124 VOLUME 12, NUMBER 4, AUGUST 2003

The Psychobiology of Stress strated powerful effects of expo-

sure to stressors on a variety of
Margaret E. Kemeny1 physiological systems. These spe-
cific changes are believed to have
Department of Psychiatry, University of California, San Francisco, San Francisco,
evolved to support the behaviors
California
that allow the organism to deal
with the threat (e.g., to fight or
The term stress is used in the sci- flee). In order for the organism to
Abstract
entific literature in a vague and in- respond efficiently, physiological
Stressful life experience can
consistent way and is rarely defined. systems that are needed to deal
have significant effects on a va-
The term may refer to a stimulus, a with threats are mobilized and
riety of physiological systems,
response to a stimulus, or the physi- physiological systems that are not
including the autonomic ner-
ological consequences of that re- needed are suppressed. For exam-
vous system, the hypotha-
sponse. Given this inconsistency, in ple, when responding to a threat,
lamic-pituitary-adrenal axis, and
this review I avoid using the term the body increases available con-
the immune system. These re-
stress (except when discussing the centrations of glucose (an energy
lationships can be bidirec-
field of stress research) and instead source) to ready the organism for
tional; for example, immune cell
differentiate the various components physical activity; at the same time,
products can act on the brain,
of stress. Stressors, or stressful life ex- the body inhibits processes that
altering mood and cognition,
periences, are defined as circum- promote growth and reproduc-
potentially contributing to de-
stances that threaten a major goal, in- tion. Although the body is adapted
pression. Although acute phys-
cluding the maintenance of one’s to respond with little ill effect to
iological alterations may be
physical integrity (physical stressors) this acute mobilization, chronic or
adaptive in the short term,
or one’s psychological well-being repeated activation of systems that
chronic or repeated provocation
(psychological stressors; Lazarus & deal with threat can have adverse
can result in damage to health.
Folkman, 1984). Distress is a negative long-term physiological and health
The central dogma in the field
psychological response to such effects (McEwen, 1998; Sapolsky,
of stress research assumes a ste-
threats and can include a variety of 1992). A wide array of physiologi-
reotyped physiological response
affective and cognitive states, such as cal systems have been shown to
to all stressors (the generality
anxiety, sadness, frustration, the change in response to stressors; in
model). However, increasing ev-
sense of being overwhelmed, or this section, I summarize the effects
idence suggests that specific
helplessness. Researchers have pro- on the three most carefully studied
stressful conditions and the spe-
posed a number of stressor taxono- systems (Fig. 1).
cific way an organism appraises
mies, most of which differentiate
these conditions can elicit qual-
threats to basic physiological needs
itatively distinct emotional and
or physical integrity, social connect- Impact on the Autonomic
physiological responses (the in-
edness, sense of self, and resources. Nervous System
tegrated specificity model). For
A number of properties of stressful
example, appraisals of threat
circumstances can influence the se- Since Walter Cannon’s work on
(vs. challenge), uncontrollabil-
verity of the psychological and phys- the fight-or-flight response in the
ity, and negative social eval-
iological response. These properties 1930s, researchers have been inter-
uation have been shown to
include the stressor’s controllability ested in the effects of stressful
provoke specific psychobiolog-
(whether responses can affect out- experience on the sympathetic
ical responses. Emotional re-
comes of the stressor), ambiguity, adrenomedullary system (the
sponses appear to have specific
level of demand placed on the indi- system is so named because the
neural substrates, which can re-
vidual, novelty, and duration. sympathetic nervous system and
sult in differentiated alterations
in peripheral physiological sys- adrenal medulla are its key compo-
tems, so that it is incorrect to pre- nents; see Fig. 1). Cannon correctly
sume a uniform stress response. proposed that exposure to emer-
PHYSIOLOGICAL EFFECTS OF gency situations results in the re-
EXPOSURE TO STRESSFUL lease of the hormone epinephrine
Keywords LIFE EXPERIENCE
stress; endocrine; autonomic; from the adrenal medulla (the core
immune; physiology; emotion; of the adrenal gland, located above
cognitive Extensive research in humans the kidney). This effect was shown
and other animals has demon- to be accomplished by the activity

Published by Blackwell Publishing Inc.

