by Matthew Hogg BSc (Hons) DipBCNH
(Originally written as coursework for a bachelor's degree in nutritional health as an academic component of Nutritional Therapist training - the contents and conclusions should be discussed with your doctor or other qualified medical practitioner)
It has long been recognised that stress in a broad sense plays a role in the pathogenesis of disease. It is only relatively recently however that medical science has begun to elucidate the mechanisms by which stress, through complex interactions between the mind and body and more specifically the nervous, endocrine and immune systems results in physiological imbalances that may instigate or maintain a state of ill-health. This essay will explore this subject in the context of Chronic Fatigue Syndrome (CFS) and investigate the efficacy of a variety of mind-body therapies in reducing symptoms whilst considering the implications for providers of orthodox and complementary and alternative medicine (CAM) and those suffering from this condition.
Many traditional healing systems dating back thousands of years incorporate the concept that the mind influences health, most notably Traditional Chinese Medicine (TCM) and Ayurveda (National Center for Complementary and Alternative Medicine (NCCAM) 2009). In the early 20th century Western researchers began to investigate the link when Cannon (1932) discovered how perception of a threatening situation by the hypothalamus sets off a cascade of systemic physiological changes to prepare the body to either flee or face the danger. He described this as the fight-or-flight response now a term synonymous with stress. Later, endocrinologist Hans Selye showed exposure to stress, whether physical or psychological, results in increased adrenal cortex size and cortisol output with corresponding suppression of the immune response (Selye 1956). These important discoveries paved the way for a paradigm shift to a more integrated view of mind and body and greater understanding of the implications this has for health and disease.
In 1980 a new branch of medicine was born and referred to as psychoneuroimmunology (PNI) a term coined by Robert Ader (Daruna 2004). Ader highlighted research demonstrating how bodily systems act in unison to maintain health and that the immune system, far from an exception to this rule, is integral to it (Daruna 2004). Subsequently, mechanisms involving molecules known as neuropeptides were discovered to play an important role in mind-body-health relationships these neuropeptides include various classes of molecules including neurotransmitters, hormones, cytokines and growth factors (Pert 1985). The key concept is that these neuropeptides are shared ligands acting as substrates for information transfer across biological systems - nervous, endocrine, immune and beyond (Schmitt 1984). For example, immune cells express receptors for, and synthesise, neuropeptides traditionally associated with the brain and regulation of mood and emotion (Weigent et al 1990) whilst conversely nerve cells respond to and produce cytokines, previously thought to be signalling molecules exclusive to the immune system (Farrar et al 1987). What this research and subsequent findings provide is empirical evidence of bidirectional communication between seemingly distinct bodily systems the psychosomatic network (Pert 1998) demonstrating the mind-body connection as physiological reality. The implications of this are that emotions represent a link between mind and body through diffuse neuropeptide-mediated communication (distinct from direct hard-wired nervous system control) and that emotional experience is inseparable from our state of health (Pert et al 1998). Prolonged exposure to negative emotions is detrimental to health a meta-analysis of 30 years of research confirmed chronic psychological stress resulted in suppression of both innate and adaptive immunity (Segerstrom & Miller 2004). PNI teaches us that imbalance in the flow of information between mind and body via neuropeptides and resultant loss of physiological homeostasis results in chronic disease states (Daruna 2004, Pert 1999), exemplified by Chronic Fatigue Syndrome (CFS).
CFS is a chronic condition characterised by physical and mental fatigue, cognitive dysfunction, sleep disturbances and flu-like symptoms, without known cause (Fukuda et al 1994). Although those with CFS are a heterogeneous cohort (Luyten et al 2008) study findings vary and are often contradictory, what is clear from neuroendocrine and immunological research is patients exhibit a loss of homeostasis spanning mind and body as well as bodily systems. Many triggers have been proposed for CFS including viruses such as Epstein-Barr (Hellinger et al 1988) and recently xenotropic murine leukaemia virus-related virus (XMRV) (Lombardi et al 2009), toxic exposure (Racciatti et al 2001) and psychological stress (Afari & Buchwald 2003) but no single cause-effect relationship has been demonstrated further suggesting CFS is caused by disruption regardless of cause of the normal functioning of the psychosomatic network.
