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Memorial Lecture: The Psychosomatic Approach to Individual Susceptibility to Disease
GASTROENTEROLOGY 67:1085-1093, 1974 Copyright© 1974 by The Willia ms & Wilkins Co.
Vol. 67 , No.6
Printed in U.S.A.
ALIMENTARY TRACT
MEMORIAL LECTURE: THE PSYCHOSOMATIC APPROACH TO INDIVIDUAL SUSCEPTIBILITY TO DISEASE GEORGE L. ENGEL, M.D.
Departments of Psychiatry and Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, N ew York
I am honored to be asked to deliver this Annual Memorial Lecture and gratified that this Association considers psychosomatic research of sufficient interest to justify this invitation. Gastroenterology has been a particularly fruitful field for psychosomatic research, the earliest studies dating back to Beaumont's observations on Alexis St. Martin in the 1820's. Since then many have studied the links between emotions, gastrointestinal function, and disease, but the claims of clinical investigators that previous experience, personality, and current life changes are significant determinants of disease susceptibility have been difficult to prove. The development of animal models for psychosomatic research marks a major advance, for it now becomes possible to investigate some of these issues in ways not possible with human subjects. In my presentation today I propose to consider immobilization-induced gastric lesions in rats as a paradigm for elaborating the complementarity between the clinical and experimental approaches to the study of the role of psychosomatic factors Received August 2, 1974. Presented as the Memorial Lecture at the Annual Meeting of the American Gastroenterological Association in San Francisco, May 25, 1974. Address requests for reprints to: Dr. George L. Engel, Department of Psychiatry, University of Rochester School of Medicine, 260 Crittenden Boulevard, Rochester, New York 14642. This study was supported by grants from the United States Public Health Service (MH 14151 and MH 11668), and the San Francisco Foundation . Dr. Engel is a Career Research Awardee of The United States Public Health Service .
in individual susceptibility to disease. By viewing such a model, first as an experimentalist and then as a clinician, I hope to suggest some new directions and perspectives for psychosomatic research in gastroenterology. In so doing I want to emphasize that the validity of the thesis being put forward is no way dependent on any relationship between the rat gastric lesions and human peptic ulcer disease. To begin we must first define the basic tasks of research in psychosomatic medicine . According to Ader, 1• 2 psychosomatic research examines the role of psychosocial variables in altering individual susceptibility to disease. Note the phraseology and emphasis. It deals not with the role of psychosocial factors in causing disease, but in altering individual susceptibility to disease. It asks why, when exposed to similar pathogenic influences, some individuals manifest disease and others do not. More specifically, it investigates the psychophysiological interactions which might be responsible for such variability in disease susceptibility. In more dynamic terms, it investigates how psychological experiences affect the development of the individual, how such experiences may become translated into altered physiological states, and how, in turn, the interaction of such altered states with physiological and biochemical responses independently induced by pathogenic stimuli determine the ultimate disease susceptibility of that individual. Whether in the clinic or in the laboratory, the primary focus of psychosomatic research is on the individual. Psychosomatic theory postulates that
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" given the presence of potentially pathogenic stimulation, conditions would be optimal for the manifestation of disease if there exists a high biologic disposition, the individual's personality structure is such that some change in the psychosocial environment is perceived as 'stressful' and the individual is unable to cope with the altered environmental circumstances. " 2 Let us now turn to Ader's work 3 on immobilization-induced gastric lesions in the rat as a demonstration of how psychosocial and other variables may be experimentally manipulated to alter susceptibility to a single pathological process . If a rat is subjected long enough to a period of physical immobilization while deprived of food and water, it will develop erosions in the glandular portion of the stomach (fig. 1). The tendency to develop such lesions depends on the degree and the duration of the immobilization. Virtually 100% rats will develop lesions within 24 hr if the restraining cage is less than 200 cc in volume. •. 5 Periods of immobilization of less than 24 hr or in cages of larger volume thus provide conditions under which the influence of other variables can be examined. For example, the 25% of fully restrained animals that develop lesions after 6 hr tend to be the ones that have the higher basal plasma pepsinogen levels, reminiscent of the findings with duodenal ulcer in man. 6 ' 9 But not all animals with high pepsinogen levels develop lesions under such conditions; in fact, lesions may develop within 6 hr in some animals with relatively low pepsinogen levels. Hence, while on a statistical basis a high pepsinogen level may be accepted as a biological indicator of an increased vulernability, it is
neither a necessary nor a sufficient condition for lesion development. But why should animals with similar biological predisposition, at least as ref1ected by plasma pepsinogen levels, nontheless differ in their susceptibility under the same experimental conditions? Many variables might be considered . For one, it could be that rats, like humans, differ in how stressful they perceive an environmental event to be, in this case, immobilization. Indeed, they might even appraise immobilization differently at different times, perhaps as a function of their biological condition at the time. Ader' 0 reasoned that just as an animal 's response to food deprivation differs depending on how recently it has been fed, so too the reaction to immobilization might vary depending on the animal's position in its 24-hr activity cycle. Typically, rats, nocturnal animals, are active for the 12 night hours and quiescent for 12 daytime hours (fig. 2) . Could immobilization at the peak of activity be more disturbing than immobilization during the trough of inactivity? This indeed proved to be the case; gastric lesions occurred significantly more often among rats immobilized during the peak of their activity. Clearly a biologically regulated internal state of the animal inf1uenced how it experienced a specific environmental circumstance and correspondingly modified susceptibility to
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CLOCK HOURS 2. Representative sa mple of activity obtained from rat housed in activity-wheel cage. Arrows indicate tim es at which anim al mi ght be subjected to immobili zation if imposed at beginning of peak (P) or trough (T) in 24-hr acti vity cycle. Published with permission from Robert Ader and Psy chosomati c Medicine (see ref. 10). FIG .
FIG . 1. Wire mesh restraining cage to immobilize rats.
