Self-Regulation of the Immune System

INTRODUCTION

The concept that we can modulate immune response through neurofeedback is a logical extension of currently accepted procedures and protocols. The extensive body of literature in psychoneuroimmunology (PNI) may lead one to wonder why this is not one of the primary areas of research utilizing biofeedback and neurofeedback. Certainly one reason must be the fact few researchers have knowledge in the disparate domains of PNI. Besides a background in biofeedback, one must have at least a rudimentary understanding of molecular biology, psychology, neuroscience, endocrinology and immunology to adequately address this field - or have access to competent individuals with whom to collaborate.

Research has elucidated extensive mediating mechanisms with a dense communication network that interfaces the central nervous system (CNS) with both the endocrine and immune systems. The brain communicates with the immune system through two known pathways, the autonomic nervous system and the hypothalamic pituitary adrenal axis - HPA (Angeli, 1994). Bullock (1985) writing in Neural Modulation of Immunity showed rather conclusively that there are autonomic nervous system fibers that go directly to the thymus where T-cells mature. More recently, Felten and Felten (1991) have demonstrated that primary lymphoid organs are heavily innervated by fibers from the sympathetic nervous system. A relatively new field called "immunoendocrinology" is uncovering numerous bilateral interactions between the immune system and neuroendocrine circuits. Researchers' Derijk and Berkenbosch writing in the International Journal of Neuroscience (1991) discuss evidence indicating that an immunoendocrine feedback loop, which they term "immune-hypothalamo-pituitary-adrenal system", is an integral part of the regulation of self tolerance. Pathology within this system is related to development of autoimmunity, a discovery that may lead to new prophylactic and therapeutic strategies.

Simply observing immune response is often proposed as key to understanding the etiology and directing the treatment of physical, psychological, and even psychosocial (Smith, 1991) disease. Many journals are dedicated to research that exposes the complex homeostatic mechanism in the immune system as it responds to stress, pathogens, trauma, pain, toxins, as

well as positive life experiences. Consequently, the application of neurofeedback techniques that reorganizes and reorients brain electrical activity can, in all probability, be utilized to modulate positively the immune response.

PERTINENT RESEARCH

An exhaustive review of the literature regarding the mind's impact on the immune system is beyond the scope of this paper, however, selected studies shall serve to illustrate this relationship. One of the most dramatic demonstrations of the intimate involvement of the brain with the immune system is drawn from a series of studies conducted by Stephen Locke of Harvard University and reported on in a book titled The Healer Within-The New Medicine of Mind and Body (1987). The researcher withdrew cancer- and virus-fighting natural killer cells from a group of depressed subjects as well as from a group of non-depressed subjects. When these killer cells were placed in contact with cancer cells, the killer cells from the non-depressed subjects surrounded the cancer cells and destroyed them while the killer cells from the depressed subjects did nothing. This might cause one to ask: How did the natural killer cells from the non-depressed subjects know what to do while the natural killer cells from the depressed subjects did not? Apparently, through complex and, as yet, not well understood mechanisms, important immune system factors can be turned on or off by the chemicals produced with certain moods. This fact caused the author to write, "Even relatively minor life stresses leave their mark on the immune system." Ruff (1984) and Pert, et al (1985) likewise reported that subjects who were made to feel helpless (a primary feature of depression) show macrophages that move more sluggishly than their counterparts from non-depressed subjects. Pert has suggested that neuropeptides are a key biochemical product of emotional expression since they appear in relatively high concentrations in the limbic system. Alteration in the production of these peptides during a depressive episode produces immune suppression through a number of pathways. One possible mechanism of this suppression that has been proposed is that corticotropin-releasing factor (CRF) a hypothalamic hormone may trigger release of adrenocorticotropin (ACTH) which stimulates the release of corticosterone - a known supressor of immune function. ACTH is secreted by the pituitary gland and acts on the adrenal gland.

In another study, Bartrop and associates (1977) found that bereaved spouses had ten times lower T-cell function after the loss of their loved one than non-bereaved individuals. In this case, T-cells, lymphocytes originally derived from the thymus gland, mediate cellular reactivity. This modulation is accomplished by delicate feedback loops involving neurotransmitters such as catecholamines, prostaglandin, somatostatin, histamine, and insulin. Autonomic changes that accompany anxiety and depression (common sequelae during bereavement) thereby play a role in immune regulation. Bartrop's findings were confirmed by M. Stein's (1981) study wherein lymphocytes of men whose wives died of cancer failed to respond to activating agents. This led the author to conclude that suppression of mitogen-induced lymphocyte stimulation appeared to be a direct consequence of bereavement - a finding he later extended to depressed individuals. Functional activity of the lymphocyte and the number of immune competent cells are decreased in clinically depressed patients.

