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Stress, Depression, and Behavior
   
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Stress, Depression, and Behavior
A Perspective on Psychoneuroimmunology

Stephen W. Bachove


INTRODUCTION

In 1680, a physician, P.P. Ferenc stated "When the parts of the body and its humours are not in harmony, then the mind is unbalanced and melancholy ensues, but on the other hand, a quiet mind makes the whole body healthy" (Ferenc, 1680). How does one take all the processes of the human body, its biology, physiology and psychology and integrate them into an entire picture of mind, body and spirit? The answer is the field of Psychoneuroimmunology. This paper will be a review of the many developments in psychoneuroimmunology published over the past ten or twenty years. There are many routes through which psychological factors influence our immune function, how stressor's duration could influence changes, the individual differences, interventions that may control immune function, and most importantly, the health consequences of psychosocial mediated immune dysregulation. 

We will see how negative affect and personal relationships influence immune regulation. An immune dysregulation may cause and be associated with a number of diseases and functional decline. The production of proinflammatory cytokines influence many conditions and can be stimulated by negative emotions, such as stress, depression and prolonged infection.

HISTORY

Psychosomatic medicine dates back to the thirties and forties, this was an anticipation of Psychoneuroimmunology (PNI). The immune system at that time was considered autonomous. In the forties, Hans Selye discussed stress as a factor influencing homeostasis. "A state of stress that in turn, depending on external moderators such as social support and on internal moderators, such as coping ability, leads to no change to psychosocial growth, or to an adverse health change" (Selye, 1980). Selye realized the hypothalamic-pituitary-adrenal axis (HPA) as mediating stress effects on health. In the sixties, George Engel coined the term "biopsychosocial model of all disease" (Engel, 1960). In the later sixties Rudolf Moos and George Solomon, pioneers in PNI, explained with their studies on rheumatoid arthritis, an autoimmune disease, that arthritics were more anxious and depressed than non-arthritics (Moos & Solomon, 1965). Their studies showed psychological well-being was serving as a protective function in the face of a genetically determined predisposition to an autoimmune disease, since the onset of autoimmune disease frequently follows a stressful life event, such as bereavement for loss of a loved one. They did further research on viruses causing illnesses that were directly related to the stress of the individual. The groups were more susceptible to virus induced infectious diseases and tumors if there was ongoing chronic stress. Solomon found that stress effects on immunity were not entirely mediated by adrenal cortical hormones, because stress could still lead to suppression of humoral (antibody) immunity in animals that were adrenalectomized, but were administered doses of corticosterone (Solomon, 1972).

Many significant research experiments followed at this time by now well-known scientists. There was a report by Bob Ader and Nick Cohen on conditioned immunosuppression in rats (Ader & Cohen, 1975). Also, David and Suzanne Felten's studies of sympathetic innervation of lymphoid organs, especially the thymus gland became landmark studies (Felten, 1988). This revealed the connections of the immune system and the role of neurotransmitters at synapse-like nervous-immunocyte junctions. Then Geraud Renoux carried immunoregulation to the cortex of the brain with the discovery of cerebrolaterally differential effects on T-cell maturation and function (Renoux, 1983). Before this the afferent (immune to the brain) limb of the brain-endocrine-immune axis was shown by changes in corticosterone levels, and in firing rates of hypothalamic neurons after an antigenic challenge (Besedovsky, 1977).

Another important finding by Blalock and Smith showed the effects of immune cytokines on the brain and neurohormones, neurotransmitters and neuropeptides on immunologically competent cells. They discovered that lymphocytes synthesize ACTH and beta-endophin (Blalock & Smith, 1981). Human stress and immunity studies continued into the nineties. Human stress and immunity have been studied in relation to depressive illness which was first shown in regard to T-cell function and NK cell activity (Schleifer, 1984). There were many studies done on social stress in primates at this time. Also noted, the outcome of a stressful encounter rather than the encounter itself is critical, and was shown by the immunosuppression of defeated fighting fish (Faisal et.al., 1989). In March of 1987 the Journal of Brain, Behavior and Immunity appeared, and Robert Ader edited the now premier text on PNI. In 1993 the Psychoneuroimmunology Research Society was established.