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PSYCHOSOMATIC APPROACH TO DISEASE
a disease associated with that circumstance. But gastric lesions do not develop in all rats immobilized during their active phase and occasionally even develop in animals in the inactive phase. Patently other factors are involved. Combining plasma pepsinogen levels and status in the activity cycle no doubt would account for more of the variance, but by no means all. The biological predisposition, as represented by plasma pepsinogen levels, and the biologically regulated internal state, as represented by the activity cycle,. still are not decisive determinants. In an elaborate series of experiments, Ader 2 • 3 then proceeded to show that a variety of early life experiences and socioenvironmental factors , acting singly or in interaction, are also influential in determining the adult animal's susceptibility to gastric lesions when immobilized. For example, rats raised in groups proved to be more susceptible to the effects of restraint than those raised alone. 11 Contrariwise, handling the animals during the preweaning period rendered them less susceptible as adults. 11 Even a prenatal effect was discovered. Handling the pregnant female rendered her offsprings more susceptible to ulcer formation when immobilized as adults, an effect evident only when the offsprings were subsequently individually housed, not when group housed. 12 And finally, by breeding rats selectively for high plasma pepsinogen and lesion susceptibility Ader 13 was able to demonstrate that varying early life experience or current socioenvironmental conditions still could modify the tendency to develop gastric lesions, even in the face of this presumably preponderant genetic effect. For example, handling in the preweaning period increases subsequent resistance to immobilization-induced gastric lesions in the genically bred high pepsinogen lesion susceptible population, just as it does in the ordinarily bred laboratory rat. It is not necessary to retain all these details. It is enough to recognize the compelling evidence that manipulation of the rat's prenatal, postnatal, early, previous,
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and current experience, all and each, can significantly influence the susceptibility to a single disease process, even among ani mals bred for high vulnerability to that disease. Similar findings have now been forthcoming from many laboratories documentating such effects in relation to a wide variety of disease states induced experimentally in animals-infections, neoplasms, metabolic disorders, vascular disease, drug reactions, etc. Further it has been discovered that the differential effects on disease susceptibility of these various manipulations are not always in the same direction. The same manipulation, such as handling or housing or electric shock, not only may influence susceptibility differently with different diseases, but also the effect on the same disease may differ depending on when in the animal's life the manipulation was carried out. For example, mortality rate to a transplanted tumor is decreased if the rat is handled during the first 10 days of life, but it is not influenced if the handling is continued throughout the 21-day preweaning period. 14 • 15 Table 1 illustrates this variability of effect of a single socioenvironmental manipulation, namely, group versus individual housing, on the response to 16 different pathogenic factors. In sum , the direction of any effect observed depends on the type and the timing of the manipulation (that is, the physiological changes induced) and the nature of the disease (that is, the physiological changes elicited by the pathogenic stimulus) . The interaction between these determines disease susceptibility. 2 This important discovery means that to define the bases for individual susceptibility to any disease, investigators must systematically explore the nature of the physiological changes induced by each of these various manipulations and elucidate their interaction with the effects of the pathogenic stimulus in question. It is no longer scientifically justified arbitrarily to designate environmental manipulations as "stressful" since what might enhance susceptibility to one disease may ameliorate it with another. This perspective underscores the
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Differential housing and susceptibility to pathogenic stimulation Measure
Spontaneous mammary tumors Spontaneous mammary tumors Spontaneous leukemia Spontaneous leukemia Walker 256 carcinosarcoma Human adenocarcinoma Trichinosis Alloxan diabetes Rumenal ulcers Rumenal ulcers Gastric erosions Gastric erosions Anaphylactic shock Hypertension Spontaneous convulsions Audiogenic seizures X-irradiation X-irradiation Encephalomyocarditis virus Amphetamine toxicity Amphetamine toxicity Amphetamine toxicity Isoproterenol toxicity
Susceptibility
Group < alone Group < alone Group < alone No difference No difference Group < alone Group > alone Group > alone Group < alone No difference Group > alone Group > alone Group > alone Group > alone Group < alone No difference Group > alone Group > alone Group < alone Group > alone Group > alone Group > alone Group < alone
Adapted from Ader, R: The influence of psychological factors on disease susceptibility in animals. In Husbandry of Laboratory Animals. Edited by ML Conality. New York, Academic Press , 1967. (For references refer to original.)
indispensability of a knowledge of the life history of the individual for understanding of disease susceptibility. And it also challenges us to wonder how on earth such effects could come about. What is it about prenatal handling or differential housing early in life, for example, which later in life modifies how the stomach responds when the rat is immobilized? Certainly the most attractive perspective is that these early experiences influence in some way how the central nervous system responds to subsequent environmental inputs. To a large extent, the biological and psychological uniqueness of the individual reflects the variability of his total life experience and the capability of his nervous system to record and respond to this experience. The nervous system continuously monitors input from the internal environment of the body and the external environment of people and things, ap-
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praises these in terms of what has gone before, and mobilizes existing or devises new response and regulatory systems, all in the service of survival, growth, and development of the individual in relation to its social organization. This capability to differentiate the novel from the familiar and to assign meaning to each in terms of potential benefit or danger is crucial in establishing the role of past and current psychosocial variables in the ultimate susceptibility to disease. From the perspective of the clinician these neural functions of appraisal and response can be operationally conceptualized in behavioral and psychological terms. For the clinician, the basic means of study is clinical observation. 16 • 17 By means of the interview, he elicits the nature and extent of the patient's awareness of changes in his body, in his mental state, or in his interpersonal and social environments. Through direct observation, the physician notes the behavior that reflects the patient's reactions to such changes. What the patient perceives and reacts to is a function both of his state at the moment and of his past history. What actually emerges into consciousness and is reported or is reflected in manifest behavior constitute but a minor fraction of the total monitoring, appraisal, and response to bodily or environmental changes that are being carried on continuously by the nervous system. The clinician works with what he can observe and with what the patient or others can report about changes from his customary fuctioning. It is from such information that the physician establishes that his patient is ill and identifies factors in his life situation, in his past experience, or in his life style which may be associated with the time of onset or the nature of the illness. From such clinical data have evolved the familiar psychosomatic formulations about psychosocial factors implicated in individual susceptibility to disease. The validity of hypotheses derived from such data can be tested in a variety of ways, one of which is recourse to animal studies. But use of animal models to validate clinically derived hypotheses is not likely to b~ productive unless the experi-
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mentalist and the clinician appreciate the complementarity of their respective approaches and search for behavioral dimensions that allow for generalizations to both populations, the animal and the human. The problem is, what can we learn from rats that might apply to humans, and vice versa? Let us test this thesis by imagining what it would be like to approach immobilization-induced gastric lesions in rats as clinicians rather than experimentalists. This would require us to act as consultants to a group of rats complaining of " ulcers. " As clinical scientists we would not be satisfied simply to make the diagnosis and institute treatment. We would want to know why these particular rats got sick when they did and why they developed ulcers rather than some other disease. We would want to learn what renders one rat vulnerable and another resistant, or the same rat vulnerable at one time and not at another. How else to begin but with careful interviews of many rats with ulcer disease? Quickly enough we would learn that some rats were having stomach trouble for the first time, while others had already had several attacks. Inquiry into the circumstances preceding onset of symptoms would lead some rats to recall that some of the episodes had occurred when for some reason they had gotten physically entangled or entrapped and for several hours could not extricate themselves. But other rats might reject such an association; they could recall similar occasions when no symptoms developed. Analysis of such variations would reveal interesting facts. Some rats might realize that entrapment was much less likely to evoke gastric symptoms if they had recently eaten. Virtually all the rats would agree that development of symptoms becomes more certain the longer it takes to escape, especially if the degree of restraint is severe. Some realize the risk of illness is greater in daytime than at night and they might speculate that perhaps sleeping is protective. A few rats make no association; as far as they are concerned symptoms come "out of the blue." An occasional rat may even claim never to have stomach trouble when restrained . Not
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only that, they may even relish the challenge of figuring out how to extricate themselves. But those animals might report other conditons under which ulcers may develop. At this point, let us take stock of where we stand in our clinical investigation . As with clinical studies of human patients, no finding emerges that is invariant or exclusive for this ulcer disease. Rats seem to vary in their susceptibility to disease, some developing it with ease and others never at all. And even the most susceptible rat reveals inconsistencies. On the other hand, a number of items turn up repeatedly, such as high incidence in some families, an association with certain patterns of infant rearing, and, most particularly, a relationship to immobilization as a precipitating event. This last is especially intriguing, the more so in light of the exceptions. Some determinants appear to be quantitative, as duration and degree. Other associations suggest physiological factors , as the protective action of food. Still others indicate the influence of a basic psychobiological state, e.g., the variations within the 24-hr activity cycle. But there remain variations where no significant association is yet apparent. Yet the conclusion seems inescapable that there is something about immobilization that has special implication for the rat. If we could only find out what it is! Such knowledge might lead to a generalization which would make understandable other circumstances associated with ulcer development, and hence to a more specific etiological principle. For the clinician the logical approach would be to ask his rat patients what immobilization means to them. And if rats could speak my guess is we would get such answers as, " Why, that's an awful thing to happen. We rats have to be free to move about. Any rats knows that! I can't tell you why, it's just so. There's a terrible feeling that something dreadful is going to happen. The worst part is not knowing what's happening nor what to do about it. Nothing works . You feel so frustrated, so helpless, sometimes you just have to give up ." Of course not all rats would feel that way. Some would scoff at our patients. "They
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just can't take it, that's all. For me it's a challenge, I enjoy figuring out how to extricate myself." Now of course we hear nothing of the sort from rats, but we do hear such accounts from patients. Many tell us that for a period of time before falling ill they had undergone some life change that had evoked uncertainly, frustration, feelings of impotence, depression, futility, or giving up. 18 Could these be the psychological equivalents for the human of physical immobilization for the rat? Such an hypothesis is in fact testable. Jay Weiss 19 of The Rockefeller University hypothesized that the inability of the immobilized rat to do anything about his situation is the significant factor in rendering it more susceptible to gastric lesions. Hence, he devised experiments which tested the effect of providing the immobilized animals with degrees of control over their situation. 19 He did this by placing rats in restraining cages of such dimensions that only minimal gastric lesioning developed even after 21 hr (fig. 3). This became the invariant condition for all animals.
