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Cited by 1,220Stress Responses and CortisolNeuropeptides and Animal PhysiologyMemory and Neural Mechanisms

Protective and damaging effects of stress mediators: central role of the brain

Open access
McEwen, Bruce S.·2006·Dialogues in Clinical Neuroscience
DOI 10.31887/dcns.2006.8.4/bmcewenPMC PMC3181832
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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.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the brain is the central organ of stress, allostasis, and allostatic load, determining what is threatening and orchestrating protective short-term responses that can become damaging when chronically dysregulated. It synthesizes animal and human evidence linking chronic stress, sleep deprivation, and psychosocial factors to structural remodeling in hippocampus, amygdala, and prefrontal cortex, and discusses lifestyle and policy interventions.

Key findings

  • Protection and damage are two sides of stress physiology: the same mediators that help cope in the short term can produce allostatic load and disease when chronically elevated or poorly regulated. Chronic stress causes atrophy of neurons in hippocampus and prefrontal cortex and hypertrophy in amygdala, while acute stress induces spine synapses in CA1 and both acute and chronic stress increase spine synapse formation in amygdala but chronic stress decreases it in hippocampus.
  • Sleep deprivation is presented as a core example of allostatic overload: restriction to 4 hours per night increases blood pressure, decreases parasympathetic tone, increases evening cortisol and insulin, and promotes appetite; 24-hour sleep deprivation decreases brain glycogen by as much as 40% in rats, and 96-hour treadmill sleep deprivation decreases dentate gyrus cell proliferation by as much as 50%.
  • Human translation links stress-related conditions to brain structure: recurrent major depression, Cushing’s disease, PTSD, and borderline personality disorder are associated with smaller hippocampal volume; duration of depressive illness predicts progressive hippocampal volume reduction; poor self-esteem and low internal locus of control are related to a 12% to 13% smaller hippocampal volume and higher cortisol during mental arithmetic stress.
  • Positive psychosocial factors matter: positive affect is associated with lower cortisol, higher heart rate variability, and lower fibrinogen response to mental stress; having three or more regular social contacts, versus zero to two, is associated with lower allostatic load scores.

Methods

  • Narrative review, not a primary study; no new data collection or systematic search strategy is described.
  • Synthesizes animal models and human structural/functional imaging, endocrine, and psychosocial studies to support a conceptual model of allostasis, allostatic load, and brain structural plasticity.
  • Main analysis is interpretive synthesis across cited literature, including figures adapted from prior work on allostatic load and the central role of the brain.

Limitations

  • The paper states that the nonlinear network of allostatic mediators cannot be measured simultaneously, so studies must rely on only a few mediators, and nonlinearity must be kept in mind when interpreting results.
  • The paper states there is very little evidence regarding effects of ordinary life stressors on human brain structure, notes contradictory findings on whether chronic restraint stress reduces BDNF mRNA, and says the role of adrenal steroids, excitatory amino acids, and other mediators has not yet been studied in amygdala and prefrontal cortex.
  • Evident from the text: as a narrative review, it lacks systematic search, inclusion criteria, and quality appraisal; many mechanistic claims derive from animal models, and much human evidence is correlational, limiting causal inference.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.31887/dcns.2006.8.4/bmcewen

Cites

141 of 141 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 179 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Alterations in amygdala and prefrontal cortex are also reported in stress-related conditions.

    “Alterations in amygdala and prefrontal cortex are also reported.”
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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 strokes and heart attacks.

    “on the other hand, chronic elevation of these same mediators -eg, chronically increased heart rate and blood pressure -produce chronic wear and tear on the cardiovascular system that can result, over time, in disorders such as strokes and heart attacks.”
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  • Premisecitation

    Chronically increased allostasis can lead to disease.

    “Because chronically increased allostasis can lead to disease, we introduced the term “allostatic load or overload” to refer to the wear and tear that results from either too much stress or from inefficient management of allostasis, eg, not turning off the response when it is no longer needed.”
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    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.

    “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.”
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    • cites [21] source

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  • Premisecitation

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

    “on the one hand, the body responds to almost any event or challenge by releasing chemical mediators -eg, catecholamines that increase heart rate and blood pressure -that help us cope with the situation;”
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  • Classified as probably not a substantial claim. 6

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    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] SheIine Yl., 1999, J Neurosci. source

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  • May combine two claims.