Other studies indicate that natural killer cell activity, which is mediated by T-cells, is significantly decreased in "stressed-out" college students who are not coping well with the demands of school (Rogers, 1979). Here it is thought that epinephrine and norepinephrine, the primary stress response syndrome hormones, decreases immune response. These studies, as well as a myriad of others, point to the fact that the immune system - at the cellular level - can be profoundly modulated by inner subjective experience (i.e., depression, bereavement, stress) as effectively as by pathogens or toxic exposure. A bidirectional circuit exists between the CNS and the immune system since activation of the immune system results in the elaboration of cytokines as well as inflammatory mediators; these mediators induce hypothalamic CRF, which stimulates the release of the same immunosuppressive molecules that mediate the response to stress (Black, 1994). To date, approximately 20 hormones and neurotransmitters have known immunological modulation potential (Khansari, 1990). These either increase or decrease in response to stresses. This indicates that the full neurochemical consequence that would have an impact on immune function is, most likely, extraordinarily complex.

There is little argument that the immune system is activated by pathogens that go on to produce global cognitive, behavioral, and physical pathology. However, this reality is but one thread in a complex feedback system that may be modulated by multiple factors. As the above studies demonstrate, the immune system exists in dynamic relationship to both interior psychological states as well as exterior environmental conditions. Through a variety of pathways the immune system is modulated by such diverse factors as: personality (Rosenman, 1964, Temoshok, 1992), odors (Cocke, 1993), exposure to humor (Dillon, 1985), physical fitness (Roth, 1985), left or right handedness (Searleman, 1987, Chengappa), seasonality and light (Kasper, 1991), and marital conflict (Kiecolt-Glaser, 1993).

THE CNS - IMMUNE SYSTEM FEEDBACK LOOP

At this point in time, the earlier supposition that the immune system acts independently of the brain has been permanently laid to rest. The discoveries from the emerging field of psychoneuroimmunology have demonstrated the close links between mental state and immunological reaction (Vollhardt, 1991). In the 1960's Russian researcher Elena Korneva produced changes in the immune system by selectively damaging different parts of the hypothalamus. George Soloman repeated her experiments and became one of the first American researchers to suggest that the central nervous system played an important role in the immune system. His work has been extended by individuals such as Marvin Stein (1981) who demonstrated that lesions of the anterior hypothalamus reduce cellular and antibody-mediated immune responses to antigenic substances. French researcher Gerard Renoux discovered immune suppression in subjects having severe brain damage to their neocortex, the brain's gray outer layer. He extended his research to brain laterality, i.e., different sides of the brain have different expressions of immune suppression, the left hemisphere having a more direct impact on the immune system.

Not only does the nervous system influence immune responses but immune responses alter nerve cell activities. Cells in the immune system function in a sensory capacity, relaying signals to the brain about such stimuli as invading pathogens (Besedovsky, 1981, 1983; Smith, 1982, 1991). In 1985, Hall coined the term "immunotransmitters" which are substances (i.e., thymic peptides, lymphokines, Etc) produced by immune cells that communicate back to the hypothalamus and the autonomic and endocrine systems. Immune cell cytokines, via direct action on the CNS, alter sleep, pain perception, and appetite level. The most potent example of the intimacy between the immune system and the brain can be seen in cases of brain injury. Immune cells secrete substances called interleukins. These cross the blood-brain barrier, gather at the site of the brain injury and stimulate the growth of glial

cells. These glial cells in turn secrete substances that help injured nerve cells to survive and grow new dendritic branches that at least partially compensate for lost nerve cells. It would seem that activated leukocytes cross the blood-brain barrier at very low levels under normal conditions and in much higher numbers during neuropathological disorders like multiple sclerosis or retroviral infections as well as in brain trauma (Couraud, 1994). The dedicated work of many psychoneuroimmunologists in their search for neuromodulatory mechanisms has led us to conclude that the immune system and the central nervous system is a hard-wired two-way feedback loop.

The exact mechanism of action of the above mentioned immune modulating feedback loops await further research, however they will become more and more important in describing how neurofeedback can enhance the immune systems ability to either maintain health or ward off disease. Our ability to describe an exact mechanism is limited by our elementary understanding of how the immune system communicates with the brain at the electrical and biochemical level. Currently, immune disregulation is in the forefront of contemporary research due to the unfortunate and truly frightening pandemic infection with the human immunodeficiency virus (HIV) and its subsequent disease, acquired immunodeficiency syndrome (AIDS), as well as increases in the rates and types of cancer.

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