Citation
Klaassens, E. R. (2010, November 30). Bouncing back : trauma and the HPA-axis in healthy adults. Retrieved from https://hdl.handle.net/1887/16190
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/16190
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Introduction and Outline of the studies
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Introduction
Why do most people bounce back after exposure to traumatic stress while others develop psychiatric disorders in the aftermath of trauma exposure?
In this dissertation, we set out to unravel part of the mechanism that underlies the complex relation between trauma exposure, stress regulation, and psychopathology.
Epidemiologic research has shown that most people experience a potentially traumatic event at least once in their lives 1. Prospective longitudinal studies show that approximately 3-10% of the individuals exposed to trauma develop psychiatric disorders such as posttraumatic stress disorder (PTSD), with women being more vulnerable than men 2-4. Even though the majority of people who are exposed to traumatic events do not develop psychiatric disorders, the public opinion as well as research has focussed on the relation between trauma exposure and increased vulnerability to the development of psychiatric disorders. An important part of this research focuses on one of the main stress regulatory systems, the hypothalamic-pituitary-adrenal (HPA)-axis. A large body of literature on this subject shows altered HPA- axis functioning in individuals with stress-related psychiatric disorders. Even though in pre-clinical studies an association has been found between exposure to stress and HPA-axis dysregulation, studies in humans on the direct relation between exposure to extreme stressors and HPA-axis regulation are scarce (Figure 1).
Figure 1. Established and hypothesized relationship between trauma exposure, the putative mediating role of the HPA-axis, and subsequent trauma-related psychiatric disorders. The first question mark represents the primary hypothesis of this dissertation.
The line drawn between ‘Trauma exposure’ and ‘No psychiatric disorder’ is made thicker than the one between ‘Trauma exposure’ and ‘Psychiatric disorder’ to visualize that the former is more frequent than the latter.
Figure 1. Established and hypothesized relationship between trauma exposure, the putative mediating role of the HPA-axis, and subsequent trauma-related psychiatric disorders. The first question mark represents the primary hypothesis of this dissertation. The line drawn between ‘Trauma exposure’ and ‘No psychiatric disorder’ is made thicker than the one between ‘Trauma exposure’ and ‘Psychiatric disorder’ to visualize that the former is more frequent than the latter.
In order to further investigate the relation between trauma exposure, HPA-
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axis dysregulation, and psychiatric disorders, the physiological responses and adaptation to stress in subjects who have been exposed to trauma or extreme stress, but (as yet) did not develop psychiatric disorders, have to be studied.
The main aim of this dissertation, therefore, is to determine whether exposure to psychological trauma is associated with dysregulation of the HPA-axis, an important part of the biological stress system.
To be able to discuss this issue properly, we will start this introduction by defining stress, psychological trauma and its related concept resilience.
In addition, background information on the main regulatory systems of the stress-response is given.
Stress
Stress can be defined as an emotional experience in response to a stressor, and manifests itself by biochemical, physiological, cognitive and behavioral changes. These changes are directed both at altering the stressor and accommodating to its effects. A stressor (or stressful event) is a physical or imagined stimulus that disturbs or threatens to disturb homeostasis. As stressors are omnipresent, stress is vital for survival. Sometimes, however, stress induces physical or psychological dysfunction. This is why stress has a negative connotation.
A special type of stress is traumatic stress. Traumatic stressors (e.g., sexual abuse, violent personal assaults or military combat) refer to those events that are beyond normal life challenges, and beyond more stressful and challenging circumstances such as divorce, losing a job, or a serious illness 5.
History of stress research
In the early 1900’s, Walter Cannon (1871-1945), an American psychologist, first described the way animals and humans respond to threat in terms of fight- or-flight reaction. He found that, when an organism is confronted with danger, the body is triggered to prepare itself for fight (e.g. struggle or combat) or flight (running away to safety) in merely seconds. In a stressful condition, the sympathetic nervous system is stimulated, as a result of which the heart rate increases, breathing becomes faster and deeper, blood vessels constrict and blood pressure rises. In addition, muscle tone increases and bodily functions that are irrelevant for fight-or-flight (e.g. the digestive system), are stopped temporarily. Glucose is released from the liver, and adrenaline starts flowing.
When the (life-) threatening situation is over, all bodily functions are restored in a matter of minutes.