    Interpretationreasoning

    Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by allostasis, but in the long run allostatic load causes changes in the body that can lead to disease.

    “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.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Over time, daily life stress results in wear and tear on the body, called allostatic load, and this reflects not only life experiences but also genetic load, lifestyle habits, and developmental experiences.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Protection and damage are the two contrasting sides of the physiology involved in defending the body against the challenges of daily life.

    “Thus, protection and damage are the two contrasting sides of the physiology involved in defending the body against the challenges of daily life, whether or not we call them “stressors.””
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    The ability to learn and remember and make decisions may be compromised by chronic stress, and may be accompanied by increased levels of anxiety and aggression.

    “Thus, the ability to learn and remember and make decisions may be compromised by chronic stress, and may be accompanied by increased levels of anxiety and aggression.”
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    Premisecitation

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

    “As an example of 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.11”
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    • cites [11] Nelson RA., 1980, Fed Proc.

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    Interpretationnone given

    The common experience of being "stressed out" has as its core the elevation of cortisol, sympathetic activity, and proinflammatory cytokines, with a decline in parasympathetic activity.

    “The common experience of being “stressed out” has as its core the elevation of some of the key systems that lead to allostatic load- Cortisol, sympathetic activity, and proinflammatory cytokines, with a decline in parasympathetic activity.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Sleep restriction to 4 hours of sleep per night increases blood pressure, decreases parasympathetic tone, increases evening cortisol and insulin levels, and promotes increased appetite, possibly through elevation of ghrelin and decreased levels of leptin.

    “Sleep restriction to 4 hours of sleep per night increases blood pressure, decreases parasympathetic tone, increases evening Cortisol and insulin levels, and promotes increased appetite, possibly through the elevation of ghrelin, a proappetitive hormone, and decreased levels of leptin.16-18”
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    • cites [16] Leproult R., 1997, Sleep.

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    Premisecitation

    The parasympathetic nervous system generally opposes the sympathetic nervous system, slows the heart, and has anti-inflammatory effects.

    “The parasympathetic nervous system also plays an important regulatory role in this nonlinear network of allostasis, since it generally opposes the sympathetic nervous system and, for example, slows the heart and also has anti-inflammatory effects.8,9”
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    Many mediators participate in allostasis and are linked together in a nonlinear network of regulation, meaning each mediator can regulate the activity of other mediators, sometimes in a biphasic manner.

    “Besides adrenaline and noradrenaline, there are many mediators that participate in allostasis, and they are linked together in a network of regulation that is nonlinear (Figure 2), meaning that each mediator has the ability to regulate the activity of the other mediators, sometimes in a biphasic manner.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Sterling P., 1988, Handbook of Life Stress, Cognition and Health. New York, NY: John Wiley & Sons;

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    Sleep deprivation by the platform method impairs retention of passive avoidance memory, impairs spatial memory in the Morris water maze, and reduces long-term potentiation in the CA1 region of the hippocampus.

    “For example, sleep deprivation by the platform (or flowerpot) method resulted in impaired retention of passive avoidance memory, a context-dependent fear memory task,25 as well as impaired performance of spatial memory in the Morris water maze32 and a reduction in longterm potentiation in the CA1 region of the hippocampus.33”
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    IL-β mRNA levels in brain increase following sleep deprivation by gentle handling and are higher in daytime than in darkness in rodents.

    “IL-β messenger ribonucleic acid (mRNA) levels in brain are reported to increase following sleep deprivation by gen tie handling and to be higher in daytime (during the normal sleep period in rodents) than in darkness (during the normal activity time for rodents).22”
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    • cites [22] Taishi P., 1998, J Interferon Cytokine Res. source

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    Some effects of early life adversity are seen on brain structure and function, and in the risk for later depression and PTSD.

    “Some of these effects are seen on brain structure and function, and in the risk for later depression and post-traumatic stress disorder (PTSD).44-46”
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    • cites [46] Vermetten E., 2006, Am J Psychiatry. source

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    Premisecitation

    A 4-hour period of sleep deprivation by gentle stimulation impairs late-phase long-term potentiation in the dentate gyrus 48 hours later, but enhances late-phase LTP in the prefrontal cortex.

