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Psychological stress and stomach ulcer: In search of an hypothesis
Experimenral Uker Produced by Behavioral Factors Brain Research BuNdin, Vol. 5, Suppl. 1, pp. 67-71. ANKHO
International Inc., 1980.
Psychological Stress and Stomach Ulcer: In Search of an Hypothesis’ ANIS MIKHAIL University
of Manitoba,
Winnipeg,
Manitoba
R3T 2N2,
Canada
MIKHAIL, A. Psychological stress and stomach ulcer: In search of an hypothesis. BRAIN RES. BULL. 5: Suppl. 1, 67-71, 1980.-An evaluation of the effects of psychological stress on ulceration leads to the following conclusions: (1) In the experimental literature, there is no convincing demonstration which indicates that psychological factors can induce ulcers. Rumenal ulcers that appeared in the early conflict experiments of Weisz and Sawrey were mainly expressions of the severe food deprivation used in these studies. Ulcers of the corpus, on the other hand, are most likely a result of the excessive and/or severe electric shock stimulation employed by recent investigators of fear or avoidance training. (2) Fear does not induce nor promote ulcer formation. Common among the diverse psychological treatments which employed the pain of shock as the US is the emotion of fear (CR). Since these treatments failed to produce ulcers that can be attributed to psychological factors, fear does not appear to be ulcerogenic. (3) An alternative to fear is the hypothesis that anger induces ulceration. Several human studies have indicated that the pathological changes associated with ulcer formation occur when anger or related emotional patterns (e.g., resentment and hostility) are provoked. (4) Future progress in ulcer research requires changes in approach and objectives. Psychophysiological disease is the product of interacting environmental and genetic variables. This view should guide the investigation of stress and ulceration. Psychological stress
Fear
Conflict
Anger
THE purpose of this report is to draw the attention search workers and clinicians to some conclusions
of rewhich have been derived from the literature on the psychology of ulcer formation. These conclusions and their underlying rationale are considered below. CONCLUSION I. IN THE EXPERIMENTAL LITERATURE, THERE IS NO CONVINCING DEMONSTRATION WHICH INDICATES PSYCHOLOGICAL FACTORS CAN INDUCE ULCERS
THAT
In a previous report [22] the present writer expressed the opinion that the literature on experimental ulcer is confused by misleading and non-replicable experiments which largely reflect experimenter bias. The ulcers that had been observed experimentally in the rat’s stomach were of two kinds: glandular and non-glandular. Mikhail et al. [22] argued that the lesions that developed in the glandular portion of the stomach, the corpus, resulted from physical stressors, mainly the intense and/or frequent electric shocks which were employed as part of the “psychological” treatments. These lesions were described as “electric injuries,” since the emotional factors involved in the treatment (i.e., conditioned fear or conflict) did not induce them or promote their development. Likewise, the lesions that developed in the non-glandular portion, the rumen, resulted from a physical deficiency, namely, the food deprivation which is known as a prerequisite of ulcer production by psychological methods. Ulcers of the rumen were described as “starvation ulcers,” since they could be induced in rats by starvation alone.
Ulcers
Early Experimental Research on the Psychology of Stomach Ulcers
Rumenal lesions were the main pathology used in measuring ulceration in the early studies of Weisz [33], Sawrey [27] and Ader [2]. The lesions were believed to be a manifestation of the conflict situations that the experimenter devised. Weisz [33] who pioneered the line of research on conflict and ulceration was a perfect example of a researcher who confined his data analysis to rumenal lesions. He found that the incidence of ulceration in the conflict and nonconflict groups of his experiment differed only in rumenal lesions which were described as “type 2” ulcers. The incidence of rumenal ulcers was found, also, to be greater in animals that were put on a schedule of food deprivation of 47 hr every 48 hr than on a 46 hr schedule. The obvious implication of this observation was ignored. Later in 1956, Weisz jointly with Sawrey [28] published an article entitled “An experimental method of producing gastric ulcers.” Clearly, these writers believed that conflict produced ulcers and that the treatment could be used as a standard method in further investigations of ulceration variables. On the basis of Weisz’ [33] work and another seemingly well controlled experiment 1271, Ader [21 investigated the relationship of some social factors to ulcer susceptibility in the rat, using the conflict method. He noticed in a number of his studies that the conflict technique, unlike the stress of restraint, produced ulcers predominantly located in the rumen. In this connection Ader [l] mentioned the following: “We have used a conflict situation such as that devised by
‘This study was supported by Grant MT-4139 from the Medical Research Council of Canada.
Copyright
0 1980 ANKHO
International Inc.-0361-9230/80/010067-05$01.00/O
68
MIKHAII.
