Placebo forte: Ways to maximize unspecific treatment effects

Medical Hypotheses 78 (2012) 744–751

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Placebo forte: Ways to maximize unspecific treatment effects Rainer Schneider ⇑, Julius Kuhl Department of Human Sciences, Personality Psychology Unit, University of Osnabrück, Osnabrück, Germany

a r t i c l e

i n f o

Article history: Received 23 December 2011 Accepted 21 February 2012

a b s t r a c t Placebo effects spark more and more interest in both medicine and psychotherapy. Neurobiological findings have helped to understand underlying biochemical and neurological mechanisms although many questions remain to be answered. One common denominator of empirical findings regarding placebo effects across a wide range of clinical conditions (e.g., depression, Parkinson’s disease, pain, neurological disorders) is the involvement of higher cognitive brain functions associated with the prefrontal cortex. It is meanwhile commonly accepted that placebo effects involve self-regulatory mechanisms whose role in mediating those effects have not been thoroughly investigated yet. We propose a theoretical framework which helps to identify relevant functional mechanisms. Drawing on psychological findings, we propose a mechanism by which placebo effects can be maximized in any type of medical and psychotherapeutic setting. Ó 2012 Elsevier Ltd. All rights reserved.

The prevailing biomedical tenet holds that illnesses can be treated best with interventions based on specific modes of action. This idea originated from the establishment of randomized controlled trials in the 1950s in clinical efficacy testing and continues to dominate evidence-based medicine. However, empirical evidence stemming from placebo research shows that administering placebo therapies neither reflect a fallback in ancient pseudo-medical times [1] nor inevitably deprive the patient of an effective treatment [2]. In this article, we propose a model that purports to explain some of the mechanisms underlying placebo effects. Or model is based on three assumptions: (1) Placebo effects are based on top-down effects treatment-related perceptions exert on the psychosomatic interface (self-regulation). (2) To be effective, self-regulation requires access to a high-level self-representational system (i.e., the ‘‘self’’) which modulates emotional and bodily states (own and others’). (3) Self-access critically depends on certain characteristics of patient and physician-patient relationship. Before explaining our three-partite model, we will give an introductory overview of the role placebo effects play in clinical practice. In medicine treatment response rates, recovery processes and therapeutic efficacy form a complex interaction pattern: Apart from so called specific effects (i.e., effects ascribable to an active medical agent/intervention), so called non-specific effects are an integral part of almost every clinical practice. Misgivings about the use of placebos are in part attributable to confounding specific

and non-specific effects when using the term placebo [3]. A (pure) placebo is unable to produce a specific therapeutic effect since it is inert.1 However, the administration of a placebo may very well ‘‘produce’’ a non-specific therapeutic effect. Over a broad range of quite varied medical conditions (cf. Table 1), placebo effects have been shown to be substantial, sometimes mimicking verum effects. They are, nonetheless, far from being fully understood. Firstly, there are virtually no longitudinal studies, and thus little is known about their time course. Secondly, for many medical conditions their size is varied. Thirdly, the probability with which they occur is difficult to predict. Fourthly, their biochemical correlates are not fully revealed. Fifthly, it is unclear whether they actually alter pathophysiology or primarily alter the perception of symptoms (see [4] for a distinction between disease and illness). In everyday practice, many heath care providers are either reluctant to acknowledge the significance of placebo effects and/ or are uncertain how to ethically justify placebo interventions [40]. Surveys show, however, that placebos are widely incorporated in primary health care [41]. In a recent Swiss survey involving over 200 general practitioners, 72% reported to make clinical use of placebos [42]. Placebo treatments were applied to increase therapeutic effectiveness (69%), treat symptoms not attributable to specific diseases (64%) or simply to meet the patients’ request for treatment (63%). Such figures show that there is an implicit understanding of the therapeutic usefulness of employing placebos even if they appear to not have a direct beneficial effect.

⇑ Corresponding author. Address: RECON – Research and Consulting, Unterer Mühlenweg 38 B, 79114 Freiburg, Germany. Tel.: +49 761 47 66 77 5. E-mail address: [email protected] (R. Schneider).

1 We use the term placebo as a summary term for all forms of placebos. Their common denominator is a lack of active ingredients significant for the illness treated.

