Evolution of the stress concept :Evolution of the stress concept :

Past and FuturePast and Future

• HeracleitesHeracleites (540-480 BC),(540-480 BC), EmpedoclesEmpedocles (500-430 BC)(500-430 BC), HippocratesHippocrates (460-375 BC)(460-375 BC) : Health = harmony ; disease = dysharmony. “Nature is the healer of disease”.

• EpicarusEpicarus (341-270 BC) (341-270 BC) : Coping with emotional events improves the quality of life : “ataraxia”, impermeability of mind.

• Buddha (563-483 BC) : India, eastern Asia, Confucius (551-479 BC) : China, philosophers and teachers.

• From the RomansFrom the Romans to Renaissance : In line with Hippocrates : Vis Medicatrix Naturae.

The GreeksThe Greeks-- “Harmony” “Balance” “Equilibrium” : “steady state” “Harmony” “Balance” “Equilibrium” : “steady state” - When threatening forces = counteracting forces put forth to neutralize - When threatening forces = counteracting forces put forth to neutralize

Claude BERNARD (1813-1878)Claude BERNARD (1813-1878)

1. “Constancy of the internal environment is the condition that life should be free and independent”.

Leçons sur les phénomènes de la vie communs aux animaux et aux végétaux, 1878. J.B. Baillère et fils, Paris (p.564).

“No more pregnant sentence was ever framed by a physiologist”. The Scottish physiologist Haldane (Respiration, Yale Univ. Press,1922, p.427).

2. “The organism maintains with the environment a precise and informed relation… in such a way that an equilibrium results from delicate and sustained compensations as it is with a very sensitive balance”.

3. “Physiology and pathology correspond each other and directly in such a way that healing corresponds to the recovery of a normal physiological state”.

4. Internal environment = fluids ; stability

1. In line with Bernard’s concept.- Homeostasis : «the stable state of fluid matrix, protected from change»- «All our living parts, both the gross and the minute, are intimately in

contact with fluids, as if immersed in it».

2. The sympatho-adrenal system assure a «homeostatic condition of internal environment» ; adrenaline in blood stream : to all the internal organs.

3. The CNS is concerned : through its receptors (external environment) and via the ANS, through the internal environment.

4. Maintenance of homeostasis involves servo-mechanisms and setpoints at local levels.

5. When homeostatic adjustments fail : pathology.

Walter CANNON (1871-1945)Walter CANNON (1871-1945) Homeostasis Homeostasis

“homeoios “ : like, similar“homeoios “ : like, similar “stasis” : stagnation, immobile, fixed “stasis” : stagnation, immobile, fixed

= steady state = steady state Fight or FlightFight or Flight

““It is chiefly freedom for the activity of the higher levels of the It is chiefly freedom for the activity of the higher levels of the

nervous system and the muscles which they govern. The nervous system and the muscles which they govern. The

alternative will be submission to the disturbances of any constants alternative will be submission to the disturbances of any constants

of the fluid matrix would impose upon us”.of the fluid matrix would impose upon us”.

Cannon, 1939

Homeostasis as a biological necessity

Walter CANNON (1871-1945)Walter CANNON (1871-1945)

Organization for physiological homeostasis. Physiol. Rev., 1929, 9, 399.

Stresses and strains of homeostasis. Amer. J. Med. Sci., 1935, 189, 1.

• The wisdom of the body, 1932, Norton and Co, NY.

During the same period :

Cushing (Harvard, 1932) and his syndrome.

Marshall (Cambridge, 1936) reviews in detail the way in which endocrine activity was affected by external factors.

• “The defects observed in different organs are constant and unvariable signs of damage to a body facing a demand or meeting the attack of any disease”.

• GAS or “biologic stress syndrome”– Alarm reaction– Then, if continues : adaptive stage of resistance

– Increase of granules secretion in adrenal cortex– Hemodilution, hyperchloremia, anabolism

– Then, if continues : stage of exhaustion

• “The concept of non-specificity in bodily reactions contrasts with the concept of specificity in medicine introduced by Pasteur”.

• “Even mere emotional stimuli produce a severe alarm reaction ; the anterior pituitary receiving virtually no significant neural input, appeared nonetheless to be influenced by the central nervous system”.

• Cannon : “I do not think these glands could help resistance and adaptation in general”.

• Not physiology but disease.

Hans SELYE (1907-1982)Hans SELYE (1907-1982) The “General Adaptation Syndrome (GAS)The “General Adaptation Syndrome (GAS)

… A syndrome produced by diverse noxious agents”. Nature, 1936, 138, … A syndrome produced by diverse noxious agents”. Nature, 1936, 138, 32.32.

