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Cited by 1,864Stress Responses and CortisolNeuropeptides and Animal PhysiologyNeuroscience and Neuropharmacology Research

Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators

Open access
McEwen, Bruce S.·2008·European Journal of Pharmacology
DOI 10.1016/j.ejphar.2007.11.071PMC PMC2474765
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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).

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Written from the paper’s full text.

TL;DR

This review argues that the brain is the central organ of the stress response and that acute stress mediators are protective/adaptive, whereas chronic or dysregulated allostasis produces “allostatic overload” that damages brain and body. It synthesizes evidence on stress-induced structural plasticity in hippocampus, prefrontal cortex, and amygdala, and discusses top-down behavioral and policy interventions.

Key findings

  • Acute stress responses promote adaptation via neural, cardiovascular, autonomic, immune, and metabolic systems, but chronic stress can promote pathophysiology through the same systems; the cumulative burden plus behaviors such as poor sleep, smoking, overeating, drinking, and inactivity is termed allostatic overload.
  • In hippocampus, chronic restraint stress causes retraction and simplification of CA3 dendrites, while repeated stress causes dendritic shortening in medial prefrontal cortex but dendritic growth in amygdala and orbitofrontal cortex; these changes are largely reversible if chronic stress lasts weeks, though it is unclear whether stress lasting months or years has irreversible brain effects.
  • Adult rat dentate gyrus produces about 9,000 new neurons per day with a half-life of 28 days; the dentate gyrus–CA3 system gives roughly 600-fold amplification of excitation and 300-fold amplification of inhibition.
  • Human findings cited include 12–13% smaller hippocampal volume in individuals with poor self-esteem and low internal locus of control, and lower allostatic load scores in people with 3 or more regular social contacts versus 0–2 contacts; a 12-month modest cortisol regimen did not cause outright neuronal loss in pigtail macaque hippocampus.

Methods

  • Narrative review synthesizing animal and human studies on stress mediators, allostasis/allostatic load, and brain structural plasticity.
  • Evidence includes rodent chronic stress and glucocorticoid studies, nonhuman primate cortisol studies, human neuroimaging, clinical studies of depression/Cushing’s disease/PTSD, and psychosocial studies.
  • Main analysis is conceptual integration of allostasis, allostatic overload, and top-down regulation of cognitive, autonomic, and neuroendocrine function; no primary data or systematic meta-analysis are reported.

Limitations

  • Stated: the interacting allostatic systems are non-linear and cannot all be measured simultaneously, so studies rely on only a few biomarkers and must interpret results with that non-linearity in mind.
  • Stated: it is not clear whether prolonged stress for many months or years may have irreversible effects on the brain; mechanistic differences between chronic restraint stress and chronic corticosterone treatment remain to be determined, and BDNF mRNA findings after chronic restraint stress are contradictory.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy, quality appraisal, or meta-analytic synthesis, and much of the mechanistic evidence comes from animal models, limiting direct causal inference in humans.

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Integrity signals

Registry

Crossref · 10.1016/j.ejphar.2007.11.071

Cites

160 of 160 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation
    § 2. Central role of the brain

    Cold and uncaring families produce long-lasting emotional problems in children.

    “Cold and uncaring families produce long-lasting emotional problems in children (Repetti et al., 2002).”
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  • Interpretationcitation

    The same mediators involved in the maladaptive consequences of sleep deprivation are involved in the natural world in adaptation to environmental changes.

    “In contrast to these potentially maladaptive consequences, the same mediators are involved in the natural world in adaptation to environmental changes (McEwen and Wingfield, 2003).”
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    Parasympathetic activity has anti-inflammatory effects.

    “Parasympathetic activity also has anti-inflammatory effects (Thayer and Lane, 2000; Borovikova et al., 2000).”
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    Chronic elevation of the same mediators, such as chronically increased heart rate and blood pressure, produces chronic wear and tear on the cardiovascular system that can result, over time, in disorders such as stroke and heart attacks.

