_____________________________________ Chapter Ten

Future Directions in Psychoneuroimmunology: Psychoelectroneuroimmunology? Paul J. Rosch American Institute of Stress, Yonkers, New York, USA Historical overview Endemiology, psychosomatic illness and stress Defining the immune system and its relationship to stress Stress, tuberculosis, streptococcal infections and the common cold Neuroendocrine-immune system interrelationships Psychoneuroimmunology and AIDS Physical/atomic communication and psychoelectroneuroimmunology Future directions References What happens in the mind of man is always reflected in the diseases of his body (René Dubos)

HISTORICAL OVERVIEW When initially invited to furnish a concluding overview to this volume, I enquired about the contents of other chapters. I hoped this would help to Stress, the Immune System and Psychiatry. Edited by B. Leonard and K. Miller © 1995 John Wiley & Sons Ltd

208 ________________________________________________ P. J. Rosch avoid repetition, and possibly address certain topics that might have been overlooked, or warranted additional emphasis. I was delighted to discover that the Foreword was being written by my friend Bob Ader, who was responsible for the term psychoneuroimmunology. I asked him to send me a draft of his comments, so that my contribution might provide some sense of continuity. In his opening paragraph, he describes psychoneuroimmunology as ‘a new hybrid discipline that has created strange bedfellows’. The subsequent discussion suggests that this refers to scientists working in seemingly disparate domains who might find unsuspected areas of common interest. However, there are other ‘strange bedfellows’ that must also be considered in contemplating the future of this flourishing field, based on past experience. This can best be appreciated by reviewing some relevant historical considerations. Although psychoneuroimmunology may be new, the belief that emotional stress, mood, or state of mind, could be responsible for causing or influencing the course of various disorders, has always been a popular belief, with firm roots in philosophy and religion since antiquity. It was emphasized in Ayurvedic principles and medical practices1 that have persisted for more than 3500 years, and are now attracting increased attention. Two thousand years ago, the Greek physician Galen, wrote that melancholy women were particularly prone to cancer of the reproductive organs, presumably because they had an excess of black bile (mélas chole)2. Galen believed that such humours, vital spirits, imagination, blood muscle, and nerves were all closely linked with one another, in some hierarchical fashion. Thus, thoughts and feelings were constantly circulating through the body, exerting their effects by direct physical contact with particular parts of our anatomy. Based on this, and some of the therapeutic approaches that resulted, as noted below, psychoneuroimmunology may have the appearance of old wine in a new bottle. Galen’s teachings and dogma dominated Western medicine completely for 16 centuries. As one commentator noted, ‘in 1559, Henry VIII’s College of Surgeons carpeted a man who dared to suspect his infallibility’3. Renaissance physicians firmly believed that imagination, thoughts and physical processes were constantly influencing one another, or that certain images or emotions stimulated particular physical parts or processes, and could even be lethal. Thus, in Shakespeare’s King Lear, Gloucester died because . . . his flaw’d heart, Alack, too weak the conflickt to support! Twixt two extremes of passion, joy and grief, Burst smilingly (Act 5, Scene 3)

Children could be influenced by the thoughts their parents had at the time of conception, because imagination ‘marks and deformes, nay, sometimes kills Embryos in the womb, hastens Births, or causes Abortions’4. Indeed, most

Psycholectroneuroimmunology ________________________________ 209 afflictions were assumed to result from powerful images or states of mind. As a consequence, physicians often directed their treatment to the patient’s imagination, as noted in Vaughan's Approved Directions for Health in 16125. Th e ph ysician mu st in vent an d dev ise some spiritual pageant to fortify and help th e imaginativ e faculty , which is corrup ted and deprav ed; yea, he must end eavo r to deceive and imprint another conceit, whether it be wise or foolish, in the patient’s braine, thereby to put out all former phantasies.

However, the importance, if not the primacy of the mind in influencing health and illness, fell into disrepute, and contemporary medicine has been shaped by other forces. The most important dates back to the 17th century French philosopherscientist, René Descartes. A mathematical genius, who worked out the treatment of negative roots and was responsible for the development of Cartesian coordinates and Cartesian angles, he essentially founded analytical geometry, and made numerous optical discoveries dealing with the reflection and refraction of light. His teachings are termed Cartesian from his name in Latin, Renatus Cartesius. Descartes attempted to apply mathematical methods to every aspect of life, rejecting existing scholastic beliefs and teachings by founding his own system based on universal doubt. After all, one thing that could not be doubted, was doubt itself. Only the action of the mind proves reality, and his motto was ‘Cogito, ergo sum’ (I think, therefore I am).6 Descartes’ enormous influence on medicine seems quite amazing, since he never made any important contributions to the biological sciences. Actually, a number of his strong beliefs were erroneous, the most egregious being his rigid refutation of Harvey’s theory of the circulation of the blood. Descartes had proposed that the heart functioned as a heat engine, and persuaded the scientific community that all the functions and structures of the body could be reduced to mechanical models that obeyed mathematical laws. The complex study of the living organism could best be pursued by investigating the workings of smaller and smaller components with correspondingly simpler and simpler functions. In the Cartesian paradigm, illness resulted from mechanical malfunction, and repairing the problem was the physician’s province. The mind or soul was a direct gift from God, beyond man’s ken, entirely separate and possibly even physically distinct from the machinery of the body. It ‘consists entirely in thinking, and for its existence, has no need of place, and is not dependent on any material thing’. Mental or emotional problems were similarly presumed to be beyond the realm of scientific study, and more properly belonged in the domain of the Church, where they indeed remained for several hundred years. This dualistic, reductionistic perspective resulted in a number of advances and discoveries, eventually establishing the doctrine that the complete comprehension of physiological processes could only be derived by understanding

