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Stress and Psychoneuroimmunology

What do you Mean I’m Stressed out?

Stress may be most simply defined as a physical or psychological stimulus that when intruding upon a person produces disequilibrium or strain (S). The nature of stress can be examined in terms of the stressor, the reaction of the individual responding to the stress, and the relationship between the stressor and the stressed.

Stressors can be categorized and ranked in several ways. Perhaps the most common means of ranking life style stressors is reflected in the Holmes and Rahe Life Changes Stress Test (, , , ). Changes for good or bad can create stress. Risk of disease is generally assumed to increase with the number of and the degree of potency of these stressors. Effects of the most powerful of these stressors are commonly said to last for as long as one year after the event.

Daily annoyances can be as provoking and unsettling as major life changes, if they are chronic. For example, being stuck in traffic, barking dogs when trying to sleep, being placed on hold, and waiting in lines can have a cumulative effect. Frustration and nonfulfillment when pursuit of a goal is thwarted often results in the feeling of loss or failure. Pressure can come from the compulsion to perform or conform. Performance pressure is quite common at work or in school where completing tasks, getting good grades, meeting expectations, or meeting deadlines can at times seem overwhelming. Pressure to conform to standards set by others can cut across all ages. A closely allied stressor to pressure is internal or external conflict. Internal conflict can result in feelings of guilt or shame for not measuring up to self-imposed standards. External conflict can result from interpersonal relationships where two people disagree on what should be done, how it should be done, or who should do it.

Occupational stressors can be subtle or overt and sometimes difficult to control. The physical surroundings may be too noisy, overly bright, with stale air, too hot or too cold, drafty, etc. Job security can be tenuous. Pay can be inadequate to establish or maintain a desired standard of living. Coworkers or employers may be angry, demanding, or unhappy and be difficult to deal with. Dealing with hostile or aggressive clientele may be draining. Needing to make life or death decisions can be daunting. Competing for limited funds or dealing with bureaucracies may be frustrating.

It has been commonly held that certain personalities are more prone to stress. We have all heard of the Type A and Type B personalities suggested by Friedman and Rosenman in the 1960s and 1970s (, , ). Type A behavior is impatient, restless, aggressive, ambitious, and urgent. Characteristics include always walking, talking, or eating quickly. People with type A tend to monopolize conversations, want to get things done rather than enjoying the process (no time to smell the roses), think in terms of quantities: distance, time, numbers; and feel threatened or challenged by other Type A folks. Type B behavior is the antithesis of Type A. It has been said that Type A personalities are more prone to heart attacks, however, recent evidence suggests that only the hostility part may be a risk factor (, , , ). Subsequent researchers have classified other stress related traits into Type C and Type D personalities (). People with Type C (cancer prone) behavior have difficulty in expressing themselves and tend to suppress their emotions. They act helpless and hopeless and make excessive use of repression and denial. They exhibit extreme control over their behavior and were thought to be prone to cancer (). Type D (depressive) personalities are characterized by negative affect and social repression manifesting in higher amounts of anger and hostility. They are said to be have increased levels of cortisol and stress () and to be at higher risk for heart disease and other stress-related illnesses ().

Of course, it should be remembered that few of us are really one pure type. Our personalities are usually a nuanced blend of several different attributes. However, the extent that each trait contributes to our behavior may help to determine our ability to handle stress. In line with these nuances, other more refined personality classifications have been used to examine PNI relationships between disease and aspects of personalities. Two of the most common tools are the Myer-Briggs Testing Inventory (MBTI) and the Eysenck’s Personality Scales. The gold standard for personality testing is generally considered to be the MBTI. It has been continuously validated and refined since its introduction in 1943 (mbtitoday.org/model.html). The MBTI took Carl Jung’s 8 categories of personality and expanded them into 16 based upon such characteristics as introversion and extroversion and sensing and intuitive types. Many of these characteristics have been related to various measures of susceptibility to stress () and we will discuss these in several sections of this article.