    “on the other hand, chronic elevation of these same mediators - e.g. chronically increased heart rate and blood pressure – produce a chronic wear and tear on the cardiovascular system that can result, over time, in disorders such as stroke and heart attacks.”
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  • Interpretationcitation
    § 2. Central role of the brain

    Different alleles of commonly occurring genes determine how individuals will respond to experiences.

    “Different alleles of commonly occurring genes determine how individuals will respond to experiences.”
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    Interpretationnone given
    § 1. Introduction

    Many other mediators, such as pro- and anti-inflammatory cytokines and the parasympathetic nervous system, are also involved in the adaptation to stressors, as well as in the negative impact of chronic stress.

    “Although glucocorticoids and catecholamines are the two defining hormones of the “fight or flight” stress response, there are many other mediators, such as pro- and anti-inflammatory cytokines and the parasympathetic nervous system, that are also involved in the adaptation to stressors, as well as in the negative impact of chronic stress, known in every day language as being “stressed out”.”
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    § 1. Introduction

    The brain is the central organ of the stress response and determines what is stressful, as well as the behavioral and physiological responses to potential and actual stressors.

    “The brain is the central organ of the stress response and determines what is stressful, as well as the behavioral and physiological responses to potential and actual stressors.”
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    § Abstract

    The adaptive plasticity of chronic stress involves many mediators, including glucocorticoids, excitatory amino acids, endogenous factors such as BDNF, PSA-NCAM and tPA.

    “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).”
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    § 1. Introduction

    The brain is also a target of stress and it changes structurally and chemically in response to both acute and chronic stressors.

    “The brain is also a target of stress and it changes structurally and chemically in response to both acute and chronic stressors.”
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    § Abstract

    Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated.

    “Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated.”
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    § Abstract

    Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems.

    “Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems.”
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    Interpretationnone given
    § 1. Introduction

    There are important differences in the effects of acute and chronic stress, as well as differences in the consequences of acute and chronic treatment with glucocorticoids.

    “Indeed, there are important differences in the effects of acute and chronic stress, as well as differences in the consequences of acute and chronic treatment with glucocorticoids.”
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    Interpretationreasoning
    § 1. Introduction

    Glucocorticoids play a role in stress-induced brain changes, but there are other mediators as well.

    “Glucocorticoids play a role in these changes, but there are other mediators as well.”
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    Premisecitation

    The body responds to almost any sudden, unexpected event by releasing chemical mediators, such as catecholamines that increase heart rate and blood pressure, and these help the individual cope with the situation.

    “on the one hand, the body responds to almost any sudden, unexpected event by releasing chemical mediators – e.g. catecholamines that increase heart rate and blood pressure – and help the individual cope with the situation”
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    Interpretationnone given
    § Abstract

    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.

    “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.”
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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given
    § Abstract

    Stress begins in the brain and affects the brain, as well as the rest of the body.

    “Stress begins in the brain and affects the brain, as well as the rest of the body.”
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    Premisecitation
    § 2. Central role of the brain

    The short form of the serotonin transporter is associated with a number of conditions such as alcoholism, and individuals who have this allele are more vulnerable to respond to stressful experiences by developing depressive illness.

    “For example, the short form of the serotonin transporter is associated with a number of conditions such as alcoholism, and individuals who have this allele are more vulnerable to respond to stressful experiences by developing depressive illness (Caspi et al., 2003).”
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    § 2. Central role of the brain

    There are enormous individual differences in the response to stress, based upon the experience of the individual early in life and in adult life.

    “There are enormous individual differences in the response to stress, based upon the experience of the individual early in life and in adult life.”
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    Premisecitation
    § 2. Central role of the brain

    Uncertainty in the food supply for rhesus monkey mothers leads to increased emotionality in offspring and possibly an earlier onset of obesity and diabetes.

    “For example, uncertainty in the food supply for rhesus monkey mothers leads to increased emotionality in offspring and possibly an earlier onset of obesity and diabetes (Coplan et al., 2001).”
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    Premisecitation

    In Spring, a sudden snowstorm is an acute stressor to birds and disrupts mating, and elevated cortisol is pivotal in directing the birds to suspend reproduction, to find a source of food and to relocate to a better mating site or at least to delay reproduction until the weather improves.

