Allostasis and allostatic load/Bibliography

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Books

• Committee on Future Directions for Behavioral and Social Sciences Research at the National Institutes of Health, Burton H. Singer and Carol D. Ryff, Editors,Board on Behavioral, Cognitive, and Sensory Sciences, National Research Council. (2001) New Horizons in Health: An Integrative Approach. National Academies Press. Full-Text Free. ISBN-13: 978-0-309-07296-0
  • Book description from website: New Horizons in Health discusses how the National Institutes of Health (NIH) can integrate research in the social, behavioral, and biomedical sciences to better understand the causes of disease as well as interventions that promote health. It outlines a set of research priorities for consideration by the Office of Behavioral and Social Sciences Research (OBSSR), with particular attention to research that can support and complement the work of the National Institutes of Health. By addressing the range of interactions among social settings, behavioral patterns, and important health concerns, it highlights areas of scientific opportunity where significant investment is most likely to improve national and global health outcomes. These opportunities will apply the knowledge and methods of the behavioral and social sciences to contemporary health needs, and give attention to the chief health concerns of the general public.
  • Excerpt referring to allostatic load: Through repeated efforts to adapt to stressful circumstances, the organism experiences a cumulative multisystem physiological toll, leading to cascading, potentially irreversible interactions between genetic predispositions and environmental factors. Over time, these cascades can contribute to large individual differences in dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, impaired immune function, altered cardiovascular reactivity, and ultimately stress-related physical and mental disorders (including chronic hypertension, coronary heart disease, diabetes, hippocampal atrophy and associated cognitive dysfunction; see Seeman et al.,1997; Seeman and Robins, 1994; McEwen, 1998; Dhabhar and McEwen, 1996; McEwen et al., 1997).

• McEwen BS, Lasley EN. (2002) The end of stress as we know it. Washington, D.C: Joseph Henry Press. ISBN 0309076404.
  • The National Academy Press
  • Book description: There's a whole new way to think about stress. Sure, some stress is inevitable, but being "stressed out" isn't. In fact, we can learn to rechannel the powerful stress activators in our lives to make us even more effective....Hamlet spoke of "suffering the slings and arrows of outrageous fortune." These days we simply use the word "stress" to describe that feeling. And if you ask 10 random people if they feel stressed, chances are that at least 9 will reply with a resounding, "Yes!" Indeed, the very way we use the word implies that we are its victims as in, "I'm under so much stress" or "I'm completely stressed out." There s now a better way to look at this picture, a way to move from victim to victor. The first step is to look to the science behind it all because in the science lies a whole new message about stress. Science allows us to understand what the stress response is and why our bodies react the way they do. Like all living creatures, we're mapped to respond instinctually in certain ways, and generally for good reasons. We know, for example, that in times of emergency, we effortlessly shift into a different biological mode. Based on our perception of the crisis, our brains initiate the "stress response" or the "flight-or-fight reaction." Our attention becomes keenly focused. Our heart and lungs accelerate to ready us for action. Our glands mobilize extra energy resources and summon the immune system to battle stations. This whole process is Nature's way of empowering us to respond swiftly, sometimes dramatically, to sudden events, while remaining mentally alert and physically prepared to meet a challenge....But what if the crisis situation does not present us with a foe to be fought? Or if fleeing is not the answer? Too often in modern times, the situations that bring on the stress response require neither the fight nor flight response for which our bodies are genetically programmed. The stress response is nevertheless likely to kick in just as it's programmed to do even though it cannot help speed us toward a resolution. Deprived of its natural successful result, the very system that s designed to protect us begins to cause wear and tear on our bodies actually bringing on illnesses as diverse and severe as asthma, diabetes, heart disease, ulcers, and increased susceptibility to colds and infections....The good news is that there are definite things that we can do to prevent this process from ultimately taking this wrong turn. New research in brain functioning allows us to understand the reactions our bodies have to various stressful circumstances. That knowledge is power the power to harness the energy stored within us and to channel it in positive ways. The End of Stress as We Know It leads us to a new appreciation of the mind body nnection so that we learn how to reduce stress and increase our overall sense of health and well-being and even turn aside the slings and arrows of life.

• Schulkin J. (2003) Rethinking homeostasis: allostatic regulation in physiology and pathophysiology. Cambridge, Mass: MIT Press. ISBN 0262194805.
  • MIT CogNet: The Brain Sciences Connection
  • From the book announcement website: Homeostasis, a key concept in biology, refers to the tendency toward stability in the various bodily states that make up the internal environment. Examples include temperature regulation and oxygen consumption. The body's needs, however, do not remain constant. When an organism is under stress, the central nervous system works with the endocrine system to use resources to maintain the overall viability of the organism. The process accelerates the various systems' defenses of bodily viability, but can violate short-term homeostasis. This allostatic regulation highlights our ability to anticipate, adapt to, and cope with impending future events....In Rethinking Homeostasis, Jay Schulkin defines and explores many aspects of allostasis, including the wear and tear on tissues and accelerated pathophysiology caused by allostatic overload. Focusing on the concept of motivation and its relationship to the central nervous system function and specific hormonal systems, he applies a neuroendocrine perspective to central motive states such as cravings for water, sodium, food, sex, and drugs. He examines in detail the bodily consequences of the behavioral and neuroendocrine regulation of fear and adversity, the endocrine regulation of normal and preterm birth, and the effects of drug addiction on the body. Schulkin's presentation of allostasis lays the foundation for further study.
  • Table of Contents: Preface; Introduction; Allostasis: The Emergence of a Concept; Central Motive States: Feedforward Neuroendocrine Systems in the Brain; Anticipation, Angst, Allostatic Regulation: Adrenal Steroid Regulation of Corticotropin-Releasing Hormone; Normal and Pathological Facilitation of Parturition by a Feedforward Endocrine Mechanism; Addiction to Drugs: Allostatic Regulation under Duress; Conclusion; References; Name Index; Subject Index.
• International Society of Psychoneuroendocrinology, Congress, (34th et al.) (2004) Biobehavioral stress response: protective and damaging effects. New York, N.Y: New York Academy of Sciences.

• McEwen BS. (2004) The end of stress as we know it. Washington, D.C: Joseph Henry Press.

• Schnurr PP, Green BL. (2004) Trauma and health: physical health consequences of exposure to extreme stress. Washington, DC: American Psychological Association.

• Eaton WW. (2006) Medical and psychiatric comorbidity over the course of life. Washington, DC: American Psychiatric Pub.

• Derek Chadwick, Jamie Goode. (2002) Endocrine Facets of Ageing. John Wiley and Sons. ISBN 0471486361, ISBN 9780471486367
  • Social and medical developments have recently led to a dramatic increase in life expectancy. This has inspired the study of organismic changes associated with healthy ageing, in particular the erosion of homeostatic capabilities in multiple endocrine systems. This book reviews advances in the understanding of endocrine facets of ageing. It considers the relative magnitudes and time courses of different endocrine adaptations in the ageing human and experimental animal, addressing the influence of external factors on the rates of progression of endocrine sequelae in ageing, the mechanisms that underlie the disarray of endocrine axes in ageing, and the implications of therapeutic reconstitution of hormones in ageing. This book: Considers the mechanisms of ageing and hormonal changes that occur with age. Discusses healthy ageing and the relationships between hormonal changes and pathophysiological conditions such as atherosclerosis and age-related bone loss. Draws together contributions from basic and clinical research, to identify and stimulate promising new research directions.
  • Contains section on allostasis, allostatic load, and aging

• Schulkin J. [editor] (2004) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. 372 pages. Cambridge University Press. ISBN 0 521 81141 4. | Google Book preview to p47, interspersed with half-dozen back-to-back pages not shown.
  • "The purpose of the book is to introduce the concept of allostasis to the reader and to place it within the context of traditional conceptions of homeostasis. Both these regulatory conceptions &mdas; homeostasis and allostasis — are broadly conceived within biological adaptations in which behavior and physiology figure prominently. It is within this context of biological adaptation that regulation of the internal milieu is understood and in which both homeostasis and allostasis have scientific legitimacy."
  • Contents: 1. Principles of allostasis: optimal design, predictive regulation, pathophysiology and rational therapeutics Peter Sterling; 2. Protection and damaging effects of the mediators of stress and adaptation: allostasis and allostatic load Bruce S. McEwen; 3. Merging of the homeostatic theory with the concept of allostatic load David S. Goldstein; 4. Operationalizing allostatic load Burton Singer, Carol D. Ryff and Teresa Seeman; 5. Drug addiction and allostasis George F. Koob and Michael LeMoal; 6. Adaptive fear and the pathology of anxiety and depression: an allostatic framework Jeffrey B. Rosen and Jay Schulkin; 7. A chronobiological perspective on allostasis and its application to shift work Ziad Boulos and Alan M. Rosenwasser; 8. Allostatic load and life cycles: implications for neuroendocrine control mechanisms John C. Wingfield; 9. Commentary: viability as opposed to stability: an evolutionary perspective on physiological regulation Michael L. Power.

Journal articles

• McEwen BS, Stellar E. (1993) Stress and the individual. Mechanisms leading to disease. Arch Intern Med 153:2093-101. PMID 8379800.

• Abstract: OBJECTIVE: This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses. DATA SOURCES: Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE. DATA EXTRACTION: Independent extraction and cross-referencing by us. DATA SYNTHESIS: Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful. CONCLUSIONS: This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed

• Schulkin J, McEwen BS, Gold PW. (1994) Allostasis, amygdala, and anticipatory angst. Neurosci Biobehav Rev 18:385-96.

• Abstract: Regions of the amygdala are involved in anticipation of negative events. Chronic anticipation of negative events leads to what we call allostatic load, or arousal pathology. Two hormones appear to be involved in arousal pathology; corticotropin-releasing hormone in the brain and glucocorticoids. We suggest that increases in corticotropin-releasing hormone, by stress or glucocorticoids, in the amygdala may have functional consequences for allostatic load. Whereas, corticotropin-releasing hormone in the parvocellular region of the paraventricular nucleus of the hypothalamus is decreased by glucocorticoids thereby under negative feedback and homeostatic control, the central nucleus of the amygdala is to some extent under positive feedback and is increased by glucocorticoids, and perhaps under allostatic control. The human and animal literature suggest that a variety of psychopathologies (e.g., melancholia) may be tied to neurohormonal signals activating regions of the amygdala

• Friedman MJ. (1997) Posttraumatic stress disorder.] J Clin Psychiatry 58 Suppl 9:33-6.

• Abstract: This article reviews concepts that help synthesize the data on posttraumatic stress disorder (PTSD), a very complex condition in terms of its etiology, psychobiology, epidemiology, comorbidity, and treatment. At least four neurobiologic systems are involved in PTSD: the catecholamine, the hypothalamic-pituitary-adrenocortical, the thyroid, and the endogenous opioid systems. Six other systems are probably or possibly implicated as well. The avoidance and hyperarousal of PTSD distort the patient's appraisal of the world. The symptoms of PTSD can be understood through models of learning and memory, which form the basis of behavioral treatments. The concepts of tonic and phasic alteration and of allostasis versus homeostasis also shed light on PTSD. In addition to PTSD, there may be other identifiable posttraumatic syndromes that might be diagnosed separately, such as "complex" PTSD. Cross-cultural issues may also affect clinical phenomenology and thereby confuse the diagnosis. Comorbid disorders may actually be clues to subtypes of PTSD. The fact that victims of PTSD are also more vulnerable to medical illnesses makes a closer relationship with primary care providers and other specialists mandatory. New approaches to prevention, treatment of chronic PTSD, psychotherapy, pharmacotherapy, and research hold promise of an improved prognosis for patients with PTSD

• McEwen BS. (1997) Hormones as regulators of brain development: life-long effects related to health and disease.] Acta Paediatr Suppl 422:41-4.

• Abstract: The life-long interplay between genes and the environment is instrumental in shaping the structure and function of the body, and these interactions apply to the brain as a plastic and ever-changing organ of the body. Hormones are key regulators of gene expression throughout the body, and the actions of hormones on the brain are instrumental in shaping sex differences and in determining the effects of stress on brain function, including the rate of brain aging. This article also introduces a new term, allostatic load, to describe the cost of adaptation to stressors. Allostasis (stability through change) refers to the output of hormones and autonomic regulators that help to maintain homeostasis, and allostatic load is the consequence of the overactivity of these systems when they are not shut off properly or are forced to be hyperactive by stressors. Key brain areas like the hippocampus are vital to the processing of information that affects how each individual adapts to and responds to potentially stressful life events, and the response of the brain through its control of endocrine and autonomic function in turn determines the degree of allostatic load that an individual will experience. This allostatic load in turn works with the intrinsic genetic susceptibility to determine the progression toward declining health

• Seeman TE, McEwen BS, Singer BH, Albert MS, Rowe JW. (1997) Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging.] J Clin Endocrinol Metab 82:2458-65.

• Abstract: Cortisol production is increased during stress, and the actions of cortisol on receptors in the brain and other body organs are involved in allostasis, the process of adaptation to stress, as well as in allostatic load, the wear and tear associated with excessive exposure to cortisol. Using data from a community-based longitudinal study of older men and women, aged 70-79 yr, we tested the hypothesis that exposure to increasing levels of cortisol is associated with declines in memory performance. Associations between 12-h urinary free cortisol excretion and performance on tests of memory (delayed verbal recall and spatial recognition), :*Abstract: ion, and spatial ability were examined. Among the women, greater cortisol excretion was associated with poorer baseline memory performance, independent of socio-demographic, health status, health behavior, and psychosocial characteristics. Moreover, women who exhibited increases in cortisol excretion over a 2.5-yr follow-up period were more likely to show declines in memory performance. By contrast, women who experienced declines in cortisol exhibited improvements in memory performance. No significant associations were found among the men. The results for the women suggest that decrements in memory performance associated with increases in cortisol may not represent irreversible effects, as declines in cortisol were associated with improvements in memory

• Seeman TE, Singer BH, Rowe JW, Horwitz RI, McEwen BS. (1997) Price of adaptation--allostatic load and its health consequences. MacArthur studies of successful aging.] Arch Intern Med 157:2259-68.

• Abstract: BACKGROUND: Exponential growth in the population of older adults presents clinicians with special concerns about factors affecting risks for declines in cognitive and physical functioning. OBJECTIVES: To examine the hypothesis that risks for such declines and for disease outcomes, such as cardiovascular disease, are related to differences in allostatic load, the cumulative physiologic toll exacted on the body over time by efforts to adapt to life experiences. To present an operational definition of allostatic load, along with preliminary evidence of its predictive validity in relation to salient outcomes of aging. METHODS: Data from a longitudinal, community-based study of successful aging were used to develop a measure of allostatic load based on 10 parameters reflecting levels of physiologic activity across a range of important regulatory systems. Allostatic load is the sum of the number of parameters for which the subject was rated in the highest-risk quartile. RESULTS: Higher allostatic load scores were associated with poorer cognitive and physical functioning and predicted larger decrements in cognitive and physical functioning as well as being associated with an increased risk for the incidence of cardiovascular disease, independent of sociodemographic and health status risk factors. CONCLUSIONS: Findings are consistent with the conceptualization of allostatic load as an index of wear and tear on the body, with elevations in allostatic load predicting an increased risk for a decline in cognitive and physical functioning as well as cardiovascular disease in a cohort of older men and women. From a clinical perspective, the concept of allostatic load may provide the basis for a more comprehensive assessment of major risks in the aging process

• Taylor SE, Repetti RL, Seeman T. (1997) Health psychology: what is an unhealthy environment and how does it get under the skin? Annu Rev Psychol 48:411-47.

• Abstract: This review explores the role of environments in creating chronic and acute health disorders. A general framework for studying the nesting of social environments and the multiple pathways by which environmental factors may adversely affect health is offered. Treating socioeconomic status (SES) and race as contextual factors, we examine characteristics of the environments of community, work, family, and peer interaction for predictors of positive and adverse health outcomes across the lifespan. We consider chronic stress/allostatic load, mental distress, coping skills and resources, and health habits and behaviors as classes of mechanisms that address how unhealthy environments get "under the skin," to create health disorders. Across multiple environments, unhealthy environments are those that threaten safety, that undermine the creation of social ties, and that are conflictual, abusive, or violent. A healthy environment, in contrast, provides safety, opportunities for social integration, and the ability to predict and/or control aspects of that environment

• Johnston-Brooks CH, Lewis MA, Evans GW, Whalen CK. (1998) Chronic stress and illness in children: the role of allostatic load.] Psychosom Med 60:597-603.

• Abstract: OBJECTIVE: Recent studies of stress have highlighted the contributions of chronic psychological and environmental stressors to health and well-being. Children may be especially vulnerable to the negative effects of chronic stressors. Allostasis, the body's ability to adapt and adjust to environmental demands, has been proposed as an explanatory mechanism for the stress-health link, yet empirical evidence is minimal. This study tested the proposition that allostasis may be an underlying physiological mechanism linking chronic stress to poor health outcomes in school-aged children. Specifically, we examined whether allostasis would mediate or moderate the link between chronic stress and health. METHOD: To test the hypothesis that allostasis contributes to the relation between chronic stress and poor health, we examined household density as a chronic environmental stressor, cardiovascular reactivity (CVR) as a marker of allostatic load, and number of school absences due to illness as the health outcome in a sample of 81 boys. RESULTS: Structural equation modeling indicated that the mediating model fit the data well, accounting for 17% of the variance in days ill. CONCLUSIONS: Results provide the first evidence that CVR may mediate the relation between household density and medical illness in children. More generally, these findings support the role of allostasis as an underlying mechanism in the link between chronic stress and health

• McEwen BS. (1998) Stress, adaptation, and disease. Allostasis and allostatic load.] Ann N Y Acad Sci 840:33-44.

• Abstract: Adaptation in the face of potentially stressful challenges involves activation of neural, neuroendocrine and neuroendocrine-immune mechanisms. This has been called "allostasis" or "stability through change" by Sterling and Eyer (Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition and Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an essential component of maintaining homeostasis. When these adaptive systems are turned on and turned off again efficiently and not too frequently, the body is able to cope effectively with challenges that it might not otherwise survive. However, there are a number of circumstances in which allostatic systems may either be overstimulated or not perform normally, and this condition has been termed "allostatic load" or the price of adaptation (McEwen and Stellar, Arch. Int. Med. 1993; 153: 2093.). Allostatic load can lead to disease over long periods. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. Examples will be given for each type of allostatic load from research pertaining to autonomic, CNS, neuroendocrine, and immune system activity. The relationship of allostatic load to genetic and developmental predispositions to disease is also considered

• Roy MP, Steptoe A, Kirschbaum C. (1998) Life events and social support as moderators of individual differences in cardiovascular and cortisol reactivity.] J Pers Soc Psychol 75:1273-81.

• Abstract: Whether prior stress increases acute stress reactivity is unresolved. The impact of life events (within the past 12 months) and social support on cardiovascular responses was investigated in 90 young male firefighters. Cardiovascular and cortisol measures were collected across baseline, arithmetic, and speech tasks; intertask recovery; and three recovery trials. Reactivity differences were not independently associated with life events. High social support was associated with greater arithmetic cardiovascular reactivity and faster recovery. Combined life events and social support grouping showed that effects of support were accentuated when event frequency was high, suggesting that life events and support interacted to sensitize future stressor responses. Support may promote the alerting response mobilization but prevent chronic allostatic load by enhancing recovery

• Schulkin J, Gold PW, McEwen BS. (1998) Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety and allostatic load.] Psychoneuroendocrinology 23:219-43.

• Abstract: Evidence supports the idea of two distinct corticotropin-releasing hormone (CRH) systems in the brain: one which is constrained by glucocorticoids and the other which is not. It is this latter system that includes two primary sites (central nucleus of the amygdala and the lateral bed nucleus of the stria terminalis) in which the regulation of CRH gene expression can be disassociated from that of the paraventricular nucleus of the hypothalamus. It is this other system that we think is linked to fear and anxiety and to clinical syndromes (excessively shy fearful children, melancholic depression, post-traumatic stress disorder and self-administration of psychotropic drugs). The excess glucocorticoids and CRH, and the state of anticipatory anxiety, contribute to allostatic load, a new term that refers to the wear and tear on the body and brain arising from attempts to adapt to adversity

• Aronsson G. (1999) Influence of worklife on public health.] Scand J Work Environ Health 25:597-604.

• Abstract: The paper discusses worklife changes with broad public health impacts. Central concepts for the analysis of the labor market are flexibility and differentiation. One conclusion is that there is ongoing polarization and differentiation--with an increased group of people in time-restricted (contingent) employment and self-employment and a reduced group of core workers. Greater demands for adaptability are being imposed on the majority of employees. Concepts related to flexibility and differentiation at an individual level are adaptability, identity formation, loss of control, trust and lack of trust, allostatic load, long-term strain, and psychological contracting. The labor market and organizational changes are discussed in relation to what can be called "institutional effectiveness". These changes refer to how institutions commissioned to act for the prevention of injuries and to contribute to worklife quality handle the new conditions. Finally, work-environment research is discussed in relation to a new and more complex pattern of exposures and interactions. One conclusion drawn is that it is becoming increasingly difficult to identify workplaces at risk

• Kirschbaum C, Hellhammer DH. (1999) Noise and Stress - Salivary Cortisol as a Non-Invasive Measure of Allostatic Load.] Noise Health 1:57-66.

• Abstract: The psychobiology of stress has received increasing attention throughout the past two decades. Physiological pathways and subjective response patterns are described in more details aiming at a better understanding of the pathways leading to health or disease under prolonged periods of stress. Technical advances in the laboratory have significantly contributed to this development. One of these methodological advances is the measurement of cortisol in saliva which has promoted psychobiological stress research both in the laboratory and in the field. The present paper provides a brief methodological background and the use of salivary cortisol assessment as an indicator of stress in human studies from this research centre. It is suggested that research on health consequences of noise exposure should include salivary cortisol as a sensitive measure of allostatic load

• Koob GF. (1999) Stress, corticotropin-releasing factor, and drug addiction.] Ann N Y Acad Sci 897:27-45.

• Abstract: The neuropeptide corticotropin-releasing factor (CRE) and related neuropeptides not only mediate hormonal responses to stressors but also have a neurotropic role in the central nervous system to mediate behavioral responses to stressors. CRF antagonists effectively block CRF responses and have effects opposite those of CRF in many stress-related situations. Recent advances suggest that in addition to CRF itself there is another CRF-related neuropeptide, urocortin, that may be involved in stress-related responses, particularly those involving appetite. At least two CRF receptors have been discovered to date, CRF-1 and CRF-2. CRF may be involved in various aspects of the addiction cycle associated with drugs of abuse. CRF appears to be activated during stress-induced reinstatement of drug taking as well as acute withdrawal from all major drugs of abuse. CRF is hypothesized to be part of an allostatic change leading to vulnerability to relapse during prolonged abstinence from drugs of abuse

• Kubzansky LD, Kawachi I, Sparrow D. (1999) Socioeconomic status, hostility, and risk factor clustering in the Normative Aging Study: any help from the concept of allostatic load?] Ann Behav Med 21:330-8.