Whatever the initial trigger(s) of CFS it is now apparent that characteristic psychoneuroimmunological dysfunction is the end result, with hypothalamic-pituitary-adrenal axis (HPA axis) dysfunction a key factor in CFS pathophysiology (Van Houdenhove et al 2009) representing an important disruption to information flow between mind and body. A large body of evidence points to blunted neuroendocrine responses to the important neuropeptides corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) and resultant mild hypocortisolism; importantly enhanced negative glucocorticoid feedback is also a consistent finding which shows dysfunctional communication not just from mind and brain (hypothalamus) to body but also in the opposite direction (Van Houdenhove et al 2009). While HPA axis dysfunction may alone explain many symptoms of CFS it is cross-system communication as elucidated by PNI concepts that may truly hold the key to its aetiology. Furthermore research has implicated that chronic low-grade inflammation is another consistent and apparently key factor in CFS pathophysiology (Klimas & Koneru 2007) with HPA axis dysfunction likely involved since hypocortisolism may lead to a hyper-immune state with excessive production of pro-inflammatory cytokines such as interleukin-1 (IL-1) (Van Den Eede et al 2007). As discussed, such neuropeptide cytokines provide bidirectional communication between immune system and brain and elevated IL-1 would usually trigger a negative feedback mechanism in which the hypothalamus down-regulates the immune response in CFS the hypothalamic receptors may be resistant to IL-1 and other neuropeptides (e.g. serotonin and vasopressin) (Demitrack & Crofford 1998) and thus the heightened immune response persists alongside cognitive changes as serotonin levels fluctuate. This has important implications for a patients experience of their illness as IL-1 and other pro-inflammatory cytokines through effects on the hypothalamus and other limbic structures induce symptoms including lethargy, pain, flu-like malaise, light fever, sleepiness, low mood and social withdrawal (Van Houdenhove et al 2009). In normal circumstances these symptoms induce sickness behaviour that forces an individual to rest thus aiding recovery from infection or other trauma in CFS however the response persists after the initial trigger has been dealt with and symptoms become chronic. Further evidence of homeostasis failure is demonstrated by disturbances in diurnal rhythms in CFS with circulating cortisol being lower in the morning and higher in the evening than in healthy controls (Nater et al 2008) and timing of melatonin secretion disrupted (Williams et al 2008) which as this neuropeptide is involved in sleep and mood regulation causes further downregulation of the immune system which not only contributes to pro-inflammatory cytokine production but also further perpetuates symptoms and morbidity as it is partly dependent on a sleep-wake cycle for full capacity (Lange et al 2010).
Therefore it can be seen that CFS can be demonstrated as a persisting inability to cope with and recover from any form of stress, and recent research indicates that this cycle of HPA axis dysfunction alongside chronic inflammatory activity associated with disturbances in diurnal neuropeptide secretion further contribute to maintenance of the disease state. There is then a clear rationale for the application of mind-body therapies. Having previously been dismissed as a form of malingering (Abbey & Garfinkel 1991), based on PNI research a biopsychosocial model of CFS has now emerged (Chew-Graham et al 2009, Luyten et al 2008). Therefore a critical evaluation of whether mind-body therapies can be used to restore a degree of homeostasis and reduce symptoms has merit alongside a discussion regarding possible implications for patients and healthcare practitioners.
It seems clear an individualised approach to care is essential. Recent research suggests although HPA axis dysfunction is well established in those with long-standing CFS it may be absent early in the illness (Cleare 2004). Orthodox medical treatment is non-standardised and is often dependent on the knowledge and attitudes of individual General Practitioners (GPs) which varies widely (Bowen et al 2005). Graded Exercise Therapy (GET) is a frontline intervention recommended by the National Institute for Health and Clinical Excellence (NICE) (2007) but there are concerns this may be ineffective and even have long-term negative consequences by further exacerbating the underlying immune dysfunction, chronic inflammation and impaired stress coping mechanisms (Twisk & Maes 2009). In contrast, mind-body therapies offer a more rational approach that in the subset of recent-onset patients may avert progression to overt HPA axis dysfunction and more severe illness. Employing interactive interventions (requiring active patient participation) may help to avoid further deterioration in homeostatic control and resulting social withdrawal that only perpetuates the illness. Such interventions might include Cognitive Behavioural Therapy (CBT), meditative techniques and yoga.
CBT is one of few interventions recommended by NICE (2007) and aims to change negative beliefs and cognition therefore encouraging positive health behaviours as it is argued by proponents the patients experience of finding they can actually accomplish activities they had presumed themselves incapable of may then reinforce positive cognition, triggering an upward spiral of therapeutic gain (NHS Choices 2008). This mind-body therapy would therefore seem ideal in CFS, particularly of recent onset. Studies using CBT in CFS tend to focus on fatigue as the endpoint although studies in insomnia show CBT can improve sleep patterns and normalise associated immune parameters (Krystal 2007) including pro-inflammatory cytokines IL-1 and tumour necrosis factor-alpha (TNF-α) implicated in daytime somnolence in CFS (Kapsimalis et al 2008). It may be that by attenuating this pro-inflammatory cascade, CBT can improve symptoms and functional capacity in recent-onset CFS patients and prevent progression towards severe HPA axis dysfunction and long-term illness. Although, a recent Cochrane review found CBT was only effective in 40% of CFS patients (Price et al 2008) Jason et al (2008) suggest it is the recent-onset subset without hypocortisolism who respond validating the proposition that CBT is best employed as early as possible. However, while some may argue that an overall success rate of only 40% puts a question mark next to the NICE guidance recommending CBT for all CFS patients, it does offer some hope and further, larger trials may elicit more information.