    “Regarding allostasis, in Spring, a sudden snowstorm is an acute stressor to birds and disrupts mating, and elevated cortisol is pivotal in directing the birds to suspend reproduction, to find a source of food and to relocate to a better mating site or at least to delay reproduction until the weather improves (Wingfield and Romero, 2000).”
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    Premisecitation
    § 2. Central role of the brain

    In rodents, abuse of the young is associated with an attachment, rather than an avoidance, of the abusive mother, an effect that increases the chances that the infant can continue to obtain food and other support until weaning.

    “Furthermore, in rodents, abuse of the young is associated with an attachment, rather than an avoidance, of the abusive mother, an effect that increases the chances that the infant can continue to obtain food and other support until weaning (Sullivan et al., 2000).”
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    Premisecitation

    Hunger for comfort foods and increased caloric intake are one result of sleep deprivation, along with depressed mood and cognitive impairment.

    “Hunger for comfort foods and increased caloric intake are one result, along with depressed mood and cognitive impairment (Dallman, 2003;McEwen, 2006).”
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    Premisecitation

    Catecholamines can increase pro-inflammatory cytokine production, whereas glucocorticoids inhibit this production.

    “Whereas catecholamines can increase pro-inflammatory cytokine production, glucocorticoids are known to inhibit this production (Sapolsky et al., 2000).”
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    Premisecitation
    § 2. Central role of the brain

    Effects of early maternal care are transmitted across generations by the subsequent behavior of the female offspring as they become mothers, and methylation of DNA on key genes appears to play a role in this epigenetic transmission.

    “Effects of early maternal care are transmitted across generations by the subsequent behavior of the female offspring as they become mothers, and methylation of DNA on key genes appears to play a role in this epigenetic transmission (Weaver et al., 2004).”
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    Premisecitation

    Bears preparing to hibernate for the winter eat large quantities of food and put on body fat to act as an energy source during the winter.

    “For allostatic load, bears preparing to hibernate for the winter eat large quantities of food and put on body fat to act as an energy source during the winter (Nelson, 1980).”
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    Interpretationreasoning

    When any one mediator is increased or decreased, there are compensatory changes in the other mediators that depend on time course and level of change of each of the mediators.

    “What this non-linearity means is that when any one mediator is increased or decreased, there are compensatory changes in the other mediators that depend on time course and level of change of each of the mediators.”
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    Interpretationreasoning
    § 2. Central role of the brain

    The brain is the key organ of the stress response because it determines what is threatening and, therefore, potentially stressful, and also controls the behavioral and physiological responses, and resulting lifestyle, which are as important to development of allostatic load and overload as the stressful experiences themselves.

    “The brain is the key organ of the stress response because it determines what is threatening and, therefore, potentially stressful, and also controls the behavioral and physiological responses, and resulting lifestyle, discussed earlier in this article, which are as important to development of allostatic load and overload as the stressful experiences themselves (Fig. 1).”
    Quote in the paperSubstantial claim

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    Premisecitation

    The effects of sleep deprivation include elevated evening cortisol, insulin and blood glucose, elevated blood pressure, reduced parasympathetic activity and elevated levels of proinflammatory cytokines, as well as the gut hormone ghrelin, which increases appetite.

    “The effects include elevated evening cortisol, insulin and blood glucose, elevated blood pressure, reduced parasympathetic activity and elevated levels of proinflammatory cytokines, as well as the gut hormone, ghrelin, which increases appetite.”
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    Premisecitation
    § 2. Central role of the brain

    Early life maternal care in rodents is a powerful determinant of life-long emotional reactivity and stress hormone reactivity, and increases in both are associated with earlier cognitive decline and a shorter lifespan.

    “Early life maternal care in rodents is a powerful determinant of life-long emotional reactivity and stress hormone reactivity and increases in both are associated with earlier cognitive decline and a shorter lifespan (Francis et al., 1999; Cavigelli and McClintock, 2003).”
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    Premisecitation

    Adrenal steroids are important mediators of remodeling of hippocampal neurons during repeated stress, and exogenous adrenal steroids can also cause remodeling in the absence of an external stressor.

