4
THE STRESS RESPONSE

In considering whether being deployed to a war zone may result in long-term health effects in veterans, it is important to ask whether the stressors experienced by the veterans during their deployment could produce the stress response. If they could, might that response lead to physiologic changes that could eventually be manifested as long-term health effects? Those questions address the issue of biologic plausibility as discussed in Chapter 2: Are there biologic mechanisms by which exposure to deployment-related stress could lead to adverse health effects? This chapter explores the research being done on why and how people and animals respond to stress. It describes the stress response, including its basic biology and physiology, and its modifiers. The chapter also surveys some of the potential adverse consequences of the stress response that can occur in organ systems after exposure to chronic stressors. The implications of the stress response for long-term health effects in humans are described in Chapters 6 and 7.

The word stress is used in many contexts and has a variety of meanings. It is often used to describe a situation characterized by real or perceived threats to a person, but it is also commonly used to refer to the body’s response to such threats. Thus, stress has been used both to describe the environmental events (the stressors) that trigger responses and to refer to the resulting changes (stress responses) that occur in the brain and the rest of the body.

The stress response enables humans and other organisms to survive unsafe and life-threatening conditions through “fight or flight,” as the response is widely called. As described below, it is a cascade of physiologic changes that is activated rapidly in emergencies. Some of the changes occur immediately, within minutes to hours; others emerge after days to weeks (Box 4-1), depending on the stressor’s severity. The repertoire of responses is similar across human cultures and other species.

One of the earliest steps in the stress response is the brain’s perception that an event is threatening, which determines how an organism responds physiologically, emotionally, and behaviorally to the stressor. Possible responses include aggression, escape, anxiety, and executive function (a complex set of behaviors). The response to the stressor—for example, the sound of a gun—is dictated by the split-second appraisal of whether it poses a genuine threat. A feature that is most refined in humans is the capacity to learn from stressful experiences, to think abstractly, and to draw on lessons when coping with harm in the future (McEwen and Lasley 2002). The lessons learned are often etched into the brain through measurable structural and functional alterations in nerve cells and networks. Human stressors are not only external; they can be internal, such as worry, guilt, or rumination about past or future events. Internal and external stressors both contribute to allostatic overload, a concept for explaining in physiologic terms the effects of chronic or cumulative stress (McEwen 2007).



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4 THE STRESS RESPONSE In considering whether being deployed to a war zone may result in long-term health effects in veterans, it is important to ask whether the stressors experienced by the veterans during their deployment could produce the stress response. If they could, might that response lead to physiologic changes that could eventually be manifested as long-term health effects? Those questions address the issue of biologic plausibility as discussed in Chapter 2: Are there biologic mechanisms by which exposure to deployment-related stress could lead to adverse health effects? This chapter explores the research being done on why and how people and animals respond to stress. It describes the stress response, including its basic biology and physiology, and its modifiers. The chapter also surveys some of the potential adverse consequences of the stress response that can occur in organ systems after exposure to chronic stressors. The implications of the stress response for long-term health effects in humans are described in Chapters 6 and 7. The word stress is used in many contexts and has a variety of meanings. It is often used to describe a situation characterized by real or perceived threats to a person, but it is also commonly used to refer to the body’s response to such threats. Thus, stress has been used both to describe the environmental events (the stressors) that trigger responses and to refer to the resulting changes (stress responses) that occur in the brain and the rest of the body. The stress response enables humans and other organisms to survive unsafe and life- threatening conditions through “fight or flight,” as the response is widely called. As described below, it is a cascade of physiologic changes that is activated rapidly in emergencies. Some of the changes occur immediately, within minutes to hours; others emerge after days to weeks (Box 4-1), depending on the stressor’s severity. The repertoire of responses is similar across human cultures and other species. One of the earliest steps in the stress response is the brain’s perception that an event is threatening, which determines how an organism responds physiologically, emotionally, and behaviorally to the stressor. Possible responses include aggression, escape, anxiety, and executive function (a complex set of behaviors). The response to the stressor—for example, the sound of a gun—is dictated by the split-second appraisal of whether it poses a genuine threat. A feature that is most refined in humans is the capacity to learn from stressful experiences, to think abstractly, and to draw on lessons when coping with harm in the future (McEwen and Lasley 2002). The lessons learned are often etched into the brain through measurable structural and functional alterations in nerve cells and networks. Human stressors are not only external; they can be internal, such as worry, guilt, or rumination about past or future events. Internal and external stressors both contribute to allostatic overload, a concept for explaining in physiologic terms the effects of chronic or cumulative stress (McEwen 2007). 49