Hans Eysenck was by most accounts one of the most influential psychologists in bringing sound science to the field of personality and intelligence. He believed that personality was determined by genetics and he was well known for linking his scales to physiological mechanisms and biological subsystems personalityresearch.org/pen.html. For example, he used factoral analysis comp9.psych.cornell.edu/Darlington/factor.htm for descriptive categorization and data from drug activity to link introversion/extraversion with the CNS, neuroticism/stability with the ANS, and psychoticism/impulse control with hormone levels. He made predictions for associations (especially with the probability of contracting certain diseases) based on his models that could be tested experimentally (). For example, a study of 2,146 people followed for 14 years seemed to validate his personality and stress inventory in predicting cancer and coronary heart disease mortality (). In a 13-year study of 1,706 people, results indicated that personality, stress, and motivational factors in drinking alcohol were determinants for risk of cancer and coronary heart disease (). It seemed that drinking to drown one’s sorrows was a greater risk factor than drinking for pleasure, and stress and amount of alcohol combined to increase that risk. Eysenck also proposed that personality and stress are mediating factors in relating consumption of depressant and stimulant drugs to incidence of cancer and heart disease (). His hypothesis that he tested in a long-scale prospective study predicted that large-scale consumption of Coca-Cola would prevent cancer and promote coronary heart disease. Results appeared to be consistent with this hypothesis.

He also argued that the method of interrogation may crucially influence the outcome in studies assessing the relationship of personality and stress to disease such as coronary heart disease and cancer ().He was able to show that without trustworthiness and understanding demonstrated by the interviewers, it was unlikely that subjects would admit to undesirable personality traits and behaviors.

Reactions or responses to stress have been characterized by Hans Selye (, ). In the 1930s, he propounded the General Adaptation Syndrome which he refined in the 1940s and 1950s (, , ). The General Adaptation Syndrome is a generalized reaction to physical or mental injury or stress. This reaction appears to occur in humans and other animals. Selye has identified three stages.

Stage 1: Alarm Reaction. Homeostasis is maintained by an evolutionarily ancient system. When a stressor occurs, the body is driven into a fight or flight process. This fight or flight reaction is characterized by secretion of adrenaline from the adrenal medulla and release of glucocorticoids by the adrenal cortex. These results in increased muscle tension, increased blood flow to the extremities, increased heart rate, increased blood pressure, increased perspiration, increased respiration rate, and inhibited digestion.

Stage 2: The Resistance Phase. Resistance includes all of the nonspecific adaptive systemic reactions elicited by chronic exposure to harmful stimuli. The neuroendocrine system becomes hyperactive and the organism is in a constant state of overstimulation. Yet acute, overt body manifestations of stress disappear as the body has adapted.

Stage 3: The Exhaustion Phase. If the stressor persists too long, the organism can no longer maintain adaptability. It becomes exhausted and physical symptoms of stress reappear. Manifestations can include high blood pressure and anxiety disorders. Or even death.

Not all stress is distressing. Distress is negative and undesired; eustress can be positive and desirable. An optimal level of eustress may be appropriately stimulatory for all of us but seems to vary with the temperament of the seeker. Eustress seekers also include adrenaline junkies: people who seek high sensory input like riding roller coasters. These folks may feel stressed when bored by low rush activities.

Interaction of the stressor with the individual being strained will vary with the stressor and the interpretation of that stressor by the individual. According to Lazarus and Folkman (, ) when we first encounter a stressor, we evaluate the nature of the threat as it relates to us. Then we evaluate our ability to resist its assault: the greater our resources the less the stress. These are cognitive evaluations based upon our values, beliefs, desires, interests, controllability, predictability, familiarity, and imminence. Interests include relevance of the potential stressor to you: if a particular stock plummeted, it could be stressful if you owned it, or not stressful if you did not. Predictability, familiarity, and controllability are related by the more control you feel over the stressor, the less stressful it is. Imminence relates to the closer the time that the event is to occur, the higher the stress.