    “Regarding the mechanism of structural remodeling, adrenal steroids are important mediators of remodeling of hippocampal neurons during repeated stress, and exogenous adrenal steroids can also cause remodeling in the absence of an external stressor.”
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    Premisecitation

    Chronic restraint stress reduces dentate gyrus proliferation whereas acute restraint does not have any measurable effect.

    “Chronic restraint stress is known to reduce dentate gyrus proliferation whereas acute restraint does not have any measurable effect (Pham et al., 2003).”
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    Premisecitation

    Emotional arousal for a rodent by being placed in a novel environment is required for adrenal steroids to enhance object recognition memory, that involves the hippocampus; the effects of adrenal steroids on this memory show an inverted U shaped dose response.

    “Emotional arousal for a rodent by being placed in a novel environment is required for adrenal steroids to enhance object recognition memory, that involves the hippocampus; the effects of adrenal steroids on this memory show an inverted U shaped dose response (Okuda et al., 2004).”
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    Premisecitation

    Elevated glucocorticoid levels in an enriched environment or during physical activity are associated with increased neurogenesis and/or cell survival, even though there are other conditions in which glucocorticoids suppress neurogenesis.

    “For neurogenesis in dentate gyrus, elevated glucocorticoid levels in an enriched environment or during physical activity are associated with increased neurogenesis and/or cell survival, even though there are other conditions in which glucocorticoids suppress neurogenesis (Mirescu and Gould, 2006).”
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    Premisecitation

    Excitatory amino acids released by the mossy fiber pathway play a key role in the remodeling of the CA3 region of the hippocampus, and regulation of glutamate release by adrenal steroids may play an important role.

    “Excitatory amino acids released by the mossy fiber pathway play a key role in the remodeling of the CA3 region of the hippocampus, and regulation of glutamate release by adrenal steroids may play an important role (McEwen, 1999).”
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    Premisecitation

    New neurons continue to be produced in the dentate gyrus throughout adult life, and CA3 pyramidal cells undergo a reversible remodeling of their dendrites in conditions such as hibernation and chronic stress.

    “there is also adaptive structural plasticity, in that new neurons continue to be produced in the dentate gyrus throughout adult life, and CA3 pyramidal cells undergo a reversible remodeling of their dendrites in conditions such as hibernation and chronic stress (Popov et al., 1992; Popov and Bocharova, 1992; McEwen, 1999).”
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    Premisecitation

    These receptors mediate a biphasic response to adrenal steroids in the CA1 region but not in the dentate gyrus.

    “these receptors mediate a biphasic response to adrenal steroids in the CA1 region although not in the dentate gyrus (Joels, 2006)”
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    Interpretationcitation

    Only more prolonged treatment by higher glucocorticoid doses are able to impair performance on more demanding tasks involving hippocampal function and they do so under conditions in which there is no neuronal loss but there are reductions in volume of hippocampal neuropil that may be due to loss of glia cells or reduction of dendritic length and branching.

    “These studies indicate that only more prolonged treatment by higher glucocorticoid doses are able to impair performance on more demanding tasks involving hippocampal function and that they do so under conditions in which there is no neuronal loss but there are reductions in volume of hippocampal neuropil that may be due to loss of glia cells or reduction of dendritic length and branching.”
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    Premisecitation
    § 2. Central role of the brain

    In childhood, individuals with an allele of the monoamine oxidase A gene are more vulnerable to abuse in childhood and more likely to themselves become abusers, and to show antisocial behaviors compared to individuals with another commonly occurring allele.

    “In childhood, individuals with an allele of the monoamine oxidase A gene are more vulnerable to abuse in childhood and more likely to themselves become abusers, and to show antisocial behaviors compared to individuals with another commonly occurring allele (Caspi et al., 2002).”
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    Premisecitation

    Certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the dentate gyrus, and the mediators of these inhibitory effects include excitatory amino acids acting via NMDA receptors and endogenous opioids.

