646305

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PPSXXX10.1177/1745691616646305Cohen et al.A Stage Model of Stress and Disease

Perspectives on Psychological Science

A Stage Model of Stress and Disease 2016, Vol. 11(4) 456­–463

© The Author(s) 2016
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DOI: 10.1177/1745691616646305
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Sheldon Cohen1, Peter J. Gianaros2, and

Stephen B. Manuck2
1
Carnegie Melon University and 2University of Pittsburgh

Abstract
In this article, we argued that the term stress has served as a valuable heuristic, helping researchers to integrate
traditions that illuminate different stages of the process linking stressful life events to disease. We provided a short
history of three traditions in the study of stress: the epidemiological, psychological, and biological. The epidemiological
tradition focuses on defining which circumstances and experiences are deemed stressful on the basis of consensual
agreement that they constitute threats to social or physical well-being. The psychological tradition focuses on
individuals’ perceptions of the stress presented by life events on the basis of their appraisals of the threats posed
and the availability of effective coping resources. The biological tradition focuses on brain-based perturbations of
physiological systems that are otherwise essential for normal homeostatic regulation and metabolic control. The foci
of these three traditions have informed elements of a stage model of disease, wherein events appraised as stressful
are viewed as triggering affective states that in turn engender behavioral and biological responses having possible
downstream implications for disease.

Keywords
stress, stress and disease, stress mechanisms

In an article in this issue of Perspectives in Psychological ago, each of these traditions was pursued by different
Science, Kagan (2016, this issue) voices a concern that networks of researchers, but the last 20 years have seen
has been discussed for more than half a century, namely, increasing integration of these approaches.
that the term stress has been so promiscuously invoked
and applied in such a biased fashion as to render it of
The epidemiologic tradition
little utility (see, for example, Appley & Trumbull, 1967).
In turn, because stress is used inconsistently across disci- In the epidemiologic tradition, investigators assess the
plines with different methodological traditions and differ- objective levels of stress posed by individual life events.
ent levels of analysis, it is often difficult to understand Implicit in this approach is that a specific life event gen-
how research from these fields fits together. In this com- erates an equivalent amount of stress for all individuals.
mentary, we provide a brief history of how the term stress Estimates of objective levels are based on normative
has been used in research on humans. We propose that (average) ratings of the stress associated with each event
stress be viewed broadly as a set of constructs represent- by individuals in the population being studied or by
ing stages in a process by which environmental demands trained judges. However, definitions of stress used to
that tax or exceed the adaptive capacity of an organism assign objective (normative) levels have varied.
occasion psychological, behavioral, and biological In an early approach, Holmes and Rahe (1967) pro-
responses that may place persons at risk for disease. posed that the more change inherent in adapting to a life
event, the greater the stress associated with that event. In
Traditions of Studying Stress
Corresponding Author:
There are several traditions of studying stress, most nota-
Sheldon Cohen, Department of Psychology, Carnegie Mellon
bly the epidemiological, psychological, and biological University, Pittsburgh, PA 15213
(Cohen, Kessler, & Underwood Gordon, 1995). Fifty years E-mail: [email protected]

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A Stage Model of Stress and Disease 457