FIG. 3. Experimental apparatus showing the avoidance-escape (foreground), yoked (center), and nonshock (rear) subjects. In addition to the tone preceding the shock, the platform on which the animals remained during the experimental session was vibrated (by means of a cam-see center, left of figure) as part of the warning signal. Published with permission from J. M. Weiss and the Ciba Foundation Symposium 8 (new serie s) Elsevier-Excerpta Medica, Amsterdam (see ref. 19).
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Two of the rats periodically received an electric shock delivered to the tail. But 1 of the rats was given an option. It could avoid or escape the shock by depressing a panel with its nose. For comparison, the 2nd rat was yoked to the 1st so that it received a shock each time the 1st did . It too had a panel to depress, but it was not connected with the circuit. Thus, it had no control over whether or not it received shock. The 3rd rat, similarly restrained, never received shock. A warning of impending shock was provided by a tone which sounded for 10 sec before each shock. By depressing the panel the 1st rat could interrupt the tone and thereby spare itself and its yoked partner a shock. If it failed to respond to the tone by panel-pressing, the flow of current began and continued until terminated by the 1st rat touching the panel. Under such conditions both the rat and its yoked partner received the shock. Thus, the 1st animal had control over the number of shocks it received . In contrast, its yoked partner received exactly the same number of shocks, but it could play no part in either preventing or terminating them. Figure 4 shows that gastric ulceration was greatest in the "helpless" (yoked) animals who had no way of influencing whether or not they got shock. The animals who had a measure of control developed more ulceration than the animals that were merely restrained without ever receiving shock, but much less than their yoked partners. Clearly, electric shock itself was not the main noxious factor, for both animals had received the same number of shocks. The important variable was what the animal could do about the shock. Other experiments refined this observation further. The most effective protection against ulcerogenesis was afforded by devising situations in which the animal received reliable feedback information that what it was doing was the right thing to avoid shock. Figure 5 contrasts the degree of ulcerogenesis in avoidance rats which received no tone warning of the regularly recurring shock with those that were provided a brief tone immediately upon performing an activity that successfully avoided shock. Such a
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Groups FIG . 4. The median of t he total len gth of gastric lesions for the nonshock, avoidance-esca pe, and yoked groups. Lesions in each subject were measured (in millimeters) and the tot al for eac h subject was computed ; the median found in eac h grou p is shown . Also, it can be seen that a small a mount of ulceration developed in nonshock anim als, whi ch resulted from the prolonged restraint and food and water deprivation during the experimental procedure. Published with permission from J. M. Weiss and the Ciba Founda tion Symposium 8 (new series ) ElsevierExcerpta Medica, Amsterdam (see ref. 19).
tone effectively reinforced the animal 's ability to know exactly what the correct things were to do to avoid shock, and thereby to master the situation. Under such conditions, even though the rat periodically neglected to press the lever and hence received a shock, ulcer formation was reduced to a leve l identical with that occurring in the control rats who never received shock. In contrast, the avoidance rats not warned by the tone had almost as much ulceration as their yoked partners . In sum , the more the animal could relate its own· activity >to avoiding shock, the more predictive its behavior, the less likely was it to develop ulceration . In contrast, the yoked animal, whose efforts produced no relevant feedback, who had no way to cope, developed the most ulceration . Such experiments move us closer to characterizing at least one of the psychological factors contributing to lowered resistance to disease , namely, loss of the
ability of the organism to predict and maintain control over its environment. To be without the information and/or the psychological and behavioral resources necessary to cope effectively with a particular life circumstance appears to be a highly significant variable. Under such conditions, the organism typically alternates between activity and inactivity, the first reflecting efforts to maintain or reestablish control, the second waiting or giving up. If its efforts succeed, or if circumstances change soon enough, illness may be averted. But the longer such cycles of struggling and inactivity go on, the greater the risk of morbidity. In this model we hypothesize two final common pathways, fruitless struggling and giving up , each with different psychophysiological implications and biochemical concomitants. ' 8 • 20 We suggest these interact differently with different pathogenic preconditions, and hence constitute variables underlying differential susceptibility to disease in different individuals. For one 5 .0
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FIG . 5. On t he left is shown the media n total length of gastric lesions which developed in nonshock, avoidance-esca pe, and yoked groups in a stress condi tion in whi ch shock was not preceded by•a warning signal. On the right is shown the amoun t of gastri c lesions whi ch developed in the same groups exposed to the sa me conditions, except that a brief feedb ack signal (tone) was given to the subjects whenever an avoid ance-esca pe response was made. Published with permission from J . M. Weiss and the Ciba Found a tion Symposium 8 (n ew series ) Elsevier-Excerpta Medi ca, Amsterd am (see ref. 19) .
