Acquiring Symptoms in Response to Odors - A Learning Perspective on Multiple Chemical Sensitivity

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Acquiring Symptoms in Response to Odors:A Learning Perspective on Multiple Chemical Sensitivity

OMER VAN DEN BERGH,a,b STEPHAN DEVRIESE,b WINNIE WINTERS,b

HENDRIK VEULEMANS,c BENOIT NEMERY,c PAUL EELEN,b ANDKAREL P. VAN DE WOESTIJNEc

bDepartment of Psychology, cFaculty of Medicine, University of Leuven, Belgium

ABSTRACT: In this chapter, a learning account is discussed as a potential expla-nation for the symptoms in multiple chemical sensitivity. Clinical evidence isscarce and anecdotal. A laboratory model provides more convincing results.After a few breathing trials containing CO2-enriched air as an unconditionedstimulus in a compound with harmless odor substances as conditioned stimuli,subjective symptoms are elicited and respiratory behavior is altered by theodors only. Also, mental images can become conditioned stimuli to trigger sub-jective symptoms. The learning effects cannot be explained by a response biasor by conditioned arousal, and they appear to involve basic associative pro-cesses that do not overlap with aware cognition of the relationship between theodors and the CO2 inhalation. Learned symptoms generalize to new odors andthey can be eliminated in a Pavlovian extinction procedure. In accordance withclinical findings, neurotic subjects and psychiatric cases are more vulnerableto learning subjective symptoms in response to odors. Consistent with a learn-ing account, cognitive-behavioral treatment techniques appear to produce bene-ficial results in clinical cases. Several criticisms and unresolved questionsregarding the potential role of learning mechanisms are discussed.

INTRODUCTION

Several excellent reviews on multiple chemical sensitivity (MCS; or idiopathicenvironmental intolerance, IEI)1–4 and special issues of journalsd document itssymptoms, prevalence, prognostic course, and possible pathogenic mechanisms.Two major features characterize this syndrome: (1) the presence of a wide variety ofnonspecific subjective symptoms, such as fatigue and weakness, cognitive diffi-culties (concentration and memory), dizziness, pounding heart, shortness of breath,anxiety, headache, and muscle tension;5,e and (2) a spatiotemporal relationshipbetween the symptoms and the presence of (often odorous) chemical substances thatare often structurally unrelated and at doses below those known to cause harmful

aAddress for correspondence: Omer Van den Bergh, Department of Psychology, University ofLeuven, Tiensestraat 102, B-3000 Leuven, Belgium. Voice: +32 16 32.60.58; fax: +32 16 32.60.55.

[email protected], for example: Toxicol. Ind. Health, 1994, 10(4,5); Environ. Health Perspect., 1997, 105;

and Occup. Med., 2000, 15(3).eThe symptoms also occur, for example, in chronic fatigue syndrome,5 fibromyalgia,5 panic

disorder,6,7 posttraumatic stress disorder,8 and hyperventilation syndrome.9

279VAN DEN BERGH et al.: A LEARNING PERSPECTIVE ON MCS

effects in the population.10 Thus, the basic questions regarding MCS are as follows:what is the origin of these symptoms and how can the link with chemical substancesbe explained?

In the present chapter, we will discuss the evidence for one potential explanation,namely Pavlovian conditioning. The evidence will not be discussed in the context ofan antithesis between psychologic and biologic explanations. Such an antithesis is,we believe, counterproductive. First, the subjective symptoms of MCS are bydefinition the result of psychologic processes. Part of their input may come from bio-logic dysregulation and part may come from mental processes, but perceptual-cognitive processes of symptom perception and interpretation are the final route toall subjective symptoms. Second, Pavlovian conditioning should be regarded as anadaptive psychobiologic process. The salivation of Pavlov’s dog is a biologicresponse, and the mental processes that trigger it have a biologic substrate. Thedifference between a psychologic and a biologic explanation is therefore mainly amatter of level of description. Nevertheless, these different levels may suggest quitedifferent approaches to treatment. In this chapter, we will argue that evidence for aPavlovian conditioning hypothesis is accumulating, that it has great explanatorypower, and that it offers interesting treatment options.