turn, this approach suggests that stress is cumulative, episodes (Brown & Harris, 1989). It is notable that those
with each additional event adding to the overall burden with a single severe event have also been found to have
of adaptation required of the individual. This was the increased risk for a range of other psychiatric and physi-
theory behind the development of early stressful life cal disorders (reviewed in Brown & Harris, 1989).
event scales. For example, in the Social Readjustment The epidemiological approach also has included stud-
Rating Scale (SRRS; Holmes & Masuda, 1974), the amount ies of exposure to single, consensually determined threat-
of change required by each of a list of 43 “major” life ening events, such as unemployment ( Jin, Shah, &
events was determined by normative ratings obtained Svovoda, 1997), divorce (Kitson, & Morgan, 1990), bereave-
from a panel of judges drawn from the population. The ment (Bowling, 1987), economic strain (Lallukka, Lahelma,
change scores (known as life change units, or LCU) for & Rankonan, 2013), and caregiving for the chronically
all events that an individual reported as occurring in a ill (Kiecolt-Glaser, Marucha, Mercado, Malarkey,
specified period (usually a year) were summed to gener- & Glaser, 1995; Schulz, Visintainer, & Williamson, 1990).
ate a measure of total change required to adapt to expe- Reliance on these single-event indicators reflects an
rienced events. Examples of events on the SRRS include underlying assumption that certain types of events are
marriage (LCU = 50), divorce (LCU = 73), being fired sufficient to generate substantial levels of threat. These
at work (LCU = 47), retirement (LCU = 45), pregnancy predominantly include threats relating to central social
(LCU = 40), and taking a vacation (LCU = 13). roles (e.g., worker, spouse, or parent; Lepore, 1995) and
Although the adaptation (change) model has been to the integrity of interpersonal relationships (Bolger,
endorsed by some (see Turner & Wheaton, 1995), it has DeLongis, Kessler, & Schilling, 1989; Cohen et al., 1998;
not held up empirically (e.g., it implied that positive Rook, 1984). They also tend to be chronic, with the event
events would have similar effects as negative ones) and or its implications lasting months or even years (Cohen
largely has been replaced by a definition of stressors as et al., 1998).
events that are consensually seen as undesirable or Overall, while the definition of what constitutes a
threatening (e.g., Brown & Harris, 1989: Paykel, Prusoff, stressful life event has varied over time, the epidemio-
& Uhlenhuth, 1971; Ross & Mirowsky, 1979; Vinokur & logical perspective has defined stress primarily by refer-
Selzer, 1975). Here self-reported stressful life event scales ence to independent ratings that reflect how others, in
are made up of events consensually seen as negative aggregate, judge the negative impact of particular events.
(threatening), such as job loss, death of a close other, and Such measures have been successful in predicting mor-
legal problems. Typically, these are not weighted bidity (e.g., depression, respiratory infections, and coro-
(weighted indices do not generally increase the correla- nary heart disease), disease progression (e.g., HIV-AIDS,
tion with disease; Turner & Wheaton, 1995) but are wound healing, and autoimmune diseases) and mortality
scored by counting the total number of negative events (reviewed by Cohen, Janicki-Deverts, & Miller, 2007).
that are endorsed.
Another example of a method for assessing stressful
The psychological tradition
life events on their objective level of threat is the Life
Events and Difficulties Schedule (LEDS; Brown & Harris, According to the epidemiological approach, individuals’
1989). Unlike simple checklists of common life stressors, experience of stress is inferred from their exposure to a life
the LEDS is a structured interview used to probe for event independently judged as threatening or requiring
details of reported events and their surrounding context. adaptive adjustment. In contrast, the psychological per-
Each event (informed by the circumstances surrounding spective stems from the observation that experiencing the
the event) then is rated for threat by a group of trained same event can be stressful for some individuals but not
raters who use prior ratings of similar events by other others. Hence, according to the psychological perspective,
LEDS raters as anchors for rating new events. The raters a stressful experience cannot be inferred by uniform refer-
then enter their own ratings in a master database, result- ence to any particular event. Rather, such an inference
ing in a growing dictionary of ratings of the “objective” necessarily depends on how such an event is construed by
(consensual) long-term threat associated with many dif- the individual. This approach is repre­sented by Lazarus
ferent life events (Wethington, Brown, & Kessler, 1995). and Folkman’s (Lazarus, 1966; Lazarus & F ­ olkman, 1984)
In the LEDS, stress is not assumed to increase with each seminal work on stress appraisal, which proposes that
additional event. Instead, any single event meeting the people appraise both the degree of potential threat posed
LEDS-defined threat-severity threshold suffices to mark by events and the availability of resources needed to cope
the presence of sufficient stress to put a person at risk for with them. Threat appraisals of events are influenced by
disease. This convention did not stem from theoretical the imminence of harm and the intensity, duration, and
considerations but rather from empirical evidence that a potential controllability of the event, as well as by indi-
single severe event is enough to predict depressive viduals’ beliefs about themselves and the environment,

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458 Cohen et al.

