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Stress: Definition and history

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Stress: Concepts, Definition and Historyq

G Fink, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
Ó 2017 Elsevier Inc. All rights reserved.

Introduction and Historical Outline of Stress Concepts 1

Hans Selye 1
Epidemiology 2
Thrifty Phenotype Hypothesis 2
Brain Plasticity 2
Genetic Susceptibility to Stress: Gene x Environment Interaction 2
Neuroendocrine and Autonomic Nervous Control of Stress Response 3
Glucocorticoids – Discovery and Clinical Importance 3
Definitions of Stress 4
Selye’s Definition of Stress – a Further Consideration 5
General Adaptation Syndrome 5
Stressors – Features of – and Lack of Stressor Sign 5
Non Specificity of Stress Response 6
Stress-Induction Across Phyla: Heat Shock Proteins 6
Concepts of Stress and Disease 6
Future Developments of Stress Concepts 7
References 7
Further Reading 9

Introduction and Historical Outline of Stress Concepts

“Stress” has been dubbed the “Health Epidemic of the 21st Century” by the World Health Organization and is estimated to cost
American businesses up to $300 billion a year. The effect of stress on our emotional and physical health can be devastating. In
a recent USA study, over 50% of individuals felt that stress negatively impacted work productivity. Between 1983 and 2009, Stress
levels increased by 10–30% among all demographic groups in the USA.
Aristotle, Hippocrates and the other Ancients were aware of stress and its adverse effects. However, Claude Bernard was the first
formally to explain how cells and tissues in multicelled organisms might be protected from stress. One of the world’s greatest phys-
iologists, Bernard, working in Paris during the second half of the 19th century, first pointed out (1859) that the internal medium of
the living organism is not merely a vehicle for carrying nourishment to cells. Rather, “it is the fixity of the milieu intérieur which is the
condition of free and independent life.” That is, cells are surrounded by an internal medium that buffers changes in acid-base, gaseous
(O2 and CO2) and ion concentrations and other biochemical modalities to minimize changes around biologically determined set-
points, thereby providing a steady state. Fifty years later, Walter Bradford Cannon, working at Harvard, suggested the designation
homeostasis (from the Greek homoios or similar and stasis or position) for the coordinated physiological processes that maintain
most of the steady states in the organism. Cannon popularized the concept of homeostasis in his 1932 book “Wisdom of the Body.”
Cannon, also coined the term fight-or-flight to describe an animal’s response to threats. The concept of fight-or-flight, also called
the acute stress response, proposes that animals react to threats with a general discharge of the sympathetic nervous system, priming
the animal for fighting or fleeing. This response was later recognized as the first stage of a general adaptation syndrome (GAS) first
postulated by Hans Selye to be a universal stress response among vertebrates and other organisms.

Hans Selye
Born in Vienna in 1907, Hans Hugo Bruno Selye, also known as the “father of stress,” began his stress research while still
a medical student in 1926. He observed that patients with a variety of illnesses had many of the same “non-specific” symptoms
that were a common response to stressful stimuli experienced by the body. These clinical observations together with experi-
ments on laboratory rats underpinned Selye’s concept of the GAS which led Selye to assert that prolonged exposure to stress
resulted in “diseases of adaptation.” That is, chronic stress, by causing the overproduction of chemicals and hormones,
produced gastro-duodenal ulcers and high blood pressure. Although the GAS hypothesis was subsequently shown to be incor-
rect, it did put stress on the map and also highlighted the fact that stress had major effects on the immune system as well as on
the adrenal glands.

q
Change History: January 2016. G Fink made some changes to the text, title of the manuscript, updated Further Reading and References section.

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2 Stress: Concepts, Definition and History

In addition to providing the first clear definition of stress, Hans Selye was also the first to recognize that homeostasis could
not by itself ensure stability of body systems under stress. He coined the term heterostasis (from the Greek heteros or other) as
the process by which a new steady state was achieved by treatment with agents that stimulate the physiological adaptive mech-
anisms. Heterostasis, could be regarded as the precursor for the concept of allostasis, first advanced by Peter Sterling and Joseph
Eyer in the 1980s (Sterling and Eyer, 1988; McEwen, 1998; Schulkin, 2004). That is, homeostasis, which has dominated phys-
iological and medical thinking since the 19th century, is thought to provide “stability through constancy.” Allostasis, on the
other hand, provides “stability through change” brought about by regulation of the set-points that adjust physiological param-
eters to meet the stress/challenge.
A different tack, focused on cognition, was taken by the eminent and influential Berkeley University Psychologist, Richard
Lazarus. At a time when psychology tried to understand human behavior by first understanding simple organisms engaging in
simple behaviors learned by associations, rewards or punishments, Lazarus instead emphasized the importance of studying cogni-
tion which he extended into stress and coping (Lazarus, 2000, 2006).