Stress and the Immune Response

A quick nano review of the stress-related anatomy and physiology is probably a good way to bring us all to a more ready understanding of stress as it relates to PNI. So here we go. For a more detailed review, please see the background sections.

I think it is convenient to begin with the brain. The cognitive higher functions of the cerebral cortex interface with the limbic system, which in turn interconnects with the hypothalamus, the septal region, and a medial region of mesencephalic tegmentum. That is a mouthful of terms, but let me explain.

As a reaction to various neurosensory and limbic signals carried by molecules in the circulatory system, the peripheral stress system becomes activated. The peripheral stress system is composed of the hypothalamic-pituitary-adrenal (HPA) axis, systemic adrenomedullary system (SAS), and the sympathetic nervous system (SNS). SAS and SNS are lumped together as the sympathetic adrenal medullary system (SAM).

Stress manifested as anxiety or depression can activate the HPA axis and the SAM axis. Many of the stress-related hormones produced by this activation have direct influence on the immune system. They include the catecholamines (epinephrine and norepinephrine), cortisol, adrenocorticotropin, growth hormone, and prolactin. Some of the overall effects of these hormones may be negative or positive depending on a space-time context. Cortisol is often elevated by depression and this elevation may adversely affect several immune system functions (). Growth hormone can be depressed in depressed patients. Normally, growth hormone can enhance immune functions ().

Some researchers believe that once cortisol levels rise, they can initiate, maintain, or magnify depression and depression associated symptoms such as poor memory, poor quality sleep, and anxiety ().

It has been speculated that the increased incidence of chronic inflammatory diseases and susceptibility to infections may be due to dysregulations of the endocrine system with increased activity of the HPA axis and decreased sex hormones (). One experiment has shown that in elderly men, stress induced increases in cortisol did not differ significantly between groups, but sensitivity to glucocorticoids increased significantly in young controls and testosterone treated elderly men, while it decreased in non-treated elderly men (F = 5.28, p<0.01). The researchers suggest that increased sensitivity to glucocorticoids after stress may protect us from stress induced pro-inflammatory cytokines, and that this mechanism is disturbed in elderly men and is partially restored by testosterone.

Salivary monoamine oxidase (MAO) A and B inhibitory activities correlate with stress. MAO inhibitors inhibit the activity of monoamine oxidase that would normally breakdown the monoamine neurotransmitters such as epinephrine, norepinephrine, serotonin and the trace amines. Thus with inhibition of MAO, the neurotransmitters are functionally more available in the synapse. Increased stress is associated with increased MAO A and B inhibitory activity (). In a stress experiment, MAO A inhibitory activity peaked at the end of the stress, and cortisol levels peaked 12 minutes after the end of the stress (). The amount of MAO inhibitory activity positively predicted the subsequent amount of cortisol rise. It is possible that increased monoamines due to the inhibition of their main metabolic enzyme for central monoamines can activate the HPA axis in the stress response (). Salivary IgA shows a similar circadian variation to that of cortisol (). Upon waking, salivary IgA and MAO inhibitor peaks, followed within the first ½ hour by cortisol (). Salivary IgA begins to fall as cortisol rises, and becomes stable 6 hours after awakening. Urinary output of endogenous MAO inhibitory activity is related to daily stress: increased MAO inhibitory activity in the urine in normal healthy people seems to be indicative of a relatively enduring state of everyday stress ().

Worry, the cognitive enumeration and anticipation of potential negative events, may affect the immune response to phobic fear. In one study, subjects with high scores of worry did not show a normal circadian rise in NK cells ().