their values and commitments, and related personality dis- and metabolic control. An assumption in the biological
positions. Coping appraisals may focus on actions designed tradition is that these physiological perturbations or reac-
to directly alter the perceived threatening event or on the tions provide support over the short term for adaptive
viability of thoughts or actions that are intended to change behavioral action or coping. Over the long term, how-
emotional and behavioral responses to the event. A threat ever, such physiological reactions may prove maladaptive
appraisal without the belief that effective coping responses and relate to risk for disease.
are available is experienced as stress, which engenders As described by Kagan, the biological tradition was
emotional responses including worry, fear, and anxiety. influenced heavily by Selye’s (1956) early work, in which
An example of the use of the appraisal approach in a stress was equated with chronic activation of one of the
specific domain is the Karasek Job Control Questionnaire body’s principal neuroendocrine axes, the hypothalamic–
( JCQ). Perceived job stress is defined as present when pituitary–adrenal (HPA) system. This tradition also has
individuals rate their own jobs as simultaneously high in deep roots in experimental psychophysiology and psy-
work demand and low in personal control over the work chosomatic medicine, where responses of the autonomic
setting (e.g., Karasek, Baker, Marxer, Ahlbom, & Theorell, nervous system have long figured prominently as mark-
1981). Others have assessed individuals’ appraisals of the ers of stress (Cannon, 1932; Mason, 1971; Weiner, 1992).
threat or negative impact associated with engaging in spe- Measured stress indicators thus commonly include the
cific social roles, such as work, marriage, or parenthood HPA-derived hormone, cortisol, and the sympathoadrenal-­
(see review by Lepore, 1995). This perspective has also medullary (SAM) mediators, epinephrine and norepi-
been applied to stressful life event scales, such that subjec- nephrine, as well as autonomically regulated, peripheral
tive (self-generated) ratings of the negative impact of physiological indices like heart rate and blood pressure.
endorsed events are summed instead of the objective, con- Patterns of response across these parameters of physiol-
sensual ratings used in earlier instruments (e.g., Sarason, ogy often vary with differences in the stimuli that evoke
Johnson, & Siegel, 1978). them, but in general, their stimulus-dependent activation,
A different approach to tapping individuals’ percep- when excessive, persistent, or repeated often, has been
tions of stress has focused on global (event-independent) viewed as a biological instantiation of stress (Cohen
appraisals. For example, the Perceived Stress Scale (Cohen, et al., 1995; Smyth, Zawadzki, & Gerin, 2013). As alluded
Kamarck, & Mermelstein, 1983) focuses on experiences to by Kagan, one problematic issue inherent to the bio-
during the last month, assessing the degree to which peo- logical tradition is that there are no agreed-upon thresh-
ple feel that the demands in their lives exceed their abili- olds that define stress for any of these parameters.
ties to cope effectively. Similarly, an adaptation of the JCQ Biological research on stress in humans historically has
(perceptions of high demand and low control) has been emphasized laboratory studies in which participants are
used to assess non-work-related stress in daily life (e.g., exposed to experimental challenges (stressors). These
Kamarck, Muldoon, Shiffman, & Sutton-Tyrrell, 2007). studies are used to identify and elucidate biological mech-
Over the years, investigators have assessed other stressor- anisms that may mediate effects of environmental stress-
related appraisals in addition to the dimension of threat, ors on more distal outcomes. In such studies, the
including appraisals of injustice, time pressure, harm or participants are exposed to tasks and stimuli of brief dura-
loss, and distress intolerance (Monroe & Kelley, 1995). tion that share certain features with objectively defined
Overall, researchers holding the psychological perspec- stressors, such as aversiveness, conflict, uncontrollability,
tive generally have defined stress as an experience that social threat, or demands for time-pressured coping. So
occurs when individuals simultaneously appraise events as the point is not that these tasks and stimuli are “stress” but
threatening or otherwise harmful and their coping that they model features of epidemiologically studied
resources as inadequate. Like objective measures of events, stressors in a controlled setting, allowing for instrumented
measures of perceived stress also have been useful in pre- investigation of evoked physiological reactions. By exten-
dicting subsequent risk for morbidity and mortality (e.g., sion, the types of autonomic and neuroendocrine
Keller et al., 2012; Nielson, Kristensen, Schnohr, & Grøn- responses typically assessed in such studies, when repeat-
bæk, 2008; Wisnivesky, Lorenzo, ­Feldman, Leventhal, & edly elicited in the context of naturally occurring stressful
Halm, 2010). life events, are thought to promote systemic biological
and cellular changes that are conducive to disease, such
as altered metabolic, immune, respiratory, and cardiovas-
The biological tradition cular functioning. Accordingly, the impact of stressor-
In the biological approach, the impact of defined stress- evoked physiological reactions is thought to constitute a
ors is indexed via perturbations of physiological systems primary pathway connecting stressful events and apprais-
that are otherwise essential for homeostatic regulation als to physical health outcomes.