Introduction

0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2012.02.022

R. Schneider, J. Kuhl / Medical Hypotheses 78 (2012) 744–751 Table 1 Overview of medical conditions where clinically relevant placebo effects may occura. Class Acute pain (experimentally induced, e.g., via adverse stimuli) Chronic pain (e.g., irritable bowel syndrome, osteopathy) Central nervous diseases (e.g., Parkinson Disease, dementia, migraine) Psychiatric and affective disorders (e.g., depression, anxiety, addiction) Immune system and endocrinology Cardiovascular diseases Performance enhancement (e.g., doping, sexual stamina, cognitive performance) a

References [5–11] [12–14] [15–20] [21–26] [27–30] [31–33] [34–39]

This list is not exhaustive.

However, many health care professionals subscribe to the prevalent deterministic approach, according to which specific mechanisms are ascribable to specific causes of actions. We feel that this view needs to be rectified. Firstly, diseases and disorders often encompass multiple pathways [43] and thus can rarely be remedied by merely treating one cause or class of symptoms. Secondly, specific effects can share common causal pathways which are in fact nonspecific. The latter reason is strikingly demonstrated by an experimental design involving hidden administration of an analgesic substance [28,44]: Patients unaware of the timing and the amount of a painkiller administered to an IV infusion report significantly reduced pain alleviation. Obviously, a drug’s potency involved effects not ascribable to its content. In a similar vein, pain relieving properties of specific neurotransmitter antagonists vanish when the drug is given outside the patient’s awareness. Hence, what is deemed specific with regard to causal pathways may turn out to be quite unspecific in nature bearing on psychological mechanisms. On the other hand, placebo effects, too, crucially depend on the patient’s interpretation of the clinical setting. This is why some researchers dub them ‘psychosocial context effects’ [45] or ‘meaning responses’ [46]. Consequently, placebo effects may be enhanced or abated by factors closely related to the context in which a placebo is given. Clearly, psychological factors may just as well produce negative perceptions of a context and thus amplify negative treatment effects. These so called nocebo effects (from Latin: nocebo = I will harm) have only recently evoked increased research interest, and much about their mechanisms is as yet unknown [47]. In the medical and therapeutic practice, nocebo effects might just be as ubiquitous as placebo effects. For example, in a study by Petrie et al. [48], patients with chest pain assigned to the control group not being reassured that their heart was healthy reported more pain although their health status did not deteriorate. Another example of nocebo effects is the package insert of drugs. Patients primed with warnings show a decline in the drug’s effect. This is corroborated by a recent review which found that effects in placebo arms of clinical trials are often accompanied by adverse effects, which appear to mimic the side effects of the verum arms [49]. Neurobiological evidence demonstrates that in patients responding to placebos (so called placebo responders) different brain regions are activated than in patients responding to specific effects (so called verum responders). Whilst there may be overlapping functional activations, the differences are at times quite striking and point to disparate underlying neuronal mechanisms. From a therapeutical point of view, this cornerstone has major implications. We now turn to the first of our three assumptions mentioned earlier:

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A three-way model of placebo functioning Before discussing our model of underlying mechanisms, it is necessary to steer clear of some methodological problems encountered in the literature. Despite the overwhelming number of publications referring to placebo effects, it is stunning how often the term is used in a misleading way. For instance, many researchers subsume placebo effects under changes observed within placebo arms. This is false for both theoretical and methodological reasons. Firstly, whether an effect is attributable to a particular experimental condition requires a control group design. However, only few clinical trials employ (natural) control groups where no substance is administered. Secondly, changes in the placebo group encompass placebo responses, that is, effects which confound placebo effects, spontaneous remissions, natural illness courses and the like [50]2. Hence, placebo effects can only be tapped when the outcome seen in the placebo arm is compared to that observed in a group not treated. However, even when no treatment is applied, patients may show clinically relevant symptoms, simply because enrollment to a clinical study may alter the perception of clinical symptoms. Thirdly, there is not a single placebo effect as such. Depending on the condition treated, the sample studied, and/or the intervention model used, placebo effects may appear across a large variety of pathways. Top-down modulation at the psychosomatic interface The question how placebo effects work is intimately tied to the question of how they are instigated. Therefore we begin our search for underlying mechanisms with an analysis of their antecedent conditions. Arguably, placebo effects depend on characteristics of the therapeutic setting/experimental treatment, the severeness of the disease or the condition treated, as well as psychological characteristics of both patient and physician. They are usually optimized when expectancy and/or learning (conditioning) are enhanced, that is when the patient expects a certain effect to take place and/or when the placebo is administered repeatedly in the same or similar context [51]. Yet, neither antecedent fully predicts placebo effects. For example, expectancies may sometimes even correlate negatively [3]. Moreover, whether placebo effects are evoked via expectancy or classical conditioning is as yet not fully resolved. It appears that introspectively experienced conditions or symptoms (i.e., pain) are both mediated by expectancy and conditioning whereas biological functions outside the awareness of the patient (i.e., hormone secretion) are mediated by conditioning only [52]. In either case, however, placebo effects are maximized by experience: formerly successful (placebo) treatments enhance both expectancy and conditioning [53]. This may be the reason why for some conditions (e.g., pain) larger effects are found when patients are classically conditioned because the immediate experience of a pain relieve in the conditioning phase reinforces the experience of an alleged pain reducing effect when later placebo is given. Positive experience with an effective placebo treatment may in fact be one central prerequisite of strong placebo effects. As shown by Chung, Price, Verne, & Robinson [54], participants who showed an analgesic placebo effect continued to show this effect in subsequent trials despite the fact that they had been debriefed as to the true nature of the intervention (i.e., placebo). Similarly, in a study investigating open-label placebo (sugar pill), irritable bowel patients reported higher global improvement, reduced symptom severity, and relief for a period up to three weeks [55]. 2 Note that some authors reverse the terms placebo effects and placebo responses (e.g., 18). In pharmacological practice, however, verum effects are net effects exempt from artifacts (i.e., effects not associated with the drug). In accordance with this, the term placebo effect should be used in a similar vein [5].

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Even this brief analysis of antecedent conditions of placebo effects contains some clues as to underlying mechanisms. Expectancies and context-dependent forms of conditioning are based on high-level cognitive processing that may contribute to top-town (‘‘self-regulatory’’) control of more elementary processes, including responses of the autonomic nervous systems, emotional reactivity, and other activities at the psychosomatic interface. Empirical evidence for such top-down effects are available from studies with humans [56,57] as well as with animals [58]. The term self-regulation refers to a particular subset of topdown control which pertains to specifically human forms of modulation of emotional and somatic process modulation. The ability to form implicit or explicit representations of own experiential states and to attach personal meaning to subjective experience seems at the core of human self-regulation [59,60]. Various components of self-representational ability are related to the activity of the prefrontal cortex (PFC). Implicit self-representations that seem more powerful than explicit are related to the right PFC. In fact, successful emotion regulation is associated with activity of a region in the (implicit) right PFC, even if instructions to control emotional responses are given explicitly [60,61]. Likewise, placebo effects have been shown to be modulated by brain areas related to self-regulatory functions. The notion that self-regulation might be the very foundation of placebo effects [3,62] increasingly gains acceptance among placebo researchers [45]. A plethora of findings associated with executive control functions show that the meaning of a context in which a placebo is given substantially depends on higher cognitive functions associated with the prefrontal cortex [63–67]. For example, in patients suffering from Alzheimer’s disease, placebo analgesic effects usually found in healthy subjects when openly giving a pain alleviating agent drastically diminish [45]. These findings are consistent with the hypothesis that impaired prefrontal functioning reduces placebo effects, presumably because no expectations are formed. Such findings also show that the generation of a conscious (explicit) expectation alone does not suffice to trigger placebo effects. Instead, a person needs to employ relevant self-regulatory abilities to exert top-down effects altering lower brain functions and bodily changes. In animal research, top-down effects modulating conditioned fear responses have been shown to be effective as long as their mediation by the hippocampus is not inhibited by excessive stress [58]. In humans, prefrontal cortical areas play an important role even for classically conditioned placebo effects. This rather astonishing finding stems from a recent study by Lui et al. [68], in which analgesia was found to be related to the increase of right prefrontal activity both during the anticipation and immediately after of the onset of the noxious stimulus.3 Specifically, the placebo effect was predominantly mediated by the activation of the right dorsolateral prefrontal cortex (rDLPFC). The DLPFC (together with the ventrolateral prefrontal cortex) is known to afford cognitive regulation of the pain system and to integrate expectation related information and negative affect associated with aversive stimuli (see also [70–72]. These findings suggest that placebo effects involving prefrontal areas both mediate the magnitude of afferent stimuli and the perception of the stimulus itself. From a psychological point of view, this is a crucial finding. Assuming that placebo effects involve self-regulation and given that these exert a top-down influence on other brain areas and bodily functions, practitioners and therapists can actively trigger or instill them to the extent that they know how to strengthen their patients’ self-regulatory competence.