and Weisz and the physical immobilization or restraint procedure. The former results in gastric ulceration confined almost exclusively, to the rumen of the stomach”. . (p. 399) Interestingly, Ader noticed also that the rats with rumenal ulcers displayed greater body weight loss than those without ulcers. A similar observation was reported earlier by Sawrey [27]. Its significance, however, escaped his attention as well as Ader’s, but it was clarified later [ 181. In his work on the effects of conditioned fear on ulcer. Mikhail [18] found that relative to controls, the rats that received either conditioned fear or shock alone tended to eat less during rest periods of the experimental treatments, to lose more body weight, and to develop rumenal ulcers. From these observations, it was inferred that as in conditioned fear, conflict and/or the shock associated with it induces rumenal ulcers through the reduction of food intake of the experimental animals which is displayed by greater body weight loss. Mikhail’s explanation is supported by two lines of research. The first indicates that shock alone or when it is paired with other stimuli (e.g., light) reduces the food intake of rats [23]. The second shows that prolonged food deprivation induces rumenal ulceration [ 141. The view [18] that conflict as a technique of ulceration is an unnecessarily complex procedure that exerts its ulcerogenic effects in a form that is no different from simple food deprivation discouraged its use. Researchers, in particular, Weisz and Sawrey abandoned the conflict method and ulcer research generally, long ago. Commenting on the early ulcer literature, ParC and Temple [26] stated that “previous experiments which purportedly manipulated psychological variables in an attempt to produce gastric lesions and which reported rumenal ulcers were not necessarily warranted in attributing psychological factors as the major cause of these ulcers especially if the experimental procedures incorporated a food deprivation component (p. 374):’ This statement is consistent with Mikhail’s view which had been expressed repeatedly in 1966 and 1969. Sawrey
Recent
Rrsearch
on Glandular
Ulceration
The realization that food deprivation was the primary agent responsible for the production of rumenal ulceration in psychological experiments led to a shift of interest from rumenal to glandular ulcers. Psychological research in the seventies investigated primarily ulceration of the corpus. These lesions were often described as stress ulcers. Since they had been induced by a variety of stressors: physical (e.g., cold or electric shock) and chemical ones (e.g., Formalin and toxic drug levels). The effectiveness of psychological stressors in the production of these ulcers is not as clear as that of the physical or chemical ones. The nearest stressor to a psychological treatment is restraint. Its emotional pattern of reactions, however, has not been identified. Be that as it may, psychologists such as Weiss [30] believed that they were on safer ground when glandular rather than rumenal ulceration was employed as a dependent variable in their experiments. The glandular lesions were attributed partially or completely to psychological rather than physical stressors (i.e., to the fear of shock rather than the electric shock itself). Weiss, for example, attributed the glandular lesions of his experiments to the fear of shock which may decrease or increase by the degree of shock predictability and/or controllability.
When the fear of shock, however, was investigated by Glavin [9] in an uncontrollable situation, it was found that clear lesions in the experimental rats and yoked controls developed only when shock intensity was high (3.5 mA). Glavin found also, that the ulceration of a group that received signalled shocks was as great as the ulceration of yoked controls that received the shocks only. It should be noted that the shocks employed by Weiss in one of his experiments 1301 were of high intensity (3.5 mA). long duration (2.0 set) and great frequency (one on an average of 60 set interval during the 19 hr of the experimental treatment). Apart from the variable of food deprivation which is displayed mainly be rumenal ulcers, there are only two variables that are capable of producing ulcers. They are the shock or the fear of shock. If, for argument’s sake, shock as an ulcerogenic agent is disregarded, then the alternative agent-fear of shock-should be examined carefully. Does the fear of shock promote the formation of experimental ulcers? In general terms, is the emotion of fear ulcerogenic? A review of the literature inevitably lead to the following conclusion. CONCLUSION
2.
FEAR DOES NOT 1NDUCE NOR PROMOTE UI.CER FORMATION
In a sensitive test situation of the effects of fear on ulcer pathogenesis, Mikhail [21] exposed ulcerated rats to conditioned fear for a period ranging from l-4 days. Contrary to expectation, the ulcers which had been induced by restraint prior to conditioning healed. Conditioned fear in the form of light paired with shock in some of the trials did not precipitate new lesions nor even sustained the old ones. The rats which were tested periodically recovered completely from glandular ulcers within 96 hr in spite of the continual exposure to conditioned fear. This means that even with prior sensitization of the stomach by the stress of restraint conditioned fear was not effective in inducing ulcers or delaying the recovery of existing ones. It was suprising to find that in all the testing periods ulcer recovery in conditioned fear rats and controls did not differ significantly. Common among the diverse procedures-conflict, avoidance, and conditioned fear-which have been employed in the production of experimental ulcer is the use of shock. In the psychological literature, it is known that pain is usually the reaction to shock, while fear is the reaction to the signal of shock. Since shock and its associated cues were the basic emotionally exciting agents in the psychological experiments of ulcer, it follows that fear was the main emotional pattern elicited in them despite their procedural diversity. The fear of shock in animals is displayed by different forms of withdrawal behavior (e.g., pressing a lever to avoid receiving a shock or crouching and defecating in response to a signal of an unavoidable shock). In Weisz’ conflict experiment, shock avoidance was displayed by the animals tendency to avoid crossing over an electrified grid in order to receive food and water. As mentioned earlier, the experimental rats differed from controls in rumenal lesions. but they did not so differ in glandular ulcers. In other words, the results of Weisz’ classic experiment are in harmony with the view that fear is not ulcergenic. In recent research, also, the attempt [8] to produce ulcers in the “executive” avoidance has failed. Similarly in rats,
of Foltz and Millett monkey by shock Weiss [31] reported that his avoidance animals had less ulceration than shockyoked controls. A difficulty in Weiss’ position is the belief
PSYCHOLOGICAL
69
STRESS AND ULCER
