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Mechanisms of Stress in Humans
Abstract
The purpose of this literature review is to summarize stress-related research to better understand the mechanisms of stress. The connections between stress and environmental, physiological, as well as neurological factors were examined. Research has shown that stress exposure was related to cognitive dysfunctions, altered attention strategies, reduced capacity to experience pleasure, and higher risktaking tendency in achieving gains. A high level of stress was associated with greater hippocampal volume loss and was found to hinder memory retrieval while enhancing memory consolidation process. Physiologically, high stress levels were linked to shortened telomeres, elevated levels of circulating inflammatory markers, as well as hypoactivation of electrodermal activity and diurnal cortisol in response to stressors. Moreover, prenatal stress exposure was found to be a risk factor that can make an individual vulnerable to develop later stress-related physical and psychological problems. Researchers have also identified protective factors that can buffer individuals from the negative impact of stress.
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Although the majority of research in the field has focused on childhood stressors as a risk factor for psychopathology, a burgeoning body of literature has focused on the possible steeling effect of moderate types of stressful events. The current study investigated the effects of proximal life stressors on prospective changes in depressive symptoms, and whether a history of moderate childhood adversity would moderate this relationship in a multi-wave study of a diverse community sample of early adolescents (N = 163, 52 % female, 51 % Caucasian). Hierarchical linear modeling was run with four waves of data. Adolescents with greater moderately severe early life events evinced a blunted depressive symptom response to changes in proximal stressful events in the previous 9 months, compared to those with fewer early moderately severe experiences of adversity. These results held after controlling for between-subject factors such as race, gender, severe early life stress, and average stress over the four waves of data. Findings indicate that greater exposure to moderate childhood stressors may buffer against the negative effects of subsequent stressors, suggesting the importance of a nuanced developmental approach to studying the effects of early life stress.
Children’s early social experiences shape their developing neurological and biological systems for good or for ill, writes Ross Thompson, and the kinds of stressful experiences that are endemic to families living in poverty can alter children’s neurobiology in ways that undermine their health, their social competence, and their ability to succeed in school and in life. For example, when children are born into a world where resources are scarce and violence is a constant possibility, neurobiological changes may make them wary and vigilant, and they are likely to have a hard time controlling their emotions, focusing on tasks, and forming healthy relationships. Unfortunately, these adaptive responses to chronic stress serve them poorly in situations, such as school and work, where they must concentrate and cooperate to do well.
But thanks to the plasticity of the developing brain and other biological systems, the neurobiological response to chronic stress can be buffered and even reversed, Thompson writes, especially when we intervene early in children’s lives. In particular, warm and nurturing relationships between children and adults can serve as a powerful bulwark against the neurobiological changes that accompany stress, and interventions that help build such relationships have shown particular promise. These programs have targeted biological parents, of course, but also foster parents, teachers and other caregivers, and more distant relatives, such as grandparents. For this reason, Thompson suggests that the concept of two-generation programs may need to be expanded, and that we should consider a “multigenerational” approach to helping children living in poverty cope and thrive in the face of chronic stress.
This article explores the concept of allostatic load and its utility as an integrative framework for thinking about the impact of chronic stress on children and adolescents. Allostatic load refers to the failure or exhaustion of normal physiologic processes that occurs in response to severe, frequent, or chronic stressors. This persistent physiologic dysregulation may lead to secondary health problems such as immunosuppression, obesity, atherosclerosis, and hypertension. Allostatic load can be measured and followed as a composite index of a group of physiologic parameters which fall outside of a normal range. Although research regarding allostatic load in children is limited, this article explores relevant studies and identifies ways in which the concept of allostatic load can be used to broaden approaches to assessment, case formulation, and treatment in children. The concept of allostatic load may be of particular interest to psychodynamic psychiatrists in recognizing the ways in which chronic stress and adverse childhood experiences lead not only to negative psychological sequelae but also to long-term health consequences including the possibility of premature death. It underscores the importance of monitoring patients' physical as well as psychological health and thinking about the complex interrelations between the two. © 2012 The American Academy of Psychoanalysis and Dynamic Psychiatry.