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individual or for one disease process the struggling phase may be the more pathogen ic, for another the giving up phase. Previous life experiences, such as handling, differential housing, and others already cited, could then be seen as influencing the set or readiness to activate one or another final common pathway in response to current life circumstances, as well as inducing in their own right sustained or permanent phy"siological or biochemical changes, e.g., enzyme induction or organ hyperfunction. Interactions among these various processes and with preexisting or concurrent pathogenic predispositions could then determine the occurrence and nature of disease development. An ingenious investigator should have no difficulty in devising experiments to test the validity of such a formulation. The concept of final common pathways to characterize the outcome of diverse life events also provides an operationally useful way of defining psychological states that appear to be associated with increased morbidity in man and in animals. Implicit in such a perspective is the meaning to the organism of the particular life event or circumstance, a meaning in part determined by what has gone on before in the life of that organism. Thus, the extent to which restraint or shock for the rat, or bereavement or promotion for the human, provoke fruitless struggle or giving up is a factor determining the probability of disease onset, provided the necessary predisposing pathogenic factors also are present at the time. We can now begin to appreciate what is common to the epidemiological studies that show that persons suffering bereavement or facing a job loss have a higher morbidity and mortality 2 '- 23 ; to the retrospective and prospective studies that show increased incidence of illness among individuals reporting many life changes during the preceding months' 8 • 2 4 - 26 ; and to the finding that persons already ill report a high incidence of psychological giving up in the period preceding disease onset. 18 These all doubtless include instances of final common pathways, some not yet elucidated. The importance of the classical
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psychosomatic studies which associated specific or typical conflict situations with particular diseases now becomes obvious. These delineated individual psychological vulnerabilities and thereby defined the types of life circumstances most likely to be threatening for such persons, and hence to initiate the sequence of responses that might culminate in a final common pathway and disease onset. It is popular these days to dismiss such concepts of so-called psychosomatic specificity, but everything in my experience over 30 years has only served to reinforce my conviction of their validity. Precise and detailed knowledge of the patient's psychological strengths and vulnerabilities clearly is an important guide for prevention and treatment. In conclusion may I say that never before have the challenges and opportunities for psychosomatic research been greater. Indeed , the time has long passed when anyone seriously concerned with the determinants of individual susceptibility to disease can any longer afford to ignore the role of psychological variables, so brilliantly demonstrated in the experimental work of Ader, Weiss, and others. Least of all can the clinician, if he is genuinely devoted to prevention of disease as well as to the care of his patient. Clinicians and clinical investigators now must begin to apply the same rigor in characterizing and analyzing the psychological status and backgrounds of their patients that they customarily apply to physiological data. Terms such as "stress ," "tension," "anxieties," "emotional upset," and the like, have about as much resolving power today as did "fevers," "catarrh," or "dropsy" in bygone eras. For physicians to continue to retard their knowledge and understanding of the psychosocial by retention of inexact terms is simply no longer acceptable. For the experimentalists the prospects are exciting indeed . With the definition of the problems to be tackled provided by the type of work cited here and the availability of a wide range of new behavioral, physiological, and biochemical techniques, the prospects are bright at last of elucidating the nature of the interactions underlying
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costerone levels, and susceptibility to gastric erosions. Psychosom Med 30:277-286, 1968 13. Ader R: Effects of early experience and differential housing on susceptibility to gastric erosions in lesion-susceptible rats. Psychosom Med 32:569-580, 1970 14. Ader R, Friedman S : Differential early experiences and susceptibility to transplanted tumor in the rat. J Comp Physiol Psycho) 59:361-364, REFERENCES 1965 1. Ader R: The role of developmental factors in 15. Ader R, Friedman S: Social factors affecting emosusceptibility to disease. Psychiatry Med (in tionality and resistance to disease in animals. IV. press) Early separation from the mother and response 2. Ader R: Early experience and susceptibility to to a transplanted tumor in the rat. Psychosom disease: The case of gastric erosions. In Ethology Med 27:119-122, 1965 and Development. Edited by SA Barnett. Clinics 16. Engel GL: Clinical observation. The neglected bain Developmental Medicine no. 47, London, sic method of medicine. JAMA 192:849- 852, 1965 Spastics International Medical Publications with 17. Engel GL: Enduring attributes of medicine relevant to the education of the physician. Ann InHeinemann Medical Books, 1973, p 37-51 3. Ader R: Experimentally induced gastric lesions. tern Med 78:587- 593, 1973 Results and implications of studies in animals. In 18. Schmale AH: Giving up as a final common pathway to changes in health . In Psychosocial Duodenal Ulcer. Advances in Psychosomatic Medicine, vol 6. Edited by H Weiner. New York, Aspects of Physical Illness . Advances in PsyBasel, S Karger, 1971, p 1-39 chosomatic Medicine, vol 8. Edited by ZJ Lipow4. Bonfils S, Liefooghe G, Gelle X, et al: 'Ulcere ski. New York, Basel, S Karger. 1972, p 20- 40 19. Weiss JM : Influence of psychological variables on experimental du contrainte du rat blanc. III. stress-induced pathology . In Physiology, Emotion Mise en evidence et analyse du role de certains and Psychosomatic Illness . Edited by R Porter, J facteurs psychologiques. Rev Franc Clin Bioi Knight. Ciba Foundation Symposium 8 (new 5:571-581, 1960 series). Amsterdam , Elsevier-Excerpta Medica, 5. Brodie DA, Hansom HM : A study of the factors 1972, p 253-280 involved in the production of gastric ulcers by the restraint technique. Gastroenterology 38:353- 20. Engel GL, Schmale AH : Conservation-withdrawal: a primary regulatory process for orga360, 1960 nismic homeostasis. In Physiology, Emotion and 6. Ader R: Plasma pepsinogen level as a predictor of Psychosomatic Illness. Edited by R Porter, J susceptibility to gastric erosions in the rat. PsyKnight. Ciba Foundation Symposium 8 (new sechosom Med 25:221-232, 1963 ries). Amsterdam, Elsevier-Excerpta Medica, 7. Ader R : Plasma pepsinogen level in rat and man. 1972, p 57- 87 Psychosom Med 25: 218- 220, 1963 21. Rees WD, Lutkins SG : Mortality of bereavement. 8. Mirsky lA, Futterman P, Kaplan S : Blood Br Med J 4:13, 1967 plasma pepsinogen. I I. The activity of the plasma 22 . Parkes CM: Bereavement, Studies of Grief in from "normal" subjects, patients with duodenal Adult Life. New York, International Universities ulcer and patients with pernicious anemia. J Lab Press, 1972 Clin Med 40:188-199, 1952 9. Mirsky lA: Physiologic, psychologic and social 23 . Jenkins CD: Social and epidemiologic factors in psychosomatic disease. Psychiatr Ann 2:8-21, determinants in the etiology of peptic ulcer. Am J 1972 Dig Dis 3:285-31 3, 1958 10. Ader, R: Behavioral and physiological rhythms 24 . Thurlow HJ : Illness in relation to life situation and sick-role tendency. J Psychosom Res and the development of gastric erosions in the 15:73-88, 1971 rat. Psychosom Med 29:345-353, 1967 11. Ader R : Effects of early experience and differ- 25. Rahe RH, Mahan JL, Arthur RJ: Prediction of near-future health change from subjects' precedential housing on behavior and susceptibility to ing life changes. Psychosom Res 14:401-406, 1970 gastric erosions in the rat. J Comp Physiol Psy26. Rahe RH : Subjects' recent life changes and their cho) 60:233-238, 1965 near-future illness reports. Ann Clin Res 4:1-16, 12. Ader R, Plaut SM: Effects of prenatal maternal handling on offspring emotionality, plasma corti1973
individual susceptibility to disease. Collaboration between clinicians and experimentalists in delineating the problems and devising appropriate means of testing hypotheses offers a promise never before available. Here lies the future of medicine.
