Stress has a different meaning for different people under different conditions. A working definition of stress that fits many human situations is a condition in which an individual is aroused by an uncontrollable aversive challenge — for example, stuck in heavy traffic on a motorway, a hostile employer, unpaid bills, or a predator. Stress leads to a feeling of fear and anxiety. Depending on the circumstances, the fear response can lead to either fight or flight.  The magnitude of the stress and its physiological consequences are influenced by the individual’s perception of their ability to cope with the stressor. The biological response to stress in Man and other mammals is orchestrated by the brain by way of the hypothalamic-pituitary-adrenal (HPA) system, the autonomic nervous system (ANS) and central (brain) circuits and neurochemical mechanisms.

Stress, Fear and Anxiety

Clinically, the fear response to a perceived threat is distinguished from anxiety, which is a generalized mood disorder that can occur in the absence of a triggering stimulus. Anxiety is characterized by feelings of discomfort, apprehension of future dangers, dread and panic. Prolonged anxiety may impede concentration and lead to irritability and restlessness. Panic attacks occur in several types of anxiety states and are characterized by a discrete period of intense fear or discomfort accompanied by somatic symptoms such as palpitations, sweating, trembling or shaking, a sensation of shortness of breath, and cognitive symptoms such as fear of losing control or depersonalization (being detached from oneself).

Stress Definitions

Stress is difficult to define. As Hans Selye, often referred to as the “father of stress”, stated  “Everybody knows what it is and no one knows what it is”.

Here are several definitions of stress. For detailed discussion see Fink (2009a).

  • ‘‘Stress is the nonspecific response of the body to any demand”. This first and most generic definition of stress was proposed in 1936 by Hans Selye.
  • ‘‘Perception of threat, with resulting anxiety discomfort, emotional tension, and difficulty in adjustment.’’
  • “Stress occurs when environmental demands exceed one’s perception of the ability to cope”
  • 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. Leadership missing and required for coping with the demands of the situation.’’
  • For the sociologist, it is social disequilibrium, that is, disturbances in the social structure within which people live.
  • A purely biological definition is that stress is any stimulus that will activate (i) the hypothalamic pituitary-adrenocortical system thereby triggering the release of pituitary adrenocorticotropin and adrenal glucocorticoids and (ii) activate the autonomic nervous system with the consequent secretion of adrenaline and noradrenaline. For details see “Stress Biology”, below.
  • 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, behavioural (motor) activity or neurochemical (adrenaline, glucocorticoid) levels. Arousal, however, can increase under either pleasurable or aversive conditions. So, second, the experience must also be perceived as aversive. Aversiveness can be defined as an indication that the subject would avoid or attenuate the intensity of the stressor if given the opportunity. The third component of the definition of stress is controllability. 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 behavioural and physiological sequelae.  A traffic delay on the motorway while driving to an important meeting without information on the cause of the delay or its likely duration is an example of how lack of control and predictability can cause stress.
  • Thus, the magnitude of neurocognitive stress (S) approximates to the product of:

Excitability/Arousal (‘E’)
Perceived aversiveness (‘A’)
Uncontrollability (‘U’)
(‘S’) =  E x A x U


In his monograph, Stress in Health and Disease, Selye underscored the fact that stress is part of our daily human experience. Stress is associated with a great variety of essentially dissimilar problems, such as surgical trauma, burns, emotional arousal, mental or physical 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 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. “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 1976).

Stress Biology

The biological response to stress is mediated by two neuroendocrine systems; the hypothalamic-pituitary-adrenal and the autonomic nervous systems (HPA and ANS, respectively). The hypothalamus of the brain, and especially the paraventricular nuclei (PVN), plays a dominant role in the control of both systems.

In the case of the HPA, hypothalamic control of the release of pituitary adrenocorticotropin (ACTH) is mediated by the 41-amino acid residue neuropeptide corticotropin releasing factor (CRF) transported from PVN nerve terminals to the anterior pituitary gland by way of the hypophysial portal vessels. The action of CRF is potentiated by the synergistic action of the nonapeptide, arginine vasopressin (AVP). ACTH stimulates the secretion of adrenal glucocorticoids which have powerful metabolic effects that promote the stress response. Homeostasis within the HPA is maintained by a precise negative feedback system by which the adrenal glucocorticoids (the afferent limb), cortisol in humans and fish or corticosterone in rodents, moderate ACTH synthesis and release (efferent limb). Allostasis, that is, change in HPA activity to cope with increased stress load, is brought about by change in feedback set point. The major sites of negative feedback are the PVN, where glucocorticoids inhibit CRF and AVP synthesis and release, and the pituitary gland, where they block the ACTH response to CRF and inhibit the synthesis of ACTH and its precursor, proopiomelanocortin (POMC). The limbic system of the brain, especially the hippocampus and amygdala, also plays a role in glucocorticoid negative feedback.