BASIC IMMUNOLOGY

The immune system is a highly complex structure which determines what parts of a healthy organism are expanded and which are harmful. There is a genetic balance of its components which have the ability to learn and adapt (Rook & Stanford, 1998). As a dynamic system the immune system has much in common with the nervous system. The cells of the immune system are spread throughout the body. They appear in the lymphoid system, blood and most tissues. If a foreign organism enters the body it is detected by white blood cells (WBCs). They then produce a response to the invasion. The stimulus is called an antigen, and it can even be a cell in the host that is mistaken as harmful to the host. Now begins the inflammation process. WBCs called granulocytes and macrophages engulf the invader. This is known as phagocytosis. The macrophage presents a small fragment of debris to a lymphocyte. When a specific antigen is recognized by a lymphocyte, they multiply or clone. After this encounter, a type of memory is generated by the lymphocytes for use in the future for more specific attacks.

The WBCs release products to other cells and structures in order to regulate activity. Non-specific hormone-like proteins called cytokines act as communicators which effect differentiations in growth and activation (Roitt, 1989). Cytokines are active in many capacities including the interaction between the nervous and immune systems. Much will be discussed about these cytokines and their relationship to stress and depression.

T-lymphocytes further subdivide into helper-T cells which stimulate cytotoxic T cells which directly lyse target cells. Another cell the B-lymphocyte mediates humoral immunity and they produce antibodies. Antibodies coat a cell and mark it for other cells. Next there are natural killer cells (NK) that are usually directed to virus-infected cells and tumor cells as well.

ASSESSMENTS OF THE IMMUNE SYSTEM

There are quantitative measures (assays) which describe counts and percentages of immune products, and functional measures assess the reaction of immune responses. Venous blood is generally used but saliva, breast milk or cerebrospinal fluid may be used for assays. These measures usually concern the multiplication of lymphocytes when a "mitogen" or inducer cell proliferation stimulates them. Another method is to measure the ability of NK cell activity to lyse tumor cells (Kiecolt-Glaser, 1988). 

No consensus exists concerning the interpretation of the magnitude of changes in a certain immune parameter. We do know however if the immune system is under heavy strain because then increased morbidity and mortality ensue. We know that if the immune system has lowered titers of a T helper cell count, that this is related to increased risk for pneumonia after chemotherapy, and can lead to infections, tumors, and eventually death in HIV-positives (Kane, 1993). Immune parameters can also be predictive of mortality in the elderly. The number of WBCs is an important clinical parameter in cancer patients after bone marrow cytotoxic treatment (Bonadonna, 1988). We also know that stress and strain from psychosocial factors can change the susceptibility to disease (Cohen, 1997).

INTERACTIONS BETWEEN IMMUNE AND NEURAL SYSTEMS

Pathways of communication consist of direct innervations of lymphoid organs and mutual production of receptor mechanisms for hormones, neurotransmitters and cytokines. Through these pathways the immune system interacts with the neuroendocrine system and integrates responses to stimuli. Stimuli may be physical, psychosocial or infectious in nature. So we now realize the lymphoid organs are supplied with sympathetic fibers. Manipulation of the nerves affects immune function. Synapses are formed between the nervous system, T-lyphocytes, and macrophages (Felten & Felten, 1991). Here is how it all works. Messengers released from nerves influence immune cells and their activity. Neurotransmitters, substance P, vasoactive intestinal peptide (VIP), and somatostatin are recognized by lymphocytes and macrophages, so local release of these substances changes movement patterns (Ottaway & Husband, 1992). Substance P is a powerful promoter of inflammation. 

Different centers of the brain are involved in immune regulation. Hypothalamic lesions affect immune variables and can inhibit allergic shock as an example (Stein, 1991). The neocortex in mice controls factors that modulate T-cell activity and it differs between left and right hemispheres (Renoux, 1983). A key finding in brain-immune interactions was the observation that interleukin-1 (IL-1), a cytokine, is an early effector in immune responses and triggers the release of corticotrophin releasing factor (CRF) in the hypothalamus. The action of CRF in the brain can affect immune function. CRF activates the hypothalamic-pituitary-adrenal (HPA) axis, and is also involved in the regulation of the autonomic nervous system (Fuchs & Sanders), 1994). So CRF is a pivotal transmitter in the host response to stressors.

The glucocorticoids that result from CRF are known for their immunosuppressive properties, but are really important for normal immunity (Ader, 1995). Activated immune cells travel in the brain and cells in the brain may release immune regulatory products like IL-1 (Hopkins & Rothwell, 1995). Now we can understand that the nervous and immune systems are physiological systems that are closely linked and share mechanisms and transmitters. They are mutually dependent on each other. Host defense against threats can be affected by psychosocial and environmental factors, and behavior can be influenced by immune activity through receptors for cytokines in regulatory centers of the brain.