Downloaded from cdp.sagepub.com at PENNSYLVANIA STATE UNIV on May 12, 2016
 CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE 125

acute psychological stressors (e.g.,

giving a speech, doing difficult
cognitive tasks), for relatively short
durations, can cause an increase in
the levels of the hormone cortisol
in the blood, saliva, and urine. This
increase is due to activation of the
hypothalamic-pituitary-adrenal
(HPA) axis (see Fig. 1). Neural
pathways link perception of a
stressful stimulus to an integrated
response in the hypothalamus,
which results in the release of corti-
cotropin-releasing hormone. This
hormone stimulates the anterior
part of the pituitary gland to re-
lease adrenocorticotropic hormone,
which then travels through the
blood stream to the adrenal glands
and causes the adrenal cortex (the
outer layer of the adrenal gland) to
release cortisol (in rodents this hor-
mone is called corticosterone). The
activation of this entire system oc-
curs over minutes rather than sec-
onds (as in the case of the ANS).
The peak cortisol response occurs
20 to 40 min from the onset of acute
Fig. 1. Schematic representation of interrelationships among the central nervous sys- stressors. Recovery, or the return to
tem (CNS), the hypothalamic-pituitary-adrenal axis, the autonomic nervous system baseline levels, occurs 40 to 60 min
(ANS), and the immune system. Dashed lines indicate ANS neural pathways, and following the end of the stressor on
solid lines indicate hormonal pathways. ACTH ⫽ adrenocorticotropic hormone;
CRH ⫽ corticotropin-releasing hormone; NE ⫽ norepinephrine. average (Dickerson & Kemeny,
2002).

of the autonomic nervous system Research has demonstrated that ex- Impact on the Immune System
(ANS). The ANS has two compo- posure to a variety of stressors can
nents: the parasympathetic nervous activate this system, as manifested Exposure to stressful experi-
system, which controls involuntary by increased output of norepineph- ences can diminish a variety of im-
resting functions (activation of this rine and epinephrine, as well as in- mune functions. For example,
system promotes digestion and creases in autonomic indicators stressful life experiences, such as
slows heart rate, e.g.), and the sym- of sympathetic arousal (e.g., in- bereavement, job loss, and even
pathetic nervous system, which creased heart rate). This extremely taking exams, can reduce circulat-
comes into play in threatening situ- rapid response system can be acti- ing levels of classes of immuno-
ations and results in increases in vated within seconds and results in logical cells called lymphocytes;
involuntary processes (e.g., heart the “adrenaline rush” that occurs inhibit various lymphocyte func-
rate and respiration) that are re- after an encounter with an unex- tions, such as the ability to pro-
quired to respond to physical pected threat. liferate when exposed to a foreign
threats. Fibers of the sympathetic substance; and slow integrated
nervous system release the neu- immune responses, such as wound
rotransmitter norepinephrine at Impact on the Hypothalamic- healing (Ader, Felten, & Cohen,
various organ sites, including the Pituitary-Adrenal Axis 2001). Individuals’ autonomic reac-
adrenal medulla, causing the re- tivity to stressors correlates with
lease of epinephrine (also known A large body of literature sug- the degree to which their immune
as adrenaline) into the bloodstream. gests that exposure to a variety of system is affected by acute labora-

Copyright © 2003 American Psychological Society

Downloaded from cdp.sagepub.com at PENNSYLVANIA STATE UNIV on May 12, 2016
126 VOLUME 12, NUMBER 4, AUGUST 2003

tory stressors. Extensive evidence duction in exploratory behavior)

