1):59-68

20. Ledoux, J. (1998) The Emotional Brain p260-261

21. Wolpe, J (1988), Panic Disorder: A product of classical conditioning. Behaviour Research and Therapy 26, 441-50

22. Kevin Hogan (1998), Tinnitus: Turning the Volume Down. (Network 3000 Publishing Company)

23. Jastreboff, P.J. (1990) Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci.Res:221-254

Williams G, Pirmohamed J, Minors D, Waterhouse J, Buchan I, Arendt J, Edwards RH (1996) Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome. Clin Physiol 16(4):327-37.

25. Whiteside TL, Friberg D (1998) Natural killer cells and natural killer cell activity in chronic fatigue syndrome. Am J Med 28;105(3A):27S-34S

26. Grillon C, Southwick SM, Charney DS (1996)The psychobiological basis of posttraumatic stress disorder. Mol Psychiatry 1(4):278-97. See also Wessely, Hotopf and Sharpe (1998), Chronic Fatigue and its Syndromes (Oxford University Press) p260-1

27. Tsigos, C., & Chrousos, G.P. (1995) The neuroendocrinology of the stress response. In: Hunt, W., & Zakhari, S., eds. Stress, Gender, and Alcohol-Seeking Behavior. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 29. Bethesda, MD: the Institute.

28. Eskay, R.L.; Chautard, T.; Torda, T.; & Hwang, D. (1993)The effects of alcohol on selected regulatory aspects of the stress axis. In: Zakhari, S., ed. Alcohol and the Endocrine System. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 23. Bethesda, MD

29. Kavelaars, A., Kuis, W., Knook, L., Sinnema, G and Heijnen, CJ. (2000) Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. Journal of Clinical Endocrinology and Metabolism 85, 2, 692-696.

30. Streeten D.H., Thomas D., Bell D.S. (2000) The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci 320(1):1-8

31. Diamond, D.M., and Rose, G. (1994). Stress impairs LTP and hippocampal-dependent memory. Annals of the New York Academy of Sciences 746, 411-14

32. Ledoux, J., (1998) The Emotional Brain (Weidenfeld & Nicolson) p240-243 For further information on the new DVD Recovery programme for ME/CFS, please visit:

Gupta, A (2009) - Updates to The Amygdala Conditioning Hypothesis for

Chronic Fatigue Syndrome (ME/CFS) - A Short Report  (DRAFT)

Summary of 2002 Paper

In my 2002 paper (1), it was hypothesised that ME/CFS is a neurobiological condition caused by a conditioned trauma in the amygdala following an acute viral, bacterial or physical insult, combined with psycho-social distress. Once the classical and operant conditioning has occurred, the amygdala in association with the insula, becomes hyper-sensitive to signals from both the body and external stimuli, and magnifies both the extent and frequency of the incoming stimuli in the sensory thalamus and cortex. This then produces the ME/CFS vicious circle, where an unconscious negative reaction to symptoms causes chronic stimulation of the HPA axis, immune reactivation/dysfunction, chronic sympathetic stimulation leading to autonomic dysfunction, mental and physical exhaustion, and a host of other distressing symptoms and secondary complications. And these are exactly the symptoms that the amygdala and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle. Recovery from ME/CFS may involve projections from the medial prefrontal cortex to the amygdala, to control the amygdala’s expressions.

Since the publication of this paper, there have been a number of subsequent findings in patients with ME/CFS, and this report seeks to show how these findings may be congruent with, and indeed offer further support to, the original hypothesis.

1. Genetic Pre-disposition to ME/CFS

So far there have been a few genes which have been implicated as representing a genetic pre-disposition to contracting ME/CFS. As an example, Lloyd et al (2008) found that certain cytokine polymorphisms significantly impacted on the severity and length of both the illness and of post-infective fatigue (2). It could be hypothesised that certain genes may increase the intensity and length of both the initial illness and subsequent post-infective fatigue, thereby promoting the likelihood of conditioning effects in the amygdala and related brain structures involved in conditioning. In conceptual terms, the more "traumatic" and intense the experience for the body and the longer it lasts, the more opportunity there is for classical and operant conditioning processes. This is true of PTSD, another conditioning disorder, where the amygdala is heavily implicated in the literature as mediating the responses. Although PTSD is a psychological disorder, the amygdala hypothesis postulates that there is no reason why the same mechanisms of unconscious conditioning cannot occur in response to intense physical threats (viral, bacterial, physiological) as well as psychological ones.