    “With respect to stress, certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the dentate gyrus, and the mediators of these inhibitory effects include excitatory amino acids acting via NMDA receptors and endogenous opioids (Gould et al., 1997).”
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    Premisecitation

    BDNF +/− mice show a less branched dendritic tree and do not show a further reduction of CA3 dendrite length with chronic stress, whereas wild-type mice show reduced dendritic branching.

    “BDNF +/− mice show a less branched dendritic tree and do not show a further reduction of CA3 dendrite length with chronic stress, whereas wild-type mice show reduced dendritic branching (Magarinos, McEwen, unpublished).”
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    Premisecitation

    Neural cell adhesion molecule (NCAM) and its polysialated-NCAM (PSA-NCAM), as well as L1 are expressed in the dentate gyrus and CA3 region.

    “Neural cell adhesion molecule (NCAM) and its polysialated-NCAM (PSA-NCAM), as well as L1 are expressed in the dentate gyrus and CA3 region”
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    Premisecitation

    These effects occur in the medial and central amygdala and not in basolateral amygdala.

    “These effects occur in the medial and central amygdala and not in basolateral amygdala”
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    Premisecitation

    Chronic stress enhances amygdala-dependent unlearned fear and fear conditioning.

    “and enhances amygdala-dependent unlearned fear and fear conditioning (Conrad et al., 1999)”
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    Premisecitation

    There are a large number of reported rapid, non-genomic actions of adrenal steroids.

    “a large number of reported rapid, non-genomic actions of adrenal steroids (Borski, 2000; Makara and Haller, 2001)”
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    Premisecitation

    Adrenal steroid receptors that are G protein coupled exist in the amphibian brain.

    “the discovery of adrenal steroid receptors that are G protein coupled in the amphibian brain (Orchinik et al., 1991)”
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    Premisecitation

    Tissue plasminogen activator (tPA) is an extracellular protease and signalling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons.

    “Tissue plasminogen activator (tPA) is an extracellular protease and signalling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons (Pawlak et al., 2005).”
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    Premisecitation

    Early life stress produces a delayed effect that reduces cognitive function and the number of CA3 neurons as well as decreased branching of hippocampal pyramidal neurons.

    “early life stress produces a delayed effect that reduces cognitive function and the number of CA3 neurons as well as decreased branching of hippocampal pyramidal neurons (Brunson et al., 2001; Brunson et al., 2005).”
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    Premisecitation

    CRF in the central amygdala is involved in control of behavioral and autonomic responses to stress, including the release of tPA that is an essential part of stress-induced anxiety and structural plasticity in the medial amygdala.

    “whereas CRF in the central amygdala is involved in control of behavioral and autonomic responses to stress, including the release to tPA that is an essential part of stress-induced anxiety and structural plasticity in the medial amygdala (Matys et al., 2004).”
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    Premisecitation

    BDNF and corticosteroids oppose each other, with BDNF reversing reduced excitability in hippocampal neurons induced by stress levels of corticosterone.

    “BDNF and corticosteroids appear to oppose each other – with BDNF reversing reduced excitability in hippocampal neurons induced by stress levels of corticosterone (Hansson et al., 2006).”
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    Premisecitation

    Amygdala volume has been reported to increase in the first episode of depression, whereas hippocampal volume is not decreased.

    “amygdala volume has been reported to increase in the first episode of depression, whereas hippocampal volume is not decreased (MacQueen et al., 2003; Frodl et al., 2003).”
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    Premisecitation

    Both mild cognitive impairment and Type 2, as well as Type 1, diabetes are recognized as risk factors for dementia.

    “both mild cognitive impairment and Type 2, as well as Type 1, diabetes are recognized as risk factors for dementia (Ott et al., 1996; de Leon et al., 2001; Haan, 2006).”
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    Premisecitation

    In post-traumatic stress disorder and borderline personality disorder, atrophy of the hippocampus has been reported.

