Influences of Suggestion on Airway Reactivity in Asthmatic Subjects

Influences of Suggestion on Airway Reactivity in Asthmatic Subjects THOMAS LUPARELLO, M.D., HAROLD A. LYONS, M.D., EUGENE R. BLEECKER, B.A., and E. R. McFADDEN, Jn., M.D. The effect of suggestion on bronchomotor tone was evaluated in a setting in which accurate, rapid, and reproducible measurements of airway resistance (Ra) could be made. Subjects with asthma, emphysema, and restrictive lung disease, as well as normal subjects, were studied. All subjects were led to believe that they were inhaling irritants or allergens which cause bronchoconstriction. The actual substance used in all instances was nebulized physiologic saline solution. Nineteen of 40 asthmatics reacted to the experimental situation with a significant increase in Ra. Twelve of the asthmatic subjects developed full-blown attacks of bronchospasm which was reversed with a saline solution placebo. The 40 control nonasthmatic subjects did not react. IHE INVESTIGATION of bronchial asthma has been concerned with the role of allergic, infectious, psychological, social, endocrinous, and hereditary factors. 1 Up to now, no single causative determinant has been isolated, and it appears that a variety of factors may be involved in the development and continuance of asthma From the Departments of Psychiatry and Medicine, State University of New York, Downstate Medical Center, Brooklyn, N. Y. Supported in part by National Institute of Mental Health Research Career Development Award K3MH 15,620 and Grants MH-13439, National Institute of Mental Health, and 5T1- HE 5485, National Heart Institute, U. S. Public Health Service. Presented in part at the Annual Meeting of the American Psychosomatic Society, Mar. 30, 1968. The authors wish to thank Mrs. Frances Klugman for her help in the preparation of the manuscript and Miss Eileen Abramoff for her help with the statistics. Received for publication Apr. 5, 1968. 819 and in the precipitation of any given acute attack. The effect of psychological stimuli on the precipitation of asthma attacks has been evaluated sporadically over the years. MacKenzie 2 noted bronchospasm in a patient with an "allergy" to roses, when he presented to her an artificial rose. More recently, Dekker and Groen 3 exposed asthmatic subjects to "meaningful emotional stimuli" and were able to measure a decrease in vital capacity in some of the subjects. Each stimulus in that study was specific for a particular subject and represented historical events in the individual's disease process. For example, one subject reported developing asthma attacks at the sight of goldfish in a bowl. When shown an artificial representation of this by the experimenters, the subject developed bronchospasm. Another individual, who had indicted dust as a trigger substance for asthma, reacted with bronchospasm

TdI3LE 1. PLI.:THYSUOGRAPHIC HI:SPOSSI.:S OF TI.:.';T SUNJI.:CTS TO TIIF. ISI~AL.STIOS OF SUGGI.:STI.:I) I~OGUS.~LI,ERGI.:SS OR IRHITAST~ ---. Ra*f TGV*$ Ga/TGV*# Sex (m. H20 ~L./ner.) (L.) (L./aec./cni. HrO 'L.) -- - - - - - ----- -- - -- - - Subjects So. dl F I ge* B 11 PI? I3 I' I B 1'1 Asthmatic 40 14 26 25.8+ 7.4 2.YL h0.27 3.13 h 1.35 2.79 11~0.493.00 +0.74 0.18 +.05 0.12 h.05 Nor~nal 10 4 6 28.7 + 1.8 1.2% +0.36 1.39 +0.37 2.86 +0.41 2.85 &0.41 0.32 &.I1 0.28.09 Restrictive 15 4 11 30.0 & 9.8 3.77 & 0.82 3.12 & 0.89 2.12 + 0.70 2.01 & 0.64 0.20 h.07 0.18 +.05 Iironchitic 15 10 5 51.8 & 14.8 8.59 & 1.44 8.95 + 1.28 3.91 h 1.02 4.03 & 1.05 0.09 +.03 0.08 &.03 * Yalues given are the mean and standari deviation. t Airway resistance. 3 Thoracic gas volume. Conductance-thoracic gas vollin~ ratio. :I Baseline meas~~rementx. TI Postirihalation measurements. - - -- TABLE: 2. EFFIXT OF SUGOI.:~TJOS os AIRW.IY ~ZI.:ACCIVITY IN AS'I'HMATIC SURJECTS Ra ---- --- -- TGV Ga/TGV (mt. HzO/L./ser.) (L.) (L./sec./rm. HtO/L.) Aslhmalic subjects.vo. H PI R PI B PI - - Clinical &thma attacks 12 2.29 &0.60 4.97 & 0.87 2.71 +0.69 3.10 h0.85 0.18 +0.0.? 0.07 +0.03 Increased Ra with no symptoms 7 2.26 & 0.35 3.72' & 0.41 2.57 + 0..%?.83 + 0.67 0.18 + 0.05 0.10 + 0.01 No reactions 21 2.16 &0.51 2.44 &0.4(\ 2.W +0.73 2.99 *0.72 0.18 +0.05 0.15 +0.05 Abbreviations and measurement valr~es are the same as in Table 1. --