Another important early contribution to the study of stress was made by Hans Selye (1907-1982), a Hungarian/Canadian endocrinologist, who was one of the first researchers to systematically study the effects of continued severe stress on the body and developed his concept of the general adaptation syndrome. He observed that individuals, who experienced changes in their lives and surroundings, were less healthy and showed more discomfort than individuals who made these changes out of free will. Selye discovered three stages of the biological reaction of organisms to severe stressors: the first phase is the alarm phase, in which the individual identifies the stressor, and the body will bring about the fight-or-flight response. In this phase, among others, the HPA-axis is activated to produce cortisol. If the stressor persists, the second phase, the so-called resistance phase develops. In this phase the body tries to adapt to the demands of the stressor but the body can not keep this up for long. Hormonal reserves are depleted, fatigue sets in and the individual enters the third and final phase: the exhaustion phase. In this phase, the body is unable to maintain normal functioning and long term damage may arise as pathological changes in the immune system and the digestive system develop. This phase can manifest itself in depression, ulcers and diabetes and can ultimately lead to death of the individual.
Selye’s model still has a substantial impact on the field of stress research today, as it provides a way of thinking about the interplay between biological and environmental factors. However, it assigns only a limited role to psychological factors, mainly because the early stress studies were conducted on animals exposed to extreme physical stressors. As studies on humans were carried out more often, the importance of psychological factors became evident. Lazarus 6 was one of the first to believe that the psychological appraisal of an event is very important in the determination of stress. Lazarus distinguished two phases in appraisal of a potential stressor 7. The first step, called primary appraisal, entails the initial evaluation of the stressor, during which the individual decides whether the stressor is ‘good’,
‘stressful’ or ‘irrelevant’. When the stressor is appraised as stressful, the individual then estimates whether the stressor can induce harm and whether action is required. If the individual decides that something must be done, secondary appraisal begins. The person evaluates the personal and social resources that are available to deal with the stressful circumstance and considers what actions to take. In addition, according to Lazarus & Folkman 7, it is believed that how people respond to stress is substantially influenced by their personalities, perceptions, and biological constitutions.
The biological stress system
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Like all other organisms, the human body needs to maintain itself in a stable, constant condition, a situation called homeostasis. Due to homeostatic regulation, all organisms are able to function effectively despite a broad range of internal as well as external stressors. The autonomic nervous system (ANS) and the HPA-axis are the main stress response systems that serve to maintain homeostasis during exposure to a stressor 8. Of key importance in these systems are the mediating hormones and neurotransmitters, such as glucocorticoids, and (nor)epinephrine. Under acute stress, the sympathetic nervous system is activated and epinephrine is released from the adrenal glands.
In the following paragraphs the physiological mechanisms of the HPA-axis will be explained and different methods for assessing HPA-axis functioning will be described.
Physiology of the HPA-axis
The HPA-axis is the central and main neuroendocrine system that helps us cope with and adapt to stressors. In normal HPA-axis functioning, exposure to a stressor results in a cascade of neuroendocrine reactions, starting with corticotropin-releasing hormone (CRH; originally named corticotropin- releasing factor; CRF) being released by the paraventricular nucleus of the hypothalamus (Figure 2). In conjunction with CRH, arginine vasopressin (AVP) is released by the hypothalamus. CRH stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). By activation of AVP receptors, AVP amplifies CRH induced ACTH secretion. In turn, ACTH stimulates the release of the glucocorticoid cortisol from the adrenal cortex. Cortisol, a steroid hormone, is the end-product of the HPA-axis and an important index of the stress system.
Cortisol acts through binding with the mineralocorticoidreceptor (MR), a high-affinity receptor, and the glucocorticoidreceptor (GR), a low-affinity receptor. Low levels of cortisol are sufficient to occupy the MR, which are situated mainly in the hippocampus and amygdala. During stress, when cortisol levels are high, also the GRs, which are present in every cell in the body, are occupied. The GR mainly acts to prevent the stress-reaction from overshooting and promote restoration after stress 9.
Cortisol affects numerous physiologic systems. It maintains basal activity of the HPA-system, activates energy to facilitate an adequate stress response, regulates blood pressure and cardiovascular function, and reduces inflammation in the case of an injury. Although cortisol has many effects that are beneficial
for our short-term survival, high levels of cortisol for a longer period of time are damaging to the body 10. The same hormonal response to stress that protects the body by promoting physiological adaptation to adverse circumstances in the short run, can lead to disease in the long run 11. When exposure to a stressor ends, the negative feedback inhibition of cortisol on the hypothalamus and pituitary gland is activated and basal hormone levels are restored.
Assessment of HPA-axis functioning
HPA-axis functioning can be assessed under basal as well as under challenged conditions (Figure 2). Basal cortisol mainly reflects adrenal functioning, whereas several challenge paradigms target different levels of the HPA-axis.
Basal cortisol assessment
Cortisol is secreted with a pulsatory diurnal rhythm, with a peak (average Figure 2. HPA-axis functioning and assessment methods.
Figure 2. HPA-axis functioning and assessment methods.
increase of 50%) approximately 30 min after awakening, and a progressive
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decline during the day with lowest levels around midnight. Basal cortisol may be assessed in several bodily fluids such as saliva, urine, blood (serum or plasma) and cerebrospinal fluid. All these fluids contain cortisol in varying compositions. Whereas salivary and urinary free cortisol consist almost entirely of the (free) biologically active fraction, in blood, less than 10% of the cortisol is free. The major part is bound to cortisol-binding globulin or other proteins and, therefore, biologically inactive 12.
