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Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences (2001)

Chapter: 2 Biobehavioral Factors in Health and Disease

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Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
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Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 40
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 41
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 42
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 43
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 44
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 45
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 46
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 47
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 48
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 49
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 50
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 51
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 52
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 53
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 54
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 55
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 56
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 57
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 58
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 59
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 60
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 61
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 62
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 63
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 64
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 65
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 66
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 67
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 68
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 69
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 70
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 71
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 72
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 73
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 74
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 75
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 76
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 77
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 78
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 79
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 80
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 81
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 82
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 83
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 84
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
×
Page 85
Suggested Citation:"2 Biobehavioral Factors in Health and Disease." Institute of Medicine. 2001. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: The National Academies Press. doi: 10.17226/9838.
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Page 86

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2 Biobehavioral Factors in Health and Disease R esearch into the bidirectional and multilevel relationships be- tween behavior and health has been aided by technology and by conceptual advances in the behavioral, biological, and medical sciences. Our understanding of the interactions between brain function and behavior has been enriched by advances in behavioral neurobiology, neuroscience, and neuroendocrinology from molecular mechanisms to psy- chological systems. Real-time imaging of the living human brain during different behavioral states has promoted our understanding of the links between human behavior and basic neurochemical processes or specific neuroanatomic pathways. Common availability of monoclonal antibod- ies, routine production of genetically altered animals, and new understand- ing of the genetic code have contributed to exploration of how genetics interacts with development and early experiences to influence both vul- nerability to disease and resistance to age-related decline. Yet much of the research knowledge is highly compartmentalized, and there is a need to integrate isolated pockets of information. This chapter addresses the interplay among biological, behavioral, and social factors in health and disease, with an emphasis on biologic factors. Subsequent chapters address behavioral and social factors in greater de- tail. 39

40 HEALTH AND BEHAVIOR STRESS, HEALTH, AND DISEASE The Stress Response Over the past 60 years or so, the study of stress has provided a major link in explaining the behavioral variables and the biological factors that influence physical health. Stress both causes and modulates a diversity of physiological effects that can enhance resistance to disease or cause dam- age and thereby promote disease. For example, stress-related hormones, such as cortisol and epinephrine, have protective and adaptive functions as well as damaging effects. This idea, first introduced by Hans Selye (1956), is reemerging in contemporary biobehavioral research (McEwen, 1998). A characteristic set of physiological effects—the “stress re- sponse”—has been identified and investigated in humans and animals (Chrousos, 1998). The primary and secondary effects of the stress response constitute the biologic pathways along which a person’s experiences, liv- ing and working conditions, interpersonal relations, lifestyle, diet, person- ality traits, and general socioeconomic status can affect the body. Indi- vidual behavior is important because it increases or decreases the pathophysiological cost of stress through diet, exercise, and other activi- ties. The stress response is an important component of the body’s regula- tory systems. The maintenance of constant and appropriate internal con- ditions and functioning in the face of changing environmental demands is called homeostasis, an idea first developed by Walter Cannon (1936). The stress response, however, primarily involves reaction in an emergency. This function evolved over millions of years and is critical to the survival of most animals, including humans, when external threats and dangers, such as predation, are encountered. The stress response consists of many co- adapted and simultaneous shifts in the physiological functioning of the cardiovascular, respiratory, muscular, metabolic, immune, and central ner- vous systems. Physiological changes can be accompanied by altered emo- tional responses, enhanced vigilance, heightened appraisal of risk, en- hanced memory storage and retrieval, and changes in motivation. The stress response is a rapid and pervasive adjustment of internal states to prepare an organism to adapt to a threat—to respond to the rigors of “fight or flight” (Chrousos, 1998). Many aspects of the stress response, however, are inappropriate or maladaptive in the context of modern postindustrial societies. The threats posed here are different from those our evolutionary ancestors faced. We

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 41 do not commonly confront acute, life-threatening assault. Instead, con- temporary humans face ill-defined, diffuse, often chronic threats that can- not be resolved by fight or flight. Nevertheless, the ancient physiologic stress response is triggered when one experiences, for example, a threat to social position, damage to important interpersonal relationships, loss of possessions, or barriers to the achievement of goals. Because many diffi- culties of contemporary life and their accompanying stress cannot be rap- idly resolved—as could many physical stressors—the stress response per- sists, homeostasis is not restored, and the response becomes dysfunctional rather than adaptive. An increasing body of evidence indicates that stress is a potent contributor to illness (Cohen and Herbert, 1996; Cohen et al., 1991; Hermann et al., 1995; Kiecolt-Glaser et al., 1996; McEwen, 1998). The continued and unproductive activation of the stress response, includ- ing the failure to shut off this response when it is not needed, called allostatic load, is discussed below. The stress response is one aspect of an array of biologic and behavioral processes that either protect or cause damage. For example, secretion of stress-related hormones, such as cortisol and the catecholamines (epineph- rine and norepinephrine), typically varies in a daily rhythm that is en- trained by the light/dark cycle and by sleep/waking patterns that are part of normal daily life. But chronic increase in cortisol throughout the diur- nal cycle is associated with negative consequences, such as accelerated bone mineral loss and hyperglycemia. Because the subjective experience of stress does not always correlate with physiological response (Kirschbaum et al., 1999), long-term measurement of hormone concentrations and of the processes that they regulate (for example, blood cholesterol concen- tration, fat accumulation, immune function, atrophy of brain structures, blood pressure), constitute an important way to connect life experience and the risk of disease. Allostasis and Allostatic Load An important new attempt to understand the relationships between environmental and behavioral challenges and stressors, the physiological responses to these events, and disease uses the terms allostasis and allostatic load. Allostasis is the maintenance of overall stability (homeostasis) through the constant adjustment and balancing of various components in the process of adapting to challenge. Sterling and Eyer (1988) first used the term to describe cardiovascular system adjustments in response to rest

42 HEALTH AND BEHAVIOR and activity states. Later, the idea was generalized to other physiologic mediators, such as adrenal cortisol and the catecholamines. Allostatic load is the wear and tear the body experiences as a result of repeated allostatic response (McEwen, 1998; McEwen and Stellar, 1993). Allostasis and allostatic load operate in all systems of the body and focus attention on the protective, as well as the damaging, property of the primary mediators of the stress response: cortisol and the catecholamines. The major aspects are summarized in Figure 2-1. First, the brain integrates and coordinates behavioral and physiologic responses (hormonal and au- tonomic) to challenge. Some challenges can be perceived as stressful; oth- ers are related to circadian rhythms and to coordination of the functions of sleep and waking with the environment. Second, individual differences in the capacity to cope with challenges are based on multilevel relation- ships between genetic, developmental, and experiential influences. Third, intrinsic to the autonomic, neuroendocrine, and behavioral responses to challenge is the capacity to adapt (allostasis); indeed, neuroendocrine re- sponses, such as the release of cortisol, are by nature protective and acute. Problems arise only when they persist, so efficient initiation and cessation of these responses is vital. Negative effects result when allostatic responses to challenge or stress occur inappropriately or are terminated inefficiently. Fourth, allostasis has a price that is related to the degree of inefficiency in the response and to the number of challenges and stressors a person expe- riences. Allostatic load is more than chronic stress. It can also reflect a genetically or developmentally induced failure to cope efficiently with the daily challenges related to the sleep/waking cycle and other experiences. And it also includes contributions of lifestyle factors, such as diet, alcohol and tobacco use, physical activity, and sleep, through their influences on the production of stress hormones. Protective and Damaging Effects of Stress Mediators A behavioral response to challenge or stress can be protective or dam- aging. The risk of harm or disease can be increased by such patterns of behavior as hostility or aggression, and it can be reduced by cooperation and conciliation. Cigarette-smoking, excessive alcohol consumption, high fat consumption, and exposure to physical hazards increase the risk, as does insufficient physical activity. The link of allostasis and allostatic load can be applied to various behavioral responses: Such behaviors as smok- ing, high alcohol consumption, and consumption of high-fat foods all have

