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This essay describes the evolution of stress as a medical scientific idea. Claude Bernard, Walter B. Cannon and Hans Selye provided key founding concepts for the current view. Bernard introduced the idea of the internal environment bathing cells - the milieu intérieur - maintained by continual compensatory changes of bodily functions. Cannon coined the word, "homeostasis," referring to a set of acceptable ranges of values for internal variables. Cannon taught that threats to homeostasis evoke activation of the sympathoadrenal system as a functional unit. Selye defined stress as a state characterized by a uniform response pattern, regardless of the particular stressor, that could lead to long-term pathologic changes. "Allostasis" was introduced as a concept in recognition that there is no single ideal set of steady-state conditions in life; instead, setpoints and other response criteria change continuously. Stress is now viewed neither as a perturbation nor a stereotyped response pattern but as a condition characterized by a perceived discrepancy between information about a monitored variable and criteria for eliciting patterned effector responses. Different stressors elicit different patterns of activation of the sympathetic nervous, adrenomedullary hormonal, hypothalamic-pituitary-adrenocortical and other effectors, closing negative feedback loops. This systems concept of stress yields predictions that observation or experimentation can test and that are applicable to normal physiology and to a variety of acute and chronic disorders.
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Evolution of concepts of stress
DAVID S. GOLDSTEIN & IRWIN J. KOPIN
Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD USA
(Received 4 December 2006; revised 15 January 2007; accepted 19 February 2007)
Abstract
This essay describes the evolution of stress as a medical scientific idea. Claude Bernard, Walter B. Cannon and Hans Selye
provided key founding concepts for the current view. Bernard introduced the idea of the internal environment bathing cells—
the milieu inte
´
rieur—maintained by continual compensatory changes of bodily functions. Cannon coined the word,
“homeostasis, referring to a set of acceptable ranges of values for internal variables. Cannon taught that threats to
homeostasis evoke activation of the sympathoadrenal system as a functional unit. Selye defined stress as a state characterized
by a uniform response pattern, regardless of the particular stressor, that could lead to long-term pathologic changes.
“Allostasis” was introduced as a concept in recognition that there is no single ideal set of steady-state conditions in life;
instead, setpoints and other response criteria change continuously. Stress is now viewed neither as a perturbation nor a
stereotyped response pattern but as a condition characterized by a perceived discrepancy between information about a
monitored variable and criteria for eliciting patterned effector responses. Different stressors elicit different patterns of
activation of the sympathetic nervous, adrenomedullary hormonal, hypothalamic-pituitary-adrenocortical and other effectors,
closing negative feedback loops. This systems concept of stress yields predictions that observation or experimentation can test
and that are applicable to normal physiology and to a variety of acute and chronic disorders.
Keywords: Allostasis, baroreceptors, cardiovascular disease, distress, exercise, homeostasis
Historical overview of stress concepts
Cannon, homeostasis and the sympathoadrenal system
In 1865, in his masterpiece, Introduction a
`
la me
´
decine
expe
´
rimentale, Claude Bernard described his earlier
observations on the role of the liver in secreting
glucose formed from glycogen stores and how his
studies of heat regulation led to the discovery of
vascular blood flow regulation by sympathetic nerves.
By a tremendously insightful generalization from such
specific observations he developed the concept that
the ability of an organism to maintain a constant fluid
environment bathing cells of the body—the milieu
inte
´
rieur”—is essential for life independent of the
external environment.
Cannon (1929a,b, 1939) subsequently coined the
term “homeostasis” to describe the maintenance
within acceptable ranges of several physiological
variables, such as blood glucose, oxygen tension and
core temperature. Mechanisms for maintaining this
stability require sensors to recognize discrepancies
between the sensed and set acceptable values and
require effectors that reduce those discrepancies—i.e.,
negative feedback systems. For instance, when the
core temperature of a mammal rises, the thermo-
regulatory system evokes sweating and diversion of
blood flow from the viscera to the skin, which
enhances heat loss; and when core temperature falls,
shivering increases heat production, while cutaneous
vasoconstriction diminishes heat loss by diversion of
blood to internal organs. Analogous negative feedback
systems regulate other physiological variables. Can-
non extended this concept to include psychosocial
threats to homeostasis. In the early 1900s he described
for the first time the acute changes in adrenal gland
secretion associated with what he called “fight or
flight” responses.
According to Cannon, a wide variety of threats
to homeostasis, such as exposure to cold, hypo-
tensive hemorrhage, traumatic pain, insulin-induced
ISSN 1025-3890 print/ISSN 1607-8888 online q 2007 Informa UK Ltd.
DOI: 10.1080/10253890701288935
Correspondence: D. S. Goldstein, Clinical Neurocardiology Section, CNP, DIR, NINDS, NIH, 10/6N252, 10 Center Drive MSC-1620,
Bethesda, MD 20892-1620, USA. Tel: 1 301 496 2103. Fax: 1 301 402 0180. E-mail: goldsteind@ninds.nih.gov
Stress, June 2007; 10(2): 109–120
hypoglycemia, or emotional distress, elicit activation of
the adrenal medulla and sympathetic nervous system.