Epidemiology
Epidemiology has been and remains central to stress studies. Numerous epidemiological studies have tried to define the effects of
social, workplace and lifestyle on stress, health and well being. Indeed, job stress is by far the major source of stress for American
adults and has escalated progressively over the past few decades. Increased levels of job stress as assessed by the perception of having
little control but many demands have been demonstrated to be associated with increased rates of heart attack, hypertension, obesity,
addiction, anxiety, depression and other disorders. In New York, Los Angeles and other municipalities, the relationship between job
stress and heart attacks is recognized, so that any police officer that suffers a coronary event on or off the job is assumed to have
a work related injury and is compensated accordingly.

Thrifty Phenotype Hypothesis

However, of the recent epidemiological studies that have generated new stress concepts, the most important perhaps remains that of
David Barker (Barker, 1995), which led to the hypothesis that fetal undernutrition in middle to late gestation programs later coro-
nary heart disease. This concept was soon extended by Hales and Barker (2001) in their “thrifty phenotype hypothesis.” The latter
proposes an association between poor fetal and infant growth and the subsequent development of type 2 diabetes and the meta-
bolic syndrome, which afflict communities in epidemic proportions. Poor nutrition in early life, it is postulated, produces perma-
nent changes in glucose-insulin metabolism. These changes include insulin resistance (and possibly defective insulin secretion)
which, combined with effects of obesity, aging and physical inactivity, are the most important factors in determining type 2 dia-
betes. Many studies worldwide have confirmed Barker’s initial epidemiological evidence, although the strength of the relationships
has varied between studies. As well as intrauterine growth restriction, maternal obesity and diabetes can be associated with disease
of the individual later in life (Rando and Simmons, 2015). Furthermore, paternal exposures can result in the later development of
metabolic disorders in the offspring, and human and animal studies suggest intergenerational transmission of the maternal or
paternal phenotype (Rando and Simmons, 2015). Several changes in epigenetic marks identified in offspring provide a likely mech-
anism by which early molecular changes result in persistent phenotypic changes (Keating and El-Osta, 2015), although additional
mechanisms yet to be uncovered cannot be excluded.

Brain Plasticity
Early life exposures, fetal and perinatal, could result in biological embedding by way of at least three plausible mechanisms: brain plas-
ticity, epigenetics (especially DNA methylation; Demetriou et al., 2015), and hormonal action. There are numerous examples of brain
plasticity, perhaps one of the most dramatic being the recruitment of new neurons and the increase in hippocampal gray matter in
scatter-hoarding animals which need to remember the location of food caches (Barnea and Nottebohm, 1994; Barnea et al., 2006)
and London Cab drivers (Maguire et al., 2006; Woollett et al., 2009) for whom spatial memory is of paramount importance. Hormonal
effects are exemplified by the possible effect of excess androgen in causing the polycystic ovary syndrome phenotype (Gur et al., 2015).

Genetic Susceptibility to Stress: Gene x Environment Interaction

With recent advances in genomics, the concept of susceptibility genes that increase the vulnerability of individuals to stressful life
events has attracted considerable research interest. Thus, for example, the work of Avshalom Caspi and associates (Caspi et al.,
2002) suggested that a polymorphism in the MAOA (monoamine oxidase A) gene promoter, which reduces MAOA expression, influ-
ences vulnerability to environmental stress, and that this biological process can be initiated by childhood abuse. Furthermore, in what
seemed to be a landmark paper Caspi et al. (2003) reported that a polymorphism in the promoter of the serotonin transporter (SERT
or 5-HTT) gene can render individuals more susceptible to stressful life events. Because SERT is also the therapeutic target for popular
antidepressant drugs, the selective serotonin reuptake inhibitors, the publication by Caspi et al. (2003) led to a flurry of research publi-
cations and subsequent meta-analyses to assess the replicability of the findings. However, the overall conclusions from primary and
meta-analyses on genetic x environmental interactions suggest that it is unlikely that there is a stable gene x environment interaction