that the ulcers which appeared in his rats were manifestations of emotional reactions (i.e., fear) rather than the excessive use of shock. This belief is opposed by the observation [9] that psychological stress procedures which involve the use of shock fail to produce ulcer unless severe and/or excessive shock stimulation is used. An additional line of observations which indirectly support the conclusion that fear is not ulcerogenic are those which showed that gastric acidity is decreased by fear. For example, Mikhail [20] tested stomach acidity of pylorus ligated rats following their exposure to conditioned fear. He found that the experimental rats that received conditioned fear in the form of light signals of mild shocks had significantly lower free acid than controls. Similarly, Pare and Livingston [25] reported a decrease in stomach acid output of rats exposed to restraint and predictable or unpredictable shock, relative to controls. In more recent research, Desiderato and Testa [4] confirmed also the inhibitory influence of fear on acid secretion. To many, the foregoing findings would not come as a surprise. For it is known that the sympathetic activity associated with fear inhibits rather than promotes gastric functions in general. Human research, also, is consistent with that of animals. Gastric functions-acid secretion, motility, and vascula&y-were inhibited in a patient (Tom) with gastric tistula when he was emotionally withdrawn, fearful or depressed [35]. Likewise, Engel, Reichsman and Segal [S], who studied an infant “Monica” with gastric listula, noticed “marked decrease in or even cessation of hydrochloric acid secretion” when the child manifested withdrawal reactions in the presence of a stranger. Bykov [3] described a set of impresive studies on a patient whose finger “was pricked for blood examination while the gastric juice was being secreted as a result of the sham feeding.” It was found that the secretion was intensely suppressed for 20-30 min and that in subsequent experimental sessions, a few days later, “the mere preparation for pricking the finger was sufftcient to inhibit the flow of gastric juice.” The decrease in the quantity of the juice was always accompanied by a reduction of its acidity. An interesting observation which is not uncommon to medical practitioners is that patients with active gastric bleeding, immediately prior to an operation, often exhibit bloodless gastric mucosa when the stomach was explored during surgery. Gray et al. [ 121explained that the bloodless mucosa “may be attributable to shunting of the blood away from the mucosal capillaries under sympathetic influences (aroused by fear of surgery).” CONCLUSION 3. AN ALTERNATIVE TO FEAR IS THE HYPOTHESIS THAT ANGER INDUCES ULCERATION
In contrast to fear, there are several studies, mainly in the human literature, which suggest that anger is more likely to be associated with ulcer pathogenic changes. For instance, “Tom” who displayed decreased gastric function under emotional passivity showed an opposing pattern of reaction under anger and related emotions (such as resentment and hostility). The anger pattern was of increased blood supply, engorgement of the mucosa, increased secretion of HCl, and increased muscular activity of the stomach. A similar reaction pattern was observed by Engel et al. [5] in their study of “Monica”. Hydrochloric acid secretion increased during periods of her irritation and rage. There is a parallel to the stomach’s specific pattern of reactions in facial emotional expression. In rage, the face flushes with blood and turns red, so does the stomach lining;
and the pallor of fear occurs in the stomach as in the face. Anger expressions appear on the face as they do in the viscera. In a study [291 of facial expression of peptic ulcer patients, the number of vertical forehead furrows were counted in 100 patients and 100 controls (non-ulcer patients). It was found that 95 of the 100 controls had two or less vertical furrows. In the duodenal ulcer group, 87 of the 100 patients had three or more vertical furrows. It should be noted that a large number of vertical forehead furrows occurs as part of the facial expression of anger when the individual frowns strongly. The specific relation of ulcer to the emotional pattern of anger has been observed, also, in Graham’s et al. [ll] work on the specificity hypothesis of psychosomatic diseases. In this study, the reported attitudes of patients with 12 different psychosomatic diseases towards a stressful event were collected. It was found that patients with the same disease used similar words to describe their attitudes. The emotional attitude which was described by duodenal ulcer patients was that of an individual who was seeking revenge, and wishing to injure a person or thing that had injured him. The following quotation is representative ‘He hurts me, so I wanted to hurt him.” Despite the plausability of the anger hypothesis of ulceration which human research suggests, little experimental animal work was conducted to test it. The procedure 1321which was used to induce aggressive gestures and stomach ulcers by stimulating pairs of rats with shock suffers from the same deficiency of the previously mentioned psychological procedures: the use of severe shock stimulation. Here again, the ulcers were a manifestation of the direct physical tissue damage of shock, not the emotion of anger and aggression. It is unlikely that the shock induced “aggression” which consists of very brief fragments of reflexive behavior is related to what is recognized as sustained true emotional aggression that is capable of inducing ulcers. It is tempting to believe that restraint ulcer is an emotional expression of anger, and that it results from the frustration and aggression associated with physical immobilization. The work of Feldman et al. [7], however, casts some doubt on the role of restraint as an emotion provoking procedure. These researchers found that restraint increases the output of ACTH even in the absence of central neural input from the brain. This observation implies that the pathogenic effects of restraint do not depend on higher central activity which is known to be a necessary component of organized emotional patterns. The specificity of anger, however, to ulceration should not be overemphasized. The difference between anger and fear may indeed be related to a more general distinction between states of activity and states of passivity. While the literature that has been reviewed earlier suggests that the passivity which is common between fear and depression is not ulcerogenic, the activity associated with anger appears to be ulcer producing. Part’s observation [24] that ulcers develop in rats that are allowed to be active in a running wheel, but not in passive rats that do not exercise is in accord with the broad rather than the narrow distinction between anger and fear. CONCLUSION 4. FUTURE PROGRESS IN ULCER RESEARCH QUIRES CHANGES IN APPROACH AND OBJECTIVES
RE-
The Specificity Hypothesis
Undoubtedly,
some situational
specificity
in emotional
70
MIKHAIL.
reaction patterns exists [lS]. The one sided interest. howin identifying an emotional pattern that is specifically conducive to ulceration has not been particularly fruitful. It appears that a balanced approach which takes into account organismic factors that affect ulcer development is necessary. This view is supported by the study of Malmo and Shagass [ 171which led to the formulation of the principle of imliviclutrl r~spotlsc-stereotype and by the demonstration that ulcer formation is influenced by genetic factors in both humans [ 131 and rats [ 181. These studies argue strongly that in designing future investigations individual differences should not be overlooked.