External Conditions Conducive to Stress (Stressors) Major Life Events Short Term Challenges Chronic Strains Environmental Exposures Cataclysmic Events (e.g., death of a loved one, (e.g., meeting deadlines) (e.g., job demands, (e.g., exposure to hazardous (e.g., hurricanes, birth of a child) poverty, abuse, materials) tornadoes) discrimination) Modifying Variables (e.g., social support, control) Perceived Stress Individual Differences Behavioral Responses (e.g., age, gender, health status, BRAIN (fight or flight, personal coping abilities) behavior—diet, smoking, drinking, exercise) Physiologic Responses (e.g., blood pressure, pulse rate) Allostasis Adaptation Allostatic Load Enduring Negative Health Outcomes FIGURE 2-1 The Stress Response and Development of Allostatic Load. Individuals experience objective psychological and environmental conditions that are conducive to stress, referred to as stressors. The percep- tion of stress is influenced by social, psychological, biophysical factors, genetics, and behavior. When the brain perceives an experience as stressful, physiologic and behavioral responses are initiated, leading to allostasis and adaptation. Over time, allostatic load can accumulate, and the overexposure to mediators of neural, endocrine, and immune stress can have adverse effects on various organ systems, leading to enduring negative health outcomes (physiological, e.g., cardiovascular disease; psychological, e.g., depression; behavioral, e.g., alcoholism). Adapted from McEwen, 1998; Israel and Schurman, 1990. Reprinted with permission from Massachusetts Medical Society. Copyright 1998. All rights re- served. Reprinted by permission of Jossey-Bass, Inc., a subsidiary of John Wiley & Sons, Inc. 43

44 HEALTH AND BEHAVIOR some perceived adaptive effects in the short-term but damaging effects if they persist. Behavior can attenuate some of the damaging effects of physi- ologic responses. For example, even a brief period of exercise can enhance glucose uptake by reducing the insulin resistance of muscle tissue (Perseghin et al.,1996). The mediators of protective and damaging effects of allostatic re- sponses are mainly adrenal steroids and catecholamines. Other hor- mones—such as dehydroepiandrosterone, prolactin, growth hormones, and the cytokines—also mediate adaptive or maladaptive effects, but their consequences are often specific to an organ or a system. Once the media- tors are released, they produce their effects by acting on cellular receptors. The effects can be classified as primary effects; secondary outcomes, which are risk factors for disease; and tertiary outcomes, which are diseases them- selves (McEwen and Seeman, 1999). The actions of the mediators adre- nal glucocorticoids and catecholamines are shown in Figure 2-2. These substances act via receptors that trigger changes throughout the target cell (including changes in gene expression) that have long-lasting conse- quences for cell function. It is important to consider the short- and long- term consequences of hormone release for cell function. There are many examples of beneficial and adverse effects of the mediators of allostatic responses. These factors are introduced here and discussed in more detail later. In the central nervous system, catecholamines and adrenal steroids promote the storage and retrieval of memories of events, pleasant and unpleasant, associated with arousal. However, adrenal steroids acting with excitatory amino acid neurotransmitters are associated with cognitive dys- function involving various mechanisms that promote atrophy and, in some extreme cases, the death of neurons, particularly in the hippocampal region. In the cardiovascular system, autonomic responses, in part because of catecholamines, promote allostasis (adaptation) by adjusting heart rate and blood pressure according to the changing demands of sleeping, wak- ing, and physical exertion. Damaging allostatic load occurs as a result of a failure to terminate blood pressure surges efficiently. This accelerates ath- erosclerosis and synergizes with metabolic hormones to accelerate non- insulin-dependent diabetes. The immune system is particularly responsive to the mediators of allostatic response. Adrenal steroids and catecholamines promote the movement of immune cells to organs or tissues where they are needed to

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 45 FIGURE 2-2 Allostasis in the Autonomic Nervous System and HPA Axis. Allostatic systems respond to stress (upper panel) by initiating the adaptive response, sustaining it until the stress ceases, and then shutting it off (recovery). Allostatic responses are initiated (lower panel) by an increase in circulating catecholamines from the autonomic nervous system and glucocorticoids from the adrenal cortex. This sets into motion adaptive pro- cesses that alter the structure and function of a variety of cellls and tissues. These processes are initiated through intracellular receptors for steroid hormones, plasma-membrane re- ceptors, and second-messenger systems for catecholamines. Cross-talk between catechola- mines and glucocorticoid-receptor signaling systems can occur. From McEwen, 1998, by permission of the Massachusetts Medical Society. All rights reserved.

46 HEALTH AND BEHAVIOR resist infection or other challenge, thereby enhancing the effectiveness of immune responses. But adrenal steroids also can increase allostatic load and suppress immune system response when they are secreted chronically or when their release from the adrenal cortex is not terminated properly. Allostatic load is associated with at least four patterns of long-term harm to the body. The first is a perception of excessive stress. This can take the form of repeated events of various types that cause recurring in- creases in the release of stress mediators. For example, the amount and frequency of economic hardship are good predictors of decline in physical and mental functioning and even death (Lynch et al., 1997b). The second pattern involves a failure to adapt to recurrence of the same stressor. This leads to overexposure to stress mediators because of the failure to dampen response to a repeated event. Most people, for example, adapt to repeated public-speaking challenges, but some continue to show elevated cortisol concentrations, which indicate a failure to adapt (Kirschbaum et al., 1995). The third pattern entails the failure to terminate the hormonal stress response or the lack of appearance of the normal trough in the daily cortisol release pattern. Examples are increased blood pressure caused by work-related stress (Gerin and Pickering, 1995), increased evening corti- sol and hyperglycemia caused by sleep deprivation (Van Cauter et al., 1997), and the chronically elevated cortisol that often accompanies de- pressive illness (Michelson et al., 1996). The fourth pattern involves in- adequate release of hormones, thus allowing other systems, such as in- flammatory cytokines, to become overactive. In the Lewis rats, for example, inadequate release of cortisol is associated with increased sus- ceptibility to inflammatory and autoimmune disturbances (Sternberg, 1997; Sternberg et al., 1996). Early Development Influences Long-Term Effects of Stress Developmental influences are implicated in susceptibility to stress- related disorders. Classic work by Levine et al. (1967), Denenberg and Haltmeyer (1967), and Ader (1968), shows that the handling of neonatal rats by experimenters leads to reduced emotionality and stress hormone reactivity throughout life. In contrast, prenatal stress increases emotional- ity and stress hormone reactivity throughout the life of the animal. Post- natal handling reverses the effects of prenatal stress (Fride et al., 1986; Wakschlak and Weinstock, 1990). Handling is believed to increase ma- ternal licking and grooming of pups, which are associated with reduced