These two effectors were thought to function as a unit
termed the “sympathoadrenal” or “sympathico-adre-
nal” system—to restore homeostasis. Rapid activation of
the sympathoadrenal system then preserves the internal
environment by producing compensatory and antici-
patory adjustments that enhance the likelihood of
survival. In 1939, Cannon formally proposed adrenaline
(called epinephrine in the USA) as the active principle of
the adrenal gland and also as the neurotransmitter of the
sympathetic nervous system (Cannon and Lissak 1939),
consistent with the functional unity of the sympathoa-
drenal system. The identity of the substance released at
sympathetic nerve terminals remained controversial
until 1946, when von Euler (1946) correctly identified
noradrenaline as the major sympathetic neurotransmit-
ter in mammals.
Cannon (1929a,b, 1939) emphasized that disparate
threats to homeostasis would incite the same
sympathoadrenal response. References to the sym-
pathoadrenal or “adrenergic” system persist (Cryer
1980; Shah et al. 1984; Sofuoglu et al. 2001; Dronjak
et al. 2004; Vogel et al. 2005), although researchers
have come to recognize that sympathetic nervous and
adrenomedullary hormonal system activities can
change differentially in different forms of stress, as
discussed below.
In the sheltered confines of a laboratory, with
controlled temperature and ad libitum water, nutrients
and calories, mammals do not seem to require an
intact sympathetic nervous system (Cannon 1931). It
has become clear, however, that even under resting
conditions, pulse-synchronous bursts of skeletal
muscle sympathetic nerve activity and plasma levels
of noradrenaline are detectable, and noradrenaline
continuously enters the venous drainage of most
organs. We also now recognize that activities of daily
life, such as meal ingestion (Patel et al. 2002), public
speaking (Gerra et al. 2001), changing posture (Lake
et al. 1976), and locomotion—i.e. not only emergen-
cies—are associated with rapid adjustments in
sympathetic nervous system outflows. Each of these
activities is associated with a somewhat different set of
apparent steady-states, directed by the brain and
determined by coordinated actions of a variety of
effector systems. These observations contributed to
the development of the concept of “allostasis,
discussed below.
Selye, the doctrine of nonspecificity, and the hypothalamic-
pituitary-adrenocortical system
We are indebted to Selye (1956) for popularizing the
concept of stress. Selye redefined the word, stress,
from its meaning in the physical world as a force that
results in a deformity and results in strain, the
opposing force tending to restore the unstressed state.
His definition of stress as being (or a state resulting in)
the “the nonspecific response of the body to any
demand upon it” (Selye 1974) was so persuasive that
it persisted and remains widely used today. By
“nonspecific” Selye meant a set of shared elements
of responses—regardless of the nature of the causative
agent, or stressor.
Selye proposed three universal stages of coping with
a stressor—the “General Adaptation Syndrome”—an
initial “alarm reaction,” analogous to Cannon’s “fight
or flight” response, a stage of adaptation, associated
with resistance to the stressor, and eventually a stage
of exhaustion and organismic death. In Selye’s early
experiments, after injection of any of a variety of tissue
extracts or of formalin into rats, the animals developed
a pathological triad of enlargement of the adrenal
glands, atrophy of lymphoid tissue in the thymus,
spleen, and lymph nodes and bleeding gastrointestinal
ulcers. It was later demonstrated that these changes
are associated with, and to at least some extent result
from, activation of the hypothalamic-pituitary-adre-
nocortical (HPA) axis. Steroids released into the
circulation from the adrenal cortex contribute to
resistance but may also be responsible for pathological
changes. Selye’s concept that prolonged stress can
produce physical disease and mental disorders is now
widely accepted.
Selye acknowledged that responses to stressors have
specific components that tend to reverse the effects of
the stressor; however, in addition to the specific
responses, there is a nonspecific stress syndrome.
Chrousos and Gold (1992) modified Selye’s doctrine
of nonspecificity, by proposing that above a threshold
intensity, any stressor elicits the nonspecific stress
syndrome.
More than a half century elapsed before Selye’s
doctrine of nonspecificity underwent experimental
testing, which failed to confirm it (Pacak et al. 1998).
Nevertheless, modern lay and even scientific literature
continues to accept the notion of a unitary stress
response. For instance, a Google search yielded about
582,000 hits for “the stress responses”. According to
WebMD, “The stress response is the set of physical
and emotional changes the human body makes in
response to a threat or stress. It sometimes is called the
‘fight-or-flight’ response” (as indicated above, it was
Cannon who introduced the latter phrase).
Just as Cannon emphasized activation of the
sympathoadrenal system to maintain homeostasis, so
did Selye and his students emphasize activation of the
HPA axis in the General Adaptation Syndrome. Selye
(1956) also introduced the term “heterostasis” (from
the Greek heteros ¼ other) to describe the establish-
ment of a new steady-state by changing the “setpoint”
to resist unusually high demands. This new steady-
state, however, is attained by treatment with remedies
that have no direct curative action but enhance the
body’s natural defenses, e.g. immunization to combat
D. S. Goldstein & I. J. Kopin110
infection (as in treatment of rabies). The concept of
changes in the homeostatic setpoint as a natural
adaptive mechanism awaited the introduction of the
notion of allostasis.
Modern concepts of stress
More modern concepts view stress as a consciously or
unconsciously sensed threat to homeostasis (McEwen
et al. 1993; Goldstein and McEwen 2002), in which
the response has a degree of specificity, depending,
among other things, on the particular challenge to
homeostasis, the organism’s perception of the stressor
and the perceived ability to cope with it (Goldstein
2001).