THE PAVLOVIAN CONDITIONING HYPOTHESIS OF MCS

In its simplest form, Pavlovian conditioning relies on the co-occurrence of twoevents. An unconditional stimulus (US; e.g., a toxic exposure or another traumaticevent) may trigger an unconditional response (UR; e.g., an array of bodily responsesand subjective symptoms). The occurrence of this US in a spatiotemporal relation-ship with a neutral f stimulus (a conditioned stimulus, CS; e.g., an odor or harmlesschemical) may endow the CS with the capacity to elicit UR-like responses that, atthat moment, become conditioned responses (CRs) (see FIG. 1).

We translated this simple Pavlovian schema into a laboratory model in order totest whether subjective symptoms induced by a physiological challenge in associa-tion with a harmless odoring chemical could be elicited by presenting the latter stim-ulus only. The basic model implied the administration of a number of breathing trialsof two minutes each (see FIG. 2). Air enriched with 7.5% CO2 served as a respiratoryUS and two odors as CSs, for example, dilute ammonia and niaouli (a mixture con-taining mainly eucalyptus oil). In the learning phase, subjects breathed one odormixed with CO2 (called the CS+ trial) and the other odor mixed with room air (calledthe CS− trial).

In the test phase, the breathing trials contained the odors only, that is, there wasno CO2. Respiratory frequency, tidal volume, end-tidal fractional concentration ofCO2, and heart rate were measured throughout the experiment and subjective symp-toms were registered after each trial. Often, conscious awareness of the contingencyrelationship between the CS+ odor and the experienced symptoms during the acqui-sition phase was also registered.

fA CS is not necessarily neutral in an absolute way, but in a relative way in that it does notelicit the same URs as the US by itself.

280 ANNALS NEW YORK ACADEMY OF SCIENCES

This experimental model replicates important features of MCS: (1) it involveshuman subjects; (2) the major dependent variable consists of a variety of subjectivesymptoms; (3) CO2 inhalation may represent a conceptual analogue for a toxicexposure; and (4) harmless odoring chemicals are introduced to serve as elicitors ofthe symptoms.

In addition, both bodily responses and subjective symptoms are measured, allow-ing investigation of the concordance/divergence among the two sets of responses. Animportant methodological advantage is also that the conditioning effect can be testedboth within subject and within odor, meaning that the subject and the odor serve astheir own controls. The following results were obtained in a series of experiments:

(1) After a few pairings of the CS+ odor with CO2, presenting the CS+ odoralone altered respiratory behavior and induced elevated levels of somaticsymptoms “as if the subjects were still breathing CO2”.11–15

(2) The learning effect was selective: conditioning effects only occurred tofoul-smelling ammonia as CS+ odor and not to neutral/pleasant-smellingniaouli as CS+ (see FIG. 2). When both CS odors were foul smelling (irri-tant ammonia and nonirritant butyric acid), learned symptoms emerged toboth, suggesting that affective valence of the odors was the critical variablefor the selective association effect.11–14

(3) The learning effect was specific: no conditioning effects appeared forsymptoms usually not provoked by CO2 (“dummy symptoms”) and theeffects could not be explained by conditioned arousal/anxiety only. Wenever observed a conditioned heart rate increase, and the effects werelargest for the subset of symptoms that are typically elicited by CO2.12–14

(4) Conscious awareness of the relationship between the odor and CO2-induced symptoms was not critical for the effects to occur. For all odorsused as CS+, the participants were roughly equally aware of the experi-mentally induced contingencies, yet they only showed conditioning effectsto foul-smelling CSs. This suggests that more basic learning processes thanthose reflected by conscious awareness are involved.12–14

FIGURE 1. Traditional Pavlovian schema (applied to MCS).