Each procedure and methodology of cortisol sampling has its advantages and disadvantages. Sampling cortisol in blood is an invasive procedure, is costly, and requires trained personnel and specialized equipment.
Furthermore, venipuncture by itself may elicit a cortisol response that could lead to artificially raised cortisol levels, not so much because of the puncture itself (the cortisol response takes about 20 min) but as a result of anticipation stress 12.
Urinary cortisol sampling is a non-invasive procedure that provides hormone levels per urine volume (24-h urine collection) or hormone values per amount of urinary creatinine (12-h overnight urine collection). Twenty-four-hour urine sample collection is preferred because it provides an integration of cortisol production over a longer period of time and is not influenced by timing of collection. However, for most people 24-h urine sampling is very impractical.
Consequently, the compliance is often poor. Overnight urine sampling is less burdensome, but this approach also has drawbacks, as cortisol values may be influenced by hydration status and muscle mass, and corrections have to be made 13.
Sampling salivary cortisol is the most commonly used method for assessing basal cortisol in psychobiological research. Its major attractiveness is that the procedure is non-invasive; it only requires chewing on a special roll of cotton. In addition, the collection procedure is stress-free, trained personnel is not necessary, and sampling can take place at home and at several time points throughout the day, thus making evaluation of the diurnal cortisol cycle possible 12. A disadvantage of salivary sampling is that it is difficult to check for compliance without the use of expensive monitoring devices.
Cortisol assessment during challenge tests
Several challenge paradigms targeting the HPA-axis at different levels are used in psychobiological stress research. A distinction can be made between psychosocial stress challenges and pharmacological stress challenges.
Examples of the psychosocial stress challenges, are cognitive stress challenges
(e.g., arithmetic tasks 14), challenges using trauma related acoustic stimuli 15 or trauma scripts 16. The most often used psychosocial stress challenge is the Trier Social Stress Test (TSST) that combines social-evaluative threat and uncontrollability. As in this thesis no psychological stress tests are used, they will not be discussed further. Among the pharmacological stress challenges are the CRH and ACTH challenge tests, the dexamethasone suppression test (DST), the dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and the metyrapone challenges 17.
The most widely used challenge test in neurobiological stress research is the low dose DST, originally developed as a screening instrument for Cushing’s disease. Ingestion of 0.5 mg of dexamethasone at 23.00h on the night before the test day leads to downregulation of the HPA-axis due to feedback inhibition. By collecting cortisol samples before and after dexamethasone administration, the feedback effects of dexamethasone on the HPA-axis can be calculated. In psychiatric populations, the DST was first used in patients with major depressive disorder (MDD), who showed non-suppression of cortisol in response to dexamethasone 18;19. In patients with PTSD, enhanced suppression of cortisol is reported 20;21.
An even more sensitive measure to study negative feedback regulation of the HPA-axis, is the combined Dex/CRH test, originally developed by Holsboer et al 22 and standardized and described in detail by Heuser in the early ’90s
23. The Dex/CRH test has been reported to differentiate between patients with MDD and healthy controls and it has therefore been argued that the Dex/
CRH test unveils subtle HPA-axis disturbances 23. The Dex/CRH test requires administration of 1.5 mg of dexamethasone orally at 23.00h on the night before the test day. On de day of the test itself, 100 μg human CRH is administered intravenously as a bolus at 15.00h (pre-CRH), and blood samples are drawn every 15 min between 15.00h and 16.45h. The administration of 1.5 mg of dexamethasone leads to downregulation of the HPA-axis due to feedback inhibition by dexamethasone, depleting the brain from cortisol. Administering CRH subsequently boosts the stress system. Alterations in ACTH and cortisol release are indicative for a disturbed HPA-axis activation. In patients with MDD, decreased cortisol suppression after dexamethasone and a larger cortisol response after subsequent CRH infusion are reported 23-25.
Psychological stress
Throughout our lives, we are not only frequently exposed to physiological stressors such as heat, cold, infections or pain but also to psychological stressors such as preparing for an exam, waiting for the results of a medical
test, loosing one’s job or breaking up with a loved one. The main difference
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between physiological stress and psychological stress is appraisal and can, therefore, be seen as interplay between the individual and the environment.
Psychological stressors can cause severe stress, in particular when an individual appraises a stressor as negative, harmful or threatening 6. When a stressor is appraised as a threat and the situation is perceived as unpredictable, uncontrollable and the situation is unwanted, the stressor will cause stress. Most stress is perceived as uncomfortable and produces only negative emotions such as anxiety, fear, sadness, or anger. A potential stressor is not by definition stressful; how a stressor is perceived by an individual predominantly determines whether it will be experienced as stressful.