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Stress: Concepts, Definition and History 3

involving the SERT, life stress and mental disorders (Fergusson et al., 2011). Whether the uncertainty regarding the suggested link bew-
een the SERT gene promoter polymorphism and susceptibility to stress reflects an artifact or problems in posthoc analysis is discussed
by Rutter et al. (2009) who conclude that “the totality of the evidence on GXE is supportive of its reality but more work is needed to
understand properly how 5HTT allelic variations affect response to stressors and to maltreatment.” In fact, recent data suggest that there
is a stable gene x environment interaction involving MAOA, abuse exposure and antisocial behavior across the life course (Fergusson
et al., 2012) as proposed in the earlier paper by Caspi et al. (2002).
Single nucleotide polymorphisms in the gene for the CRF receptor-1 have been tentatively linked to suicidal thoughts and
behavior, depression, panic disorder and fear (Ben-Efraim et al., 2011; Ishitobi et al., 2012; Wasserman et al., 2008, 2009,
2010; Weber et al., 2015). Recent genetic and functional magnetic resonance imaging (fMRI) studies have shown that a func-
tional deletion variant of ADRA2B, the gene encoding the alpha 2b-adrenergic receptor, is related to enhanced emotional
memory in healthy humans and enhanced traumatic memory in war victims (Rasch et al., 2009). The ADRA2B deletion
variant, which acts primarily as a loss-of-function polymorphism, is related to increased responsiveness and connectivity of
brain regions implicated in emotional memory (Rasch et al., 2009; de Quervain et al., 2007). In normal subjects, only carriers
of ADRA2B deletion variant showed increased phasic amygdala responses to acute psychological stress, illustrating that genetic
affects on brain function can be context (state) dependent (Cousijn et al., 2010). In twin studies, Tambs et al. (2009) have
investigated the genetic interactions and the 5 types of anxiety disorder. A recent report by Zannas et al. (2015) suggests that
cumulative lifetime stress may accelerate epigenetic aging, possibly driven by glucocorticoid-induced DNA methylation.
Taken together, the above examples illustrate that our understanding of gene x environment interactions in stress and stress-
related disorders is still at an early phase. Nonetheless, these findings have heuristic importance for further thinking and research
on genetic-environmental interactions that determine the response to stress and the development of mental disorders.

Neuroendocrine and Autonomic Nervous Control of Stress Response

In parallel with these stress concepts, major neuroendocrine advances revealed the physiological substrate for homeostasis, allosta-
sis and the stress response mechanisms. The autonomic nervous and the hypothalamic-pituitary-adrenocortical (HPA) systems
subserve the afferent and efferent limbs of the stress response in vertebrates, and are also central to maintaining homeostasis
and effecting allostasis. The term autonomic nervous system was coined in 1898 by the Cambridge Physiologist, John Newport
Langley, who was also renowned for his development (in parallel with Paul Ehrlich) of receptor theory. Controlled by the brain,
and utilizing as neurotransmitters epinephrine and norepinephrine (sympathetic nervous component) or acetylcholine (parasym-
pathetic component), the role of the autonomic nervous system in fight-or-flight and homeostasis (especially cardiovascular) was
clearly explained by Walter Cannon.
The story of our understanding of the HPA, and the concept of the neurohumoral hypothesis of anterior pituitary control, is
tortuous (Fink, 2012, 2015). The pituitary gland had long been regarded, by luminaries such as the great Harvard neurosurgeon
Harvey Cushing, as the autonomous controller of the adrenal cortex, the thyroid and the gonads. That is, the anterior pituitary
gland was considered to be the “conductor of the endocrine orchestra.” This view was reinforced by the dramatic effects of exper-
imental hypophysectomy in rodents made feasible by the parapharyngeal surgical approach to the pituitary developed by PE
Smith around 1930. However, at about the same time experiments were in progress that triggered a cascade of studies which would
eventually prove that the anterior pituitary gland is not autonomous; rather, it is controlled by the brain. These experiments,
carried out by William Rowan working alone in Edmonton Alberta in the late 1920s, showed that migration in birds was
controlled by the gonads, and that gonadal size in birds was increased many-fold by increases in day-length. Day-length and
the effects of other exteroreceptive factors, such as stress, on endocrine function together with the effects of brain tumors and trauma
in the human, lead to an acceptance of the concept that the pituitary gland is under central nervous system (CNS) control.
The neural lobe of the pituitary gland is comprised of nerve projections from the paraventricular and supraoptic nuclei of the
hypothalamus: these projections terminate on systemic blood vessels into which they release the nanopeptide neurohormones,
vasopressin and oxytocin. In contrast, the anterior pituitary gland receives no direct innervation from the brain. Rather, the CNS
control of the anterior pituitary gland is mediated by neurohormones synthesized and released from hypothalamic neurons and
transported to the anterior pituitary gland by the hypophysial portal vessels. Proof of the neurohumoral hypothesis of anterior pitu-
itary control came, first, from the elegant pituitary stalk section and pituitary grafting experiments of Geoffrey Harris and Dora
Jacobsohn, secondly, the characterization of some of the neurohormones by Andrew Schally and Roger Guillemin, for which
they were awarded the 1977 Nobel Prize for Physiology and Medicine, and, thirdly, the demonstration, first by my group, that these
neurohormones were indeed released into hypophysial portal blood (Fink, 2012, 2015; Fink and Sheward, 1989; Fink et al., 1971).
Corticotropin releasing hormone (CRH), a 41 amino acid peptide that mediates neural control of adrenocorticotropic hormone
(ACTH) release from pituitary corticotropes, was isolated and sequenced by Wylie Vale et al. (1981). A series of physiological
studies, including measurements of neurohormone release into hypophysial portal blood in vivo, have confirmed earlier views
that arginine vasopressin acts synergistically with CRH to control ACTH release (Fink, 2012; Fink et al., 1988).