2. Gene Expression in ME/CFS

Ground breaking work by Kerr et al (3,4) has shown that there is altered gene expression in 88 genes of ME/CFS patients compared to controls, with 85 being up-regulated, and 3 down-regulated. Furthermore, clustering analysis indicates that there are potentially 7 genomic subtypes which tally with differences in SF-36 and illness severity scores. It was noted that out of the 7 genomic subtypes, 3 groups had the highest level of symptom severity correlating with scores for anxiety and depression. Finally within each genomic subtype, it seems that there were differing levels of antibodies relating to both EBV and enteroviruses.

In Gupta 2002 (1), in addition to chronic arousal of the HPA axis and sympathetic systems, it is hypothesised that during the trauma, a "stress signature" effect occurs where aspects of the immune system are also re-triggered chronically after onset. This refers to conditioning in the immune system, and recent neurobiological research is showing that the rat model of immune system conditioning can also occur in humans (5). It is therefore hypothesised that these abnormal gene expressions in ME/CFS mean that the body is engaged in similar responses after the initial onset, to those that were engaged during the initial acute phase of the illness. The body may not have fully switched off endocrine and immune responses that were triggered by the initial sensitising event, even if the original viral insult is no longer active in the body.

In rats, the amygdala's involvement in conditioned immune responses has recently been confirmed, in association with the insular cortex and the hypothalamus (6). Rats were given the immunosuppressive drug cyclosporine A, together with water sweetened with saccharin. Through repeated applications, the rats associated the cyclosporine with the sweet water so that later on, feeding them the sweet water alone weakened their immune systems (the opposite effect has also been demonstrated where immune re-activation can occur as a conditioned response to sweet water following repeated exposure to a virus with sweet water). In this system, the unconditioned stimulus is the cyclosporine, and the conditioned stimulus is the sweet water.

Then in the 2005 study (6), the brains of these rats were selectively damaged at various points during the cyclosporine experiment to identify the roles of certain brain structures. The study found that rats with a damaged insular cortex displayed no conditioned immune responses no matter when the lesion was made. The insular cortex modulates sensory experiences and information about the physiological state of the body, so if this is damaged at any point, then no sensory input is received to create or modulate the conditioned reaction. If the amygdala was damaged during the first phase of conditioning, then no conditioning occurred at all, indicating that the amygdala governs the input of visceral information including information about the immune system during conditioning; it may also decide whether a particular stimulus is worthy of a conditioned response, i.e. whether the experience is traumatic enough to warrant conditioning. Interestingly, if the amygdala is damaged after conditioning has already happened, then the conditioned immune response still occurs. This would mean that the conditioned "memory" for immune responses specifically, may not be stored in the amygdala, but may reside within the insular cortex, or it may indicate that after repeated cycles, the amygdala pathways are by-passed. Hypothalamic damage only has an effect after the initial conditioning, indicating that it may simply be involved in carrying out the conditioned response as an instruction from the rest of the brain, and is not involved in conditioning itself.

It is therefore hypothesised that the up-regulation of certain genes in ME/CFS may be linked to re-stimulation of both endocrine and immune responses by the amygdala, the insular cortex, and associated brain structures involved in conditioning. It is likely that the hypothalamus carries out the instructions to stimulate the HPA axis directly from the amygdala (as has been demonstrated in animal experiments (7)), as well as aspects of the immune system. Furthermore, the amygdala also projects directly to the sympathetic nervous system.

The specific conditioning response of the brain in each patient will be unique during the chronic period, and may be reflective of the specific endocrine and immune responses during the acute phase at the beginning of the illness. As mentioned, the body may not have “fully switched off” endocrine and immune responses that were triggered by the initial sensitising event, because of the traumatic nature of the experience. In evolutionary terms, the body "errs on the side of caution"; it is better to over-respond to a suspected on-going threat, than to let the guard down and allow a potentially fatal virus to take hold. As in the case of anxiety disorders, the amygdala can make mistakes, and over-protect the body in response to a non-existent threat.

What changes after neurological learning is that symptoms detected in the body by the sensory thalamus and sensory cortex become the conditioned stimulus. They become the equivalent of the sweet water in the rat experiment. And because symptoms are detected almost continuously in the body, there is almost continuous stimulation of certain systems in the body in response. This may then cause the up-regulation of certain genes which reflect the initial conditions during onset.

Finally, Kerr et al (2008) note in their conclusion that “It was particularly interesting that in the seven genomically derived subtypes there were distinct clinical syndromes, and that those which were most severe were also those with anxiety/depression…” (3). Given that the amygdala is heavily implicated in anxiety disorders, this once again tentatively links the level of anxiety to the severity of symptoms. We could surmise that the higher the levels of anxiety, the higher the severity of conditioning in the amygdala and related brain structures causing more severe symptoms.

