Author's Note: I wrote this article in 2000. The references herein may seem somewhat dated, but I believe most of the information is relatively timeless. I welcome all critique, and I value constructive criticism more than I do praise.

On March 30-31, 2000, the National Institutes of Health in Bethesda, Maryland, held a momentous conference, “Curing Epilepsy: Focus on the Future.” The purpose of the conference was to discuss the prevention and cure of epilepsy in the coming years by implementing new directions based on new technologies and discoveries. In what appeared a dramatic development of events, leading scientists from several fields discussed exciting possibilities promising to bring medicine ever closer to more effective methods of seizure control, and even cures. Factors included increased ability to conduct human trials through greater cooperation and communication among programs across the United States; more sophisticated imaging of the brain and its functions, including more efficient miniaturization techniques and observations of cell processes; more precise probes and devices to affect brain functions; and gene therapy as a result of the Human Genome Project.

Exciting as it this truly is, the conference reflects a glaring, ongoing failure of the medical industry to include adjunctive curative factors, not only for epilepsy but for most neurological disorders, that are becoming increasingly manifest as not only effective, but necessary. An article written by Henry Dreher (1993) revealed what seemed a well kept secret. “In recent years,” he stated, “mind/body scientists have uncovered the role of mental stress in exacerbating (if not fully causing) and encyclopedic list of diseases and health complaints, from AIDS, cancer, and heart disease to allergies, back pain, and headaches. Mind/body therapies that help people manage stress often reduce the symptoms associated with these conditions and sometimes spur recovery from them” (p. 86), a well documented assertion, as shall be shown.

What probably launched the stress management philosophy beyond the treatment of conditions more obviously related to stress (cardiovascular disorders, hypertension, ulcers, etc.) was an incident involving Richard Surwit, Ph.D., a psychologist at Duke University, which took place in 1978. An endocrinologist of his acquaintance referred to him a patient who was suffering diabetes, a case so severe that the patient’s sugar levels were spiraling out of control and the bleeding in her eyes was threatening to soon end her sight. The initial purpose of the referral was for counseling centering on her personal and work lives, which presented such pressures that her blood sugar would skyrocket. Dr. Surwit implemented two specific treatments to help her build her stress-reducing skills: progressive muscle relaxation, in which she would alternately tense and relax muscles throughout her body, and biofeedback, using monitoring devices to guide her into deepening stages of relaxation. Within one week, the patient’s blood sugar levels dropped, and her physical condition stabilized. After the first month, not only had her sugar levels remained stable, but the probability of blindness had dramatically reduced. Dr. Surwit was so impressed with the unexpected effectiveness of his therapy in physiological areas that he switched his focus from cardiovascular patients to those with diabetes, and continued to achieve similar successes with many others over the ensuing decades (Dreher, 1993).

Also since then, researchers, therapists, and immunologists from all parts of the world have documented astounding results from the physical benefits of psychological intervention, issuing reports of improvements to reversals in disorders such as arterial blockage, migraine, back pain, arthritis, allergies, gastrointestinal disorders, cancer, AIDS/HIV, TMJ syndrome, eczema, psoriasis, herpes, constipation, diarrhea, gastritis, colitis, Crohn’s disease, and even warts! One of the most amazing studies was conducted jointly by psychologist Donna Andrews and neurologist Joel Reiter. Using a combination of behavior therapy, EEG biofeedback, relaxation, and other psychological counseling, they analyzed a sample of 83 patients with uncontrolled epileptic seizures between 1980 and 1985. Of this group, 83 percent gained complete control of their seizures (Dreher, 1993).

Yet, while growing numbers of studies have since been conducted on the physiological effects of stress, many data remain inconclusive, partly because of a seeming myriad of variables. Ethnicity, gender, age, education, culture, nutritional habits, and socioeconomic status (SES), were—and still are—among factors to be considered (Cohen and Williamson, 1991, pp. 10, 20). Individuals' present states of physical health are also important criteria, including how many people are ill at the inception of a given study, what specific determinants are involved, and specifically how they affect their health (ibid., p. 5).

Further complicating the process are the mental circumstances of subjects. What disorder, if any, and personality type characterize each subject, and to what comparative degree do they influence any physiological changes as opposed to stress Birmaher et al.(1994), apparently among the few to their time to deliberately address this issue, remarked that "although it is known that depressed patients experience more adverse life events than do normal controls, in most of the immune studies with MDD [major depressive disorder] patients, the effects of depression was evaluated without giving consideration to the impact of the adverse life events" (p. 672). Cohen and Williamson (1991), reviewing an extensive number of studies, sufficient to establish a norm, commented on the difficulty "to know whether these measures assess state or trait distress. It is possible that in many of these studies, life events and psychological distress measures reflect stable personality styles (negative affective or neurotic) more than the impact of environmental stressors" (p. 18).