In affective disorders such as depression and anxiety in humans, there is persistent HPA activation, often measured by elevated urinary corticosteroid over a 24-hour period. In rats, 24-hour elevation of urinary corticosterone persists for 3 days after intense stress (). Further evidence has been seen in rats that neuroendocrine changes persist for days not hours after intense stressors (). After single or repeated exposures to mild restraint and inescapable tail shock, circadian trough corticosterone levels were elevated for 3 to 5 days, adrenal and prolactin levels were persistently elevated for 24 hours, and thyroid and reproductive hormones were inhibited for 24 hours. The effects were not assessed for a longer time.

Chronic stress may impair the immune system’s ability to react to hormonal signals that should stop inflammation (). In a study of 50 healthy parents of either cancer patients or healthy children, the parents of the cancer patients reported more distress, had flatter diurnal cortisol slopes mainly due to decreased morning output, and the ability of synthetic glucocorticoid to suppress in vitro production of the pro-inflammatory cytokine IL-6 was decreased.

A statistically significant negative correlation between stress and sIgA, and decreased reported stress in response to music (although sIgA was not significantly increased by the music) was reported in a small study of reporters in a newsroom (). On the other hand, a significant increase in sIgA was seen in 66 college students exposed to 30 minutes of Muzak labeled as Environmental Music ().

Stress management has been associated with immune system reconstitution in HIV-positive gay men (). Twenty-five HIV-infected gay men were randomly assigned to a 10-week stress management intervention or a wait-list control. Subjects who received stress management had more transitional naïve T cells (CD4+CD45RA+CD29+) than controls, independent of initial number of naïve T cells and HIV virus levels.

Differences in immune system set points have been found in association with acute and persistent stress in optimists vs. pessimists (). Weekly appraisals for 3 months of acute and persistent stress were catalogued in 39 healthy women (aged 18 to 45). NK cell cytotoxicity and CD4 and CD8 counts were evaluated and acute and chronic stress had different effects on the immune system. Optimists showed better immune responses to acute stress than pessimists did. However, pessimists showed better immune responses than optimists did in response to persistent high level stress.

Mast Cells and Stress

The mast cell has been associated with many neuropathologies (, , ), and the cognoscenti have called mast cells an immune gateway to the brain () and a sensor of emotional and environmental stress (, ). Mast cells are best known as the principle effector cells of immediate hypersensitivity allergic reactions, but their most important role is as the sentry who begins the acute immediate attack on invaders. They are ideally located for this job, as they are found next to vasculature in almost all connective tissue, including the brain ().

The mast cell is loaded with mediators of inflammation including cytokines, neuropeptides, and proteolytic enzymes. Theoharides, one of the luminaries in the field of stress and mast cells, has catalogued over 50 different mediators in mast cells (). Many of these mediators are stored in secretory granules and others are produced de novo upon stimulation. It appears that there is differential control in release of these mediators (). There may be a selective release of the type of mediator depending upon the stimulus and the location of the mast cells. In fact, it seems that the type and amount of mediator released varies from organ to organ and from person to person perhaps depending upon hormonal or psychological conditions (, , , , , ).

Recently, mast cells have been shown to be implicated in diverse stress related neuroinflammatory disorders including multiple sclerosis (MS), irritable bowel syndrome (IBS), interstitial cystitis (IC), migraines and dermatoses (, , , , , , , ).

Mast cells are very active in folks who are afflicted with atopy (strong familial tendency to type I hypersensitivities: allergies). These atopic people also have a higher incidence of emotional problems and cognitive difficulties especially during allergy seasons (, , , , , ).

Mast cells are abundant in the hypothalamus and thalamus and may be implicated in exacerbations of mast cell related disorders during stressful times (, ). Common symptoms may be palpitations, dermal flushing, migraines, cognitive disturbances, and gastric upsets (). MS and migraine flare-ups are quite common during increased stress (, , ). Emotional links to exacerbations involving mast cells have been catalogued in the following neuroinflammatory disorders (): asthma, atopic dermatoses, fibromyalgia, IBS, IC, migraines, MS, neurofibromatosis, rheumatoid arthritis, and unstable angina. Acute stress has been show to degranulate intracranial mast cells (). This effect seems to be mediated via corticotropin-releasing-factor.