Vol. 67 , No.6
Printed in U.S.A.
ALIMENTARY TRACT
MEMORIAL LECTURE: THE PSYCHOSOMATIC APPROACH TO INDIVIDUAL SUSCEPTIBILITY TO DISEASE GEORGE L. ENGEL, M.D.
Departments of Psychiatry and Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, N ew York
I am honored to be asked to deliver this Annual Memorial Lecture and gratified that this Association considers psychosomatic research of sufficient interest to justify this invitation. Gastroenterology has been a particularly fruitful field for psychosomatic research, the earliest studies dating back to Beaumont's observations on Alexis St. Martin in the 1820's. Since then many have studied the links between emotions, gastrointestinal function, and disease, but the claims of clinical investigators that previous experience, personality, and current life changes are significant determinants of disease susceptibility have been difficult to prove. The development of animal models for psychosomatic research marks a major advance, for it now becomes possible to investigate some of these issues in ways not possible with human subjects. In my presentation today I propose to consider immobilization-induced gastric lesions in rats as a paradigm for elaborating the complementarity between the clinical and experimental approaches to the study of the role of psychosomatic factors Received August 2, 1974. Presented as the Memorial Lecture at the Annual Meeting of the American Gastroenterological Association in San Francisco, May 25, 1974. Address requests for reprints to: Dr. George L. Engel, Department of Psychiatry, University of Rochester School of Medicine, 260 Crittenden Boulevard, Rochester, New York 14642. This study was supported by grants from the United States Public Health Service (MH 14151 and MH 11668), and the San Francisco Foundation . Dr. Engel is a Career Research Awardee of The United States Public Health Service .
in individual susceptibility to disease. By viewing such a model, first as an experimentalist and then as a clinician, I hope to suggest some new directions and perspectives for psychosomatic research in gastroenterology. In so doing I want to emphasize that the validity of the thesis being put forward is no way dependent on any relationship between the rat gastric lesions and human peptic ulcer disease. To begin we must first define the basic tasks of research in psychosomatic medicine . According to Ader, 1• 2 psychosomatic research examines the role of psychosocial variables in altering individual susceptibility to disease. Note the phraseology and emphasis. It deals not with the role of psychosocial factors in causing disease, but in altering individual susceptibility to disease. It asks why, when exposed to similar pathogenic influences, some individuals manifest disease and others do not. More specifically, it investigates the psychophysiological interactions which might be responsible for such variability in disease susceptibility. In more dynamic terms, it investigates how psychological experiences affect the development of the individual, how such experiences may become translated into altered physiological states, and how, in turn, the interaction of such altered states with physiological and biochemical responses independently induced by pathogenic stimuli determine the ultimate disease susceptibility of that individual. Whether in the clinic or in the laboratory, the primary focus of psychosomatic research is on the individual. Psychosomatic theory postulates that
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" given the presence of potentially pathogenic stimulation, conditions would be optimal for the manifestation of disease if there exists a high biologic disposition, the individual's personality structure is such that some change in the psychosocial environment is perceived as 'stressful' and the individual is unable to cope with the altered environmental circumstances. " 2 Let us now turn to Ader's work 3 on immobilization-induced gastric lesions in the rat as a demonstration of how psychosocial and other variables may be experimentally manipulated to alter susceptibility to a single pathological process . If a rat is subjected long enough to a period of physical immobilization while deprived of food and water, it will develop erosions in the glandular portion of the stomach (fig. 1). The tendency to develop such lesions depends on the degree and the duration of the immobilization. Virtually 100% rats will develop lesions within 24 hr if the restraining cage is less than 200 cc in volume. •. 5 Periods of immobilization of less than 24 hr or in cages of larger volume thus provide conditions under which the influence of other variables can be examined. For example, the 25% of fully restrained animals that develop lesions after 6 hr tend to be the ones that have the higher basal plasma pepsinogen levels, reminiscent of the findings with duodenal ulcer in man. 6 ' 9 But not all animals with high pepsinogen levels develop lesions under such conditions; in fact, lesions may develop within 6 hr in some animals with relatively low pepsinogen levels. Hence, while on a statistical basis a high pepsinogen level may be accepted as a biological indicator of an increased vulernability, it is
neither a necessary nor a sufficient condition for lesion development. But why should animals with similar biological predisposition, at least as ref1ected by plasma pepsinogen levels, nontheless differ in their susceptibility under the same experimental conditions? Many variables might be considered . For one, it could be that rats, like humans, differ in how stressful they perceive an environmental event to be, in this case, immobilization. Indeed, they might even appraise immobilization differently at different times, perhaps as a function of their biological condition at the time. Ader' 0 reasoned that just as an animal 's response to food deprivation differs depending on how recently it has been fed, so too the reaction to immobilization might vary depending on the animal's position in its 24-hr activity cycle. Typically, rats, nocturnal animals, are active for the 12 night hours and quiescent for 12 daytime hours (fig. 2) . Could immobilization at the peak of activity be more disturbing than immobilization during the trough of inactivity? This indeed proved to be the case; gastric lesions occurred significantly more often among rats immobilized during the peak of their activity. Clearly a biologically regulated internal state of the animal inf1uenced how it experienced a specific environmental circumstance and correspondingly modified susceptibility to
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CLOCK HOURS 2. Representative sa mple of activity obtained from rat housed in activity-wheel cage. Arrows indicate tim es at which anim al mi ght be subjected to immobili zation if imposed at beginning of peak (P) or trough (T) in 24-hr acti vity cycle. Published with permission from Robert Ader and Psy chosomati c Medicine (see ref. 10). FIG .
FIG . 1. Wire mesh restraining cage to immobilize rats.
