+++
Psychoneuroimmunology
++
Psychoneuroimmunology (PNI) involves the study of the interactions of consciousness, the central nervous system (CNS), and the immune system (involving the body’s defense against infection and aberrant cell division). The compelling evidence of these studies is that the CNS influences immune function and that, conversely, the immune system can influence the CNS. The brain is normally part of the immunoregulatory network. Specifically, stimulation of the hypothalamic–pituitary–adrenal (HPA) axis leads to downregulation of immune system function in response to stress (see Figure 34-1). Stressful thoughts and emotions may reach the hypothalamus by axons projecting from the limbic system (primarily the amygdala) or from the forebrain. Corticotropin-releasing factor (CRF), produced in the hypothalamus under conditions of stress, acts on the anterior pituitary to release adrenocorticotropin hormone (ACTH), which in turn stimulates the production of corticosteroids in the adrenal cortex. Under conditions of acute stress, corticosteroids have immunosuppressive effects on the lymphoreticular system and marked antiallergic and anti-inflammatory effects.
++
++
In addition, CRF leads to release of catecholamines, which themselves may produce changes in lymphocyte, monocyte, and leukocyte functions. Opiates are also elevated with stress, and they are generally reported to be immunosuppressive. Finally, growth hormone and prolactin, which are immunoenhancing factors, are initially elevated at the onset of acute stress, but under conditions of prolonged stress their secretion is inhibited. Thus, the combined effect of elevated corticosteroids, catecholamines, and opiates, along with inhibition of growth hormone and prolactin, is to dysregulate the immune system.
++
Recent evidence indicates that chronic psychological stress can lead to increased production of proinflammatory cytokines, particularly interleukin-6 (IL-6), which is also triggered by infection and trauma. Proinflammatory cytokines have been implicated in a range of diseases in older adults that can be traced to inflammation, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain lymphoproliferative diseases or cancers (including multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia), depression, Alzheimer disease, and periodontal disease. IL-6 promotes the production of C-reactive protein, which is an important risk factor for MI. Depression and anxiety also enhance the production of proinflammatory cytokines, which is a possible mediator of the association of these disorders with increased morbidity and mortality (see Chapters 25 and 26). A recent study has shown that depressed subjects, compared with nondepressed controls, showed an impaired ability to regulate inflammation triggered by acute stress.
++
Another recent development in stress research involves the concept of “allostatic load,” which is the wear and tear on organisms that results from chronic overactivity or underactivity of allostatic systems. Allostasis refers to the body’s ability to produce hormones (e.g., cortisol) and other mediators (e.g., cytokines) that help it to adapt to novel situations or challenges. These systems, which include the autonomic nervous system (Figure 34-2), HPA axis (Figure 34-1), and the cardiovascular, metabolic, and immune systems, protect the body by responding to internal and external stress in an attempt to achieve stability through change.
++
++
Activation of allostatic systems in response to a stressor includes the release of catecholamines from nerves and the adrenal medulla, as well as the stimulation of cortisol release from the adrenal cortex via the HPA system described above. Four types of allostatic load can result from prolonged stress: (1) Repeated elevations of blood pressure over weeks or months accelerates atherosclerosis, increasing the risk of MI. (2) When adaptation to repeated stressors is lacking, there may be prolonged exposure to stress hormones. (3) There may be an inability to shut off allostatic responses after stress is terminated, leading to conditions such as hypertension or decreased bone mineral density. (4) Inadequate responses in some allostatic systems, such as cortisol secretion, may lead to compensatory increases in other systems, such as proinflammatory cytokines (which are downregulated by cortisol).
+++
Stress, Food, & Inflammation
++
Inflammation is a common link for diseases high in mortality risk, including cardiovascular disease, cancer, and diabetes. Stress and depression, as well as dietary intake, can promote inflammation through proinflammatory cytokine production. Diet influences cytokine-induced inflammation by means of the balance between omega-3 (n-3) polyunsaturated fatty acids (PUFA) and omega-6 (n-6) PUFA, with n-6 (refined vegetable oils) promoting the production of proinflammatory cytokines and n-3 (fish, fish oil, walnuts, flax seed) mitigating their production. The link between depression and inflammation interacts with dietary balance, with higher n-6/n-3 ratios showing a relationship with depression. In epidemiologic studies, greater fish consumption has been associated with a lower prevalence of depression. A diet with higher n-6/n-3 ratio can also increase vulnerability to inflammatory responses to stress. Stress, in turn, promotes unhealthy food choices that promote inflammation, with higher stress associated with decreased fruit and vegetable consumption and increased consumption of sweets and fast food. Higher stress is also associated with higher peaks in postprandial lipidemia and delayed gastric clearing of these compounds, both associated with atherogenesis.