Central control of the ANS involves the hypothalamic PVN together with various brainstem and limbic nuclei (caudal raphe, ventromedial and rostral ventrolateral medulla, the ventrolateral pontine tegmentum). The ANS plays the pivotal role in the early (immediate) response to stress. ANS action is mediated mainly by the sympathetic nervous system by way of the release of the catecholamines, noradenaline (norepinephrine) from nerve terminals and adrenaline (epinephrine) from the chromaffin cells of the adrenal medulla. This system is commonly referred to as the sympathetic-adrenomedullary system (SAM). Adrenaline and noradrenaline facilitate the stress response by triggering the synthesis and release of glucose from the liver into the blood stream, increasing rate and force of cardiac contraction and shunting blood from skin and the gastrointestinal system to the skeletal muscles.

In addition to these two canonical neural outflow systems the stress response also involves central neural circuits and neurochemical mechanisms that orchestrate the central and behavioural responses to stress. The neurochemical mechanisms involve amino acid neurotransmitters (glutamate and GABA), neuropeptides (such as CRF, urocortins and opioid peptides) and the monoamines (noradrenaline, serotonin and dopamine).


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. Bernard, working in Paris during the second half of the nineteenth 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 inte´rieur 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), 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 (see Fink 2009).

Fight or flight

Walter Cannon also coined the term fight or flight to describe an animal’s response to threat. This concept proposed that animals react to threats with a general discharge of the sympathetic nervous system, priming the animal for fighting or fleeing. Activation of the sympathetic nervous system, with the secretion of adrenaline (epinephrine) from the adrenal medulla and noradrenaline (norepinephrine) from sympathetic nerve terminals, increases heart rate and the force of heart contractions, blood pressure, and blood glucose levels and shunts blood from skin and the gastrointestinal system to skeletal muscle. These immediate stress evoked changes enable the animal to fight/resist or flee from the predator or other challenge.


Homeostasis, ‘stability through constancy’ is maintained by a self-limiting process involving negative feedback control by the output variable, which in the case of the brain (hypothalamic) –pituitary- adrenal system is the secretion of adrenal glucocorticoids. The limits of feedback control are set by a notional regulatory “set point” (Fink 2011a). Peter Sterling and Joseph Eyer introduced the term Allostasis, ‘stability through change’ brought about by central nervous regulation of the set points that adjust physiological parameters in anticipation to meet the stress/challenge. McEwen (1998) integrated the concept of allostasis to describe the adaptation process of the organism in the face of different stressors and different circumstances. That is, allostasis incorporates circadian, circannual, and other life-history changes and emphasizes their importance in maintaining the animal’s internal balance.

Allostatic Load

Allostatic load represents the cumulative impact of stressors on the body’s physiological systems over the life course. That is, Allostatic load can be defined as the “long-term cost of allostasis that accumulates over time and reflects the accumulation of damage that can lead to pathological states”. Allostatic load has been shown to predict various health outcomes in longitudinal studies, such as declines in physical and cognitive functioning, and cardiovascular morbidity and mortality. Allostatic load is measured using a point scale that combines a series of stress biomarkers of cardiovascular, immune, and metabolic function. These include: systolic and diastolic blood pressure; the levels of cortisol, adrenaline and noradrenaline; body mass index (BMI); waist-hip ratio; levels of glycated haemoglobin, triglycerides, C-reactive protein, homocysteine, total cholesterol, albumin and creatinine clearance (McEwen 2006; Peters & McEwen 2012).

“For further details on stress, its adverse effects and stress management, the reader is referred to the Encyclopedia of Stress (see link below) and the publications posted or listed under Bibliography.

For advice or consultation on stress diagnosis and management contact us for further information (see also Consulting)”


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