Mind, and – the science and clinical application of psychoneuroimmunology

Psychoneuroimmunology is a multidisciplinary field spanning , and neuro-.

MARGO DE KOOKER, BSc (Hons), MB BCh Director, Port Elizabeth Reduction Clinic, Port Elizabeth Margo de Kooker specialises in and behavioural medicine. She received her Honours in and medical degree from the University of the Witwatersrand in 1986 and 1991 respectively. Her areas of interest include psychoneuroimmunology, integral medicine, holistic lifestyle management and stress management. She is the director of the Port Elizabeth Stress Reduction Clinic and also facilitates corporate stress management, executive wellness programmes, and continuing medical education in the field of PNI.

Developing an understanding of the relationship between communication taking place.2 Specific areas of the that psychosocial factors, behaviour, immunity and health is a central modulate (the and particularly) focus in psychoneuroimmunology (PNI). A broader point of focus have been found to be rich in peptides (up to 40× more than in behavioural medicine (mind-body medicine) is the wellness other areas of the brain). Peptides secreted from the brain (in and ongoing development of the individual on all levels – physical, relation to stress or a particular mental and emotional state), via emotional, mental and spiritual. the psychosomatic network, can affect the behaviour, and migration of an immune system cell, and its ability to produce or related cytotoxic chemicals. The science of PNI This communication is also bi-directional: in immune activation Every part of the immune system is connected to the brain in some secrete the pre-inflammatory Interleukin- way, be it via a direct nervous tissue connection, or by the common 1, 6 and alpha TNF. This results in a fever and the activation of the chemical language of peptides. Branches of the autonomic nervous body’s energy-conserving responses such as withdrawal, decreased system densely innervate lymphoid tissues. The sympathetic social interaction, reduced aggression, reduced sexual behaviour, nervous system directly influences the immune system as nerve need to sleep and loss of appetite. All of these responses, which we fibres go directly to zones where T cells and macrophages are in high call ‘sickness’, are initiated by the immune system. The cytokines concentrations. Nerve endings have been observed to make small induce a stress response by the release of corticotrophin-releasing indentations on the surface of individual , which have factor (CRF) and the activation of the hypothalamic-pituitary- B-adrenergic receptors, and as a result the sympathetic nervous 1 adrenocortical (HPAC) system with a sustained increase in , system is able to mediate the brain’s influence on immunity. 3 which can result in behaviour that mimics depression. Peptide macromolecules including , , The concept of ‘a mind-body connection’ seems to downplay the , releasing factors, cytokines and endorphins are degree of integration of the various systems and many favour able to occupy specific surface receptors on all leucocytes and as the idea of a BODYMIND – an organised whole with two-way a result influence the growth, activity and protein synthesis of communication with no hierarchy of mind over body, but rather these cells. Leucocytes themselves produce peptides once only a complex system. thought to be manufactured and secreted by tissues in the brain and . T cells, for example, are able to synthesise their own adrenalin and noradrenalin. Stress and immunity Not only do various neuropeptides, hormones and nervous system Stress begins with an actual or perceived threat activating sensory mediators influence immunity, the immunological hormones or higher centres in the . Cortical fibres to the (the interleukins, interferons and tumour necrosis factors – also amygdala are activated, and the messages reach this area of the known collectively as cytokines) have significant effects on the brain, which is the primary mediator of the stress response. Other body and (affecting mood, cognitive signals, sometimes preconscious, also result in activity in the abilities and neuroendocrine functions as well as playing a role in amygdala. depression).1 receptors have been found on cells of the Once activated, the cells of the central nucleus of the amygdala endocrine system and these cells under normal or stress conditions release CRF which stimulates the brainstem to activate the manufacture various cytokines themselves. sympathetic nervous system, eventually resulting in adrenalin This complex communication between systems reflects a being released from the adrenal glands. The CRF also triggers network connecting the brain, endocrine and immune systems the release of . This is the typical ‘fight or fright’ into one functioning ‘psychosomatic network’, with systematic response, usually short lived. If the stress becomes chronic, the