that autonomic nerve fibers inner- but also appear to mimic depres- GENERALITY VERSUS
vate (enter into) immune organs and sion (e.g., alterations in learning SPECIFICITY IN THE
alter the function of immune cells and memory, anorexia, inability to PHYSIOLOGICAL
RESPONSE TO STRESSORS
residing there supports the link be- experience pleasure, reductions in
tween the ANS and the immune social behavior, alterations in
system. In addition, some of the sleep, behavioral slowing). Emerg- The central dogma of most
immunological effects of stressors ing data indicate that these cyto- stress research today is that stres-
are due to the potent suppressive kines can induce negative mood and sors have a uniform effect on the
effects of cortisol on immunological alter cognition in humans as well. physiological processes I have just
cells. Cortisol can inhibit the pro- These effects may explain affective described. Hans Selye shaped the
duction of certain cytokines (chem- and cognitive changes that have been thinking of generations of re-
ical mediators released by immune observed to be associated with in- searchers when he argued that the
cells to regulate the activities of flammatory conditions. They may physiological response to stressful
other immune cells) and suppress a also explain some depressive symp- circumstances is nonspecific,
variety of immune functions. toms associated with stressful con- meaning that all stressors, physical
Exposure to stressors can also ditions (Maier & Watkins, 1998). and psychological, are capable of
enhance certain immune processes, eliciting the triad of physiological
for example, those closely related changes he observed in his rodent
to inflammation. Inflammation is Health Implications research: shrinking of the thymus
an orchestrated response to expo- (a central immune organ), enlarge-
sure to a pathogen that creates lo- Activation of these physiologi- ment of the adrenal gland (which
cal and systemic changes condu- cal systems during exposure to a produces corticosterone), and ulcer-
cive to destroying it (e.g., increases stressor is adaptive in the short run ation of the gastrointestinal tract.
in core body temperature). How- under certain circumstances but Very little research has directly tested
ever, chronic, inappropriate in- can become maladaptive if the sys- this generality model by determining
flammation is at the root of a host tems are repeatedly or chronically whether or not differences in
of diseases, including certain au- activated or if they fail to shut stressful conditions are associated
toimmune diseases such as rheu- down when the threat no longer with distinctive physiological ef-
matoid arthritis, and may play a exists. McEwen (1998) has coined fects in humans. Modern versions
role in others, such as cardiovascu- the term allostatic load to refer to the of the generality model propose
lar disease. There is a great deal of cumulative toll of chronic overacti- that if stressors lead to the expe-
current interest in factors that pro- vation of the physiological systems rience of distress (or perceived
mote inappropriate inflammation that are designed to respond to en- stress), then a stereotyped set of
outside the normal context of in- vironmental perturbations. For ex- physiological changes will be elic-
fection. Exposure to some psycho- ample, evidence suggests that ited in the systems I have de-
logical stressors can increase cir- chronic exposure to stressors or scribed. These models also empha-
culating levels of cytokines that distress (as in posttraumatic stress size the important role of a variety
promote inflammation, perhaps be- disorder and chronic depression) of psychological and environmen-
cause stressful experience can reduce can cause atrophy in a part of the tal factors that can moderate the re-
the sensitivity of immune cells to brain called the hippocampus, re- lationships among stressor expo-
the inhibitory effects of cortisol sulting in memory loss. Chronic sure, distress, and physiological
(Miller, Cohen, & Ritchey, 2002). exposure to stressful circumstances activation (see Fig. 2). However,
Not only can the brain and pe- has also been shown to increase these newer versions are essen-
ripheral neural systems (systems vulnerability to upper respiratory tially generality models because all
that extend from the brain to the infections in individuals exposed of the factors are considered rele-
body—e.g., the ANS and HPA to a virus. Researchers have ob- vant to the extent that they buffer
axis) affect the immune system, but served effects on other health out- against or exacerbate the experi-
the immune system can affect the comes as well, but complete models ence of distress, without consider-
brain and one’s psychological state. of stress and health that document ing that different kinds of distress
In rodents, certain cytokines can all the mediating mechanisms from (e.g., different emotional responses)
act on the central nervous system, the central nervous system to the might have distinctive physiologi-
resulting in behavioral changes pathophysiological processes that cal correlates. According to these
that resemble sickness (e.g., in- control disease are not yet avail- models, distress has a uniform re-
creases in body temperature, re- able (Kemeny, 2003). lationship to physiology.

Published by Blackwell Publishing Inc.

Downloaded from cdp.sagepub.com at PENNSYLVANIA STATE UNIV on May 12, 2016
 CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE 127

intellectual, social, or financial re-

sources). Three categories of cogni-
tive appraisals have been shown to
elicit distinctive affective and phys-
iological responses.