• Abstract: OBJECTIVE: To examine the relationships between socioeconomic status (SES), psychosocial vulnerability (hostility), and allostatic load. Allostatic load refers to the cumulative physiological cost of adaptation to stress. METHOD: We examined the relationships between SES (as measured by educational attainment), hostility, and allostatic load in the Normative Aging Study, a longitudinal study of community-dwelling men aged 21 to 80 years and free of known chronic medical conditions at entry in the 1960s. In 1986, the revised Minnesota Multiphasic Personality Inventory was administered by mail, from which a hostility measure was derived by summing the scores from three Cook-Medley subscales: Hostile Affect, Hostile Attribution, Aggressive Responding. An index of allostatic load was constructed from data collected during physical exams conducted between 1987 and 1990 (i.e. measures reflecting "wear and tear" on the cardiovascular, endocrine, and metabolic systems). Cross-sectional relationships between education, hostility, and allostatic load were examined in 818 men. RESULTS: Separate linear regression analyses indicated that lower levels of educational attainment and greater hostility were both associated with higher allostatic load scores (p < .05 and p < .01, respectively). Less education was also associated with higher hostility (p < .001). When allostatic load was regressed simultaneously on education and hostility, the effect of education was attenuated, while hostility (p < .05) maintained an independent effect. CONCLUSIONS: Our findings suggest that lower levels of education and greater hostility are associated with greater "wear and tear" on the body. The effects of education on allostatic load may be mediated by hostility

• Lundberg U. (1999) Coping with Stress: Neuroendocrine Reactions and Implications for Health.] Noise Health 1:67-74.

• Abstract: A new stress model, the Allostatic Load Model, refers to the ability to achieve stability through change. The various biological functions activated during stress serve an important role in the organism's adaptation to the environment by protecting and restoring the body but may, under certain conditions, also have health damaging consequences. Two different psychoneuroendocrine stress systems are of particular interest: (1) the sympathetic adrenal medullary (SAM) and (2) the hypothalamic pituitary adrenocortical (HPA) systems. Sustained activation of the SAM system with overexposure to epinephrine (adrenaline) and norepinephrine (noradrenaline) is considered to contribute to the development of cardiovascular disease (CVD). Chronic stress exposure influencing the HPA-axis is associated with metabolic changes which also increase the risk of CVD but, in addition, also contribute to impaired immune function, diabetes, depressive symptoms and cognitive disturbances. The present paper is focused on the possible biological pathways between environmental stress and somatic illness, including the role of environmental stress for the development of musculoskeletal disorders. It is concluded that the SAM and the HPA systems play an important role in linking environmental stress to various negative health outcomes and that knowledge about these psychobiological pathways is of considerable importance for the possibilities to prevent and treat environmentally induced ill health

• McEwen BS, Seeman T. (1999) Protective and damaging effects of mediators of stress. Elaborating and testing the concepts of allostasis and allostatic load.] Ann N Y Acad Sci 896:30-47.

• Abstract: Stress is a condition of human existence and a factor in the expression of disease. A broader view of stress is that it is not just the dramatic stressful events that exact their toll but rather the many events of daily life that elevate activities of physiological systems to cause some measure of wear and tear. We call this wear and tear "allostatic load," and it reflects not only the impact of life experiences but also of genetic load; individual habits reflecting items such as diet, exercise, and substance abuse; and developmental experiences that set life-long patterns of behavior and physiological reactivity (see McEwen). Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation, but in the long run allostatic load causes changes in the body that lead to disease. This will be illustrated for the immune system and brain. Among the most potent of stressors are those arising from competitive interactions between animals of the same species, leading to the formation of dominance hierarchies. Psychosocial stress of this type not only impairs cognitive function of lower ranking animals, but it can also promote disease (e.g. atherosclerosis) among those vying for the dominant position. Social ordering in human society is also associated with gradients of disease, with an increasing frequency of mortality and morbidity as one descends the scale of socioeconomic status that reflects both income and education. Although the causes of these gradients of health are very complex, they are likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources and negative life events and the allostatic load that this burden places on the physiological systems involved in coping and adaptation

• Schulkin J. (1999) Corticotropin-releasing hormone signals adversity in both the placenta and the brain: regulation by glucocorticoids and allostatic overload.] J Endocrinol 161:349-56.

• Abstract: Glucocorticoids regulate corticotropin-releasing hormone (CRH) gene expression in the placenta and the brain. In both the placenta and two extrahypothalamic sites in the brain (the amygdala and the bed nucleus of the stria terminalis), glucocorticoids elevate CRH gene expression. One functional role of the elevation of CRH by glucocorticoids may be to signal adversity. When CRH is over-expressed in the placenta, it may indicate that the pregnancy is in danger, and preterm labor may result. When CRH is over-expressed in the brains of animals, they may become more fearful. Both situations possibly reflect allostatic mechanisms and vulnerability to allostatic overload, a condition in which biological tissue may be compromised

• Singer B, Ryff CD. (1999) Hierarchies of life histories and associated health risks.] Ann N Y Acad Sci 896:96-115.

• Abstract: Widely documented inverse associations between socioeconomic standing and incident chronic disease and mortality invite explanation in terms of pathways to these outcomes. Empirical identification of pathways, or histories, requires measures that assess cumulative wear and tear on physiological systems following from psychosocial adversity and genetic predispositions. Such an assessment, allostatic load, has been shown to predict later life mortality, incident cardiovascular disease, and decline in physical and cognitive functioning. Using data from the Wisconsin Longitudinal Study (WLS), we seek precursors to allostatic load via ordered categories of cumulative adversity relative to advantage over the life course. We operationalize these histories via unfolding economic circumstances and social relationship experiences (e.g., parent-child interactions, quality of spousal ties). Findings reveal a strong direct association between the extent of adversity relative to advantage in an ordering of these histories and likelihood of high allostatic load. Importantly, resilient individuals with economic disadvantage, but compensating positive social relationship histories also show low prevalence of high allostatic load

• Steptoe A, Cropley M, Joekes K. (1999) Job strain, blood pressure and response to uncontrollable stress.] J Hypertens 17:193-200.

• Abstract: OBJECTIVE: The association between cardiovascular disease risk and job strain (high-demand, low-control work) may be mediated by heightened physiological stress responsivity. We hypothesized that high levels of job strain lead to increased cardiovascular responses to uncontrollable but not controllable stressors. Associations between job strain and blood pressure reductions after the working day (unwinding) were also assessed. DESIGN: Assessment of cardiovascular responses to standardized behavioral tasks, and ambulatory monitoring of blood pressure and heart rate during a working day and evening. PARTICIPANTS: We studied 162 school teachers (60 men, 102 women) selected from a larger survey as experiencing high or low job strain. METHODS: Blood pressure, heart rate and electrodermal responses to an externally paced (uncontrollable) task and a self-paced (controllable) task were assessed. Blood pressure was monitored using ambulatory apparatus from 0900 to 2230 h on a working day. RESULTS: The groups of subjects with high and low job strain did not differ in demographic factors, body mass or resting cardiovascular activity. Blood pressure reactions to the uncontrollable task were greater in high than low job-strain groups, but responses to the controllable task were not significantly different between groups. Systolic and diastolic blood pressure did not differ between groups over the working day, but decreased to a greater extent in the evening in subjects with low job strain. CONCLUSIONS: Job strain is associated with a heightened blood pressure response to uncontrollable but not controllable tasks. The failure of subjects with high job strain to show reduced blood pressure in the evening may be a manifestation of chronic allostatic load

• Van CE, Spiegel K. (1999) Sleep as a mediator of the relationship between socioeconomic status and health: a hypothesis.] Ann N Y Acad Sci 896:254-61.

• Abstract: This article discusses the hypothesis that the adverse impact of low socioeconomic status (SES) on health may be partly mediated by decrements in sleep duration and quality. Low SES is frequently associated with a diminished opportunity to obtain sufficient sleep or with environmental conditions that compromise sleep quality. In a recent study, we examined carbohydrate metabolism, endocrine function, and sympatho-vagal balance in young, healthy adults studied after restricting sleep to four hours per night for six nights as compared to a fully rested condition obtained by extending the bed-time period to 12 hours per night for six nights. The state of sleep debt was associated with decreased glucose tolerance, elevated evening cortisol levels, and increased sympathetic activity. The alterations in glucose tolerance and hypothalamo-pituitary-adrenal function were qualitatively and quantitatively similar to those observed in normal aging. These results indicate that sleep loss can increase the "allostatic load" and facilitate the development of chronic conditions, such as obesity, diabetes, and hypertension, which have an increased prevalence in low SES groups

• Cohen JI. (2000) Stress and mental health: a biobehavioral perspective.] Issues Ment Health Nurs 21:185-202.

• Abstract: The influence of stress on all aspects of health and the importance of understanding the complex interaction of the mind and body has increasingly become an issue of worldwide concern. This article offers an overview of the stress response, emphasizing the interdependence of the neurobiological components--neurologic, neuroendocrine, and endocrine axes--with emotional, behavioral, and cognitive responses. Common measurements of stress are presented, including instruments that assess stressors, cognitive/affective dimensions, biological systems, and allostatic load. Understanding the role of perceived stress and the relationship between biological and psychosocial dimensions of stress and mental disorders expands the potential for effective interventions by mental health nurses

• Fava GA, Sonino N. (2000) Psychosomatic medicine: emerging trends and perspectives.] Psychother Psychosom 69:184-97.

• Abstract: Developments have occurred in all aspects of psychosomatic medicine. Among factors affecting individual vulnerability to all types of disease, the following have been highlighted by recent research: recent and early life events, chronic stress and allostatic load, personality, psychological well-being, health attitudes and behavior. As to the interaction between psychological and biological factors in the course and outcome of disease, the presence of psychiatric (DSM-IV) as well as subclinical (Diagnostic Criteria for Psychosomatic Research) symptoms, illness behavior and the impact on quality of life all need to be assessed. The prevention, treatment and rehabilitation of physical illness include the consideration for psychosomatic prevention, the treatment of psychiatric morbidity and abnormal illness behavior and the use of psychotropic drugs in the medically ill. In the past 60 years, psychosomatic medicine has addressed some fundamental questions, contributing to the growth of other related disciplines, such as psychoneuroendocrinology, psychoimmunology, consultation-liaison psychiatry, behavioral medicine, health psychology and quality of life research. Psychosomatic medicine may also provide a comprehensive frame of reference for several current issues of clinical medicine (the phenomenon of somatization, the increasing occurrence of mysterious symptoms, the demand for well-being and quality of life), including its new dialogue with mind-body and alternative medicine

• Koob GF. (2000) Neurobiology of addiction. Toward the development of new therapies.] Ann N Y Acad Sci 909:170-85.

• Abstract: Drug addiction is a chronic relapsing brain disorder characterized by neurobiological changes that lead to a compulsion to take a drug with loss of control over drug intake. The hypothesis outlined here is that knowledge of the neurochemical systems involved in the transition from drug use to the compulsive use of addiction will provide the rational basis for development of pharmacotherapies for drug addiction. Much evidence has been obtained in identifying the midbrain-basal forebrain neural elements involved in the positive reinforcing effects of drugs of abuse and more recently in the neural elements involved in the negative reinforcement associated with drug addiction. Key elements for the acute reinforcing effects of drugs of abuse include a macrostructure in the basal forebrain called the extended amygdala that contains parts of the nucleus accumbens and amgydala and involves key neurotransmitters such as dopamine, opioid peptides, serotonin, GABA, and glutamate. Withdrawal from drugs of abuse is associated with subjective symptoms of negative affect, such as dysphoria, depression, irritability and anxiety, and dysregulation of brain reward systems involving some of the same neurochemical systems implicated in the acute reinforcing effects of drugs of abuse. In addition, acute withdrawal is accompanied by recruitment of the brain stress neurotransmitter system, corticotropin-releasing factor. Animal models of craving involve not only conditioning models but also models of excessive drug intake during prolonged abstinence, post-acute withdrawal, that may reflect continued dysregulation of drug reinforcement that could lead to vulnerability to relapse and represent an important focus for pharmacotherapy. Such changes have been hypothesized to involve a change in set point for drug reward that may represent an allostatic state contributing to vulnerability to relapse and re-entry into the addiction cycle. Elucidation of the specific neuropharmacological changes contributing to this prolonged functional dysregulation will be the challenge of future research on the neurobiology of drug addiction

• McEwen BS. (2000) The neurobiology of stress: from serendipity to clinical relevance.] Brain Res 886:172-89.

• Abstract: The hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive effects in the short run and yet can accelerate pathophysiology when they are over-produced or mismanaged. Here we consider the protective and damaging effects of these mediators as they relate to the immune system and brain. 'Stress' is a principle focus, but this term is rather imprecise. Therefore, the article begins by noting two new terms, allostasis and allostatic load that are intended to supplement and clarify the meanings of 'stress' and 'homeostasis'. For the immune system, acute stress enhances immune function whereas chronic stress suppresses it. These effects can be beneficial for some types of immune responses and deleterious for others. A key mechanism involves the stress-hormone dependent translocation of immune cells in the blood to tissues and organs where an immune defense is needed. For the brain, acute stress enhances the memory of events that are potentially threatening to the organism. Chronic stress, on the other hand, causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as well as functional changes, involving the suppression of ongoing neurogenesis in the dentate gyrus and remodelling of dendrites in the Ammon's horn. Under extreme conditions only does permanent damage ensue. Adrenal steroids tell only part of the story as far as how the brain adapts, or shows damage, and local tissue modulators - cytokines for the immune response and excitatory amino acid neurotransmitters for the hippocampus. Moreover, comparison of the effects of experimenter-applied stressors and psychosocial stressors show that what animals do to each other is often more potent than what experimenters do to them. And yet, even then, the brain is resilient and capable of adaptive plasticity. Stress-induced structural changes in brain regions such as the hippocampus have clinical ramifications for disorders such as depression, post-traumatic stress disorder and individual differences in the aging process

• McEwen BS. (2000) Excessive ethanol drinking following a history of dependence: animal model of allostasis. Neuropsychopharmacology 22:581-94.

• Abstract: Alcohol withdrawal symptoms, particularly negative emotional states, can persist for months following the removal of alcohol. These protracted withdrawal symptoms have been implicated as an important trigger of relapse to excessive drinking in alcoholics and may represent a long lasting shift in affective tone as a result of chronic alcohol exposure. It was shown previously that ethanol-dependent rats increased their operant responding for ethanol when tested during the first 12 hr after withdrawal. The purpose of the present experiments was to determine the persistence of this finding by examining operant oral ethanol self-administration in rats with a history of physical dependence upon ethanol, detoxified and then allowed a two week period of protracted abstinence. The results of these experiments indicate that operant responding for ethanol was enhanced during protracted abstinence by 30-100% and remained elevated for 4-8 weeks post acute withdrawal. These results have important implications for understanding the characteristics and mechanisms underlying vulnerability to relapse

• Sluiter JK, Frings-Dresen MH, van der Beek AJ, Meijman TF, Heisterkamp SH. (2000) Neuroendocrine reactivity and recovery from work with different physical and mental demands.] Scand J Work Environ Health 26:306-16.

• Abstract: OBJECTIVES: The purpose of this study was to examine the extent to which the type or nature (physical, mental or mixed mental and physical) of work and work characteristics is related to the course of neuroendocrine reactivity and recovery from work. METHODS: Neuroendocrine reactivity and recovery were studied by measuring the urinary excretion of adrenaline, noradrenaline, and cortisol during and after 3 workdays, 1 consecutive day off, and a baseline day. The assessment was made in 3 groups of Dutch male workers (N=60) who differed in the nature (mental, physical, and combined mental and physical demands) of their work. Multilevel analyses were performed to fit linear mixed-effects models for each hormone. RESULTS: Main or interaction effects with time of day were found between the workers in combined mental and physical work and the 2 other groups of workers for cortisol, adrenaline, and noradrenaline excretion. In addition, the baseline levels of the 3 hormones were higher in the workers with combined mental and physical work when compared with the other 2 groups. The excretion rates during the workdays were higher than those on the day off, but a trend towards mobilizing less activity was found from the 1st to the 3rd workday. Job demands were negatively related to cortisol excretion. Job control and social demands at work did not affect the excretion rates of the hormones. CONCLUSIONS: Unfavorable effects on cortisol and adrenaline reactivity or recovery was found for workers with combined mental and physical demands when compared with workers doing mainly mental or mainly physical work. The results of the present study are in accordance with the cognitive activation theory and the allostatic load model

• Wust S, Wolf J, Hellhammer DH, Federenko I, Schommer N, Kirschbaum C. (2000) The cortisol awakening response - normal values and confounds.] Noise Health 2:79-88.

• Abstract: In several recent investigations it could be demonstrated that the free cortisol response to awakening can serve as an useful index of the adrenocortical activity. When measured with strict reference to the time of awakening the assessment of this endocrine response is able to uncover subtle changes in hypothalamus-pituitary-adrenal (HPA) axis activity, which are, for instance, related to persisting pain, burnout and chronic stress. Furthermore, it has been suggested that the HPA axis might serve as an indicator of allostatic load in subjects exposed to prolonged environmental noise. In the present paper four separate studies with a total of 509 adult subjects were combined in order to provide reliable information on normal values for the free cortisol response to awakening. Corresponding with earlier findings, a mean cortisol increase of about 50% within the first 30 minutes after awakening was observed. The intraindividual stability over time was shown to be remarkably high with correlations up to r=.63 (for the area under the response curve). Furthermore, the cortisol rise after awakening is rather consistent, with responder rates of about 75%. Gender significantly influenced early morning free cortisol levels. Although women showed a virtually identical cortisol increase after awakening compared to men, a significantly delayed decrease was observed. Confirming and extending previous findings, the present study strongly suggests that neither age, nor the use of oral contraceptives, habitual smoking, time of awakening, sleep duration or using / not using an alarm clock have a considerable impact on free cortisol levels after awakening. The cortisol awakening response can be assessed under a wide variety of clinical and field settings, since it is non-invasive, inexpensive and easy-to-employ. The present data provide normal values and information on potential confounds which should facilitate investigations into the endocrine consequences of prolonged exposure to environmental noise

• Bjorntorp P. (2001) Do stress reactions cause abdominal obesity and comorbidities?] Obes Rev 2:73-86.

• Abstract: 'Stress' embraces the reaction to a multitude of poorly defined factors that disturb homeostasis or allostasis. In this overview, the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system have been utilized as objective measurements of stress reactions. Although long-term activation of the sympathetic nervous system is followed by primary hypertension, consequences of similar activation of the HPA axis have not been clearly defined. The focus of this overview is to examine whether or not repeated activation of these two stress centres may be involved in the pathogenesis of abdominal obesity and its comorbidities. In population studies adrenal hormones show strong statistical associations to centralization of body fat as well as to obesity. There is considerable evidence from clinical to cellular and molecular studies that elevated cortisol, particularly when combined with secondary inhibition of sex steroids and growth hormone secretions, is causing accumulation of fat in visceral adipose tissues as well as metabolic abnormalities (The Metabolic Syndrome). Hypertension is probably due to a parallel activation of the central sympathetic nervous system. Depression and 'the small baby syndrome' as well as stress exposure in men and non-human primates are followed with time by similar central and peripheral abnormalities. Glucocorticoid exposure is also followed by increased food intake and 'leptin resistant' obesity, perhaps disrupting the balance between leptin and neuropeptide Y to the advantage of the latter. The consequence might be 'stress-eating', which, however, is a poorly defined entity. Factors activating the stress centres in humans include psychosocial and socioeconomic handicaps, depressive and anxiety traits, alcohol and smoking, with some differences in profile between personalities and genders. Polymorphisms have been defined in several genes associated with the cascade of events along the stress axes. Based on this evidence it is suggested that environmental, perinatal and genetic factors induce neuroendocrine perturbations followed by abdominal obesity with its associated comorbidities

• Coste SC, Murray SE, Stenzel-Poore MP. (2001) Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress.] Peptides 22:733-41.

• Abstract: This review highlights new information gained from studies using recently developed animal models that harbor specific alterations in corticotropin-releasing hormone (CRH) pathways. We discuss features of a transgenic mouse model of chronic CRH overexpression and two mouse models that lack either CRH receptor type 1 (CRH-R1) or type 2 (CRH-R2). Together these models provide new insights into the role of CRH pathways in promoting stability through adaptive changes, a process known as allostasis

• Koob GF, Le MM. (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97-129.

• Abstract: This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drug-taking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse

• McEwen BS. (2001) Plasticity of the hippocampus: adaptation to chronic stress and allostatic load.] Ann N Y Acad Sci 933:265-77.

• Abstract: The hippocampus is an important structure for declarative, spatial, and contextual memory and is implicated in the perception of chronic pain. The hippocampal formation is vulnerable to damage from seizures, ischemia, and head trauma and is particularly sensitive to the effects of adrenal glucocorticoids secreted during the diurnal rhythm and chronic stress. Adrenal steroids typically have adaptive effects in the short run, but promote pathophysiology when there is either repeated stress or dysregulation of the HPA axis. The damaging actions of glucocorticoids under such conditions have been termed "allostatic load", referring to the cost to the body of adaptation to adverse conditions. Adrenal steroids display both protective and damaging effects in the hippocampus. They biphasically modulate excitability of hippocampal neurons, and high glucocorticoid levels and severe acute stress impair declarative memory in a reversible manner. The hippocampus also displays structural plasticity, involving ongoing neurogenesis of the dentate gyrus, synaptogenesis under control of estrogens in the CA1 region, and dendritic remodeling caused by repeated stress or elevated levels of exogenous glucocorticoids in the CA3 region. In all three forms of structural plasticity, excitatory amino acids participate along with circulating steroid hormones. Glucocorticoids and stressors suppress neurogenesis in the dentate gyrus. They also potentiate the damage produced by ischemia and seizures. Moreover, the aging rat hippocampus displays elevated and prolonged levels of excitatory amino acids released during acute stress. Our working hypothesis is that structural plasticity in response to repeated stress starts out as an adaptive and protective response, but ends up as damage if the imbalance in the regulation of the key mediators is not resolved. It is likely that morphological rearrangements in the hippocampus brought on by various types of allostatic load alter the manner in which the hippocampus participates in memory functions and it is conceivable that these may also have a role in chronic pain perception

• McEwen BS. (2001) From molecules to mind. Stress, individual differences, and the social environment.] Ann N Y Acad Sci 935:42-9.