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 47 reactivity of the hypothalamic/pituitary/adrenal (HPA) axis (Liu et al., 1997). Use of animal models has revealed that age-related brain deterio- ration is increased by high-stress reactivity and reduced by low-stress reac- tivity (Dellu et al., 1996; Liu et al., 1997; Meaney et al., 1988). Animals that show high-stress reactivity also show a high propensity for substance abuse (Dellu et al., 1994). Studies in nonhuman primates show that early maternal deprivation alters brain serotonin functioning, increases alcohol preference, increases aggressive behavior, and decreases affiliate behaviors (Higley et al., 1996a, b; Kraemer et al., 1997). In marmosets, altered HPA axis function was found in offspring that experienced negative parenting (Johnson et al., 1996a). Individual differences in human brain aging are correlated with plasma cortisol concentration (see Lupien et al., 1994, 1998; Seeman et al., 1997), although it is not known whether there are connections to early life events. Some data suggest that extremely low birth weight (Barker, 1997; Wadhwa, 1998) and trauma in early life are risk factors that influence later health in humans (Bremner et al., 1997; Felitti et al., 1998). Studies that link life experience, especially early experience, with stress, allostatic load, and later health risks (Felitti et al., 1998; Bremner et al., 1997; De Bellis et al., 1999a, 1999b) signal the importance of research on the ef- fects of early life experiences on later stress reactivity and health. Some evidence suggests that even prenatal experiences can have long- term health consequences. In laboratory animals, prenatal stress has been linked to alterations in adrenocortical and central serotonergic and dopaminergic circuits (Nelson and Bloom, 1997). These observations led to the hypothesis (Barker and Sultan, 1995) that disease vulnerabilities in childhood and adult life result from “fetal programming” of homeostatic response set points. This is supported by Eriksson et al. (1999), who report that death from coronary heart disease (CHD) among Finnish men was associated with low birth weight and low ponderal index at birth. In addi- tion, prematurity and low birth weight resulting from maternal behaviors has been seen to increase the life-long risk of CHD (Wadhwa, 1998) and diabetes mellitus (Rich-Edwards et al., 1999). THE BRAIN AS INTERPRETER, REGULATOR, AND TARGET The brain is influenced by experiences, including stress, and it is a target of allostatic load, or long-term wear and tear. Since the IOM (1982)

48 HEALTH AND BEHAVIOR report, advances in basic neuroscience and the development of imaging technology have combined to enhance our understanding of how differ- ent regions of the brain control behavior. They reveal the plasticity and vulnerability of the brain to effects of life experiences. Advances in the neurobiology of learning and memory have provided important insights into the dynamic nature of brain function throughout life and from the level of the gene to the level of nerve-cell structure and function. Studies of the interplay between brain development and early experience have emphasized their importance in establishing patterns of brain function that persist through life. This section discusses advances in neurobiology that are particularly relevant to the brain as an interpreter of life events, as a regulator of the stress response and daily biological rhythms, and as a target of the protective and the damaging functions of stress mediators. Developmental issues are discussed later in the chapter. Neurotransmitters, Experience, and Behavior Changes in balance among neurotransmitters in the brain can influ- ence behavioral responses to potentially stressful situations, can alter the interpretation of stimuli, and might be associated with anxiety and de- pression. Research that has accelerated rapidly over the past few decades reveals that the human brain has multiple neurotransmitters and neuromodulators. The release of a neurotransmitter sends a message from one neuron to another. Neuromodulators share properties of neurotrans- mitters and hormones to regulate the general tone of neural systems. Many substances act as neuromodulators, including acetylcholine, histamine, serotonin, the catecholamines, excitatory and inhibitory amino acids, and a host of neuropeptides. In this discussion we emphasize two, serotonin and corticotropin-releasing hormone (CRH)—each with links to the stress response—while recognizing that brain function is a result of the simultaneous interactions of many hormones, neuromodulators, and neu- rotransmitters. Serotonin is a neurotransmitter with widespread influences through- out the brain. Most neurons that release serotonin are found in the raphe nuclei in the midbrain. Axons of serotonergic cells have many branches, and they project widely throughout the forebrain, cerebellum, and spinal cord (Cooper et al., 1996). The serotonin system exerts widespread influ- ence over mood and mood disorders, such emotional responses as hostility and aggression, arousal, sensory perception, and higher cognitive func-

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 49 tions. For example, low concentrations of brain serotonin are associated with increased incidence of suicide (Brown et al., 1982; Mann, 1998), impulsive aggression (Brown et al., 1982; Higley et al., 1996a, 1996b), and the abuse of alcohol and other substances (Higley et al., 1991). Experience can alter brain chemistry. One well-studied, common pathway through which the environment effects changes in the brain is the HPA axis. Briefly, to maintain appropriate internal conditions (allostasis) in response to life’s stresses, the hypothalamus releases CRH, which travels to the anterior pituitary where it causes the release of adrenocorticotropic hormone. The adrenocorticotropic hormone, in turn, controls the release of other hormones, such as cortisol, from the adrenal cortex (located on top of the kidneys). The HPA axis has been shown to be exquisitely responsive to social environment in rats (Albeck et al, 1997) and in primates (Johnson et al., 1996b; Shively et al., 1997). Social status affects the response of the HPA axis, such that hypothalamic CRH release is deficient in subordinate rats, which also show reduced testosterone con- centrations under these conditions (Blanchard et al., 1993; Albeck et al., 1997). CRH involvement in the stress response is complex, with at least one other brain system, involving the amygdala, showing an increase in CRH expression linked to anxiety disorders and depression (Schulkin et al, 1998). Furthermore, behavioral and chemical profiles often depend on the context of the stressful situation (Johnson et al., 1996b). Arousal and Memory Modulation Many people report vivid memories of events they associate with in- tense arousal or strong emotion. Sometimes called “flashbulb memories,” these illustrate that memory storage processes are modulated by the de- gree of arousal associated with an event. The amygdala is a complex col- lection of nuclei that has several functions, including control of some autonomic responses, elucidation of innate emotional responses, modula- tion of memory, and control of some aspects of male sexual behavior. The pathway for encoding memories involves the interaction of neural sys- tems in the amygdala and other brain areas, such as the hippocampus, and hormones released by the adrenal cortex (cortisol) and the adrenal me- dulla (the catecholamines epinephrine and norepinephrine). The amygdala is associated with the modulation of memories of important and arousing life events—events that have strong positive or negative emo- tional impact (affect; Cahill and McGaugh, 1998; LeDoux, 1996). It me-

50 HEALTH AND BEHAVIOR diates the effects of the degree of arousal on the storage of memories of all kinds, including those that pertain to spatial information, events, and learning habits. In relating autonomic and neuroendocrine function to memory pro- cesses, it is noteworthy that the encoding of memories is strengthened by glucocorticoids from the adrenal and by norepinephrine released from nerve terminals in the amygdala, hippocampus, and other brain regions. Substances associated with arousal, such as adrenal epinephrine and vari- ous peptide hormones, circulating outside the blood-brain barrier act to stimulate receptors in the periphery that then send neural messages to the brain via the vagus nerve (Clark et al., 1995; Williams and Jensen 1991, 1993). Modulated neural messages are then passed via the nucleus of the solitary tract to brain regions where memories are actually encoded (deQuervain et al., 1998; McGaugh et al., 1996; Roozendaal et al., 1996). In support of this mechanism, antagonism of peripheral b-receptors that respond to epinephrine released from the adrenals attenuates the memory- modulated effects of arousal (Cahill et al., 1994; Nielsen and Jensen, 1995). Those findings could be relevant to the biology of post-traumatic stress disorder and depression, which seem to involve overactive func- tioning of the amygdala (Cahill and McGaugh, 1998; Drevets et al., 1997; Sheline et al., 1998). Some important advances in animal model studies related to emo- tional experiences have recently been carried over to human brain func- tion. Human brain-imaging studies have shown that emotionally arousing information (pleasant or unpleasant) activates the amygdala and induces the formation of strong, long-term, episodic memories of that information (Cahill et al., 1996; Hamann et al., 1999). Electric stimulation of the vagus nerve in laboratory rats enhances memory (Clark et al., 1995); this finding was recently expanded to human memory for word recognition (Clark et al., 1999). Studies of learning and memory have revealed neural plasticity in- volving structural changes in brain cells and changes in gene expression. It can be seen in the remodeling of neuron structure brought about by training (Greenough and Bailey, 1988). Transcription factors involved in regulating expressions of groups of genes in brain cells also appear essen- tial to the formation of long-term memories in species as varied as fruit flies and mice (Guzowski and McGaugh, 1997; Martin and Kandel, 1996). Short-term responses of the brain to novel, arousing, or potentially threatening situations are adaptive and result in enhanced learning and in