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glucocorticoids begin to induce the locus When considering stress in an individual it is susceptibility. Removing the source of coeruleus to release its own noradrenalin wise to bear in mind not only is an obvious strategy, but this is often that acts on the amygdala, resulting in more and behavioural stressors, but physiological impossible. An alternative strategy is to production of CRF, which in turn results in stressors as well. Abnormalities in the focus on the factors that make an individual further activation of the stress pathway. immune system and pain result in a stress or disease resistant. Alleviating the secondary stress response in the central damaging effects of stress and depression by Long-term chronic increases in adrenalin nervous system. The immune system acts facilitating resilience and stress resistance secretion suppress immunity: both like a sensory organ for the brain and the should lead to an enhancement of immunity, noradrenalin and adrenalin decrease cell- response of the brain to or resulting in the prevention of disease or mediated immune responses (noradrenalin is identical to its response to a possibly remission. via alpha- and beta-adrenergic receptors, stressful stimulus. and adrenalin via an increase in interleukin The research to date is as compelling 6 (IL-6)).4 Stress itself is neither good nor bad, and concerning immuno-enhancement and while various psychosocial factors have recovery as it is concerning immuno- Chronically elevated adrenalin secretion been shown to impact on immunity and suppression and stress. Various factors have results in a shift away from cell-mediated resistance (Table I) their impact depends been linked to disease resistance and speedy defences (with decreased cytotoxicity and a on the resilience of the individual who recovery and hold much promise in the shift in CD4/CD8 ratio) as well as a decrease encounters these factors. If these factors clinical application of the field. in natural killer (NK) cell activity. If a fight- present themselves in a patient’s life they need or-flight situation (or the perception that Mood, adaptive coping, continued life to be addressed and suitable interventions one exists) becomes chronic, there can be involvement, emotional processing, social facilitated to counteract their effect, as they long-term effects, such as a decreased T-cell support, doctor-patient relationship and could interact negatively with pre-existing proliferation and suppressed immunity. spirituality, are all variables that influence conditions. healthy survival in the face of HIV infection The glucocorticoids have been found to have and other life-limiting conditions.6 significant roles to play in both autoimmune Table I. Psychosocial factors im- processes, and in immune deficiency. In linking personality traits and stress Cortisol has potent anti-inflammatory pacting on immunity resistance, Kobasa identified three attitudes and immuno-suppressive affects and is an • Absence of social support that collectively acted as a buffer against important part of the loop inner distress in the encounter with stressful • Significant loss during an immune response. The HPAC life events – she called this hardiness.7 system is responsible for cortisol release • Unemployment The attitudes of commitment, control and from the . Cortisol plays its • Loneliness challenge lay a foundation for motivation biggest role in the stress response when • Bereavement based on a sense of meaning and a sense of active control-based coping has broken • Homelessness self-efficacy, which has a positive effect on down, and the perception of control has • Retirement immunity in the face of stress.8 been lost (the stress is now overwhelming, • Suppressed unpredictable and unrelenting). • Suppressed Linville described self-complexity as the capacity to understand oneself and the world In chronic long-term stress • Denial coping in a complex, multifaceted way. It is the trait proliferation is reduced, NK cells are unable • Time urgency of having many traits and allows for flexibility to destroy cancerous and virally-infected • Living in a hazardous location in coping and provides an individual with a cells, lymph gland structure deteriorates, • Taking care of someone with a serious wide repertoire of emotional and cognitive and cognitive damage may occur, resulting disease responses to stress. Self-complex individuals in memory deficits, and depression. • Low marriage quality are more subjectively and objectively There is consistent evidence that depression • Divorce and separation resistant to stress, and show a decreased and anxiety enhance the production of • Insomnia vulnerability to anxiety, depression and 9 the inflammatory cytokines, including • Miscarriage immune dysfunction. interleukin-6, and higher levels of IL-6 were • Stroke The suppression of emotions has been associated with greater distress.5 • Surgery demonstrated to be one of the most • Exam-related distress significant psychological factors leading to 10 Bear in mind that health and potential for wellness depend on immune system dysfunction. Expressive Stress and disease an interaction between psychosocial factors, availability of writing has been shown to moderate Stress is not universally immunosuppressive, coping response, genetic factors, age, social conditions and previous medical/stress history. the distress related to negative social and there are different PNI responses to acute interactions and lack of social support in and . Acute stress (defined 11 cancer patients. Strong associations have as episodic events measured in minutes or been found between repressive coping and hours) is often associated with a short-term 12 the progression of cancer. ‘up-regulation’ of cell-mediated immunity Clinical challenges and no long-term dysfunction. Chronic An ongoing challenge in PNI research is Creating sustained and meaningful mental stress results in a decrease in circulating to deepen our knowledge of how thought, imagery has proven to be a powerful healing lymphocytes, particularly T helper cells, perception and emotion result in changes in tool. The immune system is the ideal target less efficient proliferation in response to a immunity and ultimately health. for cellular imagery and its impact on 13 challenge, fewer circulating NK cells and It is widely accepted that chronic stress and immunity has been well documented. less cytotoxicity, titres to specific depression cause immune dysfunction in Davidson et al. have shown that a short viruses are raised and there is decreased a susceptible individual; this may result in programme in ‘mindfulness meditation’ secretion of nonspecific secretory IgA. disease progression and increased disease produced lasting positive changes in