• Abstract: The social and physical environments in which we live have an enormous impact on our physiology and behavior and influence the process of adaptation, or "allostasis." Genes, early development, adult experiences, life style, and stressful life experiences all contribute to the way the body adapts to a changing environment; and these factors all help to determine the cost to the body, or "allostatic load." Studies of these processes involve the disciplines of biology and psychology, but they are incomplete without the input from other fields, such as cultural anthropology, economics, epidemiology, political science, and sociology. These fields provide a description and analysis of the social and cultural institutions and economic forces that affect individual human health. Specific examples of shared concepts and terminology are given to illustrate progress towards consilience in the study of socioeconomic determinants of health

• Seeman TE, McEwen BS, Rowe JW, Singer BH. (2001) [doi;081072698 [pii] Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging.] Proc Natl Acad Sci U S A 98:4770-5.

• Abstract: Allostatic load (AL) has been proposed as a new conceptualization of cumulative biological burden exacted on the body through attempts to adapt to life's demands. Using a multisystem summary measure of AL, we evaluated its capacity to predict four categories of health outcomes, 7 years after a baseline survey of 1,189 men and women age 70-79. Higher baseline AL scores were associated with significantly increased risk for 7-year mortality as well as declines in cognitive and physical functioning and were marginally associated with incident cardiovascular disease events, independent of standard socio-demographic characteristics and baseline health status. The summary AL measure was based on 10 parameters of biological functioning, four of which are primary mediators in the cascade from perceived challenges to downstream health outcomes. Six of the components are secondary mediators reflecting primarily components of the metabolic syndrome (syndrome X). AL was a better predictor of mortality and decline in physical functioning than either the syndrome X or primary mediator components alone. The findings support the concept of AL as a measure of cumulative biological burden

• Vermes I, Beishuizen A. (2001) The hypothalamic-pituitary-adrenal response to critical illness. Best Pract Res Clin Endocrinol Metab 15:495-511.

• Abstract: The maintenance of life depends on the capacity of the organism to sustain its equilibrium via allostasis'-the ability to achieve stability through change. Life-threatening disease induces acute adaptive responses specific to the stimulus and generalized responses when the disturbances are prolonged. These changes are associated with increased activity of the hypothalamic-pituitary-adrenal axis and may have survival value in preparing the body for fight or flight'. There is a shift towards an increase in glucocorticoid production and away from mineralocorticoid and androgen production, as well as an increase in the biological effects of glucocorticoids through an increased cortisol free fraction and an increased glucocorticoid receptor sensitivity. During the prolonged phase, there is a dissociation between high plasma cortisol and low adrenocorticotropin hormone levels, suggesting non-adrenocorticotropin hormone-mediated mechanisms for the regulation of the adrenal cortex. This hypercortisolism is in contrast to the very low dehydroepiandrosterone sulphate level, indicating an imbalance between the immunostimulatory and immunosuppressive adrenocortical hormones. The question is whether the total serum cortisol concentration represents sufficient glucocorticoid biological activity during the prolonged phase of critical illness

• Weiss F, Koob GF. (2001) Drug addiction: functional neurotoxicity of the brain reward systems.] Neurotox Res 3:145-56.

• Abstract: Drug addiction is a chronic relapsing brain disorder characterized by a compulsion to take a drug with loss of control over drug intake. The hypothesis under discussion here is that chronic drug use produces long-lasting dysfunctions in neurons associated with the brain reward circuitry, and this "functional neurotoxicity" of drugs of abuse leads to vulnerability to relapse and continued drug dependence. Several sources of reinforcement are associated with various components of the drug addiction cycle and much progress has been made in identifying the midbrain-basal forebrain neural elements involved in the positive reinforcing effects of drugs of abuse and more recently in the neural elements involved in the negative reinforcement associated with drug addiction. Key elements for the acute reinforcing effects of drugs of abuse include a macrostructure in the basal forebrain called the extended amygdala that contains parts of the nucleus accumbens and amygdala and involves key neurotransmitters such as dopamine, opioid peptides, serotonin, GABA, and glutamate. Withdrawal from drugs of abuse is associated with subjective symptoms of negative affect and dysregulation of brain reward systems involving some of the same neurochemical systems implicated in the acute reinforcing effects of drugs of abuse. In addition, the functional toxicity of acute withdrawal is accompanied by recruitment of the brain stress neurotransmitter system corticotrophin-releasing factor. During more prolonged abstinence, post-acute withdrawal, evidence is accumulating of continued dysregulation of the neural systems associated with drug reinforcement and stress, regulation that may represent more subtle but persistent functional neurotoxic effects of chronic drug use and could be responsible for long-lasting vulnerability to relapse. Such functional neurotoxicity could be hypothesized to lead to a change in set point for drug reward that may represent an allostatic state contributing to vulnerability to relapse and re-entry into the addiction cycle. Elucidation of the specific neuropharmacological changes contributing to this prolonged functional neurotoxicity will be the challenge of future research on the neurobiology of drug addiction

• Wolkowitz OM, Epel ES, Reus VI. (2001) Stress hormone-related psychopathology: pathophysiological and treatment implications.] World J Biol Psychiatry 2:115-43.

• Abstract: Stress is commonly associated with a variety of psychiatric conditions, including major depression, and with chronic medical conditions, including diabetes and insulin resistance. Whether stress causes these conditions is uncertain, but plausible mechanisms exist by which such effects might occur. To the extent stress-induced hormonal alterations (e.g., chronically elevated cortisol levels and lowered dehydroepiandrosterone [DHEA] levels) contribute to psychiatric and medical disease states, manipulations that normalize these hormonal aberrations should prove therapeutic. In this review, we discuss mechanisms by which hormonal imbalance (discussed in the frameworks of "allostatic load" and "anabolic balance") might contribute to illness. We then review certain clinical manifestations of such hormonal imbalances and discuss pharmacological and behavioural treatment strategies aimed at normalizing hormonal output and lessening psychiatric and physical pathology

• Ahmed SH, Kenny PJ, Koob GF, Markou A. (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5:625-6.

• Abstract: A paradoxical aspect of the transition to drug addiction is that drug users spend progressively more time and effort to obtain drug hedonic effects that continually decrease with repeated experience. According to the hedonic allostasis hypothesis, increased craving for and tolerance to the hedonic effects of drugs result from the same chronic alteration in the regulation of brain reward function (allostasis). Here we show in rats that repeated withdrawals from prolonged cocaine self-administration produces a persistent decrease in brain reward function that is highly correlated with escalation of cocaine intake and that reduces the hedonic impact of cocaine

• Carroll BJ. (2002) Ageing, stress and the brain.] Novartis Found Symp 242:26-36.

• Abstract: Ageing of the brain is an important factor in overall ageing and mortality, and new insights have clarified the relationship between neuroregulation and ageing. First, neuronal loss in normal ageing is now known to be a minor change. Loss of synapses through dystrophic neuronal change is the hallmark of normal ageing. Second, similar dystrophic changes occur in the brain with chronic stress. In both instances, forebrain sites experience loss of synaptic input from brainstem regulatory nuclei. Third, functional ageing is attributed in part to lifetime stress, under the concept of 'allostatic load'. Being inseparable from the functions of appraising and responding to stress, the brain is an ultimate mediator of stress-related mortality, through hormonal changes that lead to proximate pathologies like hypertension, glucose intolerance, cardiovascular disease and immunological impairment. In chronic stress the brain shows clear allostatic compensations that lead to pathology. Two subtle and chronic mechanisms that may mediate brain pathology and accelerated ageing in chronic stress are proposed. These are abnormal glucocorticoid receptor (GR) occupancy over the 24 h cycle, and elevated body temperature. These factors lead to GR-mediated tissue changes and to acceleration of general cellular ageing mechanisms. Human depression is discussed as an exemplary demonstration of these principles

• Goldstein DS, McEwen B. (2002) Allostasis, homeostats, and the nature of stress. Stress 5:55-8.

• Abstract: This essay continues discussion of a new formulation of homeostasis that uses the concepts of allostasis and homeostats. The new formulation moves beyond Cannon's concept of "homeostasis," which posits an ideal set of conditions for maintenance of the internal environment. The notion of allostasis recognizes that there is no single ideal set of steady-state conditions in life, and different stressors elicit different patterns of activation of the sympathetic nervous and adrenomedullary hormonal systems. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators--"homeostats." "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of a home temperature control system, the temperature can be maintained at any of a variety of levels (allostatic states) by multiple means (effectors), regulated by the thermostat (homeostat). Allostatic load and risks of system breakdown increase when, for example, the front door is left open in the winter. Applying these notions can aid in understanding how acute and chronic stress can exert adverse health consequences via allostatic load

• Karlamangla AS, Singer BH, McEwen BS, Rowe JW, Seeman TE. (2002) Allostatic load as a predictor of functional decline. MacArthur studies of successful aging.] J Clin Epidemiol 55:696-710.

• Abstract: Allostatic load has been proposed as a cumulative measure of dysregulation across multiple physiological systems, and has been postulated to impact health risks. In the allostatic load model, increased risk is hypothesized to result not only from large and clinically significant dysregulation in individual systems, but also from more modest dysregulation, if present in multiple systems. Our objective was to construct an allostatic load score by optimally combining several physiologic measurements, and to examine its association with future functional decline. We analyzed data from a 7-year longitudinal study of a community-based cohort, whose age at baseline was between 70 and 79 years. Canonical correlation analysis was used to study the association of 10 biological measurements representing allostatic load with declines in scores on five tests each of physical and cognitive function over two follow-up periods: 1998-1991 and 1991-1995. We used bootstrapping to evaluate the stability of the canonical correlation and canonical weights. The canonical correlation between allostatic load and the 20 decline scores was 0.43 (P =.03) and the [25th, 75th] percentile interval of its distribution over 200 bootstrapped subsamples of the cohort was [0.48, 0.53]. These findings were not substantially affected by adjusting for covariates and cardiovascular disease. We conclude that a summary measure of physiologic dysregulation, such as allostatic load, is an independent predictor of functional decline in elderly men and women

• McEwen BS. (2002) The neurobiology and neuroendocrinology of stress. Implications for post-traumatic stress disorder from a basic science perspective.] Psychiatr Clin North Am 25:469-94, ix.

• Abstract: Stress is a condition of the mind and a factor in the expression of disease that differs among individuals. In post-traumatic stress disorder (PTSD), traumatic events can create a long-lasting state of physiologic reactivity that amplifies and exacerbates the effects of daily life events. The elevated activities of physiologic systems lead to wear and tear, called "allostatic load." It reflects not only the impact of life experiences but also of genes, individual life-style habits (e.g., diet, exercise, and substance abuse), and developmental experiences that set life-long patterns of behavior and physiologic reactivity. Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation, but in the long run allostatic load causes changes in the body that lead to disease

• McEwen BS. (2002) Sex, stress and the hippocampus: allostasis, allostatic load and the aging process.] Neurobiol Aging 23:921-39.

• Abstract: The adaptive responses of the body that maintain homeostasis in response to stressors can be called "allostasis", meaning "achieving stability through change". Mediators produced by the immune system, autonomic nervous system (ANS) and hypothalamo-pituitary-adrenal(HPA) axis produce allostasis. The brain also shows allostasis, involving the activation of nerve cell activity and the release of neurotransmitters. When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body and brain that has been termed "allostatic load". Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus. Studies of the hippocampus as a target of stress and sex hormones have revealed a considerable degree of structural plasticity and remodeling in the adult brain that differs between the sexes. Three forms of hippocampal structural plasticity are affected by circulating hormones: (1) repeated stress causes remodeling of dendrites in the CA3 region; (2) different modalities of stress suppress neurogenesis of dentate gyrus granule neurons; (3) ovarian steroids regulate synapse formation during the estrous cycle of female rats. All three forms of structural remodeling of the hippocampus are mediated by hormones working in concert with excitatory amino acids (EAA) and NMDA receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, by ischemia and by severe and prolonged psychosocial stress. The aging brain seems to be more vulnerable to such effects, although there are considerable individual differences in vulnerability that can be developmentally determined. Moreover, the brain retains considerable resilience in the face of stress, and estrogens appear to play a role in this resilience. "Resilience is an example of successful allostasis in which wear and tear is minimized, and estrogens exemplify the type of agent that works against the allostatic load associated with aging." This review discusses the current status of work on underlying mechanisms for protection and damage

• Ryabinin AE, Bachtell RK, Heinrichs SC et al. (2002) The corticotropin-releasing factor/urocortin system and alcohol.] Alcohol Clin Exp Res 26:714-22.

• Abstract: This article represents the proceedings of a symposium at the RSA meeting in Montreal, Canada. The organizer was Andrey E. Ryabinin, and the chair was George F. Koob. The presentations were (1) Introduction, by Stephen C. Heinrichs; (2) Role of CRF and its receptors in the hypothalamic-pituitary-adrenal response to alcohol, by Soon Lee and Catherine Rivier; (3) A role for CRF in the allostasis of alcohol dependence, by George F. Koob and Amanda J. Roberts; (4) CRF and alcohol: Lessons from knockouts, microinjections, and microdialysis, by M. Foster Olive, Kristin K. Mehmert, R. Camarini, Joseph A. Kim, Heather N. Koenig, Michelle A. Nannini, and Clyde W. Hodge; and (5) Selective sensitivity of urocortin-containing neurons to alcohol self-administration, by Andrey E. Ryabinin and Ryan K. Bachtell

• Seeman TE, Singer BH, Ryff CD, Dienberg LG, Levy-Storms L. (2002) Social relationships, gender, and allostatic load across two age cohorts.] Psychosom Med 64:395-406.

• Abstract: OBJECTIVE: This article addresses the question of biological pathways through which social integration and support may affect morbidity and mortality risks. A new concept of cumulative biological risk, allostatic load, is used to test the hypothesis that social experiences affect a range of biological systems. Data from two community-based cohorts are examined to evaluate the consistency of findings across two different age groups. METHODS: One cohort included older adults aged 70 to 79 years (N = 765); the other cohort included persons aged 58 to 59 years (N = 106). Allostatic load was assessed using identical protocols in the two cohorts. Measures of social experience were similar but not identical, reflecting levels of social integration and support for the older cohort vs. childhood and adult experiences of loving/caring relationships with parents and spouse for the younger cohort. Gender-specific analyses were examined to evaluate possible gender differences in patterns of association. RESULTS: In the younger cohort, positive cumulative relationship experiences were associated with lower allostatic load for men and women. In the older cohort, men who were more socially integrated and those reporting more frequent emotional support from others had lower allostatic load scores; similar but nonsignificant associations were seen for women. CONCLUSIONS: Evidence from two cohorts provides support for the hypothesis that positive social experiences are associated with lower allostatic load. These findings are consistent with the hypothesis that social experiences affect a range of biological systems, resulting in cumulative differences in risks that in turn may affect a range of health outcomes

• Steptoe A, Feldman PJ, Kunz S, Owen N, Willemsen G, Marmot M. (2002) Stress responsivity and socioeconomic status: a mechanism for increased cardiovascular disease risk?] Eur Heart J 23:1757-63.

• Abstract: AIMS: Low socioeconomic status is associated with increased cardiovascular disease risk. We hypothesized that psychobiological pathways, specifically slow recovery in blood pressure and heart rate variability following mental stress, partly mediate social inequalities in risk. METHODS AND RESULTS: Participants were 123 men and 105 women in good health aged 47-58 years drawn from the Whitehall II cohort of British civil servants. Grade of employment was the indicator of socioeconomic status. Cardiovascular measures were monitored during performance of two behavioural tasks, and for 45 min following stress. Post-stress return of blood pressure and heart rate variability to resting levels was less complete after 45 min in the medium and low than in the high grade of employment groups. The odds of failure to return to baseline by 45 min in the low relative to the high grade of employment groups were 2.60 (95% CI 1.20-5.65) and 3.85 (1.48-10.0) for systolic and diastolic pressure, respectively, and 5.19 (1.88-18.6) for heart rate variability, adjusted for sex, age, baseline levels and reactions to tasks. Subjective ratings of task difficulty, involvement and stress did not differ by socioeconomic status. CONCLUSIONS: Lower socioeconomic status is associated with delayed recovery in cardiovascular function after mental stress. Impaired recovery may reflect heightened allostatic load, and constitute a mechanism through which low socioeconomic status enhances cardiovascular disease risk

• Tannenbaum B, Tannenbaum GS, Sudom K, Anisman H. (2002) Neurochemical and behavioral alterations elicited by a chronic intermittent stressor regimen: implications for allostatic load.] Brain Res 953:82-92.

• Abstract: Although stressors induce a series of adaptive neurochemical changes, sustained physiological activation associated with protracted stressor exposure may engender adverse effects (allostatic load). In the present investigation CD-1 mice exposed to a series of different stressors, twice a day over 54 days, exhibited increased signs of depression and anxiety, including increased passivity in a forced swim test, reduced aggression in a social interaction test, and delayed approach to food in a novel environment. Consistent with the view that a chronic stressor regimen affects immune-related processes, sickness behavior elicited by the proinflammatory cytokine, interleukin-1beta, was augmented in response to a chronic but not an acute stressor. Relative to nonstressed mice, median eminence serotonin was augmented by the cytokine treatment administered 24 h after chronic stressor exposure. Treatment with IL-1beta diminished plasma growth hormone levels and increased circulating corticosterone levels irrespective of the animals stressor history. It is suggested that chronic stressor exposure may instigate relatively protracted neurochemical effects, thereby influencing the behavioral responses to later psychological and systemic challenges

• Vanitallie TB. (2002) Stress: a risk factor for serious illness.] Metabolism 51:40-5.

• Abstract: The body's principal adaptive responses to stress stimuli are mediated by an intricate stress system, which includes the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathoadrenal system (SAS). Dysregulation of the system, caused by the cumulative burden of repetitive or chronic environmental stress challenges (allostatic load) contributes to the development of a variety of illnesses including hypertension, atherosclerosis, and the insulin-resistance-dyslipidemia syndrome, as well as certain disorders of immune function. The brain's limbic system, particularly the hippocampus and amygdala, is also intimately involved in the stress response. Chronically elevated corticosteroid levels induced by persisting stress may adversely affect hippocampal structure and function, producing deficits of both memory and cognition. The ability of stress to cause illness in humans is most clearly exemplified by post-traumatic stress disorder (PTSD), which consists of a predictable constellation of distressing behavioral symptoms and physiological features. An appreciable proportion of the observed variance in vulnerability to PTSD is attributable to genetic factors. The relationship of this disorder to its precipitating cause-a recent, severely traumatic event-is unambiguous. The neuroendocrinology of PTSD is noteworthy, being characterized in many adult victims by enhanced negative feedback sensitivity of glucocorticoid receptors in the stress response system, and lower than normal urinary and plasma cortisol levels. Adult patients with PTSD also have been shown to exhibit exaggerated catecholamine responses to trauma-related stimuli. On the other hand, severely maltreated prepubertal children with PTSD continue to excrete greater than normal urinary cortisol, catecholamines, and dopamine years after disclosure of the causative abuse

• Crimmins EM, Johnston M, Hayward M, Seeman T. (2003) Age differences in allostatic load: an index of physiological dysregulation.] Exp Gerontol 38:731-4.

• Abstract: This preliminary report examines variation in allostatic load by age for a large nationally representative population of the United States. It uses data on 13 indicators of physiologic dysregulation from a nationally representative sample of the US population 20 years of age and over. Allostatic load is remarkably constant in the older ages after increasing sharply in the years from 20 to 60. We hypothesize that this represents mortality selectivity of the population by physiological status

• Evans GW. (2003) A multimethodological analysis of cumulative risk and allostatic load among rural children.] Dev Psychol 39:924-33.

• Abstract: This study merged two theoretical constructs: cumulative risk and allostatic load. Physical (crowding, noise, housing quality) and psychosocial (child separation, turmoil, violence) aspects of the home environment and personal characteristics (poverty, single parenthood, maternal highschool dropout status) were modeled in a cumulative risk heuristic. Elevated cumulative risk was associated with heightened cardiovascular and neuroendocrine parameters, increased deposition of body fat, and a higher summary index of total allostatic load. Previous findings that children who face more cumulative risk have greater psychological distress were replicated among a sample of rural children and shown to generalize to lower perceptions of self-worth. Prior cumulative risk research was further extended through demonstration of self-regulatory behavior problems and elevated learned helplessness

• Gold SM, Zakowski SG, Valdimarsdottir HB, Bovbjerg DH. (2003) Stronger endocrine responses after brief psychological stress in women at familial risk of breast cancer.] Psychoneuroendocrinology 28:584-93.

• Abstract: Recent research has linked exposure to chronic stress to altered acute stress responses and suggests a sensitizing effect of chronic stress leading to a stronger endocrine and cardiovascular response to acute stressors. Substantial evidence indicates that familial breast cancer risk is a chronic life stressor with higher levels of self reported distress. In this study, we investigated whether the endocrine response to a brief psychological stressor was stronger for women at familial risk for breast cancer. Thirty-six women at normal risk of breast cancer (FR- Stress Group) and 17 women at familial risk (FR+ Stress Group) underwent a brief psychological laboratory stress test (speech task and mental arithmetic) over a 15 min period. Thirty women at normal risk not subjected to the stressful task served as controls (FR- Control Group). Plasma epinephrine, norepinephrine and cortisol were measured at baseline, directly after the stress test (15 min) and at 30 min and 45 min post baseline. Heart rate data confirmed the effectiveness of the stress regimen. While there were no significant baseline group differences in the endocrine parameters, the response curves for the familial risk group revealed stronger epinephrine and cortisol reactivity to the stress test, as confirmed by significant group by time interactions. Norepinephrine levels showed a similar pattern, but results did not reach significance. These findings are in line with previous research documenting the facilitating effects of chronic stressors on acute stress response in animals and humans and provide the first evidence in the literature of a heightened endocrine reactivity to acute psychological stress in women at familial risk of breast cancer. The heightened endocrine reactivity to the experimental tasks seen here suggests that these women may experience stronger responses to stressors in their daily lives. According to the recently proposed concept of allostatic load, repeated overly strong stress responses may cumulatively have negative health implications

• Kario K, McEwen BS, Pickering TG. (2003) Disasters and the heart: a review of the effects of earthquake-induced stress on cardiovascular disease.] Hypertens Res 26:355-67.

• Abstract: There is growing evidence that stress contributes to cardiovascular disease. Chronic stress contributes to the atherosclerotic process through increased allostatic load, which is mediated by the neuroendocrine and immune systems (sympathetic nervous system and hypothalamus-pituitary adrenal axis) and related chronic risk factors (insulin resistance syndrome, hypertension, diabetes, and hyperlipidemia). In addition, acute stress can trigger cardiovascular events predominantly through sympathetic nervous activation and potentiation of acute risk factors (blood pressure increase, endothelial cell dysfunction, increased blood viscosity, and platelet and hemostatic activation). Earthquakes provide a good example of naturally occurring acute and chronic stress, and in this review we focus mainly on the effects of the Hanshin-Awaji earthquake on the cardiovascular system. The Hanshin-Awaji earthquake resulted in a 3-fold increase of myocardial infarctions in people living close to the epicenter, particularly in women, with most of the increase occurring in nighttime-onset events. There was also a near doubling in the frequency of strokes. These effects may be mediated by changes in hemostatic factors, as demonstrated by an increase of D-dimer, von Willebrand factor, and tissue-type plasminogen activator (tPA) antigen. Blood pressure also increased after the earthquake, and was prolonged for several weeks in patients with microalbuminuria

• Koob GF. (2003) Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232-43.