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A Stage Model of Stress and Disease 459

A second line of biological research on stress focuses cortex, cingulate, insula, and amygdala. Evoked patterns
on stable individual differences in the magnitude of of activity across these and other networked brain regions
stressor-evoked physiological reactions, particularly car- are presumed to correspond to the neural processes sup-
diovascular, HPA, and cellular immune reactions to acute porting stressor appraisals and possibly emotional expe-
psychological stressors (e.g., Krantz & Manuck, 1984; rience, responding, and regulation (Gianaros & Wager,
Manuck, 1994; Manuck, Cohen, Rabin, Muldoon, & 2015). Moreover, changes in neural activity in these same
Bachen, 1991; Marsland, Bachen, Cohen, Rabin, & regions are associated with peripheral measures of stress
Manuck, 2002). A reason for this focus is that individuals physiology, including disease-relevant parameters of
with a tendency to exhibit heightened blood pressure autonomic, neuroendocrine, cardiovascular, and immune
reactivity when measured in laboratory settings, for physiology (Muscatell & Eisenberger, 2012).
instance, also are more likely to exhibit preclinical vascu- Although findings from these human imaging studies
lar disease and suffer from premature cardiovascular have begun to clarify the role of the brain in linking psy-
mortality (Carroll et al., 2012; Chida & Steptoe, 2010; chological and social stressors to physiological reactions
Gianaros et al., 2002; Jennings et al., 2004). Similarly,
­ that may contribute to disease risk, several core questions
individual differences in cellular immune reactivity relate remain. One such question is whether appraisal and
to indicators of weakened immunity (e.g., blunted anti- effector mechanisms for physiological stress responding
body responses to Hepatitis B antigen following vaccina- are overlapping and inseparable processes at the level of
tion; Marsland, Cohen, Rabin, & Manuck, 2001), and the brain. Alternative possibilities are that appraisal and
analogous individual differences in HPA activation effector response processes are initiated in parallel or are
­moderate infectious disease susceptibility in response to sequenced over time in a chain across networked brain
naturally occurring stressful life events (Cohen et al., 2002). regions. Finally, researchers have not been able to resolve
A broader view of the biology of stress in terms of whether the stressor-evoked neural activity changes that
dysregulated systems (e.g., overactivation, underactiva- covary simultaneously with peripheral physiological
tion, delayed recovery, counterregulatory rebound) has responses correspond only to the efferent commands for
begun to supplant earlier emphases equating stress with these responses or also to the afferent representation of
only overactivation of the SAM and HPA (McEwen, 1998). peripheral physiological changes. The afferent represen-
For example, research on the HPA response suggests that tation of these physiological changes through feedback
while cortisol does increase under acute stress, the HPA mechanisms to the brain may themselves serve to influ-
response to chronic stressors can be more complex, vari- ence emotional experiences and the appraisal of events
ously including a diminished cortisol release, glucocorti- that are encoded as stressors (Gianaros & Wager, 2015).
coid insensitivity, or alterations in the cortisol diurnal
rhythm (Miller, Chen, & Zhou, 2007; Miller, Cohen, & A Stage Model From Life Events to
Ritchey, 2002). These patterns of response may affect
immune and cardiovascular parameters that contribute to
Disease
disease pathogenesis (e.g., Cohen et al., 2012; Kiecolt-­ One approach to integrating the different traditions of
Glaser et al., 2005; Matthews, Schwartz, Cohen, & Seeman, studying stress is to view the various definitions as stages
2006). of a process linking environmental events to disease
Finally, a recent direction in research on human stress (cf. Cohen et al., 1995; see Fig. 1). Environmental (stress-
biology has been to characterize the brain systems that ful life) events can result in brain-based stress appraisals
appraise psychological and social stressors, as well as (threatening or not). If an event is appraised as a threat,
generate downstream physiological reactions that might it will trigger affective responses (e.g., worry, fear, or anx-
relate to disease risk (Muscatell & Eisenberger, 2012). iety) and alter the functions of the HPA, SAM, and other
Specifically, investigators in this area have used func- regulatory and neuroendocrine systems (e.g., parasym-
tional magnetic resonance imaging (fMRI) and other pathetic nervous system activity and gonadal steroids),
methods to measure neural activity while people com- having downstream implications for disease onset and
plete aversive tasks or process threatening stimuli that are severity.
modeled from laboratory-based studies of stress physiol- Brain-based stress appraisals also may affect health-
ogy. During imaging, this neural activity is measured relevant behaviors via affective responses and higher-
along with peripheral physiological reactions (e.g., blood level cognitions. For instance, behaviors used to cope
pressure) that have been implicated in disease risk with perceived negative events (e.g., decreased exercise
(Gianaros & Wager, 2015). Evidence from these brain- and sleep) or with emotional responses to negative
imaging studies indicates that psychological and social events (e.g., increased smoking and alcohol consump-
stressors engage a network of cortical and limbic regions, tion) provide important pathways by which stressful
particularly regions of the medial and lateral prefrontal events may influence disease risk. Additionally, stress