Acute stress
A single stressful event leads to an immediate reaction from the body as described by Cannon in the 1920s 26. The individual reacts to the threat with a general discharge of the sympathetic nervous system in order to mobilize the body’s resources so the person is prepared to fight-or-flight (or freeze/
fright) 27. Usually the body quickly recovers from acute stress. However, when the stressor is traumatic and a person is vulnerable, an acute stress disorder or posttraumatic stress disorder (PTSD) may develop.
Chronic stress
When a stressful situation continues for a longer period of time we speak of chronic stress. We also speak of chronic stress when there is an accumulation or repetition of acute stressors. Everything from not being able to make ends meet to marriage trouble or workplace difficulties can keep the body in a state of perceived threat and chronic stress. As a result, the body keeps secreting stress hormones and irreversible physiological damage of the brain and body may be caused. People can adapt to chronic stress to a certain degree, but when the stressor becomes a permanent part of the environment (e.g. noise, danger), it will strain their coping capacities when they are confronted with a new stressor.
Traumatic stress
In everyday language, the words ‘stressful’ and ‘traumatic’ are often used interchangeable; both words are commonly used to describe a variety of negative emotional situations or a more or less stressful event. The Diagnostic
and Statistical Manual of Mental Disorders (DSM)-IV-TR 28, however, uses a much more strict definition of the concept of psychological trauma or traumatic stress.
According to the DSM-IV-TR, for a stressful event to be classified as traumatic, two criteria have to be met: (1) the person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others (criterion A1), and (2) the person’s response involved intense fear, helplessness or horror (criterion A2). The A1 criterion also includes instances of witnessing trauma to others such as being involved in rescue operations or witnessing severe accidents. The A2 criterion, without which no diagnosis of PTSD may be given, may function as a booster of the neurobiological stress system and be responsible for reliving the traumatic event. Even though the DSM-IV-TR gives a rather extensive definition of a traumatic event, some controversy still continues to exist among experts as to exactly which events should be characterized as traumatic.
Adaptation to stress
The way a person manages the causes and consequences of stress is called coping. Coping may be seen as a process; a person’s ongoing efforts in thought and action, to manage specific demands appraised as challenging or overwhelming 6. Coping may consist of behavioral, emotional, or motivational responses and thoughts, directed either at confronting the stressor directly and thus changing the environment (problem-focused coping) or at the reduction of discomfort by regulation the emotions experienced due to the stressful event (emotion-focused coping). In other words, when we are confronted with a stressor, we try to alter the situation or we try to interpret the stressor in a different way, making it appear more favorable. When in a stressful situation we feel that our coping abilities and resources will be sufficient to meet the threat and challenge the event, we will resort to problem-focused coping. Using appropriate coping strategies for a specific situation has been associated with a good adaptation to stress and reduces the chance to develop psychiatric disorders.
However, when we feel that the stressor is uncontrollable, we will not look for ways of changing the stressor; instead, we will try to change our feelings and thoughts about it. Feeling more than adequate to deal with a difficult situation will most likely lead to little stress; feeling that one’s resources will probably not be enough will most likely lead to a large amount of stress, thus, increasing the chance to develop psychiatric disorders.
Stress- and trauma-related psychiatric disorders 1
The majority of people who are exposed to severe stress or traumatic stress do not develop psychiatric disorders and continue to live their lives seemingly unaffected. Despite this human capacity to survive and adapt to stress and psychological trauma, these situations can become so chronic or overwhelming that they become unmanageable. As a result, stress-or trauma-related psychiatric disorders such as MDD or PTSD may develop.
The main difference between stress-related disorders and trauma-related disorders is the fact that in the latter condition a traumatic (etiological) event is required as part of its definition.
Stress-related psychiatric disorders
The relationship between stressful events and psychiatric disorders seems clinically evident, as an important starting point in the treatment of a patient with, e.g., MDD is the analysis and modification of stressors. In the lives of most people, stressful events occur, ranging from life events such as moving house or loosing one’s job to extremely severe stressors such as sudden death of a loved one or a violent attack. Whether or not emotional complaints or even psychiatric disorders will develop after such an event, depends on the way in which people perceive and cope with the stressful situation and on the intensity and frequency of the stressor. When a person’s ability to cope with stress is insufficient, an imbalance in the physiological stress reaction may occur, leading to a heightened vulnerability to develop stress-related psychiatric disorders such as mood and anxiety disorders.
In some psychiatric disorders, exposure to stressful events may be an eliciting factor (e.g. in schizophrenia). In others, however, stressful or traumatic events may play a more etiological role (Figure 3).