210 ________________________________________________ P. J. Rosch what transpired at microscopic, molecular or even lower levels. The amazing discoveries of Leeuwenhock and other early microscopists, provided unanticipated strong support for this. A few decades later, the binomial nomenclature classification system of all known plants and animals by the Swedish biologist Linnaeus gave further impetus to this analytical approach. This perspective promptly permeated all the sciences, especially biology, spilling over into medicine and the delineation of disease states. By the 19th century, body and mind had been almost completely separated. Anatomists and physiologists studied the body, and the mind was left to philosophers, and subsequently to psychologists and psychiatrists. Specific physical cause and effect relationships were now believed to be responsible for illnesses. It seemed increasingly apparent that every disease had its own particular cause, and conversely, that each noxious influence or pathogen produced its personal pathological picture. This doctrine reached fruition in the germ theory of disease, propounded so eloquently by Pasteur and Koch. It propitiously coincided with a variety of deadly epidemics of infectious diseases, referred to as ‘fevers’, which were sweeping across Europe. These were primarily caused by Vibrio cholerae, discovered by Koch in 1883, and the typhoid bacillus, identified by Gaffky a year later. Around the same time, the structural concepts introduced by the German pathologist Virchow viewed all disease as due to a disorder of organs or cells, further separating psyche and soma. The discovery that scurvy and subsequently other avitaminoses were due to specific nutritional deficits verified the validity of the assumption that illness was always caused by the presence or absence of some external factor. Final proof came from the logic of Koch’s Postulates, the extraordinary efficacy of specific vitamin therapy in deficiency diseases, and the stunning successes of various vaccines and antibiotics.

ENDEMIOLOGY, PSYCHOSOMATIC ILLNESS AND STRESS This doctrine still dominates our search for the source of all illnesses ranging from mental disorders to cancer, as we continually search our external environment for causative agents or carcinogens to eradicate. We refer to the great ‘War on Cancer’ as if there were some battlefield on which a life or death struggle is waged with this dread invader. Our microscopic depiction of the enemy is replete with dramatic descriptions such as destructive, aggressive, invasive, virulent or wildly growing. We fight back by carving out cancerous tissue, cutting off its source of supply, zapping it with radiation, or destroying it with chemical compounds and physical forces. We have become preoccupied with epidemiology, the roots of which, epi (on), demos (people), logos (reason), connote something that has been thrust upon the individual.

Psycholectroneuroimmunology ________________________________ 211 What has largely been overlooked along the way, is what might be termed the ‘endemiology’ of disease7, which refers to those factors within the host that may be of equal or greater importance. However, astute physicians were always aware of the important influences of emotional and mental factors. Sir William Osler believed that it was more important to know what was going on in a patient's head than his chest to predict the outcome of pulmonary tuberculosis. He also emphasized a variety of behavioural disturbances that appeared to be associated with the development of what we now recognize as systemic lupus erythematosus8. Serious efforts to study this did not begin until the early part of this century, with Adolph Meyer’s concept of ‘psychobiology’ that directed attention to the ‘medically useless contrast of mental and physical’9. Others like Franz Alexander, the Menningers, and Flanders Dunbar subsequently developed the field of psychosomatic medicine to investigate the mechanisms of action that mediated the puzzling relationships between illness and stressful life events, personality and emotions. A detailed description of the above can be found in Dunbar’s monumental tome Emotions and Bodily Changes10. In the laboratory, Hans Selye, a brilliant Canadian investigator, was challenging conventional medicine by proposing that very different, and even opposite, noxious stimuli could produce an identical pathological picture of adrenal cortical hypertrophy, gastric ulcerations, and atrophy of thymic and lymphatic tissues. The significance of the latter was not fully appreciated at the time with respect to immune system activities. Considerable attention will be devoted to certain historical details, since if we wish to consider the future of psychoneuroimmunology, it would be wise to avoid problems that have plagued its predecessors. The concept of ‘stress’ was first presented by Hans Selye in 193611 around the same time that Flanders Dunbar introduced the term ‘psychosomatic’ into American medicine. Having had the unique privilege of collaborating closely with these two brilliant investigators, I have also been privy to their concerns, and at times, astonishment, over how the meaning and significance of both, ‘stress’ and ‘psychosomatic’ became transmogrified, as they rapidly spilled over from the scientific literature to the popular press, ultimately becoming vernacular buzz words. As Dunbar noted: This popularization of an incompletely understood terminology is both an asset an d a liability: an asset, because throu gh acqu ain tance with more facts, tho se who use the terms are made increasingly aware of their responsibility in preventive medicine; a liability, because acquaintance has been so brief that the implications are readily elaborated in a matter, somewhat disquieting to the scientists, wh o th oug ht th ey had kn own what they were talking ab ou t. One is often remin ded of the Swiss ad age: Wa ru m einfach wenn es au ch co mp liziert geht? wh ich in effect means ‘Why do any th ing simply when the same pu rp ose can be accomplished in a complicated way?’12

212 ________________________________________________ P. J. Rosch The unusual popularity and appeal of these two concepts, coupled with the difficulty in defining them or establishing the boundaries of their applicability with any degree of precision, encouraged their exploitation by all sorts of unscientific usurpers, ranging from well-meaning zealots and eager entrepreneurs, to crafty charlatans. The resultant extravagant claims and promotion of worthless wares and services has periodically prompted backlashes that obscure the authenticity of legitimate research, with the danger that the baby would be thrown out with the bath water. Selye and Dunbar were consistently cautious about making a sharp distinction between what was mere evidence, as opposed to proof. However, they had no control over others, whose untempered enthusiasm led to unwarranted conclusions and claims, often with disastrous consequences due to further media misinterpretation and manipulation. Psychoneuroimmunology runs the risk of suffering a similar fate, as the allure of its captivating cachet is abused by those who want to profit from the scientific patina it provides. As has happened so often in the past, many have gone overboard with regard to the role of emotions and personality as the cause of almost any illness, or conversely, that the healing powers of the mind, or a strong faith, can cure practically everything. It is likely that psychoneuroimmunology will increasingly attract these sorts of ‘strange bedfellows’. Not infrequently they quote legitimate, but non-relevant research, to promote their ‘clinical’ psychoneuroimmunology programmes, diets, nutritional aids, and devices, in a manner reminiscent of similar spurious claims for various stress reduction services and products.