Meditative techniques and yoga, are increasingly demonstrating many health benefits, plus mindfulness training has been shown to reduce fatigue, anxiety and depression and increase quality of life (QOL) and physical functioning in CFS patients (Surawy et al 2005). In one comparative pilot study, although not specific to CFS, mindfulness-based stress reduction (MBSR) incorporating both meditation and yoga, showed superior efficacy to CBT in improving energy and reducing pain (Smith et al 2008). Although data on physiological changes in CFS during meditative techniques specifically is lacking, studies on meditation in general suggest it activates brain regions associated with attention including the hippocampus (located in the limbic system) and increases conscious control of the autonomic nervous system (Lazar 2000) inducing the relaxation response, which in turn diminishes circulating cortisol levels promoting sleep and immune function. Another meditative technique, Transcendental Meditation (TM), has been shown to modulate the release of various neuropeptides and may also regulate feedback sensitivity of the HPA axis (Infante 1998), which couched with more recent research indicates that further closer investigation might be of value for CFS patients, particularly if these mechanisms indicate that meditative techniques could help recent-onset CFS patients restore stress coping mechanisms and resume relatively normal lives by positively influencing limbic system and HPA axis homeostatic control.
In patients with long-standing CFS however the healthcare practitioner may be well advised to adopt a gentler initial approach to mind-body intervention. These patients may be severely incapacitated, have withdrawn from social activity entirely and are often effectively bed-ridden so more passive therapies are more appropriate to begin with. External qigong in which a practitioner transfers qi (life force) to the patient with or without actual physical contact (Lee et al 2007) is a good example of such an intervention. In case studies in CFS patients this therapy has improved physical and mental functioning, often dramatically (Shin & Lee 2005). Although such limited qualitative evidence is far from conclusive proof of efficacy previous research has demonstrated psychoneuroimmunological effects directly relevant to CFS pathophysiology from this modality including increasing melatonin and the cytotoxicity of both natural killer (NK) cells and neutrophils (Lee et al 2001). NK cell function in particular appears to be universally impaired in CFS (Lorusso et al 2009). Improving NK function has been shown to reduce fatigue (Meeus et al 2009) so through this mechanism and by modulating melatonin secretion and therefore improving sleep quality, external qigong is supported by empirical evidence that may be acceptable to orthodox medicine and positive results from future large scale CFS-specific trials incorporating quantitative physiological measures could make it an important initial alternative to currently recommended interventions and enable long-term CFS patients to engage in more interactive mind-body therapies.
A case can be made that those who have suffered the symptoms of CFS for many years are likely to have understandably developed self-limiting attitudes that cause further psychological stress and PNI interactions that maintain symptoms in a self-perpetuating cycle. A fundamental shift in beliefs and attitudes may therefore be required to build therapeutic momentum. CAM practitioners are increasingly called upon to act as counsellors (Fox 2008) or such services may be provided by the National Health Service (NHS). Lazarus and Folkman (2004) talk about confrontive and emotive coping styles people exhibiting the former feel they have control over their situation and take action to overcome obstacles while those using the latter simply hold onto the emotions generated by their situation. An increased prevalence of emotive coping has been seen in CFS patients and associated with fatigue and pain severity and overall disability (Nater et al 2006). Developing spirituality can be an effective means of bringing about constructive attitudinal change and fostering positive coping styles in CFS patients. Spirituality can be seen as an over-arching state of being inclusive of beliefs about self and our relationships with other people, the environment and a higher power or state of consciousness that directs the way we behave and interact; it is seen as a component of the mind-body-spirit triad essential for health (Tacey 2004). Often sidelined or ignored by orthodoxy a substantial amount of research signals the medical profession is neglecting an important aspect of healing by adopting such an attitude. CFS patients who identify themselves as spiritual display greater acceptance of their illness which translates into adoption of positive coping styles and greater psychological well-being (Baetz & Bowen 2008), placing them in a position to seek out more interactive mind-body interventions to further improve their condition. GPs with limited time, compounded by a lack of empirical evidence, are unlikely to utilise such findings but CAM practitioners can certainly encourage the development of spirituality and Baetz and Bowen (2008) found CFS patients are more likely to be spiritual than healthy individuals, suggesting many are ultimately drawn to this path and are likely to be open to the concept.
CFS represents a significant challenge to the current paradigm of evidence-based medicine (EBM) that through NICE guidelines governs the management of patients within the NHS. The one size fits all approach this system dictates is inappropriate in the context of CFS as a biopsychosocial illness as indicated by current evidence from the diverse areas of PNI, psychology and social science and an individualised therapeutic approach is likely to yield more positive patient outcomes, an assertion supported by evidence the patient-practitioner relationship is as important as the specific therapy employed (Godfrey et al 2007). Evidence for the efficacy of diverse mind-body therapies although predominantly of a preliminary nature is encouraging and larger CFS-specific investigations are warranted, particularly in light of studies indicating such interventions often mediate and even reverse psychoneuroimmunological dysfunction that appears to both precipitate and maintain morbidity in CFS. Only CBT and counselling are likely to be available through the NHS based on current NICE (2007) guidelines suggesting CAM practitioners have a significant role to play in the management of CFS at present. Patients then are faced with utilising the principles of mind-body medicine themselves through spiritual development and meditation for example, or seeking the help of CAM practitioners and funding their own care. Greater consideration of the mind-body connection by orthodox medicine and provision of therapies in-house or by referral to individual CAM practitioners would therefore be in the best interest of all parties.