Glucocorticoids – Discovery and Clinical Importance

Finally, no outline of the history of stress concepts would be complete without mention of the characterization of the adrenocortical
glucocorticoids and their function. The glucocorticoids are steroid hormones whose secretion by the adrenal cortex is controlled by

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4 Stress: Concepts, Definition and History

ACTH. The hormones of the adrenal cortex were isolated, identified, and synthesized independently by Edward Kendall (at the
Mayo Foundation) and Tadeus Reichstein (at Zurich) and their associates. The availibility of large amounts of synthetic steroids
enabled their physiological effects to be studied. Ultimately, Philip Hench was able to test the glucocorticoid, cortisone, in the
human and demonstrated that it was a powerful anti-inflammatory agent. Also from the Mayo Foundation, Hench had previously
observed that rheumatoid arthritis was sometimes relieved during pregnancy and in some patients with jaundice, leading him to
conclude that the pain-alleviating substance was a steroid. Kendall, Hench, and Reichstein jointly were awarded the Nobel Prize for
Physiology and Medicine for 1950, and synthetic glucocorticoids continue to be used to treat arthritis, asthma, autoimmune condi-
tions and other inflammatory disorders in the human (Raju, 1999).

Definitions of Stress

Stress has a different meaning for different people under different conditions. The first and most generic definition of stress is that
proposed by Hans Selye:

Stress is the non-specific response of the body to any demand.