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a disease associated with that circumstance. But gastric lesions do not develop in all rats immobilized during their active phase and occasionally even develop in animals in the inactive phase. Patently other factors are involved. Combining plasma pepsinogen levels and status in the activity cycle no doubt would account for more of the variance, but by no means all. The biological predisposition, as represented by plasma pepsinogen levels, and the biologically regulated internal state, as represented by the activity cycle,. still are not decisive determinants. In an elaborate series of experiments, Ader 2 • 3 then proceeded to show that a variety of early life experiences and socioenvironmental factors , acting singly or in interaction, are also influential in determining the adult animal's susceptibility to gastric lesions when immobilized. For example, rats raised in groups proved to be more susceptible to the effects of restraint than those raised alone. 11 Contrariwise, handling the animals during the preweaning period rendered them less susceptible as adults. 11 Even a prenatal effect was discovered. Handling the pregnant female rendered her offsprings more susceptible to ulcer formation when immobilized as adults, an effect evident only when the offsprings were subsequently individually housed, not when group housed. 12 And finally, by breeding rats selectively for high plasma pepsinogen and lesion susceptibility Ader 13 was able to demonstrate that varying early life experience or current socioenvironmental conditions still could modify the tendency to develop gastric lesions, even in the face of this presumably preponderant genetic effect. For example, handling in the preweaning period increases subsequent resistance to immobilization-induced gastric lesions in the genically bred high pepsinogen lesion susceptible population, just as it does in the ordinarily bred laboratory rat. It is not necessary to retain all these details. It is enough to recognize the compelling evidence that manipulation of the rat's prenatal, postnatal, early, previous,
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and current experience, all and each, can significantly influence the susceptibility to a single disease process, even among ani mals bred for high vulnerability to that disease. Similar findings have now been forthcoming from many laboratories documentating such effects in relation to a wide variety of disease states induced experimentally in animals-infections, neoplasms, metabolic disorders, vascular disease, drug reactions, etc. Further it has been discovered that the differential effects on disease susceptibility of these various manipulations are not always in the same direction. The same manipulation, such as handling or housing or electric shock, not only may influence susceptibility differently with different diseases, but also the effect on the same disease may differ depending on when in the animal's life the manipulation was carried out. For example, mortality rate to a transplanted tumor is decreased if the rat is handled during the first 10 days of life, but it is not influenced if the handling is continued throughout the 21-day preweaning period. 14 • 15 Table 1 illustrates this variability of effect of a single socioenvironmental manipulation, namely, group versus individual housing, on the response to 16 different pathogenic factors. In sum , the direction of any effect observed depends on the type and the timing of the manipulation (that is, the physiological changes induced) and the nature of the disease (that is, the physiological changes elicited by the pathogenic stimulus) . The interaction between these determines disease susceptibility. 2 This important discovery means that to define the bases for individual susceptibility to any disease, investigators must systematically explore the nature of the physiological changes induced by each of these various manipulations and elucidate their interaction with the effects of the pathogenic stimulus in question. It is no longer scientifically justified arbitrarily to designate environmental manipulations as "stressful" since what might enhance susceptibility to one disease may ameliorate it with another. This perspective underscores the
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Differential housing and susceptibility to pathogenic stimulation Measure
Spontaneous mammary tumors Spontaneous mammary tumors Spontaneous leukemia Spontaneous leukemia Walker 256 carcinosarcoma Human adenocarcinoma Trichinosis Alloxan diabetes Rumenal ulcers Rumenal ulcers Gastric erosions Gastric erosions Anaphylactic shock Hypertension Spontaneous convulsions Audiogenic seizures X-irradiation X-irradiation Encephalomyocarditis virus Amphetamine toxicity Amphetamine toxicity Amphetamine toxicity Isoproterenol toxicity
Susceptibility
Group < alone Group < alone Group < alone No difference No difference Group < alone Group > alone Group > alone Group < alone No difference Group > alone Group > alone Group > alone Group > alone Group < alone No difference Group > alone Group > alone Group < alone Group > alone Group > alone Group > alone Group < alone
Adapted from Ader, R: The influence of psychological factors on disease susceptibility in animals. In Husbandry of Laboratory Animals. Edited by ML Conality. New York, Academic Press , 1967. (For references refer to original.)
indispensability of a knowledge of the life history of the individual for understanding of disease susceptibility. And it also challenges us to wonder how on earth such effects could come about. What is it about prenatal handling or differential housing early in life, for example, which later in life modifies how the stomach responds when the rat is immobilized? Certainly the most attractive perspective is that these early experiences influence in some way how the central nervous system responds to subsequent environmental inputs. To a large extent, the biological and psychological uniqueness of the individual reflects the variability of his total life experience and the capability of his nervous system to record and respond to this experience. The nervous system continuously monitors input from the internal environment of the body and the external environment of people and things, ap-
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praises these in terms of what has gone before, and mobilizes existing or devises new response and regulatory systems, all in the service of survival, growth, and development of the individual in relation to its social organization. This capability to differentiate the novel from the familiar and to assign meaning to each in terms of potential benefit or danger is crucial in establishing the role of past and current psychosocial variables in the ultimate susceptibility to disease. From the perspective of the clinician these neural functions of appraisal and response can be operationally conceptualized in behavioral and psychological terms. For the clinician, the basic means of study is clinical observation. 16 • 17 By means of the interview, he elicits the nature and extent of the patient's awareness of changes in his body, in his mental state, or in his interpersonal and social environments. Through direct observation, the physician notes the behavior that reflects the patient's reactions to such changes. What the patient perceives and reacts to is a function both of his state at the moment and of his past history. What actually emerges into consciousness and is reported or is reflected in manifest behavior constitute but a minor fraction of the total monitoring, appraisal, and response to bodily or environmental changes that are being carried on continuously by the nervous system. The clinician works with what he can observe and with what the patient or others can report about changes from his customary fuctioning. It is from such information that the physician establishes that his patient is ill and identifies factors in his life situation, in his past experience, or in his life style which may be associated with the time of onset or the nature of the illness. From such clinical data have evolved the familiar psychosomatic formulations about psychosocial factors implicated in individual susceptibility to disease. The validity of hypotheses derived from such data can be tested in a variety of ways, one of which is recourse to animal studies. But use of animal models to validate clinically derived hypotheses is not likely to b~ productive unless the experi-
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mentalist and the clinician appreciate the complementarity of their respective approaches and search for behavioral dimensions that allow for generalizations to both populations, the animal and the human. The problem is, what can we learn from rats that might apply to humans, and vice versa? Let us test this thesis by imagining what it would be like to approach immobilization-induced gastric lesions in rats as clinicians rather than experimentalists. This would require us to act as consultants to a group of rats complaining of " ulcers. " As clinical scientists we would not be satisfied simply to make the diagnosis and institute treatment. We would want to know why these particular rats got sick when they did and why they developed ulcers rather than some other disease. We would want to learn what renders one rat vulnerable and another resistant, or the same rat vulnerable at one time and not at another. How else to begin but with careful interviews of many rats with ulcer disease? Quickly enough we would learn that some rats were having stomach trouble for the first time, while others had already had several attacks. Inquiry into the circumstances preceding onset of symptoms would lead some rats to recall that some of the episodes had occurred when for some reason they had gotten physically entangled or entrapped and for several hours could not extricate themselves. But other rats might reject such an association; they could recall similar occasions when no symptoms developed. Analysis of such variations would reveal interesting facts. Some rats might realize that entrapment was much less likely to evoke gastric symptoms if they had recently eaten. Virtually all the rats would agree that development of symptoms becomes more certain the longer it takes to escape, especially if the degree of restraint is severe. Some realize the risk of illness is greater in daytime than at night and they might speculate that perhaps sleeping is protective. A few rats make no association; as far as they are concerned symptoms come "out of the blue." An occasional rat may even claim never to have stomach trouble when restrained . Not
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only that, they may even relish the challenge of figuring out how to extricate themselves. But those animals might report other conditons under which ulcers may develop. At this point, let us take stock of where we stand in our clinical investigation . As with clinical studies of human patients, no finding emerges that is invariant or exclusive for this ulcer disease. Rats seem to vary in their susceptibility to disease, some developing it with ease and others never at all. And even the most susceptible rat reveals inconsistencies. On the other hand, a number of items turn up repeatedly, such as high incidence in some families, an association with certain patterns of infant rearing, and, most particularly, a relationship to immobilization as a precipitating event. This last is especially intriguing, the more so in light of the exceptions. Some determinants appear to be quantitative, as duration and degree. Other associations suggest physiological factors , as the protective action of food. Still others indicate the influence of a basic psychobiological state, e.g., the variations within the 24-hr activity cycle. But there remain variations where no significant association is yet apparent. Yet the conclusion seems inescapable that there is something about immobilization that has special implication for the rat. If we could only find out what it is! Such knowledge might lead to a generalization which would make understandable other circumstances associated with ulcer development, and hence to a more specific etiological principle. For the clinician the logical approach would be to ask his rat patients what immobilization means to them. And if rats could speak my guess is we would get such answers as, " Why, that's an awful thing to happen. We rats have to be free to move about. Any rats knows that! I can't tell you why, it's just so. There's a terrible feeling that something dreadful is going to happen. The worst part is not knowing what's happening nor what to do about it. Nothing works . You feel so frustrated, so helpless, sometimes you just have to give up ." Of course not all rats would feel that way. Some would scoff at our patients. "They
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just can't take it, that's all. For me it's a challenge, I enjoy figuring out how to extricate myself." Now of course we hear nothing of the sort from rats, but we do hear such accounts from patients. Many tell us that for a period of time before falling ill they had undergone some life change that had evoked uncertainly, frustration, feelings of impotence, depression, futility, or giving up. 18 Could these be the psychological equivalents for the human of physical immobilization for the rat? Such an hypothesis is in fact testable. Jay Weiss 19 of The Rockefeller University hypothesized that the inability of the immobilized rat to do anything about his situation is the significant factor in rendering it more susceptible to gastric lesions. Hence, he devised experiments which tested the effect of providing the immobilized animals with degrees of control over their situation. 19 He did this by placing rats in restraining cages of such dimensions that only minimal gastric lesioning developed even after 21 hr (fig. 3). This became the invariant condition for all animals.