    “there are a variety of other anxiety-related disorders, such as post-traumatic stress disorder (PTSD) (Bremner, 2002) (Pitman, 2001) and borderline personality disorder (Driessen et al., 2000), in which atrophy of the hippocampus has been reported”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bremner, 2002 source

      Not checked in the free run.

    • cites Pitman, 2001 source

      Not checked in the free run.

    • cites Driessen et al., 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 4. Interventions: conventional vs top down

    Businesses that encourage healthy lifestyle practices among their employees are likely to gain reduced health insurance costs and possibly a more loyal workforce.

    “businesses that encourage healthy lifestyle practices among their employees are likely to gain reduced health insurance costs and possibly a more loyal workforce (Aldana, 2001; Pelletier, 2001; Whitmer et al., 2003).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Aldana, 2001 source

      Not checked in the free run.

    • cites Pelletier, 2001 source

      Not checked in the free run.

    • cites Whitmer et al., 2003 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning
    § 4. Interventions: conventional vs top down

    Because of the non-linearity of the systems of allostasis, the consequences of any drug treatment may be either to inhibit the beneficial effects of the systems in question or to perturb other systems that interact with it in a direction that promotes an unwanted side effect.

    “Because of the non-linearity of the systems of allostasis, the consequences of any drug treatment may be either to inhibit the beneficial effects of the systems in question or to perturb other systems that interact with it in a direction that promotes an unwanted side effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning
    § 4. Interventions: conventional vs top down

    Basic education, housing, taxation, setting of a minimum wage, and addressing occupational health and safety and environmental pollution regulations are all likely to affect health via a myriad of mechanisms.

    “Thus basic education, housing, taxation, setting of a minimum wage, and addressing occupational health and safety and environmental pollution regulations are all likely to affect health via a myriad of mechanisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Poor self esteem causes recurrent increases in cortisol levels during a repetition of a public speaking challenge, whereas individuals with good self esteem habituate.

    “poor self esteem has been shown to cause recurrent increases in cortisol levels during a repetition of a public speaking challenge in which those individuals with good self esteem are able to habituate, i.e., attenuate their cortisol response after the first speech (Kirschbaum et al., 1995).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kirschbaum et al., 1995 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Having a positive outlook on life and good self esteem appear to have long-lasting health consequences.

    “Having a positive outlook on life and good self esteem appear to have long-lasting health consequences (Pressman and Cohen, 2005)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pressman and Cohen, 2005 source

      Not checked in the free run.

52 of 52

  • The paper relies on this without support.

    The amygdala and prefrontal cortex contain adrenal steroid receptors.

    “Along with many other brain regions, the amygdala and prefrontal cortex also contain adrenal steroid receptors”

  • The paper relies on this without support.

    Adrenocortical hormones enter the brain and produce a wide range of effects upon it.

    “We now know that adrenocortical hormones enter the brain and produce a wide range of effects upon it.”

  • The paper relies on this without support.

    Both major depression and Cushing’s disease are associated with chronic elevation of cortisol that results in gradual loss of minerals from bone and abdominal obesity.

    “Both major depression and Cushing’s disease are associated with chronic elevation of cortisol that results in gradual loss of minerals from bone and abdominal obesity.”

  • The paper relies on this without support.

    There are many useful pharmaceutical agents (sleeping pills, anxiolytics, beta blockers and antidepressants) that are used to counteract some of the problems associated with being stressed out.

    “In fact, there are many useful pharmaceutical agents: sleeping pills, anxiolytics, beta blockers and antidepressants are all drugs that are used to counteract some of the problems associated with being stressed out.”

  • The paper relies on this without support.

    Drugs that reduce oxidative stress or inflammation, block cholesterol synthesis or absorption and treat insulin resistance or chronic pain can help deal with the metabolic and neurologic consequences of being stressed out.

    “Likewise, drugs that reduce oxidative stress or inflammation, block cholesterol synthesis or absorption and treat insulin resistance or chronic pain and can help deal with the metabolic and neurologic consequences of being stressed out.”

  • The paper relies on this without support.