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both the brain and the function of the for clinical practice be constructed and 6. Ironson G, Solomon G, O’Clereigh C, et al. immune system. The findings suggest that overriding principles established that can be Psychoimmunology of healthy survival with mindfulness, promoted as a technique to kept in mind regardless of the therapeutic HIV. 1B Symposium: Psychoneuroimmunology, morbidity, and mortality in autoimmune, viral reduce anxiety and stress, might produce approach taken. It was suggested at the and neoplastic disease processes. Psychosom Med 17 important biological effects that improve a 1977 Yale Conference that a therapeutic 2002; 64: 85. 14 person’s resilience. programme incorporating this new model 7. Kobasa SC. Stressful life events, personality, and of healing should meet four conditions: health: An inquiry into hardiness. J Pers Soc It is important to emphasise that in the Psychol 1979; 37(1): 1-11. clinical application of PNI, causation is • It should facilitate the awareness of 8. Weidenfeld SA, O'Leary A, Bandura A, Brown never implied. PNI explores the interaction behaviours and responses that are risk S, Levine S, Raska K. Impact of perceived self- between psychosocial events, stress, factors for disease. efficacy in coping with stressors on components coping and immunity, simultaneously of the immune system. J Pers Soc Psychol 1990; • It should facilitate a change in behavioural acknowledging the pre-existing biological 59(5): 1082-1094. and physiological response, thus conditions.15 9. Linville PW. Self-complexity as a cognitive buffer enhancing well-being. against stress related illness and depression. J Pers A case has been made for an ‘arthritis- • It should improve compliance. Soc Psychol 1993; 52 (4): 663-676. prone’ or ‘cancer prone’ personality 10. Pennebaker JW, Kiecolt-Glaser JK, Glaser R. – someone at risk for certain illnesses • It should facilitate a change in the way Disclosure of traumas and immune function: as a result of their attitude and coping. health care providers, at all levels, Health implications for psychotherapy. J Consult Immune dysfunction may result from stress approach clients, and assist in supporting Clin Psychol 1988; 56(2): 239-245. and maladaptive coping strategies, but it them in their efforts to improve health 11. Zakowski SG, Morton C, Ramati A, et al. must be acknowledged that other social, and alleviate suffering. Expressive writing moderates the effects of negative social interactions on distress in cancer environmental and genetic factors influence The clinical application of the field of PNI patients. Emotional Expression Research. the interaction. In short, how an individual within behavioural medicine is eclectic and Psychosom Med 2002; 64: 102. thinks, or copes with life and stress does not acknowledges the research, techniques and 12. Temoshok L. Biopsychosocial studies on necessarily cause disease. therapies suggested by contributors from cutaneous malignant melanoma: Psychosocial factors associates with prognostic indicators, PNI research has much to offer when we various disciplines. PNI itself is simply a field progression, psychophysiology, and tumour host consider patients who are diagnosed with a of scientific exploration, providing scientific response. Soc Sci Med 1985; 20 (8): 833-840. life-threatening