Stressors are imminent or perceived challenges to homeostasis. The stress response is an innate, stereotypic, adaptive response to stressors that has evolved in the service of restoring the nonstressed homeostatic set point. It is encoded in specific neuroanatomical sites that activate a specific repertoire of cognitive, behavioral and physiologic phenomena. Adaptive responses, though essential for survival, can become dysregulated and result in disease. A clear example is autoimmune disease. I postulate that depression, like autoimmunity, represents a dysregulated adaptive response: a stress response that has gone awry. The cardinal manifestation of the normal stress response is anxiety. Cognitive programs shift from complex associative operations to rapid retrieval of unconscious emotional memories acquired during prior threatening situations. These emerge automatically to promote survival. To prevent distraction during stressful situations, the capacity to seek and experience pleasure is reduced, food intake is diminished and sexual activity and sleep are held in abeyance. Monoamines, cytokines, glutamate, GABA and other central mediators have key roles in the normal stress response. Many central loci are involved. The subgenual prefrontal cortex restrains the amygdala, the corticotropin-releasing hormone/hypothalamic-pituitary-adrenal (CRH/HPA) axis and the sympathomedullary system. The function of the subgenual prefrontal cortex is moderately diminished during normal stress to disinhibit these loci. This disinhibition promotes anxiety and physiological hyperarousal, while diminishing appetite and sleep. The dorsolateral prefrontal cortex is downregulated, diminishing cognitive regulation of anxiety. The nucleus accumbens is also downregulated, to reduce the propensity for distraction by pleasurable stimuli or the capacity to experience pleasure. Insulin resistance, inflammation and a prothrombotic state acutely emerge. These provide increased glucose for the brain and establish premonitory, proinflammatory and prothrombotic states in anticipation of either injury or hemorrhage during a threatening situation. Essential adaptive intracellular changes include increased neurogenesis, enhancement of neuroplasticity and deployment of a successful endoplasmic reticulum stress response. In melancholic depression, the activities of the central glutamate, norepinephrine and central cytokine systems are significantly and persistently increased. The subgenual prefrontal cortex is functionally impaired, and its size is reduced by as much as 40%. This leads to sustained anxiety and activations of the amygdala, CRH/HPA axis, the sympathomedullary system and their sequella, including early morning awakening and loss of appetite. The sustained activation of the amygdala, in turn, further activates stress system neuroendocrine and autonomic functions. The activity of the nucleus accumbens is further decreased and anhedonia emerges. Concomitantly, neurogenesis and neuroplasticity fall significantly. Antidepressants ameliorate many of these processes. The processes that lead to the behavioral and physiological manifestations of depressive illness produce a significant decrease in lifespan, and a doubling of the incidence of premature coronary artery disease. The incidences of premature diabetes and osteoporosis are also substantially increased. Six physiological processes that occur during stress and that are markedly increased in melancholia set into motion six different mechanisms to produce inflammation, as well as sustained insulin resistance and a prothrombotic state. Clinically, melancholic and atypical depression seem to be antithesis of one another. In melancholia, depressive systems are at their worst in the morning when arousal systems, such as the CRH/HPA axis and the noradrenergic systems, are at their maxima. In atypical depression, depressive symptoms are at their worst in the evening, when these arousal systems are at their minima. Melancholic patients experience anorexia and insomnia, whereas atypical patients experience hyperphagia and hypersomnia. Melancholia seems like an activation and persistence of the normal stress response, whereas atypical depression resembles a stress response that has been excessively inhibited. It is important that we stratify clinical studies of depressed patients to compare melancholic and atypical subtypes and establish their differential pathophysiology. Overall, it is important to note that many of the major mediators of the stress response and melancholic depression, such as the subgenual prefrontal cortex, the amygdala, the noradrenergic system and the CRH/HPA axis participate in multiple reinforcing positive feedback loops. This organization permits the establishment of the markedly exaggerated, persistent elevation of the stress response seen in melancholia. Given their pronounced interrelatedness, it may not matter where in this cascade the first abnormality arises. It will spread to the other loci and initiate each of their activations in a pernicious vicious cycle.
In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing’s syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=−0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids.