Selye repeatedly emphasized the fact that the continued use of the word stress as a non-specific response to any demand was most
appropriate. Selye argued that stress is not identical to emotional arousal or nervous tension since stress can occur under or in response
to anesthesia in man and animals, and can also occur in plants and bacteria that have no nervous system. This point is elaborated
below in the context of stress-induced heat shock proteins that play a key role in cytoprotection across all three phylogenetic domains.
The word “stress,” as used by Selye, is accepted in all foreign languages, including those in which no such word existed previously.
Stress, Selye underscored, “is not something to be avoided. Indeed, it cannot be avoided, since just staying alive creates some
demand for life-maintaining energy. Even when man is asleep, his heart, respiratory apparatus, digestive tract, nervous system
and other organs must continue to function. Complete freedom from stress can be expected only after death.”
There has been much controversy and debate about Selye’s concepts and particularly Selye’s view that stress is best regarded as
a non-specific response. Because of their heuristic value, these points will be further considered below.
Other definitions, reviewed in detail by Selye in his Stress in Health and Disease (1976), include the following:
1. In behavioral sciences, stress is regarded as the “perception of threat, with resulting anxiety discomfort, emotional tension, and
difficulty in adjustment.”
2. In the group situation, lack of structure or loss of anchor “makes it difficult or impossible for the group to cope with the
requirements of the situation, and the problem of leadership and interpersonal behavior becomes one of evolving or supplying
a structure or anchor and of supplying the expertness for coping with the demands of the situation.”
3. Stress can also be defined in terms of pure neuroendocrinology. Eugene Yates, for example, defined stress as any stimulus that
will provoke the release of ACTH and adrenal glucocorticoids. Presumably, the same might apply to the equally powerful
sympathetic markers of stress, underscored earlier by Walter Cannon.
4. Selye also mentions Richard Lazarus, famous for his work in cognitive psychology and focus on the emotions. Lazarus under-
scores the difficulties of reaching a precise overarching definition of stress by setting out the following different meanings of the
term: “In spite of consistent confusion about the precise meaning of the term, stress is widely recognized as a central problem in
human life. Scientists of many disciplines have conceptualized stress but each field appears to have something different in mind
concerning its meaning. For the sociologist, it is social disequilibrium, that is, disturbances in the social structure within which
people live. Engineers conceive of stress as some external force which produces strain in the materials exposed to it. Physiologists
deal with the physical stressors that include a wide range of stimulus conditions that are noxious to the body. In the history of
psychological stress research, there has been no clear separation between physical stressors which attack biological tissue systems
and psychological stressors which produce their effects purely because of their psychological significance.”
5. In their seminal review “The Stressed Hippocampus, synaptic plasticity and lost memories,” Kim and Diamond (2002) suggest
a three-component definition of stress that can be applied broadly across species and paradigms. First, stress requires heightened
excitability or arousal, which can be operationally measured using electroencephalography, behavioral (motor) activity or
neurochemical (adrenaline, glucocorticoid) levels. Second, the experience must also be perceived as aversive. Third, there is lack
of control. Having control over an aversive experience has a profound mitigating influence on how stressful the experience feels.
The element of control (and “predictability”) is the variable that ultimately determines the magnitude of the stress experience
and the susceptibility of the individual to develop stress-induced behavioral and physiological sequelae.
Thus, the magnitude of neurocognitive stress (S) approximates to the product of:
l Excitability/Arousal (E)
l Perceived aversiveness (A)
l Uncontrollability (U)

ðSÞ ¼ E  A  U

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Stress: Concepts, Definition and History 5

Selye’s Definition of Stress – a Further Consideration

As intimated above, Hans Selye was the first to use the word stress in the context of biomedicine, and define the concept and
phenomenon of stress in a generic and non-specific manner. Selye’s definition and concept of stress has remained controversial.
For some, his definition is too biological and ignores cognitive and psychological factors, a criticism that seems to stem from
the mistaken idea that cognition is not brain/biologically based (a reversion to Rene Descartes’ outmoded doctrine that mind
and body are separate). For others, Selye’s definition is too general. Selye systematically rebutted some of these and other criticisms
(Selye, 1975). Here we review the basis for Selye’s definition of stress, and consider whether the criticisms leveled at Selye’s stress
concept are valid. Overall, our observations suggest that Selye fully understood so-called psychological or cognitive stress, and that
the generality of Selye’s stress definition has facilitated the molecular, genotypic and phenotypic analysis of stress and stress
responses across all species from bacteria to man.