Mast cells have been shown to be in intimate contact with neurons and endothelial cells (, , , ). Mast cells located in the dura mater (Latin = hard mother; one of the vascularized membranes covering the brain, which may be implicated in migraines) have estrogen receptors and are stimulated by estrogen to release vasoactive mediators (). This may help to shed some light on the higher incidence of migraines in women and their increased incidence during ovulation when estrogen levels are high ().

Mast cells may be stimulated by neurons to secrete histamine and other mediators that may cause further neural stimulation and in turn more activation of mast cells (, , , ). In the CNS, mast cells could be activated by sympathetic and parasympathetic innervation without allergic stimuli (, , ). Neuronal mediators include substance P (SP), opioids, and nerve growth factor (NGF) (, , , ). Chondroitin sulfate or heparin released from mast cells will complex with NGF and extend its plasma ½ life from minutes to several hours! (, ).

Interesting implications to migraines and MS is the observation that experimental allergic encephalomyelitis cannot be induced in mast cell deficient mice (). Chemical or stress induced activation of brain mast cells can alter the permeability of the blood brain barrier (, , , , ). This may be relevant to MS, as alterations in the blood brain barrier have been shown to precede manifestations of MS ().

Acute stress may activate intestinal or bladder mast cells and helps explain flare-ups in IBS and IC (, , , ).

Acute stress stimulates dermal mast cells (, ). Stress-related dermatological problems have led to a hypothesis that the skin has a feedback loop on the hypothalamus similar to the HPA axis (, , , , ). The first molecule released from the hypothalamus under stress is said to be corticotropin-releasing hormone (CRH) (). CRH and CRH receptors are found in the skin (, ). CRH is a powerful activator of dermal mast cells (, , ). A structurally related compound, urocortin, is even more powerful than CRH or SP (). Mast cells and CRH are also connected in the brain. Chemical or immunological mast cell activation in the hypothalamus activates the HPA axis (). This activation may be via direct activation of CRH neurons or via IL-6, which has been shown to be a CRH independent HPA activator (). And activation of the hypothalamus may increase CRH production and more mast cell activation. Of course, this is balanced by increased cortisol from the HPA axis that may decrease CRH production.

Cardiovascular symptoms are classically associated with stress. Generally, such symptoms as arrhythmias (an irregularity of the heartbeat) and tachycardia (fast heartbeats) are thought to be associated with increased sympathetic stimulation or a reflexive response to histamine-induced hypotension (low blood pressure). Recently an additional possibility has emerged: acute stress has also been shown to stimulate cardiac associated mast cells to release histamine and IL-6 (, , ). This mast cell activation may be involved in acute stress triggered myocardial infarction and unstable angina (, , ). The proinflammatory cytokine IL-6 has been shown to be an important player in coronary artery disease (CAD) and the acute coronary syndrome (, ). The cardiac effects of histamine seem to be mediated through histamine 3 receptors (q.v.) (, , ).

Mast cells have high affinity receptors for benzodiazepines (a tricyclic antidepressant) (, , ). In fact, mast cell activation can be inhibited by several tricyclic antidepressants including benzodiazepines and hydroxyzines (, ). Hydroxyzine has been effective in an RCT in treating remitting-relapsing MS (). Combination of relaxation therapy and anxiolytics has worked well in reducing the frequency and potency of migraines in children and decreasing an indicator of mast cell activity (). More work on a combination of mast cell inhibitors and anti-stress exercises for folks with atopy and depression would seem to be indicated.

NK Cells and Stress

Changes in NK cells, and proportions and functions of T cells have been associated with chronic stress. Related to those changes are alterations in various T and NK cell receptors. Flow cytometry has been used to look at the expression of NK cell associated receptors in 29 healthy adults with a bimodal age spread (). Distress was associated with significantly higher percentages of NK cells and a significantly lower percentage of CD3+ T cells. Significantly higher percentages of T cells expressed NK-associated receptors (e.g., CD94 and KIR). And there were significantly lower percentages of NK cells with KIR receptors.