3. Immune Reactivation/Dysfunction Causing Latent Virus Reactivation

In the previous section, it was hypothesised that the body is over-responding to perceived threats that may no longer exist, because of the traumatic nature of the original experience. This may cause secondary issues including the reactivation of latent viruses such as HHV-6. These latent viruses are commonly found in the general population.

If aspects of the immune system are being triggered inappropriately, then opportunistic latent viruses have the opportunity to flourish, causing secondary symptoms and issues. This may then be interpreted as evidence that persistent virus reactivation is the cause of ME/CFS, whereas it may simply represent an immune system which is dysfunctionally responding to the on-going needs of the body. If aspects of the immune system are inappropriately triggered, the overall effectiveness of the immune system is reduced and latent viruses can take hold. This may explain why some studies have found higher incidence of active infections in ME/CFS patients compared to controls, (although some results have been mixed).

Further evidence of this mechanism has been shown in a study by Nicholson et al (8), which looked at the presence of co-infections in ME/CFS patients versus patients with Autism Spectrum Disorders. The study found that both groups had higher incidence of multiple, systemic bacterial and viral infections compared to controls, but interestingly, both ME/CFS and Autism patients had very similar levels of active infections when compared to one another. Autism is a disorder where sustained amygdala hyperarousal is accepted as a model for partly explaining the disorder (9), so once again there is tentative support for the amygdala’s role in ME/CFS.

In the field of psychoneuroimmunology, many studies have shown that excessive sympathetic activity can have an immuno-suppressive effect on the body, thereby pointing to another pathway by which excessive sympathetic stimulation may compromise immune system effectiveness. A study by Fletcher et al (10)  seems to model this effect in ME/CFS patients. ME/CFS patients tend to show low natural killer cell cytotoxicity, (NKCC), and it is known that Neuropeptide Y (NPY) suppresses NKCC. NPY is concentrated in the sympathetic nerve endings, and following stress, is released together with adrenaline and noradrenaline. Fletcher et al’s study tested the hypothesis that elevation of NPY occurs in ME/CFS and that the elevation of NPY is associated with severity of clinical symptoms. They found that NPY was significantly associated with severity of clinical symptoms, and that NPY could be a potential bio-marker for ME/CFS.

4. Diagnostic Criteria - Why are there difficulties in accurately determining a set of diagnostic criteria?

A potential reason why it is difficult to determine a clear set of rules to diagnose ME/CFS, is because the nature of the conditioning may be unique in each patient. There are three main factors which may predict the unique symptomatology for each patient:

1. The severity of conditioning in the amygdala in the acute stage will predict pattern and severity of symptoms in the chronic stage, and influence the length of illness
2. The specificity of conditioning that occurs in the acute stage will reflect the specific pathology at onset - thereby determining the subsequent pattern and severity of symptoms in the chronic stage.
3. The specific timing of the conditioning will determine the resulting responses. It may also be the case that the conditioning could change over time as symptoms come and go, and as environmental factors change.

Therefore CFS, ME, Fibromyalgia, Multiple Chemical Sensitivities, Gulf War Illness, and related conditions, may represent attempts to subgroup what could be called "Amygdala Conditioned Syndromes (ACS)". These attempts are based on arbitrary diagnostic criteria, developed as a result of patient observations. The further sub-typing of ME/CFS based on genomic variance may reflect a further stage of this "chunking down" process. Even when subtypes are determined, they are often based on clustering assessments, with large amounts of cross-over between the subtypes. This does not deny the need of sub-typing, but may help explain why it is so problematic.

Recent work by Crawley et al (11) has observed the following subtypes based on primary symptomatology in paediatric ME/CFS:

1. Immune Responses (e.g. sore throats, tender lymph nodes, feeling "feverish")
2. Somatic Pain (e.g. muscle aches and pain)
2. Sensitivity (e.g. light, noise, stress)

It could be hypothesised that in the amygdala model for ME/CFS, these sub-groups simply represent the specific neuro-endocrinogical and immune responses in the brain and body present at the original sensitising event. This hypothesis is tentatively supported by work by Porter et al (12), which suggested that in research on cytokine production and expression in CFS patients, there was "a predominant bias towards pro-inflammatory pathway activation and a persistent hyperimmune response in those experiencing a viral onset". This would support the idea that in those patients with a distinct viral onset, the body continues to react in a way reflecting the original response during the onset period.