Threat Versus Challenge

Fig. 2. The generality model of stress. This model proposes that exposure to stressors
and the cognitive appraisals of those events can lead to distress. The nature of this re- According to Blascovich and To-
lationship depends on the resources available to deal with the stressors (e.g., coping
maka (1996), the experience of
skills, social support, personality factors, genetics, environmental resources). Eleva-
tions in distress cause a stereotyped physiological alteration in stress-responsive sys- threat results when the demands in
tems. Bidirectional relationships between many components of the model are a given situation are perceived to
assumed but are not indicated here. outweigh the resources. When re-
sources are perceived to approxi-
mate or exceed demands, however,
There is, however, increasing nature of the physiological re- the individual experiences a chal-
evidence for specificity in the rela- sponse to stressful circumstances lenge response. These two motiva-
tionship between stressors and and play a central role in the inte- tional states are associated with
physiology. Weiner (1992) advo- grated specificity model. Cogni- distinctive ANS alterations. In situ-
cated an integrated specificity tive appraisal is the process of cate- ations that require active responses
model of stressor physiology, argu- gorizing a situation in terms of to obtain a goal, challenge is associ-
ing that “organisms meet . . . chal- its significance for well-being (Laz- ated with increases in sympathetic
lenges and dangers by integrated arus & Folkman, 1984). Primary arousal (increased cardiac perfor-
behavioral, physiological patterns appraisal relates to perceptions of mance) coupled with reduced or
of response that are appropriate to goal threat, whereas secondary ap- unchanged peripheral resistance
the task” (p. 33). According to this praisal relates to perceptions of re- (resistance to blood flow). These
model, both behavior and physiol- sources available to meet the de- changes parallel those observed
ogy are parts of an integrated re- mands of the circumstance (e.g., with metabolically demanding aer-
sponse to address a specific envi-
ronmental condition (see Fig. 3),
and specific conditions or environ-
mental signals elicit a patterned
array of hormonal and neural
changes that are designed to ready
the organism to deal with the spe-
cific nature of the threat. In ani-
mals, specific neural and periph-
eral changes occur in concert with
behaviors such as fighting, fleeing,
defending, submitting, exerting
dominance, and hunting prey,
among others. Distinctive behav-
iors (fight, flight, and defeat) have
also been elicited by activating spe-
cific regions of the brain with exci- Fig. 3. The integrated specificity model of stress. This model proposes that exposure
tatory amino acids. to specific stressful conditions and cognitive appraisals of those conditions shape the
specific nature of an integrated psychobiological response (including emotion-moti-
vation and physiology) to promote adaptive responses to the threat. For example,
threats that are appraised as uncontrollable may lead to an integrated psychobiologi-
COGNITIVE APPRAISALS cal response that includes disengagement from the goal that is threatened by the
SHAPE PHYSIOLOGICAL stressor (manifested in withdrawal, inactivity, and reduced effort), related affective
RESPONSES states (e.g., depression), and physiological changes that support disengagement.
Threats appraised as controllable may lead to an integrated response involving en-
gagement with the threat and physiological responses supporting active coping pro-
Cognitive appraisal processes cesses. As in the generality model, resources available to deal with the stressors can
can profoundly shape the specific moderate this relationship.

Copyright © 2003 American Psychological Society

Downloaded from cdp.sagepub.com at PENNSYLVANIA STATE UNIV on May 12, 2016
128 VOLUME 12, NUMBER 4, AUGUST 2003