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 51 the acquisition of new behavioral strategies for coping. However, repeated stress can increase allostatic load and cause cognitive deficits. The hip- pocampus is important in declarative, spatial, and contextual memory pro- cesses. It also works in processing the contextual associations of strong emotions (Eichenbaum, 1997; Gray, 1982). Atrophy of the hippocampus with age has been reported in animals (Meaney et al., 1988) and humans (Lupien et al., 1998; Lupien et al., 1994) and is accompanied by cognitive impairment. The cumulative effects of life stress, as expressed by the con- cept of allostatic load, can cause impairment by at least four mechanisms (McEwen, 1997, 1999b): impairing neural excitability, causing atrophy of neurons in the Ammon’s horn region of the hippocampus, inhibiting neurogenesis in the dentate gyrus of the hippocampus, and causing per- manent loss of neurons in the hippocampus. Each process can occur some- what independently of the others, and each contributes to some degree to different pathophysiologic conditions associated with traumatic stress, de- pression, or aging. Those laboratory findings have been carried over to the human brain by magnetic resonance imaging. Hippocampal atrophy and cognitive im- pairment have been reported in conditions as diverse as Cushing’s syn- drome, post-traumatic stress disorder, and recurrent major depression (for reviews, see McEwen et al., 1997; Sapolsky, 1996). The hippocampus is susceptible to those effects and is likely not the only brain region so af- fected. Atrophy of the amygdala and the prefrontal cortex also has been reported in depressive illness (Drevets et al., 1997; Sheline et al., 1998, 1999). The reversibility or prevention of such atrophy clearly is an impor- tant topic for research, as are its implications for cognitive function. IMMUNE SYSTEM FUNCTION IN HEALTH AND DISEASE The rebirth of integrative physiology in the context of the growing pool of information about genes and gene regulation has led to the devel- opment of new interdisciplinary fields of study, such as neuroendocrine immunology and psychoneuroimmunology—the latter includes psychol- ogy and an eclectic mix of other disciplines. At the same time, the more traditional field of immunology has advanced with growing knowledge about the messengers of the immune system, the cytokines and chemo- kines. Those advances underline the importance of explaining how the immune system functions in the living body, as opposed to examining only its theoretical workings. The immune system is highly integrated

52 HEALTH AND BEHAVIOR with other physiologic systems. It is sensitive to virtually every hormone in the body, and sympathetic, parasympathetic, and sensory nerves inner- vate the organs of the immune system. These organs also produce hor- mones that affect cells in the rest of the body. The remarkable capacity to distinguish “self” from “nonself” to protect the body from infectious and malignant challenges is a hallmark of the immune system that has been studied in great detail at the cellular and molecular levels over the past 50 years. Much progress has been made recently in explaining how the body responds to environmental challenges through immunologic pathways. Research has led to development of the notion of a “danger” hypothesis in which tissue damage (and perhaps a threat to the very survival of the organism) is a signal that activates inflammatory and immune responses (Fuchs and Matzinger, 1996). The response of the immune system to en- vironmental challenge represents a coordinated pattern of gene expres- sion that results in rapid and sustained production of activated cells, secre- tory products, and effector mechanisms that persist until the challenge is eliminated. Like many other bodily and behavioral responses to challenge, im- mune system responses are initially beneficial, but when they are sustained, they can damage healthy host tissue or augment damage produced by pathogens. That potential threat is reduced by the high level of regulation of the immune system and its close integration with the autonomic and endocrine systems. Bidirectional interaction of common chemical mes- sengers and cellular receptors connects the immune system with the ner- vous system and the endocrine system. In this interactive communication between systems, sensory stimuli to the central nervous system that acti- vates the HPA axis result in the peripheral release of adrenal steroids and catecholamines, both of which can have immunoregulatory effects. Simi- larly, a challenge that induces an inflammatory response causes the release of cytokines that stimulate the peripheral and central nervous systems (Figure 2-3). This provides an important link through which the neu- roendocrine response modulates the development of an inflammatory re- sponse at the site of challenge. That is especially important in the lungs, heart, brain, and kidneys, where there are limits to the magnitude an in- flammatory response can reach without causing loss of critical function (Hermann et al., 1995). The movement of immune cells to organs and tissues where they are needed to fight infection or other challenge is highly regulated at multiple

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 53 levels, including interactions among neural, endocrine, and immune sys- tems (Fauci, 1975; Hermann et al., 1995). Steroid hormones and cat- echolamines released from the adrenals promote the movement of immune cells. These steroid hormones and catecholamines are immuno- suppressive when they are secreted chronically or when their release is not terminated properly—in which case they can actually increase sus- ceptibility to infection and malignancy (Dobbs et al., 1993; Hermann et al., 1993). A deficiency of circulating glucocorticoids and catecholamines, however, allows other immune mediators, such as cytokines, to overreact and thereby increase the risk of autoimmune and inflammatory disorders (Sternberg et al., 1992, 1989; Wilder, 1995). Neural and Endocrine Effects on the Immune System The immune system is integrated with the nervous and endocrine systems, which modulate aspects of its function. Many chemical messen- gers of the nervous and endocrine systems are immunomodulatory, and these substances are important in regulating inflammatory and immune responses (Figure 2.3) (Felten et al., 1987). The presence of receptors— for hormones, neuropeptides, and neurotransmitters—on cells of the im- mune system suggests some ways by which modulation occurs. The recep- tors provide a mechanism for other physiologic systems to modulate immune responses. Activation of the HPA axis, which leads to systemic release of potent anti-inflammatory substances, such as cortisol and other glucocorticoids, regulates inflammatory and immune responses (Berczi, 1998). The autonomic system’s part in immunoregulation also became clearer once it was demonstrated that primary and secondary lymphoid tissues are highly innervated (Bulloch and Pomerantz, 1984; Felten et al., 1987) and that immune cells in these tissues have receptors for neuro- modulators and neurotransmitters. Effects of Inflammatory and Immune Responses on the Nervous System Gaining a clear understanding of the bidirectional flow of neuroendo- crine and immune interactions had to wait for a revolution in cellular and molecular immunology. Advances in cytokine research provide a context for the study of soluble products produced by activated monocytes and lymphoid cells (circulating and stationary immune cells, respectively).

54 HEALTH AND BEHAVIOR Natural Resistance and Adaptive Immunity Cellular Cellular Cellular Trafficking Effector Function Activation Gene Expression Adhesion Growth Molecules Chemokines Cytokines Factors Ligand/Receptor Signal Transduction Transcriptional Interaction Pathways Regulation Danger Signal Tissue Infection Damage Malignancy Stressor ACTH CRH CORT HPA CNS SNS CAT FIGURE 2-3 Neuroendocrine Regulation of Immunity. Tissue damage, infection, and malignancy are hypothesized to generate a danger signal. This signal is transduced at the cellular and molecular levels leading to activation, trafficking and expression of effector functions in the immune system. Products of the immune system, including cytokines, chemokines and growth factors can stimulate the nervous system resulting in the release of steroid hormones, catecholamines, opioids. These products of nervous and endocrine activation modulate molecular and cellular events in an immune response. Adapted from Marucha and Sheridan, 1998. Reprinted with permission from the publisher, Harcourt, Inc. All rights reserved.