    Motivation and decision making and perseverance are all functions of the brain.

    “Motivation and decision making and perseverance are all functions of the brain!”

  • The paper relies on this without support.

    Animal studies of stress effects on brain structure are relevant to the human brain.

    “Much of the impetus for studying the effects of stress on the structure of the human brain has come from the animal studies summarized thus far.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Under chronic conditions, the relationship between HPA axis over-activity and disturbed sleep may be bidirectional.

    “Under chronic conditions, the relationship between HPA axis over-activity and disturbed sleep may be bidirectional as elevated evening cortisol levels are likely to disturb sleep.26,27”

    From Effects of Insufficient Sleep on Pituitary–Adrenocortical Response to CRH Stimulation in Healthy Men (2017) · cites this paper as [27]

    Section 1.2 (page unavailable) says that being stressed out can lead to sleep deprivation and that sleep deprivation can elevate evening cortisol. It does not say that elevated evening cortisol disturbs sleep, so it supports only one direction of the proposed bidirectional relationship. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Inability to handle everyday stress leads to exacerbated physiological responses and is associated with the development and course of adverse long-term health outcomes, including major depression, substance abuse, and anxiety disorders.

    “Inability to handle everyday stress leads to exacerbated physiological responses and is associated with the development and course of adverse long-term health outcomes, including a wide range of psychological disorders such as major depression, substance abuse, and anxiety disorders (Duffing et al., 2014;McEwen, 2008;Sinha, 2001).”

    From Cortisol Response to Stress: The Role of Expectancy and Anticipatory Stress Regulation (2020) · cites this paper as McEwen, 2008

  • This modulation is achieved via the effect of glucocorticoid hormones and other components of the HPA axis.

    “This modulation is achieved via the effect of glucocorticoid hormones and other components of the HPA axis [46-48, 50].”

    From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [47]

  • Chronic stress may alter receptor localization, rates of chemical reactions and transporting processes in different brain regions such as hippocampus, amygdala and prefrontal cortex, causing altered patterns of activity observable by PET, fMRI, MEG or EEG.

    “chronic stress may alter receptor localization, rates of chemical reactions and transporting processes in different brain regions, such as the hippocampus, amygdala and prefrontal cortex [44-47]”

    From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [47]

  • Stress induces changes in immune system function.

    “It is also well known that stress induces changes in the immune system function.”

    From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [47]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Cockburn, 1988, Marsupial femmes fatales, Nat. Hist., 97, 40
  2. Kaufman, 1999, Neurobiological correlates of child abuse, Biol. Psychiatry, 45, 1235

Cited by

Sorted by citations

Related

Authors
McEwen, B. S.
Affiliations
Rockefeller University (US)
Corresponding author
McEwen, Bruce S.
ORCID
McEwen, Bruce S.
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
2008-04
Volume
583
Issue
2-3
Pages
174-185
ISSN
0014-2999 (ISSN-L)
DOI
10.1016/j.ejphar.2007.11.071
PMC
PMC2474765
OpenAlex
W1969412681
Semantic Scholar
4539d1634a572be94a61dd8b352135577b48fa33
Cited by
1,864
References
160
Citations by year
2026: 69 · 2025: 85 · 2024: 90 · 2023: 90 · 2022: 111 · 2021: 119 · 2020: 139 · 2019: 110 · 2018: 116 · 2017: 115 · 2016: 123 · 2015: 94 · 2014: 102 · 2013: 95 · 2012: 118
FWCI
7.09
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • European Journal of Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (MH-41256, R37MH041256, P50MH058911, R01MH041256, 5-P50MH58911)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
chronic stress, stress hormones, glucocorticoids, allostatic overload, hippocampus, prefrontal cortex, amygdala, neuroplasticity, brain-derived neurotrophic factor, PSA-NCAM, tissue plasminogen activator, excitatory amino acids, lifestyle habits, mental illness, top-down control, physical activity, social support, neuroendocrine function, autonomic function
MeSH terms
Animals, Mental Disorders, Brain, Glucocorticoids, Humans, Stress, Physiological, Allostasis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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