Using this concept further, Fibromyalgia may be a condition where the initial sensitising event is likely to involve physiological insults rather than viral or bacterial ones. In fact Fibromyalgia tends to be a condition precipitated by physical injuries, accidents, or previous chronic pain syndromes (e.g. back pain), and may be combined with psycho-social distress.

It should be noted, however, that many patients report that symptoms can sometimes change over time, indicating that even the conditioning may vary as the patient responds to on-going environmental stimuli.

In conclusion, although there may be heterogeneity in the symptomatology of patients, there may be homogeneity in the underlying cause.  

5. "Amygdala Retraining" as a Potential Treatment for ME/CFS?

Since 2000, I have been working on how the amygdala and associated brain structures' responses can be reconditioned or "retrained", so that the brain discontinues the hypothesised over-stimulation of various neurobiological systems. In animal studies, fear conditioning responses are "extinguished" through the creation of a "safety neurone", which projects from the medial pre-frontal cortex to the amygdala, to stop its over-zealous reactions (13). In this way, the neurobiology of extinction processes has been informing the development of these novel "neurological" amygdala retraining techniques, which are very different to existing tools such as CBT and GET. They are designed to control the amygdala's responses without the use of pharmaceuticals, and there has been an on-going refinement of these techniques based on patient feedback.

There are some interesting parallels between the neurobiology of extinction processes in fear responses, specifically Post Traumatic Stress Disorder (PTSD), and ME/CFS. In PTSD, Milad et al (2006)(14) conducted a review of human studies which indicated that “PTSD is characterized by failure of the mPFC (medial prefrontal cortex) to sufficiently inhibit the amygdala.”, and that “prefrontal areas homologous to those critical for extinction in rats are structurally and functionally deficient in patients with PTSD.” In ME/CFS, there have also been studies which have found abnormalities in the prefrontal cortex. Okada et al (2004) (15), reported an average 11.8% reduction in grey-matter volume in the bilateral prefrontal cortex in patients with ME/CFS compared to healthy controls, a volume reduction which paralleled the severity of the fatigue of the patients. Furthermore, De Lange et al (2008) (16) reported that “there is a significant increase in prefrontal grey matter volume as a result of CBT in CFS patients,” and that “the degree of success of CBT outcome was related to the degree of recovery in grey matter volume in the lateral prefrontal cortex.” Once again, these parallels do not in themselves prove the connection between the amygdala and ME/CFS, but they do tentatively support the hypothesis that ME/CFS may ultimately be a brain disorder. The prefrontal cortex in ME/CFS may be affected such that its ability to control the amygdala’s expression based on inappropriate conditioning may be compromised.

A recent clinical audit (17) of Amygdala Retraining Techniques (ART) with 33 patients revealed that over 90% of patients improved using these techniques, and two-thirds of patients reached a full recovery (or close to that mark) within one year. (The paper is scheduled to be published June 2009). There were no controls used in this study, and further randomised controlled trials are being sought to test the validity of these treatments.  

Conclusion

Research is required to further validate aspects of the Amygdala Hypothesis for ME/CFS, as well as the Amygdala Retraining Techniques (ART).

REFERENCES

1. Gupta, A. Unconscious Amygdalar Fear Conditioning in a Subset of Chronic Fatigue Syndrome Patients. Medical Hypotheses Volume 59, Issue 6, 12 November 2002, Pages 727-735



2. Vollmer-Conna U, Piraino BF, Cameron B, Davenport T, Hickie I, Wakefield D, Lloyd AR; Dubbo Infection Outcomes Study Group. Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection. Clin Infect Dis. 2008 Dec 1;47(11):1418-25.



3. Kerr JR, Burke B, Petty R, Gough J, Fear D, Mattey DL, Axford JS, Dalgleish AG, Nutt DJ. Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes. J Clin Pathol. 2008 Jun;61(6):730-9.



4. Zhang L, et al  - Microbial Infections in Eight Genomic Subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (Source: Abstract of presentation to IACFS/ME Conference, Mar 2009, Reno, Nevada)



5. Marion U, Goebel et al. Behaviourial Conditioning of Antihistamine Effects in Patients with Allergic Rhinitis. Psychotherapy and Psychosomatics, Vol 77, No.4, pages 227-234; May 2008



6. Pacheco-López G, Niemi MB, Kou W, Härting M, Fandrey J, Schedlowski M. Neural substrates for behaviorally conditioned immunosuppression in the rat. J Neurosci. 2005 Mar 2;25(9):2330-7.