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 55 These low-molecular-weight products of mononuclear cells are secreted during inflammatory and immune responses. They were shown to be pro- duced by several types of cells; to have several kinds of biologic activity; and to be pleiotropic, affecting cells in many physiologic systems (Arai et al., 1990). The cytokines initiate action by binding to specific receptors on target cell surfaces, and many of them have multiple signaling func- tions including autocrine (secretion of a substance that stimulates the secretory cell itself), paracrine (the target cell is close to the secretory cell, such as neurotransmitters in the brain), and endocrine (the chemical sig- nal can travel long distances from the secretory cells to the target tissue, via the blood or lymph systems). The pleiotropy of cytokines led to inves- tigations of inflammatory and immune interactions with the nervous sys- tem and to the development of the idea that the immune system commu- nicates with the brain through the release of proinflammatory cytokines (Besedovsky et al., 1986). Proinflammatory cytokines released in periph- eral tissues function as hormones, and biologically are associated with the development and expression of behaviors associated with illness (Dantzer et al., 1998; Maier et al., 1998) and can induce chronic stress responses (Shanks et al., 1998). The recognition that cytokines, particularly those that are proinflam- matory, communicate with the brain and influence activation of the HPA axis led to investigations of neuroendocrine responses in the etiology of inflammatory (Chrousos, 1995) and autoimmune diseases. Associations between stress responses and autoimmunity have been studied in condi- tions as diverse as rheumatoid arthritis (Heijnen et al., 1996; Sternberg et al., 1989, 1992), inflammatory bowel disease (Anton and Shanahan, 1998), systemic lupus erythematosus (Utz et al., 1997), and multiple scle- rosis (Griffin and Whitacre, 1991). Other studies have examined neu- roendocrine responses and immune system reactivity in asthma (Barnes, 1986; Busse et al., 1995; Kang et al., 1998), atopic dermatitis (Buske- Kirschbaum et al., 1998), and allergy (Anderzen et al., 1997). Stress and Immune System Function The recognition of the importance of bidirectional communication between neural, endocrine, and immune systems through shared ligands and receptors led to a major research emphasis on immunoregulation by hormones, peptide neuromodulators, and neurotransmitters. The primary function of the immune system is to protect the host from infectious and

56 HEALTH AND BEHAVIOR malignant challenges. Acute stress enhances immune function, and it does so in part by promoting immune cell translocation to sites of immune challenge (Dhabhar et al., 1995, 1996), whereas chronic stress has the opposite effect: it impairs immune function (Dhabhar and McEwen, 1999; Hermann et al., 1995). Various aspects of immune function in states of stress-induced neuroendocrine activation, with a primary emphasis on negative, immunosuppressive outcomes, have been reported (Dobbs et al., 1993; Kiecolt-Glaser et al., 1996). One important factor in whether a person will develop respiratory infection after challenge with an infectious virus is lack of social support (Cohen, 1995; Cohen et al., 1991). In studies of two-party relationships, marital discord was found to affect general health and immunity signifi- cantly (Kiecolt-Glaser et al., 1997). Because immune system functioning is studied best when the system has been provoked, examinations of stress and immunity have considered the effectiveness and durability of the immune response after the adminis- tration of vaccines in humans. The stress of taking a university examina- tion (Glaser et al., 1992) and the chronic stress of being a caregiver (Kiecolt-Glaser et al., 1996; Glaser et al., 1998) were used to characterize responses to vaccination during a stressful period. In each case, the anti- body responses to vaccines were poorer in the stressed than in the nonstressed groups. Similar studies of the mechanisms of neuroendocrine/immune inter- actions have been performed in animals. Studies of experimental viral infections in mice demonstrate that both the HPA axis and the sympa- thetic system alter virus-induced pathophysiology under conditions of im- posed experimental stress (Hermann et al., 1993). The stress response also can suppress specific components of natural resistance and adaptive im- mune responses to viral infection, both acute (Dobbs et al., 1993; Sheridan et al., 1991) and latent (Bonneau et al., 1991; Kusnecov et al., 1992). Environmental stress suppresses immunity and enhances the pathogenic- ity of bacteria, particularly that caused by facultative intracellular para- sites, such as mycobacteria (Brown et al., 1993). Wound healing and other physiologic processes that require substan- tial proinflammatory responses (including cytokine, chemokine, and growth factor gene expression) are affected by environmental and behav- ioral stress. The stress of long-term caregiving to dementia patients delays the healing of full-thickness, cutaneous-punch biopsy wounds (Kiecolt- Glaser et al., 1995). Acute stress induced by taking academic examina-

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 57 tions delayed the healing of mucosal wounds in the oral cavity; the delay was associated with diminished proinflammatory cytokine responses in the peripheral blood of those who experienced the stress (Marucha et al., 1998). In animal models, restraint stress caused activation of the HPA axis, which was shown to suppress movement of immune cells to wound sites (Padgett et al., 1998). The effects of disaster-related stress responses on the immune system have been studied (Ironson et al., 1997; Solomon et al., 1997). Major effects of distress of natural disasters include alterations in natural and adaptive immunity, as indicated by lower natural killer-cell cytotoxicity (NKCC) and lower numbers of circulating T lymphocytes. People who were tested after surviving Hurricane Andrew had lower NKCC and fewer suppressor T cells (CD8+) and helper T cells (CD4+) than did compari- son subjects (Ironson et al., 1997). Alterations in NKCC were related to psychologic and behavioral factors: Survivors reported greater loss of re- sources, greater post traumatic disorder symptomology, and more negative intrusive thoughts than did control subjects. Those observations are con- sistent with conclusions drawn from a growing literature on psychologic stressors and immunity, which has shown NKCC to be diminished by be- reavement (Irwin et al., 1987), marital discord (Kiecolt-Glaser et al., 1987), and exposure to earthquakes (Solomon et al., 1997). The observed reductions in measures of natural and adaptive immu- nity were statistically significant in a stressed population but did not sug- gest increased risk for infection or disease in any individual. However, these studies demonstrate that natural disasters, industrial accidents, and psychosocial events are stressors that can affect human immunophysiology and thereby affect both mental and physical well-being. ADDITIONAL FACTORS INFLUENCE LONG-TERM EFFECTS OF STRESS Resilience People differ widely in resilience to and recovery from illness, injury, or surgery and in overcoming adversity. However, relatively little is known about the physiology of resilience and good health. Resilience undoubt- edly consists of more than just the absence of allostatic load. It is thought to be the product of cellular processes that protect and build cells and tissues—processes that involve some reserve capacity and resistance to

58 HEALTH AND BEHAVIOR the damaging effects of stressors. Promising research includes how ana- bolic hormones, such as growth hormone and insulin, and neurotrophic factors work in the brain as they are related to voluntary exercise and to recovery from injury and illness. For example, voluntary exercise in rats (running in an activity wheel) increases expression of messenger RNA for a neurotrophin that protects neurons from death and that promotes neuroplasticity and synaptic transmission (Oliff et al., 1998). It is not known, however, what advantages increased neurotrophin concentrations confer on the brains of exercising animals. The animals might be more resilient in the face of severe stress, or their brains might deteriorate more slowly with age. Although the role of neurotrophin regulation in exercise is not known, it has been reported that voluntary exercise increases pro- duction of new neurons in the dentate gyrus of the hippocampus, the brain region that is important in spatial and declarative memory (van Praag et al., 1999). The study of factors that promote resilience, still poorly defined, is important as a complement to the more traditional approach of studying the damaging effects of stress mediators. Therefore, it will be important for research to relate human life histories, stress, and allostatic load to the production of such substances as the neurotrophins, which are related to tissue growth and repair. It also will be important to identify the influence of social support mechanisms and of individual attitudes that promote beneficial physiologic states associated with the capacity to repair dam- aged tissues and to protect against pathogens and toxic agents, such as free radicals (Epel et al., 1998; Ryff and Singer, 1998; Seeman and McEwen, 1996; Singer et al., 1998; Taylor et al., 1997). Coping Coping efforts are important moderators of the impact of stress on health (Baum and Posluszny, 1999). Coping is defined as volitional man- agement of stressful events or conditions and regulation of cognitive, be- havioral, emotional, and physiological responses to stress (Compas et al., 1999; Lazarus and Folkman, 1984). Various classifications of coping re- sponses have been proposed, including coping to solve a problem versus coping to manage emotions, cognitive versus behavioral coping, approach versus avoidance coping, and coping intended to achieve (primary) con- trol over the stressor (the source of stress) versus (secondary) control over response to the stress (emotions).