Birmaher et al. (1994) incurred many of these difficulties in their quest "to determine whether adolescents with major depressive disorder have disturbances in their cellular immunity and to study whether the immunological changes detected are specific to depression or are general responses to stress" ([Abstract], p. 671). They meticulously selected subjects for their study according to exclusionary criteria outlined in DSM-III-R (Diagnostic and Statistic Manual of Mental Disorders, 3rd Ed., Revised), using interviewing methods such as the Schedule for Affective Disorders and Schizophrenia-Present Episode and Epidemiologic (K-SADS-P and K-SADS-E, respectively). Functional tests, including lymphocyte proliferation response to activity of natural killer (NK) cells and nonspecific mitogens, and enumerative tests, including white blood cell (WBC) counts and differential counts on subsets comprising NK and T cells, were carefully conducted under controlled environments. Results were thoroughly analyzed through several different statistical methods to screen data for outliers, normalize error variance, and evaluate relationships (p. 673). Yet the researchers concluded that implications of their findings were "not yet clear," again citing "few studies of the effects of stress on [the] immune system and health status [of the adolescent]," which implied a dearth of previous groundwork (p. 675).

Scientific breakthrough, nonetheless, finally came with the grasp of neuropeptides — neurotransmitters comprising proteins and hormones that do the transmitting between neurons. Where they were once deemed to work only at axons of the synapses, science now could better identify their function, their effect upon the body's immune system, and the effect of emotional states on neuropeptides themselves (Clayman et al., "Neurotransmitter," 1989, p. 725; Cohen and Williamson, 1991, p. 7; Schneider and Tarshis, 1986, pp. 161-164). Now, more fundamental processes could be considered.

Science has long known, relatively, that the brain itself can influence immune function via the pituitary gland. The gland's hormones and peptides join the bloodstream where, working with the autonomic nervous system, they directly control the immune system (Donovan, 1988, p. 140). Antibodies (protein molecules, produced by humoral lymphocytes that bind to pernicious microorganisms and render them impotent) are also affected. As Featherstone (1996) explained, "From the cell's perspective, stress is any condition that results in the accumulation of unfolded or malfolded proteins" (p. 1438).

This budding knowledge has fostered a surge in research on immunological response to stress. One report was detailed during a 1994 meeting of the Psychoneuroimmunology Research Society, for example, that involved a series of studies of individuals with ailments such as HIV infection, chronic fatigue syndrome, Alzheimer's disease, hypersensitivity, and breast cancer. These studies commonly shared two hypotheses: (a) Severe chronic stress directly represses the function of the immune system, a process that (b) can be reversed or diminished by strategically increasing the ability to cope. Employing both cross-sectional and longitudinal methods (though not always simultaneously) and carefully assessing risk factors, the team performed alternating and concurrent case studies and applications of various, purposely dissimilar stimuli. Various techniques and incidences, including support groups, hypnosis, timely surgery, and private nursing care for the elderly, showed average immunological improvements in every category. Conversely, where stressors were ignored, immune systems regressed (Goodkin, Fletcher, and Cohen, 1995, pp. 183-184).

Continued research in psychoneuroimmunology (PNI) has produced further understanding that the central nervous system (CNS) and the immune system are interrelational; that is, they work bidirectionally. As Adler, Cohen, and Felten (1995) imparted, "In the neural-immune concept the brain has specific, two-way pathways to the immune system" ([Abstract], p. 99). Specifically, not only does the CNS influence the immune system through production and excretion of hormones, regulation of neurotransmitters, and direct nerval connections, but cytokines (hormone-like proteins), produced within the immune system, cross the blood-brain barrier and influence the function of the CNS (Cohen and Herbert, 1996, p. 113). This realization adds to the previous knowledge that cytokines also work within the immune system itself, regulating the intensity and duration of immune responses (Stedman's, 1995, p. 437).

Consequently, contemporary researchers such as Petrie, Booth, and Davison (1995), through correlational studies, can further associate trauma with increased illness (p. 224). Nee (1995) additionally pointed to chronic stressful situations, such as full-time caretaking of Alzheimer's patients, as evident direct causes of immunodeficiency (p. 259). Moreover, mood disorders have been related to aberrations within the immune system and occurrences of viral infection (Herdman, Gough, and Liskowski, 1995, p. 88). The 1994 issue of American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) reflects growing acceptance of this concept. For example, "The presence of an Adjustment Disorder may complicate the course of illness in individuals who have a general medical condition" (p. 624).