/I(J.\~Y/individuals eventually leading to disease of one type or another (p, 13):’ Levi’s model suggests that in studying the precursors of ulcer disease (e.g.. acid and pepsin secretion) the effects of stressors of which some might be specifically potent (e.g., anger provoking situations) should be tested on individuals who have a tendency to respond with a stereotyped psychophysiological pattern (e.g., increased secretion of acid and/or pepsin) which predisposes them to the disease. It is doubtful that progress will be achieved in ulcer research without a balanced attention to both sides of the interacting variables.
In his personality theory, Hans Eysenck [6] repeatedly stated that behavior is the product of interaction between genotypic variations and environmental influences. Despite the obvious validity of the statement, psychologists in their study of behavior have stressed environmental influences to the almost complete exclusion of biological factors that are transmitted genetically. Ulcer research suffered from the same deficiency which is noted in other areas of psychology: disregard of the genetic determinants of the disorder. Like Eysenck, Lennart Levi [16] stressed the role of the combined effects of environmental psychosocial stimuli and organismic psychobiological program (i.e., past experience and genetic factors) in mediating psychophysiological disease. In describing his model, he mentioned the following: “Every psychosocial change can act as a stressor in Selye’s sense of the word. In response to such an exposure, and in accordance with the phylogenetically old adaptation pattern (psychobiological program) which man has in common with his prehistoric ancestors and with all primates, the neuroendocrine system becomes activated, preparing the organism for physiological activity, e.g., fight or flight, even in situations where such reactions are clearly inadequate. The resulting increase in “Stress (Selye)” may lead to an “increased rate of wear and tear” in the organism, in prrdis-
It has been generally accepted that the mechanisms and precursors of ulcer are varied. In this regard, Grossman 1341 mentioned that “when we speak of duodenal ulcer we are speaking of a whole group of diseases which share only a hole in the duodenum as the manifestation and there may be many pathogenic mechanisms operating.” Implied in Grossman’s statement is that the study of the effect of psychological stress on ulceration directly, as in the majority of psychological experiments, is not so revealing. Little is learned from experiments which demonstrate that a “hole” in the gastrointestinal tract can be developed by a psychological procedure. A more relevant research goal is the identification of the pathophysiological reactions which are partly manifested by ulcer formation. A great deal of research information is lost by concentrating on the end product, ulcers, in psychological experimentation. Indeed, it may turn out that psychologically mediated gastrointestinal changes do not initiate ulcers altogether and that their effects is limited to sustaining them. It is worth noting that in Mikhail’s work [21] conditioned fear did not initiate new ulcers nor did it delay the healing of existing ones in rats. The possibility still remains, however. that anger mediated changes may sustain ulcers in predisposed animals or human.
ever,
REFERENCES I. Ader. H. Susceptibility to gastric lesions in the rat. ./. /Vcj/rrop.\~chitrt. 4: 399-408, 1963. 2. Ader, H., R. Tatum and C. C. Beels. Social factors affecting emotionality and resistance to disease in animals: I. Age of separation from the mother and susceptibility to gastric ulcers in the rat. .I. c’onq~. ph.vsio/. Ps.vcho/. 53: 446-454, 1960. 3. Bykov, K. M. The C‘rrehrul Cortex a/~cl the 111ter.t7crlOr,wrl.\. Moscow: Foreign Languages Publishing House, 1959. 4. Desiderato, 0. and M. Testa. Shock-stress, gastric secretion and habituation in the chronic gastric fistula rat. Ph~siol. BehtrlV. 16: 67-73, 1976. 5. Engel, G. L., F. Reichsman and H. L. Segal. A study of an infant with gastric tistula: 1. Behavior and the rate of total hydrochloric acid secretion. P.s.~choson~. Mctl. IS: 374-398, 1959. 6. Eysenck, H. J. The Bidogiccrl Bo.\i.s c$Pcr.votmIity. Springfield, Ill.: C. C. Thomas, 1967. 7. Feldman, S., N. Conforti, I. Chowers and J. Davidson. Pituitary-adrenal activation in rats with medial basal hypothalamic islands. Acrcr Etdoc~r.63: 405-414. 1970. 8. Foltz, E. L. and F. E. Millett. Experimental psychosomatic disease states in monkeys: I. Peptic ulcer--“executive” monkeys. .I. SI~I~. Rc.,. 4: 445-453. 1964.
and control of experimental 9. Glavin, G. B. The pathogenesis gastric ulceration in the rat. Doctoral dissertation, University of Manitoba, 1975. 10. Glavin, G. B. and A. A. Mikhail. Stress and ulcer etiology in the rat. Ph~.sio/. Bchtr,,. 16: 135-139, 1976. I I. Grace. W. J. and D. T. Graham. Relationship of specific attitudes and emotions to certain bodily diseases. P.\l,c.lro~~~rr. .llcc/. 14: 243-2.51, 1952. H. Dolcini and 1. Zaidman. The 12. Grav. ~~,. S. J.. J. T. Arabehetv. microcirculation of gastric mucosa: Effects of neural, hormonal, and pharmacological factors. In: Pathophy.sio/ogy of‘ I’cptic~ b’kcr. edited by S. C. Skoryna. Montreal: McGill University Press, 1963. op. 193-209. B. ‘and M. Hauge. A catamnestic investigation of 13. Harvald, Danish twins. Drlrr. M&Bull. 3: 15&158, l9Sh. of ulcers in the pro14. Hoelzel, F. and E. De Costa. Production stomach of rats by protein restriction. Pro<.. Shack. <‘r/_ Hi<)/. .Mc,c/. 29: 382-384, 1932. IS Lacey, J. I., J. Kagan, B. C. Lacey and H. A. Moss. The viaceral level: Situational determinants and behavioral correlates of autonomic response patterns. In: Exprr.ssiotl c!f the Errfotiotr.~ in Mutz. edited by P. H. Knapp. New York: International Univer\ity Press, 1963, pp. 161-196.