DEFINING THE IMMUNE SYSTEM AND ITS RELATIONSHIP TO STRESS That we do not learn from the experiences of history, may be the most important lesson that history has to teach. There is a natural, but dangerous, tendency to believe that just because you have given something a name, that somehow you have defined and understood what it is. Everyone thinks they know what stress is, but in reality, nobody does. Attempting to explain it in objective terms is like trying to nail a piece of jelly to a tree. Despite more than a half century of valiant attempts, there is still no satisfactory scientific definition of stress. The blur between mind, brain, soul, spirit, psyche, feelings and emotions, similarly hampers our understanding of exactly what psychosomatic or psychoneuroimmunology really means, or should include. Everyone refers, often with an air of authority, to ‘immune system function’, characterizing it as suppressed, depressed, compromised, stimulated, enhanced, etc. In point of fact, our current conception of exactly what the immune system consists of, or where it is located, is probably rudimentary.

Psycholectroneuroimmunology ________________________________ 213 We recognize that there are rapid humoral responses, as well as delayed, cellmediated processes, each with various components and markers. Immune system function can be ‘measured’ by numerous criteria, including lymphokines and all sorts of antibodies in blood, saliva, urine, and other body fluids. Specialized natural killer, helper, or supressor cells, bear descriptive names which suggest their general functions. Others are represented by combinations of confusing letters, numbers and symbols, with presumed prognostic potential. Thus CD4+, and/or CD4+/CD8+ ratios are currently viewed as the most accurate barometer of immune system status in HIV infection, but even the AIDS alphabet soup is constantly increasing. Attention is now being focused on NK-associated CD16+ (leu11) leu7– and CD16+ (leu11) leu7+ lymphocyte subsets, the inducer subset (CD45RA+CD4+) which activates suppressor/ cytotoxic (CD8+) cells, and the recently discovered CD26 receptor molecule, which may provide the gateway the virus requires to gain entry into CD4 cells. In AIDS, CD4+ helper-T cells may have two separate responses, Th1 and Th2 which seem to be involved in cell-mediated and humoral immunity respectively. During ‘stress’, a cascade of varied immune responses have been observed, including a reduction in cytokines that stimulate both Th1 responses and macrophages (IL-2, IL-12, IFN-γ, as well as an increase in cytokines that promot e t he growth an d differenti at ion o f Th2 and B-ly mph ocytes (IL-4 , IL-10). Immune system status can be evaluated by older and relatively cruder techniques, such as macrophage activity by chemiluminescence following stress, and responses involving properdin, opsonins and complement C3. There are assays for an increasing number of identifiable individual cytokines including interleukins (IL), interferons (IFN), tumour necrosis factors (TNF) and transforming growth factors (TGF), each of which may also possibly provide information about the rate of disease progression and length of survival in certain diseases. Much of the research dealing with the effects of stress on immune system function is based on in vitro studies of the effect of mitogens such as phytohaemagglutinin (PHA), or concanavalin A (ConA) on T-cell activity. However, it is not known whether these mirror in vivo immune responses that accurately reflect resistance to infectious agents or other stressors. One must also appreciate that the standards and accuracy of various immunological measurements and assays may differ in laboratories throughout the world, or that results might depend on whether pokeweed or some other mitogen was used in a specific study. When it comes to evaluating the effects of ‘stress’ on immune system function, the picture becomes much more complex and confusing. In response to a specific stressor, some of these ‘measurements’ might go up, suggesting improved capabilities, while others decline or are relatively unaffected. In addition, the changes observed might be quite different, depending on the nature,

214 ________________________________________________ P. J. Rosch intensity and duration of the stressor. Even in fairly well-defined situations, such as the effect of loss of a spouse on T-cell mitogenic or natural killer (NK)-cell activity, one must appreciate that this most stressful life change event would be perceived quite differently in the devoted survivor of 40 years of a wonderful marriage, as opposed to the feelings of a young widow, for whom the departure of an abusive, wife-beating, alcoholic mate was a welcome relief. One cannot assume something is stressful just because it seems it should be. The presence or absence of a strong social support system, and various psychosocial factors are important modifying factors in evaluating the effects of stressors, as has been recently emphasized in attempts to evaluate the contribution of stress to Graves’ disease and coronary heart disease13. Age, sex, psychological status, prior experience and genetic factors are additional modifying factors. These and other caveats must be considered when evaluating sweeping statements and conclusions about the effect of ‘stress’ on ‘immune function’, or therapeutic triumphs based on psychoneuroimmunological approaches.

STRESS, TUBERCULOSIS, STREPTOCOCCAL INFECTIONS AND THE COMMON COLD Few experienced physicians would deny that stressful emotions can have important influences on health. The question is how these are mediated, how reproducible are they in the same person and how consistently can they be demonstrated in different individuals? As noted previously, Osler recognized the significant impact stress could exert on the course of tuberculosis (TB). Thirty years ago, a retrospective study also demonstrated that the magnitude of antecedent stressful life change events were much greater in TB sanatorium workers who contracted the illness, than healthy control employees14. The same year, an examination of healthy schoolchildren revealed that pneumococci could be cultured in 50% and β-haemolytic streptococci in almost one third15. However, the large majority of those harbouring these potential pathogens never developed signs or symptoms of any infection, and in those who did, the seriousness of the illness varied tremendously. This suggested that host factors were the most important influences in determining both susceptibility to, and severity of subsequent disease. Because of an improved ability to make accurate diagnoses, confirm temporal relationships to stressful events, and monitor relevant immune system parameters, infectious diseases would appear to offer an exceptionally fertile field for documenting psychoneuroimmunological relationships. There has been considerable research in this area. In one very early study, 16 families kept daily diaries of disruptive life events, and throat cultures and ASO (antistreptolysin) titres were obtained periodically, as well as during acute