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 59 Coping efforts are important in the process of adaptation to illness. Several consistent findings have emerged from prospective longitudinal studies of breast cancer patients from diagnosis through treatment and recovery (Carver et al., 1993; Epping-Jordan et al., 1999; Stanton and Snider, 1993). Successful coping is facilitated by optimism—the tendency to anticipate positive outcomes. Through the use of strategies including acceptance, positive thinking, and problem solving, optimism is associ- ated with lower psychological distress (reduced symptoms of anxiety and depression). Conversely, pessimistic thinking is associated with coping that involves avoidance and social withdrawal, which are related to higher symptoms of anxiety and depression (Carver et al., 1993; Epping-Jordan et al., 1999). Patients who are more prone to poor coping have histories of social isolation, recent losses, or multiple obligations (Rowland, 1990). Breast cancer patients who learn to use more direct and confronta- tional coping strategies are less distressed than are those who use avoid- ance and denial (Holland and Rowland, 1990). Furthermore, a “fighting spirit” about the illness leads to a probability of longer survival (Green and Berlin, 1987; Greer et al., 1979; Watson et al., 1990). Research sug- gests that the belief that one has control over the cause of the disease leads to poor outcome, whereas belief in control over the course of the disease leads to better outcome (Watson et al., 1990). Psychosocial stress has been reported to lead to higher relapse rates in metastatic breast cancer (Ramirez et al., 1989). However, several studies report no significant ef- fect of psychosocial variables on the course of carcinoma (Angell, 1985; Cassileth et al., 1985; Jamison et al., 1987). Although stress can affect immune function and health, most of the observed effects are relatively small and within the range of normal im- mune function (Glaser et al., 1999). Therefore, stress-induced immune system changes that are related to disease are likely to be the result of multiple small simultaneous changes in the immune system. Measurement of multiple aspects of the immune system and their interactions is thus necessary to reveal the subtle and complex relationships among stress, immune function, and disease. Study of the effects of coping efforts on stress and immunologic responses is also important because coping might be a crucial mediator of the stress/immune relationship that can be modi- fied through behavioral interventions. In addition to possible effects on disease onset and etiology, stress also can disrupt the behaviors that normally enhance healthy functioning and protect a person from illness (discussed further in Chapter 3). This can be

60 HEALTH AND BEHAVIOR seen in the association between stress and health risk behaviors, such as smoking (Shiffman et al., 1996), poor diet, and lack of exercise (Greeno and Wing, 1994), and in health-compromising responses to stress that include increased autonomic arousal and elevated blood pressure (Baum and Posluszny, 1999). Extensive research documents that expression of emotions has benefi- cial effects on both emotional and physical well-being (Esterling et al., 1999; Pennebaker, 1997). But emotional regulation does not involve the unmodulated ventilation of emotions or the containment or suppression of feelings; rather, successful regulation of emotion appears to involve the controlled and modulated expression and release of feelings in ways that contribute to an increased understanding of those emotions and their meaning. Research by Pennebaker and colleagues (1997) shows that writ- ing about deep feelings is a powerful way to regulate emotional expression. Writing about emotions is associated with improved mood, fewer health problems, and enhanced immune function (Petrie et al., 1995, 1998). The specific mechanisms through which regulation of emotional expression affects health are not fully understood and are the subject of continuing research. However, the regulated expression of emotions through writing is a potentially important component of interventions to change health behavior. Gender In animal models and possibly also in humans, there are gender differ- ences in vulnerability to brain damage or brain remodeling as a result of stress (see Galea et al., 1997; Uno et al., 1989). Although the gonadal hormones are important influences in the development of gender differ- ences in early life, hormones and experience also can change brain struc- ture and function in adult life (Greenough and Bailey, 1988; McEwen and Alves, 1999; McEwen, 1999b)—an indication that there is considerable life-long plasticity in the nervous system. And although the role of hor- mones is a hallmark of sexual differentiation, experience and social fac- tors also are critical, especially in humans and nonhuman primates (Goy, 1970; McEwen, 1999a; Reinisch et al., 1987). Social Influences People live in social groups and as members of societies. It is well known that social class or socioeconomic position has a profound effect

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 61 on health through multiple pathways (Adler et al., 1994; Antonovsky, 1967; Marmot et al., 1991; Syme and Berkman, 1976). Since the 1982 predecessor to this report (IOM, 1982), it has become evident that the degree of a given country’s social inequality is related to health in that society (Kaplan et al., 1996; Wilkinson, 1992). And the degree of social integration or connection and the social networks in which people are embedded are related to morbidity and mortality (Berkman, 1995; House et al., 1988). Like economic inequality, social cohesion and social capital are associated with health (Kawachi et al., 1997). Moreover, there are characteristics of the work environment that can produce job stress and significantly influence workers’ health (Karasek and Theorell, 1990). These topics are developed more fully in Chapter 4. Physiologic sys- tems that could mediate the effects of stressful social circumstances on health are discussed here. CARDIOVASCULAR HEALTH AND DISEASE Cardiovascular health and disease provide an example of the interac- tions of behavioral, psychologic, and social factors. This discussion of CHD will be used to point out the biological effects of stress and the psychosocial influences that exist. Despite progress in elucidating the role of genetics in human disease, it is clear that no single cause of CHD can be identified and that these conditions develop as a result of complex interactions among multiple factors. One example of the effects of disparate factors on the incidence of cardiovascular disease is provided by a recent analysis of changing mortal- ity patterns in Russia (Notzon et al., 1998). Over a 4-year period after the breakup of the former Soviet Union, mean life expectancy declined by 5 years. Most of the decline could be attributed to increased mortality in men aged 25 to 64 because of accidents and cardiovascular disease. Fac- tors implicated in the dramatic change in death rates included economic instability, chronic stress, depression, and the increased use of alcohol and tobacco. Stress and Cardiovascular Function Stress clearly is important in cardiovascular health and disease. There is general agreement that acute stress can trigger acute cardiovascular events (Muller and Tofler, 1990), but the more subtle influences of chronic stress and allostatic load are not well understood. The effects of psychoso-

62 HEALTH AND BEHAVIOR cial stressors are mediated through the central nervous system, so it is relevant to review several pathways through which the brain affects bodily processes related to cardiovascular function. Much new information about function and measurement has contributed to our explanation of the rela- tionships. The autonomic nervous system regulates internal bodily functions, including all aspects of cardiovascular function. The autonomic system maintains appropriate internal states (homeostasis) and enables the body to respond to external threats perceived as stressors. It has two primary divisions: the sympathetic and parasympathetic. The sympathetic nervous system permits response to extreme conditions: fight or flight. The para- sympathetic nervous system modulates functions under resting conditions. Both blood pressure and heart rate are modulated through the autonomic nervous system. There is strong evidence that increased sympathetic activity is a fea- ture of many cases of hypertension in young adults. Cardiac output in- creases in the early stages of hypertension and decreases with advancing age. With age, peripheral vascular resistance increases, largely because of remodeling (rerouting) and hypertrophy (overgrowth) of blood vessel walls. Sympathetic activity also can affect the development of atheroscle- rosis. Mechanisms include increasing insulin resistance, a known risk fac- tor for cardiovascular disease; hemodynamic effects on the arterial wall; and direct metabolic effects, such as increased plasma triglycerides and alteration in the metabolism of low-density lipoproteins (Julius, 1993). Furthermore, increased sympathetic activity can increase the risk of car- diovascular disease through the effects of adrenal epinephrine on platelet aggregation and the development of left ventricular hypertrophy. There is experimental evidence that increased heart rate (Beere et al., 1984) and increased blood pressure variability are both risk factors for atherosclerosis (Sasaki et al., 1994). Decreased heart rate variability itself is associated with the presence of CHD and is a risk factor for cardiovascular morbidity. But it is not known whether this association is causal. For example, re- duced heart rate variability might be a consequence of artherosclerotic damage to the carotid sinuses, which could cause impaired baroreceptor reflexes. Laboratory studies demonstrate that cardiovascular disease can be pro- duced by chronic social stress. Hypertension can be elicited in some strains of mice, but not in others (Henry et al., 1986), and the hypertensive con-