Trauma-related psychiatric disorders
For centuries it has been noticed that after experiencing extremely stressful, life threatening events, some people develop complaints of fear, anxiety, fatigue, and hyper arousal. This condition was called a variety of names, such as soldiers’ heart (Civil War), shell shock or combat fatigue (World War I), and battle fatigue (World War II). These days, the symptoms that may develop after experiencing traumatic events are diagnosed as PTSD.
Only as recently as 1980, PTSD has been added to the DSM-III and officially recognized as an emotional disorder 29. While many people still tend to
associate PTSD with soldiers, the disorder can develop in every individual who has experienced a traumatic event. Acute stress disorder is a psychiatric condition that arises in response to an extreme or traumatic stressor. Acute stress disorder may resolve itself with time (usually within 4 weeks) or it may develop into a more severe disorder such as PTSD (Figure 3).
As said before, different people will react differently to similar events. One person may experience an event as traumatic while another person would not suffer trauma as a result of the same event. In other words, not all people who experience a potentially traumatic event will actually become psychologically traumatized; fortunately only a minority develops psychiatric disorders (Figure 4).
Trauma and the stress-system
In patients with trauma-related psychiatric disorders neurobiological alterations of the stress-system have been found.
In 1986, Mason et al 30 were the first to describe low urinary cortisol levels in patients with posttraumatic stress disorder (PTSD). In a subsequent study
Mood disorders:
- Dysthymic disorder - Major depressive disorder - Bipolar I and II disorders - Cyclothymic disorder Anxiety disorders:
- Generalized anxiety disorder - Panic disorder with and without
agoraphobia - Specific phobia - Social phobia
- Obsessive-compulsive disorder - Posttraumatic stress disorder - Acute stress disorder Adjustment disorders
Stress-related disorders
- Posttraumatic stress disorder - Acute stress disorder
Trauma-related disorders
Posttraumatic stress disorder Symptoms:
- Re-experiencing Flashbacks Bad dreams Frightening thoughts - Avoidance
Staying away from reminders Feeling emotionally numb Feeling strong guilt/depression Losing interest in activities Trouble remembering the event - Hyperarousal
Being easily startled Feeling tense or "on edge"
Having difficulty sleeping Having angry outbursts.
Figure 3. Overview of the main stress-related and trauma-related disorders.
Figure 3. Overview of the main stress-related and trauma-related disorders.
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the same research group replicated the results 31. They concluded that these findings suggest a physiological adaptation of the HPA-axis to chronic stress.
Later, comparable results were found with respect to day curves of cortisol in blood and saliva, by the same group as well as others 32-34.
Much of the data on the neurobiology of resilience comes from animal models but literature on studies in humans is growing.
Preclinical studies
Evidence from studies in non-human primates as well as in humans, precludes that trauma exposure early in life may alter the set-point of the HPA-axis in such a way that dysregulation in later life may be stronger and longer lasting then after trauma exposure during adulthood 35;36. Studies investigating the effect of postnatal maternal separation in rodents, have consistently demonstrated that early life stress may permanently alter brain regions and neurotransmitter systems that have been implicated in the pathophysiology of depression and PTSD. For example, maternal separation has been associated with chronic hyper-responsivity of the HPA-axis in rats, Figure 4. Trauma, trauma-related psychiatric disorders, and resilience.
Figure 4. Trauma, trauma-related psychiatric disorders, and resilience.
with exaggerated anxiety and/or fear related responses to stress 37. In contrast, handling of rat pups during their postnatal development has been shown to reduce anxiety-like behaviour; adult rats handled during infancy, showed a reduced ACTH and corticosterone response to stress 9. Similar to findings in rodents, adult rhesus-monkeys that have been maternally deprived during infancy exhibit increased pituitary-adrenal and behavioural responses to acute stress, as well as signs of behavioural despair 38.
Clinical studies with childhood trauma
Evidence has shown that adversities during childhood, such as physical and sexual abuse, emotional neglect and early loss, increase vulnerability to stress-related psychiatric disorders 39. The Netherlands’ Prevalence study of Maltreatment of Youth 40 estimated the prevalence of childhood trauma (i.e., emotional or physical neglect, medical neglect, sexual abuse, physical abuse, and psychological abuse) to be 30 cases of maltreatment per 1,000 children in the age range of 0-17. The majority of these children suffered from physical and emotional neglect, a quarter of whom also suffered from sexual and/or physical abuse. Per 1,000 children, 1.3 were the victim of sexual abuse, and physical maltreatment occurred in 5.2 children per 1,000.
Research has shown that childhood trauma exposure can have detrimental effects on brain function, because the brain is still developing. Specifically in infancy and early childhood, the developing HPA-axis is under strong social regulation and vulnerable to disturbances in the absence of sensitive, responsive care giving 36. In maltreated children with depressive and anxiety disorders, elevated basal cortisol levels have been reported 41 and maltreated children with chronic PTSD showed elevated 24-h urinary cortisol concentrations compared to normal controls 42.