or life-limiting illness. Their data that support the development of a more 13. Rider MS. Achterberg J. Effect of music assisted mental and emotional well-being at the time sensitive, integrative, multidisciplinary imagery on and lymphocytes. of, and prior to, their diagnosis can have a approach to patients. Biofeedback Self Regul 1989; 14: 247-257. significant effect on disease progression and 14. Davidson R. Kabat-Zinn J, Schumacher J, prognosis. Assisting a patient in managing References Rosekranz M, Muller D, Santorelli SF. Alterations stress, as well as recognising and dealing 1. Evans P, Hucklebridge K, Clow A. Mind, Immunity in brain and immune function produced by and Health: The Science of Psychoneuroimmunology. mindfulness meditation. Psychosom Med 2003; with psychosocial factors that may interact London: Free Association Books, 2002: 3. 65: 564-570. negatively with existing conditions, is 2. Pert CB, Ruff MR, Weber RJ,et al. Neuropeptides 15. Biondi M. Effects of stress on immune functions: imperative. Broadening the individual’s and their receptors: a psychosomatic network. J an overview. In: Ader R, Felten DL, Cohen N, scope of attention, cognition and action, and Immunol 1985; 135(2): 820s-826s. eds. Psychoneuroimmunology, 3rd ed. San Diego: building of physical, intellectual and social 3. Maier SF, Watkins LR, Fleshner M. Academic Press, 2001: 189-226. resources facilitates self-efficacy, optimism, Psychoneuroimmunology. The interface between 16. Kiecolt-Glaser JK, McGuire l, Robles TF, et resilience and health.16 behaviour, brain and immunity. American al. Emotions, morbidity, and mortality: new Psychologist 1994; 49: 1004-1017. perspectives on psychoneuroimmunology. Ann 4. Song C, Leonard B. Fundamentals of Rev Psychol 2002; 53: 83-107. Conclusion Psychoneuroimmunology. New York: John Wiley 17. Schwartz GE, Weiss SM. Yale Conference on and Sons Ltd., 2000: 4. Behavioural Medicine: A proposed definition The challenge in an emerging discipline has 5. Kiecolt-Glaser JK, McGuire l, Robles TF, et and statement of goals. J Behav Med 1977; 1(1): always been in its clinical application. al. Emotions, morbidity, and mortality: new 3-12. Working from a scientific basis in such perspectives on psychoneuroimmunology. Ann a diverse field requires that guidelines Rev Psychol 2002; 53: 83-107.

In a nutshell • Psychoneuroimmunology (PNI) is a multidisciplinary field spanning immunology, psychology and neuro-endocrinology. • The bi-directional communication occurs between the brain, endocrine and immune systems reflects a functional ‘psychosomatic network’. • Chronic stress influences all aspects of the psychosomatic network. • Various psychosocial factors impact on immunity and resistance, their impact depends on the resilience of the individual who encounters these factors. • Hardiness, self-complexity and balanced emotional expression are important buffers against stress and immune dysfunction. • Mood, adaptive coping, continued life involvement, emotional processing, social support, doctor-patient relationship and spirituality, are all variables that can influence disease progression from a PNI perspective. • Managing stress, identifying relevant psychosocial factors and promoting self-efficacy, optimism and resilience is an important facet of comprehensive health care.

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