    “Furthermore, a 4-hour period of sleep deprivation by gentle stimulation impaired the latephase long-term potentiation (LTP) in the dentate gyrus 48 hours later, but had the opposite effect of enhancing latephase LTP in the prefrontal cortex.36”
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    • cites [36] Romcy-Pereira R., 2004, Eur J Neurosci. source

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    Catecholamines can increase proinflammatory cytokine production, whereas glucocorticoids inhibit this production.

    “Whereas catecholamines can increase proinflammatory cytokine production, glucocorticoids are known to inhibit this production.5”
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    • cites [5] Sapolsky RM., 2000, Endocr Rev.

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    The brain is the master regulator of the neuroendocrine, autonomic, and immune systems, along with behaviors that contribute to unhealthy or health lifestyles, which influence allostasis.

    “The brain is the master regulator of the neuroendocrine, autonomic, and immune systems, along with behaviors that contribute to unhealthy or health lifestyles, which, in turn, influence the physiological processes of allostasis (Figure 3).2”
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    • cites [2] Sterling P., 1988, Handbook of Life Stress, Cognition and Health. New York, NY: John Wiley & Sons;

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    In the marsupial mouse, only males die after mating, due to a response to mating that reduces corticosteroid-binding globulin for glucocorticoids and renders them more active throughout the body.

    “In the case of the marsupial mouse, it is only the males that die after mating, due apparently to a response to mating that reduces the binding protein, corticosteroid-binding globulin (CBG), for glucocorticoids and renders them much more active throughout the body.15”
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    • cites [15] Cockburn A., 1988, Natural History.

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    In spring, a sudden snowstorm causes stress to birds and disrupts mating, and stress hormones direct birds to suspend reproduction, find food, relocate to a better mating site, or delay reproduction until weather improves.

    “As an example of allostasis, in spring, a sudden snowstorm causes stress to birds and disrupts mating, and stress hormones are 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.10”
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    • cites [10] Wingfield JC., 2000, Coping with the Environment: Neural and Endocrine Mechanisms. Vol. IV. New York, NY: Oxford University Press.

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    Premisecitation

    Glycogen in white matter decreases by as much as 40% in rats deprived of sleep for 24 hours by novelty and gentle handling, and is reversed by recovery sleep.

    “Another noteworthy effect of sleep deprivation is regulation of the level of glycogen, found predominantly in white matter, which is reported to decrease by as much as 40% in rats deprived of sleep for 24 hours by novelty and gentle handling, and reversed by recovery sleep.26,27”
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    Proinflammatory cytokine levels are increased, along with performance in tests of psychomotor vigilance, and this has been reported to result from a modest sleep restriction to 6 hours per night.

    “Proinflammatory cytokine levels are increased, along with performance in tests of psychomotor vigilance, and this has been reported to result from a modest sleep restriction to 6 hours per night.19”
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    Interpretationreasoning

    The brain is the key organ of the stress response because it determines what is threatening, and therefore stressful, and controls the behavioral and physiological responses.

    “The brain is the key organ of the stress response because it determines what is threatening, and therefore, stressful, and also controls the behavioral and physiological responses that have been discussed earlier in this article (see Figure 3).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Fat accumulation in captive zoo bears eating too much and not exercising can be called allostatic overload, associated with pathophysiology.

    “The accumulation of fat under these latter conditions can be called “allostatic overload,” referring to a condition that is associated with pathophysiology.”
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    Sleep deprivation is associated with increases in fighting behavior after deprivation of REM sleep, and increased aggression in the form of muricide after phencyclidine administration after sleep deprivation.

    “Sleep deprivation has also been associated with increases in fighting behavior after deprivation of rapid eye movement (REM) sleep;37 there is also a report of increased aggression in the form of muricide after phencyclidine administration after sleep deprivation.38”
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    Premisecitation

    Allostatic overload resulting from chronic stress in animal models causes atrophy of neurons in the hippocampus and prefrontal cortex and hypertrophy of neurons in the amygdala.