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460 Cohen et al.

may promote a variety of health-impairing behaviors

including cigarette smoking and substance abuse (Bickel
& Marsch, 2001; Fields, Lange, Ramos, Thamotharan, &
Rassu, 2014; Sweitzer, Donny, Dierker, Flory, & Manuck,
2008). Finally, appraisals of stress and their affective
sequelae can influence interpretations of physiological
sensations, such as defining sensations as symptoms and
symptom clusters as diseases that in turn influence
health-care seeking, and adherence to medical regimens
(Cohen & Williamson, 1991; Erickson, Creswell, Verstynen,
& Gianaros, 2014; Pennebaker, 1983; Smyth et al., 2013).
The stage model implies that each sequential compo-
nent of the stress process is more proximal to and hence
more predictive of illness outcomes than the preceding.
For example, a disease-relevant biological-stress-response
measure should be a better predictor than measures of
stressful life events or perceived stress. We want to
emphasize that this is a heuristic model designed to illus-
trate the potential integration of the environmental, psy-
chological, and biological approaches. Although the
model presents an ordered series of stages, we recognize
that other mechanisms may be at play, and all the stages
may not be required. For example, environmental
demands can put persons at risk for disorder even when
appraisal does not result in perceptions of stress and
negative emotional responses; the process of coping
itself (even when it is successful and environmental
demands are appraised as benign) may directly result in
physiological and behavioral changes that place a person
at risk for disease (Cohen, Evans, Krantz, & Stokols, 1986).
Finally, although the figure presents the model as unidi-
rectional, we recognize that there are feedback loops
(e.g., depressed affect may result in negatively biased
appraisal of the threat posed or of coping resources).
Overall, this perspective allows evidence from any of
the stages of stress to be integrated with downstream
counterparts, for instance, as in testing hypotheses posit-
ing mediating mechanisms. The ultimate aim is to eluci-
date all points in pathways leading from stressful events
and their appraisals to specific clinical outcomes, although
impediments of cost and practicality and the inherent
limitations of human research hinder full realization of
this goal. Nonetheless, increasing progress has been
made in establishing predicted links across two or more
Fig. 1.  A heuristic model of the stress process designed to illustrate the
potential integration of the environmental, psychological, and biologi-
stages so that gaps in the understanding of stress-illness
cal definitions of stress. Although the figure presents an ordered series relationships are being filled (cf. Miller, Chen, & Cole,
of stages, we recognize that other mechanisms may be at play, and 2009). Particularly informative is the emergence of exper-
all the stages may not be required. Moreover, although the model is imental models of disease susceptibility and studies of
unidirectional, we recognize that there are potential feedback loops as
well. HPA = hypothalamic–pituitary–adrenal system, SAM = sympatho- disease-relevant biological processes mediated by stress-
adrenal-medullary mediators. evoked autonomic and neuroendocrine reactions. For
example, a series of studies has shown that chronic stress
heightens forms of impulsive decision making such as (assessed as either life events or globally perceived stress)
delay discounting—a relative preference for immediate heightens susceptibility to the common cold among indi-
rewards over larger rewards delayed in time—that in turn viduals inoculated with an upper respiratory virus (e.g.,