Psycholectroneuroimmunology ________________________________ 215 infections. It was found that stressful events and rising ASO titres were much more likely to precede rather than follow clinical illness. It is most significant that when stressful events involved the entire family, streptococcal and nonstreptococcal infections quadrupled!16 Other research also demonstrated a link between stress and increased respiratory infections17, infectious mononucleosis 18 , ulcerative gingivitis19,20 and onset or recurrence of genital herpes21-23. Most of these studies attempted to demonstrate concomitant changes in immune system markers which would support a psychoneuroimmunological relationship. Unfortunately, too many may assume that if immune system changes occur in association with some disease, then it follows that the mind, brain, emotions, or central nervous system mediates, or at least can influence its clinical expression. It is essential to distinguish between association and causation, and to separate causation from contribution. Depression of certain immune system parameters may be associated with, and in certain instances, could seemingly contribute to, the development of certain infections and malignancies. This might apply to CD4+ and CD8+ relationships in Pneumocystis carinii pneumonia and Kaposi’s sarcoma in AIDS. It has been shown that the stress of bereavement can result in lowered levels or reduced activity of certain markers for immune system integrity. These changes could imply a lowered resistance to viral linked infections, or malignancies, since similar patterns may also be seen in some patients with these conditions. However, it would be incorrect and quite premature to conclude from this that stress causes colds or cancer. It may provide suggestive evidence, but that is very far from proof. Association never proves causation. Some of the most convincing evidence of the contributory role of stress to clinical infections, comes from research on the common cold. Nasal reactions and susceptibility to colds have long been linked to emotional stress. People who are overwhelmed may say they have had ‘a snoot full’ or that they are ‘paying through the nose’. Guys and Dolls, a popular play and film, reflected the great interest in psychosomatic medicine in the 1940s. These few excerpts from Adelaide’s lament vividly reflect what was contemporary common knowledge about what caused colds and how useless treatment was:24 In other words, just from waiting around for that plain little band of gold, A person can develop a cold. You can feed her all day with the vitamin A and the Bromo Fizz, But the medicine never gets anywhere near where the trouble is. If she’s getting a kind of a name for herself and the name ain’t his, A person can develop a cold.

216 ________________________________________________ P. J. Rosch You can spray her wherever you figure the streptococci lurk, You can give her a shot for whatever she’s got, but it just won’t work. If she is tired of getting the fish eye from the hotel clerk, A person can develop a cold. From a lack of community property, and a feeling she’s getting too old, A person could develop a bad, bad cold.

In 1950, the same year that Guys and Dolls appeared, the Common Cold Research Unit in Salisbury, England, reported that only one of 19 normal subjects exposed for a considerable time to individuals who were sneezing and coughing due to colds, ever exhibited any evidence of infection25. At the same time, Tom Holmes reported his research on the relationship between life situations, emotions, and colds26. He once told me that his interest in stressrelated illness was kindled by frequent reports from friends and patients that they were most apt to ‘catch a cold’ when in-laws came to visit for a protracted period, and that this eventually led him to the development of the HolmesRahe scale27. There have been several studies designed to demonstrate the link between stress and colds, and the mechanisms involved. The most impressive report emanates from the same prestigious Common Cold Unit in Salisbury, more than four decades after the study referred to above28. Subjects received nasal drops containing one of five respiratory viruses, and stress levels were evaluated by scores obtained from combining three standard measures that included severity of current negative emotions as well as life change events over the preceding year. Infection rates, as judged by specific antiviral IgA and IgG antibodies and levels of neutralizing antibodies ranged from 75 to 90%, but clinical colds occurred in only 25-50%. The rates for both laboratory evidence of infection and clinical colds correlated precisely with the magnitude of psychological stress scores for each of the viruses. A logical conclusion would appear to be that stress resulted in increased infection and clinical disease because it depressed immune system function and lowered host resistance. However, even had this been supported by appropriate immunological data, there are still alternative explanations. Forty years ago, in a series of elegant studies, Wolf demonstrated that feelings of guilt, humiliation, resentment, hostility, and similar suppressed, stressful emotions, were associated with increased swelling, secretion, and hyperaemia of the nasal mucosa, often causing nasal obstruction. This was verified both by careful physical examination, and biopsies of the nasal mucosa29. It has been shown that swelling of the nasal mucosa renders individuals much more susceptible to local infection30. These responses are medi-

Psycholectroneuroimmunology ________________________________ 217 ated by increased parasympathetic and cholinergic activity. In contrast, in the ‘fight or flight’ response to acute stress, which is accompanied by a state of heightened vigilance and anxiety, just the opposite findings are seen3l. Because of catecholamine induced vasoconstriction, there is shrinkage and pallor of the nasal mucosa, and nasal breathing is clearer, which makes sense from a teleological viewpoint. Holmes and co-workers also indicated how surprised they were to find that the nasal mucosa in reactive individuals would either swell or shrink depending on the nature of some threatening event32. This illustrates some of the pitfalls that can be associated with claims for stress-induced, psychoneuroimmunologically mediated illness. With respect to the common cold, where common beliefs, as well as scientific research support a causal connection, involuntary humoral or autonomic activities that influence ciliary function and local nasal membrane defences may be more important than psychologically mediated immune system mechanisms. Both autonomic and immune system responses will vary considerably, based on the nature, intensity and duration of the stressful emotion being implicated. The stress of infection may also involve unsuspected neuroendocrine activities that are triggered by immune responses, as evidenced by studies of cytokines which are released in excessive quantities during septic shock due to bacterial endotoxins, with deleterious consequences. Most of the interest in septic shock has focused on the role of interleukins and tumour necrosis factor, and ways to block their activity. However, macrophage migration inhibitory factor (MIF), one of the first human cytokines identified, which inhibits macrophages from moving towards a chemotactic stimulus, is also involved. It is elaborated by activated T cells, but in a recent report, it was shown that when cultured pituitary cells and whole pituitary glands were stimulated with bacterial endotoxin, they also produce MIF in substantial quantities33. In mice injected with a sub-lethal amount of endotoxin, MIF production was increased, and recombinant pituitary MIF markedly potentiated lethal endotoxin effects. Conversely, antiserum to MIF completely protected the mice from death due to endotoxaemia, which could have important clinical implications. But why should MIF be secreted by the pituitary? What is it doing there?