+++
Effect of Psychological Interventions on the Immune System
++
In a series of studies on asymptomatic men following notification of human immunodeficiency virus (HIV) seropositivity, a 10-week program of cognitive behavioral stress management and aerobic exercise training programs buffered distress responses and immune alterations. The same intervention had positive effects on mood and immune function in gay men whose disease had become symptomatic. Meta-analyses of the placebo effect have shown positive effects in various inflammatory and immune-related diseases, including asthma, cancer symptoms (pain and appetite), Crohn disease, chronic fatigue, duodenal ulcer, irritable bowel syndrome, and multiple sclerosis (relapse frequency). A meta-analytic review showed that three classes of interventions could reliably alter immune function. Hypnosis with immune suggestions showed a positive influence on total salivary immunoglobulin A (IgA) concentration and neutrophil adherence, along with a modest suppression of intermediate-type hypersensitivity erythema. These effects were mediated through relaxation. Some studies have shown differential delayed skin sensitivity reactions on the right and left arm of subjects depending on which arm was suggested under hypnosis to show no changes. Conditioning interventions, in which a neutral stimulus is initially paired with an immune-modulating stimulus and later elicits the immune changes on its own, were able to enhance natural killer (NK) cell cytotoxicity. Disclosure interventions, which encourage patients to write essays about previously inhibited stressful experiences, have shown some success in reducing antibody titers to Epstein–Barr virus and enhancing the body’s control over latent herpes simplex virus production.
+++
Stressful Life Events
++
In 1967, Holmes and Rahe published a scale of 43 life events, along with a method of quantifying life changes according to the amount of readjustment they require for the average person. This scale allowed greater quantitative precision in life change and illness studies and provided a pivotal methodological leap that broke through the circularity in which the stressful life changes had been measured in terms of illness outcome, rather than in terms of the inherent magnitude of the stressor. Questionnaires based on this and similar scales have gathered data on several populations globally. Retrospective studies have shown a relationship between recent life change and a host of pathological outcomes, such as sudden cardiac death, onset of MI, occurrence of fractures, pregnancy and birth complications, aggravation of chronic illness, tuberculosis, multiple sclerosis, diabetes, onset of leukemia in children, and onset of mental disorders such as depression and schizophrenia. Prospective studies, particularly those conducted on US Navy populations while deployed at sea, predicted future illness based on life change scores prior to deployment and subsequently verified the accuracy of those predictions by inspection of medical records.
++
Recent attention has focused on individual and situational variables that may mediate the relationship between life change and illness. Among the psychological variables that seem to mediate the stress response are locus of control (including the extent to which individuals prefer control in their lives and how much control they perceive they have over specific life events), need for stimulation, openness to change, stimulus screening, self-actualization, the use of denial, the presence of social supports, and emotional self-disclosure. In one study of Illinois Bell executives during the divestiture of AT&T, those executives who experienced high levels of stressors while remaining healthy differed from those with high stressors and high illness on a dimension of “hardiness.” This personal characteristic consists of “the 3 Cs”: a strong commitment to self, work, family, and other important values; a sense of control over one’s life; and the ability to see change as a challenge rather than a threat. More recently researchers suggest a “fourth C”: coherence, a belief that one’s internal and external environments are predictable and that things will work out as well as can be expected.
++
More recent studies of resilience (a concept related to hardiness) have focused on the neurochemical and hormonal feedback systems that dampen or switch off the stress response (HPA axis and sympathetic nervous system response described above). Among these resilience chemicals are DHEA (dehydroepiandrosterone), which lessens the effects of cortisol, and neuropeptide Y, which counters the effects of CRF at the anterior pituitary. These stress inhibitory mechanisms may be more prevalent in people who show a greater resiliency or hardiness in response to stressful events. Yet to be examined is the question of whether levels of these feedback chemicals are modifiable in response to stress management training or other psychological interventions.