3 Pavlovian conditioning is usually associated with lower brain functions like e.g. the brain stem, the amygdala, the hypothalamus, and the insular [69].

Self-access as a prerequisite of placebo-effects Self-regulation is not a one-dimensional phenomenon but consists of many sub-functions [73]. So far, no systematic attempts have been made to establish which self-regulatory mechanism correlate with which placebo effects. For instance, whether in placebo analgesia involvement of the prefrontal cortex is accompanied by reduction of anxiety, re-interpretation of the aversive stimulus, or the deliberate or implicit diversion from the pain causing source, has as yet to be established. It is conceivable that the underlying psychological mechanisms of placebo effects vary both across different medical and psychological conditions and across patients (i.e., there may differential effects in the self-regulatory functions). The identification of specific neurotransmitters involved in expectancy-mediated placebo effects, e.g., sensitivity of receptors of the endogenous opioid systems in placebo analgesia [74,75], activity of dopaminergic pathways in placebo responders suffering from Parkinson’s disease [17,18,20] or depression [22,26,76] may provide further clues for understanding the psychological mechanisms involved. For example, the central striatum and the limbic system, which play a pivotal role for human motivation because they are tightly bound to reward mechanisms and approach behavior [77], help to understand motivational mechanisms involved in placebo effects. Specifically, the firing rate of dopamine neurons has been shown to be linked to the anticipation of reward in a linear fashion, that is, the more probable the reward the more neurons fire [78]. Furthermore, the prefrontal cortex stimulates these reward-related brain areas thereby altering their activity and modifying behavior and experience [79]. These top-down mechanisms may additionally reduce anxiety or distress-related symptoms triggered by brain negative affect sensitive brain areas (e.g., the amygdala) which would otherwise enhance adverse symptoms of an illness [80]. Such biochemical mechanisms are reminiscent of psychological self-regulatory mechanisms like e.g., self-motivation, self-relaxation or other affect-regulatory mechanisms. Due to the lack of direct evidence as to which psychological functions underlie placebo effects the jury is still out how placebo effects should best be provoked in a clinical setting. One promising way to approach placebo effects stems from a psychological analysis of the self conceived as a functional system. How can self-regulatory mechanisms supporting affect regulation be explained on the psychological level of analysis? Recent advances in psychotherapy highlight the role of the self in all ‘‘self’’-regulatory functions, especially self-regulation of affect [81]. Moreover, effective and sustainable affect regulation seems to depend on an implicit selfrepresentational system rather than on explicit self-conceptions and deliberate control [82]. In fact, deliberate control is associated with effort and energy-consumption [83] and with the resurgence of suppressed cognitive or emotional contents [84]. The implicit self is associated with right hemispheric activity whereas explicit self-reflection is associated with the left-hemisphere [59,82]. As mentioned earlier the self is conceived of as a mental system that is needed for parallel processing of all personally relevant information. The workings of the self in the context of personality functioning are described in Personality-Systems-Interaction (PSI) Theory [85,86]. In this theory, the self is regarded as part of an extended experiential network called extension memory (EM). The mechanisms of EM are holistic and (vastly) implicit in nature. The personally relevant part of EM is called the self. It consists of an extended network of knowledge abstracted from autobiographical experiences, including contextual knowledge, declarative knowledge, personal preferences, needs, or feelings. Thus, for a physician to accurately respond to the patients’ needs, he/she has to simultaneously and implicitly register and adjust own feelings,