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(5) A straightforward extinction procedure, involving a series of unreinforcedCS exposures, readily reduced the learned symptoms.14

(6) Once symptoms to one odor were learned, they generalized to newly pre-sented odors provided that they had a negative affective valence (i.e., werefoul smelling). For example, subjects conditioned to have symptoms toammonia showed elevated symptoms also to (first time presented) foul-smelling butyric acid and acetic acid, but not to fresh-smelling citricaroma.15

(7) Mental cues and images can also serve as CSs: Merely evoking an image ofa situation that was previously paired with the experience of CO2-inducedsymptoms elicited those symptoms and altered respiratory behavior.Again, negative emotional valence of the images appeared to be an impor-tant modulator: learning effects only showed up when the imagined situa-tions were stressful.16

(8) Although both (respiratory) symptoms and altered respiratory behaviorwere learned, the symptoms in the test phase were not a reflection of theactual (learned) physiologic responses. Rather, the symptoms were relyingon an activated memory representation of the symptoms experienced in theacquisition phase. This activation process was automatic in that it requiredlittle or no conscious mental resources.13

(9) Important individual differences occurred:(a) The level of neuroticism or negative affectivity (NA) in normals modu-lated the conditioning effects: Learned symptoms and their generalizationto new odors were, overall, more elevated in a group of subjects scoringhigh on negative affectivity.13,15

(b) The learning effects on symptoms were overall stronger in a group of“psychosomatic” patients. This suggests that psychopathological groupsare more vulnerable to learning symptoms.12

The latter findings are strikingly similar with the fact that neuroticism or NA is a riskfactor for developing MCS17 and that psychiatric populations are more likely to devel-op MCS. Especially high rates of MCS are found in patients suffering from medicallyunexplained symptoms such as chronic fatigue syndrome and fibromyalgia.18

Overall, this set of experimental data provides strong evidence for the plausibilityof a learning explanation for MCS. In general, our effects were highly reliable,although they were limited in magnitude and well below clinical levels. However,learning theory implies that much stronger USs produce stronger learning effects,reduce the likelihood of extinction, and enhance generalization. For obvious reasons,stronger USs are difficult to apply in humans for experimental purposes.

MCS WITHIN A CONTEMPORARY VIEW ONPAVLOVIAN CONDITIONING

Although the experimental model sketched above apparently represents astraightforward application of Pavlov’s classical procedure, this does not mean thatPavlov’s original mechanistic theoretical framework applies to explain the results.Contemporary views heavily rely on an information processing framework (see


FIG. 3), linking Pavlovian conditioning even to forms of causal reasoning.18 An ex-tensive discussion of these more liberal theoretical views is beyond the scope of thischapter. Only a few aspects will be mentioned here and their potential implicationsfor MCS will be discussed in the next section.

If a CS is co-occurring in some regular manner with a US, an associative link witha certain strength is formed between the memory representations of the two events.A CS allows for the prediction of an upcoming US, implying the activation of thememory representation of the US, which in turn may elicit (adaptive) conditionedCRs. The associative link does not depend on actual pairings of the CS and US only,but on the informational value of other relevant events as well (see, e.g., phenomenasuch as blocking, latent inhibition, etc.).19 In animals, actual events are the mainsource of information, but humans also possess other sources that may modulatetheir expectancy once a CS occurred. Davey20 (see FIG. 3), for example, lists situa-tional, verbally and culturally transmitted information, existing beliefs, and emo-tions elicited by the CS.

An activated memory representation of a US does not directly translate into a re-sponse either. Learning and performance appear quite distinct phenomena: a learnedassociation may remain behaviorally silent in some conditions and suddenly showup in other conditions. Conditioning effects may also be modulated by postcondi-tioning manipulations. For example, when an organism has learned a tone-shockrelationship, subsequent presentations of a much stronger shock alone may induce areevaluation of the US in memory and inflate later CRs to the CS.19 In Davey’s mod-el,20 reevaluation of acquired associations in humans may occur through verbally

FIGURE 3. A contemporary schema of Pavlovian conditioning. From reference 20.


transmitted information, interpretations given to interoceptive cues, cognitive re-hearsal, and coping strategies (see FIG. 3). In summary, several processes may mod-ulate the formation of associative links and their translation into behavioral output.

Some reviews and editorials about MCS give only brief consideration to associa-tive learning, if at all, and subsequently dismiss it as being inadequate. Often, this isbased upon an impoverished view on conditioning processes. We will elaborate onsome criticisms within a contemporary view on associative learning.