++
Increased use of mobile phones, smartphones, and the Internet has established new norms for work and connectivity in industrialized countries. Although allowing broader and more rapid access to information than ever before in human history, as well as increasing flexibility for work location and hours among many workers, these technologies also exact a toll on human health. In a recent Swedish study of young adults, high mobile phone use was a predictor of stress, sleep disturbance, and depression at a 1-year follow-up. Increased use of social media to interact frequently with friends near and far presents a paradox. On the one hand these media facilitate engagement with social support networks, which are a well-established stress buffer. Chatting and instant messaging are among the high-frequency activities of those in Generation Y (born after 1980). On the other hand, these media also lead to communication overload, the taxing of working memory through multitasking, distractibility, and guilt induced by the social expectation of immediacy of response and constant availability.
+++
Stress in America Survey
++
The Stress in America survey published by the American Psychological Association (APA) revealed that those who serve as caregivers—providing care to both the aging and chronically ill—for their family members report higher levels of stress, poorer health, and a greater tendency to engage in unhealthy behaviors to alleviate that stress than the population at large. According to estimates from the National Alliance for Caregiving, 65.7 million Americans served as caregivers for an ill or disabled relative in the past year. In the APA survey, 55% of caregivers (median age 49 years) felt overwhelmed by the amount of care required by chronically ill or aging family members. Caregivers were more likely than those in the general population to report that they are doing a poor or fair job of managing stress and getting enough sleep. Mean stress level of caregivers (on a scale of 1–10) was 6.5 compared to 5.2 for the general public. Caregivers reported being poorer in health than the rest of the nation, with greater rates of high cholesterol, high blood pressure, overweight/obesity, and depression. Other survey findings were that caregivers were more likely than the general population to have chronic illness, to lie awake at night, to have poor nutrition, to skip a meal, and to get sick five or more times a year.
+++
Work-Related Stress and Burnout
++
The demands of the workplace in industrialized societies are a persistent and intense stressor. Job strain is defined as a combination of high job demands and low perceived control. In a prospective study of healthy young adults (Cardiovascular Risk in Young Finns study), job strain was associated with increased carotid atherosclerosis among the men, but not the women.
++
In another prospective study, the degree of job stress over time increased the risk of the metabolic syndrome in a linear fashion. Subjects with lower grades of employment suffered disproportionately from the effects of stress as a risk factor for the metabolic syndrome, with men showing more susceptibility than women. Burnout is a syndrome associated with unrelenting stress and has been studied extensively as a phenomenon in a variety of work settings and professions, including physicians. It includes symptoms of emotional exhaustion, depersonalization, and a decreased sense of personal accomplishment. In a prospective study, burnout was associated with an increased risk of type 2 diabetes in apparently healthy individuals.
++
In Japan, the concept of karoshi, or death from overwork, has received government attention in recent decades. Rapid growth in industrialization following World War II led to production efficiencies placing pressure on Japanese workers, who often worked overtime without additional compensation. A new phenomenon of sudden death among high-level businessmen who were previously healthy brought attention to these stressful work environments. In 2008 in a well-publicized case a company was ordered to pay 200 million yen to a man who overworked until he fell into a coma. Among statistics published by the Japanese Ministry of Health, Labor, and Welfare in 2007 for the previous year, 189 workers had died from overwork, many from heart attacks and strokes, and 208 more had become severely ill.
+++
The Role of Acute and Chronic Stress in Cardiac Disease
++
Acute stress activates the sympathetic nervous system (Figure 34-2), which leads to increases in heart rate and blood pressure, coronary vasoconstriction, and decreased myocardial electrical stability. Several behavioral and emotional events have been implicated as probable triggers of acute coronary syndromes (MI and sudden cardiac death) in vulnerable individuals, especially events within a 1-to 2-hour period before the onset of symptoms.
++
Behavioral triggers include physical exertion (more common in men than women), sexual activity, sleep disturbance, and heavy consumption of alcohol. Well-studied emotional triggers include earthquakes, sporting events, war, high-pressure deadlines at work, and anger. In one study, the relative risk of acute MI in the 2 hours following an anger episode was 2.3, and in comparison with a control period 24 hours earlier it was 4.0. This effect was independent of age, sex, cardiovascular risk factors, and use of beta-blockers. The risk of anger triggering an MI was inversely related to socioeconomic status. In a large-scale study, the relative risk of anger triggering an MI was 9.0 compared to usual levels of anger, but when limiting the analysis to patients who had no premonitory symptoms the relative risk increased to 15.7.