obic exercise. Threat, in contrast, ical systems (Cacioppo, 1994). For tion and physiology) that are tied
although also associated with example, social isolation has a very to the nature of the threat experi-
sympathetic arousal involving in- significant effect on health, which enced. A number of researchers
creased cardiac performance, is as- is likely mediated by the physio- have found that different neural
sociated with increased peripheral logical systems described here. and autonomic pathways are acti-
resistance, leading to increased Other social processes can regulate vated during different emotional
blood pressure. Thus, different physiological systems as well. For experiences. Thus, specific emo-
cognitive appraisals can result in example, place in a dominance hi- tions, in all likelihood, play a cen-
distinctive patterns of ANS reactiv- erarchy has a significant effect on tral role in the nature of the phys-
ity with potentially distinguishable physiological systems. Subordinate i o l ogical response to stressful
implications for health. The issue animals, who have low social sta- conditions. A more intensive eval-
here is not degree of activation of tus, demonstrate a more activated uation of the role of distinct emo-
the sympathetic nervous system, HPA axis, higher levels of cytokines tions would be an important con-
but rather distinctive qualities of that promote inflammation, and tribution to future stress research.
activation depending on the spe- other physiological changes com- It is most likely that distinctions
cific nature of the cognitive ap- pared with their dominant counter- will be observed when researchers
praisal process. parts. A meta-analytic review has evaluate patterns of physiological
demonstrated that demanding per- change across systems, rather than
formance tasks elicit HPA activation relying on single response systems
Perceived Control when one’s social status or social self- (e.g., cortisol level), and when
esteem is threatened by perfor- emotional behavior is assessed in
Animal and human research mance failures, but these effects are conjunction with self-report data.
demonstrates that uncontrollable greatly diminished when this social-
circumstances, or those perceived status threat is not present (Dick-
as uncontrollable, are more likely erson & Kemeny, 2002). Cognitive Recommended Reading
to activate key stressor-relevant appraisals of social status and so-
systems than are circumstances cial self-esteem appear to play an Dickerson, S.S., & Kemeny, M.E.
that the organism perceives to be important role in these effects (Dick- (2002). (See References)
Kemeny, M.E., & Gruenewald, T.L.
controllable. For example, when erson, Gruenewald, & Kemeny, in (2000). Affect, cognition, the im-
rodents with and without control press). mune system and health. In E.A.
over exposure to identical stressors Mayer & C. Saper (Eds.), The bio-
are compared, those with control logical basis for mind body interac-
show a reduced cortisol response. tions (pp. 291–308). Amsterdam:
CONCLUSIONS Elsevier Science.
A meta-analysis (a statistical analy- Lazarus, R.S., & Folkman, S. (1984).
sis that summarizes findings across (See References)
studies) has demonstrated that hu- The research findings on cogni- Sapolsky, R.M. (1992). (See Refer-
mans who are exposed to stressors tive appraisal and physiological ences)
in an acute laboratory context are systems lead to two important con- Weiner, H. (1992). (See References)
significantly more likely to experi- clusions. First, depending on the
ence HPA activation if the stressors nature of the eliciting conditions,
are uncontrollable than if they are different patterns of physiological Acknowledgments—This article is dedi-
controllable (Dickerson & Kemeny, response can occur. Second, when cated to the memory of Herbert Weiner, a
2002). Threats that are appraised as cognitive appraisals of conditions pioneer in the field of stress research, who
profoundly shaped the thinking of the
controllable but in fact are uncon- are manipulated, distinctive physi- generations of stress researchers he
trollable have been shown to elicit ological effects can be observed trained.
less severe physiological alter- within the same context. Therefore,
ations (e.g., in the immune system) the way the individual thinks
than those appraised as uncontrol- about the situation may override
lable. the impact of the specific nature of Note
the conditions themselves.
In the integrated specificity 1. Address correspondence to Mar-
Social Cognition model of stressful experience, garet E. Kemeny, Health Psychology
Program, Department of Psychiatry,
stressful conditions and appraisals Laurel Heights Campus, University of
The social world has a powerful of them elicit integrated psychobio- California, 3333 California St., Suite
effect on stress-relevant physiolog- logical responses (including emo- 465, San Francisco, CA 94143.

Published by Blackwell Publishing Inc.

Downloaded from cdp.sagepub.com at PENNSYLVANIA STATE UNIV on May 12, 2016
 CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE 129