Although homeostasis suggests constancy of values
for variables, ranges of acceptable values are now
recognized to be decidedly inconstant. There are
diurnal variations in body temperature, heart rate and
blood pressure. In addition, adaptations to different
stressors include alterations in acceptable levels for
monitored variables. Sterling and Eyer introduced the
term, allostasis, to describe the attainment of
stability by natural alterations in acceptable ranges of
variables attending the adjustments of the cardiovas-
cular system during rest and activity (Sterling et al.
1988). Such alterations are distinct from treatment-
induced alterations (Selye’s “heterostasis” discussed
above). The brain is the site at which effects of
stressors are sensed and appropriate coordinated
behavioral and neuroendocrine responses initiated.
Adaptations involving allostasis to cope with real,
simulated, or imagined challenges are determined by
genetic, developmental and previous experiential
factors. While they may be effective for a short
interval, over time the alterations may have cumulative
adverse effects. For instance, chronic elevation of
blood pressure to ensure adequate blood flow to the
brain might eventually lead to atherosclerosis and
stroke or coronary occlusion. Risk of such adverse
effects is termed “allostatic load.
Principles of operation of homeostatic syste ms
Central to a systems concept of stress is that the body
possesses numerous homeostatic comparators, which
have been called “homeostats” (Goldstein 1995a,b).
Each homeostat compares information supplied by a
sensor with a setpoint for responding, determined by a
regulator or set of regulator mechanisms (Figure 1).
A sufficiently large sensed discrepancy between
afferent information about the level of the monitored
variable and the setpoint for responding elicits altered
activities of effectors, the actions of which decrease the
discrepancy in the monitored variable.
Homeostatic systems operate according to a few
principles that despite their simplicity can explain
some complex physiological phenomena and might
help resolve controversial issues in the area of stress
and disease.
Negative feedback regulation
In a home temperature control system, the thermo-
stat plays a central role, by sensing discrepancy
between the setpoint, determined by a regulator (the
home owner) and the temperature, which produces
differential bending of metal bands in the thermostat
(the sensor). This type of system is a classical
example of regulation by negative feedback. Relation-
ships among components of homeostatic systems can
be positive or negative; in a negative feedback loop,
there is an odd number of negative relationships in
the loop (note the odd number of (2 ) signs in
Figure 1). It can be shown mathematically that
in response to a constant perturbing influence (e.g.
cold external temperature), a system regulated by
negative feedback yields a stable level of the
monitored variable somewhere between the sensed
and set values.
Physiological homeostatic systems also include
regulation by negative feedback. Increases in values
of the monitored variable result in changes in effector
activity that oppose and thereby “buffer” changes in
that variable. This feedback regulation can be
modulated at several levels and therefore can be
quite complex.
A large array of homeostatic systems detect
perturbations of monitored variables. In line with the
home heating analogy, this includes afferent infor-
mation to the brain about cutaneous and blood
temperature, leading to altered activities of cholinergic
and noradrenergic nerve fibers in the skin that regulate
sweating and vasomotor tone (Frank et al. 1997).
PERTURBATION
AFFERENT
INFORMATION
MONITORED
VARIABLE
EFFECTORS
REGULATOR
HOMEOSTAT
STRESS
Figure 1. A systems definition of stress.
Concepts of stress 111
Disruption of a negative feedback system, such as
by blockade of afferent information or by dysfunction
of a homeostat, increases the variability of levels of the
monitored variable. Thus, baroreceptor deafferentia-
tion increases the variability of blood pressure, as does
bilateral destruction of the nucleus of the solitary
tract, the likely brainstem site of the arterial barostat
(Nathan and Reis 1977). As shown in Figure 2, in
humans, treatment of head and neck cancer by local
irradiation accelerates carotid arteriosclerosis, and
encasement of baroreceptors in rigidified carotid
sinuses can help explain the development of labile
blood pressure years later (Sharabi et al. 2003).
Induction of a positive feedback loop threatens
homeostasis, by accelerating changes in levels of the
monitored variable. Examples of positive feedback
loops include tilt-induced neurally mediated syncope
and heat shock. A pattern of adrenomedullary
hormonal system stimulation and sympathetic nor-
adrenergic system inhibition often precedes fainting
(Goldstein et al. 2003), as indicated by an accelerating
increase in the plasma adrenaline level and concurrent
decline in forearm vascular resistance (Figure 3).
Ordinarily, humans can tolerate even extremely hot
external temperature, by evaporative heat loss,
promoted by thermoregulatory sweating mediated by
the sympathetic cholinergic system and cutaneous
vasodilation mediated by local sympathetic noradren-
ergic inhibition (Figure 4). In this setting plasma
noradrenaline levels increase, probably reflecting
increased sympathetic outflows to visceral organs
and skeletal muscle, promoting shunting of blood
from the core to the periphery, while plasma adrena-
line levels change relatively little (Kukkonen-Harjula
et al. 1989; Gisolfi et al. 1991; Brenner et al. 1997;
Niimi et al. 1997); however, activation of the
adrenomedullary hormonal system, such as by
exceeding an anerobic threshold during exercise,
dehydration, hypoglycemia, emotional distress and
myocardial dysfunction, might interfere with evapora-
tive heat loss and also induce a positive feedback loop,
with rapid precipitation of heat shock and even death
(Figure 5).