STRESS AND THE IMMUNE SYSTEM

Inflammation is the first stage of immune activation. It may result from virus, heat, debris, and other factors. In the acute phase reaction the immune cells are activated. Acute phase proteins which use stored energy reserves are produced. Stress hormones are one part of the change in this metabolism. This phase releases hormones, neuropeptides and cytokines to regulate an attack and also initiate the healing process. The changes in physiology and behavior at this stage are called "sickness behavior" (Dantzer, 1998). The organism will reorganize its behavior for its needs. Humans regulate body temperature through metabolism and also by behavioral means to optimize conditions during microbial challenge.

The brain uses cytokines as internal signals of sickness. Substances that cause fever, pyrogens such as IL-1 and IL-6, also exert effects that resemble the hypothalamic symptoms of clinical depression and causes changes in appetite, motivation and sleep (Stein & Miller, 1991). Sickness response is a well-organized motivational state that directs behavior so as to promote recuperation.

Stress can be viewed as a sudden and intense disturbance of homeostasis, which can influence the central nervous system (CNS), the endocrine system or the immune system (Kusnecov & Rabin, 1994). Just as in the inflammation response there is a disturbance of equilibrium. All the neuroendocrine factors involved in the stress reaction affect some aspect of the immune response. Experimental studies implicate activity of the HPA axis, the sympathetic nervous system (SNS), and other pathways in immune modulating stress responses (Ader, 1995). Increases in NK cells in blood after mental stressors can be stopped by blockade of B-adrenergic receptors with Propanolol (Schedlowski, 1999). The changes from acute stress are not seen in chronically stressed individuals, because there is a downregulation of sensitivity to protect the body from overstimulation. Patterns in physiologic changes in stress response vary due to factors such as the individual interpretation of their situation, and the coping strategies applied (Steptoe, 2000). Another source of variation is in the frequency and duration of stressors. 

Immune effects of acute and chronic stress differ. Some immunologic responses adapt in the short-term stress, while chronic stress is connected with maladaptations. The adaptive effect of acute stress is part of the innate portion of the immune system. As an example, performed on rats, an inescapable shock to the tail will stimulate macrophages and the acute phase response, and will also speed the time to resolve local inflammation (Deak, 1999). Stress and immune interaction is very complicated and different parts of the immune system may react in opposite ways after exposure to a stressor. Also depending on the study design, decreases and increases in tumor growth have been noted in experiments (Kort, 1994).

Effects of acute stress have much in common with immune activation. Common brain circuits are activated following mental stress or an immunologic challenge. So stress is a multimodal disturbance of homeostasis. It has been hypothesized that immune cells and nerve cells communicated in the periphery before the distant brain position evolved (Ottaviani, 1993). This may explain the special communication across the blood-brain barrier. Biological and behavioral changes are part of the organism's active defense strategy and are basically favorable host reactions against a threat. As we think about the health viewpoint in medical treatment, by-products of disease must be distinguished from true defenses. A more simplified view of stress is immunosuppressive, in general, and should be balanced to other effects that are adaptive to the organism.

IMMUNOLOGY AND PSYCHOLOGICAL BALANCE

The balance of activity within the immune system is reflected in the physical and mental well-being of an individual. The most common causes of death in hospitals are pathological states due to improper balances between the good and the bad inflammatory states, as in multiple organ dysfunction syndrome, a systemic and not a local process (Bone, 1996). In such cases our dynamic system looses its ability to restore levels of homeostasis. Recent research has shown that the nervous system is helping to regulate between pro- and anti-inflammatory processes (Heijnen, 2000). If the HPA stress system is blocked anywhere, a normal animal will die from inflammation after an immune challenge. For example, blocking the glucocorticoid receptor at the HPA axis produces a 100% mortality in rats after injecting inflammatory causing bacteria (Sternberg, 1989). This tells us that negative feedback is required from the nervous system to keep destructive processes at low levels.

Stress and reactions against infection are actually favorable host reactions. Acute stress is an innate part of the immune system. Chronic stress can contribute to morbidity of the organism when homeostasis cannot be regained (McEwan, 1998). In other words, there are short-term adaptations especially in the immune and cardiovascular systems and in the brain. The major hormonal stress mediators, the catecholamines and glucocorticoids fit this scheme. The effects of glucocorticoids on immune functions can be immuno-enhancing or immunosuppressive at different concentrations. High levels of glucocorticoids might cause memory deficits and atrophy of the hippocampus (Lucien, 1998). The hippocampus is important in cognition and in downregulation of stress circuits.