7. Ledoux, J. (1998), The Emotional Brain (Pheonix) chapters 6-9



8. Nicholson G., Nicholson N., Haier J., (2009) Similarities of CFS and Autism Spectrum Disorders: Comparison of Blood Co-Infections. (Source: Abstract of presentation to IACFS/ME Conference, Mar 2009, Reno, Nevada. By Nicolson GL, Nicolson NL, Haier J. The Institute for Molecular Medicine, Huntington Beach, California, USA; Department of Surgery, University Hospital, Munster, Germany. )



9. Kleinhans NM, Johnson LC, Richards T, Mahurin R, Greenson J, Dawson G, Aylward E. Reduced Neural Habituation in the Amygdala and Social Impairments in Autism Spectrum Disorders. Am J Psychiatry. 2009 Feb 17. [Epub ahead of print]



10.  Fletcher AM, Ironson G, Antoni M, Hurwitz B, Klimas N. Neuropeptide Y (NPY): Correlates with Symptom Severity in Chronic Fatigue Syndrome. Abstract of presentation to IACFS/ME Conference, Mar 2009, Reno, Nevada


11.  Crawley E, Emond A, May M. Do Patterns of Symptoms Suggest Distinct Subtypes of Pediatric Chronic Fatigue Syndrome? (Source: Abstract of presentation to IACFS/ME Conference, Mar 2009, Reno, Nevada)



12.  Porter, N.S. Jason L.A., Herrington, J.A., Sorenson, M. The Importance of Viral vs. Non-Viral Onset Subgrouping in an ME/CFS Community Sample: Differences in Cytokine Production and Expression (Source: Abstract of presentation to IACFS/ME Conference, Mar 2009, Reno, Nevada)



13. Quirk GJ, Garcia R, González-Lima F (2006). Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry. Aug 15;60(4):337-43



14.  Milad MR, Rauch SL, Pitman RK, Quirk GJ. (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol. 2006 Jul;73(1):61-71.



15.  Okada T et al. (2004). Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. BMC Neurol 2004; 4(1): 14



16.  de Lange FP, Koers A, Kalkman JS, Bleijenberg G, Hagoort P, van de Meer JW, Toni I. (2008). Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain. 2008 Jun 28.



17.  Gupta, A. Amygdala Retraining Techniques May Improve Outcomes for Patients with Chronic Fatigue Syndrome: A Clinical Audit of Subjective Outcomes in a Small Sample (Submitted for Publication)

How XMRV Retrovirus Findings May Fit With The Amygdala Hyperarousal Model for ME/CFS

Ashok Gupta MA(Cantab), MSc | info@guptaprogramme.com | www.guptaprogramme.com

Background

Recently scientists from the Whittemore Peterson Institute (WPI) led by Dr Mikovits, claim to have discovered a retroviral link to ME/CFS (1). This pioneering research has identified a retrovirus called XMRV, shown to be active in two-thirds of patients (published), and antibodies for the virus were present in 95% of patient (unpublished research).

Mikovits' team said further research must now determine whether XMRV directly causes CFS, is just a passenger virus in the suppressed immune systems of sufferers, or a pathogen that acts in concert with other viruses that have been implicated in the disorder by previous research.

A recent study carried out by Imperial College London attempted to mimic the results of the WPI study (2). They found no evidence of XMRV infection in the blood samples of 186 patients fitting the CDC criteria. They conclude that “Although we found no evidence that XMRV is associated with CFS in the UK, this may be a result of population differences between North America and Europe regarding the general prevalence of XMRV infection, and might also explain the fact that two US groups found XMRV in prostate cancer tissue, while two European studies did not”.

The purpose of this paper is to hypothesise how these findings may fit with the Amygdala Hyperarousal Model for ME/CFS (3).

Three Potential Hypotheses

Overall there are three broad hypotheses that we can infer from the findings so far, as per Mikovits’ statement:

1. The XMRV virus directly causes the symptoms of ME/CFS
2. The XMRV virus indirectly causes ME/CFS by suppressing the immune system in concert with other pathogens, allowing opportunistic viral and bacterial infections to flourish causing the symptoms of ME/CFS
3. The XMRV virus is simply a passive opportunistic infection which establishes itself due to general suppression and dysfunction of the immune system from another source. (This general immune dysfunction may be caused by autonomic dysfunction as a result of amygdala hyperarousal).