There are some examples of beneficial effects of a
positive feedback loop. For instance, if bleeding is to
be terminated by blood clotting, acceleration of clot
formation by its own initiation is a useful positive
feedback process. While distress can be a protective,
50
0
Control Pt. 1 Pt. 2 Pt. 3
BP
mm Hg
24 hours
100
150
200
250
Figure 2. Twenty-four hour ambulatory blood pressure monitoring records for a control subject and three patients (Pt) with baroreflex
failure as a late sequela of neck irradiation.
TIME FROM TILT START (minutes)
50403020100
1
10
100
Syncope
60–10
0.1
TILT
FRACTION OF BASELINE
EPI
NE
FVR
MAP
Figure 3. Values for arterial plasma adrenaline (EPI), noradrenaline (NE), forearm vascular resistance (FVR) and mean arterial pressure
(MAP) in a patient with tilt-induced syncope. Grey arrows highlight changes in EPI and FVR preceding hypotension and syncope.
D. S. Goldstein & I. J. Kopin112
such as by initiating flight, distress can also be involved
in positive feedback. If cognitive recognition of the
effects of released adrenaline enhances anxiety and
promotes further adrenaline release, the results could
be disastrous.
Multiple effectors
Home temperature control systems usually include
multiple effectors. The redundancy comes at relatively
little cost, compared with three advantages. The
multiplicity extends the range of external tempera-
tures that can be tolerated to maintain constant the
internal temperature; when a single effector fails to
function, others are activated to compensate, helping
to maintain the temperature at about the set level; and
one can pattern the use of the effectors as appropriate
to maximize economy and efficiency (Goldstein 2001;
Goldstein 2006).
Analogously, physiological homeostatic systems
frequently use multiple effectors to govern values for
the monitored variable. An example would be insulin,
glucagon, adrenaline, cortisol and growth hormone in
regulation of blood glucose levels. Effector redun-
dancy extends the ranges of control of monitored
variables.
Compensatory activation. Having multiple effectors
enables compensatory activation of alternative
effectors, assuming no change in homeostat settings
(Figure 6). Examples of compensatory activation in
physiology include augmentation of sympathoneural
responsiveness by adrenalectomy, hypophysectomy,
or thyroidectomy (Udelsman et al. 1987; Goldstein
et al. 1993; Fukuhara et al. 1996).
Outside Heat
Skin T
o
Sensors
Regulator
SCS
Sweat
Blood T
o
Sensors
Skin Blood Flow
Heat
Loss
Skin
Temperature
Blood
Temperature
SNS
Thermostat
Figure 4. Overview of thermoregulatory mechanisms.
SCS ¼ sympathetic cholinergic system; SNS ¼ sympathetic
noradrenergic system.
Thermostat
Skin
Temperature
Outside Heat
Skin T
o
Sensors
Regulator
SNS
Blood
Temperature
Sweat
Blood T
o
Sensors
Skin Blood Flow
Heat
Loss
Heat
Gain
Metabolism
AHS
DistressAnerobic State
Heart Failure /
Arrhythmia
Hypoglycemia
SCS
Figure 5. Hypothetical changes associated with heat shock. AHS ¼ adrenomedullary hormonal system. Note positive feedback loop,
indicated by a circuit with all (þ ) signs, as well as interference with a negative feedback loop, indicated by an even number of (2 ) signs.
Concepts of stress 113
Compensatory activation of alternative vasoactive
systems after destruction of the sympathetic nor-
adrenergic system (Gauthier et al. 1972; Julien et al.
1990) helps to explain why many workers, including
Cannon, erroneously concluded that the sympathetic
nervous system acts only as an “emergency” system.
Stressor-specificity. After adequately sensitive assay
methods of plasma levels of noradrenaline and
adrenaline became available, evidence rapidly
accumulated for different noradrenergic vs. adrenergic
responses in different situations (Robertson et al. 1979;
Young and Landsberg 1979; Cryer 1980; Young et al.
1984). A new concept began to emerge, in which
noradrenaline levels, and thereby overall sympathetic
nervous “activity,” would play key roles in appropriate
distribution of blood volume and homeostasis of blood
pressure (or blood delivery to the brain), such as during
orthostasis, cold exposure, mild blood loss, locomotion,
exercise, altered salt intake and water immersion.
Adrenaline levels, reflecting the adrenomedullary
hormonal system “activity, respond to global or
metabolic threats, such as hypoglycemia, hemorrhagic
hypotension, exercise beyond an anerobic threshold,
asphyxiation, emotional distress and shock. Evidence
also accumulated for an association between
noradrenaline and active escape, avoidance, or attack,
and an association between adrenaline and passive,
immobile fear.
Thus, in contrast with Selye’s doctrine of non-
specificity, according to the allostatic concept of stress
responses, acceptable activities of effector systems are
coordinated in relatively specific patterns, including
neuroendocrine patterns. These patterns serve differ-
ent needs, and the sympathetic nervous and adreno-
medullary hormonal systems play important roles in
many of them. For instance, the level of sympathetic
nervous system activation predominates in response
to orthostasis, moderate exercise and exposure to
cold, whereas the level of adrenomedullary hormonal
system activation predominates in response to
glucoprivation and emotional distress.
In terms of the body’s thermostat, studies of
humans exposed to cold or with mild core hypother-
mia have provided support for the notion of primitive
specificity of neuroendocrine stress responses. Cold
exposure increases plasma noradrenaline levels, with
little if any increases in plasma adrenaline levels,
consistent with sympathetic neuronal activation and
relatively less adrenomedullary hormonal activation.