Behavior and neuroendocrine signals actually tune the immune system toward a balance. Feedback and information from the immune system to the brain is part of this regulatory process. An example has been proposed that the cytokines can change corticosteroid receptor balance in the hippocampus, which probably causes a prolonged activation of the HPA axis during immune responses (DeKloet, 1994). A well-balanced state in the body's regulatory systems is necessary for normal psychological functioning. Psychological factors can also change the balance in the nervous and immune systems.

DEPRESSION
IMMUNE CORRELATIONS TO DEPRESSION

Evidence has shown that major depression is associated with immune variations. Not including the present, thirty-five independent study samples were done through 1991, and all found depression to be related to alterations in mitogen induced lymphocyte proliferation and natural killer (NK) cell activity (Herbert & Cohen, 1993). One early hypothesis of depression proposes that a deficit of brain noradrenaline (NA) and/or serotonin (5-HT) may be involved in symptoms of this illness (Baldessarini, 1975). Research up to the present day has proven to us that most all of the theories proposed concerning serotonin, dopamine, corticosteroids, cytokines, and killer cells all play a role in stress and depression. Another important theory back in 1989, suggests that depression is a disorder in the HPA axis and causes an increase in secretion of CRF, which stimulates ACTH and cortisol release (Bateman & Solomon, 1989). It is interesting to note that most of the theories proposed in the 80s and 90s, hold up today as valid research. Also proposed back in 1991, the macrophage theory of depression was deemed significant. In this hypothesis the abnormal secretion of some cytokines, such as interleukin-1 (IL-1) and interferon-alpha (INF-alpha), results in disordered secretions of CRF, ACTH, prolactin, and cortisol (Smith, 1991).

At this point the author would like to point to the obvious references from past research because most present day theories rest on the shoulders of these past scientific giants in the field of psychoneuroimmunology. Also the premier researcher in the field and especially with research on stress and depression was Robert Sapolsky; he also revealed changes in the sizes of the amygdala and hippocampus from chronic stress, leading to depression (Sapolsky, 1996). 

Whatever changes in the CNS or in the endocrine system, different aspects of immune function are affected. We now know that noradrenergic and cholinergic terminals innervate the thymus gland and bone marrow. There are also different neuropeptide, neurotransmitter and hormone receptors on lymphocytes and monocytes. We must also remember that in addition cytokines produced by immune cells and microglia exert different effects on the brain, endocrine and immune systems. At the cellular level, a reduction of mitogen-stimulated lymphocyte proliferation, neutrophil phagocytosis, and an elevated monocyte count have been reported in depression (Leonard, 1990). Also found in depressed patients is an increase in total white cell number with an increase in neutrophils and a decrease in lymphocytes (Maes, 1992).

Past research at the subcellular level has revealed that serum and plasma concentrations of immunoglobulin, complement, and acute phase proteins are changed (Healy, 1991). Another study showed increases in immunoglobulin A and M, compliment C3 and C4, and acute phase proteins (Song, 1994). The concentrations of cytokines IL-1, INF-alpha, and tumor necrosis factor (TNF) are raised and IL-2 is reduced in depressed people (Smith, 1991). This is now taught in advanced biological psychology courses. 
At the organ and system level, it has also been reported that the weights of the thymus gland and the spleen are reduced, and the adrenal gland is increased during stress and depression (Dohmus & Metz, 1991).

GLUCOCORTICOIDS, DEPRESSION AND CHRONIC STRESS

Synthetic glucocoticoids in the treatment of inflammatory disease are usually attributed to their potent anti-inflammatory action. This is due to the inhibition of the synthesis and release of proinflammatory cytokines. Not all cytokines are suppressed by glucocorticoids. The dual action of glucocorticoids on cytokine concentrations can act synergistically with cytokines. Many cytokine receptors are actually upregulated by glucocorticoids, including IL-1, IL-2, IL-4, IL-6, INF gamma and TNF alpha (Weigers, 1998). The diverse effects of the glucocorticoids on immune function may be explained by the fact that by increasing the number of high affinity IL-2 receptors on the surface of T-cells, the proliferative response of these cells is increased, even though production of IL-2 is decreased (Weigers, 1995). It seems that glucocorticoids enhance rather than reduce the biological response, by increasing sensitivity of the target cell for certain cytokines. Thus, the glucocorticoids appear to increase the course of a biological response, and if delayed, could be detrimental to the organism. It also appears that glucocorticoids may act synergistically to induce immunoglobulin E, which is a mediator of allergic diseases (Wu, 1991). This is relevant when we see increased allergies in depressed patients.