Time courses of effects, relative to intensity and duration, of stress upon NK cell activity are interesting. Acute pain has most often been reported to result in suppressed NK cell cytotoxicity (NKCC) (, , ). However, one study noted NKCC increased slightly in response to electrical stimulation; and this effect was abolished when anesthesia was used prior to the stimulation (). In rats an experiment reported that nonmanaged surgical pain suppressed NKCC which in turn increased surgery mediated enhanced colonization of metastatic tumor cells (, ).

NK cells are one of the primary defenses against viruses, and they can be negatively influenced by chronic stress (, ). But, it has also been reported that acute stress may temporarily enhance NK cell activity (). Nevertheless, it has also been observed that after a prolonged acute stressful period, there may also be a recovery window when NK activity is compromised (, ). This has suggested that pain, changes in immune status and incidence of some diseases may be related (). Substantiating this hypothesis is a study of the influence of stress and pain associated with a root canal treatment (RCT) upon NK cell cytotoxicity and symptoms of upper respiratory illness in the following month (). Peripheral blood was drawn from 33 RCT patients immediately before the procedure, 30 minutes after local anesthesia, and 30 minutes after the RCT. A comparison group of 14 people underwent a parallel time course without the RCT. Blood was assayed for cortisol and NKCC, and all subjects kept a health diary for the post RCT month. Compared to controls, the patients demonstrated significant increase in NKCC between their baseline and the RCT, and a significant decrease in NKCC between the RCT and after the RCT. Post-RCT NKCC was negatively correlated with pain during RCT (r = -0.48, p<0.01), negatively correlated with pain 2 hours after the RCT (r = -0.43, p<0.05), and negatively correlated with pain 6 hours after the RCT (r = -0.44, p<0.05). At two weeks post RCT, significantly more illness symptoms were reported in patients vs. controls (Wilcoxon rank sum = 4.78, p = 0.03). Discriminant function analysis was able to correctly classify 88% of the subjects to the illness category based on the predictor variables post-RCT NKCC, pain, and stress levels (F(3,21) = 8.23,p<0.001).

Stressors

People under stress tend to adopt maladaptive health habits such as excess alcohol consumption, drug abuse, decreased exercise, lack of sleep, and poorer eating habits (, , ). These bad habits put them at additional risk for the consequences of stress. This may result in compromised endocrine and immune responses, and improper cardiovascular functions.

Low socioeconomic status across various populations shows a strong correlation to most causes of morbidity and mortality (, , , , ). The correlative with immune alterations seems to be chronic stress including unemployment (), job burnout (, , ), and job strain ().

Three factors that are influenced by and influence people to smoke cigarettes are stress, performance, and body weight. And if nicotine addicted smokers are deprived of nicotine their attentional and cognitive abilities suffer ().

Childhood family environments may be responsible for accumulating risks for mental health problems, major chronic diseases, and premature mortality (). Dysfunctional families are often characterized by conflict and aggression, and are cold, neglectful and nonsupportive. Interactions with genetic determinants make children vulnerable to aberrant emotional functioning and social competence. This additive stress coupled with bad health practice, especially drug abuse, may also have a negative influence on stress-related biological response systems including SAM and HPA.

Age differences in stress, coping, and appraisals were evaluated in the Normative Aging Study (). Middle-aged, young-old and old-old categories were used. Middle-aged were more likely than the older groups to appraise their problems as challenges or annoyances. The old-old folks claimed to have no problems and expended less effort in coping with them when problems occurred. The type of problem varied systematically with age; however, there were no age differences in perceived stressfulness of the problem, harm or loss appraisals, appraisals of helplessness, number of reported emotions, or efficacy of coping. The studies authors suggest that this may mean that nature of stress changes with age from episodic to chronic, which in turn affects the processes of appraisal and coping.