Hans SELYE (1907-1982)Hans SELYE (1907-1982)« The stress of life » 1956 McGraw-Hill, NY« The stress of life » 1956 McGraw-Hill, NY

“I should have called my phenomenon the «strain reaction» and that which causes it “stress”, which would parallel the use of these terms in physics. Hence, I was forced to create a neologism and introduce the word “stressor” for the causative agent, retaining stress for the resulting condition. Stress and strain in physics correspond to stressor and stress in biology and medicine”.

The stress of life, 1956, pp. 50-51.

“Stress is the non-specific result of any demand upon the body, be the effect mental or somatic”. “The exact nature of the stressor becomes largely irrelevant”.

1940-1970 : Profound changes in medicine. 1940-1970 : Profound changes in medicine. ————

The Concept : The Concept : “… More should be learned about the influence a social … More should be learned about the influence a social system has on the health of its memberssystem has on the health of its members”.

————————- Donnison : - Donnison : Civilisation and DiseaseCivilisation and Disease, 1938., 1938.- Halliday : - Halliday : Psychosocial Medicine : a Study of the Sick SocietyPsychosocial Medicine : a Study of the Sick Society, 1948., 1948.- Wolff : Wolff : Stress and DiseaseStress and Disease, 1952 (cf Engel)., 1952 (cf Engel).- Dohrenwend : Dohrenwend : Stressful Life Events : their Nature and EffectsStressful Life Events : their Nature and Effects, 1974 , 1974 (cf Hinkle).(cf Hinkle).- Insel and Moos : Insel and Moos : Health and the Social EnvironmentHealth and the Social Environment, 1974., 1974.- Kurstin : Kurstin : Theoretical Principles of Psychosomatic medicineTheoretical Principles of Psychosomatic medicine, 1976., 1976.- Weiner : Weiner : Psychobiology of Human DiseasePsychobiology of Human Disease, 1977., 1977.- Henry and Stephens : Henry and Stephens : Stress, Health, and the Social EnvironmentStress, Health, and the Social Environment, 1977., 1977.

1948 : Cortisone

P.S. Hench (and E. Kendall)

1949 : First report for a medical role of “substance E” (cortisone) in rheumatoid arthritis

1950 : Nobel Prize

1954 : More than 200 diseases treated by the hormone

A. Munck et al, Endoc. Rev., 1984, 5, 25-44

A. Angelucci,Europ. J. Pharmacol., 2000, 405, 139-147

1. Stressors are external events or conditions that affect the organism : they impinge on an organism that has specific characteristics .

2. Lazarus R. “Adaptational equation” : Two central elements cognitive appraisal : Plays a major role in the transaction between the person

and the potentially stressful environment. Individual differences, of most relevance in human research, have to do with the cognitive appraisal of stressors.

Coping : After appraising the stressor, the organism will use one or more coping strategies in an attempt to adjust to the situation. Individual differences and predispositions play a key role either for successful coping (stress management, strategies, skills) or for maladjustement.

“The explosion of interest in the various emotions is a very important and desirable change of fashion in the social and biological sciences, from an emphasis on a valuable but limited concept, stress, to a broad, richer and clinically more useful concept, emotion”.

A move from hypophysis to cortexA move from hypophysis to cortexA cognitive – motivational – relational theoryA cognitive – motivational – relational theory

Lazarus R.Lazarus R. : : Psychological stress and the coping process, 1966, McGraw-Hill, NY.Psychological stress and the coping process, 1966, McGraw-Hill, NY.

- Selye’s concept stands largely in the position of having been neither refuted nor confirmed experimentally.

- There is an apparent incompatibility of the GAS with the concept of homeostasis ; the three phases have not been re-evaluated in terms of associated levels of pituitary-adrenal cortical activity.

- A noteworthy aspect of Selye’s observation was that the anterior pituitary, while receiving virtually no significant neural input, appeared nonetheles to be influenced by the CNS.

- The well established implication of psychoendocrine research for endocrine regulation seemed not to be appreciated.

John W. MasonA re-evaluation of the concept of “non specificity”

in stress theory.J. Psychiat. Res., 1971, 88, 323-333

Mason’s PrinciplesMason’s Principles

- Psychological influences are among the most potent natural stimuli known to affect the pituitary-adrenal cortical activity, in particular novelty, uncertainty, unpredictability.

- There are marked individual differences in the response to any particular situation. The response depends on how that individual interprets this particular situation, what are his goals, and what are his expectancies and defence mechanisms.

- The measurement of pituitary-adrenal activity offers a particularly interesting, sensitive, and objective index of the psychological or emotional state of the individual.

“To all of us that have been involved in this type of research the Mason’s principles are amazingly representative of what we believe to be consensus”. A. Ursin, 1998.