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50 GULF WAR AND HEALTH BOX 4-1 Physiologic Changes During the Stress Response Early Phase of the Stress Response (Duration: Minutes to Hours) • Increased heart rate and blood pressure • Increased respiration • Mobilization of energy from liver and body fat • Sharpening of attention and cognition • Increased fear conditioning (learning) • Blunting of pain • Altered intestinal motility Later Phases of the Stress Response (Duration: Days to Weeks) • Enhanced immune system • Suppression of appetite and digestion • Suppression of growth • Suppression of reproduction • Persistence of increased heart rate and blood pressure in some cases • Persistence of increased cortisol in some cases • Release of stress hormones When a stressor is eliminated, the stress response may shut off quite slowly or not at all (McEwen and Lasley 2002). It is the long-term activation of the stress response—long after the threat has ceased—that poses the greatest risk to human health. Paradoxically, the human stress response is life-saving in the short term (and is adaptive) when immediate stressors are confronted, but it can lead to illness or disease when stressors are severe, recurrent, or persistent in the long term (and is maladaptive). Although many veterans consider deployment, particularly combat, to be highly stressful and even traumatic, there are many periods during deployment when stressors are not traumatic but are severe and persistent (for example, separation from family and worry about home or work). Prolonged exposure to such stressors, whether in military or civilian life, can overwhelm otherwise healthy people and can lead to health-damaging behaviors, such as smoking and excessive drinking, in an attempt to alleviate the stress. CENTRAL ROLE OF THE BRAIN Once the brain interprets a situation as threatening, it assumes immediate control over the endocrine, cardiovascular, immune, and digestive system. The brain relies on an elaborate communication network that includes hormones, neurotransmitters, chemicals associated with the immune system, and other molecular signals. This section discusses the various regions of the brain involved in the body’s response to stress, the effects of the brain on other organ systems that play roles in the stress response, and the feedback mechanisms that occur in response to acute and chronic stress. The stress response is spearheaded by the hypothalamus-pituitary-adrenal (HPA) axis in the peripheral stress-response pathway and by the sympathetic nervous system in the central

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THE STRESS RESPONSE 51 stress-response pathway. The sympathetic system activates internal organs (such as heart, lungs, and liver) and mobilizes energy to respond to stressors. The parasympathetic nervous system does the opposite, preserving energy, putting a brake on the heart rate, increasing intestinal activity, relaxing muscles in the gastrointestinal system, and decreasing inflammation. Those functions have earned the parasympathetic system the nickname “rest and digest,” compared with the “fight or flight” of the sympathetic system. The stress response is adaptive (it promotes survival), but it is maladaptive if it is chronically activated over a long time. Long-term activation of the stress response can cause abnormalities in the brain or in other parts of the body. Reticular Activating System In response to any stimulus, including stimuli that are novel or potentially threatening, a primary brain system that is activated is the reticular activating system (RAS). Without activation of the RAS there would be no stress response or waking behavior; indeed, loss of RAS function results in a persistent vegetative state. The RAS works closely with the cholinergic, noradrenergic, and serotonergic systems of the brainstem and influences other brain areas, such as the cerebral cortex, hypothalamus, amygdala, and cerebellum. Novel and potentially threatening stimuli, such as a loud sound, induce a massive output from the RAS that does three things: it activates the pontine reticular formation to potentiate the startle response, which is part of a general protective system (the eyes close, flexion in humans lowers the head from danger, and muscles tighten in preparation for attack from an enemy); it activates the thalamus to trigger synchronization of fast rhythms between the thalamus and cortex that “awaken” the cortex, placing it in a “ready” position; and it participates with forebrain structures in activating the hypothalamus to trigger the HPA axis and the surge of epinephrine from the adrenal medulla. The “fight or flight” response is therefore a brainwide and bodywide response to novelty and threat that involves activation of the RAS with other coordinated brain systems. The RAS is dysregulated in anxiety disorders and depression. In fact, some of the first symptoms of posttraumatic stress disorder (PTSD) and depression are sleep-wake problems (see Chapter 5). Both disorders are marked by increased vigilance and increased REM-sleep drive, which can result in vivid dreaming and REM-sleep intrusion into waking, for example, hallucinations (Pfaff 2005). In some cases, the RAS can be activated directly by inputs to the brainstem from the periphery, such as a loud sound, pain, touch, or signals from the gut via the vagus nerve. For the other senses, the sensory information reaches the RAS via the amygdala, which also can respond directly to a stimulus, such as a loud sound, pain, or touch. Importance of the Amygdala The stress response begins with sensory information about a stressor—its visual images, sounds, smells, touch, or other sensations (Figure 4-1). Information from sensory nerve cells in peripheral tissues is relayed to several regions of the brain, including the hypothalamus, thalamus, somatosensory cortex, nucleus of the solitary tract, ventral lateral medulla, and the parabrachial nucleus and insular cortex. Each of those regions sends signals to the amygdala (in the temporal lobes of the cerebrum) which integrates all the incoming sensory signals (Bonne et al. 2004) and to the hypothalamus. The amygdala consists of collections of cell types (nuclei) that form the “extended amygdala.” The extended amygdala consists of the central and basolateral nucleus of the amygdala, and the lateral bed nucleus of the stria terminalis (BNST) (Alheid and Heimer 1988; Davis and Whalen 2001). The BNST also receives input from the