CRITICISMS AND UNRESOLVED QUESTIONS

What Is the US in MCS?

The conditioning hypothesis is often rejected on the grounds that, very often, noprevious toxic exposure is found in the history of an MCS patient. Referring toPavlov’s prototypical dog, Staudenmayer21 phrased this as “where is the meat?”. Inother words, there would be no US. We suggest that, for instance, regular stress-induced hyperventilation episodes in a “chemical context” may act as a US in thesame way as shown in our experiments with CO2-induced hyperventilation. How-ever, because learning processes may loosen the link between symptoms and theirphysiological correlates (see above), a one-to-one relationship between hypocapniaand the presence of symptoms should not be considered critical for this hypothesis.22

This view may explain a number of observations: (1) the origin of MCS appears in somecases to be linked to episodes of stress and not to toxic exposures;23 (2) a substantialoverlap exists among the symptoms of MCS and those of hyperventilation, such asintermittent flares of fatigue and weakness, dizziness or light-headedness, cognitivedifficulties (concentration and memory), shortness of breath, sore throat, dry mouth,palpitations and “racing heart”, gastrointestinal problems, and feelings of anxiety ordepression;4,9,11,24 (3) the exposure of MCS patients to their chemical triggerinduced hyperventilation in 73% of them.25 In some cases, both hyperventilation andtoxic exposures may be involved. For example, a toxic exposure may be a primary US,causing conditioned symptoms and anxiety to odoring substances or specific “contami-nated” environments. Subsequent exposures to the CS may induce hyperventilation aspart of anticipatory anxiety, and in this way become a secondary US.

What Is the CS?

The likelihood for a given cue (CS) to become associated with a US is determinedby a number of variables. One is its salience, which may in turn be influenced byculturally transmitted information, preexisting beliefs, and/or emotional reactions toavailable cues (see FIG. 3). For example, the belief that the air is chemically pollutedmay facilitate associating symptoms to perceived chemicals. Even thoughts andmental images may function as CSs for learned symptoms, as was shown in one ofour studies16 (see above). The images in that study were selected as being relevantfor panic, but it would be interesting to investigate mental images relevant for MCSas well. For example, imagining being in polluted places may potentially come toserve as mental CSs. As a consequence, tangible or measurable CSs may not alwaysbe present in the environment or perceivable to an outside observer.


This may explain why the incidence and prevalence of MCS appear to vary be-tween geographical areas. Although epidemiological data are scarce, MCS appearsto be very much an American disease and much less a European disease. WithinEurope, the distribution is likely to vary depending on the level of awareness ofenvironmental pollution and the salience of cues.

Why Do Not All Toxic Exposures Lead to MCS?

A similar question has been dealt with extensively in the context of conditioningmodels of fear and anxiety: why is it that severe traumatic events produce PTSD inonly 30% of the cases?26 The probability of MCS following a US (toxic exposure orhyperventilation) may be determined by aspects of the US, the CS, characteristics ofthe individual, and/or their interaction. Actually, this was typically shown in a recentexperiment:15 learning effects only occurred in subjects scoring high on negativeaffectivity (NA) who had a foul-smelling odor (ammonia) as CS. Subjects with thesame number and intensity of USs, but having had a neutral/fresh odor as CS and/ornot scoring high on NA, did not show effects.

NA in MCS patients may contribute in several ways to the development of MCS.First, a toxic exposure or a hyperventilation episode may impact stronger upon personswith NA and produce stronger autonomic responses as internal responses (URs). Sec-ond, persons high on NA may interpret these URs as more threatening, thus affecting theexperienced intensity. Third, NA may bias persons to link negative events (US) to nega-tive cues in their environment (CS). Fourth, such subjects may comparatively be moreaffected by culturally transmitted information about the presence and toxicity of environ-mental chemicals and hence form more explicit preexisting beliefs in this regard. Fifth,persons with NA may be more vulnerable to postconditioning cognitive processes:worrying and catastrophical interpretations after a toxic or hyperventilatory eventmay increase the CRs (see below).

Why Is There No Spontaneous Extinction?