Evaluation

There are two broad aspects to the immune system, TH1 and TH2. TH1 involves Natural Killer (NK) cells whose job it is to identify and destroy viruses. The TH2 side of the immune system involves, amongst other things, antibodies which respond to threats. There is evidence in the literature that patients with ME/CFS are “TH2” biased, i.e. the TH2 aspect of the immune system is over-activated, causing suppression of the TH1 side and high levels of inflammatory cytokines; patients have lower Natural Killer (NK) cell immunity. This bias may mean that opportunistic viruses and bacterial infections can no longer be kept at bay effectively by the TH1 side of the system.

RNase L conducts a function of holding the virus at bay until NK cells are available to eradicate the pathogen, however even the RNase L’s ability to perform this function can be compromised over time if TH2 dominates for too long. RNase L dysfunction was also reported in the prostate cancer cases of XMRV, although later research has not found a genetic link. In ME/CFS, any suspected Rnase L deficiency many simply be due to chronic TH2 dominance. If TH2 dominates for too long, it can be hypothesised that viruses such as HHV-6, Epstein Barr Virus (EBV), CMV and Parvovirus B19 can flourish, as well as bacterial infections such as mycoplasma and chlamydia pneumonia.

It has been established that the majority of neurodegenerative disease, fatiguing illnesses and neurobehavioral disease patients have chronic bacterial and viral infections. (4). In fact the WPI research claimed to have found higher levels of XMRA in “atypical” MS and Autism.

The XMRV virus may simply represent one of many viral and bacterial infections present in the blood of ME/CFS patients, and that many of these previous infections (including EBV) had been previously prematurely suspected as the root cause of ME/CFS. There have been many previous studies which have shown similar results to those found for XMRV. As an example, a 2002 study found that out of 261 patients with ME/CFS, 68.6% of patients had active mycoplasma bacterial infection present compared to 5.6% of controls, a similar result to that found for XMRV (5). A 2003 study found that 30.5% of CFS patients had active HHV-6 virus present, but only 9% of controls (6). For Chlamydia pneumoniae it was 7.8% of CFS patients compared to 1% of controls (6). For Parvovirus B19, it was detected in 40% of CFS patients but only 15% of controls (7).

What was interesting in the 2003 (6) study was that having one particular infection did not predict the likelihood of having another infection. This may indicate that the infections themselves are not cumulatively affecting the strength of the immune system to fight off opportunistic infections, but that a general immune deficiency is allowing particular types of infections to establish themselves in a pattern unique to each patient.

According to the WPI research, 4% of healthy controls had active XMRV virus in their blood (versus 67% of ME/CFS patients), which is similar to the levels of active mycoplasma infection in healthy controls. Therefore presence of active XMRV does not necessarily predict ME/CFS, and would not support the first hypothesis. If 4% of the US population were found to have active XMRV pathogen in their blood, this would amount to over 10 million people. Yet there is no evidence that XMRV causes cancer where it is active, or that it has any effect on health. It is merely a suspected link in 23% of prostate cancer cases where it is found in 1% of surrounding tissue, with no causal link established at this stage; one hypothesis is that its presence is simply linked to immune deficiency. Once again, the XMRV virus was found in 6% of benign biopsies showing that its presence may be widespread in the general USA population. Further research however is critical.

It may be that XMRV may be a localised virus to the USA, especially since a recent report from Germany (8) found that out of 589 biopsies carried out on prostate cancer cases, not a single patient showed any evidence of XMRV.  They conclude that “One possible reason for this could be a geographically restricted incidence of XMRV infections.” (8)  This seems to fit in with the findings of Imperial College London, in that no evidence of XMRV was found in the blood sample of 186 ME/CFS patients in the UK (2).

If 95% of ME/CFS patients show antibodies to XMRV (yet unpublished data from Mikovits’ team), yet only 67% show active virus, this could indicate that a third of ME/CFS patients no longer had the active XMRV virus, yet still were suffering from ME/CFS. If this is confirmed to be true, then the first hypothesis would seem redundant, and XMRV could only be the root cause of ME/CFS if the second hypothesis were correct, i.e. that XMRV had adversely affected the long term performance of the immune system. Alternatively the presence of antibodies could imply that the virus is still active in more that 67% of patients, but had not been picked up through previous methods. It would also be interesting to know the percentage of healthy controls that tested positive for XMRV antibodies which has not been revealed.