These allusions in DSM-IV reflect studies such as those cited by Adler, Cohen, and Felten (1995). One event involved herpes simplex virus infection (HSV-1) among clinically depressed patients where clinical depression was associated with increased circulation of neutrophils (one of three types of granular leukocytes, or white cells) coupled with decreased generation and activity of NK cells and B-lymphocytes. Replication of latent HSV upon acute depression drew assumptions that revival of latent virus in the brain may modify the activity of neurotransmitters, implicating development of certain mental disorders (p. 110).

This rearrangement of leukocytes is important since effective response of the immune system depends not only on their total numbers, but also their proper balance, i.e., among neutrophils, monocytes, and lymphocytes (Cohen and Herbert, 1996, p. 114). Neutrophils, for instance, normally comprise 54 to 65 percent of the total (Stedman's, "Neutrophil," 1995, p. 1207). Substantial deviation from this range, then, may implicate alterations in the function of the immune system in enumerative tests (Cohen and Herbert, 1996, ibid.).

Alarmingly, new evidence points to the additional possibility of certain chronic distresses as causal factors in brain damage. Recent improvements in the resolution of magnetic resonance imaging (MRI) have led to Sapolsky's (1996) hypothesis that resultant hypercorticoidism — excessive production of hydrocortisone (cortisol), the principal element of the glucocortoid (GC) group of hormones—leads to atrophy of the hippocampus. Although GCs, and norepinephrine and epinephrine (adrenaline), are vital for urgent physical responses such as evading danger, sustained secretion can be deleterious (p. 749; cf. Khalsa, 1997, pp. 8-9; Schneider and Tarshis, 1986, p. 158).

Sapolsky (1996) cited a study of Vietnam veterans with posttraumatic stress disorder (PTSD) in Biological Psychiatry by Gurvits, Pitman, et al. (in press as of Sapolsky's article) that found, among the approximately half who were secreting abnormal amounts of GCs, "significant 22 and 26% reductions in volumes of the right and left hippocampi, respectively" (Sapolsky, p. 749). Sapolsky noted another analysis in the same publication by Bremner et al. (in press) that "found a 12% atrophy of the left hippocampus in adults with PTSD associated with childhood abuse (with near significant atrophy in the right hippocampus)" (Sapolsky, ibid.). Not wanting to draw a careless induction, Sapolsky declines to assert that trauma (combat or abuse) or resulting PTSD can be associated with atrophies nor concludes that GCs mediate them. However, he suggested an analogy to Cushing's syndrome, where "GCs are overproduced as a result of hypothalamic, pituitary, adrenal, or pulmonary tumor, and there is bilateral hippocampal atrophy" (ibid.). "However," he continued, "the defining abnormality in Cushing [sic] syndrome is GC excess, making it a likely culprit in causing atrophy" (p. 750).

In an interesting rebuttal to Sapolsky's (1996) article, Yehuda (1997) cited emergency room blood samples of rape victims whose cortisol responses "were attenuated in women who had prior trauma and who were more likely to develop PTSD" (p. 1662). She added that vehicular accident victims incurring PTSD "also showed reduced amounts of cortisol within hours" of the trauma (ibid.). While granting that Sapolsky's data regarding Cushing's disease supports his hypothesis,

the other clinical studies cited do not. For example, although hippocampal volumes are reportedly smaller in trauma survivors with [PTSD] as compared with . . . [those] without PTSD and in nonpsychiatric (control) subjects, the amount of circulating GC is actually chronically lower in people with PTSD. . . . Furthermore, although there has been a general presumption that the concentration of cortisol present at the time of trauma is higher in survivors who develop PTSD . . . recent evidence suggests that the opposite might be correct. (ibid.)

Sapolsky (1997) countered that his view does not regard depressives, but ex-depressives, maintaining that PTSD is not considered responsible much as the period of original trauma. "It is the hippocampal atrophy—found many years after the (well-documented) GC hypersecretion seen in . . . depressives and after the (likely) GC hypersecretion during the traumatic stressors— that was so striking in these studies." He pointed out, moreover, that the combat veterans and abuse victims suffer longstanding trauma, not of brief duration, such as that inflicted upon rape and accident victims (p. 1662). He further exposed the relative antiquity of Yehuda's citations when MRIs produced "one-tenth the resolution of the current ones (5.0 versus 0.5 mm, respectively), and could not distinguish the hippocampus from amygdala" (p. 1663).