Repeated nonreinforced exposures to conditioned odors should produce extinc-tion of the learned responses. Because most patients cannot avoid being exposed toodorous substances, the question is why do symptoms not extinguish in patients. Aselection bias may operate here because only patients present themselves to doctorsand hospitals, and little is known about the course of events in those subjects whosesymptoms do gradually decline after a toxic accident. Also, the persistence of thesymptoms may be due to extensive avoidance behavior, preventing exposure to crit-ical cues for a duration sufficiently long to allow extinction. More importantly, how-ever, is recent evidence showing that Pavlovian extinction does not produceunlearning.27,28 Rather, additional knowledge is acquired in such a procedure,implying that, in some contexts or at some moments in time, the learned CS-USrelation does not hold. Conditioning, therefore, is like learning a rule (CS predictsUS) and extinction is like learning contextually dependent exceptions-to-the-rule(CS predicts US, but not now/here28). Thus, what is extinguished in one context maystill emerge in another.

Several processes modulating conditioning can also retard or prevent extinction,such as very intense USs in subjects high on neuroticism29 and postconditioning pro-


cesses (mental rumination, worrying, catastrophic thinking acting as reevaluationsof the US; see above). To the extent that hyperventilation is involved, each new epi-sode potentially induced by anticipatory stress will reinforce the existing associationand prevent effective extinction as well.

Range of Stimuli Amenable to Generalization

Devriese et al.15 demonstrated that learned symptoms generalized from the CSodor to newly presented odors, following stimulus valence as a generalizationgradient (i.e., generalization occurred to foul-smelling odors, but not to neutral orpositively valent ones). However, patients often show symptoms to perfumes, freshodors, and even tastes and foods. Again, stronger USs than we used in our experi-ments may broaden the range of stimuli amenable to generalization.30 In addition,several variables promoting blurring or forgetting about the attributes of the CS(duration, context shifts) may substantially broaden the generalization gradient.31

Also, existing cognitive schemata may play a role. For example, the conviction thatperfumes also contain certain chemicals or that both air quality and foods are con-taminated by similar chemical substances may turn these items into negative onesand broaden the generalization gradient. Furthermore, the a priori conviction that aconfrontation with some chemical may be dangerous may evoke anticipatory anxietyand hyperventilation, causing new conditioning experiences and establishing self-fulfilling prophecies.

What Is the Actual UR/CR?

In our experiments, we applied CO2 inhalation as a US and we registered subjec-tive symptoms, breathing behavior, and (sometimes) heart rate as URs. In reality, atoxic exposure or other negative event as US may trigger a wide variety of URs inboth mental and bodily systems, including the autonomic, immune, and endocrineresponses. Up to now, little is known about the causal role of these systems to explainthe symptoms of MCS patients. Indeed, observed differences in autonomic re-sponses to odors or other stimuli between patients and normals may be a result ratherthan a cause of patient status or simply be correlates of higher neuroticism. Even lessis known about the potential role of conditioned modulation of autonomic, immune,and endocrine responses in MCS to explain the symptoms of MCS (see Siegel andKreutzer32 for interesting suggestions).

It should be noted that co-occurring variations in conditioned physiological andsubjective responses should not readily be interpreted as a causal path from theformer to the latter. Each dependent variable may be controlled by different mecha-nisms, as we demonstrated in one experiment.13 Learned respiratory symptoms stillshowed up when a manipulation (a reaction time task) overruled the conditionedalterations of respiratory behavior and prevented them to occur. This suggests thatacquired symptoms are depending on learned perceptual-cognitive processes under-lying symptom perception and not on the presence of altered respiratory behavior.

More detailed analyses of these perceptual-cognitive mechanisms in MCSpatients are needed: Do MCS patients have an attentional bias towards odors andsymptoms? Do they have a negative interpretation bias? Do they ruminate and/orcatastrophize about causes and consequences of their illness? How do they attribute


symptoms to causes? All these processes have been shown to have an importantimpact upon somatic symptoms and to contribute to a self-perpetuating cycle inmany ways.33

Conditioning and (Neural) Sensitization

Neural sensitization refers to an increasing intensity of responses to stimuli, suchas drugs, as a result of repeated intermittent exposure. In MCS, it is hypothesizedthat olfactory, limbic, mesolimbic, and related pathways of the CNS are involved.34,35

Sensitization effects are more likely with stronger stimuli and in conditions ofphysical and psychological stress. A special case is time-dependent sensitization(TDS),36 which specifies that the increase in the response is not just a matter ofrepeated exposures, but also of the time interval between initial and later exposures.