++
Examination of the stored electrocardiograms of 200 New York area patients with implantable cardioverter-defibrillators showed differences in ventricular tachyarrhythmias triggering cardioverter-defibrillator therapy before and after the World Trade Center attack of September 11, 2001. There was a 2.3-fold increase in ventricular tachyarrhythmias during the month after 9/11, relative to other months between May 2001 and October 2002. Similar to the data from the 1996 European football championships mentioned above, in a study examining daily cardiovascular disease events in Munich during the 2006 World Cup, cardiovascular emergencies increased 2.7 times in men and 1.8 times in women on the days when Germany was participating in the quarterfinals and semifinals. On these days, MI and major arrhythmia admissions increased three times compared with the same day in previous years. The highest incidence of cardiac events occurred during the first 2 hours of the games.
++
In addition to promoting unhealthy behaviors, chronic stress activates and reactivates the sympathetic nervous system. Repeated sympathetic stimulation increases heart rate and blood pressure, and autonomic nervous system dysregulation leads to decreased heart rate variability and baroreflex dysfunction, which has been associated with cardiovascular disease events. Depression increases levels of inflammatory markers, including fibrinogen, C-reactive protein, IL-6, and tumor necrosis factor. Chronic stressors also activate the HPA axis producing hypercortisolemia, which in turn promotes central obesity and insulin resistance, risk factors for cardiovascular disease.
++
Chronic work stress, defined as high demands and low control, was associated with cardiovascular disease events in a study of 10,308 middle-aged London-based civil servants, with work stress contributing a relative risk of 1.68. Associations were found between work stress and negative behaviors, such as low physical activity and poor diet, and pathophysiologic consequences, such as decreased heart rate variability and an increase in morning cortisol.
++
In the Caregiver Health Effects study, 400 caregivers showed a 63% higher mortality rate than noncaregiving control subjects over a 4-year period. The increased mortality was particularly evident in caregivers who already had known cardiovascular disease. In a series of physiologically oriented studies, the San Diego Caregiver study examined possible pathways between caregiving and cardiovascular disease. Distressed caregivers had an increased risk for developing hypertension when followed over a 6-year period. Caregivers also had increased levels of D-dimer (a circulating procoagulant factor), more sleep disruption, and higher levels of circulating inflammatory cytokines.
+++
Personality Influences on Cardiovascular Disease
++
Recent research has examined the relationship between coronary heart disease and a personality constellation that includes hostility, anger, cynicism, suspiciousness, and excessive self-involvement. Hostility is conceptualized as comprising three elements: the emotion of anger; its expression; and cognitions of cynical mistrust. Using well-validated measures of the cognitive aspect of hostility, studies have linked higher hostility scores with subsequent coronary events like hospitalizations for angina, nonfatal MI, stroke, and congestive heart failure. Higher hostility has also been associated with coronary risk factors, such as increased plasma homocysteine levels, triglycerides, body mass index, waist-to-hip ratio, glucose levels, alcohol consumption, and smoking. In a study of middle-aged women, each 1-point increase in hostility scores predicted a significantly higher intimal–medial thickening in the carotid arteries.
++
Females have been noted to respond to stress with a “tend-and-befriend” way of coping, in contrast with the “fight-or-flight” model that may be more characteristic of males. When confronted with stress, females tend to engage in nurturing activities that protect themselves and their offspring and that enhance social support, which has been identified as a powerful stress buffer. In particular, there may be links between estrogen and a blunting of oxytocin, which is implicated in the fight-or-flight response. The “tend-and-befriend” response may also lower blood pressure.