Weiss J.M., 1972

• Both stress and arousal are abstractions or hypothetical constructs that clarify independent/dependent variable relationships ; they are analogous concepts.

• The pituitary-adrenal system is a part of the arousal system and is an extremely reliable and sensitive measure of arousal as well as stress.

• The construction of a psychoendocrine model should begin with an identification and description of the cognitive mechanisms involved.

• The major stimulations of arousal are novelty, uncertainty, and conflict. The cognitive operation common to all these independent variables is one of comparison and appraisal.

J.W. HENNESY and S. LEVINE (1979)J.W. HENNESY and S. LEVINE (1979)

Stress, Arousal and the Pituitary System : a Psychoendocrine Hypothesis. Stress, Arousal and the Pituitary System : a Psychoendocrine Hypothesis. Prog. Psychobiol. Physiol. Psychol., 1979, Prog. Psychobiol. Physiol. Psychol., 1979, 88, 133-178., 133-178.

Adapted from A.R. Kagan and L. Levi, 1974

• 2 types :- Mineralocorticoid (MRs)

Bind corticosterone-cortisol with high affinity- Glucocorticoid (GRs) : 1/10 the affinity of MRS

• Hippocampus : both ; most other regions : GRs.

• At rest : MRs already occupied when corticosteroid levels are low (GRs partially occupied).

• Stress : GRs fully activated.

• Activation of MRs : guarantee a stable background of neuronal firing, contributes to its « proactive » role in maintaining homeostasis.

• Activation of GRs (+MRs) : enhanced calcium influx, stronger spike-frequency accomodation and marked responses to biogenic amines (in final, a reactive mode of recovery).

– Reul JMHM, de Kloet ER. Endocrinology, 1985, 117, 2505-25011.– Joels M, de Kloet ER. Science, 1989, 245, 1502-1565.– De Kloet ER. Front. Neuroendocrinol., 1991, 12, 95-164.

Corticosteroid receptors in the brainCorticosteroid receptors in the brain

From homeostasis to pathology

Homeostasis_______________

Allostasis_______________

Pathology_____________

• Normal set point

• Physiologic equilibrium

• No anticipation of demand

• No adjustment based on history

• Adjustment carries no price

• No pathology

• Changing set point

• Compensated equilibrium

• Anticipation of demand

• Adjustment based on history

• Adjustment and acco- modation carry a price

• Leads to pathology

• Breakdown

• Outside equilibrium

• No anticipation anymore

• No adjustment possible

• External interventions needed : treatments

• Disease; epigenetic mechanisms

1990-20001990-2000PROFOUND CHANGES IN AMERICAN MEDICINE : PROFOUND CHANGES IN AMERICAN MEDICINE :

DELETERIOUS SOCIETIES AND HEALTHDELETERIOUS SOCIETIES AND HEALTH————

• A. Sen : A. Sen : Inequality reexamined, Inequality reexamined, 1992.1992.• S. Wolf, J.G. Bruhn : S. Wolf, J.G. Bruhn : The Power of ClanThe Power of Clan, 1998., 1998.• N. Adler, M. Marmot, B.S. Mc Ewen, J. Stewart : N. Adler, M. Marmot, B.S. Mc Ewen, J. Stewart : Socio-economic Socio-economic Status and Health in Industrial Nations. Social, Psychological Status and Health in Industrial Nations. Social, Psychological

and Biological Pathwaysand Biological Pathways, 1999., 1999.• M. D. Glantz, J. L. Johnson : M. D. Glantz, J. L. Johnson : Resilience and Development : Positive LifeResilience and Development : Positive Life AdaptationsAdaptations, 1999., 1999.• M. Marmot, R.G. Wilkinson : M. Marmot, R.G. Wilkinson : Social determinants of HealthSocial determinants of Health, 1999., 1999.• R. Wilkinson : R. Wilkinson : Unhealthy SocietiesUnhealthy Societies, , The afflictions of inequalities, 1The afflictions of inequalities, 1999.999.• D.G. Myers : D.G. Myers : The American ParadoxThe American Paradox, 2000, 2000..• R.D. Putman : R.D. Putman : Bowling alone, Bowling alone, 2000.2000.• Institute of Medecine : Institute of Medecine : Health and Behavior. The Interplay of Biological, Health and Behavior. The Interplay of Biological,

Behavioral, and Societal Influences,Behavioral, and Societal Influences, 2001. 2001.• I. Kawachi, B.P. Kennedy : The Health of Nations : I. Kawachi, B.P. Kennedy : The Health of Nations : Why inequality is Harmful to Why inequality is Harmful to your Healthyour Health, 2002., 2002.• I. Kawachi, L.F. Berkman : I. Kawachi, L.F. Berkman : Neighborhoods and health, Neighborhoods and health, 2003.2003.• M. Marmot, R.G. Wilkinson : M. Marmot, R.G. Wilkinson : Social determinants of HealthSocial determinants of Health : The solid facts: The solid facts,, 2003.2003.• M. Marmot : Status syndrome : M. Marmot : Status syndrome : How your social standing directly affectsHow your social standing directly affects your health and life expectancyyour health and life expectancy, 2004., 2004.