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A Stage Model of Stress and Disease 461

Cohen, Tyrrell, & Smith, 1993). Recent experimental find- Bickel, W. K., & Marsch, L. (2001). Toward a behavioral eco-
ings suggest this effect is mediated by downregulation of nomic understanding of drug dependence: Delay discount-
the glucocorticoid receptor, which diminishes cortisol- ing processes. Addiction, 96, 73–86.
dependent modulation of inflammatory responses to Bolger, N., DeLongis, A., Kessler, R. C., & Schilling, E. A.
(1989). Effects of daily stress on negative mood. Journal of
infection and, in turn, promotes worsened cold symp-
Personality and Social Psychology, 57, 808–818.
tomatology (Cohen et al., 2012). In another example,
Bowling, A. (1987). Mortality after bereavement: A review of
aggregated measures of momentary task demands in the literature on survival periods and factors affecting sur-
daily life (assessed by ecological momentary assessment) vival. Social Science & Medicine, 24, 117–124. doi:10.1002/
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who were not on drugs to lower blood pressure. More- New York, NY: Guilford Press.
over, this association was partially mediated by higher Cannon, W. B. (1932). The wisdom of the body. New York, NY:
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only possible with suitable animal models, which in the acute mental stress are associated with 16-year cardiovas-
ideal are coextensive with human research (e.g., Capitanio cular disease mortality. Psychophysiology, 49, 1444–1448.
& Cole, 2015; Cohen et al., 1997; Kaplan et al., 1987; doi:10.1111/j.1469-8986.2012.01463.x
Manuck, Marsland, Kaplan, & Williams, 1995). Chida, Y., & Steptoe, A. (2010). Greater cardiovascular
In sum, we believe that the term stress has served as a responses to laboratory mental stress are associated with
valuable heuristic that has helped to highlight the simi- poor subsequent cardiovascular risk status: A meta-analy-
larities between research findings on different stages of sis of prospective evidence. Hypertension, 55, 1026–1032.
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Cohen, S., Evans, G. W., Krantz, D. S., & Stokols, D. (1986).
Admittedly, the term stress is used too broadly and some-
Behavior, health, and environmental stress. New York, NY:
times in confusing ways. However, the diversity of per- Plenum Press.
spectives that the term has spawned has provided a basis Cohen, S., Frank, E., Doyle, W. J., Skoner, D. P., Rabin, B. S.,
for understanding the processes through which environ- & Gwaltney, J. M., Jr. (1998). Types of stressors that
mental adversities influence disease processes. We hope increase susceptibility to the common cold in adults. Health
that future studies will include multiple stages of the Psychology, 17, 214–223. doi:10.1037/0278-6133.17.3.214
model (from environment through brain to disease) in Cohen, S., Hamrick, N., Rodriguez, M. S., Feldman, P. J.,
order to further validate this approach as a conceptual Rabin, B. S., & Manuck, S. B. (2002). Reactivity and vul-
tool for understanding the stress process. nerability to stress-associated risk for upper respira-
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Author Contributions doi:10.1097/00006842-200203000-00014
Cohen, S., Janicki-Deverts, D., Doyle, W. J., Miller, G. E., Frank, E.,
All the authors contributed to writing of the manuscript. Rabin, B. S., & Turner, R. B. (2012). Chronic stress, glu-
cocorticoid receptor resistance, inflammation, and dis-
Acknowledgments ease risk. PNAS: Proceedings of the National Academy of
The authors are grateful to Denise Janicki-Deverts and Tom Sciences of the United States of America, 109, 5995–5999.
Kamarck for their comments on an earlier version of this doi:10.1073/pnas.1118355109
article. Cohen, S., Janicki-Deverts, D., & Miller, G. E. (2007).
Psychological stress and disease. Journal of the American
Declaration of Conflicting Interests Medical Association, 298, 1685–1687. doi:10.1001/
jama.298.14.1685
The authors declared that they had no conflicts of interest with
Cohen, S., Kamarck, T., & Mermelstein, R. (1983). A global
respect to their authorship or the publication of this article.
measure of perceived stress. Journal of Health and Social
Behavior, 24, 385–396. Retrieved from http://www.jstor
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