MACROPHAGE THEORY OF DEPRESSION

Of all the endocrine changes that are reported to occur in stress and depression, cortisol hypersecretion is the most frequently observed. There is a qualitative difference between the circadian pattern of cortisol secretion in the depressed patient, and that following a stressful stimulus. The height of the plasma cortisol concentration occurs six hours earlier in the depressed patient. The ACTH concentration is also elevated and the concentration of CRF in the cerebrospinal fluid is raised in depressed patients (Linkowski, 1987). There is a close association between plasma glucocorticoids and immune function as we have seen previously. A prolonged increase in glucocorticoids in depression leads to a decrease in the sensitivity of the CRF and also to the glucocorticoid receptors in the brain, pituitary, and on the immune cells (Dinan, 1994). This reduces the inhibitory effect to these steroid hormones on cellular immunity.

What causes the adrenal steroid abnormalities in depression? The proinflammatory cytokine IL-1 is partly responsible. IL-1 has a direct action on the hypothalamus leading to the increased release of CRF. IL-1 has been shown to stimulate ACTH and growth hormone secretion (Goetzl, 1988). Also the direct effect of IL-1 on the HPA axis secretes ACTH, and there is also evidence that macrophages secrete ACTH, and all this directly stimulates the adrenals to synthesize cortisol.

Cytokines are large hydrophilic molecules and passive diffusion across the blood-brain barrier is probably minimal (Hopkins, 1995). The cytokines in the periphery can act on the circumventricular organs that lack a functional blood-brain barrier. Cytokine from the periphery bind directly to glial cells, which in turn produce cytokines and other mediators such as the prostaglandins, especially E2 (PGE-2). Also certain neurons in the preoptic nucleus have receptors for IL-1 and 6, and TNF-alpha (Schettini, 1990).

There is now substantial evidence to show that major depression is accompanied by acute phase protein response, and increased secretion of prostaglandins, and by an excessive secretion of proinflammatory cytokines. These suggest that immune activation may play a role in the pathogenesis of depression and provides a basis for the macrophage theory of depression (Smith, 1995). Inflammatory cytokines or lipopolysaccharides (LPS) administered to animals or man provokes an extensive set of symptoms that are identical to those found in major depression. These changes affect not only the psychological state of the individual but also with changes in the activity of the HPA axis that is similar to those seen in depression. There is also evidence that the increase in the circulatory concentrations of IL-1 and 6 mediate the acute phase protein response. Elevated positive acute phase proteins and a reduction in the serum trytophan concentration characterize this (Song, 1994).

Proinflammatory cytokines such as IL-1 modulate central serotonergic functions. IL-1 also activates the serotonin transporter directly. This was another hypothesis for depression now known to be true. A reduction in the serum tryptophan concentration, associated with elevated acute phase proteins, and an enhanced reuptake of serotonin caused by action of IL-1 on the serotonin transporter, contributes to a malfunction of the serotonin system and cause depression. This is why we have the SSRI class of medications. These drugs suppress the proinflammatory cytokines (Xia, 1996). We know that the proinflammatory cytokines can act as common mediators for the action of external (psychosocial) and internal (toxins) stressors that are now known to play a crucial role in the cause of depression.

There are many exciting developments to come relating to the interactions between the immune system and the brain in patients subject to chronic stress or suffering from depression. Over the next ten years the future of psychoneuroimmunology will depend on research into the basic physiologic processes that are caused by the neuroendocrine-immune interactions, and the relevance of these interactions to the development and outcome of psychiatric illness. 

BEHAVIORS AND IMMUNE BUFFERING EFFECTS

It is important to understand that social interactions, belief systems, intimacy, and exercise are modalities and behaviors that may change a negative impact on psychological stress on the immune system and health. This may also contribute to the maintenance of health during the aging process. The influences of these behaviors suppress activation of areas in the brain responsible for altering immune function. Look at any of the papers written by Dr. Janice Kiecolt-Glaser over the past ten years and you will find a wealth of information on the immune system and behaviors influencing our health.

Fluctuations occur in the neuroanatomy of the brain during life. Alzheimer's disease is a prime example. With severe acute stress there may be a change in the size of the hippocampus (Gurvitis, 1996), and with high levels of chronic stress we see the same (Brenner, 1997). Chronic elevations of glucocorticoids induce stress and may cause anatomical and functional alterations of the hippocampal neurons (Sapolsky, 1996). The glucocorticoid response to stress may be influenced by physical contact between young offspring and the mother (Liu, 1997), which emphasizes the multiple environmental factors that influence the interrelationships between the mind and health. The glucocoricoids also contribute to cognitive function, with decreased function associated with higher glucocoticoid levels (Lupien, 1994).