General Adaptation Syndrome

Hans Selye first put stress on the map with the GAS. In search of a new hormone, Selye injected extracts of cattle ovaries into rats. The
injection caused the following characteristic triad:
1. the adrenal cortex became enlarged and discharged lipid secretory granules
2. the thymus, spleen, lymph nodes and all other lymphatic structures showed severe involution
3. deep bleeding ulcers appeared in the stomach and duodenum
Selye at first thought that these effects were due to a new hormone in the extracts. But soon found that all toxic substances –
extracts of kidneys, spleen, and even toxicant not derived from living tissue – produced the same syndrome.
Selye surmised that the response to the injection of toxic substance reflected his “classroom concept” of “the syndrome of just
being sick” That is, “adrenal enlargement, thymico-lymphatic involution and gastrointestinal ulcers were the omnipresent signs of
damage to the body when under attack. The three changes thus became (for Selye) the objective indices of stress and the basis for the
development of the entire stress concept.”
First described in a note to Nature in 1936 (Selye, 1936), the GAS has three stages: alarm; resistance; exhaustion. In the alarm
stage, the body shows changes characteristic of the first exposure to the stressor – these changes generally coincide with the sympa-
thetic discharge that enables the fight-or-flight phenomenon of Cannon. If the stressor continues and is compatible with adaptation,
features of the alarm reaction disappear and resistance develops. Prolonged exposure to the stressor may result in exhaustion and
finally death.
One of the most important findings of GAS is the stress-induced thymico-lymphatic involution which highlighted for the first
time that stress has a major impact on the immune system – and that was in 1936 – more than 20 years before the discoveries of
lymphocyte recirculation by James Gowans and acquired immunological tolerance by MacFarlane Burnet and Peter Medawar!
Selye’s discovery began the field of neuroimmunomodulation.
Selye soon became aware of the fact that the adrenal enlargement of the GAS was associated with increased secretion of gluco-
corticoids (cortisol or corticosterone) that “induce glycogenolysis, thereby supplying a readily available source of energy for the
adaptive reactions necessary to meet the demands made by the stressors. In addition, they facilitate various other enzymatically
regulated adaptive metabolic responses and suppress immune reactions as well as inflammation, assisting the body to coexist
with potential pathogens.” Selye asserted that glucocorticoids are needed for the acquisition of adaptation primarily during the
alarm reaction. Selye’s view that glucocorticoids enhance and mediate the stress response has been upheld with the additional
concepts that glucocorticoids play a permissive role that primes the body’s stress response systems and also prevent overshoot of
the defense systems. Overshoots in the body’s defense system are perhaps most dramatically seen in major inflammatory cataclysms
called cytokine storms and the consequent systemic inflammatory response syndromes that play a key role in the lethality of avian
influenza and have also occurred in response to the injection of certain antibodies (Suntharalingam et al., 2006). Exogenous
synthetic glucocorticoids such as methylprednisolone remain a mainstay of the treatment of cytokine storms.
The GAS is clearly a consequence of extreme stress. The three components of the GAS have not withstood the test of time as
indices of stress as Selye had originally proposed. Rather, the main biological markers of stress have long been behavioral observa-
tions and tests and measures of sympathetic and HPA activation. In the case of the latter the measurement of glucocorticoid concen-
trations in blood, either alone or in parallel with plasma concentrations of ACTH, have been used as the main biological indices of
stress. So, in spite of its heuristic value, and its importance for triggering the concept of stress-induced neuroimmunomodulation,
the concept of the GAS has lost scientific currency.

Stressors – Features of – and Lack of Stressor Sign

Selye, in Stress in Health and Disease (Selye, 1976), underscored the fact that “Stress is part of our daily human experience, but it is
associated with a great variety of essentially dissimilar problems, such as surgical trauma, burns, emotional arousal, mental or phys-
ical effort, fatigue, pain, fear, the need for concentration, the humiliation of frustration, the loss of blood, intoxication with drugs or
environmental pollutants, or even the kind of unexpected success that requires an individual to reformulate his lifestyle. Stress is
present in the businessman under constant pressure; in the athlete straining to win a race; in the air-traffic controller who bears

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6 Stress: Concepts, Definition and History

continuous responsibility for hundreds of lives; in the husband helplessly watching his wife’s slow, painful death from cancer; in
a race horse, its jockey and the spectator who bets on them.” Selye went on to argue that “while all these subjects face quite different
problems they respond with a stereotyped pattern of biochemical, functional and structural changes essentially involved in coping
with any type of increased demand upon vital activity, particularly adaptation to new situations.”
Selye also asserted that stressors have no sign as far as evoking the stress response. That is the response will be the same “whether the
agent or situation being faced is pleasant or unpleasant; all that counts is the intensity of the demand for readjustment or adaptation
that it creates.” Selye underscored this point with the following poignant example: “The mother who is suddenly told that her only son
died in battle suffers a terrible mental shock; if years later, it turns out that the news was false and the son unexpectedly walks into her
room alive and well, she experiences extreme joy. The specific results of the two events, sorrow and joy, are completely different, in fact
they are opposite to each other, yet their stressor effect – the nonspecific demand for readjustment to a new situation – is the same.”

Non Specificity of Stress Response

Selye seemed to have been driven to find specificity in the response to different types of stressors. Thus, in Stress in Health and Disease
(Selye, 1976) he wrote:

It is difficult to see at first how such essentially different things as cold, heat, drugs, hormones, sorrow and joy could provoke an identical biologic
reaction. Nevertheless this is the case; it can now be demonstrated by highly objective, quantitative biochemical and morphologic parameters that
certain reactions are totally non-specific and common to all types of agents, whatever their superimposed specific effects may be.