FIG. 3. Experimental apparatus showing the avoidance-escape (foreground), yoked (center), and nonshock (rear) subjects. In addition to the tone preceding the shock, the platform on which the animals remained during the experimental session was vibrated (by means of a cam-see center, left of figure) as part of the warning signal. Published with permission from J. M. Weiss and the Ciba Foundation Symposium 8 (new serie s) Elsevier-Excerpta Medica, Amsterdam (see ref. 19).
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Two of the rats periodically received an electric shock delivered to the tail. But 1 of the rats was given an option. It could avoid or escape the shock by depressing a panel with its nose. For comparison, the 2nd rat was yoked to the 1st so that it received a shock each time the 1st did . It too had a panel to depress, but it was not connected with the circuit. Thus, it had no control over whether or not it received shock. The 3rd rat, similarly restrained, never received shock. A warning of impending shock was provided by a tone which sounded for 10 sec before each shock. By depressing the panel the 1st rat could interrupt the tone and thereby spare itself and its yoked partner a shock. If it failed to respond to the tone by panel-pressing, the flow of current began and continued until terminated by the 1st rat touching the panel. Under such conditions both the rat and its yoked partner received the shock. Thus, the 1st animal had control over the number of shocks it received . In contrast, its yoked partner received exactly the same number of shocks, but it could play no part in either preventing or terminating them. Figure 4 shows that gastric ulceration was greatest in the "helpless" (yoked) animals who had no way of influencing whether or not they got shock. The animals who had a measure of control developed more ulceration than the animals that were merely restrained without ever receiving shock, but much less than their yoked partners. Clearly, electric shock itself was not the main noxious factor, for both animals had received the same number of shocks. The important variable was what the animal could do about the shock. Other experiments refined this observation further. The most effective protection against ulcerogenesis was afforded by devising situations in which the animal received reliable feedback information that what it was doing was the right thing to avoid shock. Figure 5 contrasts the degree of ulcerogenesis in avoidance rats which received no tone warning of the regularly recurring shock with those that were provided a brief tone immediately upon performing an activity that successfully avoided shock. Such a
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Groups FIG . 4. The median of t he total len gth of gastric lesions for the nonshock, avoidance-esca pe, and yoked groups. Lesions in each subject were measured (in millimeters) and the tot al for eac h subject was computed ; the median found in eac h grou p is shown . Also, it can be seen that a small a mount of ulceration developed in nonshock anim als, whi ch resulted from the prolonged restraint and food and water deprivation during the experimental procedure. Published with permission from J. M. Weiss and the Ciba Founda tion Symposium 8 (new series ) ElsevierExcerpta Medica, Amsterdam (see ref. 19).
tone effectively reinforced the animal 's ability to know exactly what the correct things were to do to avoid shock, and thereby to master the situation. Under such conditions, even though the rat periodically neglected to press the lever and hence received a shock, ulcer formation was reduced to a leve l identical with that occurring in the control rats who never received shock. In contrast, the avoidance rats not warned by the tone had almost as much ulceration as their yoked partners . In sum , the more the animal could relate its own· activity >to avoiding shock, the more predictive its behavior, the less likely was it to develop ulceration . In contrast, the yoked animal, whose efforts produced no relevant feedback, who had no way to cope, developed the most ulceration . Such experiments move us closer to characterizing at least one of the psychological factors contributing to lowered resistance to disease , namely, loss of the
ability of the organism to predict and maintain control over its environment. To be without the information and/or the psychological and behavioral resources necessary to cope effectively with a particular life circumstance appears to be a highly significant variable. Under such conditions, the organism typically alternates between activity and inactivity, the first reflecting efforts to maintain or reestablish control, the second waiting or giving up. If its efforts succeed, or if circumstances change soon enough, illness may be averted. But the longer such cycles of struggling and inactivity go on, the greater the risk of morbidity. In this model we hypothesize two final common pathways, fruitless struggling and giving up , each with different psychophysiological implications and biochemical concomitants. ' 8 • 20 We suggest these interact differently with different pathogenic preconditions, and hence constitute variables underlying differential susceptibility to disease in different individuals. For one 5 .0
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FIG . 5. On t he left is shown the media n total length of gastric lesions which developed in nonshock, avoidance-esca pe, and yoked groups in a stress condi tion in whi ch shock was not preceded by•a warning signal. On the right is shown the amoun t of gastri c lesions whi ch developed in the same groups exposed to the sa me conditions, except that a brief feedb ack signal (tone) was given to the subjects whenever an avoid ance-esca pe response was made. Published with permission from J . M. Weiss and the Ciba Found a tion Symposium 8 (n ew series ) Elsevier-Excerpta Medi ca, Amsterd am (see ref. 19) .