Disturbances in HPA-axis regulation have not only been reported in children and adolescents with a history of trauma exposure, but also in adults who were maltreated as children as well. Much of the literature on childhood trauma and HPA-axis regulation in adults has focused on stress reactivity. The results of these studies vary, depending both on current psychiatric diagnosis and on the methodology of HPA-axis testing. Increased ACTH levels after CRH infusion were reported in PTSD patients with a history of childhood trauma compared to PTSD patients without such a history 43. Cortisol levels were not increased. In another study, maltreated men and women with PTSD both had an elevated cortisol response to a social stressor 14. Depressed women with a history of childhood maltreatment had an elevated cortisol response to the Trier Social Stress Test (TSST) compared to depressed women who were not
maltreated during childhood 44.
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Interestingly, altered HPA-axis functioning has not only been found in maltreated women with psychiatric disorders 44;45, but more recently also in early traumatized individuals without current psychiatric disorders 46-48. The results of these studies suggest that altered HPA-axis functioning is not so much specifically linked to psychiatric disorders but more to trauma exposure.
Clinical studies with adult trauma
A large body of literature exists on trauma exposure during adulthood, PTSD and HPA-axis regulation. The majority of studies have been conducted on deployment related trauma exposure. The relationship between trauma exposure, psychiatric disorders, and HPA-axis functioning is complicated. First, PTSD is not always accompanied by low cortisol levels; some studies found high levels 49;50, whereas other studies found no evidence for cortisol changes in PTSD 51. Second, most people who are exposed to psychological trauma do not develop a psychiatric disorder 52. Third, trauma-exposed people, who do not suffer from PTSD or other psychiatric morbidity, nevertheless may have HPA- axis disturbances. For instance, de Kloet et al 21 found no difference in cortisol suppression after dexamethasone and the cortisol response to awakening between veterans with PTSD and trauma-exposed veterans without PTSD, but both groups had significantly lower cortisol levels compared to healthy, non-trauma-exposed civilian controls. As in the studies on childhood trauma, these results suggest that alterations in HPA-axis regulation are related to trauma exposure rather than PTSD. The results reported by de Kloet et al 21 emphasize the need for studies on the relationship between PTSD, HPA-axis and trauma to include not only a non-trauma-exposed healthy control group but also a trauma-exposed healthy control group.
Although exposure to trauma may be associated with dysregulation of the HPA-axis, other factors may be responsible for the reported differences between trauma-exposed and non-exposed healthy subjects. For instance, if the trauma-exposed healthy group consists of soldiers and the non-exposed group of civilians, the differences in HPA-axis function may be caused by military training or differences in personality that preceded trauma exposure.
More generally, differences in HPA-axis may be involved in what makes a subject resilient to the development of psychiatric disorders after severe stress and trauma. Other factors that may have influenced the outcomes of previous studies are differences with respect to the prevalence of lifetime psychiatric disorders. None of the aforementioned studies did systematically exclude subjects with a history of psychiatric disorders, even though patients
who have recovered from prior psychiatric disorders may demonstrate subtle HPA-axis changes, due to so-called ‘scarring’ 53-56.
Resilience to trauma
Contrary to what is generally assumed, resilience to the development of psychiatric disorders after trauma exposure is not rare. Of all individuals who are exposed to traumatic events, approximately 90% do not develop psychiatric disorders or significant psychiatric symptoms 2;3. Resilient individuals may experience transient disturbances in normal functioning (e.g. several weeks of sporadic preoccupation or restless sleep), but normally exhibit stable healthy functioning across time, as well as the capacity for generative experiences and positive emotions 57. According to Bonanno, resilience distinguishes itself from recovery; the latter he describes as a trajectory in which normal functioning temporarily gives way to threshold or sub threshold symptoms of psychopathology (e.g., symptoms of PTSD or MDD). By contrast, resilience reflects the ability to maintain relatively stable, healthy, levels of psychological and physical functioning following an isolated and potentially traumatic event.
Resilience, he therefore argues, is more than the absence of psychopathology.
Understanding resilience is essential in achieving a broad understanding of human responses to stress and trauma 58. Resilience in adults was first studied in the late ‘70s of the last century and was first investigated in populations with significant medical problems or undergoing stressful life events 59;60 as well as in children capable of progressing through normal development despite exposure to significant adversity 61. Later studies turned to understanding the psychosocial determinants of resilience in trauma-exposed adults. Over the years, the term resilience has been used in the context of trauma exposure such as combat trauma, violent assault, accidents or natural disasters. In this context, resilient individuals are those who experience a traumatic event and do not develop PTSD 57;62. Psychosocial factors include active coping and facing fears, optimism and positive emotions, belief in an internal locus of control, social competence and social support, cognitive reappraisal, and a purposeful life and spirituality 63.