• Abstract: Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition

• Koob GF. (2003) Neuroadaptive mechanisms of addiction: studies on the extended amygdala.] Eur Neuropsychopharmacol 13:442-52.

• Abstract: A conceptual structure for drug addiction focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic neuroadaptive mechanisms involved in the development of drug addiction. The brain reward system implicated in the development of addiction is comprised of key elements of a basal forebrain macrostructure termed the extended amygdala and its connections. Neuropharmacologic studies in animal models of addiction have provided evidence for the dysregulation of specific neurochemical mechanisms not only in specific brain reward circuits (opioid peptides, gamma-aminobutyric acid, glutamate and dopamine) but also recruitment of brain stress systems (corticotropin-releasing factor) that provide the negative motivational state that drives addiction, and also are localized in the extended amygdala. The changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for development of dependence and relapse in addiction

• Korte SM, De Boer SF. (2003) A robust animal model of state anxiety: fear-potentiated behaviour in the elevated plus-maze.] Eur J Pharmacol 463:163-75.

• Abstract: Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed

• McEwen B, Lasley EN. (2003) Allostatic load: when protection gives way to damage.] Adv Mind Body Med 19:28-33.
• McEwen BS. (2003) Mood disorders and allostatic load.] Biol Psychiatry 54:200-7.

• Abstract: The brain controls both the physiologic and the behavioral coping responses to daily events as well as major stressors, and the nervous system is itself a target of the mediators of those responses through circulating hormones. The amygdala and hippocampus interpret what is stressful and regulate appropriate responses. The amygdala becomes hyperactive in posttraumatic stress disorder (PTSD) and depressive illness, and hypertrophy of amygdala nerve cells is reported after repeated stress in an animal model. The hippocampus expresses adrenal steroid receptors. It undergoes atrophy in several psychiatric disorders and responds to repeated stressors with decreased dendritic branching and reduction in number of neurons in the dentate gyrus. Stress promotes adaptation ("allostasis"), but a perturbed diurnal rhythm or failed shutoff of mediators after stress ("allostatic state") leads, over time, to wear and tear on the body ("allostatic load"). Neural changes mirror the pattern seen in the cardiovascular, metabolic, and immune systems, that is, short-term adaptation versus long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in brain. Allostatic load is seen in major depressive illness and may also be expressed in other chronic anxiety disorders such as PTSD and should be documented

• McEwen BS, Wingfield JC. (2003) The concept of allostasis in biology and biomedicine.] Horm Behav 43:2-15.

• Abstract: Living organisms have regular patterns and routines that involve obtaining food and carrying out life history stages such as breeding, migrating, molting, and hibernating. The acquisition, utilization, and storage of energy reserves (and other resources) are critical to lifetime reproductive success. There are also responses to predictable changes, e.g., seasonal, and unpredictable challenges, i.e., storms and natural disasters. Social organization in many populations provides advantages through cooperation in providing basic necessities and beneficial social support. But there are disadvantages owing to conflict in social hierarchies and competition for resources. Here we discuss the concept of allostasis, maintaining stability through change, as a fundamental process through which organisms actively adjust to both predictable and unpredictable events. Allostatic load refers to the cumulative cost to the body of allostasis, with allostatic overload being a state in which serious pathophysiology can occur. Using the balance between energy input and expenditure as the basis for applying the concept of allostasis, we propose two types of allostatic overload. Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in activation of the emergency life history stage. This serves to direct the animal away from normal life history stages into a survival mode that decreases allostatic load and regains positive energy balance. The normal life cycle can be resumed when the perturbation passes. Type 2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction. The latter is the case in human society and certain situations affecting animals in captivity. In all cases, secretion of glucocorticosteroids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters, and inflammatory cytokines wax and wane with allostatic load. If allostatic load is chronically high, then pathologies develop. Type 2 allostatic overload does not trigger an escape response, and can only be counteracted through learning and changes in the social structure

• McEwen BS. (2003) Interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging.] Metabolism 52:10-6.

• Abstract: Individual differences in the aging process can be conceptualized as an accumulation of wear and tear of daily experiences and major life stressors that interact with the genetic constitution and predisposing early life experiences. The neuroendocrine system, autonomic nervous system, and immune system are mediators of adaptation to challenges of daily life, referred to as allostasis, meaning "maintaining stability through change." Physiological mediators such as adrenalin from the adrenal medulla, glucocorticoids from the adrenal cortex, and cytokines from cells of the immune system act upon receptors in various tissues and organs to produce effects that are adaptive in the short run but can be damaging if the mediators are not shut off when no longer needed. When release of the mediators is not efficiently terminated, their effects on target cells are prolonged, leading to other consequences that may include receptor desensitization and tissue damage. This process has been named "allostatic load," and it refers to the price the tissue or organ pays for an overactive or inefficiently managed allostatic response. Therefore, allostatic load refers to the "cost" of adaptation. This article discusses the mediators of allostasis and their contributions to allostatic load as well as their role in resilience of the aging organism to stressful experiences

• McEwen BS. (2003) Early life influences on life-long patterns of behavior and health. Ment Retard Dev Disabil Res Rev 9:149-54.

• Abstract: The stability of a child's early life has profound effects on physical and mental health, and unstable parent-child relationships, as well as abuse, can lead to behavioral disorders and increased mortality and morbidity from a wide variety of common diseases later in life. One common consequence, namely, depressive illness, is associated with chemical imbalances in the brain and hormonal dysregulation, constituting a form of allostatic load that alters interpretations of stimuli and influences, behavioral, and hormonal responses to potentially stressful situations. The brain not only encodes information and controls the behavioral responses but it is also changed structurally by those experiences. Structural changes in the hippocampus and amygdala, which are important brain structures for cognition and emotion, are representative of what may be occurring throughout the brain as a result of allostatic load resulting from the chronic stress of a disorder such as depression. Such structural changes include dendritic debranching and hypertrophy, cell proliferation, and synaptic remodeling; they are produced by the combined overactivity of stress hormones and endogenous neurotransmitters. These mediators are normally involved in adaptation, but can also promote damage when they are dysregulated and over-active. They are very likely to be strongly biased by early life experiences. The findings from animal models thus provide a basis for understanding potential mechanisms of environmental and developmental determinants of individual differences in human stress reactivity, as well as anxiety, depression, and a host of related systemic disorders. There is an increasing amount of translational research that is beginning to tie the basic research to clinical outcomes of individuals exposed to abusive or inconsistent care-giving in early life. A major goal of studies on this important topic is to define times in development and strategies for intervening to prevent or reverse the effects of adverse early life experiences. Although prevention is clearly the preferable route, some degree of reversal of psychopathology and pathophysiology caused by early life adversity appears to be an achievable goal

• Schnorpfeil P, Noll A, Schulze R, Ehlert U, Frey K, Fischer JE. (2003) Allostatic load and work conditions.] Soc Sci Med 57:647-56.

• Abstract: Adverse work characteristics and poor social support have been associated with an increased risk for cardiovascular disease and other adverse health outcomes in otherwise apparently healthy adults. We undertook a cross-sectional study to evaluate the relationship between objective health status and work characteristics in industrial workers in Germany. Volunteers (n=324) were recruited from a representative random sample (n=537) of employees of an airplane manufacturing plant. Psychosocial work characteristics were assessed by the 52-item, 13-subscale salutogenetic subjective work analysis (SALSA) questionnaire, which assesses potentially salutogenic and pathogenic conditions. Factor analysis revealed three factors: decision latitude, job demands and social support. Biological health status was determined by the revised allostatic load score with 14 components: body-mass index, waist-to-hip ratio; systolic and diastolic blood pressure; plasma levels of C-reactive protein (CRP), tumor-necrosis factor-alpha, HDL, cholesterol, dehydroepiandrosterone sulfate; glycosylated hemoglobin; urinary cortisol, epinephrine, norepinephrine, and albumin. Score points were given for values in the high-risk quartile (maximum=14). General linear models revealed that older individuals and men had significantly higher allostatic load scores than younger participants or women. Of the SALSA factors, only job demands related significantly to allostatic load. The effect of demands was stronger in older individuals. Post-hoc analysis showed possible positive associations between high job demands and blood pressure or CRP, and between low social support and nocturnal excretion of cortisol or plasma levels of CRP. We conclude that this cross-sectional study on industrial employees found a weak association between a health summary score based on objective medical data and self-reported adverse work characteristics

• Schulkin J. (2003) Allostasis: a neural behavioral perspective.] Horm Behav 43:21-7.
• Stumvoll M, Tataranni PA, Stefan N, Vozarova B, Bogardus C. (2003) Glucose allostasis.] Diabetes 52:903-9.

• Abstract: In many organisms, normoglycemia is achieved by a tight coupling of nutrient-stimulated insulin secretion in the pancreatic beta-cell (acute insulin response [AIR]) and the metabolic action of insulin to stimulate glucose disposal (insulin action [M]). It is widely accepted that in healthy individuals with normal glucose tolerance, normoglycemia can always be maintained by compensatorily increasing AIR in response to decreasing M (and vice versa). This has been mathematically described by the hyperbolic relationship between AIR and M and referred to as glucose homeostasis, with glucose concentration assumed to remain constant along the hyperbola. Conceivably, glucose is one of the signals stimulating AIR in response to decreasing M. Hypothetically, as with any normally functioning feed-forward system, AIR should not fully compensate for worsening M, since this would remove the stimulus for the compensation. We provide evidence from cross-sectional, longitudinal, and prospective data from Pima Indians (n = 413) and Caucasians (n = 60) that fasting and postprandial glucose concentrations increase with decreasing M despite normal compensation of AIR. For this physiologic adaptation to chronic stress (insulin resistance), we propose to use the term "glucose allostasis." Allostasis (stability through change) ensures the continued homeostatic response (stability through staying the same) to acute stress at some cumulative costs to the system. With increasing severity and over time, the allostatic load (increase in glycemia) may have pathological consequences, such as the development of type 2 diabetes

• von KR, Dimsdale JE, Patterson TL, Grant I. (2003) Acute procoagulant stress response as a dynamic measure of allostatic load in Alzheimer caregivers.] Ann Behav Med 26:42-8.

• Abstract: Allostasis designates processes of bodily adaptation to stressful challenges, whereas allostatic load means the costs of wear and tear to the body as a consequence of inefficient allostasis. In distressed dementia caregivers, an acute procoagulant stress response might be one dynamic mediator of allostatic load relevant to cardiovascular endpoints. An interviewer assessed the number of negative life-events independent from caregiving over 4 weeks in 37 spousal Alzheimer caregivers (M age +/- SD = 72 +/- 6 years). Baseline procoagulability scores and procoagulability scores in response to a 15-min speech task included plasma thrombin/antithrombin III complex, D-dimer, von Willebrand factor, tissue-type plasminogen activator, and plasminogen activator inhibitor 1 levels. Allostatic load was defined as the difference in procoagulability scores from baseline to speech, using standardized (z-score) transformations. Speech stress significantly increased heart rate (p =.017), systolic blood pressure (p =.002), and diastolic blood pressure (p <.001). The number of negative life-events (M +/- SD 2.8 +/- 2.0) correlated with allostatic load (r =.367, p =.026). After controlling for age and smoking, which together explained 32% of the variance in the allostatic load (R2 =.324), F(2, 34) = 8.14, p =.001, the number of negative life-events accounted for an additional 13% of that variance (Delta R2=.125), Delta F(1, 33) = 7.49, p =.010. The finding is compatible with the concept of allostasis and allostatic load, suggesting that higher combined caregiving and life distress levels are associated with more dysfunctional hemostatic responses to acute mental stress. The acute procoagulant stress response might constitute a dynamic mediator of allostatic load in Alzheimer caregivers

• Weinstein M, Goldman N, Hedley A, Yu-Hsuan L, Seeman T. (2003) Social linkages to biological markers of health among the elderly.] J Biosoc Sci 35:433-53.

• Abstract: The social environment and exposure to life challenge affect a person's physical and emotional well-being. The present research uses a population-based study of the elderly in Taiwan to elaborate the cumulative physiological costs--as reflected in biological markers of risk factors known to have adverse consequences for health--of challenge and unfavourable position in social hierarchies and networks. Overall, biological markers of risk among the elderly are similar in Taiwan and the United States. However, male and female Taiwanese elderly are at lower risk for illness associated with indicators of DHEA-S, while women are at higher risk for illness associated with elevated blood pressure, and men at lower risk for illness associated with total/HDL cholesterol, and glycosylated haemoglobin. There are strong and statistically significant effects of position in social hierarchy (education) and challenge (recent widowhood and a perception of high demands) on an index of cumulative risk (allostatic load). Membership in social networks and participation in social activities have expected, but not statistically discernible, effects

• Angeli A, Minetto M, Dovio A, Paccotti P. (2004) The overtraining syndrome in athletes: a stress-related disorder.] J Endocrinol Invest 27:603-12.

• Abstract: Physical exercise is a type of allostatic load for several endocrine systems, notably the hypothalamic-pituitary-adrenal (HPA) axis. Athletes undergoing a strenuous training schedule can develop a significant decrease in performance associated with systemic symptoms or signs: the overtraining syndrome (OTS). This is a stress-related condition that consists of alteration of physiological functions and adaptation to performance, impairment of psychological processing, immunological dysfunction and biochemical abnormalities. Universally agreed diagnostic criteria for OTS are lacking. The pituitary-adrenal response to a standardized exercise test is usually reduced in overtrained athletes. This HPA dysfunction could reflect the exhaustion stage of Selye's general adaptation syndrome. The most attractive hypothesis that accounts for the observed neuro-endocrine-immune dysregulation is the Smith's cytokine hypothesis of OTS. It assumes that physical training can produce muscle and skeletal trauma, thus generating a local inflammatory reaction. With the excessive repetition of the training stimulus the local inflammation can generate a systemic inflammatory response. The main actors of these processes are the cytokines, polypeptides that modulate HPA function in and outside the brain at nearly every level of activity. It is hoped that future research will focus on endogenous risk factors for morbidities related to the neuro-endocrine-immune adaptation to exercise

• Bay E, Kirsch N, Gillespie B. (2004) Chronic stress conditions do explain posttraumatic brain injury depression.] Res Theory Nurs Pract 18:213-28.

• Abstract: Psychosocial and biologic mechanisms are implicated in depression after traumatic brain injury (TBI). Using McEwen's stress theory of allostasis as a guidepost, this study examined whether pre- and postinjury chronic stress conditions could explain post-TBI depressive symptoms. Seventy-five community-dwelling persons who sustained a mild-to-moderate TBI and were within 2 years of the injury participated in this cross-sectional study. The participants completed measures of chronic stress and depression, measured with the Neurobehavioral Functioning Inventory. Data were collected also on brain injury severity. Using multiple regression analysis, the frequency of childhood adversities and postinjury stress explained post-TBI depression. When time-since-injury was in the regression model, the frequency of preinjury stressors and postinjury stress significantly explained post-TBI depressive symptoms while the combined effect of childhood adversity with postinjury stress was not significant in explaining depressive symptoms. Pre- and postinjury chronic stress explained post-TBI depressive symptoms. These findings support stress-diathesis theory within the psychiatric literature and a linkage between chronic stress, an indicator of allostatic load, and post-TBI depression. These findings are important for nurse specialists working with persons who sustained brain injury, for chronic stress can be buffered by efficient and effective support systems

• Hellhammer J, Schlotz W, Stone AA, Pirke KM, Hellhammer D. (2004) [doi Allostatic load, perceived stress, and health: a prospective study in two age groups.] Ann N Y Acad Sci 1032:8-13.

• Abstract: Overactivity of the hypothalamus-pituitary-adrenal axis (HPAA) has been observed in the presence of acute stress and, under chronic conditions, in disorders such as depression and anorexia nervosa as well as in cardiovascular and metabolic disorders. However, there may be other stress-related disorders (fatigue, pain, etc) that seem to be associated with mild hypocortisolism. This suggests that two major subtypes of the HPAA response to stress need to be discriminated. In this study, we investigated 76 subjects with and without hypocortisolism, respectively, over a 1-year period. Surprisingly, hypocortisolemic subjects had a lower allostatic load but they scored higher on measures of depression, perceived stress, and physical complaints. We propose a protective role of the hypocortisolemic stress response on cardiovascular and metabolic disorders, particularly in the elderly

• Koob GF. (2004) Allostatic view of motivation: implications for psychopathology.] Nebr Symp Motiv 50:1-18.
• Kopp MS, Rethelyi J. (2004) Where psychology meets physiology: chronic stress and premature mortality--the Central-Eastern European health paradox. Brain Res Bull 62:351-67.

• Abstract: A substantial and still growing body of research tries to link different psychological models and chronic diseases, with special emphasis on cardiovascular disease. These efforts have established several conceptual bridges that connect psychological alterations and psychosocial factors to the risks, onset and prognosis of cardiovascular disease. However, several different models have been suggested. Depression and learned helplessness are two central psychological models that have been shown to have major explanatory power in the development of chronic diseases. In this respect the so called Central-Eastern European health paradox, that is the morbidity and mortality crisis in these transforming societies can be regarded as a special experimental model. In this review chronic stress is proposed as an integrating theory that can be applied to different psychological models. Chronic stress and allostatic load has been shown to lead to typical pathogenetic results in animal experiments. Chronic stress theory is applicable to the explanation of the suddenly changing patterns of premature mortality rates in transforming societies. Literature and the different models in the field of psychology, behavioural sciences, and epidemiology are reviewed in terms of the chronic stress theory. The applicability of these results are investigated for further research, clinical and policy implications

• McEwen BS. (2004) Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci 1032:1-7.

• Abstract: Stress promotes adaptation, but prolonged stress leads over time to wear-and-tear on the body (allostatic load). Neural changes mirror the pattern seen in other body systems, that is, short-term adaptation vs. long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in the brain. Many of these processes are seen in major depressive illness and may be expressed also in other chronic anxiety disorders. The brain controls the physiological and behavioral coping responses to daily events and stressors. The hippocampal formation expresses high levels of adrenal steroid receptors and is a malleable brain structure that is important for certain types of learning and memory. It is also vulnerable to the effects of stress and trauma. The amygdala mediates physiological and behavioral responses associated with fear. The prefrontal cortex plays an important role in working memory and executive function and is also involved in extinction of learning. All three regions are targets of stress hormones. In animal models, neurons in the hippocampus and prefrontal cortex respond to repeated stress by showing atrophy, whereas neurons in amygdala show a growth response. Yet, these are not necessarily "damaged" and may be treatable with the right medications

• Seeman T, Glei D, Goldman N, Weinstein M, Singer B, Lin YH. (2004) Social relationships and allostatic load in Taiwanese elderly and near elderly. Soc Sci Med 59:2245-57.

• Abstract: Despite the increasing evidence linking aspects of the social environment to a range of health outcomes, important questions remain concerning the precise mechanisms or pathways through which social circumstances exert their influence. Biological pathways are one important area of current research interest. Using data from the Social Environment and Biomarkers of Aging Study (SEBAS) in Taiwan, we examined relationships between social environment characteristics and an index of cumulative biological dysregulation ("allostatic load," AL) in near elderly (NE) (aged 54-70) and elderly Taiwanese (aged 71+). Longitudinal data on levels of social integration and extent of social support were used to predict cumulative AL at the final survey year. Linear regression analyses revealed that among the NE, presence of a spouse between 1996 and 2000 was associated with lower AL in 2000 among men, but not women. Among the elderly, ties with close friends and/or neighbors were found to be significantly related to lower AL for both men and women. Perceived qualities of these social relationships did not show consistent associations with AL. This relatively modest set of significant relationships stands in contrast to somewhat stronger patterns of findings from studies in Western societies. Cross-cultural differences between Western societies and an East Asian society such as Taiwan raise the intriguing possibility that contextual, normative influences on social experience affect the patterns of association between features of these social worlds and the physiological substrates of health

• Seeman TE, Crimmins E, Huang MH et al. (2004) Cumulative biological risk and socio-economic differences in mortality: MacArthur studies of successful aging. Soc Sci Med 58:1985-97.

• Abstract: Previous research has suggested that socio-economic status (SES) differences in mortality are only partially explained by differences in life-style, psychological and social factors. Seven year mortality data (1988-1995) from the MacArthur Study of Successful Aging, a longitudinal study of adults, aged 70-79, from New Haven, CT; East Boston, MA; and Durham, NC; were used to test the hypothesis that a cumulative measure of biological dysregulation ("allostatic load"), reflecting multiple regulatory systems, would serve as a further mediator of SES differences in mortality. Logistic regression analyses revealed that a cumulative index of biological risk explained 35.4% of the difference in mortality risk between those with higher versus lower SES (as measured by less than high school education versus high school or greater educational attainment). Importantly, the cumulative index provided independent explanatory power, over and above a measure of doctor-diagnosed disease, though the latter also contributed to education-related variation in mortality risks. The summary measure of biological risk also accounted for more variance than individual biological parameters, suggesting the potential value of a multi-systems view of biological pathways through which SES ultimately affects morbidity and mortality

• Stumvoll M, Tataranni PA, Bogardus C. (2004) The role of glucose allostasis in type 2 diabetes. Rev Endocr Metab Disord 5:99-103.
• Ursin H, Eriksen HR. (2004) The cognitive activation theory of stress. Psychoneuroendocrinology 29:567-92.

• Abstract: This paper presents a cognitive activation theory of stress (CATS), with a formal system of systematic definitions. The term "stress" is used for four aspects of "stress", stress stimuli, stress experience, the non-specific, general stress response, and experience of the stress response. These four meanings may be measured separately. The stress response is a general alarm in a homeostatic system, producing general and unspecific neurophysiological activation from one level of arousal to more arousal. The stress response occurs whenever there is something missing, for instance a homeostatic imbalance, or a threat to homeostasis and life of the organism. Formally, the alarm occurs when there is a discrepancy between what should be and what is-between the value a variable should have (set value (SV)), and the real value (actual value (AV)) of the same variable. The stress response, therefore, is an essential and necessary physiological response. The unpleasantness of the alarm is no health threat. However, if sustained, the response may lead to illness and disease through established pathophysiological processes ("allostatic load"). The alarm elicits specific behaviors to cope with the situation. The level of alarm depends on expectancy of the outcome of stimuli and the specific responses available for coping. Psychological defense is defined as a distortion of stimulus expectancies. Response outcome expectancies are defined as positive, negative, or none, to the available responses. This offers formal definitions of coping, hopelessness, and helplessness that are easy to operationalize in man and in animals. It is an essential element of CATS that only when coping is defined as positive outcome expectancy does the concept predict relations to health and disease

• Valdez GR, Koob GF. (2004) Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism. Pharmacol Biochem Behav 79:671-89.