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52 GULF WAR AND HEALTH hippocampus (a part of the brain in the medial temporal lobe). Both the central nucleus of the amygdala and the lateral BNST, when activated, transmit impulses to several other regions of the brain, including the locus coeruleus, which uses norepinephrine (also called noradrenalin) to send signals to numerous other parts of the brain. Several parts of the hypothalamus and many of the same brainstem nuclei activate the sympathetic nervous system, which with the locus coeruleus forms part of the “central stress response,” preparing for fight or flight. The hypothalamus is especially important for regulating the sympathetic nervous system because it receives sensory input from virtually the entire body, including the amygdala and BNST. Stressor Amygdala Central RAS, Other Brain Bed Nucleus of Stress Areas Involved in Stria Terminalis Stress Response Response ACTH CRH Hypothalamus Cortisol Pituitary Adrenal Glands Hippocampus/ Prefrontal Cortex Negative Feedback Peripheral Stress Response FIGURE 4-1 Stress-response pathways. NOTE: ACTH = adrenocorticotrophic hormone, CRH = corticotropin-releasing hormone, RAS = reticular activating system. The sympathetic nervous system uses epinephrine to stimulate the inner region of the adrenal gland to secrete large amounts of epinephrine and other catecholamines1 into the circulation. The surge of epinephrine floods the brain and peripheral tissues, thereby producing the full-fledged fight or flight response: faster heartbeat, greater energy, more blood flow to skeletal and cardiac muscle, dilation of the pupils and airways, and higher blood glucose concentration and so on. With chronic stress, however, the sympathetic nervous system may 1 Catecholamines are a class of hormones and neurotransmitters that includes epinephrine and dopamine.

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THE STRESS RESPONSE 53 remain reactive and produce catecholamines for many years. That is commonly seen in people with anxiety disorders who have increased heart rates and blood pressure. Long-term increase in catecholamines can produce chronic inflammation, as discussed later in the chapter. The Hypothalamus-Pituitary-Adrenal Axis In the peripheral stress pathway, the hypothalamus secretes corticotropin-releasing hormone (CRH), which acts on the pituitary to secrete corticotropin (also known as adrenocorticotropic hormone). Corticotropin enters the bloodstream and acts on the adrenal cortex to induce release of the glucocorticoid hormone cortisol. This pathway is known as the HPA axis or peripheral stress response (Chrousos and Gold 1992; Selye 1956). Cortisol is distributed to body tissues where it serves several functions, such as replenishing energy lost to the epinephrine surge, increasing cardiovascular tone; enhancing memory for avoiding danger in the future; preserving energy; and, if necessary, activating immune-cell migration to areas of the body where there is infection or injury (McEwen and Lasley 2002). Cortisol also has key functions in the brain: it acts to increase arousal, vigilance, attention, and formation of memories (Charney 2004). It can also act in the amygdala and BNST to increase production and release of CRH from the hypothalamus. Cortisol also facilitates fear conditioning (Roozendaal et al. 2006). However, if the cortisol surge is large and prolonged, it can suppress growth, tissue repair, reproduction, digestion, and inflammation (Sapolsky 2003). When cortisol reaches the brain it exerts a negative feedback on the HPA axis. First, it binds to glucocorticoid receptors in the hippocampus (McEwen et al. 1968), which projects into the hypothalamus, and binds to glucocorticoid receptors in the hypothalamus. Cortisol binding in both the hippocampus and the hypothalamus acts to turn off CRH production and release by the hypothalamus (Herman et al. 1989; McEwen et al. 1992). The net effect is that high cortisol concentrations reaching the brain inhibit the HPA axis (McEwen 2002b; Vermetten and Bremner 2002). Thus, glucocorticoids, such as cortisol, enhance CRH in the amygdala and help to turn on the HPA axis when activated by stress, and a feedback mechanism turns the HPA axis off at the level of the hypothalamus and pituitary (see Figure 4-1). It is the balance between activation via the amygdala and inhibition via the hypothalamus, prefrontal cortex, and hippocampus that determines HPA activity and how rapidly it is turned on and off. The hippocampus plays a key role in shaping memories; it forms explicit memory, which is the ability to recollect an event consciously and to assemble its pieces to form a coherent memory of the whole event. The opposite, nondeclarative memory, refers to memories not consciously recalled, for example, such skills as playing the piano and reading. For fearful memories, the hippocampus works with the amygdala and the prefrontal cortex of the brain. The prefrontal cortex modulates the actions of the amygdala, usually through inhibition, and thus can control cortisol secretion and activation of the parasympathetic and sympathetic nervous systems (Radley et al. 2006; Thayer and Brosschot 2005). The prefrontal cortex also participates in attention, decision making and sense of control, working memory, extinction of fear memories, and other aspects of cognitive flexibility (Hariri et al. 2006; McDougall et al. 2004). The effects of cortisol (peripheral pathway) and epinephrine (central pathway) are not restricted to the central nervous system (CNS). Many other tissues respond to cortisol and communicate with the CNS in a bidirectional manner. Of particular concern for the stress response is the immune system. In the acute phase of the stress response, the immune system fights infection and repairs wounds by boosting immunity. Some immune cells (such as leukocytes, white blood cells) are rapidly deployed from the circulation to the skin, where they