Neural sensitization has been contrasted with conditioning as a potential modelfor MCS.2,34,37 Both basic forms of learning are often distinguished as nonassocia-tive (implying one stimulus) and associative learning (implying two stimuli becom-ing associated), respectively. Despite some apparent procedural differences, Ramsayand Woods38 in an astute analysis of conditioning cogently argued that also sensiti-zation to drugs represents a form of associative learning, provided that the properanalysis is made of what actually constitutes the US, UR, CS, and CR.g In this view,contrasting sensitization and conditioning regarding the processes involved may notbe fruitful. One important difference at the procedural level, however, is that a sen-sitization paradigm requires a reactivity to an initial exposure of a stimulus, whereasa conditioning paradigm does not (see table 1 in Bell et al.40). Given the wide varietyof potential triggers of MCS symptoms, many of which are completely harmless andnever before elicited even the slightest symptom, it appears reasonable to assumethat a new response was learned toward a chemical rather than that a preexisting onewas sensitized. In addition, for many of the hypothesized neurobiological processesin (often animal) sensitization studies, it remains to be seen how they actually relateto subjective symptoms in humans triggered by harmless chemicals.

Implications for Treatment

One of the important implications from our perspective as opposed to a toxico-logical view concerns the treatment options. For example, a learning perspectivesuggests a cognitive-behavioral approach implying exposure to the symptom-provoking stimulus, whereas toxicological or immunological reasoning may actuallyadvise avoidance behavior. Consistent with our perspective is that systematic desen-sitization (SD), a behavioral treatment technique relying on extinction and counter-conditioning principles, has been shown to produce positive treatment results.41–43

Because the efficacy of a treatment is no proof of the correctness of its rationale,37

controlled large-scale treatment studies are needed to corroborate the efficacy ofcognitive-behavioral treatment for MCS. They should also assess whether the effectsmainly involve reduction of associated avoidance behavior, of associated autonomicarousal, or also of the very symptoms of MCS. In addition, because extinction effects

gInteroceptive cues, associated with the presence of the drug in the body, may serve as CSs.39

Those situations may erroneously appear as nonassociative.


appear highly sensitive to contextual conditions (see above), care should be taken toenhance the generalization of extinction effects in order to improve its effectiveness.44

CONCLUDING REMARKS

Our laboratory experiments have convincingly documented the plausibility of anassociative learning model for MCS: odor stimuli that have been associated with aphysiologic challenge inducing symptoms may subsequently elicit comparablesymptoms by themselves. It should be noted, however, that a Pavlovian paradigmmainly refers to a procedure stimulating the formation of associative connections,which in turn can initiate and modulate different perceptual-cognitive and physio-logic processes underlying the experience of symptoms. In addition, because severalexternal, cognitive, and emotional factors may modulate both the probability ofassociation formation and their expression into observable effects (see above),20 Pav-lovian conditioning should not be regarded as a specific explanation, but as an openframework stimulating the search for critical processes underlying MCS symptoms.

Although the account sketched above offers testable predictions for further inves-tigations, it implies tough challenges for the scientific community. Indeed, it hasbeen suggested that CSs need not necessarily be observable to an outside observer;that hyperventilation may be involved as an important mechanism, but should not bepresent during every symptom episode; and that several hard to measure mentalprocesses may play a critical role. However, the involvement of processes that aredifficult to measure may actually be the very reason why MCS is still poorlyunderstood.

ACKNOWLEDGMENTS

This work was supported by Grant No. G.0399.98 N (Fund for ScientificResearch, Flanders, Belgium) and Grant No. OT-97/16 (Research Council of theUniversity of Leuven).

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Acquiring Symptoms in Response to Odors - A Learning Perspective on Multiple Chemical Sensitivity

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