    “Allostatic overload resulting from chronic stress in animal models causes atrophy of neurons in the hippocampus and prefrontal cortex, brain regions involved in memory, selective attention, and executive function, and causes hypertrophy of neurons in the amygdala, a brain region involved in fear and anxiety, as well as aggression.21”
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    Premisecitation

    In hibernating mammals, dendritic remodeling is reversible and occurs within hours of the onset of hibernation and wakening from torpor.

    “Indeed, in species of mammals that hibernate, dendritic remodeling is a reversible process, and occurs within hours of the onset of hibernation in European hamsters and ground squirrels, and it is also reversible within hours of wakening of the animals from torpor.60,61,71”
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    • cites [60] Popov VI., 1992, Neuroscience. source

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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.83”
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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 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 N-methyl-D-aspartate (NMDA) receptors and endogenous opioids.68”
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    Premisecitation

    One granule neuron innervates on average 12 CA3 neurons, and each CA3 neuron innervates on average 50 other CA3 neurons via axon collaterals, as well as 25 inhibitory cells via other axon collaterals, resulting in a 600-fold amplification of excitation and a 300-fold amplification of inhibition.

    “One granule neuron innervates, on the average, 12 CA3 neurons, and each CA3 neuron innervates, on the average, 50 other CA3 neurons via axon collaterals, as well as 25 inhibitory cells via other axon collaterals. The net result is a 600-fold amplification of excitation, as well as a 300-fold amplification of inhibition, that provides some degree of control of the system.58”
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    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.58”
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    The short form of the serotonin transporter is associated with 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.52”
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    CRF in the paraventricular nucleus regulates ACTH release from the anterior pituitary gland, whereas CRF in the central amygdala is involved in control of behavioral and autonomic responses to stress, including release of tPA that is essential for stress-induced anxiety and structural plasticity in the medial amygdala.

    “CRF in the paraventricular nucleus regulates ACTH release from the anterior pituitary gland, whereas 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.85”
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    • cites [85] Matys T., 2004, Proc Natl Acad Sci U S A. source

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    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 show antisocial behaviors.

    “In childhood, individuals with an allele of the monoamine oxidase A gene are more vulnerable to abuse in childhood and more likely to them- selves become abusers and to show antisocial behaviors compared with individuals with another commonly occurring allele.53”
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    Dendritic reorganization is found in both dominant and subordinate rats undergoing adaptation of psychosocial stress in the visible burrow system, and it is independent of adrenal size.

    “Such dendritic reorganization is found in both dominant and subordinate rats undergoing adaptation of psychosocial stress in the visible burrow system, and it is independent of adrenal size.70”
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    Premisecitation

    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. 51”
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    Premisecitation

    NCAM, PSA-NCAM, and L1 are expressed in the dentate gyrus and CA3 region, and their expression is regulated by 21-day chronic restraint stress.

    “Neural cell adhesion molecule (NCAM) and its polysialated-NCAM (PSA-NCAM), as well as L1 are expressed in the dentate gyrus and CA3 region, and the expression of both NCAM, L1, and PSA-NCAM are regulated by 21d CRS.76”
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    Premisecitation

    21-day chronic restraint stress leads to depletion of clear vesicles from mossy fiber terminals and increased expression of presynaptic proteins involved in vesicle release.

    “Moreover, 21d chronic restraint stress (CRS) leads to depletion of clear vesicles from mossy fiber terminals and increased expression of presynaptic proteins involved in vesicle release.73-75”
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    Premisecitation

    Restraint stress elevates extracellular glutamate levels, leading to induction of glial glutamate transporters and increased activation of phosphoCREB.

    “Among the consequences of restraint stress is the elevation of extracellular glutamate levels, leading to induction of glial glutamate transporters, as well as increased activation of the nuclear transcription factor, phosphoCREB.72”
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    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.

    “Neurotrophic factors also play a role in dendritic branching and length in that 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 and McEwen, unpublished data).”
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    In the adult rat, 9000 new neurons are born per day, and survive with a half-life of 28 days.

    “In the adult rat, 9000 new neurons are born per day, and survive with a half -life of 28 days.64”
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    New neurons continue to be produced in the dentate gyrus throughout adult life, and CA3 pyramidal cells undergo reversible remodeling of their dendrites in conditions such as hibernation and chronic stress.