The lack of specificity of Selye’s definition of stress has been the subject of considerable criticism. Indeed, Pacak and Palkovits
(2001) carried out a series of experiments that demonstrate that different stressors activate different stress biomarkers and different
regions of the brain. Thus, for example, low blood glucose concentrations (glucopenia) or hemorrhage activate both the sympa-
thetic and HPA systems; hyperthermia, cold and formalin injection selectively activate the sympathetic system. On the basis of these
data, Pacak and Palkovits conclude that each stressor has its own specific neurochemical signature. However, since these stress
indices are limited to just two neurohumoral systems, and since for most stressors there is at least some overlap in response, it
is not clear that this approach invalidates Selye’s definition, Stress is the non-specific response of the body to any demand, which would
probably be unassailable had Selye omitted the term “non-specific.”

Stress-Induction Across Phyla: Heat Shock Proteins

Whatever the shortcomings Selye’s definition of stress for the human, it is probably appropriate for the vast majority of living organ-
isms. Living cells are classified into three main evolutionary lines, or phylogenetic domains; Bacteria (eubacteria), Archaea (formerly
archaebacteria), and Eucarya (eukaryotes – which encompass all plants and animals through to man). The cellular response to stress
in all three phylogenetic domains is represented at the molecular level by the stress-induced synthesis of stress or heat shock proteins
(Hsps), of which molecular chaperones and proteases represent two well-characterized families. The heat shock response was
discovered in 1962 by Ferruccio Ritossa, who observed a pattern of Drosophila salivary gland chromosome puffs that were induced
in response to transient exposure to elevated temperatures (Ritossa, 1962, 1996). Since then, many studies have shown that the heat
shock response is ubiquitous and highly conserved in all organisms from bacteria to plants and animals. It is an essential defense
mechanism for protection of cells from a wide range of stressors, including heat shock, alcohols, ischemia, inhibitors of energy
metabolism, heavy metals, oxidative stress, fever, or inflammation, which depending on amplitude and duration can all cause
cell death by apoptosis or necrosis. The heat shock response can protect against stress-induced cell death by way of a cell-
protective process known as thermotolerance or cytoprotection, in which exposure of cells to mild stress conditions, sufficient to
induce the expression and accumulation of Hsps, protects against a subsequent challenge from another stress that is, by itself, lethal.
Although their precise function remains to be determined, the high degree of conservation of these Hsps across species, coupled
with their importance in cell survival in various conditions, suggests that Hsps are critical for both normal cellular function and
survival after a stress. Several cytoprotective functions have been attributed to Hsps and, in particular, the HSP70 family. These
include (1) the folding of proteins in various intracellular compartments, (2) the maintenance of structural proteins, (3) the refold-
ing of misfolded proteins, (4) translocation of proteins across membranes and into various cellular compartments, (5) the preven-
tion of protein aggregation, and (6) the degradation of unstable proteins. Hsps also serve as modulating signals for immune and
inflammatory responses, and may have a role in cytokine production.
So, for the heat shock response to stressful stimuli, Selye’s Stress is the non-specific response of the body (or cell) to any demand would
appear to be appropriate.

Concepts of Stress and Disease

There is a vast literature on the role or possible role of stress in the causation and/or excacerbation of disease in most organ systems
of the body. Here attention will focus on mental disorders. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of

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Stress: Concepts, Definition and History 7