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individual or for one disease process the struggling phase may be the more pathogen ic, for another the giving up phase. Previous life experiences, such as handling, differential housing, and others already cited, could then be seen as influencing the set or readiness to activate one or another final common pathway in response to current life circumstances, as well as inducing in their own right sustained or permanent phy"siological or biochemical changes, e.g., enzyme induction or organ hyperfunction. Interactions among these various processes and with preexisting or concurrent pathogenic predispositions could then determine the occurrence and nature of disease development. An ingenious investigator should have no difficulty in devising experiments to test the validity of such a formulation. The concept of final common pathways to characterize the outcome of diverse life events also provides an operationally useful way of defining psychological states that appear to be associated with increased morbidity in man and in animals. Implicit in such a perspective is the meaning to the organism of the particular life event or circumstance, a meaning in part determined by what has gone on before in the life of that organism. Thus, the extent to which restraint or shock for the rat, or bereavement or promotion for the human, provoke fruitless struggle or giving up is a factor determining the probability of disease onset, provided the necessary predisposing pathogenic factors also are present at the time. We can now begin to appreciate what is common to the epidemiological studies that show that persons suffering bereavement or facing a job loss have a higher morbidity and mortality 2 '- 23 ; to the retrospective and prospective studies that show increased incidence of illness among individuals reporting many life changes during the preceding months' 8 • 2 4 - 26 ; and to the finding that persons already ill report a high incidence of psychological giving up in the period preceding disease onset. 18 These all doubtless include instances of final common pathways, some not yet elucidated. The importance of the classical
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psychosomatic studies which associated specific or typical conflict situations with particular diseases now becomes obvious. These delineated individual psychological vulnerabilities and thereby defined the types of life circumstances most likely to be threatening for such persons, and hence to initiate the sequence of responses that might culminate in a final common pathway and disease onset. It is popular these days to dismiss such concepts of so-called psychosomatic specificity, but everything in my experience over 30 years has only served to reinforce my conviction of their validity. Precise and detailed knowledge of the patient's psychological strengths and vulnerabilities clearly is an important guide for prevention and treatment. In conclusion may I say that never before have the challenges and opportunities for psychosomatic research been greater. Indeed , the time has long passed when anyone seriously concerned with the determinants of individual susceptibility to disease can any longer afford to ignore the role of psychological variables, so brilliantly demonstrated in the experimental work of Ader, Weiss, and others. Least of all can the clinician, if he is genuinely devoted to prevention of disease as well as to the care of his patient. Clinicians and clinical investigators now must begin to apply the same rigor in characterizing and analyzing the psychological status and backgrounds of their patients that they customarily apply to physiological data. Terms such as "stress ," "tension," "anxieties," "emotional upset," and the like, have about as much resolving power today as did "fevers," "catarrh," or "dropsy" in bygone eras. For physicians to continue to retard their knowledge and understanding of the psychosocial by retention of inexact terms is simply no longer acceptable. For the experimentalists the prospects are exciting indeed . With the definition of the problems to be tackled provided by the type of work cited here and the availability of a wide range of new behavioral, physiological, and biochemical techniques, the prospects are bright at last of elucidating the nature of the interactions underlying
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costerone levels, and susceptibility to gastric erosions. Psychosom Med 30:277-286, 1968 13. Ader R: Effects of early experience and differential housing on susceptibility to gastric erosions in lesion-susceptible rats. Psychosom Med 32:569-580, 1970 14. Ader R, Friedman S : Differential early experiences and susceptibility to transplanted tumor in the rat. J Comp Physiol Psycho) 59:361-364, REFERENCES 1965 1. Ader R: The role of developmental factors in 15. Ader R, Friedman S: Social factors affecting emosusceptibility to disease. Psychiatry Med (in tionality and resistance to disease in animals. IV. press) Early separation from the mother and response 2. Ader R: Early experience and susceptibility to to a transplanted tumor in the rat. Psychosom disease: The case of gastric erosions. In Ethology Med 27:119-122, 1965 and Development. Edited by SA Barnett. Clinics 16. Engel GL: Clinical observation. The neglected bain Developmental Medicine no. 47, London, sic method of medicine. JAMA 192:849- 852, 1965 Spastics International Medical Publications with 17. Engel GL: Enduring attributes of medicine relevant to the education of the physician. Ann InHeinemann Medical Books, 1973, p 37-51 3. Ader R: Experimentally induced gastric lesions. tern Med 78:587- 593, 1973 Results and implications of studies in animals. In 18. Schmale AH: Giving up as a final common pathway to changes in health . In Psychosocial Duodenal Ulcer. Advances in Psychosomatic Medicine, vol 6. Edited by H Weiner. New York, Aspects of Physical Illness . Advances in PsyBasel, S Karger, 1971, p 1-39 chosomatic Medicine, vol 8. Edited by ZJ Lipow4. Bonfils S, Liefooghe G, Gelle X, et al: 'Ulcere ski. New York, Basel, S Karger. 1972, p 20- 40 19. Weiss JM : Influence of psychological variables on experimental du contrainte du rat blanc. III. stress-induced pathology . In Physiology, Emotion Mise en evidence et analyse du role de certains and Psychosomatic Illness . Edited by R Porter, J facteurs psychologiques. Rev Franc Clin Bioi Knight. Ciba Foundation Symposium 8 (new 5:571-581, 1960 series). Amsterdam , Elsevier-Excerpta Medica, 5. Brodie DA, Hansom HM : A study of the factors 1972, p 253-280 involved in the production of gastric ulcers by the restraint technique. Gastroenterology 38:353- 20. Engel GL, Schmale AH : Conservation-withdrawal: a primary regulatory process for orga360, 1960 nismic homeostasis. In Physiology, Emotion and 6. Ader R: Plasma pepsinogen level as a predictor of Psychosomatic Illness. Edited by R Porter, J susceptibility to gastric erosions in the rat. PsyKnight. Ciba Foundation Symposium 8 (new sechosom Med 25:221-232, 1963 ries). Amsterdam, Elsevier-Excerpta Medica, 7. Ader R : Plasma pepsinogen level in rat and man. 1972, p 57- 87 Psychosom Med 25: 218- 220, 1963 21. Rees WD, Lutkins SG : Mortality of bereavement. 8. Mirsky lA, Futterman P, Kaplan S : Blood Br Med J 4:13, 1967 plasma pepsinogen. I I. The activity of the plasma 22 . Parkes CM: Bereavement, Studies of Grief in from "normal" subjects, patients with duodenal Adult Life. New York, International Universities ulcer and patients with pernicious anemia. J Lab Press, 1972 Clin Med 40:188-199, 1952 9. Mirsky lA: Physiologic, psychologic and social 23 . Jenkins CD: Social and epidemiologic factors in psychosomatic disease. Psychiatr Ann 2:8-21, determinants in the etiology of peptic ulcer. Am J 1972 Dig Dis 3:285-31 3, 1958 10. Ader, R: Behavioral and physiological rhythms 24 . Thurlow HJ : Illness in relation to life situation and sick-role tendency. J Psychosom Res and the development of gastric erosions in the 15:73-88, 1971 rat. Psychosom Med 29:345-353, 1967 11. Ader R : Effects of early experience and differ- 25. Rahe RH, Mahan JL, Arthur RJ: Prediction of near-future health change from subjects' precedential housing on behavior and susceptibility to ing life changes. Psychosom Res 14:401-406, 1970 gastric erosions in the rat. J Comp Physiol Psy26. Rahe RH : Subjects' recent life changes and their cho) 60:233-238, 1965 near-future illness reports. Ann Clin Res 4:1-16, 12. Ader R, Plaut SM: Effects of prenatal maternal handling on offspring emotionality, plasma corti1973
individual susceptibility to disease. Collaboration between clinicians and experimentalists in delineating the problems and devising appropriate means of testing hypotheses offers a promise never before available. Here lies the future of medicine.