    “However, because the DG-CA3 system is so delicately balanced in its function and vulnerability to damage, 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.58,60,61”
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    • cites [60] Popov VI., 1992, Neuroscience. source

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    Premisecitation

    Adrenal steroids are important mediators of remodeling of hippocampal neurons during repeated stress, and exogenous adrenal steroids can 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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] source

      Not checked in the free run.

    • cites [58] source

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  • May combine two claims.

    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.

    “CRF in the hippocampus is expressed in a subset of GABA neurons (Cajal-Retzius cells) in the developing hippocampus, and 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.86,87”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] source

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    • cites [87] source

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

    Premisecitation

    The dentate gyrus-CA3 system is believed to play a role in memory of sequences of events, although long-term storage of memory occurs in other brain regions.

    “As to why this type of circuitry exists, the dentate gyrus (DG)-CA3 system is believed to play a role in the memory of sequences of events, although longterm storage of memory occurs in other brain regions.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] source

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  • May combine two claims.

    Premisecitation

    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.50”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] source

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    Premisecitation

    Having the Val66Met allele of the BDNF gene affects hippocampal volume, memory, and mood disorders.

    “Yet another example is the consequence of having the Val66Met allele of the brain-derived neurotrophic factor (BDNF) gene on hippocampal volume, memory, and mood disorders.54-57”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [54] source

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    • cites [55] Hariri AR., 2003, J Neurosci. source

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    • cites [56] source

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    • cites [57] source

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  • May combine two claims.

    Premisecitation

    Tissue plasminogen activator is an extracellular protease and signaling molecule 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, see below) is an extracellular protease and signaling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons.77”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Pawlak R., 2005, Proc Natl Acad Sci U S A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 deoxyribonucleic acid (DNA) on key genes appears to play a role in this epigenetic transmission.49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] source

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  • May combine two claims.

    Premisecitation

    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.47,48”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] source

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    • cites [48] source

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  • May combine two claims.

    Premisecitation

    Chronic stress for 21 days or longer impairs hippocampal-dependent cognitive function and enhances amygdala-dependent unlearned fear and fear conditioning.

    “Moreover, chronic stress for 21 days or longer impairs hippocampal-dependent cognitive function58 and enhances amygdala-dependent unlearned fear and fear conditioning,100 which are consistent with the opposite effects of stress on hippocampal and amygdala structure.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] source

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    • cites [100] source

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  • May combine two claims.

    Premisecitation

    Chronic stress increases aggression between animals living in the same cage, likely reflecting hyperactivity of the amygdala.

    “Chronic stress also increases aggression between animals living in the same cage, and this is likely to reflect another aspect of hyperactivity of the amygdala.39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] source

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  • May combine two claims.

    Premisecitation

    Acute stress induces spine synapses in the CA1 region of hippocampus, and both acute and chronic stress increase spine synapse formation in amygdala, but chronic stress decreases it in hippocampus.

    “Acute stress induces spine synapses in the CA1 region of hippocampus98 and both acute and chronic stress also increases spine synapse formation in amygdala,95-99 but chronic stress decreases it in hippocampus.77”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [98] source

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    • cites [95] source

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    • cites [96] Liston C., 2003, J Neurosci. source

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    • cites [97] Melchor JP., 2003, J. Neurosci. source

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    • cites [99] source

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    • cites [77] Pawlak R., 2005, Proc Natl Acad Sci U S A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brain regions such as the hippocampus, amygdala, and prefrontal cortex show altered patterns of activity in PET and fMRI, and demonstrate changes in volume with recurrent depression: decreased volume of hippocampus and prefrontal cortex and amygdala.

    “Moreover, brain regions such as the hippocampus, amygdala, and prefrontal cortex show altered patterns of activity in positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), and also demonstrate changes in volume of these structures with recurrent depression: decreased volume of hippocampus and pre frontal cortex and amygdala (Figure 4.).104-106”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] SheIine Yl., 1999, J Neurosci. source

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    • cites [105] source

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    • cites [106] source

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  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] source

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    • cites [111] Starkman MN., 1981, Arch Intern Med. source

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  • May combine two claims.

    Premisecitation

    These effects occur in the medial and central amygdala and not in basolateral amygdala, and the release of CRH acting via CRH1 receptors appears to be responsible.