It seems very likely that adopting stress-buffering behaviors can change the negative effects of stress and depression on the quality of health and life. The ability to develop coping skills to buffer the effect of stress on health is important. For instance, lack of control of one's work environment is associated with increased morbidity (Marmot, 1997). Stressor-induced alterations of the hormonal concentrations of plasma can be modulated by behavioral characteristics of an individual. It is important to understand how the brain and the types of coping skills will influence how stress will alter the hormones and the immune system, as they perceive a stressor.

A relationship suggesting ties between psychology and physiology is found in the increased susceptibility to diseases such as asthma, allergies and autoimmune diseases in subjects with depression (Vogt, 1994). Early life experiences may modify an individual's later life hormonal response to stress. It is not just experiencing an acute stressor that influences the central nervous system and the hormonal response, but the background on which the acute stressor is applied that contributes to the characteristics of the response. We must develop skills that provide capabilities to minimize the effect of stress on altering physiological parameters. Chaos outside the brain may mirror chaos inside the brain. The brain may act as a filter that alters the impact of outside environments.

Whether environmental factors such as social support, physical fitness, a sense of humor and optimism can contribute to the ability of the brain to filter the outside world from the inside and its hormonal intricacies may be speculative, but we are making leaps by way of research. There does seem to be a basis for making assumptions that there are behaviors that truly can buffer or add to the buffering capabilities of the brain. Now the author will elucidate on the findings and results of these environmental factors and there effects on our psychology.

SOCIAL INTERACTIONS

There are consistent indications that social interactions have a positive effect on reducing morbidity and mortality (Cassel, 1976. Even the perception of receiving emotional support through social interactions is an important contributing factor in the reduction of mortality (Penninx, 1997). Low levels so social ties have a strong association with mortality than does a loss of social ties (Cerhan & Wallace, 1997). There is an association between negative life events, health and social support. The association of negative life events is the strongest in people with lower levels of social support (Sarason, 1985).

If one is performing a research project, first one must take into account some of the mechanisms and pathways in the brain and other systems that are affected. First these negative events activate pathways in the brain that alter hormones in which the immune system resides and suppress immune function. Then we must prevent buffering skills from halting stress effects on hormonal alteration. We can also alter sleep habits and nutrition and even increase alcohol, tobacco, or non-prescription drugs. These will all increase susceptibility to illness. Of course, we can use one of these in a controlled environment.

Now if one takes one group of subjects who have the perception of being loved and cared about by one's parents, we find that this has an influence on disease susceptibility as time goes on. If we take another group of subjects who rated their parents low in parental caring, it will be noted some time in the future, as in many similar studies, that there is an increase in cardiovascular disease, hypertension, ulcers and alcoholism. Again, a researcher can make an experiment more complex. This may prove that the social environment one experiences during adolescence can influence a person's longevity.

Another common example of a typical research project relates to strokes. After an initial stroke there may be more rapid recovery and better post-stroke function present in subjects with social support. Apparently social support is one of the great buffers for disease susceptibility (Glass, 1995). If one sets up two sets of subjects with different personality types, some types may be more comfortable in certain social situations. As is well known the brain must be the primary organ that determines personality and also modulates immune function. Our study will show correlations between personality characteristics and disease. We know what can happen to those with a type A personality. It has been noted by Scheier (1995) that this is in fact correct. Here are some possible ideas on what one may find in this experiment:  

1. An increase in an expression of anger and hostility will probably increase the risk of developing cardiovascular disease. This would be rather easy to prove as some angry, hostile people may have a myocardial infarction.

2. In another project we can look for those people who suppress their emotions. It pays to be emotional and let it all out. Over the years there has been proof that emotional suppression is associated with an increased risk of cancer. Buffering this with social support, exercise, group therapies, good nutrition, vitamin therapy, meditation and relaxation techniques will show and have shown in many studies that these can improve cancer and prolong life in those with a terminal illness.

3. Another common study with much proof in almost all cases of chronic illness, is that those who are depressed or have a depressed affect may have an increased risk of death after a myocardial infarction. Depression will cause more problems in any chronic disease and will create more pain in association with it. A study separating groups who are depressed because of their diseases, and those who undergo therapy and antidepressant medications for their depression, will show improvement in most cases.