Mild core hypothermia also increases antecubital
venous levels of noradrenaline but not adrenaline
(Frank et al. 2002). Both noradrenaline and adrena-
line levels in arterial plasma increase in this setting,
but with larger noradrenaline responses (Goldstein
and Frank 2001). These findings make sense, in that
one can maintain body temperature effectively by
sympathetically-mediated cutaneous vasoconstric-
tion, piloerection and shivering. When these mechan-
isms give way, and core temperature falls, then high
circulating adrenaline levels increase generation of
calories (Staten et al. 1987), associated with the
experience of distress, which motivates escape and
avoidance, and augments noradrenaline release from
sympathetic nerve terminals for a given amount of
nerve traffic (Chang et al. 1994).
Effector redundancy introduces the potential for
patterned effector responses. Patterning of neuro-
endocrine, physiological and behavioral effectors
increases the likelihood of adaptation to the particular
challenge to homeostasis, providing another basis for
natural selection to favor the evolution of systems with
multiple effectors. As summarized in Figure 7, across
a range of stressors, adrenomedullary hormonal
system activation seems to correlate better with HPA
axis activation than with sympathetic nervous system
OUTSIDE TEMP.
CORE
TEMP.
THERMOSTAT
SNS THY
AFFERENT
INFORMATION
Figure 6. Model of compensatory activation of the sympathetic
noradrenergic system (SNS) by thyroidectomy. THY: thyroid;
TEMP: temperature.
++++
Active Escape/Avoidance
++++
Hemorrhage, No Hypotension
++ ++ +
Laboratory Mental Challenge
++ ++ ++
Social Stress in Monkey
++++
Surgery
Cardiac Arrest +++ ++++++
Cold Exposure, No Hypothermia
0 + +++
Exercise
+ ++ +++
Fainting
++ 0++++
Immobilization in Rat
++++ ++++++++
Glucoprivation
++++++++
Hemorrhagic Hypotension
++++ +++
Pain
++ +++++
Passive/Immobile Fear
++ ++++
Public Performance
++ ++++
Exercise to Exhaustion
++ +++++++
+++
Cold Exposure, Hypothermia
++++
AHS SNSHPA
Figure 7. Relative intensities of activation of the HPA axis,
adrenomedullary hormonal system (AHS) and sympathetic
noradrenergic system (SNS) during exposure to different
stressors, based on literature review.
D. S. Goldstein & I. J. Kopin114
activation, in contrast with Cannon’s concept of a
unitary sympathoadrenal system. Differential changes
in adrenomedullary and sympathoneural outflows are
particularly clear in the setting of cold exposure, which
features sympathetic noradrenergic activation, and
fainting or hypoglycemia, which feature adrenome-
dullary hormonal system activation. Thus, “sym-
pathoadrenal imbalance, with high adrenaline levels
and smaller or no increases in noradrenaline levels,
often precedes fainting (Goldstein et al. 2003); and in
response to hypoglycemia, increases in plasma
noradrenaline levels result entirely from adrenome-
dullary stimulation, since elevated plasma noradrena-
line does not occur in adrenalectomized subjects
(DeRosa et al. 2004).
For each stressor, neuroendocrine and physiologi-
cal changes are coupled with behavioral changes. For
instance, the regulation of total body water in
humans depends on an interplay between behavior
(the search for water and drinking), an internal
experience or feeling (thirst), and the elicitation of a
neurohumoral response pattern (in this case domi-
nated by vasopressin, the antidiuretic hormone; and
to a lesser extent angiotensin, a potent stimulator of
drinking). Evoked changes in homeostat function
often produce not only neuroendocrine and physio-
logical effects but also behavioral responses; however,
because of traditional boundaries among physiology,
endocrinology and psychology, interactions produ-
cing integrated patterns of response remain incom-
pletely understood.
Selye recognized that during the stage of resistance,
exposure to a novel stressor can produce an exaggerated
response. This observation presaged the concept of
“dishabituation, in which neuroendocrine responses to
stressors depend on the prior experience of the organism
with respect to qualitatively different stressors (Graessler
et al. 1989; Nisenbaum et al. 1991; Abercrombie 1992;
Rusnak et al.2001; Kvetnansky etal.2003;Dronjaketal.
2004; Kvetnansky 2004; Radikova et al. 2004; Liu et al.
2005).
Effector sharing
Different homeostats can regulate the activity of the
same effector system. For instance, the osmostat and
barostat share the arginine vasopressin effector
(Quillen and Cowley 1983), illustrated in Figure 8.
Systems definition of stress
Even a simple homeostatic reflex reflects stress, when
a perceived discrepancy between a setpoint for a
monitored variable and information about the actual
level of that variable elicits compensatory responses to
decrease the discrepancy. Thus, one way of looking at
stress is as a condition where expectations, whether
genetically programmed, established by prior learn-
ing, or deduced from circumstances, do not match the
current or anticipated perceptions of the internal or
external environment, and this discrepancy between
what is observed or sensed and what is expected or
programmed elicits patterned, compensatory
responses (Figure 1).
