How persistent are the changes?

need to write a review regarding two articles and rather you agree or disagree with the writer. Relate those article with slides that have attached with article to support your opinion on the article.

Sustained stress can have numerous pathologic effects. Among the molecules that mediate such effects are the adrenal steroid hormones, including the human glucocorticoid (GC) hydrocortisone. Along with epinephrine (adrenaline) and norepinephrine, GCs are essential for surviving acute physical stress (evading a predator, for example) but they may cause adverse effects when secretion is sustained, such as when waiting to hear about a grant renewal (1). Excessive exposure to GCs has adverse effects in the rodent brain, particularly in the hippocampus, a structure vital to learning and memory and possessing high concentrations of receptors for GCs (2). A few days of stress or GC overexposure “endangers” hippocampal neurons, compromising their ability to survive seizures or ischemia; as the likely underpinning of this, the steroids worsen the poor regulation of glutamate and calcium that occurs during such neurologic insults. Over the course of weeks, excess GC reversibly causes atrophy of hippocampal dendrites, whereas GC overexposure for months can cause permanent loss of hippocampal neurons. Although a few studies suggest that similar effects occur in the brains of primates (3), there has been virtually no evidence for GC-induced damage in the human. Some new, exciting studies present the first such evidence. A first example, recently published by Sheline and colleagues at Washington University School of Medicine, concerns major depression (4). Approximately half of depressive patients studied secrete abnormally high amounts of GCs. Although investigators had searched with magnetic resonance imaging (MRI) for hippocampal atrophy in depressives, these studies could not distinguish the hippocampus from neighboring structures or used geriatric depressives with brain-wide atrophy from an array of diseases. The authors of the new study report MRIs with far more resolution than in previous studies and have excluded individuals with neurologic, metabolic, or endocrine diseases. They have found significant reductions in the volume of both hippocampi (12% in the right and 15% in the left) when comparing individuals with a history of depression to age-, education-, gender-, and height-matched controls. No change in overall brain volume was observed. The individuals studied had been depression-free for months or decades and, at the time of the study, had normal GC concentrations. The investigators ruled out several confounding variables: alcohol or substance abuse, electroconvulsive therapy, and current use of antidepressants. Remarkably, there was a significant correlation between the duration of the depression and the extent of atrophy (see figure, top panel). A similar relation is seen in patients with Cushing’s syndrome: GCs are overproduced as a result of a hypothalamic, pituitary, adrenal, or pulmonary tumor, and there is bilateral hippocampal atrophy (5). Unfortunately, for control values the authors of this study had to rely on comparisons with published data from MRI scans. However, as an impressive internal control, among the Cushingoid individuals, the extent of GC hypersecretion correlated with the extent of hippocampal atrophy (which also correlated with the extent of impairment in hippocampal-dependent cognition) (see figure, middle panel). No atrophy occurred in the caudate nucleus, a brain region with few GC receptors (6). Additional evidence of the relation between GCs and hippocampal function has emerged from studies of individuals with posttraumatic stress disorder (PTSD). In Vietnam combat veterans with PTSD, Bremner and colleagues found a significant 8% atrophy of the right hippocampus (and near significant atrophy of the left) (7). In a study in Biological Psychiatry (in press), Gurvits, Pitman, and colleagues also examined Vietnam veterans with PTSD and found significant 22 and 26% reductions in volumes of the right and left hippocampi, respectively (8). Finally, in another study, also in press in Biological Psychiatry, Bremner et al. found a 12% atrophy of the left hippocampus in adults with PTSD associated with childhood abuse (with near significant atrophy in the right hippocampus) (9). The studies controlled for age, gender, education, and alcohol abuse-and the Bremner studies-ruled out depression as a confounding variable as well. There is some uncertainty as to the anatomical specificity ofthe effect. In the studies by Bremner, the results were only presented as absolute hippocampal volume, and there were nearly as large (but nonsignificant) reductions in volumes of the amygdala, caudate nucleus, and temporal lobe. However, the study by Gurvits et al. showed hippocampal atrophy after correction for whole-brain volume, with no atrophy in the amygdala. E 2700 E 2500 0. > 2300 – E 2100- % 0 S 1700. -1 0 I.. . S Time depressed (days) a.0044 C E .0040 o 0 > .0036 E .0032 _ 0_ .0024 E a E 0 E o 0 0 0. 