Stress response syndromes in breast cancer, melanoma, and Hodgkin’s disease have begun to be investigated ().

Simple acts such as public speaking can produce significant elevations in blood pressure. For example, in a study of 40 nurses during change of shifts, blood pressures and heart rates were faster during speaking to individual nurses or groups of nurses than resting levels, and when speaking to groups were higher than speaking to individuals (). And in a study of 52, fifth-grade children, rapid and significant increases in blood pressure and heart rate were observed when they read aloud (). Twenty-seven percent of the measurements were greater than the 95% of normal pressure for the child’s sex and age. How this lability may relate to future adult hypertension appears to remain unexplored.

Psychosocial risk factors of job stress, social isolation, and interpersonal conflict may influence coronary artery disease and its progression to CHD (). Inconsistent results of psychosocial interventions coupled with methodological limitations make it difficult to know if these psychosocial interventions have any benefit.

Inordinate sympathetic systolic reactivity to stress is associated with atherosclerosis and hypertension, and may be important in the etiology of stroke, especially ischemic stroke (). Men who were high reactors and poorly educated had 2.90 times greater stroke risk than low reactors who were well educated (n = 2,303; mean age, 52.8 ±5.1; 2.90 95% CI, 1.66 to 5.08).

Exaggerated blood pressure response to mental stress has also been shown to be an independent correlate of atherosclerosis at least in one group of men (). A study of middle-aged men from Eastern Finland, The Kuopio Ischemic Heart Disease Risk Factor Study, found that hopelessness contributes to progression of carotid atherosclerosis, especially among men who had early evidence of atherosclerosis, and there may be a dose effect (). Kuopio is a longitudinal study of unestablished and traditional risk factors for ischemic heart disease, mortality and other outcomes.

Academic examinations have found a place in stress research, as they are distinct and predictable types of real life stressors (, ). The stress of anticipation and participation in academic examinations has frequently provoked changes in several mental and physical parameters. Hormones such as cortisol, prolactin, DHEA, and testosterone have been studied (, , , , , ). Increased anxiety and negative mood are commonly seen (, , , ). Increases in cholesterol and serum lipids have been described (16250770, 232553). Time to heal wounds was increased in one experiment (). Immune function has shown to be compromised in several studies (, , , , , , , , ).

However, a 2003 review of the use of academic examinations in stress research has raised some questions about limitations academic examinations as a suitable model in PNI (). The review suggests that there are problems with terminology (types of examinations), difficulty of examinations, confounders in within-subject comparisons, and timing of repeated measurements. Timing of collecting biological fluids is especially important. As the review points out, in addition to hormonal ultradian and circadian rhythms, cortisol levels may take up to 10 days to return to normal after examinations (4), effects of steroid hormones may persist for hours (5), and catecholamines have ½-lives of less than 10 minutes (5). To better control for these variables they suggest the following. A brief survey of state but not trait anxiety should be administered at the time of the examination and at a comparable non-examination time for the controls. An objective measure of test difficulty (6) or at least a comparison of the test mean and score distributions might indicate the difficulty and allow comparisons across studies. Control groups would be better served if they used controls with similar background stress but without test pressure. Alternatively, longitudinal studies could use the test subjects for their own controls.

Psychological Stress and Virus

Acute psychological stress induced change in the cellular immune response to latent Epstein Barr virus (EBV) has been shown in 25 healthy EBV-positive medical students (). The stress of a 3-day block of examinations decreased the proliferative response (i.e., the immune system was less reactive) to 5 of 6 EBV polypeptides. Subjects who were above average in seeking support were not as immune suppressed: they showed lower proliferative responses to only 3 of the EBV polypeptides and higher levels of antibody to EBV virus capsid proteins.