• Abstract: Alcoholism is a chronic relapsing disorder, accompanied by alterations in psychological and physiological functioning, which reaches an addictive state where an individual demonstrates uncontrollable compulsive alcohol drinking and impairment in social and occupational functioning. Withdrawal is one of the defining characteristics of dependence, characterized by impaired physiological function and enhanced negative affect, and is thought to be a major contributing factor to relapse. The negative emotional aspects of withdrawal appear to be more involved in continued alcohol craving because physical withdrawal symptoms are not highly correlated with relapse in alcoholics. Allostasis describes maintaining stability outside the homeostatic range by varying the internal milieu to match environmental demands. This concept has been applied to neurobiological models of drug addiction and is thought to contribute to the vulnerability of drug addicts to relapse, as addicts continue to use drugs in order to maintain their psychological state within a homeostatic range. With regard to alcohol, two neuropeptides appear to be involved in the regulation of alcohol-related stress, corticotropin-releasing factor (CRF), which is associated with an increased stress response and negative affect, and neuropeptide Y (NPY), a neuropeptide with anxiolytic properties. The hypothesis to be developed in the present review is that a dysregulation of the CRF and NPY systems significantly contributes to the motivational basis of continued alcohol-seeking behavior during alcohol dependence. It appears that increases in CRF contribute to the negative affective state that is strongly associated with alcohol withdrawal, and NPY provides a motivational basis to consume alcohol because the anxiolytic effects of alcohol, which are strongly associated with relapse, appear to be regulated in part by this neuropeptide

• Ahmed SH, Koob GF. (2005) Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function. Psychopharmacology (Berl) 180:473-90.

• Abstract: RATIONALE: The transition from initial drug use to drug addiction has been proposed to result from an allostatic decrease in reward function driven by an overactivation of brain antireward processes. OBJECTIVES: How decreased reward function explains compulsive drug use is not entirely clear at present, and is still a subject for debate. METHODS: We present a quantitative model of cocaine self-administration that integrates pharmacokinetic, pharmacodynamic, and motivational factors to address this question. The model assumes that reward system responsivity is a homeostatically regulated process where the desired level of responsivity (called the reward set point) is initially different from the baseline level. The reduction or correction of this difference or error in reward function would drive cocaine self-administration. RESULTS: Theoretical data obtained by computer simulation fit the experimental data obtained in animals self-administering cocaine (i.e., the within-session pattern of self-injections, the shape and curvature of the dose-injection function, the nonlinear relationship between drug intake and regulated drug effects). Importantly, simulation of an allostatic decrease in reward system responsivity exacerbates the initial error that drives self-administration, thereby increasing both the intake of, and the motivation for, the drug. This allostatic change manifests as a vertical shift in the dose-injection function similar to that seen in animals with escalating cocaine self-administration. CONCLUSIONS: The present model provides a satisfactory explanation of escalated drug intake and suggests a novel negative reinforcement view of addiction based on an allostatic decrease in reward function

• Allsworth JE, Weitzen S, Boardman LA. (2005) Early age at menarche and allostatic load: data from the Third National Health and Nutrition Examination Survey. Ann Epidemiol 15:438-44.

• Abstract: PURPOSE: To examine whether there is an association between early age at menarche and allostatic load-a measure of cumulative biologic risk-using data from the Third National Health and Nutrition Examination Survey (NHANES III). METHODS: A total of 2470 (weighted N=25,544,838) women aged between 17 and 30 years with interview and examination data who did not report oral contraceptive use before menarche and were not missing data on the exposure or outcome were included. Early menarche was defined as menarche at age 10 or younger. The allostatic load score was the sum of the number of 11 components for which an individual had a value within the high-risk range. RESULTS: The prevalence of early menarche was 7%. Although the overall allostatic load scores were low when compared with older adults, the mean allostatic load score was higher among those with menarche at ages 10 or younger compared with those with later ages at menarche (1.99 vs. 1.33). After adjusting for age, race/ethnicity, level of education, household poverty income ratio, smoking, and depression history, women with high allostatic load scores had more than 2 times the odds as those with low scores of experiencing menarche at age 10 or earlier (OR=2.18; 95% CI, 1.29-3.68). CONCLUSIONS: This study is the first to report and examine the relationship between age at menarche and allostatic load. Future studies involving prospective measurement of allostatic load biomarkers may prove essential for disentangling the association between allostatic load and early age at menarche

• Bay E, Hagerty B, Williams RA, Kirsch N. (2005) Chronic stress, salivary cortisol response, interpersonal relatedness, and depression among community-dwelling survivors of traumatic brain injury.] J Neurosci Nurs 37:4-14.

• Abstract: Depression is a common mood disorder after traumatic brain injury (TBI). Largely, study of this phenomenon is theoretical and without biological measures. This explanatory study, guided by McEwen's allostasis model of stress, examined relationships among chronic stress, salivary cortisol profiles, post-injury depression, and interpersonal relatedness. Seventy-five participants, who were or had participated in outpatient brain injury rehabilitation therapies and experienced mild-to-moderate levels of brain injury, were recruited for this cross-sectional study. Salivary cortisol levels showed the usual patterns of circadian rhythmicity, and those with milder injuries had higher 8 am cortisol levels. Salivary cortisol values were not related to measures of chronic stress, interpersonal relatedness, or depression with two exceptions. The 8 am and noon mean values were significantly greater for those who reported more pre-injury childhood adversity, while the 8 pm cortisol mean level was associated with the frequency of pre-injury stressful life events. For this outpatient sample, salivary cortisol levels do not appear to be elevated after TBI or to lack circadian rhythmicity as previously reported. There may be some value in using this measure as a correlate with persons treated in specialized TBI clinics who report pre-injury chronic stress, but future studies are needed with TBI persons who were not treated in specialized clinics or were not taking medications known to influence the hypothalamic-pituitary-adrenal axis

• Berga SL, Loucks TL. (2005) The diagnosis and treatment of stress-induced anovulation.] Minerva Ginecol 57:45-54.

• Abstract: Behaviors that activate the hypothalamic-pituitary-adrenal (HPA) axis or suppress the hypothalamic-pituitary-thyroidal (HPT) axis can disrupt the hypothalamic-pituitary-gonadal (HPG) axis in women and men. Individuals with functional hypothalamic hypogonadism typically engage in a combination of behaviors that serve as psychogenic stressors and present metabolic challenges. Complete recovery of gonadal function depends upon restoration of the HPA and HPT axes. Hormone replacement strategies have limited benefit because they do not promote recovery from these allostatic endocrine adjustments in the HPA and HPT axes. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of hypothalamic hypogonadism represent only an alteration in the hypothalamic-pituitary-ovarian (HPO) axis. Further, use of sex hormones masks deficits that accrue from altered HPA and HPT function. Long-term deleterious consequences of stress-induced anovulation may include an increased risk of cardiovascular disease, osteoporosis, depression, other psychiatric conditions, and dementia. Although fertility can be restored with exogenous administration of gonadotropins or pulsatile GnRH, fertility management alone will not permit recovery of the HPA and HPT axes. Failure to reverse the hormonal milieu induced by stress may increase the likelihood of poor obstetrical, fetal, or neonatal outcomes. In contrast, behavioral and psychological interventions that address problematic behaviors and attitudes have the potential to permit resumption of ovarian function along with recovery of the HPT and HPA axes. Full endocrine recovery offers better individual, maternal, and child health

• Bhatia V, Tandon RK. (2005) Stress and the gastrointestinal tract. J Gastroenterol Hepatol 20:332-9.

• Abstract: Stress, defined as an acute threat to homeostasis, evokes an adaptive or allostatic response and can have both a short- and long-term influence on the function of the gastrointestinal tract. The enteric nervous system is connected bidirectionally to the brain by parasympathetic and sympathetic pathways forming the brain-gut axis. The neural network of the brain, which generates the stress response, is called the central stress circuitry and includes the paraventricular nucleus of the hypothalamus, amygdala and periaqueductal gray. It receives input from the somatic and visceral afferent pathways and also from the visceral motor cortex including the medial prefrontal, anterior cingulate and insular cortex. The output of this central stress circuit is called the emotional motor system and includes automatic efferents, the hypothalamus-pituitary-adrenal axis and pain modulatory systems. Severe or long-term stress can induce long-term alteration in the stress response (plasticity). Corticotropin releasing factor (CRF) is a key mediator of the central stress response. Two CRF receptor subtypes, R1 and R2, have been described. They mediate increased colonic motor activity and slowed gastric emptying, respectively, in response to stress. Specific CRF receptor antagonists injected into the 0 block these visceral manifestations of stress. Circulating glucocorticoids exert an inhibitory effect on the stress response by receptors located in the medial prefrontal cortex and hippocampus. Many other neurotransmitters and neuroimmunomodulators are being evaluated. Stress increases the intestinal permeability to large antigenic molecules. It can lead to mast cell activation, degranulation and colonic mucin depletion. A reversal of small bowel water and electrolyte absorption occurs in response to stress and is mediated cholinergically. Stress also leads to increased susceptibility to colonic inflammation, which can be adaptively transferred among rats by sensitized CD4(+) lymphocytes. The association between stress and various gastrointestinal diseases, including functional bowel disorders, inflammatory bowel disease, peptic ulcer disease and gastroesophageal reflux disease, is being actively investigated. Attention to the close relation between the brain and gut has opened many therapeutic avenues for the future

• Carlson ED, Chamberlain RM. (2005) Allostatic load and health disparities: a theoretical orientation. Res Nurs Health 28:306-15.

• Abstract: Eliminating racial and ethnic health disparities requires restructuring the biomedical models that have focused on the individual as the level of analysis and emphasized the parts rather than the whole. A recently developed understanding of human physiology and adaptive regulation, constructs of allostasis and allostatic load, provides a theoretical orientation that needs to be explored. Thus, the purpose of this article is to present an orientation of allostasis and allostatic load as a theoretical framework for exploring health disparities. This article will (a) present a general background on the evolution of relevant physiologic theories, (b) offer the general theoretical definitions and explanations of allostasis, allostatic load, and mediation processes, (c) examine empirical evidence for the constructs, and (d) discuss the implications of this orientation for health disparities research

• Day TA. (2005) 10.1016/j.pnpbp.2005.08.005 Defining stress as a prelude to mapping its neurocircuitry: no help from allostasis. Prog Neuropsychopharmacol Biol Psychiatry 29:1195-200.

• Abstract: The way in which researchers conceptualise and thus define stress shapes the way in which they approach the task of mapping the brain's stress control pathways. Unfortunately, much of the research currently being done on stress neurocircuitry is occurring within a poorly developed conceptual framework, a framework that limits the depth of the questions that our studies ask, and even our ability to fully appreciate and make use of the data that they yield. Consequently, any attempt to improve our conceptual framework merits close attention. In that regard it is notable that in recent years it has been argued that the concept of homeostasis should be supplemented by the concepts of allostasis (literally 'stability through change') and allostatic load (in effect, the cost of allostasis). One of the purported benefits of this change has been that it will clarify the concept of stress. A close review of the arguments leads us to conclude that the introduction of the concept of allostasis has largely occurred as a result of misunderstandings and misapprehensions concerning the concept of homeostasis. In terms of understanding how the organism operates, it is not clear that the concepts of 'allostasis' or 'allostatic load' offer us anything that was not already apparent, or at least readily derivable, from an accurate reading of the original concept of homeostasis. Not surprisingly then, these more recently proposed concepts also offer little help in clarifying our understanding of stress. Indeed, rather than clarifying the concept of stress, the primary effort appears to be directed at subsuming the concept of stress within the concept of allostasis, which has the inadvertent effect of collapsing the study of homeostatic responses and stress responses together. This seems to be out of step with the fact that there is now considerable evidence that the brain does indeed possess certain pathways that merit the title of 'stress neurocircuitry'. The attempt to subsume the concept of stress within the concept of allostasis is also counter-productive in that it distracts stress researchers from the important task of developing conceptual frameworks that allow us to tackle fundamental issues such as how the organism differentiates stressful from non-stressful challenges

• Evron T, Moyal-Segal LB, Lamm N, Geffen A, Soreq H. (2005) RNA-targeted suppression of stress-induced allostasis in primate spinal cord neurons. Neurodegener Dis 2:16-27.

• Abstract: Peripheral acetylcholine levels notably control the synthesis in macrophages of pro-inflammatory cytokines; however, it remains unclear whether this peripheral regulatory pathway affects central nervous system neurons. To explore the interrelationship between neuronal cholinergic homeostasis and peripheral inflammatory responses in primates, we used spinal cord sections from cynomolgus monkeys after 7 days oral or intravenous treatment with Monarsen oligonucleotide. Monarsen is an antisense oligonucleotide 3'-protected by 2'-oxymethylation, which was proved to induce selective destruction of the stress-induced acetylcholinesterase splice variant AChE-R mRNA. Handling stress predictably suppressed neuronal choline acetyl transferase (ChAT) and the vesicular acetylcholine transporter (VAChT) in all treated monkeys. In Monarsen-treated animals, we further observed suppression of stress-induced increases in plasma AChE activities. Corresponding decreases in AChE-R mRNA were seen in spinal cord neurons, associated with parallel decline patterns in the mRNA encoding for the splice factor SC35 (the levels of which co-increase with those of AChE-R) as well as in the neuronal pro-inflammatory interleukins IL-1beta and IL-6. The antisense effects showed direct dose dependence and were inversely associated with neuronal cell size. These findings suggest a causal association between neuronal cholinergic allostasis and inflammatory reactions in primates and support the peripheral use of RNA-targeted intervention with AChE-R accumulation for the management of both stress and inflammatory responses

• Galambos SA, Terry PC, Moyle GM, Locke SA, Lane AM. (2005) [pii;10.1136/bjsm.2005.018440 [doi] Psychological predictors of injury among elite athletes.] Br J Sports Med 39:351-4.

• Abstract: OBJECTIVES: To establish injury rates among a population of elite athletes, to provide normative data for psychological variables hypothesised to be predictive of sport injuries, and to establish relations between measures of mood, perceived life stress, and injury characteristics as a precursor to introducing a psychological intervention to ameliorate the injury problem. METHODS: As part of annual screening procedures, athletes at the Queensland Academy of Sport report medical and psychological status. Data from 845 screenings (433 female and 412 male athletes) were reviewed. Population specific tables of normative data were established for the Brunel mood scale and the perceived stress scale. RESULTS: About 67% of athletes were injured each year, and about 18% were injured at the time of screening. Fifty percent of variance in stress scores could be predicted from mood scores, especially for vigour, depression, and tension. Mood and stress scores collectively had significant utility in predicting injury characteristics. Injury status (current, healed, no injury) was correctly classified with 39% accuracy, and back pain with 48% accuracy. Among a subset of 233 uninjured athletes (116 female and 117 male), five mood dimensions (anger, confusion, fatigue, tension, depression) were significantly related to orthopaedic incidents over the preceding 12 months, with each mood dimension explaining 6-7% of the variance. No sex differences in these relations were found. CONCLUSIONS: The findings support suggestions that psychological measures have utility in predicting athletic injury, although the relatively modest explained variance highlights the need to also include underlying physiological indicators of allostatic load, such as stress hormones, in predictive models

• Golay A, Ybarra J. (2005) [pii;10.1016/j.beem.2005.07.010 [doi] Link between obesity and type 2 diabetes.] Best Pract Res Clin Endocrinol Metab 19:649-63.

• Abstract: The relationship between obesity and diabetes is of such interdependence that the term 'diabesity' has been coined. The passage from obesity to diabetes is made by a progressive defect in insulin secretion coupled with a progressive rise in insulin resistance. Both insulin resistance and defective insulin secretion appear very prematurely in obese patients, and both worsen similarly towards diabetes. Thus, the classic 'hyperbolic relationship' between insulin resistance and insulin secretion and the 'glucose allostasis concept' remain prevailing concepts in this particular field of knowledge. An increase in overall fatness, preferentially of visceral as well as ectopic fat depots, is specifically associated with insulin resistance. The accumulation of intramyocellular lipids may be due to reduced lipid oxidation capacity. The ability to lose weight is related to the capacity to oxidize fat. Thus, a relative defect in fat oxidation capacity is responsible for energy economy and hampered weight loss

• Hogue CJ, Bremner JD. (2005) [pii;10.1016/j.ajog.2005.01.073 [doi] Stress model for research into preterm delivery among black women.] Am J Obstet Gynecol 192:S47-S55.

• Abstract: The disparity between black and white infant mortality rates increased over the last decade, despite overall improvement in infant survival. Because most black infant deaths are related to preterm delivery, the discovery of the cause of premature birth in general and excess premature birth for black infants in particular is of paramount importance for reproductive health research. Substantial theoretic support exists for maternal stress as a risk factor for preterm birth. Traumatic events early in life may sensitize the adult to contemporary stresses and increase her vulnerability to stress-induced neuroendocrine or infection/inflammatory pathways to early parturition. In addition, an individual may prematurely age as a result of cumulative stress or a major traumatic event. This "stress age," which is synonymous with the concept of weathering and similar to the concept of allostatic load, may affect parturition through chronic conditions (such as hypertension) and in poorly understood pathophysiologic mechanisms that are related to increased chronologic age. One potential measure of stress age is maternal serum dehydroepiandrosterone sulfate. Maternal stress is a potential explanatory factor for excess preterm delivery among black women because of their exposure to racism-associated stress. However, few studies have addressed this question, and results are mixed. Future etiologic research must take into account the complexities of the measurement of stress age and past and current exposures to stress, which includes internalized racism and interpersonal racism

• Iribarren J, Prolo P, Neagos N, Chiappelli F. (2005) [doi Post-traumatic stress disorder: evidence-based research for the third millennium.] Evid Based Complement Alternat Med 2:503-12.

• Abstract: The stress that results from traumatic events precipitates a spectrum of psycho-emotional and physiopathological outcomes. Post-traumatic stress disorder (PTSD) is a psychiatric disorder that results from the experience or witnessing of traumatic or life-threatening events. PTSD has profound psychobiological correlates, which can impair the person's daily life and be life threatening. In light of current events (e.g. extended combat, terrorism, exposure to certain environmental toxins), a sharp rise in patients with PTSD diagnosis is expected in the next decade. PTSD is a serious public health concern, which compels the search for novel paradigms and theoretical models to deepen the understanding of the condition and to develop new and improved modes of treatment intervention. We review the current knowledge of PTSD and introduce the role of allostasis as a new perspective in fundamental PTSD research. We discuss the domain of evidence-based research in medicine, particularly in the context of complementary medical intervention for patients with PTSD. We present arguments in support of the notion that the future of clinical and translational research in PTSD lies in the systematic evaluation of the research evidence in treatment intervention in order to insure the most effective and efficacious treatment for the benefit of the patient

• Korte SM, Koolhaas JM, Wingfield JC, McEwen BS. (2005) [pii;10.1016/j.neubiorev.2004.08.009 [doi] The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease.] Neurosci Biobehav Rev 29:3-38.

• Abstract: Why do we get the stress-related diseases we do? Why do some people have flare ups of autoimmune disease, whereas others suffer from melancholic depression during a stressful period in their life? In the present review possible explanations will be given by using different levels of analysis. First, we explain in evolutionary terms why different organisms adopt different behavioral strategies to cope with stress. It has become clear that natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves) within a population. The existence of these personality types (Hawks-Doves) is widespread in the animal kingdom, not only between males and females but also within the same gender across species. Second, proximate (causal) explanations are given for the different stress responses and how they work. Hawks and Doves differ in underlying physiology and these differences are associated with their respective behavioral strategies; for example, bold Hawks preferentially adopt the fight-flight response when establishing a new territory or defending an existing territory, while cautious Doves show the freeze-hide response to adapt to threats in their environment. Thus, adaptive processes that actively maintain stability through change (allostasis) depend on the personality type and the associated stress responses. Third, we describe how the expression of the various stress responses can result in specific benefits to the organism. Fourth, we discuss how the benefits of allostasis and the costs of adaptation (allostatic load) lead to different trade-offs in health and disease, thereby reinforcing a Darwinian concept of stress. Collectively, this provides some explanation of why individuals may differ in their vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and non-aggressive Doves in a population. A conceptual framework is presented showing that Hawks, due to inefficient management of mediators of allostasis, are more likely to be violent, to develop impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, chronic fatigue states and inflammation. In contrast, Doves, due to the greater release of mediators of allostasis (surplus), are more susceptible to anxiety disorders, metabolic syndromes, melancholic depression, psychotic states and infection

• McEwen BS. (2005) Stressed or stressed out: what is the difference?] J Psychiatry Neurosci 30:315-8.

• Abstract: The term "allostasis" has been coined to clarify ambiguities associated with the word "stress". Allostasis refers to the adaptive processes that maintain homeostasis through the production of mediators such as adrenalin, cortisol and other chemical messengers. These mediators of the stress response promote adaptation in the aftermath of acute stress, but they also contribute to allostatic overload, the wear and tear on the body and brain that result from being "stressed out". This conceptual framework has created a need to know how to improve the efficiency of the adaptive response to stressors while minimizing overactivity of the same systems, since such overactivity results in many of the common diseases of modern life. This framework has also helped to demystify the biology of stress by emphasizing the protective as well as the damaging effects of the body's attempts to cope with the challenges known as stressors

• Murali R, Chen E. (2005) [doi Exposure to violence and cardiovascular and neuroendocrine measures in adolescents.] Ann Behav Med 30:155-63.

• Abstract: BACKGROUND: Exposure to violence has clear, detrimental psychological consequences, but the physiological effects are less well understood. PURPOSE: This study examined the influence of exposure to violence on biological basal and reactivity measures in adolescents. METHODS: There were 115 high school student participants. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), HR variability (HRV), and cortisol levels were recorded during baseline and a laboratory stressor. The Exposure to Violence interview was administered and assessed two dimensions: total observed violence and total personally experienced violence. These were then divided into component parts: lifetime frequency, proximity, and severity. RESULTS: Greater total experienced violence was associated with increased basal SBP (r = .19, p < .05) and decreased acute stress reactivity in terms of SBP (beta = -.13, p = .05), HR (beta = -.21, p = .00), and HRV (beta = .13, p = .05). Lifetime frequency of experienced violence was associated with higher basal DBP (r = .33, p < .05), HR (r = .33, p < .05), and cortisol (r = .53, p < .00), and decreased SBP (beta = -.27, p < .05) and DBP (beta = -.31, p < .05) reactivity. Exposure to violence is associated with increased biological basal levels in adolescents, supporting allostatic-load research and decreased cardiovascular reactivity, supporting the inoculation effect. CONCLUSIONS: The findings illustrate that being a victim of violence has more pervasive biological consequences than witnessing violence and that the accumulation of stressful experiences has the greatest effect on biological markers

• Rokutan K, Morita K, Masuda K et al. (2005) Gene expression profiling in peripheral blood leukocytes as a new approach for assessment of human stress response.] J Med Invest 52:137-44.