NEUROENDOCRINE-IMMUNE SYSTEM INTERRELATIONSHIPS There are numerous other immune system responses that automatically provoke other pertinent endocrine and nervous system activities34 . IL-1, a cytokine involved in orchestrating immune responses, also stimulates the release of corticotropin releasing factor (CRF) by the hypothalamus. This, in turn, stimulates the pituitary to secrete ACTH, resulting in increased adrenal

218 ________________________________________________ P. J. Rosch glucocorticoid production. These hormones have powerful immunomodulating properties, particularly with respect to suppression of immune responses. Regulation of ACTH secretion by IL-1 might represent a feedback loop that could demonstrate a meaningful brain-immune system relationship35. There are numerous other bidirectional communication links between the brain and the immune system, and these have been deftly depicted by Reichlin36, to whom I am indebted for permission to reproduce Figure 1. As indicated neural influences can override the normal negative feedback relationships between the pituitary and the adrenal cortex, as well as the thyroid and other target glands not shown here. However, some may not be under the control of higher centres. Even if this could be demonstrated, we should not automatically assume that all immune system responses can be influenced by thoughts or feelings.

PSYCHONEUROIMMUNOLOGY AND AIDS Thirty years ago, George Solomon hung a sign on his office door proclaiming it a ‘Psychoimmunology Laboratory’. In 1984, two decades later, he listed 10 hypotheses that should be able to be proved to support the contention that the central nervous system and immune system are closely linked37. In 1985, there were 14, in 1987, 35 (with citations), by 1988 the list had grown to 65, and at the end of 1992 it was over 100!38 Nowhere is this explosion of interest more impressive or more important, than in the subject of AIDS. In the first edition of Ader’s Psychoneuroimmunology, a monumental compilation of relevant areas of interest published in 1981, there is no reference to AIDS or the human immunodeficiency virus (HIV) in its index39. In the second edition, published 10 years later, the concluding chapter was devoted to this and included 150 pertinent references40. Similarly, the annotated bibliography Mind and Immunity published in 1983 contained no references to AIDS41. A subsequent compilation of the literature by the same editor published in 1986, had only one citation, dealing with the treatment of emotional problems in AIDS patients42. As indicated, there is probably no other disorder more important to study. AIDS is now the leading cause of death in young American males, and some estimates suggest that by the end of this decade, over 100 million individuals, or 2% of the world’s population, will harbour HIV. Nor is it likely that any other field could prove more fertile for discovering how CNS-immune system relationships are mediated. Much more is known about the immunological characteristics of various stages of AIDS than any other disorder. Since it is possible to identify seemingly healthy individuals who harbour the virus without any signs or symptoms of this disease, it should be feasible to monitor its subsequent progress. This would allow us to determine whether certain

Psycholectroneuroimmunology ________________________________ 219

Figure 1 Some hypothalamic pituitary adrenal interactions and relationships with peripheral immunocompetent cells. These may be influenced by external and internal stimuli that affect circadian rhythms, as well as various types of emotional and physical stress. Sp ecific cy to kines released by activated T cells in resp onse to bacterial endotoxin can induce the release of corticotropin releasing ho rmon e (CRH) and vaso pressin (VP) from the hy po thalamus, bo th of which stimulate corticotropin (ACTH) secretion. CRH also activates autonomic nervous system responses through multisynaptic descen d in g path way s. Ad ren al medu llary secretio n of ep inep h rine synergizes CRH and VP activities and increases ACTH→cortisol prod uctio n. Circu latin g cortisol inhibits peripheral immu no competent cells, reducing their secretion of cytokines, peptides, and other substances involved in mediating inflammatory responses. ACH den o t e s a ce t y l c h o l i n e , 5 - H T s er o t o n i n , NE n o r e p i n ep h r i n e, G AB A γ-amin ob uty ric acid, IL in terleuk in , and IL-1 -RA interleu kin-1 receptor antagonist. Adapted from Reichlin36

220 ________________________________________________ P. J. Rosch emotional states or types of stress can hasten or retard the clinical appearance and course of AIDS, and more importantly, whether this can be influenced by higher centres in the brain. There have been major advances in identifying individual cytokines (IL, IFN, TNF, TGNF) that appear to be markers for disease progression and long-term survival, although it is not clear whether they reflect cause or effect. There are numerous anecdotal reports of AIDS patients who have apparently had a complete and seemingly spontaneous remission, or are alive well past the date it had been predicted they would succumb. In many instances, this has been attributed to a marked change in attitude and lifestyle, or exercise, special diets, stress reduction strategies, herbal remedies, faith healing and other ‘naturopathic’ interventions. Immunological studies in some patients have confirmed corroborative changes in immune parameters associated with disease progression. AIDS patients who benefited from exercise and stress reduction interventions, showed corresponding improvement in T4/T8 ratios, T4 cell counts, CD45RA+CD4+ inducer subset values, NK-cell cytotoxicity, etc.43-45. As a consequence, stress management strategies are increasingly being included in treatment approaches46. If we had more accurate and sensitive ways to measure the efficacy of such interventions with respect to their ability to reduce stress levels significantly, it might help to explain why some infected individuals can remain healthy for such long periods of time. This could also lead to promising new therapies. It has been proposed that an imbalance in Th1-type and Th2-type responses may be a factor in disease progression, and these are associated with changes in INF and interleukin cytokines47. In vitro studies suggest that interleukin 12 may reverse this process, and if verified by clinical trials, could represent ‘a renaissance in immunotherapy’48. There is also intriguing new evidence that certain individuals may have a natural resistance to the virus not detectable using standard measurements. A very recent report describes seven individuals who tested negative for HIV in the conventional serum enzyme immunoassay, but had a positive urine antibody response49. All had a history of exposure, and in one, whose partner was HIV-1 positive, more sophisticated cell-mediated immune response investigations did confirm HIV-1 infection. This suggests an ability to fight off the virus with specialized killer cells more powerful than presently identified antibodies. If so, this might lead to the development of more effective drugs and vaccines for AIDS. The point is that monitoring a high risk group utilizing more advanced and precise testing techniques could help to uncover unsuspected CNS-immune system pathways that would both confirm the importance of such links and improve treatment approaches. However, there are many different coloured, interwoven threads that must be unravelled in this complex fabric. It is not clear what threshold of immune system impairment renders the individual particularly susceptible to CNS