+++
Positive Cognitive Styles
++
Evidence is accumulating from a variety of studies that optimism, perceptions of personal control, and a sense of meaning are protective of physical health. These cognitive resources assume special significance in helping people cope with intensely stressful events. Even unrealistically optimistic expectations appear to slow down the progression of disease in men infected with HIV. In a study of healthy older adults, a sense of coherence (one indicator of resilience) moderated the association between anticipation of moving and reduced NK cell lysis, with a low sense of coherence associated with poorest levels of NK cell lysis. In a recent study of the cognitive and psychological sequelae of the 2011 Japanese earthquake and tsunami among survivors in the primary disaster area, posttraumatic stress had a major impact on self-perceived quality of life 3 months after the disaster. The study authors concluded that reducing negative cognitions would have a greater impact than positive re-appraisals on lowering depression and anxiety in this early stage of response. It was expected that positive re-appraisals leading to posttraumatic growth (PTG) would occur over longer time frames. Similar to the time course of recovery from other disasters, it was expected that PTG would include enhanced relationships with others, a sense of new possibilities, self-perceived personal strength, a sense of purpose in life, the concept of ikigai (meaningfulness), and a deepened spirituality.
+++
Religion and Spirituality
++
Several studies have shown a relationship between religious or spiritual practice and health outcomes. “Religion” can be considered a collection of beliefs and practices that are external expressions of spiritual experience. These expressions can be organizationally based or private, but are usually grounded in a collective tradition. “Spirituality” can be considered an orientation toward or experiences with the transcendent, existential, or sacred dimensions of life. That which is transcendent or sacred is considered as something beyond oneself, whether it be conceptualized as a divine being, higher power, nature, spirit, or the ultimate ground of being. It is possible for people to engage in religious activities independent of having spiritual experiences, just as some people consider themselves intensely spiritual without being religious. Some consider their religious practice to be a pathway toward spirituality.
++
Types of studies on the religion–health connection have included cross-sectional as well as prospective and retrospective studies where participation in religious or spiritual practice is correlated with some health outcome measure, as well as intervention studies in which subjects were randomized into treatment and control groups. Correlational studies of religious or spiritual involvement and health outcomes have shown a positive association with longer life; less cardiovascular disease; less hypertension; more engagement in health-promoting behaviors; decreased risk of depression, anxiety, substance abuse, and suicide; better coping with illness; and better health-related quality of life. Among the intervention studies the best evidence for efficacy with health outcomes has been with religiously oriented cognitive therapy, meditation, 12-step fellowships, forgiveness therapy, and intercessory prayer. These studies need further replication with better designed controls.
++
Both religion and spirituality represent a heterogeneous group of belief systems, religious practices, and spiritual experiences. Most of the research linking religious or spiritual practice to health outcomes does not account for this heterogeneity, and thus the generalizability of results is limited. Nevertheless, the growing accumulation of evidence of positive health correlates of religion and spirituality warrants not only more sophisticated research but the attention of clinicians seeking to improve the health of patients.
++
CASE ILLUSTRATION 1 (CONTD.)
Social History: At the follow-up appointment, the physician took a social history, which revealed that the patient had been smoking a pack of cigarettes every day for the last 35 years but did not use alcohol or street drugs. Although never married, she had been involved in a 10-year relationship with her boyfriend, who suffered from severe emphysema and was dependent on oxygen. Three years previously this man had assumed responsibility for raising his two granddaughters (ages 8 and 11 years) because his daughter, the girls’ mother, was a drug addict serving time in prison. The patient was not consulted about this custody decision. She accepted the stressor out of love for her partner, who was also dependent on her. The oldest granddaughter was now age 14 and had become unruly, rebellious, sexually active, and aggressive. She had asked the patient for help obtaining birth control. Although the patient wanted to leave this demanding social situation, she saw it as her responsibility to care for her partner and the two children. The history correlated these recent life events with increased frequency of migraines and initiation of daily use of Tylenol #3.
Physician Facilitation of Emotional Self-Disclosure: The physician actively listened to the patient’s self-disclosure, which was accompanied by crying. At the end of the interview the patient thanked the physician, who noted that she had not complained of migraines during that visit.
++
In allowing the patient to disclose her psychological and social stressors, the physician was able to gain relevant information within a biopsychosocial perspective of patient care. Relevant stressors potentially contributing to this patient’s medical symptoms included caregiving for a disabled partner, having to assume a parenting role of grandchildren, and a self-expectation of a way of loving her partner that allowed no escape for her from an uncontrollable situation. In allowing the patient’s emotional self-disclosure, there was an immediate effect on mitigating migraine symptoms. Going forward from this interview, it was important for the physician to have a pathway to navigate and orchestrate the various biological, psychological, and social interventions relevant to this patient’s condition.