0. If 12 10 9 8 7 0 00 :: 6 5 u u iu Ju 4U Months of combat exposure Do stress-induced glucocorticoids cause brain atrophy?ssi Relation between hippocampal volume and (top) duration of depression among individuals with a history of major depreon [from (4)], (middle) extent of cortisol hypersecretion among Cushingoid patients [adapted from (5)], and (bottom) duration of combat exposure among veterans with or without a history of posttraumatic stress disorder [from (7)]. Cortisol is another term for the human GC hydrocortisone. It is not clear whether the atrophy is associated with trauma (combat or abuse) or with succumbing to PTSD (which occurs in 5 to 20% of such traumatized individuals). In the Gurvits study, control groups consisted of healthy volunteers (matched for age, education, and other characteristics) and matched veterans with a history of combat exposure but no PTSD. In the combat veterans, both with and without PTSD, longer durations of combat were associated with smaller hippocampi (see figure, bottom panel). However, because the PTSD patients sustained longer combat exposure than did the controls who had experienced combat but did not have PTSD, it was impossible to dissociate combat from PTSD as a predictor of atrophy. In contrast, in the Bremner combat study (in which there was no non-PTSD combat control group), combat duration did not predict extent of atrophy. Finally, in the childhood abuse study (in which there were no non-PTSD childhood abuse contrQls), it was not posSCIENCE * VOL. 273 * 9 AUGUST 1996 Why Stress Is Bad for Your Brain Robert M. Sapoisky The author is in the Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA. to IMPiTwo-Itel”W1111111IR 749 0 on November 28, 2011 Downloaded from sible to dissociate the PTSD from the trauma. Each of these studies has some weaknesses, but they are countered by complementary strengths in the other studies. Are GCs the damaging agents? Depression is accompanied by numerous physiological abnormalities, and it has not been demonstrated that the hippocampal atrophy occurs only among depressives who overproduce GCs. Moreover, among individuals with PTSD, there is no information as to the extent of the GC stress response during the trauma (or what additional physiological changes occur then). Thus, in these cases, it is not clear whether GCs mediate the atrophy. However, as noted, the defining abnormality in Cushing syndrome is GC excess, making it a likely culprit in causing atrophy. How persistent are the changes? Although the Cushingoid atrophy reverses with correction of the endocrine abnormality (6), in the PTSD and depression studies, the atrophy occurred months to years after the trauma or the last depressive episode, and at a time when patients did not hypersecrete GCs. Thus, these long-standing changes could conceivably represent irreversible neuron loss. The PTSD and depression studies present a problem of causality. Given the cognitive role of the hippocampus, a smaller hippocampus might be more likely to lead to being assigned frontline combat duty rather than a skilled task at headquarters. Furthermore, given the evidence ofdepression as a disorder of “learned helplessness,” a smaller hippocampus might predispose toward depression (that is, less cognitive capacity to detect efficacious coping responses and thus greater vulnerability to learned helplessness). Finally, PTSD individuals, before joining the military, had high rates of learning disorders and delayed developmental landmarks that could reflect cerebral atrophy (10). Thus, a small hippocampus could be a cause, rather than a consequence, of the trauma or stressor in these studies. However, there is no plausible way in which a small hippocampus predisposes one toward the pituitary or adrenal abnormalities of the Cushingoid patients, or toward being a victim of childhood abuse. Should this literature ultimately show that sustained stress or GC excess can damage the human hippocampus, the implications are considerable. It would then become relevant to question whether the high-dose GC regimes used to control many autoimmune and inflammatory diseases have neuropathological consequences. (Both therapeutic and experimental administration of GCs to humans results in memory impairment.) In addition, in the rodent the extent of lifetime GC exposure can influence the likelihood of “successful” hippocampal and cognitive aging (11); similar issues must be examined conceming our own dramatic differences in cognitive aging. References 1. A. Munck etal., Endocr. Rev. 5, 25 (1984). 