4. Related to the above is exactly what the person's attitude is? Pessimistic or fatalistic attitudes have an increased influence on survival in patients with AIDS, cancer and cardiovascular disease. One's thoughts are the power. We see this in brain transmitters on functional MRIs. There are relationships between serotonin, dopamine, norepinephrine, and many others in association with attitudes, and in turn, the immune system (Glaser & Kiecolt-Glaser, 1994).

There is an association between personality characteristics and the hormonal response to stress. Healthy male exposed to the same stressor for five days showed different responses in cortisol levels. The highest levels come from the subjects that had characteristics of low self-esteem, negative self-concept, depressed mood, and other health problems (Kirschbaum, 1995). Many research projects could be performed to see if a change in socialization skills and frequency of time spent in personally meaningful social activities interact with personality to inhibit disease and mortality. There is no doubt in this author's opinion that changes will benefit our thoughts and in turn our health. Here is a good example of preventive medicine.

SOCIAL SUPPORT, IMMUNE FUNCTION AND IMPROVED HEALTH

We now realize that social support is capable of producing a hormonal situation that promotes the effective function of the immune system. This support must be meaningful to these individuals. Remember it is the perception of the support that is most important. Males with frequent high levels of support had lower levels of urinary cortisol, epinephrine and norepinephrine. The lower the hormones the more enhanced is the immune function (Seeman & McEwen, 1996). 

Another interesting observation is that having at least six social ties is associated with a decreased risk of becoming infected upon a deliberate exposure to influenza virus (Cohen, 1997). How does this happen? The presence of friends activates areas of the brain that inhibit stressor-induced activation of the HPA-axis or the SNS. The "friendship perception areas" (FPA) of the brain activates the HPA-axis. Repeated activation of these areas by the perception of social support contributes to "habituating" them to activation, leading to the need for increased intensity of input for activation.

In caregiver's to a spouse with Alzheimer's disease, the function of NK cells were studied (Esterling, 1996). NK function was decreased in caregivers in comparison to non-caregiving controls. Those subjects with more social support had greater NK cell function than subjects without social support. Differences in immune function and health were studied in separated and divorced men and matched controls (Kiecolt-Glaser, 1988). Married controls had fewer illnesses and produced more antibodies in response to immunization antigen. Beneficial effects were also seen with medical students at times of stress, who had adequate social support, which proved to be a useful stress-buffering tool (Glaser, 1985).

BELIEF SYSTEMS

Another activity that has been found to have a beneficial effect on health and may function as a buffer that prevents stress from altering the immune system is religious or spiritual beliefs. An increased feeling of happiness and a feeling of usefulness were associated with religious beliefs. There is decreased heart disease, emphysema and cirrhosis of the liver in people who regularly attend church services (Comstock, 1972). Mortality has been found to be lower for those who regularly attend services (Levin, 1994). Probably attending services fulfilled all the health promoting CNS functions that are provided through social support.
As far as PNI goes, here is how this works. Interleukin-6 (IL-6) is produced by several different cell types, one of which is the macrophage. Increased IL-6 may indicate the presence of an infection or inflammation. IL-6 was measured in the plasma of older individuals who regularly attended church services or did not attend (Koenig, 1997). An elevated plasma level of IL-6 was present in fewer of the church-going people, which may be interpreted to indicate that there was less infectious disease or inflammation. Can turning to religion at a time of medical illness contribute to changing the course of the illness? Yes. The true mechanisms are unknown. It may be related to activities of relaxation and reducing the SNS activity. There is also responsiveness to catecholamines in relaxation trained groups. If people receive health benefits from belief systems, regardless of the mechanism, a significant advantage to religion will have been provided.

SENSE OF HUMOR

There is probably a specific area in the brain that when activated produces laughter (Fried, 1998). This area may be located in the supplementary motor cortex and when activated, inhibitory signals are received at areas of the brain that induce the activation of the SNS and the HPA-axis. It has also been noted that hearty laughter will decrease plasma levels of cortisol and epinephrine (Berk, 1989).
Salivary concentrations of IgA are also increased when people experience a humorous episode (Dillon, 1985). Laughter may produce a hormonal cascade similar to that produced by social support, with all the health benefits. The best examples of this can be seen in the works of Norman Cousins (1991). Laughter may be one of the best medicines!