PSYCHOLOGICAL
STRESS AND ULCER
16. Levi, L. Stress and Distress in Response to Psychosocial Srimuli. Oxford: Pergamon Press, 1972. 17. Malmo, R. B. and C. Shagass. Physiologic study of symptom mechanisms in psychiatric patients under stress. Psychosom. Med. 11: 25-29, 1969. 18. Mikhail, A. A. A study of the effects of anxiety on the recovery from gastric ulceration in emotionally reactive strains of rats. Doctoral dissertation, University of London, 1%6. 19. Mikhail, A. A. Relationship of conditioned anxiety to stomach ulceration and acidity in rats. J. camp. physiol. Psycho/. 68: 623-626,
1%9.
20. Mikhail, A. A. Effects of acute and chronic stress situations on stomach acidity in rats. J. camp. physiol. Ps.rcho/. 74: 23-27, 1971. 21. Mikhail, A. A. Stress and ulceration in the glandular and nonglandular portions of the rat’s stomach. J. camp. phyiol. Psychol. 85: 636-642,
1973.
22. Mikhail, A. A., V. A. Kamaya and G. B. Giavin. Stress and experimental ulcer: Critique of psychological literature. Can. Psycho/. Rev. 19: 296-303, 1978. 23. Pare, W. P. Stress and consummatory behavior in the albino rats. Psychol. Rep. 16: 399-405, 1%5. 24. Pare, W. P. The activity-stress ulcer model: frequency and chronicity. Physiol. Beha;. 16: 6%7&i, 1976. 25. Pare, W. P. and A. Livingston. Shock predictability and gastric secretion in the chronic gastric fistula rat. Physiol. Behov. 11: 521-526, 1973.
71
26. Pare, W. R. and L. J. Tempie. Food deprivation, shock stress and stomach lesions in the rat. Physiol. Behav. 11: 371-375, 1973. 27. Sawrey, W. L., J. J. Conger and E. S. Turrell. An experimental investigation of the role of psychological factors in the production of gastric ulcers in rats. J. camp. physiol. Ps.vchol. 49: 457-461, 1956. 28. Sawrey, W. L. and J. D. Weisz. An experimental method of producing gastric ulcers. J. camp. ph.vsio/. Psychol. 49: 26F 270, 1956. 29. Trujillo, N. P. and T. A. Warthin. The frowning sign multiple forehead furrows in peptic ulcer. J. Am. Med. Ass. 205: No. 6,
218, August 5, 1%8. 30. Weiss, J. M. Effects of predictable and unpredictable shock on development of gastrointestinal lesions in rats. Proc. 76th Ann. Conv. APA 3: 281-282, 1968. 31. Weiss, J. M. Effect of coping responses on stress. J. camp. physiol. Psycho/. 65: 251-268, 1968. 32. Weiss, J. M., L. A. Pohorecky, S. Salmon and M. Gruenthal.
Attenuation of gastric lesions by psychological aspects of aggression in rats. J. camp. physiol. Psycho!. 90: 252-259, 1976. 33. Weisz, D. The etiology of experimental ulceration. Psychosom. Med. 19: 61-73, 1957. 34. Wolf, S., T. P. Almy, W. H. Bachrach,
H. M. Spiro, R. A. Sturdevant and H. Weiner. The role of stress in peptic ulcer disease. J. Human Stress 5: 27-37. 1979. 35. Wolf, S. and H. C. Wolff. Human Gastric Function. London: Oxford University Press, 1947.
International Inc., 1980.
Psychological Stress and Stomach Ulcer: In Search of an Hypothesis’ ANIS MIKHAIL University
of Manitoba,
Winnipeg,
Manitoba
R3T 2N2,
Canada
MIKHAIL, A. Psychological stress and stomach ulcer: In search of an hypothesis. BRAIN RES. BULL. 5: Suppl. 1, 67-71, 1980.-An evaluation of the effects of psychological stress on ulceration leads to the following conclusions: (1) In the experimental literature, there is no convincing demonstration which indicates that psychological factors can induce ulcers. Rumenal ulcers that appeared in the early conflict experiments of Weisz and Sawrey were mainly expressions of the severe food deprivation used in these studies. Ulcers of the corpus, on the other hand, are most likely a result of the excessive and/or severe electric shock stimulation employed by recent investigators of fear or avoidance training. (2) Fear does not induce nor promote ulcer formation. Common among the diverse psychological treatments which employed the pain of shock as the US is the emotion of fear (CR). Since these treatments failed to produce ulcers that can be attributed to psychological factors, fear does not appear to be ulcerogenic. (3) An alternative to fear is the hypothesis that anger induces ulceration. Several human studies have indicated that the pathological changes associated with ulcer formation occur when anger or related emotional patterns (e.g., resentment and hostility) are provoked. (4) Future progress in ulcer research requires changes in approach and objectives. Psychophysiological disease is the product of interacting environmental and genetic variables. This view should guide the investigation of stress and ulceration. Psychological stress
Fear
Conflict
Anger
THE purpose of this report is to draw the attention search workers and clinicians to some conclusions
of rewhich have been derived from the literature on the psychology of ulcer formation. These conclusions and their underlying rationale are considered below. CONCLUSION I. IN THE EXPERIMENTAL LITERATURE, THERE IS NO CONVINCING DEMONSTRATION WHICH INDICATES PSYCHOLOGICAL FACTORS CAN INDUCE ULCERS
THAT
In a previous report [22] the present writer expressed the opinion that the literature on experimental ulcer is confused by misleading and non-replicable experiments which largely reflect experimenter bias. The ulcers that had been observed experimentally in the rat’s stomach were of two kinds: glandular and non-glandular. Mikhail et al. [22] argued that the lesions that developed in the glandular portion of the stomach, the corpus, resulted from physical stressors, mainly the intense and/or frequent electric shocks which were employed as part of the “psychological” treatments. These lesions were described as “electric injuries,” since the emotional factors involved in the treatment (i.e., conditioned fear or conflict) did not induce them or promote their development. Likewise, the lesions that developed in the non-glandular portion, the rumen, resulted from a physical deficiency, namely, the food deprivation which is known as a prerequisite of ulcer production by psychological methods. Ulcers of the rumen were described as “starvation ulcers,” since they could be induced in rats by starvation alone.