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54 GULF WAR AND HEALTH protect wounds against viruses, bacteria, and fungi. They are summoned there by cytokines, which are released at the wound site (Dhabhar 2000). Cytokines are small proteins that are secreted most typically by immune cells and signal or activate other immune cells. Functioning somewhat as hormones do, they regulate the immune response to infection and injury. The communication link between the HPA axis and the immune system is strong: lymphocytes and macrophages (types of white blood cells) have receptors for cortisol, and some immune-related cells in the brain have receptors for cytokines (Reiche et al. 2004) and are activated by cortisol. In response to chronic stress, a long-term increase of glucocorticoids, such as cortisol, can dysregulate and suppress immune function, as discussed later. Allostasis The classic fight or flight response entails activation of epinephrine and cortisol with resulting increases in immune function, energy mobilization (in the form of glucose), and enhancement of memory, which helps to avoid the threat in the future. To maintain homeostasis, the brain regulates the stress response by inducing the body to release chemical mediators— including neurotransmitters, immune-system messengers, and hormones, including cortisol and epinephrine, a process called allostasis (McEwen 1998, 2005, 2007; McEwen and Wingfield 2003). Homeostasis refers to stability in various physiologic characteristics, such as body temperature, pH, and oxygen tension, which are tightly regulated within narrow ranges that promote survival. The chemical mediators of allostasis are released from the sympathetic and parasympathetic branches of the nervous system but are also released from the immune, cardiovascular, and metabolic systems. Their interactions occur through a nonlinear network, that is, mediators from each system regulate the production of others in a series of checks and balances. Corresponding to multiple mediators of the stress response, there are multiple pathways by which they regulate it. In the sympathetic system, for example, greater activity of proinflammatory cytokines, signaling molecules used by the immune system, elicits greater activity of anti-inflammatory cytokines—that is, negative feedback—and negative regulation by the parasympathetic and glucocorticoid pathways. Parasympathetic activity working through the acetylcholine receptors on immune cells reduces production of proinflammatory cytokines (Tracey 2002). In other words, as the activity of proinflammatory cytokines increases, other systems can produce the opposing activity. That example shows how homeostasis can be achieved through numerous routes using a common set of interacting mediators (McEwen 2007). Allostatic Load and Overload Allostatic load refers to the burden of chronic stress and altered personal behaviors (“lifestyle”) that results from effects of overuse and dysregulation of the mediators of allostasis (Figure 4-2; McEwen 1998). Allostatic load is often manifested by fatigue, anger, frustration, and feeling out of control. Those feelings can lead to sleep loss (McEwen 2006, 2007), anxiety,

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THE STRESS RESPONSE 55 Pre-Existing Stress Load of Brain and Body. Chronic Life Stressors Chaos, Conflict, Lack of Control Anxiety, Mood Changes, and Disturbed Sleep Overeating, Heavy Drinking, Smoking, No Exercise Health-Damaging Behaviors Increase in Chronic Physiologic Stress Burden (Allostatic Overload) Chronically Increased Heart Dysregulated Stress Response Rate, Blood Pressure, Insulin, Inflammatory Cytokines, Hyperlipidemia Adverse Health Outcomes Hypertension, Diabetes, Obesity, Coronary Heart Disease, Depression, Gastrointestinal Disorders, Fatigue, Pain FIGURE 4-2 How chronic stress can affect behavior and health. All people have some pre-existing load of stressful experiences reflected in brain and body. Chronic life stressors (such as interpersonal conflicts, care-giving, pressure at work, and crowded and noisy living and working conditions) can affect people by creating a sense of chaos, conflict, and a lack of control. The result of the chronic stressors will often be chronic anxiety and depressed mood with poor-quality sleep. Anxiety, mood changes, and inadequate sleep can lead to self-medication through eating “comfort foods,” excessive alcohol drinking, smoking, and neglecting regular exercise. Together with the anxiety, depressed mood, and poor sleep, these behaviors dysregulate the normal physiological activities and create a chronic stress burden (allostatic overload). The dysregulated stress response involves increased cortisol, insulin, and inflammatory cytokines at night; along with increased heart rate and blood pressure; and reduced parasympathetic tone. If this abnormal dysregulated state persists for months and years, there are likely to be adverse health outcomes, such as hypertension, coronary heart disease, stroke, obesity, diabetes, arthritis, major depression, gastrointestinal disorders, chronic pain, and chronic fatigue. depression, and such health-damaging behaviors as overeating (Dallman et al. 2003), smoking, and excessive drinking (Anda et al. 1990; Dube et al. 2002). Those behaviors, in turn, increase and dysregulate the body’s mediators normally involved in allostasis. When one mediator, such