Psycholectroneuroimmunology ________________________________ 221 influences, what types or forms of stress are the most important in this regard, and most importantly, what the significance of disturbances in various immune system markers is to eventual health consequences. Although these and other factors have been studied separately, this may have little practical significance, unless they are integrated with the effects of other modulating influences, such as social support50, particularly when attempting to evaluate the effects of stress13. As depicted in Figure 2, life on earth consists of a hierarchy of living systems, ranging upwards from atoms, molecules, cells, organs and tissues, to people, families, corporations and societies. Disruption of homeostasis at any of these tiers can reverberate up and down the line, and the highest and lowest levels may not yet be defined. A ‘biopsychosocioecological’ perspective that acknowledges communication links with the biosphere, may be required to fully appreciate the entire spectrum of stimuli that can affect higher centres in the brain. A variety of studies have confirmed a relationship between geomagnetic disturbances and increased rates of emotional and psychiatric disorders. These important interrelationships must be kept in mind, since psychoneuroimmunological test tube results may not accurately reflect what happens in vivo.

PHYSICAL/ATOMIC COMMUNICATION AND PSYCHOELECTRONEUROIMMUNOLOGY In the final analysis, all of this boils down to the simple observation that good health depends on good communication—good communication within the internal environment of any constituency, and good communication between the component and the external environment. That holds true whether one chooses to look at the health of a simple cell or a societal system. Over the years, our appreciation of communication in the body has progressed from various organs talking to one another via hard-wired connections, to humoral pathways. Communication is currently viewed at a chemical/molecular level, as signals transmitted by specific molecular messengers that dock at specified receptor sites. However, this model does not explain such observations as the increased incidence of birth defects associated with the use of electric blankets during pregnancy, reports of increased rates of malignancy in connection with proximity to high power lines, geomagnetic influences on behaviour, the biobehavioural effects of acupuncture, therapeutic touch, the placebo effect, and numerous other widely acknowledged, but poorly understood phenomena. These, as well as significant physiological responses to such subtle energies as weak cranioelectrical stimulation, pheromones, and feeble olfactory, photic and auditory stimuli, cannot be explained in terms of Newtonian physics, or thermodynamic laws governing ionic flux across cell membranes.

222 ________________________________________________ P. J. Rosch

Figure 2 Information flow in hierarchical living systems

All communication in the body essentially takes place at a physical/ atomical level, as ions pass back and forth through the cell membrane due to local changes in electrical tension which open and close specific channels. As suggested previously51, it seems increasingly plausible that the cell wall is more than a protective barrier studded with receptor sites for small peptides. It is quite likely that it can also sense and respond to a variety of subtle energy stimuli directly, and at a more basic level than our current appreciation of intercellular communication. Nordenstrom has presented impressive evidence for the existence of an electrical circulatory system in the body, and such a paradigm could explain many of the mysteries referred to above52,53. Thus, EEG waves may not merely be the noise of the machinery of the brain, but rather reflect messages and signals being sent by the mind to other parts of the

Psycholectroneuroimmunology ________________________________ 223 body. A fuller comprehension of this may require thinking in terms of what might be called psychoelectroneuroimmunology. Some psychoneuroimmunological observations may be mediated by unanticipated pathways and mechanisms not yet fully appreciated. The therapeutic benefits of a firm social support system in AIDS and cancer seem to have a more rational basis when viewed in this light, and there is already some evidence to support the influence of subtle energies in these disorders54-55. It is clear that exposure to ultraviolet radiation can cause or at least facilitate the development of common skin cancers. Such subtle energies can also accelerate the progression of AIDS, which may explain why the skin lesions in HIV infected individuals are seen most often on the face, neck, and other exposed areas of the skin56. There is considerable evidence that non-thermal exposure of immune system cells to extremely low frequency electromagnetic fields (300 Hz) can produce changes that would affect in vivo immune activity57. Similarly, non-ionizing electromagnetic energy can also produce changes in neuroendocrine and musculoskeletal tissues, and both of these effects may be mediated by calcium-regulating activities at cell membranes. Weak chemical pollutants, changes in weather patterns and climate, light/dark rhythms, and lack of gravitational influences during space flight are other subtle energy stimuli that can affect immune system function58. There are even claims that electromagnetic forces may be used to treat AIDS59. Energies generated internally by emotions and intense mental activities might also be capable of influencing immune activities, a concept that might be referred to as psychoelectoneuroimmunology. It has been suggested that life on earth began in the Precambrian era as a result of geomagnetic forces that formed the first biological molecules, such as proteins, from amino acids60. Geomagnetic influences undoubtedly exerted continuing strong influences during the course of man’s lengthy evolution, and such communication pathways clearly persist in lower forms of life, including fish and animals, who may be sensitive to impending earthquakes and weather changes. From a Darwinian perspective, it appears likely that somewhere back in our phylogenetic past, the immune system was part of the brain, and became partially separated anatomically as more sophisticated and specialized forms of life developed. Some immune cells remained in the brain, while other neurons may have sent axons to the spleen, bone marrow, and other tissues. This might explain why certain viruses are tropic for both immune and brain cells, and why immune system cells have receptors for brain neurotransmitters and neuropeptides. The brain and the immune system are also the only parts of the body that have the capacity to ‘remember’. As knowledge of the role of the immune system in health and disease expands and is clarified, there will be vigorous attempts to determine how CNS influences may modulate such activities. Such future efforts will undoubtedly include topics such as allergic and hypersensitivity states, immunosuppression