LUPARELLO T AL 821 when presented with a sealed glass container filled with dust. Those experiments have demonstrated that certain asthmatics are sensitive to perceptual cues which are capable of affecting bronchomotor tone. However, the heterogeneity of the stimuli employed was such that it was not possible to make meaningful comparisons within the group of subjects. In addition, the respiratory end point chosen was an indirect and relatively insensitive measure of airway obstruction. The present study was undertaken to overcome these problems and to gain an impression of the prevalence of psychological stimuli as factors in the precipitation of asthma attacks. The independent variable chosen was suggestion, since it could be clearly defined, uniformly applied to all subjects, and easily controlled in a laboratory setting. Changes in airway resistance (Ra) were measured directly by body plethysmography. In addition, it became possible to determine whether the effects of suggestion on bronchomotor tone were unique for asthmatics or were shared by subjects with other lung diseases. Methods The data were obtained from 40 asthmatic subjects. The diagnosis of asthma was based on a characteristic history of episodic attacks of reversible bronchospasm associated with a family or personal history or both of allergy, and on an absence of irreversible mechanical defects within the lungs. The subjects were told that they were cooperating in a study related to the control of air pollution and that the experimenters were trying to determine the concentrations at which a variety of substances in the atmosphere would induce attacks of wheezing. It was indicated to each subject that he would be inhaling five different concentrations of an irritant or allergen which the subject had previously indicted as being associated with his asthmatic attacks. The subject was led to believe that he would be exposed to progressively increasing concen- VOL XXX, NO. 6, 1968 trations of this substance, whereas the material actually presented to him, in all instances, was physiologic saline solution. Ra and thoracic gas volume (TGV) were measured in a Collins body plethysmograph, prior to the onset of any test inhalation. 4 Ra and TGV were calculated as the mean of five successive measures of each variable. Resistance was converted to its reciprocal or conductance (Ga) and was expressed as a conductance thoracic gas volume ratio (Ga/TGV) in order to correct for a variation in lung volume during testing. 8 The normal range for this ratio is 0.13 to 0.35 L.sec./cm. H 2 O/L. After baseline data were obtained, the subjects inhaled over a 30-sec. period ten deep breaths of the suggested "allergen" or "irritant" from a DeVilbiss nebulizer. Following this, Ra and TGV were measured at 1-min. and 4-min. postinhalation intervals, with each measurement representing the mean of 5 determinations at each interval. This procedure was repeated for each new suggested "increased concentration" of the bogus allergen or irritant given to the subject. In the event the subject experienced dyspnea or wheezing, the inhalations were stopped and a placebo in the form of nebulized physiologic saline solution was administered; the subjects were told that they were receiving Isuprel. The Ga/TGV ratios were then determined 3 min. after administering the placebo. As control subjects, 10 normal individuals, 15 subjects with sarcoid or with tuberculosis (restrictive lung diseases), and 15 individuals with chronic bronchitis were investigated in the same manner, except that they were told the inhalants were 5 different concentrations of industrial air pollutants which cause bronchial irritation and difficulty in breathing. Results The data are summarized in Table 1. The mean age of the asthmatic subjects was 25.8 years with a standard deviation (S.D.) of 7.4 years. There were 26 women and 14 men. The mean baseline Ra was 2.22 ± 0.27 cm. H 2 O/L./sec. This was associated with a TGV of 2.79 ± 0.49 L. which produced a Ga/TGV ratio of 0.18