Social capital refers to aspects of social relationships, levels of trust among citizens norms of reciprocity and mutual aids, which act as moral resources for individuals and facilitate collective action for mutual benefit. It represents the resources available to individuals through their social affiliations and membership in community organizations. It inheres in the structure and quality of social relationships among individuals, norms and sanctions concerning the way that people behave toward one another.

Social capital

From : M. Marmot, 2004

- “Social exclusion and social rejection decreases pro-social behavior, interfere with emotional responses, impairs the capacity for empathic understanding of others”.

- “The social and physical pains share common physiological mechanisms. Moreover rejected people have impaired self-regulation abilities”.

J.M. Twenge et al, J. Person. Social Psychol., 2007, 92, 56-66

G. Mac Donald, M.R. Leary, Psychol. Bull., 2005, 131, 202-223

R.F. Beaumeister et al, J. Person. Social Psychol., 2005, 88, 589-604

Social rejection and social exclusion

Low socio-economic environments, poor subjective social status and

position on the social ladder, social inequalities, are associated with increased

stress processes which, in turn, predict an increased frequency of diseases,

behavioral pathologies and psychopathological conditions. Earlier the

deleterious environments appear during infancy, more profound are the

development of personality traits such as hostility and hopelessness.

Epigenetic alterations of gene expression in selected brain regions are

produced (prefrontal cortex, amygdala, hippocampus) that regulate cognitive-

emotional responses to stress. These effects define an increased vulnerability

for poor health, and psychopathology over the life span.

Social pathologies

Adapted from N.M. Cameron et al,

“ The programming of individual differences in defensive responses and reproductive strategies in the rat through variations in maternal care ”,

Neurosci. Biobehav. Rev., 2005, 29, 843-865

BIOBEHAVIORAL DISORDERS

... drug use and various addiction

… impulse control disorders

... eating disorders

... violence and personality disorders

... disordered affective states and chronic anxiety

… suicide

… child psychopathology and behavioral disturbances

... hyperactivity and attentional deficits

... obsessive-compulsive states

… chronic fatigue

… sleep problems

… muscular-skeletal pains

etc... etc...

GeneticBackground Development

Deleterious(or protective)

Perinatal

Environments

EpigeneticMechanisms

VulnerablePhenotype

Allostatic state

Life events

Trauma

Unhealthy society

State / Trait

BiobehavioralDisorders

Drug abuse

Psychopathology

SystemicDiseases

Long-termMaladaptation

Coping

Social support

Resilience

After the completion of my last effort to define stress (Levine and Ursin, 1991), I made myself the promise that I would never again engage in what I consider a futile exercise.

S. Levine 2005, p. 3 (Handbook of stress and the brain, T. Steckler et al, ed.)

Robin Hood Index : the proportion of aggregate income that must be redistributed from rich to poor households in order to attain perfect equality of incomes across households

From Kawachi and KennedyThe Health of Nations. 2002

From Kawachi and KennedyThe Health of Nations. 2002

From Kawachi and KennedyThe Health of Nations. 2002

From Kaplan et al,Brit. Med. Jl. 1996

“We define stress as state of disharmony, or threatened homeostasis. The adaptive response can be specific or can be generalized and more specific”.

Chrousos G.P. and Gold P.W., JAMA, 1992, 267, 1244-1252

“Stress may be defined as a real or interpreted threat to the physiological or psychological integrity of an individual that results in physiological and/or behavioral responses. In biomedicine, stress often refers to situations in which adrenal glucocorticoids and catecholamines are elevated because of an experience”.

in disturbance of homeostasis and reinstatement of the balance B. Mc Ewen, 2000, pp. 588-649, (Encyclopedia of stress, Fink G. ed.)

“The major problem with the concept of stress is that we are confronted with a composite, multidimensional concept. All existing definitions include some components. We can identify three main subclasses. These subclasses can be identify as the input (stress stimuli), the processing systems, including the subjective experience of stress and the output (stress responses). One basic difficulty is that these subclasses interact, as a complex system with feedback and control loops, no less but no more complicated than any other of the body’s self-regulated systems. This system affects many other biological processes and may function as a common alarm and drive system, whenever there is a real or apparent challenge to the self-regulating systems of the organism”.

S. Levine and H. Ursin, 1991, p. 3-21, (Stress Neurobiology and Neuroendocrine M.R. Brown and G.F. Koob eds.)