Despite Sapolsky's (1997) apparent contradiction to his 1996 article regarding his ignorance of the specific causes of hippocampal atrophy and his debatable allusion to especially rape as an acute rather than chronic trauma, he presented a cogent viewpoint from the perspective of advanced technology. The arrival of newer MRIs has indeed incited a "spate of studies" (p. 1663), producing weighty evidence that various forms of distress can, and do, wreak dramatic destruction on their victims' brain cells. Sapolsky (1996) correctly added that these issues "must be examined concerning our own dramatic differences in cognitive aging" (p. 750).

The effects of distress, however, are not limited to neural atrophy and cardiopulmonary and infectious diseases. Kiecolt-Glaser et al. (1995) asserted that "cellular immunity has an important role in the regulation of wound repair" (p. 1194). To test their assumption, they had studied 13 women who cared for Alzheimer's patients (relatives) versus 13 controls of similar age (mean 62.3) and income after excluding those with conditions that would affect healing (e.g., diabetes, cancer, autoimmune disease, recent surgery, applicable medication, etc.). Although smoking is known to slow healing, substantially more controls smoked, prompting the team to discount that factor. Subjects received a small wound (punch biopsy) in the same location, which was then observed by photographs and hydrogen peroxide (wound was healed when foaming ended). Blood drawn revealed significantly less production of interleukin-1? (cytokines that enhance proliferation of B cells) in the caregivers, whose healing took an average nine days longer (pp. 1194-1196).

The newest [at that time] development in PNI was perhaps the most astonishing. Siever and Frucht (1997) revealed that certain stressors not only affect hormones and neurotransmitters and their actions, but may "act directly on the genome to regulate the transcription of genetic information into the proteins," altering the very structure of neurons and modulating their future responses. Dangers lie in the possibility of altering the number of receptor sites at the synapses, unexpectedly stimulating or blocking receptors, and inhibiting the cells ability to create new connections (p. 216). This, however, is a well known consequence of drug abuse.

The new development is that transcription of the genes may "transcend a single generation." Trauma, in other words, "may reach so deeply into our biology as to modify the expression of genes" (ibid.). Siever and Frucht (1997) offered the example of Holocaust survivors, many who exhibit chronic symptoms of PTSD. Many of their children, who never experienced the trauma, display similar abnormalities (ibid.). Licinio, Gold, and Wong (1995) called attention to the adrenocorticotropic hormone (ACTH), which acts as a mediator for stress response, inflammation, and interactions between the nervous and immune systems. Apparently, certain chronic stressors can alter the behavior of ACTH "initiating a series of events leading to changes in gene transcription" (p. 104). Though the mechanism is not yet well understood, this should incite and intensify a sense of urgency in addressing stress.

It is worthy of mention, incidentally, that the respective social, psychological, and physiological environments can form a "cycle of stress degeneration," as Khalsa (1997) described it, or a bidirectional, continuous loop. Stressors can originate from any of them, intensifying as they oscillate among them and impose an altering influence upon each of them (pp. 41-44, 276-280; cf. Larson and Chastain, 1990, pp. 451-455; Schlosser, 1990, pp. 136-139).

Cohen and Williamson (1991) provided the illustration:

Behavioral changes occurring as adaptations or coping responses to stress may also influence immunity. For example, persons under stress tend to engage in poor health practices. . . . [e.g.,] increased smoking, drinking, and changes in diet. . . . Stressed persons often engage in social coping—drawing on the resources of their social networks. Increased interaction with others results in greater probability of exposure to infectious agents and consequent infection. . . . It may also be that disease [in turn] causes greater stress, or [other factors, e.g., age or social class], put people at higher risk for both stress and disease. (pp. 8-10)

Physiological implications, then, relate to the way one interprets a stressor. From this perspective, a stressor is relatively insignificant until it has raised an individual's anxiety level beyond the ability to cope (Cohen and Williamson, 1991, p. 5). Siever and Frucht (1997) believed that the major difference between, for example, depression and posttraumatic stress disorder is the way the body reacts to chronic stress. "Supersensitive cortisol receptors, yielding enhanced feedback inhibition, and abnormally low baseline level, and a very strong response to stimulation," they explained, "may reflect a system that is primed to react to sudden physical emergencies" (p. 215).

As evidenced, disease occurs at the cellular and molecular levels, and so does distress. Their complex, interrelational, bidirectional, and cyclical implications comprise a most difficult, yet challenging and even promising area of science. Their societal pervasiveness also makes it a most pressing area to address.