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56 GULF WAR AND HEALTH as cortisol, is present in excessive or insufficient amounts, other mediators are also changed. Over the course of days, weeks, and longer, allostatic load eventually can disrupt health, a condition called allostatic overload or toxic chronic stress response. Allostatic overload is maladaptive: it serves no useful purpose and predisposes the body to disease. Allostatic load and allostatic overload are points on a continuum. The pattern, frequency, and duration of stressors are important determinants of the severity of the outcome, as are a person’s response to the stressors. Four types of physiologic responses lead to allostatic load and overload (Figure 4-3). Two of them are related to individual differences in the stress response: prolonged response (B) and inadequate response (C). The other two are related to chronic stressor characteristics: repeated exposure (D in the figure) and lack of adaptation (E). Initially, the health consequences of allostatic load or overload are early indicators of possible later disease, such as hypertension, obesity, increased cholesterol, bone mineral loss, muscle protein loss, memory impairment, and increased anxiety. MODIFIERS OF THE STRESS RESPONSE Many factors may alter a person’s response to stress, including genetic makeup, early-life history, and the degree to which the stressor can be controlled. Research is under way on all those, primarily in animal models. Each is discussed below. Genes Many aspects of the stress response—such as learned and innate fear (see, for example, Shumyatsky et al. 2005), reward, social behavior, and resilience (Charney 2004)—are likely to be under the influence of particular genes. Genes determine which proteins will be made and where they will be made. The same gene might have slightly different sequences (alleles) that alter the protein production. An example of allelic variation occurs in the gene that codes for the serotonin-transporter protein. That protein removes serotonin—a chemical messenger in the brain that affects emotions, mood, behavior, and thought—from the synaptic cleft between nerve cells after it is released by a presynaptic cell. A short allele makes less of this protein than the long allele found in most people, thus altering serotonin transmission (Hariri et al. 2006). In some studies, people with the short allele are prone to more anxiety and more likely to acquire conditioned fear responses (Hariri et al. 2006). Furthermore, they are more likely to develop depression but only if they were maltreated in childhood (Caspi et al. 2002). Thus, just having the short allele does not necessarily lead to depression, but combined with early life stress it can increase the risk of depression. Conversely, people with the longer allele (and higher levels of serotonin transporter) were less likely to develop depression even if they had been maltreated in childhood; the longer allele protected them. That is an example of gene-environment interactions in which a medical condition cannot be predicted only by a gene or only by a serious life event but requires a combination of a genetic factor and an environmental event for the outcome to occur. Researchers have investigated the mechanisms that might explain such gene-environment interactions. For example, Ichise et al. (2006) examined the same interactions between a short serotonin-transporter allele and exposure to early-life stress in rhesus monkeys. Monkeys reared by peers rather than by their mothers—a stressful condition—showed a decrease in serotonin

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THE STRESS RESPONSE 57 FIGURE 4-3 Chronicity of stressors. Top panel (A) shows a normal stress response that is turned on by the stressor and shut off when the stressor is terminated. Individual stress responses may be prolonged (B) or inadequate for the situation (C). The repetition of stressful events (D) and lack of adaptation to similar stressors (E) can lead to toxic stress and a chronic stress burden. SOURCE: Adapted with permission from McEwen (1998). binding in several regions of the brain involved in the stress response (for example, the amygdala, hypothalamus, hippocampus, and raphe nucleus). The authors suggested that early-life stress affects the development of the serotonin system and that it might account for some of the behavioral abnormalities—including greater alcohol consumption, aggressiveness, and impaired