EXERCISE

Here we have one of the most important buffers to stress and depression. There are numerous studies on humans and animals that show exercise produces alteration of the function of the immune system. Exercise minimizes the effect of stress on alterations to immune function. Exercise has a beneficial effect on health by reducing cardiovascular disease, stroke, and malignancy. This is how it works. Exercise produces alterations of the plasma concentration of glucocorticoids and catecholamines that are similar to those produced by a psychological stressor. Alterations of immune function would be expected to be produced by exercise. There are many ways and reasons how exercise alters the immune system. Some factors are intensity, duration and frequency, fitness of the person, chronic stressors in the subject's life, developmental characteristics, and social support are all considerations (Kiecolt-Glaser, 1994).

The effect of exercise on peripheral blood leukocyte numbers in sedentary and physically fit males and females, with a mean age of 25, was closely studied (Moyna, 1996). Using six minute incremental increases, measurements revealed an exercise-induced increase in leukocyte counts. All lymphocyte subsets increased, with a greater increase in CD8 than CD4 lymphocytes, lowering the CD4:CD8 ratio. The number of NK cells showed the largest increase. Plasma catecholamine concentrations also increased (Moyna. 1996). What does this all mean? This is all similar to the effect of psychological stress on the immune system (Manuck, 1991). This trend indicates that exercise has an enhancing effect on the quantitative and qualitative components of the immune system. Even though it may not increase the ability to cope with a stressor, it still provides enhancement of immune function and more resistance to disease.

Whether the improvement of health occurs because of an effect on the immune system or because of an increased ability to cope with psychological stressors still has not been determined by all studies. Probably exercise increases coping abilities for stress, because people who engage in regular exercise have less depression and more feelings of well-being than those that are sedentary. It is obvious that the buffering effect of exercise in the immune system is beneficial to health.

There are several diseases for which exercise has been reported to be a factor in modulating its course. A reduction in breast cancer by 37% is associated with leisure-time exercise (Thune, 1997). A beneficial effect of exercise and lean body mass has found a reduction of colon cancer in women (Martinez, 1997). A reduced risk of developing an ischemic stroke has been seen with regular exercise (Sacco, 1998). It is possible that a lifelong pattern of exercise may reduce the risk of developing a malignant tumor, cardiovascular disease, or a cerebrovasular disease. Mortality is also reduced by exercise. 

Maintenance of immune function as an individual ages may contribute to a healthier quality of life with less infectious, autoimmune and malignant diseases. If exercise does contribute to maintenance of immune function, and this is probably a certainty, it may serve as an important component of preventive medicine. There may be a reduction of death rates in older people who exercise regularly. PNI scientists are not sure whether exercise actually contributes to the reduction of mortality through the immune system. It is possible that people who exercise have other stress buffering skills not found in sedentary people (Fraser, 1997). Many studies in the elderly have shown an increase in NK cell activity, alterations in lymphocyte subsets, cytokine production and delayed type hypersensitivity skin test reactivity (Rall, 1996). The incidence of upper respiratory infections was lower in physically fit elderly subjects than in other individuals (Gueldner, 1997).
A question to be considered is to whether exercise will be of benefit to enhancing immune function in all individuals or in only certain subsets. More research is being done. Regardless of the mechanisms, the fact that fewer infections are found in physically fit people is encouraging. It is likely that a factor in longevity is exercise. Health experts need to determine how to optimize involvement in exercise programs for those that find difficulty in exercising more. 

SUMMARY AND CONCLUDING COMMENTS

The scientific activity embodied in psychoneuroimmunology has demonstrated the interconnectivity of bodily systems in a way that gives credence to the notion of unity. The pathways have shown that signaling between systems is complex and multidirectional. Future research must isolate mechanisms and integrate an approach that tracks individuals over time and in natural circumstances. There must be a coordination of epidemiology, public health, and individual health care at a global level. If science monitors a large number of variables, it may be possible to isolate individuals at the highest risk of a demise within a given time span, and realize that not all people will be afflicted. 

From birth to becoming a senior, hormones present in our bodies influence our immune system function and our health in general, and this is all directed by the brain. Many consider psychoneuroimmunology as a young discipline, maybe because it is just beginning to provide an understanding of the mind/body/spirit health connection. The contributions of psychologists, immunologists, endocrinologists, and all others involved in clinical care of the patient will be required to develop our understanding of the mechanisms which are operative in this great mind/body connection, and how to apply all this information and knowledge to maintaining mental and physical health as we age. There is always a long way to travel on the scientific road of life. Progress will continue to be updated in this 21st Century by hypotheses, experiments and research, and the quality of life will improve for the benefit of all the people.

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