Distress
Distress is cognitive recognition of a condition that is
aversive to the organism, as evidenced by motivation
for learning to escape or avoid the stressor. Distress is
a subclass of stress that depends on the character,
intensity, and meaning of the stressor as perceived by
the organism and on the organism’s perceived ability
to cope with it. According to this concept, for an
organism to experience distress requires conscious-
ness, to interpret the situation in terms of the ability to
cope. This notion can help explain the finding
(Figure 9) that sedation with the benzodiazepine,
alprazolam, attenuates the ACTH and adrenaline
responses to glucoprivation (Breier et al. 1992).
Selye (1974) characterized distress as unpleasant or
harmful. The systems view of stress does not assume
an equivalence of noxiousness (i.e. negatively reinfor-
cing properties) with production of pathological
HEART FAILURE
AVP
CARDIAC
OUTPUT
HIGH PRESSURE
BARORECEPTORS
OSMOLALITY
SENSORS
SERUM
OSMOLALITY
BAROSTAT
OSMOSTAT
Figure 8. Model of effector sharing. The “barostat” and “osmostat” share the arginine vasopressin (AVP) effector.
Concepts of stress 115
changes; that is, it does not assume that distress causes
disease.
Homeostatic responses do not necessarily cause
distress, but distress can be part of a positive feedback
loop. This applies not only to neuroendocrine aspects
of those responses (such as the glucose counter-
regulatory actions of pituitary-adrenocortical and
adrenomedullary stimulation during insulin-induced
hypoglycemia) but also to psychological aspects (such
as conditioned aversive and instrumental avoidance
learning). Distress responses evolved and probably
continue to be expressed even in higher organisms,
including humans who actually are only rarely exposed
to truly “fight-or-flight agonistic encounters, because
of the importance of those responses in instinctive
communication.
Allostasis and allostatic load
Levels of physiological activity required to re-establish
or maintain homeostasis differ, depending on con-
tinually changing conditions in which the organism
finds itself—e.g., running vs. standing vs. lying down.
“Allostasis,” a term used by Sterling and Eyer in 1988
(McEwen 1998), refers to levels of activity required
for the individual to “maintain stability through
change”—i.e., to adapt (McEwen 1998; Schulkin
et al. 1998; McEwen 2000).
In terms of the present theory, “allostasis” refers to
the set of apparent steady-states maintained by
multiple effectors. In the analogy of the home
temperature control system, one can regulate tem-
perature at different levels, by appropriate use of
effectors. Among individuals, levels of glucose, blood
pressure, body temperature, metabolism, and so forth
are normally held stable at different levels, with
different patterns of effector activation.
Homeostat resetting redefines the conditions
required to maintain homeostasis. Regulation around
an altered apparent steady-state is the essence of
allostasis. This would be analogous to a different
thermostatic setting in the home in winter compared
to the summer. Resetting alters activities of multiple
effector systems required to maintain allostasis, at least
for short durations. Allostatic settings can change
dynamically. An example is the regulation of blood
glucose in the context of exercise. Even in anticipation
of the need for metabolic fuel, by activation of “central
command” the blood glucose level tends to increase;
during light to moderate exercise, increased glucose
production typically balances increased glucose utiliz-
ation, so that blood glucose does not change; and
intense exercise is often associated with hyperglycemia.
During stress, short-term changes in homeostatic
settings generally enhance the long-term well-being
and survival of the organism. Responses during
exercise provide an obvious example. When super-
imposed on a substrate of pathology, however,
homeostatic resetting can cause harm. For instance,
in the setting of ischemic heart disease, global or
patterned increases in sympathetic outflows from
homeostat resetting would increase cardiac work, the
resulting imbalance between oxygen supply and
demand precipitating angina pectoris, myocardial
infarction, or sudden death.
Allostatic load
“Allostatic load” (McEwen and Stellar 1993) refers to
effects of prolonged continuous or intermittent
activation of effectors involved in allostasis. In the
analogy of the home temperature control system,
allostatic load would increase if a window or door were
left open. In this situation, one or more effectors might
be activated frequently or even continuously. An even
more extreme example would be having the air
conditioner and the furnace on at the same time, as is
in an apartment in the spring when there is a warm day
before the boilers have been shut down. Continued
use of the furnace and air conditioner in opposition to
one another, an example of an inefficient “allostatic
state, consumes fuel and contributes to wear-and-
tear on both pieces of equipment. Long-term allostatic
load—the wear-and-tear cost of adaptation—provides
a conceptual basis for studying long-term health
consequences of stress (Figure 10).
Medical and psychological consequences
of stress
As noted above, induction of a positive feedback loop
in a homeostatic system evokes a type of instability
in which levels of the monitored variable accelerate.
0 150
1
CONCENTRATION (pg/ml)
1000
100
10
PLACEBO
ALPRAZOLAM
0 150
ACTH
ADRENALINE
“DISTRESS”
TIME (minutes)
Figure 9. Plasma concentrations of corticotropin (ACTH) and
adrenaline before and at 150 minutes after injection of 2-
deoxyglucose into healthy volunteers, in the context of
pretreatment with placebo or alprazolam. Differences between
placebo and alprazolam conditions might reflect distress (gray
rectangles).
D. S. Goldstein & I. J. Kopin116
An example would be renin-angiotensin-aldosterone
system activation in congestive heart failure. Acti-
vation of this system increases sodium retention and
vascular tone, leading to increased cardiac preload
and afterload that worsen the congestive heart failure.
Therefore, treatment with an angiotensin-converting-
enzyme inhibitor or angiotensin II receptor blocker
can successfully treat congestive heart failure (Kluger
et al. 1982).