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58 GULF WAR AND HEALTH impulse control—seen in the peer-reared monkeys (Barr et al. 2004). Such studies may elucidate the neural circuits governing the stress response and how they interact with the environment and on some of the variation in response to stress. Early-Life Stress In the 1950s, Harlow found that lack of maternal care and handling is a severe form of early-life stress. Rhesus monkeys that had been “raised” by artificial mothers (made of bare wires) were stricken with terror when they were placed in novel situations (Harlow 1974), and those raised by their peers showed more anxiety and hyperarousal than monkeys raised by their biologic mothers (Mineka and Suomi 1978). Early-life stress has been associated with increases in cortisol and other markers of increased HPA-axis activity (Levine 1962). In rats, normal maternal handling during infancy leads to a life-long increase in the number of glucocorticoid receptors in the hippocampus, whereas a lack of maternal handling decreases the number of glucocorticoid receptors in the stressed animals, and the decreases persist into adulthood and old age (Meaney et al. 1985, 1988). A greater density of glucocorticoid receptors after normal handling would be expected to increase negative feedback between the hippocampus and the HPA (see Figure 4-1) and result in greater inhibition of the HPA axis after a stressful event, which in turn would lead to a less reactive HPA axis, lower cortisol concentrations, and more rapid initiation of the stress response. But the lower density of receptors in the heavily stressed offspring would be expected to reduce negative feedback and lead to greater reactivity of the HPA axis, higher cortisol concentrations, and more prolonged stress response. Higher cortisol concentrations, which persisted from youth through old age, were indeed found in nonhandled (stressed) animals. At greater ages, the excess secretion of cortisol was associated with structural changes in the hippocampus and with deficits in spatial memory (Meaney et al. 1988). Normal maternal care led to lower concentrations of corticotropin and cortisol, indications of a less reactive HPA axis (Liu et al. 1997; Meaney et al. 1985; Sapolsky et al. 1986). Evidence that early-life stress results in an overreactive HPA axis has come also from studies of CRH. As described earlier, CRH is released by the hypothalamus under the regulatory influence of the hippocampus, prefrontal cortex, and amygdala, and it signals the pituitary gland to release corticotropin, which leads to a release of cortisol by the adrenal gland (see Figure 4-1). Primates reared under conditions of early-life stress (unpredictable conditions for the mother to find food) displayed persistent increases of CRH throughout adulthood (Coplan et al. 1996). The timing of exposure to the stressor was important: CRH decreased when the stressful condition occurred later in infancy (Mathew et al. 2002). Those studies have helped to establish that early- life stress has permanent effects on the regulation of the HPA axis. Human studies have demonstrated associations that appear to be consistent with the findings on early-life stress in animal studies. In a study of the effects of childhood abuse in New Zealanders followed from birth until their 30s, an association was found between childhood abuse and chronic inflammation in adulthood. The inflammatory marker C-reactive protein—a better marker for myocardial infarction than cholesterol concentrations—was found to be above normal in many of the young adults known to have been abused. A dose-response relationship was seen between the level of abuse and the concentration of C-reactive protein (Danese et al. 2007).

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THE STRESS RESPONSE 59 Controllability One important modifier of the stress response is the degree to which a stressor is perceived as controllable (Maier and Watkins 2005). Animal studies have indicated that a sense of control is an important aspect of hardiness. Experiments have shown that animals with control over the amount of shock they received fared much better those deprived of control (Maier et al. 1969; Seligman and Maier 1967; Weiss 1968). Rats that lacked control of the shock they received ate less, lost more weight, developed more ulcers, had higher resting blood pressure and higher plasma cortisol, displayed less aggression in the face of an intruder, were less responsive on standard measures of pain sensitivity and reactivity, and had more immunosuppression (Maier and Watkins 1998); they also had changes in epinephrine in the locus coeruleus and hypothalamus (Weiss et al. 1981). Similar experiments in dogs (Chourbaji et al. 2005; Overmier and Seligman 1967; Vollmayr and Henn 2001) found that those given inescapable shocks failed to avoid later shocks even when they were able to, a behavior called learned helplessness. The biologic mechanism that underlies how uncontrollable stress might lead to deficits in escape appears to be abnormal activation of two brainstem nuclei: the dorsal raphe nucleus and the locus coeruleus (Maier et al. 1995). Activation of neurons there leads to the release of the neurotransmitters serotonin and norepinephrine into almost all parts of the brain, where they modify cellular activity. However, the mechanism by which those primitive brainstem nuclei mediate the complex cognitive process required to judge the uncontrollability of a stressor has been unclear. It has recently been shown in rats that stress always activates the brainstem nuclei, but activation is inhibited by the prefrontal cortex, a brain structure that appears to be dysregulated in people with PTSD (see Chapter 5) (Amat et al. 2005). Thus, a dysfunctional prefrontal cortex in PTSD could perhaps exacerbate a feeling of being out of control. Animal studies illustrate the potential role of perception of control in the stress-response process. CHRONIC STRESS AND HEALTH Activation of the stress response ensures survival in the short term, but is maladaptive when its activation persists as a result of chronic, severe, or repeated stress. Chronic stress can lead to adverse health outcomes that affect multiple body systems such as the CNS and the endocrine, immune, gastrointestinal, and cardiovascular systems. Stress-induced abnormalities are due to dysregulation of a common set of mediators: cortisol, epinephrine, and immune- system cytokines. The model of stress-related illness is built on evidence of interrelationships between stress hormones and other systems, including the endocrine and immune systems. Stress hormones can trigger interactions between the endocrine and immune systems that culminate in a state of chronic inflammation. Stress-induced chronic inflammation appears to be a driving force behind wide-ranging conditions linked to stress, such as obesity, heart disease, diabetes, and chronic pain (Black and Garbutt 2002; Black et al. 2006; Malarkey and Mills 2007). Research on the role of inflammation with the CNS is focusing on interrelationships between immune cells, cytokines, and nearby neurons situated in regions of the brain implicated in stress-related disorders (MacPherson et al. 2005). This section reviews some of those adverse health effects; in many cases, they are markers of disease or symptoms rather than specific diseases.