224 ________________________________________________ P. J. Rosch and problems related to organ transplantation, immunological aspects of various malignancies, immunodeficiency diseases, autoimmune disorders, and the contribution of autoimmune disturbances to the aging process. However, it is a giant leap from in vitro research to the living organism. It is also not clear whether all animal studies can be extrapolated to humans because of a variety of confounding psychosocial influences that cannot be reduplicated. Although one of the earliest studies in laboratory animals with autoimmune disease clearly demonstrated that conditioning could alter immune responses and significantly prolong life, and this has been repeatedly confirmed, it is still uncertain how the practising physician can utilize this information.

FUTURE DIRECTIONS In concluding his Foreword, Dr Ader emphasizes that future progress in this field will require ‘careful research, new methodologies, and communication between scientists in traditionally distinct fields’. It will also need ‘the imagination of successive generations of creative researchers and clinicians’. It is of more than passing interest, that both Selye and Ader frequently referred to the accidental experiments that led to their propaedeutic concepts as ‘serendipitous’. This adjective is derived from the title of Walpole's fairy tale, The Three Princes of Serendip, whose heroes made unexpected felicitous and fortuitous discoveries of things they were not looking for. Serendipity has the connotation of stumbling upon something by blind luck. Many do not realize that the author also stressed that these individuals possessed keen powers of observation and discernment, and that this sagacity played an important role in their good fortune. Pasteur noted, ‘Chance only favours the prepared mind’. The majority of discoveries in medicine and biology have been uncovered unexpectedly, or have had some element of chance, particularly those which have been the most important and revolutionary. As Claude Bernard pointed out ‘A discovery is generally an unforeseen relation not included in a theory, otherwise it would be foreseen’. In other instances, major advances have come more from the ability to bring together discoveries in different specialized areas, than as a result of focused laboratory investigations. A good example of this is the discovery of DNA by Watson and Crick, who put together bits of evidence in chemistry, physics and biology. Comparatively little original research was required, and their success was due to the ability to synthesize the information already available because they understood the language of sister disciplines. If history repeats itself, advances in psychoneuroimmunology will also come from unexpected quarters and seemingly irrelevant activities. The distinguished medical historian Sigerist has emphasized that the success of a discovery also often depends on the timing of its appearance, and the

Psycholectroneuroimmunology ________________________________ 225 interaction of these advances with cultural attitudes61. Because the media is now immediately aware of all new advances, and often tends to sensationalize them, psychoneuroimmunological research is apt to be driven by societal pressures. Patients will be concerned and confused about exactly how much they can influence their own health by self-directed measures. Given a choice, most of them would rather substitute skills for pills. But they will also want answers to many questions. Can ‘positive’ emotions and feelings such as those engendered by a powerful faith, humour, curiosity, strong social support, or what Selye termed ‘eustress’, really bolster immune defences? If so, does this apply to everyone? What pathways and circuits are involved in transmitting such messages from the mind to the body’s defence systems? Will it be possible to tune in to such conversations to get a better handle on the language or languages being spoken, or to enlarge our vocabulary? How can we influence the dialogue? If we understood how such effects are mediated could we possibly learn how to stimulate, simulate, or emulate them? While we are accumulating information at a rapid rate, more often than not, this new knowledge provides little wisdom. Rather, it serves more to illustrate how little we know, rather than how much. As new research findings are made available, there are important caveats with respect to interpreting their clinical significance and applications. Few experienced physicians would deny the salubrious rewards of a positive fighting attitude, or developing a sense of confidence, conviction and certitude. However, there is always the danger that some zealots will go overboard in proclaiming and expounding on the unlimited potential power of the mind or an unqualified faith. We have already witnessed this in some cancer patients, who eschew conventional therapies that could be life saving, to pursue some ‘natural’ approach that offers more hype than hope. The other side of the coin is that nothing could be more cruel than adding to the guilt of a cancer patient by implying that their illness or failure to respond to treatment is due to some defect in character, or inability to cope with stress. Claude Bernard, who developed the concept of the milieu intérieur (internal environment) emphasized that good health and life itself was dependent on the ability to maintain its relative constancy. Fifty years later, Walter Cannon termed the integrated physiological processes required to maintain this steady state, homeostasis, from the Greek homios, meaning similar, and stasis, or position. A few decades after Cannon, Hans Selye demonstrated that disease was often due to insufficient, inappropriate, or excessive adaptive responses to stressors that threatened homeostasis. The theoretical constructs of all these brilliant investigators could obviously only go as far as contemporary scientific knowledge permitted. The term ‘hormone’ did not come into existence until 25 years after Bernard’s death. Canon could only refer to the humoral substance or substances involved in his ‘fight or flight’ response as something he called ‘sympathin’. Selye’s research coincided with the