Another example may be fainting reactions(Figure3).
Fainting is preceded by high circulating adrenaline
levels and yet withdrawal of sympathetic vasoconstrictor
tone (Mosqueda-Garcia et al. 1997; Goldstein et al.
2003). This elicits skeletal muscle vasodilation, and
total peripheral resistance to blood flow falls. If there
were enough “shunting” of blood to the skeletal muscle,
then blood flow to the brainstem might fall. The person
would not feel “right. This could evoke more
adrenomedullary secretion of adrenaline, and the
consequent neurocirculatory positive feedback
loop would lead to critical brainstem hypoperfusion
and loss of consciousness within seconds to minutes.
In people who faint repeatedly, it is often the case
that between episodes they do not feel completely
normal. Patients who are susceptible to neurocardio-
genic syncope may complain of chronic fatigue,
headache, chest pain, orthostatic intolerance, diffi-
culty concentrating and heat intolerance, which can
be debilitating. The patients also have tonic suppres-
sion of noradrenaline spillover from the heart
(Goldstein et al. 2002). In essence this may reflect
consequences of long-term allostatic load, as dis-
cussed below.
Induction of a positive feedback loop “nested” in a
larger system that includes negative feedback can lead
to a new steady-state group of settings and values for
monitored variables, rather than “explosion” of the
system. For example, a distressing situation might
elicit fear, resulting in release of noradrenaline in the
brain and adrenaline in the periphery, both of which
could augment vigilance behavior and heighten the
experience of distress, resulting in greater fear
(Aston-Jones et al. 1994). The organism could enter
an “escape mode,” with a different set of homeostatic
regulatory settings; however, there is a risk of the
positive feedback loop leading to a behavioral
“explosion, panic, or a pathophysiologic “explosion,
pulmonary edema. The notion of induction of a
nested positive feedback loop can also provide a model
for developmental changes in adolescence, where
stability would actually be abnormal, but there is a
greater chance for both psychological and physiologi-
cal disorders to emerge.
The systems view of stress and the concept of
allostasis can help understanding of chronic as well as
acute medical consequences of stress. Chronic
activation of allostatic effectors in allostatic states
promotes allostatic load. For instance, chronic
elevations in adrenomedullary and HPA outflows
might worsen insulin resistance, and chronic cardiac
sympathetic activation might accelerate cardiovascu-
lar hypertrophy and development of heart failure
(Rundqvist et al. 1997).
Another application of the homeostatic idea to
medical consequences of stress is in terms of the
perceived ability to cope. As noted above, an organism
experiences distress upon sensing that the effector
responses will not be sufficient to restore or maintain
allostasis. In contrast with distress, stress does not
imply a conscious experience. For instance, even
heavily sedated humans have substantial adrenome-
dullary stimulation in response to acute glucoprivation.
Indeed, the greater extent of the adreno-medullary
response to the same stressor in alert than in sedated
humans might provide a measure of the distress.
Distress instinctively elicits observable signs and
pituitary-adrenocortical and adrenomedullary acti-
vation (Goldstein 1995a,b; Goldstein 2001). Via
these neuroendocrine changes, distress could worsen
pathophysiologic processes. For instance, because of
adrenomedullary activation, in a patient with coronary
artery stenosis distress could elicit cardiovascular
stimulation and produce an excess of myocardial
oxygen consumption over supply, precipitating myo-
cardial infarction or lethal ventricular arrhythmias.
Moreover, long-term distress could augment both the
High Stress
Aging
Allostatic Load
Clinical Status
Aging
Symptom
Threshold
Low Stress
Figure 10. Predicted effects of stress and aging on allostatic load and clinical status, based on a kinetic model.
Concepts of stress 117
risk of a mood disorder and the risk of worsening
coronary artery disease.
Long-term physical or mental consequences of
stress would depend on long-term effects of allostatic
load. Prolonged, intensive activation of effector
systems could exaggerate effects of intrinsic defects
in any of them, just as increased air pressure in a tyre
could expand and eventually “blow out” a weakened
area. It is not difficult to imagine that repeated or long-
term stress or distress could lead to a medical or
psychiatric “blowout.
Maintenance of allostatic states requires energy.
This requirement is perhaps clearest in allostasis of
core temperature. In mammals, maintenance of a
constant core temperature accounts for a substantial
proportion of total body energy expenditure at rest.
One may hypothesize that reducing allostatic load
exerts beneficial health effects, just as one may
hypothesize that excessive allostatic load exerts
deleterious health effects. In the analogy of the home
temperature control system, maintaining a tempera-
ture of 66 degrees Fahrenheit in the summer would
require a great expenditure of energy and involve
cooling systems being on continuously, whereas in the
winter, maintaining the same temperature would be
energy-efficient. One can imagine that the likelihood
of system breakdown would depend on the extent of
long-term energy use by the effector systems.
Chronic effector system activation might alter the
efficiency of the homeostatic system itself. For
instance, chronic sympathetic nervous stimulation of
the cardiovascular system could promote cardiovas-
cular hypertrophy, “splinting” arterial baroreceptors
in stiff blood vessel walls, in turn contributing to
systolic hypertension and the risk of heart failure,
kidney failure and stroke.
Moreover, an inappropriately large adrenomedul-
lary response to a stressor might exaggerate the
experience of emotional distress (Schachter and
Singer 1962). Exaggerated distress responses might
increase the risk of worsening an independent
pathologic process, such as in panic-induced angina
pectoris (Mansour et al. 1998; Wilkinson et al. 1998).