2. B. McEwen, Prog. Brain Res. 93, 365 (1992); R. Sapolsky, Semin. Neurosci. 6, 323 (1994). 3. H. Uno et al., J. Neurosci. 9, 1705 (1989); R. Sapolsky et al., ibid. 10, 2897 (1990); A. Magarinos etal., ibid. 16, 3534 (1996). 4. Y. Sheline et al., Proc. Natl. Acad. Sci. U.S.A. 93, 3908 (1996). 5. M. Starkman et al., Biol. Psychiatry 32, 756 (1992). 6. M. Starkman, personal communication. 7. J. Bremner et al., Am. J. Psychiatry 152, 973 (1995). 8. T. Gurvits etal., Biol. Psychiatry, in press. 9. J. Bremner et al., ibid., in press. 10. T. Gurvits et al., J. Neuropsychiatry Clin. Neurosci. 5, 183 (1993). 11. M. J. Meaney et al., Science 239, 766 (1988); A. Issa et al., J. Neurosci. 10, 3247 (1990). STATs Find That Hanging Together Can Be Stimulating Stewart Leung, Xiaoxia Li, George R. Stark Transcription factors activate the synthesis of messenger RNAs from DNA, thereby changing the function of cells. A few years ago, a new family of transcription factorsthe STATs (signal transducers and activators of transcription)-was described that mediates the action of a large and vastly important class of signaling molecules, the cytokines and growth factors. Each cytokine or growth factor activates a distinct set of genes to produce very distinct effects on the cell, yet there are only a limited number of STATs to mediate these signals. How do these few STATs generate a specific response for each cytokine or growth factor? Part of the answer to this puzzle is provided in a report by Xu et al. in this week’s issue of Science (1 ). The STATs exist as latent transcription factors in the cytoplasm. After binding of the growth factor or cytokine to its receptor, the STAT is activated by tyrosine phosphorylation (2-4); it then migrates to the nucleus, binds to specific DNA elements, and activates the transcription of nearby genes. The six STAT family members form homoor heterodimers in which the phosphotyrosine of one partner binds to the SH2 (SRC homology 2) domain of the other (5). These dimers bind to palindromic GAS sequences that have similar affinities for different STATs. The new work by Xu et al. (1) describes how each cytokine elicits a specific transcriptional response when each must use a limited number of factors and when the target DNA elements distinguish relatively poorly among these factors. In investigating a region of the human interferon-y (IFN-y) gene that contains clusters of GAS elements, these authors found that homodimers of STATs 1, 4, 5, and 6 all bind, but with different footprints. Their observations suggest that STAT dimers may cooperate in binding to clustered GAS elements and that the details of this cooperation may help to determine the cytokine specificity of the response. The STAT proteins share blocks of homology, arrayed over their entire 800-amino acid length, and it is likely that similar domains have similar functions: (i) The SH2 domain near residue 600 is highly conserved, as is a tyrosine near residue 700, which becomes phosphorylated upon activation. In addition to binding the phosphotyrosine of another STAT, the SH2 domain also mediates the binding of STATs to specific phosphotyrosine residues of activated cytokine receptors (6-8). (ii) The COOH-termini of STATs mediate transcriptional activation, and phosphorylation of a serine residue in this region of STATs 1la, 3, 4, and 5 enhances this activity (9). In contrast, the acidic COOH-terminal region of STAT2 can activate transcription without phosphorylation (10). (iii) STATs contain a DNA binding domain near residues 400 to 500 (11). (iv) STAT2-STAT1 heterodimers bind to an additional protein, p48, to form the major transcription factor generated in response to IFN-ox. The region comprising residues 150 to 250 of STAT1 interacts with p48 (12). Other STAT dimers may also interact with p48 (or similar proteins) to form more complex oligomeric transcription factors. Xu et al. (1) have found a new function for the NH2-terminal domains of STATs 1 and 4: Mediating cooperative binding of these STATs to tandem GAS sites. Deletion of 90 amino acids from the NH2-terminus of STAT4 did not affect its binding to a single GAS site but abolished the cooperative binding of two STAT4 dimers to a double site. Furthermore, a peptide representing the SCIENCE * VOL. 273 * 9 AUGUST 1996 The authors are in the Department of Molecular Biology, Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. E-mail: starkg@ IrwI 750 on November 28, 2011 Downloaded from