the American Psychiatric Association recognizes two stress disorders: Acute Stress Disorder and Posttraumatic Stress Disorder. For
the diagnosis of Acute Stress disorder the individual, while experiencing the trauma or after the event, must have at least three of
several dissociative symptoms such as a subjective sense of numbing, detachment, or absence of emotional responsiveness, reduc-
tion in awareness of surroundings, depersonalization, or dissociative amnesia. Following the trauma, the traumatic event is persis-
tently reexperienced, the individual avoids stimuli that may arouse recollections of the traumatic event, and has anxiety or increased
arousal. The trauma causes clinically significant distress or impairment in social, occupational, or other important areas of
functioning.
Posttraumatic Stress Disorder (PTSD) is defined as a condition in which a traumatic event is persistently reexperienced in the
form of intrusive recollections, dreams or dissociative flashback episodes. Cues to the event lead to distress and are avoided, and
there are symptoms of increased arousal. To meet the diagnostic criteria of the DSM-5, the full symptom picture must be present
for more than 1 month, and the disturbance must cause clinically significant distress or impairment in social, occupational, or other
areas of functioning.
PTSD has only been accepted officially as a mental disorder since 1980, when it was included, amid considerable controversy, in
the DSM-III. References to the after effects of psychological trauma (1) date back as far as the third century BC, (2) achieved
prominence during the early period of the railroad in Britain when rail travel, then precarious and physically traumatic, gave rise
to a syndrome called railway spine or postconcussion syndrome, and (3) were regarded as the basis for hysteria around the turn
of the 19th Century by neurologists and psychiatrists such as Jean-Martin Charcot, Pierre Janet and Sigmund Freud. Long before
PTSD was included in any diagnostic system, Charles Dickens wrote A Tale of Two Cities, which (published in 1859) can be
considered as an early case report of PTSD (Huber and te Wildt, 2005). Interest in PTSD increased dramatically during the First
World War: Charles Samuel Myers was the first to coin the term and report case histories of “shell shock” (Myers, 1915) which
described a condition that afflicted many troops who screamed and wept uncontrollably, froze and could not move, became
mute and unresponsive and lost their memory, sensations and capacity to feel. Pat Barker’s monumental trilogy, Regeneration,
deals poignantly with the psychological traumas of war and the nature of shell shock. The condition occurred again in vast
numbers of people as a consequence of the Second World War. However, it was the psychological trauma experienced by
Vietnam veterans and their demand for compensation that lead to the inclusion of PTSD in the DSM-III as a condition that
occurred both in civilian (eg, rape trauma syndrome, battered woman syndrome, abused child syndrome) and military trauma
response syndromes.

Future Developments of Stress Concepts

This brief account of some of the definitions and concepts of stress show that there is still much to be done in the area of stress
research. Thus, with respect to gene-environmental interactions, work on susceptibility genes has just begun, and there is still
room for expanding our knowledge about the role in stress of epigenetic factors and other mechanisms of gene control such
as RNA interference. On the basis of previous theories, it seems likely that Barker’s “Fetal origins” hypothesis might be honed
and revised and may lead to a robust understanding of the metabolic syndrome and diabetes type 2. New powerful computer
analysis of brain imaging and electrical recording may help to resolve the many questions that surround consciousness and
cognition. The vexed cause- and –effect questions regarding the influence of stress in mental disorders, cancer and other diseases
need to be answered. We have witnessed in the last 25 years how Selye’s cherished and widely accepted axiom that stress is the
cause of gastric ulceration (one of the three components of the GAS) was modified by the careful observations and courageous
perseverance of Barry Marshall and Robin Warren who demonstrated that, in fact, many gastro-duodenal ulcers are caused by
a microbe, Helicobacter pylori, that is, readily amenable to treatment with antibiotics. And yet, some types of stress, especially
physical trauma, can in the absence of Helicobacter pylori cause gastric ulceration (Fink, 2011). Thus, the relative potency for ulcer
causation of stress compared with Helicobacter pylori, and the possible interaction between the two causes needs to be determined.
These and other biological questions about stress are likely to be tractable – rational and rigorous biology will almost certainly
win the day.
However, the causes of human stress, acute and posttraumatic, are largely social and sociological, political and irrational (beliefs
in religious and racial superiority). Our continuing strife and conflict reflect in part man’s innate, often irrational (limbic-brain
generated) aggressive drive for conquest, territory, acquisition, and reproduction of the species. Perhaps the fact that man is such
a smart political animal works against us, and could ultimately lead to our stressful self-destruction. It is not clear that anything
short of the impossible – amygdalectomy at birth – can protect man from this fate.

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Further Reading

Armitage, J.A., Khan, I.Y., Taylor, P.D., Nathanielsz, P.W., Poston, L., 2004. Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong
is the evidence from experimental models in mammals? J. Physiol. 561, 355–377.
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De Maio, A., Santoro, M.G., Tanguay, R.M., Hightower, L.E., 2012. Ferruccio Ritossa’s scientific legacy 50 years after his discovery of the heat shock response: a new view of
biology, a new society, and a new journal. Cell Stress Chaperones 17, 139–143.
Eriksson, J.G., 2005. The fetal origins hypothesisd10 years on. Br. Med. J. 330, 1096–1097.
Fink, G. (Ed.), 2007. Encyclopedia of Stress, second ed., Elsevier, Oxford.
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Rutter, M., 2012. Achievements and challenges in the biology of environmental effects. Proc. Acad. Sci. 109 (Suppl. 2), 17149–17153.

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