Ulcers
Early Experimental Research on the Psychology of Stomach Ulcers
Rumenal lesions were the main pathology used in measuring ulceration in the early studies of Weisz [33], Sawrey [27] and Ader [2]. The lesions were believed to be a manifestation of the conflict situations that the experimenter devised. Weisz [33] who pioneered the line of research on conflict and ulceration was a perfect example of a researcher who confined his data analysis to rumenal lesions. He found that the incidence of ulceration in the conflict and nonconflict groups of his experiment differed only in rumenal lesions which were described as “type 2” ulcers. The incidence of rumenal ulcers was found, also, to be greater in animals that were put on a schedule of food deprivation of 47 hr every 48 hr than on a 46 hr schedule. The obvious implication of this observation was ignored. Later in 1956, Weisz jointly with Sawrey [28] published an article entitled “An experimental method of producing gastric ulcers.” Clearly, these writers believed that conflict produced ulcers and that the treatment could be used as a standard method in further investigations of ulceration variables. On the basis of Weisz’ [33] work and another seemingly well controlled experiment 1271, Ader [21 investigated the relationship of some social factors to ulcer susceptibility in the rat, using the conflict method. He noticed in a number of his studies that the conflict technique, unlike the stress of restraint, produced ulcers predominantly located in the rumen. In this connection Ader [l] mentioned the following: “We have used a conflict situation such as that devised by
‘This study was supported by Grant MT-4139 from the Medical Research Council of Canada.
Copyright
0 1980 ANKHO
International Inc.-0361-9230/80/010067-05$01.00/O
68
MIKHAII.
and Weisz and the physical immobilization or restraint procedure. The former results in gastric ulceration confined almost exclusively, to the rumen of the stomach”. . (p. 399) Interestingly, Ader noticed also that the rats with rumenal ulcers displayed greater body weight loss than those without ulcers. A similar observation was reported earlier by Sawrey [27]. Its significance, however, escaped his attention as well as Ader’s, but it was clarified later [ 181. In his work on the effects of conditioned fear on ulcer. Mikhail [18] found that relative to controls, the rats that received either conditioned fear or shock alone tended to eat less during rest periods of the experimental treatments, to lose more body weight, and to develop rumenal ulcers. From these observations, it was inferred that as in conditioned fear, conflict and/or the shock associated with it induces rumenal ulcers through the reduction of food intake of the experimental animals which is displayed by greater body weight loss. Mikhail’s explanation is supported by two lines of research. The first indicates that shock alone or when it is paired with other stimuli (e.g., light) reduces the food intake of rats [23]. The second shows that prolonged food deprivation induces rumenal ulceration [ 141. The view [18] that conflict as a technique of ulceration is an unnecessarily complex procedure that exerts its ulcerogenic effects in a form that is no different from simple food deprivation discouraged its use. Researchers, in particular, Weisz and Sawrey abandoned the conflict method and ulcer research generally, long ago. Commenting on the early ulcer literature, ParC and Temple [26] stated that “previous experiments which purportedly manipulated psychological variables in an attempt to produce gastric lesions and which reported rumenal ulcers were not necessarily warranted in attributing psychological factors as the major cause of these ulcers especially if the experimental procedures incorporated a food deprivation component (p. 374):’ This statement is consistent with Mikhail’s view which had been expressed repeatedly in 1966 and 1969. Sawrey
Recent
Rrsearch
on Glandular
Ulceration
The realization that food deprivation was the primary agent responsible for the production of rumenal ulceration in psychological experiments led to a shift of interest from rumenal to glandular ulcers. Psychological research in the seventies investigated primarily ulceration of the corpus. These lesions were often described as stress ulcers. Since they had been induced by a variety of stressors: physical (e.g., cold or electric shock) and chemical ones (e.g., Formalin and toxic drug levels). The effectiveness of psychological stressors in the production of these ulcers is not as clear as that of the physical or chemical ones. The nearest stressor to a psychological treatment is restraint. Its emotional pattern of reactions, however, has not been identified. Be that as it may, psychologists such as Weiss [30] believed that they were on safer ground when glandular rather than rumenal ulceration was employed as a dependent variable in their experiments. The glandular lesions were attributed partially or completely to psychological rather than physical stressors (i.e., to the fear of shock rather than the electric shock itself). Weiss, for example, attributed the glandular lesions of his experiments to the fear of shock which may decrease or increase by the degree of shock predictability and/or controllability.
When the fear of shock, however, was investigated by Glavin [9] in an uncontrollable situation, it was found that clear lesions in the experimental rats and yoked controls developed only when shock intensity was high (3.5 mA). Glavin found also, that the ulceration of a group that received signalled shocks was as great as the ulceration of yoked controls that received the shocks only. It should be noted that the shocks employed by Weiss in one of his experiments 1301 were of high intensity (3.5 mA). long duration (2.0 set) and great frequency (one on an average of 60 set interval during the 19 hr of the experimental treatment). Apart from the variable of food deprivation which is displayed mainly be rumenal ulcers, there are only two variables that are capable of producing ulcers. They are the shock or the fear of shock. If, for argument’s sake, shock as an ulcerogenic agent is disregarded, then the alternative agent-fear of shock-should be examined carefully. Does the fear of shock promote the formation of experimental ulcers? In general terms, is the emotion of fear ulcerogenic? A review of the literature inevitably lead to the following conclusion. CONCLUSION
2.