    “These effects occur in the medial and central amygdala and not in basolateral amygdala, and the release of CRH acting via CRH1 receptors appears to be responsible.85”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Matys T., 2004, Proc Natl Acad Sci U S A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “Interestingly, amygdala volume has been reported to increase in the first episode of depression, whereas hippocampal volume is not decreased.107,108”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] source

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    • cites [108] source

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  • May combine two claims.

    Premisecitation

    Poor self-esteem and low internal locus of control are related to higher cortisol levels during a mental arithmetic stressor.

    “Furthermore, poor self-esteem and low internal locus of control have been related to a 12% to 13% smaller volume of the hippocampus, as well as higher Cortisol levels during a mental arithmetic stressor.124,125”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [124] source

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    • cites [125] source

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  • May combine two claims.

    Premisecitation

    Both MCI and type 2, as well as type 1, diabetes are recognized as risk factors for dementia.

    “and both MCI and type 2, as well as type 1, diabetes are recognized as risk factors for dementia.117-119”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [117] source

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    • cites [118] source

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    • cites [119] source

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  • May combine two claims.

    Premisecitation

    Repeated stress causes dendritic shortening in medial prefrontal cortex but produces dendritic growth in neurons in amygdala and orbitofrontal cortex.

    “Repeated stress causes dendritic shortening in medial prefrontal cortex.89-95 but produces dendritic growth in neurons in amygdala,95 as well as in orbitofrontal cortex.96”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [89] source

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    • cites [90] source

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    • cites [91] source

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    • cites [92] source

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    • cites [93] Brown SM., 2005, Cereb Cortex.

      Not checked in the free run.

    • cites [94] source

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    • cites [95] source

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    • cites [96] Liston C., 2003, J Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because of the nonlinearity 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 nonlinearity 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
    • Rests on an assumption: The systems dysregulated in allostatic overload interact with each other and perform normal functions when properly regulated.

  • May combine two claims.

    Premisecitation

    The Experience Corps program improves the physical and mental health of the elderly volunteers.

    “Not only does this program improve the education of the children, It also benefits the elderly volunteers and Improves their physical and mental health.135”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] source

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

    Premisecitation

    Almost any amount of moderate physical activity helps, and it is not necessary to become an extreme athlete.

    “Concerning physical activity, it is not necessary to become an extreme athlete, and seemingly almost any amount of moderate physical activity helps.127,128”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] Bernadet P., 1995, J Cardiovasc Pharmacol. source

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    • cites [128] Rovio S., 2005, Lancet. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Making neighborhoods safer and more congenial and supportive can improve opportunities for positive social interactions and increased recreational physical activity.

    “Likewise, making neighborhoods safer and more congenial and supportive130 can improve opportunities for positive social interactions and increased recreational physical activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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63 of 63

  • The paper relies on this without support.

    The mind involves the whole body, and there is two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms.

    “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.”

  • The paper relies on this without support.

    Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals.

    “Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals.”

  • The paper relies on this without support.

    The most common stressors operate chronically, often at a low level.

    “The most common stressors are therefore ones that operate chronically, often at a low level, and that cause us to behave in certain ways.”

  • The paper relies on this without support.

    The systems dysregulated in allostatic overload interact with each other and perform normal functions when properly regulated.

    “all of the systems that are dysregulated in allostatic overload are also systems that interact with each other and perform normal functions when properly regulated.”

  • The paper relies on this without support.

    Basic education, housing, taxation, setting of a minimum wage, and policies and programs addressing occupational health and safety and environmental pollution regulations affect health via multiple mechanisms.

    “Thus, basic education, housing, taxation, setting of a minimum wage, and policies and programs addressing occupational health and safety and environmental pollution regulations are all likely to affect health via a myriad of mechanisms.”
5 of 5

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?

  • Repeated or sustained stress exposure leads to chronic allostatic load, with dysregulation of glucose metabolism and neuroendocrine function and chronic low-grade inflammation.

    “Repeated or sustained stress exposure leads to chronic allostatic load, with dysregulation of glucose metabolism and neuroendocrine function and chronic low grade inflammation.”

