Creative consulting: psychoneuroimmunology, the mindbody

Traditionally, medicine has kept the mind separate from the body. Now things are changing as people realise that the psyche and the soma are constantly interacting. In the sixth article in our series, David Reilly and Tansy Harrison look at the science of sewing the head back onto the body

The neat flat medical world that used to separate the body from the mind is turning out to be round. Yet on this separation we built a medical system organised into head doctors and body doctors, with some of them specialising in smaller bits. Thinking of the cardiac system and its diseases as unrelated to the emotions, or separate from the individual person, is proving to be unscientific. A new word to describe some aspects of this joined-up-ness is "psychoneuroimmunology" and the world will never be flat again. We should now speak of the "mindbody," according to Candice Pert, a codiscoverer of endorphine.

David Reilly and Duncan McCabe

Mindbody

In the good old days you caught an infection by chance and then bits of the body--called the immune system--fought it. The doctors diagnosed it and prescribed something to kill the bugs. It was nice to be nice to the patient, but the "real" medicine got on with the molecular manipulations. There are cracks in this view, into which some are now driving a wedge. As far back as 1919, Ishigami noted that stress influenced the development of pulmonary tuberculosis.¹ Since then a number of studies have recorded higher levels of stress before the development of a clinical infection (including experimentally induced colds).²

This could be due to confounding factors--for example, diet--so some researchers began to focus more narrowly. In 1963 there was a report on the suppression of the Mantoux reaction (the skin test for tuberculosis immunity) through hypnosis.³ That did not fit in with the medicine of the day and was largely ignored. Decades later, an understanding is now emerging of a complex world of interactions between our mental and emotional selves and our neural, endocrine, and immune functions.

A key early observation was the 1970s experiments where rats were given a flavoured solution at the same time as injections of cyclophosphamide (an immunosuppressive drug that induced gut upset).⁴ Unsurprisingly, they developed aversion to the liquid--but they then began to die off from the harmless liquid without the cyclophosphamide (the more liquid, the more deaths). Ader coined the term "psychoneuroimmunology" and research documenting the conditioning of non-specific and specific immune responses increased.^{2 5 6}

How might this work? What are the mind-body links? Much is unknown, but consider some papers and reviews of this emerging picture and think about the clinical implications as you read.

Hormonal links

The classical hypothalamus-pituitary-adrenal axis (HPA), which plays a central role in affecting immune responses, is a key part of the mindbody. Immune cells have receptors for the HPA molecules, and hormones--like glucocorticoids--alter their function, number and distribution.⁷ Stress activates the HPA system, directly increasing susceptibility to infections, and the system also influences non-immune host defences and could affect the virulence of infectious agents.²

Nervous system wiring

Until recently, it was not realised that the nervous system connects directly to the immune system and that this is an important route for two way communication. In fact, nerves innervate lymphoid tissue--for example, the thymus, spleen, bone marrow, and lymph nodes. They even make direct contact and change the responses of the cells of the immune system.^{5 6 8 9}

White cells: our mobile brains?

The brain talks to white cells, and it seems they talk back. Communication molecules of the nervous system are traditionally called neurotransmitters, and for the immune system they are called cytokines. Actually, these molecules are secreted and recognised by both systems.^{7 10 11} Our white cells not only have receptors for what were thought of as neurotransmitters, they secrete neurotransmitters. So where does that leave the brain? We have a sort of mobile nervous system and the immune and hormonal system are linked. Lymphocyte derived "cytokines" feed back on the HPA.^{7 12 13}. More directly, cytokines also directly affect the brain. Inject cytokines into a rat and its behaviour changes: it becomes socially withdrawn. Cytokines have been shown to directly affect fever, sleep, eating, mood, and other aspects of behaviour which may explain some of our changes during illness⁷: "Leave me alone, I'm not hungry." Many substances from the brain and immune system are potential mediators in our mindbody, including interleukins, interferons and other cytokines, neurotransmitters--for example, adrenaline, dopamine, and histamine, and neuropeptides--for example, endorphins.

David Reilly

You move me as I move you
round this cell of captured white
you reflect me as I reflect you
like the moment between night and light
we feel together
captured like dust in moon lights
falling through the window of this white cell

Our stationary brain

Many regions of the brain change in response to an immune challenge. Studies of brain lesions and electrophysiological techniques show changes in both neuronal firing rates and turnover of neurotransmitters. Much is unknown, but proposed neuronal circuits that modulate the immune response include participation of the reticular formation, amygdala, limbic system, medial frontal cortex, and the hypothalamus.¹⁴

The mindbody in action: stressors and antistressors

"Stress" impacts on immune function and disease susceptibility.^{5 15} Most, but not all, stressors have an adverse effect. One of the earliest studies in humans looked at lymphocytes taken from people around the time of bereavement. The isolated cells are "depressed": they respond less to stimulations of cell function.¹⁶

Medical students show reduced immune responsiveness on the first day of final exams compared to pre-exam and post-exam
periods.¹⁷ Students with good coping styles--that is, those who get less stressed and anxious, produced the strongest immune responses to hepatitis B vaccination on day three of their exams.¹⁸