• Abstract: Stress is the coordinated physiological processes to maintain a dynamic equilibrium under stressful conditions. The equilibrium is threatened by certain physiological and psychological stressors. Stressors trigger physiological, behavioural, and metabolic responses that are aimed at reinstating homeostasis. The hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system play an essential role in the stress response. Excessive,prolonged, or inadequate response that is termed as "allostasis" or "allostatic load" leads to pathological outcomes. Dysregulation of the HPA axis activity is involved in the pathogenesis of stress-related disorders including major depression. The complex brain-immune-endocrine network regulates the HPA axis, and hereditary predisposition as well as environmental factors such as traumatic experiences in early life also modifies the capacity of an individual to cope. Therefore, it is difficult to correctly assess the complex stress response. We have developed a microarray carrying 1,467 cDNAs that were selected to specifically measure stress response in peripheral blood leukocytes. Using this tool, we have succeeded to objectively assess individual response to acute psychological stress and to detect unique expression profiles in patients with depression. Gene expression profile in peripheral blood leukocytes may be a potentially useful for the detection of disease-associated, abnormal stress responses

• Seplaki CL, Goldman N, Glei D, Weinstein M. (2005) [pii;10.1016/j.exger.2005.03.002 [doi] A comparative analysis of measurement approaches for physiological dysregulation in an older population.] Exp Gerontol 40:438-49.

• Abstract: The theory of allostatic load describes how the cumulative experience of emotional challenges and stressful events over the life course may take a significant physiological toll on multiple interrelated systems of the body. Various summary measures of these effects have been proposed in the literature, but few studies focus on systematically evaluating them. We use data from a population-based sample of older Taiwanese to compare the explanatory power and cross-sectional predictive performance of several measures of allostatic load for diverse health outcomes. We find that choices regarding which biomarkers to include in a summary measure and how the measure is formed have modest effects across the basic prediction models we evaluate. Our findings suggest that count-based summary measures incorporating risk at both high and low tails and measures that preserve the continuous properties of the biological variables are strategies that may yield stronger predictions of a wider array of health outcomes than other measures. These fundamental insights are useful for researchers in search of empirical formulations of allostatic load and for those who are focused on the development of improved measurement strategies

• Szanton SL, Gill JM, Allen JK. (2005) [pii;10.1177/1099800405278216 [doi] Allostatic load: a mechanism of socioeconomic health disparities?] Biol Res Nurs 7:7-15.

• Abstract: Although research on health disparities has been prioritized by the National Institutes of Health, the Institute of Medicine, and Healthy People 2010, little has been published that examines the biology underlying health disparities. Allostatic load is a multisystem construct theorized to quantify stress-induced biological risk. Differences in allostatic load may reflect differences in stress exposure and thus provide a mechanistic link to understanding health disparities. The purpose of this systematic review is to examine the construct of allostatic load and the published studies that employ it in an effort to understand whether the construct can be useful in quantifying health disparities. The published literature demonstrates that allostatic load is elevated in those of low socioeconomic status (SES) as compared to those of high SES. The reviewed articles vary in the justification for inclusion of variables. Recommendations for future research are made in the contexts of measurement, methodology, and racial composition of participants

• Tucker KL. (2005) [pii Stress and nutrition in relation to excess development of chronic disease in Puerto Rican adults living in the Northeastern USA.] J Med Invest 52 Suppl:252-8.

• Abstract: Although health disparities are well documented among minority populations, they have not been fully explained by socio-economic status. We have demonstrated that Puerto Rican elders in Massachusetts are significantly more likely to have physical disability, depression, cognitive impairment, diabetes and other chronic health conditions than do non-Hispanic white elders living in the same neighborhoods. This suggests that the disparity is not due only to physical or neighborhood location, and that other factors must be influencing these differences. In that study, we also showed that the Puerto Rican elders had diets that were limited in diversity and were relatively low in micronutrient content. In our ongoing cohort study within our Boston Puerto Rican Center for Population Health and Health Disparities, we are investigating the relationships between psychosocial stress, its effect on physiologic burden or "allostatic load" and, in turn, how this is associated with the functional outcomes previously identified as areas of health disparity: depression, cognitive impairment and functional limitation. We further propose that the association between life stress, physiologic response and chronic conditions is modified by nutritional status, with a focus on B vitamins and antioxidant vitamins

• Turner-Cobb JM. (2005) [pii;10.1080/10253890500095200 [doi] Psychological and stress hormone correlates in early life: a key to HPA-axis dysregulation and normalisation.] Stress 8:47-57.

• Abstract: Substantial recent research has focused on examining hormone indicators of psychosocial stress and on how relationships between stress and hormone changes might be linked to chronic illness. Particular attention has been paid to disease progression in cancer and HIV/AIDS. This focus has generated a plethora of research which has contributed both theoretically and clinically to the understanding of disease experience and the rate of disease progression. Measurement of salivary cortisol levels and diurnal variation has substantially advanced research methodology. Applying the unifying concept of allostasis and accumulated lifetime stress, this review attempts to assess the relevance of psychological and stress hormone correlates to disease resistance and health, through an examination of such correlates on the experience and outcomes of stress during childhood. Focus is on the role and importance of naturalistic social stress experiences such as school transition in healthy children, with emphasis on salivary cortisol as an endocrine marker of HPA-axis activation. It is argued that differing research perspectives offer valuable insight into the often assumed but largely unexplored links between early life experience and subsequent physical health outcomes in adulthood. Longitudinal studies incorporating measures of acute physical health outcome and of learning and memory are clearly needed

• Wikby A, Ferguson F, Forsey R et al. (2005) [pii An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans.] J Gerontol A Biol Sci Med Sci 60:556-65.

• Abstract: In the previous OCTO longitudinal study, we identified an immune risk phenotype (IRP) of high CD8 and low CD4 numbers and poor proliferative response. We also demonstrated that cognitive impairment constitutes a major predictor of nonsurvival. In the present NONA longitudinal study, we simultaneously examine in a model of allostatic load IRP and compromised cognition in 4-year survival in a population-based sample (n = 138, 86-94 years). Immune system measurements consisted of determinations of T-cell subsets, plasma interleukin 6 and cytomegalovirus and Epstein-Barr virus serology. Interleukin 2 responsiveness to concanavalin A, using data from the previous OCTO (octogenarians) immune study, hereafter OCTO immune, was also examined. Cognitive status was rated using a battery of neuropsychological tests. Logistic regression indicated that the IRP and cognitive impairment together predicted 58% of observed deaths. IRP was associated with late differentiated CD8+CD28-

• Crews DE, Zavotka S. (2006) [pii Aging, disability, and frailty: implications for universal design.] J Physiol Anthropol 25:113-8.

• Abstract: Throughout the world all populations are seeing burgeoning numbers of "elders", defined as persons aged 65 year and older. In many countries, including Japan, the United States, Norway, Sweden and the United Kingdom, those aged over 65 are at or approaching 15% of the population. As their numbers have increased, so have their health care expenses, leading to extensive research on the health, well being, and life expectancy of these increasingly older elders. Today this group is further sub-divided: the young-old ages 65-74, the old-old ages 75-84, and the oldest-old ages 85+, for both health care and research purposes. However broad variation still characterizes even these groupings. Rates of frailty and disability increase with increasing age among these elders. For example, inabilities to complete at least one activity of daily living increased from about 5-7% at ages 65-69 years to about 28-36% at ages 85+ in 1987. Death rates continue to decline at all ages past 50 years and rates of disability seem to be doing the same. For the foreseeable future, we may expect increasing numbers of older, frail elders than in previous decades. Thus, people are not only living longer, they generally are healthier at advanced ages than were previous cohorts, thus "old age" disabilities of the 20th century will be put off to even older ages during the 21st century. As yet there is no clear way to assess senescent changes in humans, although activities of daily living, allostatic load, and frailty indices have all been suggested. One future need is greater development and use of universal and accessible design in all aspects of the built environment

• Geronimus AT, Hicken M, Keene D, Bound J. (2006) [pii;10.2105/AJPH.2004.060749 [doi] "Weathering" and age patterns of allostatic load scores among blacks and whites in the United States.] Am J Public Health 96:826-33.

• Abstract: OBJECTIVES: We considered whether US Blacks experience early health deterioration, as measured across biological indicators of repeated exposure and adaptation to stressors. METHODS: Using National Health and Nutrition Examination Survey data, we examined allostatic load scores for adults aged 18-64 years. We estimated probability of a high score by age, race, gender, and poverty status and Blacks' odds of having a high score relative to Whites' odds. RESULTS: Blacks had higher scores than did Whites and had a greater probability of a high score at all ages, particularly at 35-64 years. Racial differences were not explained by poverty. Poor and nonpoor Black women had the highest and second highest probability of high allostatic load scores, respectively, and the highest excess scores compared with their male or White counterparts. CONCLUSIONS: We found evidence that racial inequalities in health exist across a range of biological systems among adults and are not explained by racial differences in poverty. The weathering effects of living in a race-conscious society may be greatest among those Blacks most likely to engage in high-effort coping

• Glover DA. (2006) [pii;10.1196/annals.1364.039 [doi] Allostatic load in women with and without PTSD symptoms.] Ann N Y Acad Sci 1071:442-7.

• Abstract: Allostatic load (AL) is the cumulative physiological "cost" of prolonged stress. An AL composite measure successfully predicts morbidity and mortality among the elderly but has not been reported in "high stress" samples with posttraumatic stress disorder (PTSD). Accordingly, AL was measured in mothers (ages 29-55) of pediatric cancer survivors and control mothers of healthy children. A significant "dose-response" pattern (high to low AL) emerged: cancer mothers meeting all PTSD criteria, cancer mothers with no/low symptoms, and controls, respectively. Results indicate elevated AL can be detected in relatively young women with high stress histories, and particularly those with PTSD

• Goertzel BN, Pennachin C, de Souza CL, Maloney EM, Jones JF, Gurbaxani B. (2006) [doi Allostatic load is associated with symptoms in chronic fatigue syndrome patients.] Pharmacogenomics 7:485-94.

• Abstract: OBJECTIVES: To further explore the relationship between chronic fatigue syndrome (CFS) and allostatic load (AL), we conducted a computational analysis involving 43 patients with CFS and 60 nonfatigued, healthy controls (NF) enrolled in a population-based case-control study in Wichita (KS, USA). We used traditional biostatistical methods to measure the association of high AL to standardized measures of physical and mental functioning, disability, fatigue and general symptom severity. We also used nonlinear regression technology embedded in machine learning algorithms to learn equations predicting various CFS symptoms based on the individual components of the allostatic load index (ALI). METHODS: An ALI was computed for all study participants using available laboratory and clinical data on metabolic, cardiovascular and hypothalamic-pituitary-adrenal (HPA) axis factors. Physical and mental functioning/impairment was measured using the Medical Outcomes Study 36-item Short Form Health Survey (SF-36); current fatigue was measured using the 20-item multidimensional fatigue inventory (MFI); frequency and intensity of symptoms was measured using the 19-item symptom inventory (SI). Genetic programming, a nonlinear regression technique, was used to learn an ensemble of different predictive equations rather just than a single one. Statistical analysis was based on the calculation of the percentage of equations in the ensemble that utilized each input variable, producing a measure of the 'utility' of the variable for the predictive problem at hand. Traditional biostatistics methods include the median and Wilcoxon tests for comparing the median levels of subscale scores obtained on the SF-36, the MFI and the SI summary score. RESULTS: Among CFS patients, but not controls, a high level of AL was significantly associated with lower median values (indicating worse health) of bodily pain, physical functioning and general symptom frequency/intensity. Using genetic programming, the ALI was determined to be a better predictor of these three health measures than any subcombination of ALI components among cases, but not controls

• Gurbaxani BM, Jones JF, Goertzel BN, Maloney EM. (2006) [doi Linear data mining the Wichita clinical matrix suggests sleep and allostatic load involvement in chronic fatigue syndrome.] Pharmacogenomics 7:455-65.

• Abstract: OBJECTIVES: To provide a mathematical introduction to the Wichita (KS, USA) clinical dataset, which is all of the nongenetic data (no microarray or single nucleotide polymorphism data) from the 2-day clinical evaluation, and show the preliminary findings and limitations, of popular, matrix algebra-based data mining techniques. METHODS: An initial matrix of 440 variables by 227 human subjects was reduced to 183 variables by 164 subjects. Variables were excluded that strongly correlated with chronic fatigue syndrome (CFS) case classification by design (for example, the multidimensional fatigue inventory [MFI] data), that were otherwise self reporting in nature and also tended to correlate strongly with CFS classification, or were sparse or nonvarying between case and control. Subjects were excluded if they did not clearly fall into well-defined CFS classifications, had comorbid depression with melancholic features, or other medical or psychiatric exclusions. The popular data mining techniques, principle components analysis (PCA) and linear discriminant analysis (LDA), were used to determine how well the data separated into groups. Two different feature selection methods helped identify the most discriminating parameters. RESULTS: Although purely biological features (variables) were found to separate CFS cases from controls, including many allostatic load and sleep-related variables, most parameters were not statistically significant individually. However, biological correlates of CFS, such as heart rate and heart rate variability, require further investigation. CONCLUSIONS: Feature selection of a limited number of variables from the purely biological dataset produced better separation between groups than a PCA of the entire dataset. Feature selection highlighted the importance of many of the allostatic load variables studied in more detail by Maloney and colleagues in this issue [1] , as well as some sleep-related variables. Nonetheless, matrix linear algebra-based data mining approaches appeared to be of limited utility when compared with more sophisticated nonlinear analyses on richer data types, such as those found in Maloney and colleagues [1] and Goertzel and colleagues [2] in this issue

• Johnson TE. (2006) [pii;10.1016/j.exger.2006.09.006 [doi] Recent results: biomarkers of aging.] Exp Gerontol 41:1243-6.

• Abstract: This communication reviews recent papers attempting to identify Biomarkers of Aging (BoA). A BoA is a biological parameter that will predict functional capability at some later age. Few, if any, BoA have been found and this review describes the recent search for BoA. Among others that have been put forward are IL6 and other markers of inflammation, allostatic load, and corticosterone, which have been described primarily in humans. Work in model systems as well as theoretical work are also reviewed

• Kahn JR, Pearlin LI. (2006) Financial strain over the life course and health among older adults.] J Health Soc Behav 47:17-31.

• Abstract: This paper focuses on financial strain across the life course as a condition underlying health inequalities observed in later life. The analysis is based on data from 1167 adults 65 years and older collected as part of the 'Aging, Stress and Health Study". Relying on retrospective data about hardship experienced over the life course, we find that long-term financial hardship is reflected in a range of health outcomes at late life, even after controlling for the effects of current financial circumstances. Moreover, the sheer persistence of hardship matters more than its episodic occurrence or timing, so that the health effects of early hardship may be obviated if followed by no further hardship. This pattern offindings is consistent with the notion of allostatic load, the cumulative damage done to health and well-being under the burden of an unrelenting stressor in a critically important life domain

• Karlamangla AS, Singer BH, Seeman TE. (2006) [pii;10.1097/01.psy.0000221270.93985.82 [doi] Reduction in allostatic load in older adults is associated with lower all-cause mortality risk: MacArthur studies of successful aging.] Psychosom Med 68:500-7.

• Abstract: OBJECTIVES: To study the association between change in allostatic load (a risk score constructed from multiple biological markers) over a 2.5-year period and mortality in the following 4.5 years in older adults. METHODS: We measured 10 physiologic parameters at baseline (1988) in a cohort of 171 high-functioning, community-dwelling, 70- to 79-year-old adults. These measurements were repeated 2.5 years later, in 1991. Summary allostatic load scores for 1988 and 1991 were created as the weighted sum of the 10 biological markers and their second-order terms. Mortality status (alive or dead) for participants was determined 4.5 years later, in 1995. The association between change in allostatic load score (1988-1991) and subsequent mortality (1991-1995) was studied using logistic regression. RESULTS: Compared with participants whose allostatic load score decreased between 1988 and 1991, individuals whose allostatic load score increased had higher risk of all-cause mortality between 1991 and 1995 (15% versus 5%, p = .047). Adjusted for age and baseline allostatic load, each unit increment in the allostatic load change score was associated with mortality odds ratio of 3.3 (95% confidence interval, 1.1-9.8). CONCLUSION: Our results suggest that even in older ages, change in risk scores can be followed to improve assessment of mortality risk

• Kudielka BM, von KR, Preckel D, Zgraggen L, Mischler K, Fischer JE. (2006) [pii;10.1016/j.biopsycho.2005.09.001 [doi] Exhaustion is associated with reduced habituation of free cortisol responses to repeated acute psychosocial stress.] Biol Psychol 72:147-53.

• Abstract: We investigated the association between exhaustion and the habituation of free cortisol responses to repeated stress exposure. The study comprised 25 healthy male subjects (38-59 years) who were confronted three times with the Trier Social Stress Test. Mean cortisol responses showed the well-known general habituation effect. A two-way interaction day by exhaustion (p<0.05) indicated that mean cortisol responses vary across stress sessions depending on the extent of exhaustion. Linear regression revealed a negative dose-response relationship between exhaustion and the degree of habituation (p<0.02). We identified 19 individuals showing a response habituation (negative slope) and 6 individuals showing a response sensitization over the three sessions (positive slope) with the latter reporting higher exhaustion scores. It might be hypothesized that impaired habituation to repeated exposure to the same stressor could reflect a state of increased vulnerability for allostatic load. Absence of normal habituation might be one potential mechanism how exhaustion relates to increased disease vulnerability

• Lindfors P, Lundberg O, Lundberg U. (2006) [pii;10.1097/01.psy.0000232267.56605.22 [doi] Allostatic load and clinical risk as related to sense of coherence in middle-aged women.] Psychosom Med 68:801-7.

• Abstract: OBJECTIVE: To investigate how physiologic dysregulation, in terms of allostatic load and clinical risk, respectively, relates to sense of coherence (SOC) in women with no previously diagnosed pathology. METHODS: At baseline, 200 43-year-old women took part in a standardized medical health examination and completed a 3-item measure of SOC, which they completed again 6 years later. According to data from the medical examination, two different measures of physiologic dysregulation were calculated: a) a measure of allostatic load based on empirically derived cut points and b) a measure of clinical risk based on clinically significant cut points. RESULTS: In line with the initial hypotheses, allostatic load was found to predict future SOC, whereas clinical risk did not. In addition to baseline SOC and nicotine consumption, allostatic load was strongly associated with a weak SOC at the follow-up. CONCLUSIONS: The better predictive value of allostatic load to clinical risk indicates that focusing solely on clinical risk obscures patterns of physiologic dysregulation that influence future SOC

• Maloney EM, Gurbaxani BM, Jones JF, de Souza CL, Pennachin C, Goertzel BN. (2006) [doi Chronic fatigue syndrome and high allostatic load.] Pharmacogenomics 7:467-73.

• Abstract: STUDY POPULATION: We examined the relationship between chronic fatigue syndrome (CFS) and allostatic load in a population-based, case-control study of 43 CFS patients and 60 nonfatigued, healthy controls from Wichita, KS, USA. METHODS: An allostatic load index was computed for all study participants using available laboratory and clinical data, according to a standard algorithm for allostatic load. Logistic regression analysis was used to compute odds ratios (ORs) as estimates of relative risk in models that included adjustment for matching factors and education; 95% confidence intervals (CIs) were computed to estimate the precision of the ORs. RESULTS: CFS patients were 1.9-times more likely to have a high allostatic load index than controls (95% CI = 0.75, 4.75) after adjusting for education level, in addition to matching factors. The strength of this association increased in a linear trend across categories of low, medium and high levels of allostatic load (p = 0.06). CONCLUSION: CFS was associated with a high level of allostatic load. The three allostatic load components that best discriminated cases from controls were waist:hip ratio, aldosterone and urinary cortisol

• McEwen BS. (2006) Protective and damaging effects of stress mediators: central role of the brain.] Dialogues Clin Neurosci 8:367-81.

• Abstract: The mind involves the whole body and two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals. It is notjust the dramatic stressful events that exact their toll, but rather the many events of daily life that elevate and sustain activities of physiological systems and cause sleep deprivation, overeating, and other health-damaging behaviors, producing the feeling of being "stressed out." Over time, this results in wear and tear on the body which is called "allostatic load," and it reflects not only the impact of life experiences but also of genetic load, individual lifestyle habits reflecting items such as diet, exercise, and substance abuse, and developmental experiences that set life-long patterns of behavior and physiological reactivity. Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by the process known as allostasis, but in the long run allostatic load causes changes in the body that can lead to disease. The brain is the key organ of stress, allostasis, and allostatic load, because it determines what is threatening and therefore stressful, and also determines the physiological and behavioral responses. Brain regions such as the hippocampus, amygdala, and prefrontal cortex respond to acute and chronic stress by undergoing structural remodeling, which alters behavioral and physiological responses. Translational studies in humans with structural and functional imaging reveal smaller hippocampal volume in stress-related conditions, such as mild cognitive impairment in aging and prolonged major depressive illness, as well as in individuals with low self-esteem. Alterations in amygdala and prefrontal cortex are also reported. Besides pharmaceuticals, approaches to alleviate chronic stress and reduce allostatic load and the incidence of diseases of modern life include lifestyle change, and policies of government and business that would improve the ability of individuals to reduce their own chronic stress burden

• McEwen BS. (2006) [pii;10.1016/j.metabol.2006.07.008 [doi] Sleep deprivation as a neurobiologic and physiologic stressor: Allostasis and allostatic load.] Metabolism 55:S20-S23.