Chronic stress was evaluated in a group of chronically stressed individuals living next to Three-Mile Island (TMI) nuclear power plant (). Compared to controls, the TMI group showed:

Increased neutrophils, which were positively correlated with increased epinephrine levels.
Fewer B cells, T-suppressor/cytotoxic cells, and NK cells.
Antibody titers to latent herpes simplex virus were significantly different.
IgG and IgM to non-latent rubella virus were comparable.

Herpes simplex type 1 and type 2 reactivation and recurrent disease seem to be correlated to up-regulation of some effector molecules during times of acute and chronic stress (). These include epinephrine, IL-6, cyclic AMP, glucocorticoids, and prostaglandins. However, in a sample of 58 women aged 20 to 44 years, persistent stressors and highest levels of anxiety were associated with recurrence of genital herpes infections in women, but not with short-term stressors or transient depressive or angry moods and menstrual cycles (). A lag of one week was seen between the persistent stress and the herpes outbreak (OR = 1.08 per unit of stress; 95% CI: 1.01-1.15; p = 0.03), and an increased rate of recurrence was seen in the month following the greatest amount of anxiety (p = 0.03).

Stress has also been shown in mice to decrease memory cytotoxic T cells capacity to limit virus levels of Herpes simplex on the mucosal site of infection but not on the latent virus in the sensory ganglia ().

One small study of nine people noted a correlation between mood, herpes labialis recrudescence in a 3-month period, and NK cells and epinephrine (). The week preceding recrudescence, NK cells were 58 units higher in those afflicted than in the overall group mean (227 units). Also during that week, increased NK cells were associated with a discontented mood (r = 0.64; p = 0.05). Nevertheless, compared to the week when the herpes appeared, the NK cells were significantly lower (T1,9 = 2.70; p<0.05) and the serum epinephrine levels were also significantly less (T1,9 = 2.41; p<0.05).

A 6-month prospective study of 36 patients with recurrent genital HSV identified several psychological and immunological predictors of recurrent outbreaks (). Folks who had higher levels of stress over the 6-months had lower levels of CD4 and CD8 cells. People with high levels of anxiety, hostility, or depressive mood had a lower proportion of CD8 cells. And, people who had high levels of depressive mood and did not report having other infections, had a greater rate of HSV recurrence.

Stress and Sympathetic Modulation

There is some evidence that stress reduction may affect local inflammation and that effect in at least one experimental setting may be due to neurogenic sympathetic modulation (). In an RCT, 28 men and 22 women were taught imagery-based relaxation and then randomized. On one evening, the subjects were exposed to one of the following: a stressful 20-minute Stroop test, a relaxation tape, or a control video. These were followed by an intradermal injection of capsaicin to the forearm. For one hour, the size of the flare at the injection site was monitored and cardiovascular variables, adrenocorticotrophic hormone, cortisol, and norepinephrine were measured at regular intervals. The stress and the control groups did not differ in the flare size. However, the group that received the relaxation tape had a significantly smaller maximum size flare than either one. Maximum flare size and total amount of flare was predicted by increases in heart rate, norepinephrine, and systolic blood pressure before the capsaicin injection but not after injection.

Benign prostatic hyperplasia (BPH) may be influenced by psychological factors operating upon the sympathetic nervous system and the hypothalamic-pituitary-gonadal axis. Urologic function, stress and hostility were evaluated in 83 men with BPH (). Higher self-reported recent stress and hostility were associated with higher residual urine volumes (p<0.05). But, higher lifetime stress was associated with lower prostate volumes and less residual urine (p<0.05). And stress and hostility were not associated with self-reported ratings of urological symptoms.

Psychological Stress and Wound Healing

Several studies have assessed the effects of psychological stress on wound healing (, ). For example, the effects of psychological stress on wound healing in caregivers of patients with Alzheimer’s disease has been investigated in 13 women caregivers (mean age 62.3) and 13 controls (mean age 60.4) matched for age and family income (). Healing was assessed on a 3 mm punch biopsy reacting to hydrogen peroxide by foaming. Healing was considered to be no more foaming. Healing took signifi