It is only in recent years that significant scientific and technological advances have made it possible to begin to understand the underlying biological processes associated with resilience. In addition to the broad range of psychosocial factors that promote resilience, numerous hormones, neurotransmitters and neuropeptides are involved in the acute psychobiological responses to stress.
Also, an individual’s genetic make-up determines the degree of adaptability
to adverse exposure. Findings from studies on psychosocial, psychobiological
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and genetic influences on biological responses to stress can help to outline an integrative model of resilience.
The studies in this dissertation mainly focus on psychobiological resilience and in particular on HPA-axis regulation.
Outline
Aims and hypotheses
The main aim of this dissertation was to study the association between trauma exposure and HPA-axis functioning in healthy people without a history of psychiatric disorders. We want to answer the question whether exposure to trauma can lead to HPA-axis dysregulation in the absence of psychiatric disorders. For this purpose, we studied HPA-axis regulation in mentally healthy trauma-exposed and non-trauma-exposed individuals. In order to rule out any effects of lifetime psychiatric disorders only individuals who were free of lifetime DSM-IV psychiatric disorders were included. We hypothesized that trauma-exposed healthy individuals show dysregulation of the HPA-axis compared to non-trauma-exposed healthy controls.
If trauma exposure, indeed, alters stress-regulation, another important question that has to be answered is whether trauma exposure is associated with altered HPA-axis regulation irrespective of moment of trauma exposure in the lifespan. Therefore, in this dissertation, we studied the effect of trauma exposure during adulthood as well as during childhood on HPA-axis regulation in individuals without current and lifetime psychiatric disorders. In addition, by including military peacekeepers as well as civilian subjects, we were able to differentiate between underlying factors such as psychological profile or military-related factors. We hypothesized that individuals who are drawn to choose a potentially dangerous profession may differ in HPA-axis regulation from a community sample.
Study populations
We compared basal HPA-axis function and HPA-axis reactivity between psychologically healthy trauma-exposed and non-trauma-exposed subjects in three different trauma subgroups: (1) women with and without a history of childhood trauma, (2) military peacekeeping veterans, and (3) train drivers and conductors. All individuals who participated in the studies were free of current and lifetime DSM-IV-TR axis I psychiatric disorders.
Women with childhood trauma
The first study group in this dissertation consists of women who were abused during childhood. When the trauma took place, these women were children, and therefore more vulnerable, dependent, and unable to take control of the situation. This may also influence the consequences of the trauma. In this group, we addressed the effect of trauma exposure during childhood on HPA-axis functioning during adulthood. We hypothesized that the maltreated, psychologically healthy women show altered HPA-axis functioning compared to the non-maltreated controls.
Military veterans
Since the end of World War II, Dutch military have been participating in over 50 peacekeeping and combat operations. From 1956 onwards, the majority of operations in which the Dutch have participated are peacekeeping operations.
Even though peacekeepers usually are not active in an actual war zone, the potentially traumatic or stressful experiences, most of which are beyond the realm of normal human experience, are numerous. Reports of being shot at, seeing others being killed or injured and witnessing severe human suffering, are frequent. The veterans for this study came from a randomly selected group of peacekeepers, most of whom have been deployed to high risk missions in Lebanon (1979-1985) and former Yugoslavia (1992-1995).
We addressed the effect of deployment related trauma exposure in men who work in a stressful and potentially dangerous profession. We hypothesized that the trauma-exposed, psychologically healthy veterans show altered HPA- axis functioning compared to non-trauma exposed veterans as well as non- trauma exposed civilian controls.
Railway employees
The last study group in this dissertation consists of Dutch railway employees.
In the last two decades, there has been an increase in seriously adverse events experienced by train employees. Situations such as person-under-train accidents, suicides, and passenger aggression, ranging from severe verbal aggression to assault with a weapon, are something many railway employees experience regularly. Every year, approximately 180 person-under-train suicides take place and approximately 100 passengers get injured in accidents involving trains in the Netherlands (Inspectie VWS – Veiligheidsbalans 2008).
In this group, we addressed the effect of adult trauma on HPA-axis functioning in healthy individuals who are at risk of encountering unpredictable
and infrequent traumatic events as part of their every day job, without being
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especially selected or trained for these encounters. We hypothesized that the trauma-exposed, psychologically healthy train employees show altered HPA- axis functioning compared to non-trauma-exposed controls.
Trauma assessment
In this dissertation we defined trauma according to the definition given by the DSM-IV-TR. All individuals who participated in the studies had to meet both criterion A1 and A2 for at least one traumatic event. Trauma exposure was assessed with self-report questionnaires as well as a trauma interview. The A2 criterion was addressed by asking all participants to score the impact of every event at the time of exposure (0=no impact, 1=negative, 2=very negative) and by explicitly defining the meaning of these answer categories (e.g. a very negative impact is defined as being subjected to an intense feeling of fear, helplessness or horror). All participants from the trauma-exposed group scored a very negative impact on one or more of the traumatic events.