References Dickerson, S.S., & Kemeny, M.E. (2002). Acute McEwen, B.S. (1998). Protective and damaging ef-
stressors and cortisol responses: A theoretical inte- fects of stress mediators. New England Journal
gration and synthesis of laboratory research . of Medicine, 338, 171–179.
Ader, R., Felten, D.L., & Cohen, N. (2001). Psycho-
Manuscript submitted for publication.
neuroimmunology (3rd ed.). New York: Aca- Miller, G.E., Cohen, S., & Ritchey, A.K. (2002).
demic Press. Kemeny, M.E. (2003). An interdisciplinary re- Chronic psychological stress and the regula-
search model to investigate psychosocial co- tion of pro-inflammatory cytokines: A gluco-
Blascovich, J., & Tomaka, J. (1996). The biopsycho- factors in disease: Application to HIV-1
social model of arousal regulation. Advances in corticoid resistance model. Health Psychology,
pathogenesis. Brain, Behavior & Immunity, 17, 21, 531–541.
Experimental Social Psychology, 28, 1–51. 562–572.
Cacioppo, J.T. (1994). Social neuroscience: Auto- Lazarus, R.S., & Folkman, S. (1984). Stress, ap- Sapolsky, R.M. (1992). Neuroendocrinology of the
nomic, neuroendocrine, and immune responses praisal, and coping. New York: Springer. stress-response. In J.B. Becker, S.M. Breedlove,
to stress. Psychophysiology, 31, 113–128. & D. Crews (Eds.), Behavioral endocrinology
Maier, S.F., & Watkins, L.R. (1998). Cytokines for (pp. 287–324). Cambridge, MA: MIT Press.
Dickerson, S.S., Gruenewald, T.L., & Kemeny, psychologists: Implications of bidirectional
M.E. (in press). When the social self is threat- immune-to-brain communication for under- Weiner, H. (1992). Perturbing the organism: The biol-
ened: Shame, physiology and health. Journal of standing behavior, mood, and cognition. Psy- ogy of stressful experience. Chicago: University
Personality. chological Review, 105, 83–107. of Chicago Press.

Gender and Cardiovascular Disease: greater in men than women. Gen-

der differences in many aspects of
A Psychobiological and the disease are striking. Under-
standing the contribution of both
Integrative Approach physiological and psychological
factors to these gender differences
Catherine M. Stoney1
can be informative.
Department of Psychology, Ohio State University, Columbus, Ohio There are still misconceptions
about the gender disparity in the
rate of CAD. Although heart dis-
Abstract stand heart disease in both ease is the leading cause of death
Coronary artery disease is men and women. for men, it is also the leading cause
the most common cause of of death for women in all industri-
morbidity, mortality, and eco- Keywords alized nations. Cardiovascular dis-
nomic loss in all industrialized coronary artery disease; gender ease accounts for twice as many
countries. Although there are differences; stress reactivity deaths among women as do all
gender differences in the prev- cancers combined. One of every
alence, causes, symptoms, treat- two women will die of a heart at-
Coronary artery disease (CAD) tack, stroke, or other cardiovascu-
ment, and outcome of heart
is the number-one cause of death, lar illness, but the diagnosis of the
disease, the differences are
disability, and economic loss for disease occurs 10 years later, on av-
complex and often misunder-
people in all industrialized coun- erage, in women than in men.
stood. These gender differences
tries. CAD is most commonly due Thus, among young and middle-
are a function of psychological
to obstruction of the arteries of the aged individuals, far greater num-
influences, physiological influ-
heart by atherosclerosis (the accu- bers of men than women die of
ences, and an interaction of the
mulation of cholesterol, other fats, CAD. However, across all ages,
two. Understanding these com-
and other cells in the arteries), CAD kills more women than men
plex interactions and how they
which causes a decreased blood every year because of the greater
differentially influence the de-
flow to the heart. In the United proportion of women among the
velopment and progression of
States, CAD is responsible for elderly population. For both men
heart disease will ultimately
about 25% of all deaths per year. and women, understanding fac-
contribute to a greater under-
The incidence of CAD increases tors leading to the initiation, pro-
standing of how to integrate
with age among men and women, gression, diagnosis, and treatment
information from medicine
but the rate of increase is greatest of heart disease is therefore criti-
and epidemiology with that
among women after the age of cally important.
from psychology and behav-
menopause. Although CAD mor- The gender differences associ-
ioral medicine. Ultimately, it is
tality in the United States has de- ated with CAD fall into at least
this integrated approach that
clined by more than 50% in the three important categories: risk fac-
will allow us to better under-
past 40 years, the decline has been tors, clinical symptoms and diag-

Copyright © 2003 American Psychological Society

Downloaded from cdp.sagepub.com at PENNSYLVANIA STATE UNIV on May 12, 2016