DOI: 10.1126/science.275.5306.1662 Science 275, 1662 (1997); Rachel Yehuda Stress and Glucocorticoid This copy is for your personal, non-commercial use only. colleagues, clients, or customers by clicking here. If you wish to distribute this article to others, you can order high-quality copies for your following the guidelines here. Permission to republish or repurpose articles or portions of articles can be obtained by (this infomation is current as of November 28, 2011 ): The following resources related to this article are available online at version of this article at: Updated information and services, including high-resolution figures, can be found in the online This article cites 8 articles, 2 of which can be accessed free: This article has been cited by 4 articles hosted by HighWire Press; see: Neuroscience This article appears in the following subject collections: registered trademark of AAAS. 1997 by the American Association for the Advancement of Science; all rights reserved. The title Science is a American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the on November 28, 2011 Downloaded from Stress and Glucocorticoid In his Perspective “Why stress is bad for your brain” (1), Robert M. Sapolsky concludes that glucocorticoid (GC) excess, sometimes a result of sustained stress, is a “likely culprit in causing [hippocampal] atrophy [in humans].” Although the data demonstrating reduced hippocampal volume in Cushing’s disease provide supporting evidence for this hypothesis, the other clinical studies cited do not. For example, although hippocampal volumes are reportedly smaller in trauma survivors with posttraumatic stress disorder (PTSD) as compared with those in survivors without PTSD and in nonpsychiatric (control) subjects, the amount of circulating GC is actually chronically lower in people with PTSD as compared with these other groups (2). Furthermore, although there has been a general presumption that the concentration of cortisol present at the time of the trauma is higher in trauma survivors who develop PTSD as compared with that in those who do not, recent evidence suggests that the opposite might be correct. For example, a longitudinal study of rape victims found that cortisol responses (obtained from emergency room blood samples within hours after the rape) were attenuated in women who had prior trauma and who were more likely to develop PTSD, as compared with the cortisol responses of similarly traumatized women who did not develop PTSD (3). Motor vehicle accident victims who subsequently developed PTSD also showed reduced amounts of cortisol within hours following this trauma, as compared with amounts in such victims who had no subsequent psychiatric disorder or who developed major depression (4). Higher concentrations of cortisol at the time of the accident were associated with subsequent major depression (4). Although the blood cortisol samples were not obtained in studies (3, 4) while the trauma was actually occurring, making it technically impossible to rule out that concentrations of cortisol were higher during the trauma in those who subsequently developed PTSD, it seems unlikely that these concentrations would be high enough to permanently damage the hippocampus for the brief duration (minutes to hours) during which these traumatic events actually occurred, even though this brief duration was enough to precipitate PTSD. GC excess may also not be the underlying cause of the smaller hippocampal volumes observed in a study by Sheline et al. of remitted depression (5). Although it is well established that about half of depressed patients are hypercortisolemic, the only study that directly examined this issue found no differences between depressed patients and normal controls (6). Although Sheline et al. observed smaller hippocampi in their study group, the remitted depressed subjects were not hypercortisolemic at the time of the hippocampal volume assessment. Furthermore, there is no evidence that subjects were ever hypercortisolemic, even though they had a past history of depression. Because subjects were elderly (with a mean age of 68) and had psychiatric treatment histories, a number of factors other than GC excess may have contributed to the smaller hippocampal volumes. Although Cushing’s disease, PTSD, and depression have been associated with smaller hippocampal volumes, it is unlikely that a common etiology explains the neuroanatomical findings, because each disorder presents a different clinical picture. In Cushing’s there is clearly GC excess, but not necessarily stress exposure. Because successful treatment reverses some of the hippocampal atrophy (7), this effect appears to be at least partially state-dependent, and may not be associated with permanent or long-term consequences. In PTSD, patients have been exposed to traumatic stress, but there is little evidence of GC excess. The most ambiguous observations are those made of depressed patients. However, unlike the data on Cushing’s disease, the findings presented in the Sheline et al. study suggest a more permanent, nonstate-dependent phenomenon, because smaller hippocampi were observed in the absence of both an excess of GC and clinical symptomatology, whereas these changes may be less obvious while patient are depressed and actively hypersecreting GC (6). One way to approach these studies is to use them as an opportunity to critically examine some of our assumptions about the relationship between stress and GC excess. Given that sustained stress and trauma are often associated with low cortisol in humans, stress should no longer be defined by GC excess any more than GC excess should be taken as evidence of stress. These terms, therefore, should not be used interchangeably. In the aggregate, the data suggest that it is necessary to search for biologic mechanisms other than cortisol toxicity that might account for hippocampal atrophy (for example, excitatory amino acids). Moreover, because the effects of stress do not appear to be uniform, it would be appropriate to carefully delineate the conditions under which stressors are more or less likely to influence brain plasticity, as well as the risk factors that account for individual differences in GC responses to stress (8). Rachel Yehuda Posttraumatic Stress Program, Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA E-mail: REFERENCES ______________ 1. R. M. Sapolsky, Science 273, 749 (1996). 