FEAR DOES NOT 1NDUCE NOR PROMOTE UI.CER FORMATION
In a sensitive test situation of the effects of fear on ulcer pathogenesis, Mikhail [21] exposed ulcerated rats to conditioned fear for a period ranging from l-4 days. Contrary to expectation, the ulcers which had been induced by restraint prior to conditioning healed. Conditioned fear in the form of light paired with shock in some of the trials did not precipitate new lesions nor even sustained the old ones. The rats which were tested periodically recovered completely from glandular ulcers within 96 hr in spite of the continual exposure to conditioned fear. This means that even with prior sensitization of the stomach by the stress of restraint conditioned fear was not effective in inducing ulcers or delaying the recovery of existing ones. It was suprising to find that in all the testing periods ulcer recovery in conditioned fear rats and controls did not differ significantly. Common among the diverse procedures-conflict, avoidance, and conditioned fear-which have been employed in the production of experimental ulcer is the use of shock. In the psychological literature, it is known that pain is usually the reaction to shock, while fear is the reaction to the signal of shock. Since shock and its associated cues were the basic emotionally exciting agents in the psychological experiments of ulcer, it follows that fear was the main emotional pattern elicited in them despite their procedural diversity. The fear of shock in animals is displayed by different forms of withdrawal behavior (e.g., pressing a lever to avoid receiving a shock or crouching and defecating in response to a signal of an unavoidable shock). In Weisz’ conflict experiment, shock avoidance was displayed by the animals tendency to avoid crossing over an electrified grid in order to receive food and water. As mentioned earlier, the experimental rats differed from controls in rumenal lesions. but they did not so differ in glandular ulcers. In other words, the results of Weisz’ classic experiment are in harmony with the view that fear is not ulcergenic. In recent research, also, the attempt [8] to produce ulcers in the “executive” avoidance has failed. Similarly in rats,
of Foltz and Millett monkey by shock Weiss [31] reported that his avoidance animals had less ulceration than shockyoked controls. A difficulty in Weiss’ position is the belief
PSYCHOLOGICAL
69
STRESS AND ULCER
that the ulcers which appeared in his rats were manifestations of emotional reactions (i.e., fear) rather than the excessive use of shock. This belief is opposed by the observation [9] that psychological stress procedures which involve the use of shock fail to produce ulcer unless severe and/or excessive shock stimulation is used. An additional line of observations which indirectly support the conclusion that fear is not ulcerogenic are those which showed that gastric acidity is decreased by fear. For example, Mikhail [20] tested stomach acidity of pylorus ligated rats following their exposure to conditioned fear. He found that the experimental rats that received conditioned fear in the form of light signals of mild shocks had significantly lower free acid than controls. Similarly, Pare and Livingston [25] reported a decrease in stomach acid output of rats exposed to restraint and predictable or unpredictable shock, relative to controls. In more recent research, Desiderato and Testa [4] confirmed also the inhibitory influence of fear on acid secretion. To many, the foregoing findings would not come as a surprise. For it is known that the sympathetic activity associated with fear inhibits rather than promotes gastric functions in general. Human research, also, is consistent with that of animals. Gastric functions-acid secretion, motility, and vascula&y-were inhibited in a patient (Tom) with gastric tistula when he was emotionally withdrawn, fearful or depressed [35]. Likewise, Engel, Reichsman and Segal [S], who studied an infant “Monica” with gastric listula, noticed “marked decrease in or even cessation of hydrochloric acid secretion” when the child manifested withdrawal reactions in the presence of a stranger. Bykov [3] described a set of impresive studies on a patient whose finger “was pricked for blood examination while the gastric juice was being secreted as a result of the sham feeding.” It was found that the secretion was intensely suppressed for 20-30 min and that in subsequent experimental sessions, a few days later, “the mere preparation for pricking the finger was sufftcient to inhibit the flow of gastric juice.” The decrease in the quantity of the juice was always accompanied by a reduction of its acidity. An interesting observation which is not uncommon to medical practitioners is that patients with active gastric bleeding, immediately prior to an operation, often exhibit bloodless gastric mucosa when the stomach was explored during surgery. Gray et al. [ 121explained that the bloodless mucosa “may be attributable to shunting of the blood away from the mucosal capillaries under sympathetic influences (aroused by fear of surgery).” CONCLUSION 3. AN ALTERNATIVE TO FEAR IS THE HYPOTHESIS THAT ANGER INDUCES ULCERATION
In contrast to fear, there are several studies, mainly in the human literature, which suggest that anger is more likely to be associated with ulcer pathogenic changes. For instance, “Tom” who displayed decreased gastric function under emotional passivity showed an opposing pattern of reaction under anger and related emotions (such as resentment and hostility). The anger pattern was of increased blood supply, engorgement of the mucosa, increased secretion of HCl, and increased muscular activity of the stomach. A similar reaction pattern was observed by Engel et al. [5] in their study of “Monica”. Hydrochloric acid secretion increased during periods of her irritation and rage. There is a parallel to the stomach’s specific pattern of reactions in facial emotional expression. In rage, the face flushes with blood and turns red, so does the stomach lining;