Psychological factors can affect reactivation of latent viral infections, including herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and HIV. Acute and chronic stress is linked with increased antibodies to the viruses, indicating an increase in viral antigens associated with a reduction in cell mediated immunity (which usually controls the viral infection). Immune function is also influenced by anxiety, sleep deprivation, abortion, divorce, family illness, academic stress, anticipation of HIV test results, unemployment, and war.^{2 14 15} In addition to the impact of stress, many other internal and external factors have been shown to affect the immune system and disease, including personality, psychiatric illness, coping style, positive attitudes, relaxation, hypnosis, meditation, guided imagery, humour, and social support.^{6 15}

Clinical implications

The links between stress and life circumstances are well established, but charting possible psychoneuroimmunology links from this all the way to the white cell is a new field, with early, and sometimes inconsistent, results. Exploring the clinical or community medicine implication of the mindbody is perhaps still too radical (some of your teachers will not have heard yet of psychoneuroimmunology). Here are a few areas where some work has been done.

Infections

In tuberculosis and in HIV infection, like other latent viral infections, psychological factors may promote virus reactivation, resulting in progression of the disease. Evidence is conflicting here, but some studies have shown a reduction in NK and cytotoxic T cells in patients with HIV under stress.¹⁹ Low social support has also been correlated with a significantly faster decline in CD4 count.²⁰ Studies of psychotherapy, stress management techniques, and pharmacological conditioning in patients with HIV have produced beneficial effects but, like other areas, require further investigation.^{2 6} Hypnosis and psychotherapy have been proposed to alleviate or decrease symptoms--for example, in recurrent oral or genital herpes infections.²

Cancer

One study looked at a six week structured group intervention (health education, problem solving skills regarding diagnosis, stress management, and psychological support) in patients with stage I or II malignant melanoma. Short term effects included a reduction in psychological stress and immunological changes (increased number and activity of NK cells). Follow up at six years showed reduced recurrence and mortality rates in the intervention compared with the control group.^{21 22}

Group therapy and self hypnosis for women with metastatic breast cancer has been shown to extend survival by an average of 18 months.²³ We would be likely to find psychoneuroimmunology changes here, but, as with infectious diseases, there are many confounding factors that make studies in groups of cancer patients more challenging--for example, stage of disease, chemotherapy, radiotherapy, lifestyle, etc.

Psychiatric disorder

There is evidence linking various psychiatric disorders with impaired immunological functions; complex interactivity as predicted by a mindbody perspective.^{6 14} Certainly, serious depression and mania suppress components of immunity. It has even been suggested that monocytes, macrophages, and T cells may have an aetiological role in schizophrenia.²⁴

Autoimmune diseases

Psychological factors have been associated with the onset and progression of a range of these diseases including systemic lupus erythematosus, Crohn's disease, ulcerative colitis, diabetes, rheumatoid arthritis, and myasthenia gravis, and psychoneuroimmunology mechanisms may play a role. Perhaps the early work suggesting we can sometimes learn to suppress over-reactive immune responses might bring clinical benefit here. In one study, a woman experienced in meditation showed that she was able to voluntarily suppress a delayed type hypersensitivity skin test reaction to varicella zoster virus, and in vitro studies confirmed a reduction in lymphocyte stimulation to the virus. She was also subsequently able to return her response to the previously established norm.²⁵ Conditioning might be used for clinical benefit, and one case study outlined its use in the treatment of a child with systemic lupus erythematosus.²⁶

The future

Psychoneuroimmunology is important. It can help the "medical model" adapt towards a more holistic approach. You would do well to consider its implications for your patients. Sometimes there is more evidence for the usefulness of emotional, psychological, and behavioural interventions than purely "medical" treatments. As Roger Sturrock, the rheumatologist, once remarked about autoimmune diseases, "If you settle the patient, the illness then often settles."

There are also risks here. This world may no longer be flat, but, for some, it might now become psychoneuroimmunology shaped. This can be used to fuel unrealistic hopes, adding to the "guilt industry"--the shadowy world of mind-body-alternative medicine. If you tell someone that stress reduction, visualisation, changes in attitude, etc, might help their recovery, they can subconsciously think, "Well then, maybe I caused this illness, and it is now my fault I am not getting better." (Recall the earlier study of nocebo.²⁷) Sometimes we can forget that it is natural to get sick, to age, and to die. Nothing stops this in the end. Psychoneuroimmunology changes are only one part of the bigger picture, to be added to the many other dimensions of change we have looked at earlier in this series--like compassion, motivation, symbolic impact, and changes of belief and behaviour. Yes, these might result in psychoneuroimmunology changes, but as Zen teachings say, "Do not mistake the finger that points at the moon, for the moon."

David Reilly, consultant physician Homeopathic Hospital, Glasgow
Email: davidreilly1@compuserve.com

Tansy Harrison, preregistration house officer, Royal Alexandra Infirmary, Paisley


studentBMJ 2002;10:89-130 April ISSN 0966-6494

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