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 63 sequences of behavioral stress can be potentiated in genetically normo- tensive animals by a high-sodium diet (Anderson, 1994). In animals, the combination of emotional stress and high sodium intake has been associ- ated with a greater increase in blood pressure than results from either factor alone (Staesson et al., 1994). Other studies show that subordinate female cynomolgus monkeys have more atherosclerosis than do dominant females, and the difference ap- pears to be related to suppression of the release of cardioprotective ova- rian hormones (Shively and Clarkson, 1994). Atherosclerosis develops faster in dominant male monkeys when they are defending their social position or re-establishing it in an unstable social hierarchy (Manuck et al., 1995). The combination of a high-fat diet with psychosocial stress accelerates the disease process (Brindley and Rolland, 1989). Studies of chronic stress among people have yielded inconsistent find- ings: some show activation of the HPA axis and others show its suppres- sion (Ockenfels et al., 1995). Although anticipation or experience of acute stress activates the HPA axis (Smyth et al., 1998), the degree of activa- tion with repeated exposure to stress is greatly variable (Kirschbaum et al., 1995). The importance of personality, emotion, and social environment in the development of cardiovascular disease is a subject of controversy, but there is evidence that anger, whether expressed openly or repressed, is associated with an increased risk of hypertension (Everson et al., 1998). Job-related stress is also important. The combination of high job demands and low control is associated with hypertension (Schnall et al., 1992). Blood pressure tends to be highest in the workplace, but the increase in blood pressure in people with high-strain jobs is seen at work, at home, and during sleep (Schnall et al., 1992). An imbalance between income and expenditure is associated with high blood pressure (Chin-Hong and McGarvey, 1996; Dressler, 1991). The prevalence of hypertension in humans varies greatly from one society to another, and it appears to be strongly influenced by society and culture factors. For example, epidemiologic studies indicate that the tran- sition from life in traditional tribal community to urbanized Western soci- ety is associated with an increase in blood pressure (Cruz-Coke, 1987; Poulter et al., 1988, 1990), although it is unclear whether this effect is the result of changes in diet or of psychosocial stress.

64 HEALTH AND BEHAVIOR Behavioral and Psychosocial Factors Psychosocial factors can influence the course of chronic human dis- ease along several pathways. Behavior that has perceived short-term ben- efits, such as mood-enhancement induced by cigarette-smoking or exces- sive alcohol consumption, but that causes long-term injury constitutes one (Chapter 3). Another involves the influence of social and environ- mental factors, such as socioeconomic status or stress on disease processes (Chapter 4). A third consists of individual psychological factors, such as hostility and depression, that interact with the other two pathways to increase susceptibility to illness. The evidence for a role for these psycho- logical factors in cardiovascular disease is described below. Hostility Hostility is the psychosocial variable most often associated with the incidence of CHD (Booth-Kewley and Friedman, 1987). In the context of physical health, hostility is defined usually as a stable attribute character- ized by mistrusting cynicism that leads to antagonistic or aggressive be- havior and feelings of anger (Miller et al., 1996). The extent to which hostility is a personality trait or a behavioral coping response to environ- mental stimuli, however, is not known. Most of the research on hostility has been done in men. Interest in hostility and CHD evolved from earlier research on the type A behavior pattern, an idea originally formulated by Friedman and Rosenman (1974). Type A behavior was characterized by a sense of time urgency, loud and explosive speech, hostility, and competitiveness. Early studies supported an association between type A behavior and the devel- opment of CHD (Review Panel, 1981), but later research failed to con- firm the association (Case et al., 1985; Shekelle et al., 1985a, 1985b). The original type A behavior data-set was reanalyzed by two teams of investi- gators to examine inconsistencies and identify variables within the multi- faceted type A behavior patterns that were most predictive of CHD (Chesney et al., 1988; Matthews et al., 1977). These analyses revealed that hostility was the best variable for distinguishing men who developed heart disease from men who did not (Hecker et al., 1988; Matthews et al., 1977). Many prospective studies confirmed the relationship between hos- tility, as assessed by interviews and questionnaires, and CHD incidence (Barefoot et al., 1983; 1989; Dembroski et al., 1989; Houston and Kelly, 1987; Shekelle et al., 1983). Significant associations also have been found

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 65 between hostility and cardiac mortality (Koskenvuo et al., 1988; Shekelle et al., 1991). Considered together, the cumulative findings constitute sub- stantial evidence of the link between hostility and various aspects of CHD. Although some studies have not found an association (Hearn et al., 1989; Leon et al., 1988; McCranie et al., 1986), the positive reports outnumber negative ones (Scheier and Bridges, 1995). One reason for this inconsis- tency is that the assessment of hostility often relies on self reports, and people might tend to underreport this socially undesirable trait (Helmers et al., 1995). There is a hypothesis that people who are hostile have exaggerated cardiovascular reactivity to stress and that this either contributes to the development of atherosclerosis (Matthews et al., 1998) or triggers acute events (Rozanski et al., 1999). However, hostility also is correlated with increased likelihood of smoking, with decreased likelihood of quitting smoking (Lipkus et al., 1994), and with lower socioeconomic status (Bare- foot et al., 1991; Carroll et al., 1997). Each of these will increase allostatic load. Anger Anger is a psychological state thought to be related to hostility. Ex- pression of anger has been shown to trigger myocardial infarction. In a study of patients undergoing coronary angiography, recall of anger was a potent stimulus that induced vasoconstriction in diseased coronary arter- ies, but not in healthy arteries (Boltwood et al., 1993). The recall of anger can also produce an acute impairment in ventricular function in patients with CHD (Ironson et al., 1992). Vital Exhaustion One common premonitory symptom of myocardial infarction is vital exhaustion, a state of excessive fatigue, increased irritability, and demoral- ization (Appels et al., 1987). A prospective study of 3877 city employees in Rotterdam, The Netherlands, compared the risk of coronary heart dis- ease among those scoring in the highest third on a measurement scale of exhaustion to those with lower scores. Vital exhaustion predicted myocar- dial infarction with a relative risk of 2.28—a relatively robust effect for a behavioral predictor (Appels and Mulder, 1989). There appears to be no correlation between the severity of CHD and vital exhaustion score, so it

66 HEALTH AND BEHAVIOR is unlikely that subclinical coronary disease causes the observed fatigue (Kop et al., 1996). Vital exhaustion also has been reported to predict re- currence of arterial blockage after coronary angioplasty (Kop et al., 1994). Job stress is associated with vital exhaustion and is a risk factor for cardio- vascular disease (Everson et al., 1997; Keltikangas-Jarvinen et al., 1996a, 1996b; Kop et al., 1998; Lynch et al., 1997a; Raikkonen et al., 1996). Depression Depression affects about half of patients who experience myocardial infarction. Depression predicts significantly poorer outcome with heart disease (Denollet et al., 1996; Denollet and Brutsaert, 1998; King, 1997) and roughly doubles the risk of recurrent cardiovascular events (Barefoot et al., 1996; Barefoot and Schroll, 1996; Frasure-Smith et al., 1995). About half of postinfarction patients with depression have a history of depression before the onset of CHD, and there is some evidence suggesting depres- sion as a risk factor for a first infarction (Sesso et al., 1998). The associa- tion between depression and mortality seems to be the same in men and women (Frasure-Smith et al., 1999). However, the prevalence of postinfarction depression is about twice as high in women as in men (Carney et al., 1990). It is unlikely that depression is a consequence of CHD, inasmuch as the occurrence of depression often precedes any dis- ease symptoms and there is no relationship between severity of depression and severity of coronary arterial disease (Carney et al., 1995). Depression is associated with increased sympathetic and decreased parasympathetic tone, as manifested by increased plasma catecholamine concentrations, increased heart rate, and decreased heart rate variability. Myocardial infarctions tend to happen most commonly between 6 A.M. and noon, the time of day that parallels the normal circadian rhythm of sympathetic activity. But the cycles of catecholamines and cortisol are disturbed in people who have depression, peaking earlier in the day than in nondepressed people. Depressed people are more likely than nondepressed people to have myocardial infarction during the night or very early in the morning (Carney et al., 1995). Twenty years ago it was suggested that the presence of depression pre- dicted a higher subsequent incidence of cancer (Shekelle et al., 1981). Although a large cohort study of employees at Western Electric reported an elevated rate of subsequent cancers among those diagnosed with de- pression, this finding was not confirmed in a more recent large-scale co-