In summary, this essay describes the evolution from
Bernard’s concept of stability of the internal environ-
ment to present concepts of stress. Cannon described
homeostasis through feedback regulation of physio-
logical processes. Selye popularized the notion of
stress and emphasized the nonspecific responses to
stressors. He described pathological changes with
severe or prolonged stress. Subsequent studies
revealed arrays of specific mechanisms enlisted to
respond to perceived threats to stability and safety.
The importance of changes in homeostatic require-
ments as a means of adaptation to stressors emerged in
the concept of allostasis, and potentially deleterious
effects of allostasis as allostatic load. Multiple systems
are required to meet the needs for allostasis. Genetic,
environmental and experiential factors are major
determinants of mechanisms and outcomes of allo-
static load. These more recent concepts provide a
basis for explaining and predicting physical and
psychiatric effects of acute and chronic stress.
Stress is an interdisciplinary topic, and understanding
health consequences of stress requires an integrative
approach. Research and ideas about stress must move
beyond considering only one effector system, such as the
“sympathoadrenal system”, and only one monitored
variable, such as serum glucose levels, to incorporate
multiple effectors and multiple homeostatic systems that
are regulated in parallel. They must also move beyond
the notion of a single set of ideal values for monitored
variables—homeostasis—to incorporate dynamic
changes in homeostatic settings—allostasis. It has
become evident that allostasis usually involves multiple
systems, and more complete understanding of stress
requires a full appreciation of these systems and their
interactions. Merging of the homeostatic definitions of
stress and distress with the concept of allostasis should
provide a better understanding of the roles of stress and
distress in chronic diseases and alsoprovide a conceptual
basis for the further development of scientific integrative
medicine.
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D. S. Goldstein & I. J. Kopin120
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... Although it is considered a negative aspect, its response is there to check on how to tackle this homeostasis (equilibrium). [61] In acute stress, there is a functioning system of the autonomic nervous system (ANS) which gets activated with the following axis known as the hypothalamic-pituitary-adrenal (HPA) axis this controls the functioning of the blood pressure, heart rate, digestion, hormone release, and respiration. [62] How does the sensory system and endocrine framework work during distressing circumstances? ...
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... Research has indicated that blue light exerts a calming effect on broilers (Prayitno et al., 1997a) and therefore, it has been cited as a positive tool to reduce fear during brooding and rearing, in routine management practices that may elicit fear, such as bird handling and other possible environmental stressors, or during the pre-slaughter phase, including crating and transportation (Adamczuk et al., 2014, Mohamed et al., 2014. Stress, another affective state that may directly impact animal welfare, occurs when the animal perceives any physical or psychological situation as a threat to its homeostasis (Goldstein and Kopin, 2007). A stress response is followed by the activation of the hypothalamic-pituitary-adrenal (HPA) axis, where glucocorticoids and catecholamines are synthesized (Veissier and Boissy, 2007). ...
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Thesis
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This accessible work is the first in more than seventy-five years to discuss the many roles of adrenaline in regulating the "inner world" of the body. David S. Goldstein, an international authority and award-winning teacher, introduces new concepts concerning the nature of stress and distress across the body's regulatory systems. Discussing how the body's stress systems are coordinated, and how stress, by means of adrenaline, may affect the development, manifestations, and outcomes of chronic diseases, Goldstein challenges researchers and clinicians to use scientific integrative medicine to develop new ways to treat, prevent, and palliate disease. Goldstein explains why a former attorney general with Parkinson disease has a tendency to faint, why young astronauts in excellent physical shape cannot stand up when reexposed to Earth's gravity, why professional football players can collapse and die of heat shock during summer training camp, and why baseball players spit so much. Adrenaline and the Inner World is designed to supplement academic coursework in psychology, psychiatry, endocrinology, cardiology, complementary and alternative medicine, physiology, and biochemistry. It includes an extensive glossary. © 2006 The Johns Hopkins University Press. All rights reserved.
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In the article by S. Schachter and J. Singer, which appeared in Psychological Review (1962, 69(5), 379-399) the following corrections should be made: The superscript "a" should precede the word "All" in the footnote to Table 2. The superscript "a" should appear next to the column heading "Initiates" in Table 3. The following Tables 6-9 should be substituted for those which appeared in print. (The following abstract of this article originally appeared in record 196306064-001.) It is suggested that emotional states may be considered a function of a state of physiological arousal and of a cognition appropriate to this state of arousal. From this follows these propositions: (a) Given a state of physiological arousal for which an individual has no immediate explanation, he will label this state and describe his feelings in terms of the cognitions available to him. (b) Given a state of physiological arousal for which an individual has a completely appropriate explanation, no evaluative needs will arise and the individual is unlikely to label his feelings in terms of the alternative cognitions available. (c) Given the same cognitive circumstances, the individual will react emotionally or describe his feelings as emotions only to the extent that he experiences a state of physiological arousal. An experiment is described which, together with the results of other studies, supports these propositions. (PsycINFO Database Record (c) 2006 APA, all rights reserved).
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Objective: This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses.Data Sources: Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE.Data Extraction: Independent extraction and cross-referencing by us.Data Synthesis: Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful.Conclusions: This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.(Arch Intern Med. 1993;153:2093-2101)