    From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [22]

    The ‘Definition of stress, allostasis, and allostatic load’ section links repeated stressors and prolonged stress responses to allostatic load. The ‘Being “stressed out”’ section describes altered cortisol and insulin levels and increased proinflammatory cytokines with sleep restriction. These passages support neuroendocrine changes and inflammatory activity, but do not establish that repeated stress causes dysregulated glucose metabolism or specifically chronic low-grade inflammation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Allostatic load dysregulates this dynamic process, which can result in inadequate biological responses to stress, with failure to mount an appropriate stress response and/or poor stress recovery, with diminished ability to return to pre-stress values across various parameters.

    “Allostatic load dysregulates this dynamic process, which can result in inadequate biological responses to stress, with failure to mount an appropriate stress response and/or poor stress recovery, with diminished ability to return to pre-stress values across various parameters 7, 22.”

    From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [22]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Chronic activation of the HPA axis can lead to dysregulated cortisol output.

    “Chronic activation of the HPA axis can lead to dysregulated cortisol output 22.”

    From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [22]

  • Repeated stimulation of the stress system as a result of chronic stress is thought to lead to dysregulation across several inter-related systems.

    “Repeated stimulation of the stress system as a result of chronic stress is thought to lead to dysregulation across several inter-related systems 22 .”

    From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [22]

  • Allostasis is a dynamic process, and it manifests in response to challenge, whereby a brisk biological activation occurs as the body mobilizes to deal with the stressor, followed by a swift recovery back to baseline values.

    “Allostasis is a dynamic process, and it manifests in response to challenge 22, whereby a brisk biological activation occurs as the body mobilizes to deal with the stressor, a process that is followed by a swift recovery back to baseline values.”

    From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [22]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Two different articles are assigned the same journal pages

    Minor

    References 96 and 97 name different articles but give both the same year, journal, volume, and complete page range. Both cannot occupy pages 8867-8871 of that volume.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 9

  1. Sterling P., 1988, Handbook of Life Stress, Cognition and Health. New York, NY: John Wiley & Sons;, 629
  2. Sapolsky RM., 2000, Endocr Rev., 21, 55
  3. Wingfield JC., 2000, Coping with the Environment: Neural and Endocrine Mechanisms. Vol. IV. New York, NY: Oxford University Press., 211
  4. Nelson RA., 1980, Fed Proc., 39, 2955
  5. Cockburn A., 1988, Natural History., 97, 40
  6. Leproult R., 1997, Sleep., 20, 865
  7. Brown SM., 2005, Cereb Cortex., 30, 1
  8. Acheson SD., 1998, Independent Inquiry into Inequalities in Health Report. London: The Stationery Office;
  9. AbbruzzeseR.O'Malley and Brown release detailed plan to support Maryland's aging population. Press Release. Jan. 24, 2006

Cited by

Sorted by citations

Related

Authors
McEwen, B. S.
Affiliations
Rockefeller University (US)
Corresponding author
McEwen, Bruce S.
ORCID
McEwen, Bruce S.
Venue
Dialogues in Clinical Neuroscience
Publisher
Informa UK Limited
Published
2006-12-31
Volume
8
Issue
4
Pages
367-381
ISSN
  • 1294-8322 (ISSN-L)
  • 1958-5969
DOI
10.31887/dcns.2006.8.4/bmcewen
PMC
PMC3181832
OpenAlex
W155479038
Semantic Scholar
bfcf6f7e8aeea0388fa7bd7c870f36cc5e6fa449
Cited by
1,220
References
141
Citations by year
2026: 76 · 2025: 79 · 2024: 77 · 2023: 95 · 2022: 68 · 2021: 74 · 2020: 93 · 2019: 65 · 2018: 56 · 2017: 90 · 2016: 68 · 2015: 67 · 2014: 57 · 2013: 48 · 2012: 46
FWCI
9.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Dialogues in Clinical Neuroscience (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
chronic stress, allostatic load, allostasis, mind-body problem, hippocampus, amygdala, prefrontal cortex, stress hormones, hippocampal volume, mild cognitive impairment, major depressive disorder, self-esteem, stress-related disorders, lifestyle intervention
MeSH terms
Brain, Humans, Self Concept, Sleep Deprivation, Social Support, Stress, Psychological

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 2026-10-10.

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

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