2. R. Yehuda et al., Am. J. Psychiatry 152, 982 (1995). 3. H. Resnick, R. Yehuda, R. K. Pitman, D. Foy, ibid., p. 1675. 4. A. C. McFarlane et al., personal communication. 5. Y. Sheline et al., Proc. Natl. Acad. Sci. U.S.A. 93, 3908 (1996). 6. D. Axelson et al., Psychiatry Res. 47, 163 (1993). 7. M. Starkman, personal communication [reference 6 in (1)]. 8. R. Yehuda, Risk Factors for Posttraumatic Stress Disorder (American Psychiatric Association, Washington, DC, in press). 4 October 1996; accepted 27 November 1996 Response: A literature stretching back decades demonstrates the deleterious effects of stress and of GCs in the hippocampus of laboratory animals. My Perspective considered recent evidence that the same might occur in humans. Yehuda, a leading PTSD researcher, has questioned some of this evidence. How could GCs cause the hippocampal atrophy seen in patients with depression and PTSD, when circulating GC concentrations are normal in the former and below normal in the latter? The absence of elevated GC at the time of study (as noted in my Perspective) is not a problem. The study of Sheline et al. (1) was not of depressives, but of ex-depressives. In the case of PTSD, it is not the period of the posttraumatic stress disorder that is the alleged culprit, but the period of the traumatic stress itself. No one knows what GC concentrations are during a traumatic stress in a human, but 60 years of research suggests that concentrations will be elevated, a likelihood Yehuda appears to accept. It is the hippocampal atrophy— found many years after the (well-documented) GC hypersecretion seen in approximately half of depressives and after the (likely) CG hypersecretion during the traumatic stressors—that was so striking in these studies. With regard to the relative brevity of the stressor, I would not anticipate finding hippocampal atrophy in rape or accident victims. The literature comes from combat veterans (2, 3) and from individuals with a history of childhood abuse (4). These are not traumas of brief duration, but of months to years. As the most explicit example of this, in one study (3) the extent of atrophy was predicted by the severity of TECHNICAL COMMENTS SCIENCE z VOL. 275 z 14 MARCH 1997 1662 z on November 28, 2011 Downloaded from the combat exposure, a measure reflecting repeated trauma (with questions such as “How often were you in danger of being injured or killed in the line of duty?”) (5). As Yehuda points out, all stressors and all stimuli of GC secretion are not the same, and duration of stress is certainly relevant. In my Perspective, I raised a challenge to those studying the biological correlates of PTSD, which is to determine whether these correlates are a consequence of the trauma or if they predispose the individual towards being in the subset of trauma victims who suffer PTSD. This issue confounds the current discussion. However, among combat veterans both with and without PTSD (3), greater severities of combat exposure were associated with smaller hippocampi—thus, amid the complexities of trying to understand cause and effect in PTSD, it was combat stress, and not the subsequent PTSD in a subset of individuals, that was relevant to the instances of hippocampal atrophy. Yehuda notes an earlier study that did not find hippocampal atrophy in hypercortisolemic depressives. That 1993 imaging study used magnetic resonance imagers (MRIs) with one-tenth the resolution of current ones (5.0 versus 0.5 mm, respectively), and could not distinguish hippocampus from amygdala. It was the development of newer MRIs that prompted the current spate of studies. Yehuda notes that in considering the hippocampal atrophy in Cushing’s disease, depression, and PTSD, “it is unlikely that a common etiology explains the neuroanatomical findings.” I agree. The closest animal model for the reversible atrophy in the Cushing’s patients is excitatory amino acid– dependent retraction of dendritic processes, while the closest model for the more persistent atrophy in the other two cases is neuron loss. Much more work is needed— given that there are now only a handful of human studies—particularly in differentiating between depression with or without GC hypersecretion, in carrying out prospective studies of trauma victims, and in determining whether actual neuron loss has occurred in cases of persistent atrophy. Robert M. Sapolsky Department of Biology, Stanford University, Stanford, CA 94305, USA REFERENCES AND NOTES ___________________________ 1. Y. Sheline et al., Proc. Natl. Acad. Sci. U.S.A. 93, 3908 (1996). 2. J. Bremner et al., Am. J. Psychiatry 152, 973 (1995). 3. T. Gurvits et al., Biol. Psychiatry, in press. 4. M. Stein et al., Am. Psychiatric Assoc. Syllab. Proc. Summary 148, 113 (abstr. 62C) (1995). 5. T. Keane et al., J. Consult. Clinic. Psych. 1, 53 (1989). 28 October 1996; accepted 27 November 1996 z SCIENCE z VOL. 275 z 14 MARCH 1997 1663 on November 28, 2011 Downloaded from

What is stress

The sum of all nonspecific effects of factors that can act on the body to increase energy consumption significantly above basal level
–In the short term, stress is adaptive and helps individuals cope with emergency situations

–In the long term, stress is maladaptive

A stressor is anything that throws the body out of homeostatic balance

Physiological Systems and Endocrine Glands Affected by Stress




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