• Abstract: Sleep has important homeostatic functions, and sleep deprivation is a stressor that has consequences for the brain, as well as many body systems. Whether sleep deprivation is due to anxiety, depression, or a hectic lifestyle, there are consequences of chronic sleep deprivation that impair brain functions and contribute to allostatic load throughout the body. Allostatic load refers to the cumulative wear and tear on body systems caused by too much stress and/or inefficient management of the systems that promote adaptation through allostasis. Chronic sleep deprivation in young healthy volunteers has been reported to increase appetite and energy expenditure, increase levels of proinflammatory cytokines, decrease parasympathetic and increase sympathetic tone, increase blood pressure, increase evening cortisol levels, as well as elevate insulin and blood glucose. Repeated stress in animal models causes brain regions involved in memory and emotions, such as hippocampus, amygdala, and prefrontal cortex, to undergo structural remodeling with the result that memory is impaired and anxiety and aggression are increased. Structural and functional magnetic resonance imaging studies in depression and Cushing's disease, as well as anxiety disorders, provide evidence that the human brain may be similarly affected. Moreover, brain regions such as the hippocampus are sensitive to glucose and insulin, and both type 1 and type 2 diabetes mellitus are associated with cognitive impairment and (for type 2 diabetes mellitus) increased risk for Alzheimer's disease. Animal models of chronic sleep deprivation indicate that memory is impaired along with depletion of glycogen stores and increases in oxidative stress and free radical production. Taken together, these changes in brain and body are further evidence that sleep deprivation is a chronic stressor and that the resulting allostatic load can contribute to cognitive problems, which can, in turn, further exacerbate pathways that lead to disease

• Seplaki CL, Goldman N, Weinstein M, Lin YH. (2006) Measurement of cumulative physiological dysregulation in an older population.] Demography 43:165-83.

• Abstract: The allostatic load framework postulates that an important pathway connecting the social environment with health involves biological responses to stressful stimuli and the subsequent dysregulation of interrelated physiological systems. We formulate a new measure for cumulative physiological dysregulation using a grade of membership model estimated with biodemographic data from a national sample of older Taiwanese persons. We investigate associations between the measure and physical, psychological, and cognitive function. The results provide insights into the relationships between a set of biological profiles and various health outcomes, identify limitations of earlier approaches, and underscore next steps in the development of improved for mulations of physiological dysregulation

• Stewart JA. (2006) [pii The detrimental effects of allostasis: allostatic load as a measure of cumulative stress.] J Physiol Anthropol 25:133-45.

• Abstract: Since its inception in the 1980s, through further developments during the 1990s, and continuing today, the paradigm of allostatic load (AL) has becomed an important paradigm for predicting senescence and mortality. AL is a cumulative measure of the effects of multiple stressors and the process of responding to stressors on the soma. AL measurements of individuals is being tested on various samples and species and being reported across a variety of medical and social science journals. From the ISI Web of Science, all articles published between January 2000 and June 2005 with AL in any default category were obtained and transferred to Endnote. These articles, categorized as theory/review or data-driven, human or animal, and variability in risk factors used to estimate AL, are reviewed here. Only two of 90 reports were published in anthropological journals, likely, at least partly, because research on AL has focused more on western, industrialized populations where data are more easily obtained. From 2000-2005, 12 of 42 data-driven reports focused on elderly humans. Studies of animal models also are common (0 in 2000, but 4 in 2004 covering 21 species). During the last year, multiple additional potential physiological variables have been tested as measures of AL (10 to 20 in any one article). In the past half decade, AL also has been introduced to a wide range of disciplines, including psychology, anthropology, gerontology, veterinary medicine, and medical specialties, as a viable research theme. AL appears to provide a useful method for determining cumulative somatic stress such as that seen with senescence and frailty at older ages

• Thayer JF, Sternberg E. (2006) [pii;10.1196/annals.1366.014 [doi] Beyond heart rate variability: vagal regulation of allostatic systems.] Ann N Y Acad Sci 1088:361-72.

• Abstract: The autonomic nervous system (ANS) plays a role in a wide range of somatic and mental diseases. Whereas the role of the ANS in the regulation of the cardiovascular system seems evident, its role in the regulation of other systems associated with allostasis is less clear. Using a model of neurovisceral integration we describe how the ANS and parasympathetic tone in particular may be associated with the regulation of allostatic systems associated with glucose regulation, hypothalamic-pituitary-adrenal (HPA) axis function, and inflammatory processes. Decreased vagal function and heart rate variability (HRV) were shown to be associated with increased fasting glucose and hemoglobin A1c levels, increased overnight urinary cortisol, and increased proinflammatory cytokines and acute-phase proteins. All of these factors have been associated with increased allostatic load and poor health. Thus, vagal activity appears to play an inhibitory function in the regulation of allostatic systems. The prefrontal cortex and the amygdala are important central nervous system structures linked to the regulation of these allostatic systems via the vagus nerve. Finally, the identification of this neurovisceral regulatory system may help to illuminate the pathway via which psychosocial factors may influence health and disease

• Tsatsoulis A, Fountoulakis S. (2006) [pii;10.1196/annals.1367.020 [doi] The protective role of exercise on stress system dysregulation and comorbidities.] Ann N Y Acad Sci 1083:196-213.

• Abstract: The human body, when under threat, elicits a set of neuroendocrine responses, including an increased secretion of glucocorticoids (GCs) and catecholamines from the adrenal gland and the activation of the sympathetic nervous system. These hormonal secretions allow a "fight or flight" response by mobilizing endogenous substrate and inducing a state of insulin resistance in the liver and skeletal muscles. Although the stress response was essential in ancient times to survive physical aggression, this threat has disappeared in our industrialized societies. However, in today's environment, the same stress responses can be elicited by emotional stimuli or professional and social stress. Such psychological stress may be protracted and unrelated to an increased metabolic demand. Thus, the energy mobilized is not used but is stored in visceral fat depots by the combined action of hypercortisolism and hyperinsulinemia. In addition, chronic activation of the stress system causes suppression of the gonadal, growth hormone (GH), and thyroid axes. These metabolic disturbances, in concert, lead to the clinical expression of a number of comorbidities including central obesity, hypertension, dyslipidemia, and endothelial dysfunction, all components of the metabolic syndrome and cardiometabolic risk factors. Moreover, chronic stress has deleterious effects on the brain and, in particular, affects hippocampal structure and function leading to cognitive and mood disturbances. Importantly, this stress-induced clinical phenotype is likely to be exaggerated in the presence of physical inactivity, resulting in a "stress-induced/exercise deficient" phenotype. Assuming that the stress response is a neuroendocrine mechanism that occurs in anticipation of physical action, then physical activity should be the natural means to prevent the consequences of stress. Indeed, accumulating evidence documents the beneficial effects of regular exercise in preventing or ameliorating the metabolic and psychological comorbidities induced by chronic stress. These benefits are thought to derive from a central effect of exercise to reduce the sensitivity to stress and also peripheral actions influencing metabolic functions and, in particular, insulin sensitivity and the partitioning of fuels toward oxidation rather than storage. It is concluded that chronic psychosocial stress, in the presence of physical inactivity, is likely to contribute to the epidemic of cardiometabolic and emotional disease of our current society. The way to prevent and combat this burden is by regular exercise

• Bedi US, Arora R. (2007) Cardiovascular manifestations of posttraumatic stress disorder.] J Natl Med Assoc 99:642-9.

• Abstract: Posttraumatic stress disorder (PTSD) involves the onset of psychiatric symptoms after exposure to a traumatic event. PTSD has an estimated lifetime prevalence of 7.8% among adult Americans, and about 15.2% of the men and 8.5% of the women who served in Vietnam suffered from posttraumatic stress disorder (PTSD) > or =15 years after their military service. Physiological responses (increase in heart rate, blood pressure, tremor and other symptoms of autonomic arousal) to reminders of the trauma are a part of the DSM-IV definition of PTSD. Multiple studies have shown that patients suffering from PTSD have increased resting heart rate, increased startle reaction, and increased heart rate and blood pressure as responses to traumatic slides, sounds and scripts. Some researchers have studied the sympathetic nervous system even further by looking at plasma norepinephrine and 24-hour urinary norepinephrine and found them to be elevated in veterans with PTSD as compared to those without PTSD. PTSD is associated with hyperfunctioning of the central noradrenergic system. Hyperactivity of the sympathoadrenal axis might contribute to cardiovascular disease through the effects of the catecholamines on the heart, the vasculature and platelet function. A psychobiological model based on allostatic load has also been proposed and states that chronic stressors over long durations of time lead to increased neuroendocrine responses, which have adverse effects on the body. PTSD has also been shown to be associated with an increased prevalence of substance abuse. With this review, we have discussed the effects of PTSD on the cardiovascular system

• Clark MS, Bond MJ, Hecker JR. (2007) [pii;10.1080/13548500500429338 [doi] Environmental stress, psychological stress and allostatic load.] Psychol Health Med 12:18-30.

• Abstract: The mechanism by which chronic caregiving stress results in poor health is not well understood. The objective was to determine whether such a mechanism may be allostatic load, a novel concept specifying physiological systems that may suffer cumulative wear and tear following chronic stress, leading collectively to poor health. The study examines the association of allostatic load with environmental and psychological stress in the contexts of dementia caregiving and relinquishment of care, and is a 2-year longitudinal comparison of three groups: 80 new dementia spouse caregivers, 120 veteran caregivers, and 60 non-caregivers. Data comprised allostatic load markers and environmental and psychological stress measures. Cross-lagged analyses produced a statistically significant association between psychological stress and one allostatic load component (primary mediators). Psychological stress was a better predictor of primary mediators than environmental stress. Primary mediators rose with time for caregivers, but not for non-caregivers. A greater rise was evident for caregivers who had relinquished their role by the second year, although the level of psychological stress actually declined. Primary mediators are a key component of the relationship between allostatic load and prior stress. When allostatic load is treated as an outcome of stress, it is important to distinguish environmental and psychological stress

• Davies PT, Sturge-Apple ML, Cicchetti D, Cummings EM. (2007) [pii;10.1037/0012-1649.43.4.918 [doi] The role of child adrenocortical functioning in pathways between interparental conflict and child maladjustment.] Dev Psychol 43:918-30.

• Abstract: This study examined the interplay between interparental conflict and child cortisol reactivity to interparental conflict in predicting child maladjustment in a sample of 178 families and their kindergarten children. Consistent with the allostatic load hypothesis (McEwen & Stellar, 1993), results indicated that interparental conflict was indirectly related to child maladjustment through its association with individual differences in child cortisol reactivity. Analyses indicated that the multimethod assessment of interparental conflict was associated with lower levels of child cortisol reactivity to a simulated phone conflict between parents. Diminished cortisol reactivity, in turn, predicted increases in parental reports of child externalizing symptoms over a 2-year period. Associations between interparental conflict, child cortisol reactivity, and child externalizing symptoms remained robust even after demographic factors and other family processes were taken into account

• Evans GW, Kim P, Ting AH, Tesher HB, Shannis D. (2007) [pii;10.1037/0012-1649.43.2.341 [doi] Cumulative risk, maternal responsiveness, and allostatic load among young adolescents.] Dev Psychol 43:341-51.

• Abstract: The purpose of this study was to examine the impact of cumulative risk exposure in concert with maternal responsiveness on physiological indicators of chronic stress in children and youth. Middle-school children exposed to greater accumulated psychosocial (e.g., family turmoil, poverty) and physical (e.g., crowding, substandard housing) risk factors manifested higher levels of allostatic load, a physiological marker of cumulative wear and tear on the body caused by the mobilization of multiple, physiological response systems. This effect was longitudinal, residualizing allostatic load 3-4 years earlier when the youth were in elementary school. This effect, however, occurred only among adolescents with mothers low in responsiveness. Cumulative risk was also associated with dynamic cardiovascular processes in response to an acute stressor (mental arithmetic). Higher risk was associated with muted reactivity and slower, less efficient recovery in blood pressure. These dynamic cardiovascular effects occurred irrespective of maternal responsiveness

• Glei DA, Goldman N, Chuang YL, Weinstein M. (2007) [pii;10.1097/PSY.0b013e318157cba6 [doi] Do chronic stressors lead to physiological dysregulation? Testing the theory of allostatic load.] Psychosom Med 69:769-76.

• Abstract: OBJECTIVES: To explore three questions: 1) Do chronic stressors predict physiological dysregulation? 2) Is that relationship moderated by characteristics of the individual and his or her social environment? and 3) Do perceived levels of stress mediate the relationship between stressors and dysregulation? METHODS: Data come from a nationally representative, longitudinal study of older Taiwanese (n = 916). Regression models are used to examine the relationship between the number of life challenges (i.e., stressors) during 1996 to 2000 and physiological dysregulation (in 2000) based on 16 biomarkers that reflect neuroendocrine function, immune system, cardiovascular function, and metabolic pathways. We include interaction terms to test whether psychosocial vulnerability moderates the impact of stressors. Additional models evaluate the mediating effects of perceived stress. RESULTS: We find a positive association between the number of stressors and physiological dysregulation. The results indicate that this relationship is stronger for persons with greater psychosocial vulnerability, but even so, the magnitude of the effect remains modest. We find some evidence that the level of perceived stress mediates the relationship between chronic stressors and physiological dysregulation. CONCLUSIONS: Our results provide some support for the theory of allostatic load, although the relationship between life challenges and physiological dysregulation is weak. The evidence also supports the stress-buffering hypothesis: the combination of low social position, weak social networks, and poor coping ability is associated with greater physiological consequences of life challenges

• Goldstein DS, Kopin IJ. (2007) Evolution of concepts of stress. Stress 10:109-20.

• Abstract: This essay describes the evolution of stress as a medical scientific idea. Claude Bernard, Walter B. Cannon and Hans Selye provided key founding concepts for the current view. Bernard introduced the idea of the internal environment bathing cells - the milieu interieur - maintained by continual compensatory changes of bodily functions. Cannon coined the word, "homeostasis," referring to a set of acceptable ranges of values for internal variables. Cannon taught that threats to homeostasis evoke activation of the sympathoadrenal system as a functional unit. Selye defined stress as a state characterized by a uniform response pattern, regardless of the particular stressor, that could lead to long-term pathologic changes. "Allostasis" was introduced as a concept in recognition that there is no single ideal set of steady-state conditions in life; instead, setpoints and other response criteria change continuously. Stress is now viewed neither as a perturbation nor a stereotyped response pattern but as a condition characterized by a perceived discrepancy between information about a monitored variable and criteria for eliciting patterned effector responses. Different stressors elicit different patterns of activation of the sympathetic nervous, adrenomedullary hormonal, hypothalamic-pituitary-adrenocortical and other effectors, closing negative feedback loops. This systems concept of stress yields predictions that observation or experimentation can test and that are applicable to normal physiology and to a variety of acute and chronic disorders

• Gunnar M, Quevedo K. (2007) [doi The neurobiology of stress and development.] Annu Rev Psychol 58:145-73.

• Abstract: Stress is a part of every life to varying degrees, but individuals differ in their stress vulnerability. Stress is usefully viewed from a biological perspective; accordingly, it involves activation of neurobiological systems that preserve viability through change or allostasis. Although they are necessary for survival, frequent neurobiological stress responses increase the risk of physical and mental health problems, perhaps particularly when experienced during periods of rapid brain development. Recently, advances in noninvasive measurement techniques have resulted in a burgeoning of human developmental stress research. Here we review the anatomy and physiology of stress responding, discuss the relevant animal literature, and briefly outline what is currently known about the psychobiology of stress in human development, the critical role of social regulation of stress neurobiology, and the importance of individual differences as a lens through which to approach questions about stress experiences during development and child outcomes

• Hamilton NA, Catley D, Karlson C. (2007) Sleep and the affective response to stress and pain. Health Psychol 26:288-95.

• Abstract: OBJECTIVE: The current study examined sleep disturbance (i.e., sleep duration, sleep quality) as a correlate of stress reactivity and pain reactivity. DESIGN AND OUTCOME MEASURES: An ecological momentary assessment design was used to evaluate the psychosocial functioning of men and women with fibromyalgia or rheumatoid arthritis (N=49). Participants recorded numeric ratings of pain, the occurrence of a stressful event, as well as positive and negative affect 7 times throughout the day for 2 consecutive days. In addition, participants reported on their sleep duration and sleep quality each morning. RESULTS: Sleep disruption was not found to be an independent predictor of affect. However, sleep was found to buffer the relationship between stress and negative affect and the relationship between pain and both positive and negative affect. CONCLUSION: These results are consistent with a model in which good-quality sleep acts as a biobehavioral resource that minimizes allostatic load

• Johner RL. (2007) Allostatic load: single parents, stress-related health issues, and social care.] Health Soc Work 32:89-94.

• Abstract: This article explores the possible relationships between allostatic load (AL) and stress-related health issues in the low-income single-parent population, using both a population health perspective (PHP) and a biological framework. A PHP identifies associations among such factors as gender, income, employment, and social support and their potential effect on health outcomes. A PHP also recognizes physiological and pathological manifestations of the body such as stress (mental or somatic) and individual biological parameters (for example, glucose levels) as health determinants. AL uses an aggregate score of individual biological parameters as a health measure that is exacerbated through repetitive movement of physiologic systems under stress. The social work profession should incorporate knowledge of both PHP and AL into its theory and practice domains for effective care of vulnerable populations such as single-parent families

• Kim Y, Laposky AD, Bergmann BM, Turek FW. (2007) Repeated sleep restriction in rats leads to homeostatic and allostatic responses during recovery sleep. Proc Natl Acad Sci U S A 104:10697-702.

• Abstract: Recent studies indicate that chronic sleep restriction can have negative consequences for brain function and peripheral physiology and can contribute to the allostatic load throughout the body. Interestingly, few studies have examined how the sleep-wake system itself responds to repeated sleep restriction. In this study, rats were subjected to a sleep-restriction protocol consisting of 20 h of sleep deprivation (SD) followed by a 4-h sleep opportunity each day for 5 consecutive days. In response to the first 20-h SD block on day 1, animals responded during the 4-h sleep opportunity with enhanced sleep intensity [i.e., nonrapid eye movement (NREM) delta power] and increased rapid eye movement sleep time compared with baseline. This sleep pattern is indicative of a homeostatic response to acute sleep loss. Remarkably, after the 20-h SD blocks on days 2-5, animals failed to exhibit a compensatory NREM delta power response during the 4-h sleep opportunities and failed to increase NREM and rapid eye movement sleep times, despite accumulating a sleep debt each consecutive day. After losing approximately 35 h of sleep over 5 days of sleep restriction, animals regained virtually none of their lost sleep, even during a full 3-day recovery period. These data demonstrate that the compensatory/homeostatic sleep response to acute SD does not generalize to conditions of chronic partial sleep loss. We propose that the change in sleep-wake regulation in the context of repeated sleep restriction reflects an allostatic process, and that the allostatic load produced by SD has direct effects on the sleep-wake regulatory system

• Langelaan S, Bakker AB, Schaufeli WB, van RW, van Doornen LJ. (2007) [doi Is burnout related to allostatic load?] Int J Behav Med 14:213-21.

• Abstract: BACKGROUND: Burnout has a negative impact on physical health, but the mechanisms underlying this relation remain unclear. To elucidate these mechanisms, possible mediating physiological systems or risk factors for adverse health in burned-out employees should be investigated. GOAL: The aim of the present study among 290 Dutch managers was to explore whether allostatic load mediates the relationship between burnout and physical health. METHOD: Burned-out managers, as identified with the Maslach Burnout Inventory General Survey (MBI-GS), were compared with a healthy control group with regard to their allostatic load. The allostatic load index included eight parameters: Body-mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), C-reactive protein (CRP), high-density lipoprotein (HDL), cholesterol, glycosylated hemoglobin (HbA1C) and glucose. RESULTS: Contrary to expectations, burned-out managers did not differ from healthy managers with regard to their scores on the allostatic load index. An additional analysis, using groups of managers in the extreme deciles of exhaustion (the core symptom of burnout), did also not reveal differences in allostatic load. CONCLUSION: Burnout seems not to be associated with this proxy measure of allostatic load. The mediating physiological mechanisms between burnout and objective physical health remain to be elucidated

• Le MM. (2007) Historical approach and evolution of the stress concept: a personal account. Psychoneuroendocrinology 32 Suppl 1:S3-S9.

• Abstract: As a matter of research or as a process, stress remains one of the most cited construct in biomedical literature; a medline survey accounts for more than 210,000 citations since 1970. It is difficult to define. It is frequently used in a vague manner, including undifferently the agent, the process, and the response. The concept is multidimensional and composite, including emotion and arousal. Stress has an implicit: it implies alteration of a theoretical balance or equilibrium within physiological systems, and it seems to characterize a process leading to disease. Large individual differences exist in the way to react to a stressor. Psychological and cognitive determinants are central for the course of the process. The homeostasis concept is not useful anymore and has been replaced by the more accurate and flexible concept of allostasis. The physiological hormonal and neural bases of this process are now identified. New perspectives identify stressors, chronic or not, to be a source of vulnerabilities through epigenetic mechanisms and a series of biobehavioral disorders characteristic of our modern civilizations. The evolution of the concept is not linear. It has been enriched by recent neurobiological-neuroendocrinological discoveries and also by behavioral-cognitive sciences

• Manoli I, Alesci S, Blackman MR, Su YA, Rennert OM, Chrousos GP. (2007) Mitochondria as key components of the stress response. Trends Endocrinol Metab 18:190-8.

• Abstract: The exquisitely orchestrated adaptive response to stressors that challenge the homeostasis of the cell and organism involves important changes in mitochondrial function. A complex signaling network enables mitochondria to sense internal milieu or environmental changes and to adjust their bioenergetic, thermogenic, oxidative and/or apoptotic responses accordingly, aiming at re-establishment of homeostasis. Mitochondrial dysfunction is increasingly recognized as a key component in both acute and chronic allostatic states, although the extent of its role in the pathogenesis of such conditions remains controversial. Genetic and environmental factors that determine mitochondrial function might contribute to the significant variation of the stress response. Understanding the often reciprocal interplay between stress mediators and mitochondrial function is likely to help identify potential therapeutic targets for many stress and mitochondria-related pathologies

• Maselko J, Kubzansky L, Kawachi I, Seeman T, Berkman L. (2007) [pii;10.1097/PSY.0b013e31806c7c57 [doi] Religious service attendance and allostatic load among high-functioning elderly.] Psychosom Med 69:464-72.

• Abstract: OBJECTIVE: To examine the association between frequency of religious service attendance and an index of cumulative physiological dysregulation as measured by allostatic load (AL) (systolic and diastolic blood pressure, waist/hip ratio, high-density lipoprotein and total cholesterol, glycosylated hemoglobin, cortisol, serum dihydroepiandrosterone sulfate, norepinephrine, and epinephrine).There is growing empirical evidence of a positive relationship between religious engagement and better clinical health outcomes. However, studies exploring the subclinical levels of physiological dysregulation are rare; hence, the physiological processes underpinning the religion-health relationship are not well understood. METHODS: In 1988, 853 participants from the MacArthur Successful Aging Study provided information on the frequency of religious service attendance as well as blood and urine samples needed to obtain measures for a ten-item cumulative AL index. Gender-stratified multivariate linear regression models were used to estimate the direction and magnitude of the association between weekly religious service attendance and AL. RESULTS: At least weekly religious service attendance was associated with lower AL levels among women (b = -0.47; p < .01), but not among men (b = 0.02; p = .88) in models that statistically controlled for age, income, education, marital status, and level of physical functioning. This relationship could not be attributed to the association between religious attendance and any one or two of the components of the AL index. It also was not explained by either higher physical functioning or social integration. CONCLUSION: Cumulative physiological dysregulation may be one mechanism through which religious engagement may influence a diverse range of clinically relevant health outcomes

• Mays VM, Cochran SD, Barnes NW. (2007) Race, race-based discrimination, and health outcomes among African Americans. Annu Rev Psychol 58:201-25.