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 67 hort trial (Zonderman et al., 1989). Zonderman et al. (1989) found no relationship between two measures of depressive symptoms and cancer morbidity or mortality in a large population. The researchers used con- tinuous and not categorical measures of depression, leaving open the pos- sibility that severe clinical depression could be associated with elevated cancer risk. However, this and earlier studies lend little support to the idea that depression increases cancer risk (Fox, 1989). Fox’s reanalysis of the original observation suggests that a combination of depression and expo- sure to toxins could have accounted for the apparent association (Fox, 1989). However, a study by Penninx et al. (1998) did find in a sample of 5000 elderly people that consistent symptoms of depression were predic- tive of an almost 2-fold elevation in risk of cancer incidence. Thus, de- pression does not seem to predict cancer incidence, but it is elevated among those who have cancer. Anxiety, Worry, and Hope Anxiety and worry have recently received renewed attention as risk factors for cardiovascular disease. Two prospective studies have shown that anxiety predicts the development of CHD (Sloan et al., 1999), and worry- ing is an important component of anxiety. Men who worry a lot were found to be at increased risk for CHD (Kubzansky et al., 1997). Hope and optimism, in contrast, have been suggested as important components of psychological well-being and as factors that can contribute to good physical health (Scheier and Carver, 1985; Snyder et al., 1991). A lack of hope is commonly thought to adversely affect health (Scheier and Carver, 1992). However, only recently has there been empirical sup- port for this. One major challenge for researchers and health care provid- ers was to develop ways to measure hope and hopelessness. Hopelessness, as assessed by one question on a four-item questionnaire designed to mea- sure depressed affect, reliably predicted fatal and nonfatal CHD events in a cohort of more than 2800 initially healthy men and women (Anda et al., 1993). Similarly, a two-item hopelessness scale significantly predicted all-cause mortality, the incidence of myocardial infarction and cancer, and death from violence and injury in a sample of 2428 men in the Kuopio ischemic heart disease study in Finland (Everson et al., 1996). Those and similar findings support the general idea that psychosocial factors are im- portant determinants of physical health and disease.

68 HEALTH AND BEHAVIOR DEVELOPMENTAL TRAJECTORIES Development is important in the biological and behavioral processes that preserve health or lead to human disease throughout life. Cumulative experience, adaptive plasticity, physical and social exchange with sur- rounding environments, and genetic predisposition interact to influence development. The unique physiology of each person, partly encoded in the genome and partly determined by prior physical exposures and social experiences, generates the individual behaviors that influence morbidity and mortality. Although developmental status is a continuing factor in health out- comes over life, it has heightened salience for immediate and long-term health responses during infancy, early childhood, and adolescence. These periods are characterized by extremely rapid biological and psychosocial change. The resolution of the developmental challenges faced at these times determine set points for homeostatic systems, as well as for adopting crucial health-related attitudes and behaviors. These outcomes, in turn, determine trajectories for subsequent biobehavioral functioning that can have long-term effects on health. Therefore, the periods of infancy, early childhood, and adolescence are highlighted here. Early childhood, infancy, and even prenatal experiences appear to have long-term consequences for health because they influence the bio- logical mechanisms that underlie stress reactivity. There are sociocultural consequences of these experiences as well (NRC, 2000). A secure attach- ment with a parenting person provides a protective modulator of the en- vironmental influences on an infant. The mother/child attachment is af- fected by the infant’s temperament, which is characterized by reactions to stimuli, the tone of the emotional expression (positive or negative), activ- ity level, and sociability. There is increasing evidence that temperament has a biological base (Boyce et al., 1992), including a genetic component that is heavily influenced by experience (van der Boom, 1994). The mi- nority of infants who have difficult temperaments can experience attach- ment problems and high levels of stress, with consequences for their stress responses as adults. Unresponsive, insensitive, or abusive parenting also can lead to atypical emotional development. Research with infants of de- pressed mothers, for example, has shown that diminished parental respon- siveness is associated with changes in infant emotional regulation and the balance of left vs. right frontal cortical activation (Dawson et al., 1997). A disproportionate number of severely deprived infants raised in Roma- nian orphanages exhibited abnormalities in cognitive, emotional, and lin-

BIOBEHAVIORAL FACTORS IN HEALTH AND DISEASE 69 guistic development (Fisher et al., 1997). They also showed retarded growth and higher rates of infectious diseases (Albers et al., 1997; Hostetter et al, 1991). Stress in young children can influence future health. Although cur- rently limited to retrospective analyses, studies of physical and sexual abuse in childhood suggest variable but elevated risk for later depression, soma- tization, excessive rates of health care use, homelessness, and other indi- cators of behavioral maladaptation (Cheatsy et al., 1998; Herman et al., 1997; Salmon and Calderbank, 1996; Styron and Janoff-Bulman, 1997). A recent prospective controlled study (Heim et al., 2000) found that, during a relatively mild stress task involving public speaking and mental arithmetic, those with a history of sexual abuse showed significantly el- evated concentrations of adrenocorticotropic hormone. This was most pronounced in participants who exhibited symptoms of major depression at the time of testing. The results provide support for increased stress vulnerability and altered HPA axis function in adults who were abused as children (Heim et al., 2000). Elevated prolactin response to serotonin challenge has been found among abused children (Kaufman et al., 1998; Pine et al., 1997), suggesting that the experience could be associated with dysregulation of serotonergic neurotransmission. Activation of specific neuroendocrine systems, such as the HPA axis, also has been found in conditions of normative, acute stress, such as that which accompanies the transition to primary school (Boyce et al., 1995), and prolonged extreme neglect and sensory deprivation, such as adverse rearing in a Romanian orphanage (Gunnar, 1998). Furthermore, chronic stressors in early child- hood could impair the emergence of higher cognitive processes such as memory (Nelson and Carver, 1998). The potential for “recovery” from prolonged, severe early adverse experiences through later enrichment is still unknown. All are important areas for research. Behavioral factors, such as physical activity and diet, are significant in setting health trajectories in children. Nearly half of American children are not regularly physically active, and physical activity declines dramati- cally among older children (U.S. Department of Health and Human Ser- vices, 1996). In the United States, children currently are 20–30% less active than is recommended by the World Health Organization (Salbe et al., 1997). Childhood activity is associated with relative weight, parental obesity, and the proportion of time spent outdoors (Klesges et al., 1990). These statistics are important because the prevalence of overweight chil- dren between the ages of 6 and 11 in the National Health and Nutrition

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Health and Behavior reviews our improved understanding of the complex interplay among biological, psychological, and social influences and explores findings suggested by recent research—including interventions at multiple levels that we can employ to improve human health.

The book covers three main areas:

  • What do biological, behavioral, and social sciences contribute to our understanding of health—including cardiovascular, immune system and brain functioning, behaviors that influence health, the role of social networks and socioeconomic status, and more.
  • What can we learn from applied research on interventions to improve the health of individuals, families, communities, organizations, and larger populations?
  • How can we expeditiously translate research findings into application?
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