One way the link within the second hypothesis could be established, is to test whether the presence of active XMRV predicted higher levels of other opportunistic viruses and bacterial infections. According to the second hypothesis, presence of active XMRV should predict suppression of the immune system and further opportunistic pathogens. However, as previously mentioned, there is little evidence that having one opportunistic pathogen in ME/CFS predicts the likelihood of having another, therefore cumulative immune deficiency caused by XMRV attack is unlikely, otherwise previous studies would have highlighted this finding in the blood of ME/CFS patients. This once again seems to tentatively support the third hypothesis, in that XMRV may simply be a passive opportunistic virus similar to other herpes viruses such as HHV-6 and EBV. Even if presence of XMRV did predict the likelihood of secondary infection, it would still be difficult to infer causality.

The Amygdala Hyperarousal Model and XMRV

The Amygdala Hyperarousal model states that ME/CFS and Fibromyalgia may be caused by a conditioned trauma in the amygdala following an acute viral, bacterial or physical insult, combined with psycho-social distress. Once the classical and operant conditioning has occurred, the amygdala in association with the insula, become hyper-sensitive to signals from both the body and external stimuli, and magnify both the extent and frequency of the incoming stimuli in the sensory thalamus and cortex. This then produces the ME/CFS vicious circle, where an unconscious sensitivity reaction to symptoms causes chronic stimulation of the HPA axis, immune reactivation/dysfunction, chronic sympathetic stimulation leading to autonomic dysfunction, mental and physical exhaustion, allergies, compromised detoxification, mitochondria dysfunction, oxidative stress and a host of other distressing symptoms and secondary complications. And these are exactly the symptoms that the amygdala, the insula, and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle.

The Amygdala model predicts that there is likely to be TH2 dominance over TH1 due to overstimulation of the sympathetic nervous system. This has already been extensively documented in many studies of sympathetic overactivity due to acute stress and anxiety (9, 10, 11). Although an ME/CFS patient may not necessarily mentally experience acute stress or anxiety, the model predicts that the physiological aspects of the stress response are chronically engaged, thereby causing disruption in various systems of the body including the immune system. TH2 will dominate over TH1, causing a likely increase in opportunistic viral and bacterial pathogens such as XMRV, as well as an increase in allergic responses due to TH2 over-sensitivity, as well as increased propensity to produce antibodies. There is extensive evidence of increased chemical and physical sensitivities in patients. The parasympathetic system is suppressed, compromising digestive and detoxifying processes in the body.

Once the sympathetic autonomic system is conditioned to be chronically activated, it is very difficult for autonomic and Th1/Th2 balance to be restored. Opportunistic viruses and bacterial infections flourish, in themselves causing further symptoms in addition to the ones caused directly by amygdala hyperarousal.

In the field of Psychoneuroimmunology, many studies have shown that excessive sympathetic activity can have an immuno-suppressive effect on the body via Neuropeptide Y release, thereby pointing to another pathway by which excessive sympathetic stimulation may compromise immune function. A study by Fletcher et al (12) seems to model this effect in ME/CFS patients. ME/CFS patients tend to show low natural killer cell cytotoxicity, (NKCC), and it is known that Neuropeptide Y (NPY) suppresses NKCC. NPY is concentrated in the sympathetic nerve endings, and following stress, is released together with adrenaline and noradrenalin. Fletcher et al’s study tested the hypothesis that elevation of NPY occurs in ME/CFS and that the elevation of NPY is associated with severity of clinical symptoms. They found that NPY was significantly associated with severity of clinical symptoms, and that NPY could be a potential bio-marker for ME/CFS. This shows a direct link between levels of symptoms, and sympathetic overactivity where the most likely culprit is amygdala hyperarousal.

The WPI team are working on the hypothesis that many of the symptoms of ME/CFS may be caused by XMRV attacking the cells of the immune system, thereby compromising immunity. However, there is potentially another culprit for reduced immunity as discussed: chronic sympathetic activity. This has already been shown to suppress general immunity and especially TH1 function, whilst at the same time causing TH2 dominance, inappropriately stimulating allergic responses in the immune system. (9,10,11)

There is a possibility that XMRV somehow directly affects TH1 function, and simultaneously directly affects the autonomic nervous system, however there is no evidence of this and further research is required.

What is most interesting about the XMRV announcement is that the team also found higher levels of XMRV in people with Autism and atypical Multiple Sclerosis (as yet unpublished). A study by Nicholson et al (13) looked at the presence of co-infections in ME/CFS patients versus patients with Autism Spectrum Disorders. The study found that both groups had higher incidence of multiple, systemic bacterial and viral infections compared to controls, but interestingly, both ME/CFS and Autism patients had very similar levels of active infections when compared to one another. Autism is a disorder where sustained amygdala hyperarousal is accepted as a model for partly explaining the disorder (14), so once again there is tentative support for the amygdala’s role in ME/CFS.