• Abstract: Persistent and vexing health disadvantages accrue to African Americans despite decades of work to erase the effects of race discrimination in this country. Participating in these efforts, psychologists and other social scientists have hypothesized that African Americans' continuing experiences with racism and discrimination may lie at the root of the many well-documented race-based physical health disparities that affect this population. With newly emerging methodologies in both measurement of contextual factors and functional neuroscience, an opportunity now exists to cleave together a comprehensive understanding of the ways in which discrimination has harmful effects on health. In this article, we review emerging work that locates the cause of race-based health disparities in the external effects of the contextual social space on the internal world of brain functioning and physiologic response. These approaches reflect the growing interdisciplinary nature of psychology in general, and the field of race relations in particular

• McEwen BS. (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87:873-904.

• Abstract: The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging. Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis"). The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids. Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course. Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses. As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience

• McIntyre RS, Soczynska JK, Konarski JZ et al. (2007) Should Depressive Syndromes Be Reclassified as "Metabolic Syndrome Type II"? Ann Clin Psychiatry 19:257-64.

• Abstract: BACKGROUND: A nascent explanatory theory regarding the pathophysiology of major depressive disorder posits that alterations in metabolic networks (e.g., insulin and glucocorticoid signaling) mediate allostasis. METHOD: We conducted a PubMed search of all English-language articles published between January 1966 and September 2006. The search terms were: neurobiology, cognition, neuroprotection, inflammation, oxidative stress, glucocorticoids, metabolic syndrome, diabetes mellitus, insulin, and antidiabetic agents, cross-referenced with the individual names of DSM-III-R/IV/-TR-defined mood disorders. The search was augmented with a manual review of article reference lists; articles selected for review were determined by author consensus. RESULTS: Disturbances in metabolic networks: e.g., insulin-glucose homeostasis, immuno-inflammatory processes, adipokine synthesis and secretion, intra-cellular signaling cascades, and mitochondrial respiration are implicated in the pathophysiology, brain volumetric changes, symptomatic expression (e.g., neurocognitive decline), and medical comorbidity in depressive disorders. The central nervous system, like the pancreas, is a critical modulator of the metabolic milieu and is endangered by chronic abnormalities in metabolic processes. We propose the notion of "metabolic syndrome type II" as a neuropsychiatric syndrome in which alterations in metabolic networks are a defining pathophysiological component. CONCLUSION: A comprehensive management approach for depressive disorders should routinely include opportunistic screening and primary prevention strategies targeting metabolically mediated comorbidity (e.g., cardiovascular disease). Innovative treatments for mood disorders, which primarily target aberrant metabolic networks, may constitute potentially novel, and disease-modifying, treatment avenues

• Shannon M, King TL, Kennedy HP. (2007) Allostasis: a theoretical framework for understanding and evaluating perinatal health outcomes. J Obstet Gynecol Neonatal Nurs 36:125-34.

• Abstract: OBJECTIVE: To explore the theory of allostasis within the context of childbearing women's perceptions or experiences of stress and perinatal health outcomes. DATA SOURCES: Articles published in refereed journals and selected chapters from published books that addressed physiological and psychological effects of perceived or actual stress experiences, or both, including the theory of allostasis, on health outcomes. STUDY SELECTION: Qualitative, quantitative, and review articles that focused on psychoneurohormonal responses to physical and psychological stress in pregnant and nonpregnant human cohorts and the theory of allostasis. DATA EXTRACTION AND SYNTHESIS: The impact of abnormal allostatic states in childbearing women in response to physiological and psychological perceptions or experiences of stress, or both was analyzed. There is a growing body of epidemiologic evidence to support the relationship between maternal stress and adverse pregnancy outcomes. CONCLUSIONS: The theory of allostasis provides a framework for understanding and evaluating the complex elements of stress, coping, and adaptation during childbearing on perinatal health outcomes and has the potential to provide new insight into previously unexplained adverse perinatal events

• Sonino N, Tomba E, Fava GA. (2007) Psychosocial approach to endocrine disease. Adv Psychosom Med 28:21-33.

• Abstract: In recent years, there has been growing interest in the psychosocial aspects of endocrine disease, such as the role of life stress in the pathogenesis of some conditions, their association with affective disorders, and the presence of residual symptoms after adequate treatment. In clinical endocrinology, exploration of psychosocial antecedents may elucidate the temporal relationships between life events and symptom onset, as it has been shown to be relevant for pituitary (Cushing's disease, hyperprolactinemia) or thyroid (Graves' disease) conditions, as well as the role of allostatic load, linked to chronic stress, in uncovering a person's vulnerability. After endocrine abnormalities are established, they are frequently associated with a wide range of psychological symptoms: at times, such symptoms reach the level of psychiatric illness (mainly mood and anxiety disorders); at other times, however, they can only be identified by the subclinical forms of assessment provided by the Diagnostic Criteria for Psychosomatic Research (DCPR). Indeed, in a population study, the majority of patients suffered from at least one of the three DCPR syndromes considered: irritable mood, demoralization, persistent somatization. In particular, irritable mood was found to occur in 46% of 146 patients successfully treated for endocrine conditions, a rate similar to that found in cardiology and higher than in oncology and gastroenterology. Long-standing endocrine disorders may imply a degree of irreversibility of the pathological process and induce highly individualized affective responses. In patients who showed persistence or even worsening of psychological distress upon proper endocrine treatment, the value of appropriate psychiatric interventions was underscored. As it happened in other fields of clinical medicine, a conceptual shift from a merely biomedical care to a psychosomatic consideration of the person and his/her quality of life appears to be necessary for improving effectiveness in endocrinology. The DCPR have been demonstrated to be a valuable tool for psychological assessment in the various phases of endocrine disease from diagnostic to follow-up periods

• Wei Q, Hebda-Bauer EK, Pletsch A et al. (2007) Overexpressing the glucocorticoid receptor in forebrain causes an aging-like neuroendocrine phenotype and mild cognitive dysfunction. J Neurosci 27:8836-44.

• Abstract: Repeated stress enhances vulnerability to neural dysfunction that is cumulative over the course of the lifespan. This dysfunction contributes to cognitive deficits observed during aging. In addition, aging is associated with dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis, leading to a delayed termination of the stress response. This delay, in turn, increases exposure to glucocorticoids and exacerbates the likelihood of neural damage. Here we asked whether similar effects could emerge at an early age as a result of genetic variations in the level or function of the brain glucocorticoid receptor (GR). We investigated the effect of forebrain-specific overexpression of GR on LHPA axis activity. Transgenic mice with GR overexpression in forebrain (GRov) display normal basal circulating adrenocorticotropic hormone and corticosterone levels. However, young GRov mice exhibit a number of LHPA alterations, including a blunted initial response to acute restraint stress followed by a delayed turn-off of the stress response. This deficit in negative feedback is paradoxical in the face of elevated GR levels, resembles the stress response in aged animals, and continues to worsen as GRov mice age. The neuroendocrine dysregulation in young GRov mice is coupled with a mild cognitive deficit, also consistent with the accelerated aging hypothesis. The molecular basis of this phenotype was examined using microarray analysis of the hippocampus, which revealed a broad downregulation of glutamate receptor signaling in GRov mice. Thus, even in the absence of chronic stress, elevation of GR gene expression can lead to an increased allostatic load and result in an "aging-like" phenotype in young animals

• Weiss R, Cali AM, Dziura J, Burgert TS, Tamborlane WV, Caprio S. (2007) Degree of obesity and glucose allostasis are major effectors of glucose tolerance dynamics in obese youth. Diabetes Care 30:1845-50.

• Abstract: OBJECTIVE: One of the signals for the beta-cell to maintain an adequate response to worsening insulin sensitivity is elevated ambient glycemia, namely the concept of "glucose allostasis." We examined whether glucose allostasis can be demonstrated using oral glucose tolerance tests (OGTTs) and the effects of the dynamics of beta-cell demand on longitudinal changes of glucose tolerance in obese youth. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of 784 OGTTs of obese youth was used to demonstrate the concept of allostasis, and a longitudinal assessment of 181 subjects was used to examine the effects of changes in beta-cell demand and the degree of obesity on glucose tolerance. RESULTS: Glucose allostasis can be demonstrated using indexes derived from an OGTT. Increasing beta-cell demand and the degree of obesity at baseline were independently related to elevations in ambient glycemia over time. Baseline BMI Z score was a significant contributor to elevated glucose levels on the second OGTT, while the change in degree of obesity during follow-up was not. CONCLUSIONS: Increasing beta-cell demand related to worsening insulin sensitivity and the degree of obesity per se have independent roles in the development of elevated glucose levels over time. This implicates that peripheral insulin sensitization and/or beta-cell enhancement alongside a significant reduction in obesity may be needed to prevent the development of altered glucose metabolism in obese youth

• Weiss SJ. (2007) Neurobiological alterations associated with traumatic stress. Perspect Psychiatr Care 43:114-22.

• Abstract: PURPOSE: The purpose of this article is to describe the effects of traumatic stress on brain structure and function, and the relationship of these neurobiological changes to symptoms experienced after trauma. CONCLUSIONS: Exposure to traumatic stress is associated with changes in the limbic system, the hypothalamic-pituitary-adrenal axis, and key monoamine neurotransmitters. Different neurobiological alterations can be linked to specific symptoms of hyperarousal, dissociation/numbing, and reexperiencing of the trauma. PRACTICE IMPLICATIONS: Understanding what is happening in the brain can inform more targeted treatment for various symptoms that the individual may be experiencing

• Anderson GC. (2008) Allostatic load and failure to progress. J Obstet Gynecol Neonatal Nurs 37:2-3.
• Bellingrath S, Weigl T, Kudielka BM. (2008) [pii;10.1080/10253890802042041 [doi] Chronic work stress and exhaustion is associated with higher allostastic load in female school teachers.] Stress1.

• Abstract: Epidemiological studies have shown that chronic work stress or unfavourable psychosocial work conditions are prospectively associated with different adverse health outcomes. The aim of the present cross-sectional study was to investigate the relationship between work-related chronic stress as well as exhaustion and a cumulative measure of physiological wear-and-tear called allostatic load (AL). AL could be a possible biological pathway for how chronic work stress and exhaustion lead to health impairments in the long run. As the teaching profession has been proposed to be a potentially high stressful occupation, chronic work stress (effort-reward-imbalance) and exhaustion were assessed in 104 female school teachers. AL was first analyzed according to McEwen's classical model comprised of ten parameters including cortisol, epinephrine and norepinephrine, dehydroepiandrosterone-sulphate (DHEA-S), waist/hip-ratio (WHR), glycosylated haemoglobin (HbA1c), high-density lipoprotein (HDL), total cholesterol/HDL-ratio, and systolic and diastolic blood pressure. Additionally it was extended to include tumor-necrosis-factor-alpha (TNF-alpha), C-reactive protein (CRP), fibrinogen, D-dimer, percent-body-fat, triglycerides, and glucose levels. A substantial proportion of our sample was highly exhausted whereas relatively few teachers showed high effort-reward-imbalance. AL scores were significantly higher in women high on effort-reward-imbalance or suffering from exhaustion. Although all teachers had been in a good health status, chronic work stress as well as exhaustion appears to be associated with changes in a multi-system summary indicator of physiological risk

• Gebicke-Haerter PJ, Tretter F. (2008) The systems view in addiction research. Addict Biol 13:449-54.

• Abstract: The wealth of information accessible on the molecular level after completion of sequencing of the human and other genomes and in conjunction with new high-throughput technologies like microarrays has paved the way for research on whole systems rather than on single components. Here we describe exemplarily the construction of a rather complex molecular network involved in alcohol addiction by using information from DNA-microarray studies in alcohol-dependent animals. In this network, haemoglobin downregulation in different parts of the brain reward system plays a central role in affecting synaptic plasticity, circadian rhythmicity and opioid receptors. Furthermore, we discuss the dynamic aspect of biological systems with respect to repeated and intermittent drug intake. This aspect can best be captured by the allostatic model on the molecular level. Using a molecular oscillator model where levels of oscillations are changed by repetitive drug administration, changes in set point adjustment are described that underlay allostatic shifts in drug reinforcement processes

• Grassi-Oliveira R, Ashy M, Stein LM. (2008) Psychobiology of childhood maltreatment: effects of allostatic load?] Rev Bras Psiquiatr 30:60-8.

• Abstract: OBJECTIVE: Facing an adverse physical or psychosocial situation, an individual is forced to adapt in order to survive. Allostasis is the term used to refer to adapting processes used to maintain the stability of an organism through active processes. When allostatic response is excessive or inefficient, the organism develops an allostatic load. The cascade of molecular and neurobiological effects associated with childhood abuse and neglect could be an example of allostatic response that could precipitate allostatic load in organism still vulnerable during its development. This article reviews the psychobiological consequences related to childhood abuse and neglect. METHOD: A selective review with a systematic procedure was performed to investigate studies showing explicit association between childhood maltreatment and psychobiological/neurobiological consequences. We searched electronic database MedLine-PubMed to identify English-language articles from 1990 to 2007. RESULTS: From 115 articles we selected 55 studies from MedLine and 30 from their reference lists, in a total of 85 articles (JCR IF range: 1-31.4; median: 5.88). Only 29 studies showed direct and explicit association between them. CONCLUSION: Structural consequences of childhood maltreatment include disruptive development of corpus callosum, left neocortex, hippocampus, and amygdale; functional consequences include increased electrical irritability in limbic areas, frontal lobe dysfunctions and reduced functional activity of the cerebellar vermis; and neurohumoral consequences include the reprogramming activity of hypothalamo-pituitary-adrenal (HPA) axis and subsequently the stress response

• Hamilton NA, Affleck G, Tennen H et al. (2008) Fibromyalgia: the role of sleep in affect and in negative event reactivity and recovery. Health Psychol 27:490-7.

• Abstract: OBJECTIVE: Fibromyalgia (FM) syndrome is a chronic pain condition characterized by diffuse muscle pain, increased negative mood, and sleep disturbance. Until recently, sleep disturbance in persons with FM has been modeled as the result of the disease process or its associated pain. The current study examined sleep disturbance (i.e., sleep duration and sleep quality) as a predictor of daily affect, stress reactivity, and stress recovery. DESIGN AND MEASURES: A hybrid of daily diary and ecological momentary assessment methodology was used to evaluate the psychosocial functioning of 89 women with FM. Participants recorded numeric ratings of pain, fatigue, and positive and negative affect 3 times throughout the day for 30 consecutive days. At the end of each day, participants completed daily diary records of positive and negative life events. In addition, participants reported on their sleep duration and sleep quality each morning. RESULTS: After accounting for the effects of positive events, negative events, and pain on daily affect scores, it was found that sleep duration and quality were prospectively related to affect and fatigue. Furthermore, the effects of inadequate sleep on negative affect were cumulative. In addition, an inadequate amount of sleep prevented affective recovery from days with a high number of negative events. CONCLUSIONS: These results lend support to the hypothesis that sleep is a component of allostatic load and has an upstream role in daily functioning

• Joels M. (2008) The concept of allostasis and allostatic load. Eur J Pharmacol 583:173.
• Kapczinski F, Vieta E, Andreazza AC et al. (2008) Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 32:675-92.

• Abstract: Current literature on the effects of chronic stress in general health converges to the concept of allostatic load (AL). AL is the bodily 'wear and tear' that emerges with sustained allostatic states. In the field of bipolar disorder (BD), AL offers an important clue as to why patients who undergo recurrent mood episodes are clinically perceived as less resilient. In addition, AL helps explaining the cumulative disruptive health effects of intermittent episodes and stressors. Stress- and episode-induced changes in brain regions involved in the emotional circuitry may lead to dysfunctional processing of information, which would render BD patients more vulnerable to subsequent environmental stressors, episodes, and drugs of abuse. Mood stabilizing agents exert opposite effects than chronic stress in neurons, increasing neuroprotective factors what may help to quench the cycle of affective episode recurrence and neural and bodily deterioration. Therefore, AL provides an explanatory link to apparently unrelated findings such as cognitive impairment and higher rates of physical comorbidity and mortality that are observed in the course of BD and further highlight the importance of effective long-term prophylaxis

• Logan JG, Barksdale DJ. (2008) Allostasis and allostatic load: expanding the discourse on stress and cardiovascular disease. J Clin Nurs 17:201-8.

• Abstract: AIM: The aim of this discursive paper is to introduce allostasis and allostatic load, which are relatively new concepts proposed to explain physiological responses to stress, and to suggest ways in which allostasis theory can be applied to the development of clinical interventions to increase resilience for producing better health outcome. BACKGROUND: Common explanations of stress have failed adequately to explicate its association with health and chronic illness. Allostasis is the extension of the concept of homeostasis and represents the adaptation process of the complex physiological system to physical, psychosocial and environmental challenges or stress. Allostatic load is the long-term result of failed adaptation or allostasis, resulting in pathology and chronic illness. DISCUSSION: The concepts of allostasis and allostatic load introduced the idea that external challenges initiate allostasis and chronic stress causes allostatic load that can be measured with multiple biomarkers. Finding from several studies suggests that higher allostatic load is associated with worse health outcomes. Resilience represents successful allostasis and strategies can be implemented to enhance resilience and thereby improve health outcomes. CONCLUSIONS: This theoretical model provides a comprehensive explanation of the human body's adaptation processes in response to stress and the results of failed adaptation over time. In addition, combining the concepts of allostasis and resilience may help us to understand and implement clinical strategies better to reduce or prevent the debilitating physiological and psychological effects of chronic stress and chronic illness. RELEVANCE TO CLINICAL PRACTICE: Clinical practice should be based on a solid theoretical foundation to improve health outcomes. Strategies to manage stress and increase resilience along with clinical interventions to manage the physiological responses to chronic stress are necessary to assist in preventing and controlling the detrimental effects of chronic disease on human life

• McEwen BS. (2008) Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol 583:174-85.

• Abstract: Stress begins in the brain and affects the brain, as well as the rest of the body. Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems. Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated. The burden of chronic stress and accompanying changes in personal behaviors (smoking, eating too much, drinking, poor quality sleep; otherwise referred to as "lifestyle") is called allostatic overload. Brain regions such as hippocampus, prefrontal cortex and amygdala respond to acute and chronic stress and show changes in morphology and chemistry that are largely reversible if the chronic stress lasts for weeks. However, it is not clear whether prolonged stress for many months or years may have irreversible effects on the brain. The adaptive plasticity of chronic stress involves many mediators, including glucocorticoids, excitatory amino acids, endogenous factors such as brain neurotrophic factor (BDNF), polysialated neural cell adhesion molecule (PSA-NCAM) and tissue plasminogen activator (tPA). The role of this stress-induced remodeling of neural circuitry is discussed in relation to psychiatric illnesses, as well as chronic stress and the concept of top-down regulation of cognitive, autonomic and neuroendocrine function. This concept leads to a different way of regarding more holistic manipulations, such as physical activity and social support as an important complement to pharmaceutical therapy in treatment of the common phenomenon of being "stressed out". Policies of government and the private sector play an important role in this top-down view of minimizing the burden of chronic stress and related lifestyle (i.e. allostatic overload)

• O'Donnell E, Harvey PJ, De Souza MJ. (2008) Relationships between vascular resistance and energy deficiency, nutritional status and oxidative stress in oestrogen deficient physically active women. Clin Endocrinol (Oxf)

• Abstract: Objective: Oestrogen deficiency contributes to altered cardiovascular function in premenopausal amenorrheic physically active women. We investigated whether other energy deficiency-associated factors might also be associated with altered cardiovascular function in these women. Design: A prospective observational study was completed at a research facility at the University of Toronto. Participants: Thirty-two healthy premenopausal women (18-35 years old) were studied: 9 sedentary and ovulatory; 14 physically active and ovulatory; and 8 physically active and amenorrheic. Measurements: We measured calf vascular resistance, resting heart rate, dietary energy intake, resting energy expenditure and serum measures of homocysteine, high-sensitivity C-reactive protein, oxidized low-density lipoproteins, total T(3), ghrelin, leptin, and insulin. Results: Groups were similar (P>0.05) in age (25.1+/-0.8 years; mean +/- SEM), weight (57.3+/-1.1 kg), and BMI (21.4+/-0.3 kg/m(2)). Resting vascular resistance and ghrelin were highest (P<0.05, main effect), and total T(3) and energy expenditure adjusted for fat free mass lowest (P<0.05, main effect) in oestrogen deficient women. Using pooled data for stepwise multiple regression modeling: ghrelin and resting energy expenditure adjusted for fat free mass were associated with resting vascular resistance (R(2)=0.398, P=0.018); adjusted dietary energy intake was associated with peak-ischemic vascular resistance (R(2)=0.231, P=0.015). Adjusted resting energy expenditure (r=0.624, P<0.001) and total T(3) correlated (r=0.427, P=0.019) with resting heart rate. Homocysteine, high-sensitivity C-reactive protein and oxidized low-density lipoproteins were similar (P>0.05, main effect) among the groups, and were unrelated to cardiovascular measures. Conclusion: Altered resting vascular resistance in premenopausal oestrogen deficient physically active amenorrheic women is not associated with vascular inflammation or oxidative stress, but rather with parameters that reflect metabolic allostasis and dietary intake, suggesting a potential role for chronic energy deficiency in vascular regulation

• van DG, Buwalda B. (2008) Neurobiology of the metabolic syndrome: an allostatic perspective. Eur J Pharmacol 585:137-46.
• Abstract: The metabolic syndrome is a cluster of more or less related metabolic and cardiovascular derangements including visceral obesity, insulin resistance, blood and tissue dislipidemia, high blood pressure and it is often associated with neuroendocrine and immunological dysregulations. The aetiology of this syndrome is clinically highly relevant because it predisposes to life-threatening complications, such as Diabetes Mellitus, kidney failure, cardiovascular disease, and certain types of cancer. Contributing factors include a sedentary life-style combined with increased dietary fat intake and psychosocial stress. From a biological viewpoint, however, the metabolic syndrome can be considered as a maladaptive consequence of an initially successful adaptation to high environmental demands. As opposed to pre-historic times - when environmental demands were usually energy-costly (e.g., fight/flight/hunt) and nutritional resource often inadequate - energy-utilizing actions serve no longer an optimal solution to deal with environmental demands of current human society. This paper describes the interactions between psychosocial stress and nutrition and how these may affect emotional and metabolic components of the metabolic syndrome. A deeper understanding of these interactions is necessary to come to effective treatment and prevention of the metabolic syndrome in the future.