and the pallor of fear occurs in the stomach as in the face. Anger expressions appear on the face as they do in the viscera. In a study [291 of facial expression of peptic ulcer patients, the number of vertical forehead furrows were counted in 100 patients and 100 controls (non-ulcer patients). It was found that 95 of the 100 controls had two or less vertical furrows. In the duodenal ulcer group, 87 of the 100 patients had three or more vertical furrows. It should be noted that a large number of vertical forehead furrows occurs as part of the facial expression of anger when the individual frowns strongly. The specific relation of ulcer to the emotional pattern of anger has been observed, also, in Graham’s et al. [ll] work on the specificity hypothesis of psychosomatic diseases. In this study, the reported attitudes of patients with 12 different psychosomatic diseases towards a stressful event were collected. It was found that patients with the same disease used similar words to describe their attitudes. The emotional attitude which was described by duodenal ulcer patients was that of an individual who was seeking revenge, and wishing to injure a person or thing that had injured him. The following quotation is representative ‘He hurts me, so I wanted to hurt him.” Despite the plausability of the anger hypothesis of ulceration which human research suggests, little experimental animal work was conducted to test it. The procedure 1321which was used to induce aggressive gestures and stomach ulcers by stimulating pairs of rats with shock suffers from the same deficiency of the previously mentioned psychological procedures: the use of severe shock stimulation. Here again, the ulcers were a manifestation of the direct physical tissue damage of shock, not the emotion of anger and aggression. It is unlikely that the shock induced “aggression” which consists of very brief fragments of reflexive behavior is related to what is recognized as sustained true emotional aggression that is capable of inducing ulcers. It is tempting to believe that restraint ulcer is an emotional expression of anger, and that it results from the frustration and aggression associated with physical immobilization. The work of Feldman et al. [7], however, casts some doubt on the role of restraint as an emotion provoking procedure. These researchers found that restraint increases the output of ACTH even in the absence of central neural input from the brain. This observation implies that the pathogenic effects of restraint do not depend on higher central activity which is known to be a necessary component of organized emotional patterns. The specificity of anger, however, to ulceration should not be overemphasized. The difference between anger and fear may indeed be related to a more general distinction between states of activity and states of passivity. While the literature that has been reviewed earlier suggests that the passivity which is common between fear and depression is not ulcerogenic, the activity associated with anger appears to be ulcer producing. Part’s observation [24] that ulcers develop in rats that are allowed to be active in a running wheel, but not in passive rats that do not exercise is in accord with the broad rather than the narrow distinction between anger and fear. CONCLUSION 4. FUTURE PROGRESS IN ULCER RESEARCH QUIRES CHANGES IN APPROACH AND OBJECTIVES
RE-
The Specificity Hypothesis
Undoubtedly,
some situational
specificity
in emotional
70
MIKHAIL.
reaction patterns exists [lS]. The one sided interest. howin identifying an emotional pattern that is specifically conducive to ulceration has not been particularly fruitful. It appears that a balanced approach which takes into account organismic factors that affect ulcer development is necessary. This view is supported by the study of Malmo and Shagass [ 171which led to the formulation of the principle of imliviclutrl r~spotlsc-stereotype and by the demonstration that ulcer formation is influenced by genetic factors in both humans [ 131 and rats [ 181. These studies argue strongly that in designing future investigations individual differences should not be overlooked.
/I(J.\~Y/individuals eventually leading to disease of one type or another (p, 13):’ Levi’s model suggests that in studying the precursors of ulcer disease (e.g.. acid and pepsin secretion) the effects of stressors of which some might be specifically potent (e.g., anger provoking situations) should be tested on individuals who have a tendency to respond with a stereotyped psychophysiological pattern (e.g., increased secretion of acid and/or pepsin) which predisposes them to the disease. It is doubtful that progress will be achieved in ulcer research without a balanced attention to both sides of the interacting variables.
In his personality theory, Hans Eysenck [6] repeatedly stated that behavior is the product of interaction between genotypic variations and environmental influences. Despite the obvious validity of the statement, psychologists in their study of behavior have stressed environmental influences to the almost complete exclusion of biological factors that are transmitted genetically. Ulcer research suffered from the same deficiency which is noted in other areas of psychology: disregard of the genetic determinants of the disorder. Like Eysenck, Lennart Levi [16] stressed the role of the combined effects of environmental psychosocial stimuli and organismic psychobiological program (i.e., past experience and genetic factors) in mediating psychophysiological disease. In describing his model, he mentioned the following: “Every psychosocial change can act as a stressor in Selye’s sense of the word. In response to such an exposure, and in accordance with the phylogenetically old adaptation pattern (psychobiological program) which man has in common with his prehistoric ancestors and with all primates, the neuroendocrine system becomes activated, preparing the organism for physiological activity, e.g., fight or flight, even in situations where such reactions are clearly inadequate. The resulting increase in “Stress (Selye)” may lead to an “increased rate of wear and tear” in the organism, in prrdis-
It has been generally accepted that the mechanisms and precursors of ulcer are varied. In this regard, Grossman 1341 mentioned that “when we speak of duodenal ulcer we are speaking of a whole group of diseases which share only a hole in the duodenum as the manifestation and there may be many pathogenic mechanisms operating.” Implied in Grossman’s statement is that the study of the effect of psychological stress on ulceration directly, as in the majority of psychological experiments, is not so revealing. Little is learned from experiments which demonstrate that a “hole” in the gastrointestinal tract can be developed by a psychological procedure. A more relevant research goal is the identification of the pathophysiological reactions which are partly manifested by ulcer formation. A great deal of research information is lost by concentrating on the end product, ulcers, in psychological experimentation. Indeed, it may turn out that psychologically mediated gastrointestinal changes do not initiate ulcers altogether and that their effects is limited to sustaining them. It is worth noting that in Mikhail’s work [21] conditioned fear did not initiate new ulcers nor did it delay the healing of existing ones in rats. The possibility still remains, however. that anger mediated changes may sustain ulcers in predisposed animals or human.
ever,
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