Trauma exposure during childhood, was assessed with the Dutch translation of the Childhood Trauma Questionnaire (CTQ-SF) 64;65, a 25-item retrospective inventory that provides brief, reliable and valid screening for histories of abuse and neglect. We also used the Early Trauma Inventory (ETI) a structured trauma interview designed to assess traumatic experiences before the age of 18 66. The Dutch translation of the ETI 67 was not only used in our study on childhood trauma but also in both studies on adult trauma to be able to assess possible childhood trauma exposure and to control for its potential effect on HPA-axis regulation.
Deployment related trauma was assessed with the Combat Exposure Scale (CES), a 7-item self-report measure that assesses combat stressors experienced by combatants. A weighted sum score can be calculated which can then be classified into 1 of 5 categories of combat exposure, ranging from light to heavy 68. Trauma exposure during deployment was further assessed with an 11-item self-report questionnaire that asked about the experience of potentially traumatizing events (e.g., being directly in the line of fire, being held at gunpoint, having to aid in the removal or burial of human remains, being severely injured) and the number of times this event occurred. This questionnaire was based on a questionnaire used to study Dutch UNIFIL veterans 69.
Trauma exposure amongst the train drivers and conductors was assessed with a 7-item self-report questionnaire, designed specifically for this study population. The questionnaire asked about the experience of possible traumatic
events that are known to occur on a regular basis while working as a train driver or train conductor (i.e., being subjected to severe verbal aggression, physical aggression or sexual assault, being spat in the face, being threatened with a weapon, and being involved in person-under train accidents, suicides or any other severe work related accidents or near-accidents).
HPA-axis assessment
In our studies we assessed basal HPA-axis regulation as well as HPA-axis reactivity to a stressor. As a measure of basal HPA-axis activation we assessed the salivary cortisol response to awakening as well as the salivary cortisol diurnal decline. To assess intra-individual variability 70, salivary cortisol samples were collected on two consecutive days. The Dex/CRH test was used to measure HPA-axis reactivity to a neuroendocrine stressor.
Outline of the studies
Chapter 2 describes a study on trauma exposure during childhood and its effect on HPA-axis regulation during adulthood in women free of lifetime psychiatric disorders. Because psychiatric disorders that exist in adults with a history of childhood trauma are diverse and HPA-axis alterations in MDD and PTSD are found to be opposite, it is difficult to hypothesize what the effects of trauma exposure during childhood on HPA-axis functioning in adulthood may be. We can therefore only hypothesize that trauma exposure in childhood is associated with an altered cortisol response in reaction to the Dex/CRH challenge test.
In chapter 3 we described a study on the mental health of Dutch peacekeeping veterans, 10-25 years after deployment, and its association with deployment-related traumatic events. Our hypothesis was that the majority of peacekeeper veterans would not show mental health problems 10-25 years after deployment. We also hypothesized that the mental health problems we would encounter would be associated to the deployment related traumatic events.
Chapter 4 describes a study on the association between deployment related trauma exposure (as described above) and current HPA-axis regulation in male peacekeeping veterans. We assessed diurnal salivary cortisol as well as the cortisol and ACTH response to the Dex/CRH test in trauma-exposed veterans and non-trauma exposed male veterans and male civilian controls, all without lifetime psychiatric disorders. Our hypothesis was that trauma-exposed peacekeepers would show lower basal
cortisol as well as a decreased cortisol response to the Dex/CRH challenge
1
test compared to non-trauma-exposed veterans and non-trauma-exposed civilian controls.
In chapter 5 we report on an investigation into trauma exposure in relation to the salivary cortisol response to awakening as well as the diurnal decline, and HPA-axis reactivity to the Dex/CRH test in male railway employees without lifetime psychiatric disorders. Our hypothesis was that trauma-exposed railway employees showed lower cortisol levels in basal as well as challenged conditions compared to non-trauma-exposed controls.
Research on trauma exposure during adulthood, PTSD and HPA-axis regulation showed mixed results. By conducting two meta-analyses (chapter 6) we aimed to establish whether trauma exposure during adulthood is directly responsible for HPA-axis dysregulation or whether this only occurs in conjunction with PTSD symptomatology. In the first meta-analysis we calculated pooled effect sizes (Hedges’s g) of cortisol levels of trauma-exposed and non-trauma-exposed subjects without current psychiatric disorders. In the second meta-analysis we compared effect sizes (Hedges’s g) of cortisol outcome measures between trauma- exposed individuals with and without PTSD.
This dissertation ends with a general discussion (chapter 7). Main results will be summarized and discussed. Implications of the presented studies and suggestions for future research will be addressed
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