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64 GULF WAR AND HEALTH grade inflammatory processes that set in motion the pathologic changes that lead to cardiovascular disease (Black and Garbutt 2002; Black et al. 2006). That hypothesis draws from evidence that during the acute stress response, cortisol, catecholamines, angiotensin, and other stress hormones induce the liver and abdominal fat tissue to release proinflammatory cytokines and other inflammatory mediators. Inflammatory molecules, when increased for a long time, lead to a chronic state of inflammation, especially in abdominal fat and vasculature, which contribute to insulin resistance. Inflammation in the vasculature is manifested by recruitment and adherence of white blood cells to the vascular lining and their migration to the inner portions of the lining, binding of receptors to LDL particles, and growth of fibrous tissue. Those processes set the stage for plaque development (Libby 2002). A key marker of the inflammatory process in the circulatory system is C-reactive protein, an independent predictor of cardiovascular risk (Kardys et al. 2006; Libby 2002). In a prospective study, older adults who were current or former caregivers for Alzheimer’s disease patients and harbored chronic hostility or pain had more inflammation, as measured by C-reactive protein, when other risk factors were accounted for, than did noncaregiver controls (Graham et al. 2006). Gastrointestinal System and Brain-Gut Axis Research is advancing our understanding of the interaction between stress and emotional trauma and the effects on the brain-gut axis, particularly with respect to irritable bowel syndrome (IBS) and other functional gastrointestinal disorders, such as functional dyspepsia (Dilley et al. 2005; Drossman 2005; Longstreth et al. 2006). IBS is the most common gastrointestinal condition seen in primary-care or gastroenterology practice; it is clinically manifested by symptoms of abdominal pain and altered bowel habit (for example, diarrhea, constipation, or both). Those symptoms are produced and amplified by gut-related stressors (such as eating, physical activity, and hormonal changes) or by other stressors, such as abuse, a history of trauma, or psychosocial comorbidities. The stressors appear to disrupt the brain-gut neurophysiologic regulatory pathways that alter intestinal motility and visceral sensation thresholds either centrally or peripherally. Figure 4-4 shows the relative prevalence of IBS according to severity and shows the relative contributions of peripheral and psychosocial factors to severity. In effect, more severe psychosocial disturbance, including abuse and war trauma, leads to greater symptom reporting, poorer health status, greater psychologic comorbidity, and poorer quality of life. Several lines of evidence support the concept of dysregulation of stress circuitry in IBS that is linked to and affects gut function (and vice versa). The evidence includes altered CRH and corticotropin reactivity to stress and an increased gut response (motility and pain) to CRH (Dinan et al. 2006; Fukudo et al. 1998; Sagami et al. 2004; Tache et al. 2005) which can be blocked by CRH antagonists (Sagami et al. 2004); increased mucosal inflammatory activity (Chadwick et al. 2002); stress-caused loss of the integrity of the intestinal mucosal barrier to bacterial pathogens and other toxins, which in turn causes entry or release of toxic substances that lead to inflammation and nerve sensitivity (Barbara et al. 2006, 2007; Soderholm et al. 2002; Yang et al. 2006); and altered brain regulation of incoming visceral pain signals leading to an increased pain experience that is enhanced by stress (Chang et al. 2003; Drossman et al. 2003; Naliboff et al. 2001; Ringel et al. 2003a,b). There is also evidence that the mediating mechanisms of reduction in pain can be evaluated with brain imaging (Drossman et al. 2003).