The present study examined whether and how stressor diversity, the extent to which stressor events are spread across multiple types of stressors, contributes to daily affective well-being through the adult life span. Stressor diversity was examined as a unique predictor of daily affect and as a moderator of stressor exposure and stressor reactivity effects. Analyses span 2 independent studies of daily stress: the National Study of Daily Experiences with N = 2,022 adults, aged 33 to 85 years, assessed over T = 8 days, and the Intraindividual Study of Affect, Health, and Interpersonal Behavior with N = 150 adults, aged 18 to 89 years, assessed over T = 63 days. Across both studies, older age was associated with less stressor diversity. Additionally, multivariate multilevel models indicated higher stressor diversity was linked with better affective well-being. Age, however, was not a consistent moderator of such associations. The combination of low stressor diversity and high stressor exposure is discussed as an operationalization of chronic stressors, and this combination was associated with particularly high negative affect and low positive affect. We believe further work will benefit from including both the frequency and diversity of stressor experiences in analyses in order to better characterize individuals' stressor experiences. (PsycINFO Database Record
Many dysfunctional and chronic pain conditions overlap. This review describes the different modes of chronic deregulation of the adaptive response to stress which may be a common factor for these conditions. Several types of dysfunction can be identified within the hypothalamo-pituitary-adrenal axis: basal hypercortisolism, hyper-reactivity, basal hypocortisolism and hypo-reactivity. Neuroactive steroid synthesis is another component of the adaptive response to stress. Dehydroepiandrosterone (DHEA) and its sulfated form DHEA-S, and progesterone and its derivatives are synthetized in cutaneous, nervous, and adipose cells. They are neuroactive factors that act locally. They may have a role in the localization of the symptoms and their levels can vary both in the central nervous system and in the periphery. Persistent changes in neuroactive steroid levels or precursors can induce localized neurodegeneration. The autonomic nervous system is another component of the stress response. Its dysfunction in chronic stress responses can be expressed by decreased basal parasympathethic activity, increased basal sympathetic activity or sympathetic hyporeactivity to a stressful stimulus. The immune and genetic systems also participate. The helper-T cells Th1 secrete pro-inflammatory cytokines such as IL-1-β, IL-2, IL-6, IL-8, IL-12, IFN-γ, and TNF-α, whereas Th2 secrete anti-inflammatory cytokines: IL-4, IL-10, IGF-10, IL-13. Chronic deregulation of the Th1/Th2 balance can occur in favor of anti- or pro-inflammatory direction, locally or systemically. Individual vulnerability to stress can be due to environmental factors but can also be genetically influenced. Genetic polymorphisms and epigenetics are the main keys to understanding the influence of genetics on the response of individuals to constraints.
This study explored prospectively the effects of dispositional and situational optimism on mood (N = 90) and immune changes (N = 50) among law students in their first semester of study. Optimism was associated with better mood, higher numbers of helper T cells, and higher natural killer cell cytotoxicity. Avoidance coping partially accounted for the relationship between optimism and mood. Among the immune parameters, mood partially accounted for the optimism-helper T cell relationship, and perceived stress partially accounted for the optimism-cytotoxicity relationship. Individual differences in expectancies, appraisals, and mood may be important in understanding psychological and immune responses to stress.
Both acute stressful life events and ongoing strains are thought to confer vulnerability to emotional disorders. Unremitting stressful conditions may be particularly pathogenic, but prior research has struggled to delimit chronic versus transient stressful experiences. We aimed to isolate stable stressors-theorized to be indicators of a latent stress proneness trait-and to examine their effects on the temporal course of depression and panic disorder. We recruited 677 patients diagnosed with an emotional disorder and administered interviews for psychopathology and life stress 3 times over 12-month intervals. Trait-state-occasion modeling revealed that 74% of the variance in life stress was stable over the follow-up period. These stable stressors were associated with a more refractory course of depression and, to a smaller degree, panic disorder over time. In addition, neither gender nor participation in cognitive-behavioral therapy affected the persistence of environmental stress over the study time frame. We discuss implications of these findings for explaining depression recurrence, improving psychological interventions for emotional disorders, and the measurement and evaluation of stress proneness. (PsycINFO Database Record
Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and, to a lesser extent, in the noradrenergic neurons of the locus coeruleus (LC). Most cases of PD are idiopathic and sporadic and are believed to be the result of both environmental and genetic factors. Here, to the best of our knowledge, we report the first evidence that chronic restraint stress (8 h/day, 5 days/week) substantially reduces nigral DA and LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after 2 weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16 weeks. This reduction was accompanied by robust microglial activation and oxidative stress and was marked by nitrotyrosine in the SNpc and LC of the midbrain. These results indicate that chronic stress triggers DA and noradrenergic neurodegeneration by increasing oxidative stress, and that activated microglia in the substantia nigra and LC may play an important role in modulating the neurotoxic effects of oxidative stress. Taken together, these data suggest that exposure to chronic stress triggers DA and noradrenergic neurodegeneration, which is a cause of PD.
Copyright © 2015. Published by Elsevier Inc.