This is a very important finding because of the differences and commonalities between ME/CFS and Autism. We would not necessarily expect any commonalities with respect to infections as the conditions seem to have a very different neurobiological basis. However, the common factor may be sustained amygdala hyperarousal, but due to very different causes. The sustained amygdala hyperarousal in Autism may develop in early childhood due to socio-biological reasons, whereas sustained amygdala hyperarousal in ME/CFS may develop as a result of several co-curring acute factors triggering a conditioned trauma in the amygdala later in life. Both conditions then result in a unique pattern of chronic sympathetic stimulation, but for very different reasons, causing similar levels and types of opportunistic viral and bacterial infections. It is likely that the level of hyperarousal in ME/CFS is much more severe and dwarfs that of Autism, but both conditions exhibit enough of a chronic long term sympathetic response to result in opportunistic infections.

Several recent studies have reported abnormalities in amygdala volume in Autism. (15,16). Furthermore, most studies in Autism show abnormal processing by the brain and the amygdala in response to emotional stimuli, and continual background amygdala hyperarousal is once again suspected (14). Further research is required to test any abnormalities in the function of the amygdala in patients with ME/CFS, which may not show up on standard brain scans. It would be interesting to understand the levels of active XMRV virus and antibodies in Autism.

Finally there are a host of physical changes in the brains and bodies of ME/CFS patients which have been well documented and which are consistent with the concept of chronic autonomic dysfunction. These findings cannot be ignored as a result of the XMRV announcement, but need to fit within an integrated hypothesis.

There are many patients who do recover from ME/CFS and Fibromyalgia over time, and yet may not have taken any kind of anti-viral medication. This may indicate that changes that a patient themselves initiate, may be enough to strengthen the immune system, bring the body back to homeostasis, and eradicate opportunistic infections such as the suspected XMRV.

How Amygdala Retraining Might Reduce XMRV and other Opportunistic Pathogen Levels

Amygdala retraining aims to reduce the stimulation of the sympathetic nervous system by creating a projecting neurone from the prefrontal cortex to the amygdala to control its over-zealous reactions. This in turn would reduce the sympathetic overload, allowing TH1/Th2 ratios to gradually return to normal, allowing the body’s own immune system to fight off opportunistic infections such as the suspected XMRV. Symptoms from amygdala hyperarousal (including changes in the brain), and symptoms from opportunistic infections would then subside, as well as any allergic effects of TH2 dominance.
 
Amygdala retraining aims to bring homeostasis back to the body after a period of imbalance, where the balance between the sympathetic and parasympathetic systems returns to normal, as does the TH1/TH2 balance.

Conclusion

The WPI findings are indeed a step forward in ME/CFS research, and are significant findings. However, further research is required to validate the idea that XMRV is a contributing factor in the pathogenesis of ME/CFS, versus being simply another passive co-curring infection such as mycoplasma, HHV-6 and EBV.

The Imperial College London study (2) attempted to detect XMRV in patients in the UK, and found no evidence. This would lead us to tentatively conclude that XMRV may represent an opportunistic pathogen localised to North America, although much more research is required to validate that conclusion.

Amygdala retraining aims to reduce the levels of opportunistic infections such as the suspected XMRV virus by strengthening the immune system through balancing the TH1/TH2 ratio and bringing the body back to homeostasis.

Future Research
Further research is required to answer the following questions:

1. What was the percentage of healthy controls that tested positive for XMRV antibodies? (The 3.7% figure seems to be referring to the percentage of healthy controls which tested positive for XRMV virus DNA rather than antibodies in unpublished research)
2. What percentage of people with Autism display evidence of active virus or antibodies?
3. What percentage of patients with other neurodegenerative disease, fatiguing illnesses and neurobehavioral disease show evidence of XMRV?
4. Can the studies be replicated effectively across the ME/CFS population?
5. Can the studies be replicated in different parts of the world?
6. Why are controls which have active XMRV not displaying obvious pathology?

References

1. Mikovits JA et al. Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science. 2009 Oct 8
2. Erlwein O, Kaye S, McClure MO, Weber J, Wills G, et al. (2010) Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome. PLoS ONE 5(1): e8519. doi:10.1371/journal.pone.0008519
3. Gupta, A. Unconscious Amygdalar Fear Conditioning in a Subset of Chronic Fatigue Syndrome Patients. Medical Hypotheses Volume 59, Issue 6, 12 November 2002, Pages 727-735
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