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THE STRESS RESPONSE 65 Y N R O JU TI IN C ES FE N T IN O IE M D R O HIGH H S ES Y N, R ST ET IO XI S G FE NS N Peripheral Signaling A RE PI LI Prevalence O EP C of IBS D R SE O PO U B A CNS Signaling LOW MILD MODERATE SEVERE Severity of IBS FIGURE 4-4 The brain-gut axis and IBS. Relative prevalence of IBS according to severity, and relative contributions of peripheral (left side of triangle) and psychosocial (right side of triangle) factors to severity. Most patients have mild to moderate IBS symptoms with increased peripheral-nerve signaling. However, a smaller group of patients with moderate to severe symptoms also have impaired modulation of pain at the CNS level, which is enabled by psychosocial factors (such as trauma, abuse, life stress, psychosocial comorbidities, and poor coping). These patients experience increased symptoms at the level of the CNS signaling. Factors that may contribute to CNS signaling include life stress and abuse. Activation of IBS symptoms results from physiologic dysfunction that occurs peripherally (for example, motility disturbances or intestinal infection with inflammation). The peripheral stimuli send signals from the colon up the spinal cord to the thalamus and then to the brain via two pathways. The brain regions innervated by those pathways, which are activated in response to painful colorectal stimuli, include the somatosensory cortex—the area responsible for localization and intensity of peripheral sensations—and the limbic system, including the thalamus, insula, amygdala, and anterior cingulate cortex, which is linked to emotional stress and cognitive interpretation of pain. The brain has the ability to turn down the incoming signals through descending inhibitory pathways that modulate pain transmission and incoming signals are thus downregulated at the level of the spinal cord. As discussed earlier, CRH secretion and the HPA axis can also regulate inflammation, including that of the bowel mucosa. In IBS, however, the normal regulatory mechanisms of the brain-gut axis are dysfunctional, and there is impaired regulation of visceral pain (Naliboff et al. 2001) and altered HPA reactivity. The latter disrupts normal control of mucosal immune function that results in inflammation via cytokine activation (Dinan et al. 2006). With brain imaging, it can be shown that psychosocial difficulties (such as anxiety and life stress, including abuse or trauma, hypervigilance, and maladaptive coping) can impair those regulatory mechanisms (Drossman 2005). The presence and intensity of

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66 GULF WAR AND HEALTH symptoms depends on the degree of activity of the peripheral signals and how they are modulated by the CNS in the face of stress or other modifying factors. That model can be generalized to include other medical conditions. Most people with fibromyalgia, chronic fatigue, or other pain syndromes will have milder symptoms because their dysfunction is mostly peripheral, with little input from the CNS. But patients with more severe symptoms, greater symptom reporting, greater psychosocial disturbance, and poorer health status and quality of life will have greater CNS contributions to their symptoms. With increasing CNS dysregulation, the ability to filter incoming peripheral and visceral signals is impaired, and a person will report more symptoms (Chang et al. 2003; Clauw and Chrousos 1997; Sternberg 1995); this helps to explain the clinical similarity of those conditions when they are severe. CONCLUSIONS The stress response, the body’s reaction to stress, can be life-saving (and be adaptive) in the short term when a person confronts immediate stressors but can lead to illness or disease (and be maladaptive) in the long term when stressors are severe, recurrent, or persistent. In response to deployment-related stress, physiologic changes occur in the body, may persist for a long time after deployment has ended, and may result in symptoms and disorders that appear soon after exposure to the stressor or become evident only years later. Some biologic factors and life experiences can modify a person’s response to stress, including genes, early-life events, and the degree to which the stressor is perceived to be controllable. Those factors might help to explain the differences in people’s reactions to stress and the development of subsequent health effects. The studies discussed in this chapter provide a context for understanding why people deployed to a war zone may report more symptoms than people who are not deployed—the stress response results in a cascade of physiologic changes that can have profound effects on multiple organ systems. War-zone stressors might produce disruption in brain systems that mediate responses to stress and in central pain regulatory pathways that can result in greater reporting of physical and emotional symptoms. The continuation of altered physiologic states over months and years can contribute to the accumulation of a chronic stress burden that has adverse long-term health consequences. The possible long-term manifestations of those altered states in veterans are discussed in Chapters 5, 6, and 7. Much progress has been made in understanding the physiologic mechanisms of the stress response, particularly in animal models, but work remains to be done in human studies. Research on the effect of stressors on the endocrine, immune, cardiovascular, and gastrointestinal systems demonstrates the complexity of the interactions between those systems. REFERENCES Alheid GF, Heimer L. 1988. New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience 27(1):1-39. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. 2005. Medial prefrontal cortex determined how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neurosciences 8:365-371.

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