226 ________________________________________________ P. J. Rosch development of endocrinology as a fully fledged discipline, and the discovery of ACTH and cortisone, and their dramatic effects in clinical disorders. There was only a hint that such things as brain neurotransmitters even existed, much less played a prime role in participating in the response to stress. What happened in the body when homeostasis was disturbed by some stressor, was viewed as automatic and involuntary. Such adaptive reactions had been progressively developed over the course of evolution. If they resulted in illness, this was something over which we had no volitional control. Infectious diseases resulted from exposure to pathogenic microbes, and similarly could not be modified by self-directed measures. Even if one’s state of mind could influence clinical consequences, it was obvious that there was no way for scientists to study, much less prove this. Not everyone agreed with this assessment, and if history is able to teach us anything, it may be instructive to review some aspects of this debate. On induction into the prestigious Académie Française, Pasteur’s acceptance speech stressed that true knowledge could only be attained by experimental methods that adhered to strict scientific standards. He also emphasized that problems related to emotions or faith, were not, and could never be, an appropriate subject for scientific study62. The presiding officer, Ernest Renan, was Professor of Sanskrit at the Collège de France, where he had come under the influence of Claude Bernard, the Professor of Experimental Medicine. Bernard had insisted that the essential ingredient for true scientific investigation was doubt. This was not meant to imply a stubborn and sterile scepticism, but rather a thoughtful, reflective, questioning process, which encouraged a free range of imagination and initiative. As we have elsewh ere ex p lain ed , do u b t is th e fo u n d atio n of ex p erimen tatio n ; yet we must not confuse philosophic doubt with that systematic negation which casts doubt on the very principles of science. We must doubt only theories, and we must doubt even them only to the point of experimental determinism.... Wh ereas the scho lastic is prou d, in toleran t, an d does not accept contradiction , the experimenter who is always in doubt and never believes that he has achieved absolute certainty, succeeds in becoming the master of phenomena, and in bring63 ing nature under his power.

In his response, Renan praised Pasteur’s achievements, but took issue with his conviction that it was possible to study the problems of life only by the scientific method of objective experimentation. He doubted the certainty of Pasteur’s Cartesian conviction that it was impossible to study scientifically such things as the role of emotions and faith, or that the experimental method was the only way to acquire knowledge64 . Historians, sociologists, and philosophers also conducted studies and reached rational conclusions based on scientific principles. He believed that feelings, behaviour, and even religious dogma, should eventually succumb to scientific study.

Psycholectroneuroimmunology ________________________________ 227 Psychoneuroimmunology offers the prospect of confirming this prediction. It may also provide a portal that permits a glimpse into unsuspected communication pathways between the central nervous system and subtle external and internal environmental influences, widely recognized, but previously not susceptible to scientific scrutiny. Future advances may also confirm the necessity of viewing the ultimate health of the organism as dependent not only on physicochemical phenomena that affect biological function, but also on proper spiritual relationships with society and perhaps the universe. It is of more than passing interest that Claude Bernard devoted the last chapter of his famous Introduction to the Study of Experimental Medicine to the philosophical and social aspects of this subject. In the first section of this, entitled The False Application of Physiology to Medicine he states: Observing physicians look on a living organism as a little world contained in the great world, like a kind of ephemeral living planet whose motions are ruled by laws which we discover by simple observation, so as to see the progress and evolution of vital phenomena in health or disease, but without ever being able to alter their natural course in any way.

Similarly, Walter Cannon’s epilogue to The Wisdom of the Body was entitled Relations of Biological and Social Homeostasis65. Pasteur was a great admirer of Bernard. He wrote a review praising his seminal and unique contributions to cheer Bernard up during a protracted illness, and referred to him as ‘a man I loved and admired’66. Their seats were next to each other at the Academy, and they often engaged in lively debates, the most famous dispute being over how alcohol was produced when grape juice turned to wine. They were also part of the three-man French commission appointed in 1865 to study the epidemic that was killing 200 Parisians daily. Although Koch later identified Vibrio cholerae as the culprit, others, like the hygienist Max von Pettenkoffer, doubted that the bacillus by itself could cause the disease. To prove this, he obtained a culture freshly isolated from a fatal case in the current Hamburg epidemic, and swallowed a large amount, considerably in excess of any normal exposure. This was done on an empty stomach whose acidity had previously been neutralized by ingesting a sufficient amount of sodium carbonate, since Koch had shown that these were the most favourable conditions to promote the growth of the organism. Although large numbers of active bacilli could be cultured from the stools, he experienced no a d v e r s e s y m p t o m s o t h e r t h a n m i l d d i a r r h o e a . Two o f h i s s t u d e n t s , Metchnikoff and Emmerich, who subsequently became famous bacteriologists, repeated the experiment with the same result. Although none of these scientists doubted that the bacillus was the causa vera of cholera, it was apparent that its implantation did not guarantee contracting the illness. Although the germ theory of infectious disease seemed indisputable, numerous other psychosocial and environmental factors were obviously involved when

228 ________________________________________________ P. J. Rosch it came to clinical disease. However, as indicated elsewhere, theories do not have to be correct, only facts do67. Some theories are valuable because of their heuristic merit, in that they encourage others to discover new facts, that prove them incorrect, and lead to the development of new theories. Some current psychoneuroimmunological assumptions may eventually fall into this category. It is likely that Pasteur was aware of the cholera ingestion experiments, which were conducted two years before he died, since Metchnikoff was devoted to him during his final days. It is alleged that on his deathbed, Pasteur said ‘Bernard avait raison. Le germe n’est rien, c’est le terrain qui est tout’. [Bernard was right. The microbe is nothing, the soil is everything.] In a sense this exemplifies what every ‘compleat’ physician comes to recognize, namely, that many times it is more important to know what kind of patient has the disease, than what kind of disease the patient has. Psychoneuroimmunological research may offer important insights into this. Hopefully, it will provide ways for individuals to become more proficient in promoting health, preventing disease, and improving the results of conventional therapies. It offers the promise of developing an ability to harness the wisdom of the body, and the vis medicatrix naturae (healing ways of nature), if such things do in fact, actually exist. There are numerous existing problems and pitfalls associated with this quest. What we, must avoid is creating others. As noted in the conclusion of a previous article devoted to this issue: Abraham Lincoln may have provided the formula when he suggested to his law partner, ‘L et no t a worship of th e past no r a confusio n of the presen t keep us from an attempt to plan wisely for the future’. There are myriad discoveries open to the educated, inquisitive, but uncluttered mind, and as we mature in our knowledge and appreciation of the art of healing and the science of medicine, we sh ou ld strive to feel ‘only th e check rein , not th e cu rb, the bind er, or the hobb le’ 68 in the pursuit of that elusive synthesis .

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