822 SUGGESTION AND ASTHMA 5.05- FIG. 1. Mean Ga/TGV ratio values of 12 asthmatic subjects developing clinical signs and symptoms of bronchospasm in response to the inhalation of a supposed allergen or irritant, and the subsequent response following the administering of a placebo. ± 0.05 L./sec./cm. H 2 O/L. Following exposure to the suggested allergen or irritant (i.e., saline solution), the Ga/TGV ratios of the entire group fell to an abnormal level (mean Ga/TGV ratio 0.12 ± 0.05; p = 0.001 by t test). This change was effected by an increase in the Ra to 3.43 ± 1.35 cm. H 2 O/L./sec, while the TGV only increased to 3.00 ± 0.74 L. This clearly indicated that the Ga/TGV ratios fell because of a disproportionate rise in Ra. Correlation between baseline values and postinhalation Ga/TGV ratios in the entire group of asthmatics indicated that the changes produced in this ratio were not a function of the initial value (r = 0.05). Twelve of the 40 subjects developed full-blown clinical attacks of asthma with dyspnea and wheezing. The mean Ga/ TGV ratio of these 12 individuals dropped from a baseline ratio of 0.18 ± 0.03 to 0.07 ± 0.03 L./sec./cm. H 2 O/L. following inhalation of the supposed noxious substance (Table 2). Following the administration of a placebo, the Ga/ TGV ratio rose to 0.13 ± 0.04 L./sec./ cm. H 2 O/L. (Fig. 1). An analysis of variance for correlated means reveals significant differences between the baseline values and the lowest Ga/TGV ratios following inhalation of the supposed irritant or allergen, and between this lowest value and that obtained 3 min. following the giving of a placebo. Further analysis by Duncan's New Multiple Range Test showed that there was a significant difference between the baseline levels and the lowest ratio values (p < 0.001) and between the pre- and post placebo administration values (p < 0.001). Seven of the 40 subjects responded with an increased Ra (Table 2) so that their Ga/TGV ratios fell below accepted normal levels. However, the degree of airway obstruction associated with these changes was not of sufficient magnitude to induce signs and symptoms of acute bronchospasm (Ga/TGV ratio baseline values, 0.18 ± 0.05; Ga/TGV postinhalation values, 0.10 ± 0.01). The remaining 21 asthmatic subjects did not respond to the experimental manipulation (Table 2), and there was minimal change in their Ra (Ga/TGV ratio baseline values, 0.18 ± 0.05; Ga/TGV ratio postinhalation values, 0.15 ± 0.05; p = N.S.). Figure 2 shows the characteristic responses of 2 subjects who reacted to the inhalation of bogus allergens with bronchospasm and the responses of 2 asthmatic subjects who, under similar test conditions, did not react with bronchospasm. No changes were found in the Ra or Ga/TGV ratios of the normal, restrictive, or bronchitic subjects studied (Table 1). It is of interest to note that the mean baseline Ga/TGV ratio of the bronchitic group was in the abnormal range (Ga/ TGV ratio value, 0.09 ± 0.03 L./sec./ cm. H 2 O/L., and it might be argued that significant changes in the Ra of this population would be missed because of the large baseline TGV. However, several asthmatic subjects were observed who had equivalently abnormal baseline Ga/ PSYCHOSOMATIC MEDICINE

LUPARELLO ET AL. 823 TGV ratio values but who still responded to the experimental situation with a marked fall in Ga/TGV ratio values (e.g., a baseline Ga/TGV ratio value of 0.12, followed by a postinhalation Ga/ TGV ratio value of 0.04, observed in one subject). Discussion The data demonstrate that an appropriately supplied suggestion is capable of influencing the airway caliber of 47.53! of the asthmatic subjects investigated. Bronchoconstriction or dilatation could be accomplished, depending upon the suggestion supplied. This phenomenon was not observed in normal subjects or in subjects with bronchitis or restrictive lung diseases. It cannot be argued that the asthmatics developed their attacks by chance alone under the stresses of the experimental situation, since this would not account for the dramatic reversal of the bronchospasm in those subjects who received a placebo under the same test conditions. The following observation illustrates that the response of the subjects was related specifically to the suggestion. One subject, who was given the suggestion that she was inhaling pollen, developed hay fever as well as bronchospasm. As part of another experiment, she was given the suggestion that the inhalant was dust and the subject then had only an asthma attack without hayfever. On a third occasion, following exposure to supposed "pollen," she once more reacted with hayfever as well as asthma. Although the independent variable in the present study has been referred to as suggestion, it may be that such a designation is an over simplification. It is possible that certain elements of conditioning may also be operating. If an individual has repeatedly associated the FIG. 2. Solid lines represent the responses of 2 asthmatic subjects who reacted to the inhalation of suggested allergens with bronchospasm (expressed as a fall in the Ga/TGV ratio value). Broken lines represent the responses of 2 asthmatic subjects who did not react to the same test stimulus. NON REACTORS CONTROL 1 2 3 4! INHALATION OF SUGGESTED ALLERGEN OR IRRITANT YOL XXX, NO. 6, 1968

824 SUGGESTION AND ASTHMA onset of asthma attacks with the presence of a specific agent, it is possible that contiguous stimuli may assume a conditional stimulus value. The present study, however, does not provide sufficient information to permit a distinction to be made about the various types of learning which could be instrumental in bringing about the phenomenon observed in this investigation. With the demonstration that asthmatics can be divided into two populations namely, those who react to suggestion with changes in lung mechanics and those who do not, it becomes relevant to inquire about other possible differences between these two populations. For example, are there differences between the two groups in personality, duration of illness, frequency of attacks, or allergic diathesis? These questions cannot be answered on the basis of the available information, and further studies are required before any meaningful comparisons of the two asthmatic populations can be made along these parameters. The changes in the Ga/TGV ratio observed in the present study occurred primarily because of a fall in airway conductance. The rapidity of both the responses and their reversibility point to a change in smooth-muscle tone as the most likely explanation. 6 In another study, we have demonstrated that atropine is capable of blocking the bronchoconstriction induced by suggestion, 7 indicating that the response of airways to this stimulus is mediated through cholinergic efferent pathways. This hypothesis is in keeping with the observations of Simonsson et al. s Those authors have shown that stimulation of subepithelial receptors will trigger reflex airway constriction, which is eliminated by atropine blockade of the efferent limb of the reflex arc. The present study indicates that activation of efferent fibers can occur at a central level without direct stimulation of the afferent side. The exact site of stimulation of the efferent fibers and the mechanism by which they are activated is unknown. Asthma is a complex disease process, the pathogenesis of which remains unknown. In the light of the present findings, a meaningful assessment of the precipitants of asthma and the treatment of any given asthmatic patient must necessarily include an appraisal of the role played by suggestion. If an individual associates a specific agent with the onset of his asthmatic attacks, there is a likelihood that contact with that substance when the asthmatic is aware of it will induce an asthma attack, regardless of whedier that agent at that time is physiologically active. Subsequent provocative tests for diagnostic purposes, if done with the subject's knowledge of the test substance, will probably only enhance the asthmogenic potential of that substance. Similarly, the expectation* of the patient will have a marked influence on the efficacy of any given therapeutic.regimen. Research related to the psychophysiology of asthma must necessarily institute suitable controls for the influence of suggestion. In such experiments, it often becomes extremely difficult to provi.de adequate controls for the large number of complex, interacting psychological variables presumed to be operating. In those instances, it is especially important to be sure that the subject is not responding to subtle cues being communicated by the experimenter. Such cues could operate as a suggestion for a particular response, which would then confound rather than clarify the psychophysiology of asthma. Summary The effect of suggestion on the pulmonary mechanics of subjects with bronchial asthma, of subjects with restrictive lung diseases, of emphysematous subjects, and of normal individuals was PSYCHOSOMATIC MEDICINE

LUPARELLO ET AL. 825 studied by whole-body plethysmography. Following baseline measurements of Ra, each subject was told that he would be inhaling progressively increasing concentrations of an allergen or irritant which would induce bronchospasm. The substance actually given was nebulized physiologic saline solution. After inhalation of the bogus allergen or irritant, the mean Ra of the entire group of asthmatic subjects rose significantly. This was brought about by a marked rise in the Ra of 19 of the 40 asthmatic subjects. Of those 19 asthmatic subjects who reacted, 12 developed full-blown attacks of asthma with wheezing and dyspnea. All asthma attacks were successfully treated with a saline solution placebo, and 3 min. after the inhalation of the placebo, the Ra had returned to baseline levels. The normal subjects and those subjects with restrictive and nonasthmatic, obstructive lung diseases did not react to the inhalation of suggested bogus irritants or allergens with significant changes in Ra. Downstate Medical Center 450 Clarkson Ave. Brooklyn, N. Y. 11203 References 1. STEIN, M. "Etiology and mechanisms in the Development of Asthma." In The First Hahnemann Symposium on Psychosomatic Medicine. Lea, Philadelphia, 1962, p. 149. 2. MACKENZIE, J. N. The production of "rose asthma" by an artificial rose. Amer J Med Sci 91:45, 1886. 3. DEKKER, E., and GROEN, J. Reproducible psychogenic attacks of asthma. / Psychosom Res 1:58, 1956. 4. DuBois, A. B., BOTELHO, S. Y., and COMROE, J. H., JR. A new method for measuring airway resistance in man using a body plethysmograph: Values in normal subjects and in patients with respiratory disease. / Clin Invest 35:327, 1956. 5. BRISCOE, W. A., and DuBois, A. B. The relationship between airway resistance, airway conductance and lung volume in subjects of different age and body size. / Clin Invest 37.1279, 1958. 6. WIDDICOMBE, J. G. Regulation of tracheobronchial smooth muscle. Physiol Rev 43:1, 1963. 7. MCFADDEN, E. R. JR., LUPARELLO, T., LYONS, H. A., and BLEECKEB, E. R. The mechanisms of action of suggestion in the induction of acute asthma attacks. In preparation. 8. SIMONSSON, B. G., JACOBS, F. M., and NADEL, J. A. Role of autonomic nervous system and the cough reflex in the increased responsiveness of airways in patients with obstructive airway disease. / Clin Invest 46.1812, 1967. VOL XXX, NO. 6, 1968