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assessments, and experiences and to retrieve treatment-relevant knowledge bases. More importantly, the patient can ‘‘open’’ his or her self only to the extent that he or she has a chance to perceive the caregiver’s self. One does not become personal unless the interaction partner becomes personal. This analysis has an important implication: If access to the implicit (‘‘personal’’) self is essential for self-regulation of emotional and somatic processes (including placebo effects), becoming personal becomes an essential requirement for effective support of any treatment aiming at self-regulatory mechanisms. For a better understanding of the processes involved, it is useful to mention three additional systems which interact with the self system, according to PSI theory. These three additional systems are called intention memory (IM), object recognition (OR), and intuitive behavior system (IBS). Each system has a set of different functional characteristics and thus operates in a different way. For example, IM maintains specific goals and intentions and cooperates with sequential and analytical thinking. Practitioners who mainly activate their IM often appear rather mechanistic and sparsely empathetic. Although a mere clinical and cognitive understanding may suffice to understand a patient’s complains and medical condition, IM does not afford to ‘‘fully’’ (holistically) comprehend a patient4. This is also true for object recognition (OR) because it focuses on details (‘‘objects’’) that are isolated from their context, and for IBS that focuses only on information relevant for immediate action. Neither OR nor IBS lend themselves to activating the patient’s ‘‘personal’’ self because their scope is too limited to develop an extensive understanding of the patient as a person. OR can be valuable when it focuses on single details, such as deviations and changes in the patient’s well-being. However, because it is predominantly directed at detecting single details and discrepancies in perception, it does not provide an integration of multiple (i.e., nonclinical) aspects of the patient as the self does (and extension memory supporting it). According to PSI theory, the limited integrative capacity of intuitive behavior (IB) results from its focus on ongoing behavior: Personal understanding requires occasional shifts from intuitive interaction toward the high-level experiential system (i.e., the self), which is capable of integrating many personally relevant experiences into a coherent framework [87]. Health care providers who mainly intuitively interact with their patients by activating their IBS do appear quite approachable and caring and can stimulate the patient’s awareness for the ‘‘here and now’’ [88]. However, IBS facilitates immediate interaction (e. g. perceiving and responding to the expressed emotions) without supporting personal understanding. This is because IBS is activated when the environment is positive and accepting and when a spontaneous and gregarious, yet noncommittal interaction suffices. Besides its parallel-processing and high-level integrative potential, there is yet an additional reason for the self and extension memory to be conducive to placebo effects. EM provides several self-regulatory functions that have an impact on cognitive and bodily functions [86]. In PSI theory, more than forty self-regulatory competencies are distinguished and separately assessed [89]. Some of those components are more implicit (e.g., self-relaxation), whereas other self-regulatory functions are more conscious and effortful (e.g., impulse control). Especially the self-regulatory competencies associated with EM are facilitated by a positive atmosphere and positive attention [90]. Against this backdrop, it becomes clear that key features of an intervention maximizing placebo effects require high self-regulatory competencies on behalf of the physician: Activating the system level presumably receptive to placebo effects (i.e., EM) requires the therapist to activate the same

4 An extreme example of intention memory-like thinking is when a doctor treats as a sick organ and the clinical treatment associated with it.

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high level of personality functioning. According to this view, patients learn to regulate their emotions and bodily processes by internalizing emotion regulation occurring in the interaction with the therapist.

Self-development through person-centered interaction How can the implicit self be defined in functional terms and how can it be developed? From a functional point of view, the implicit self can be defined as a parallel-distributed (holistic) and implicit level of representation which derives a sense of identity, personal needs and competencies from personally relevant autobiographical episodes [86]. Given that the implicit self provides both affect regulatory abilities and an experiential network of what to expect across a vast variety of situations, it is a promising candidate for placebo effects. We already mentioned the reason why the quality of the interaction with the patient is a crucial requirement for his or her self to be activated (to ‘‘open up’’). How can this interaction be optimized in order to activate the patient’s self system? Carl Rogers [91] was one of the most influential proponents of self-development in psychotherapy. Therefore, to understand how placebo effects can be maximized and what factors should be heeded, it is helpful to first revisit the four constituents of a clinical setting enabling patients to develop their self-regulatory skills. According to Rogers [92], a clinical relationship between therapist (or physician) and patient consists of the following features: a. empathy b. acceptance c. authenticity These three key points have recently been extended by an additional one which Ritz-Schulte et al. [90] dub. d. personal presence. It is widely accepted, that the first three components build the foundation of any sustainable clinical relationship. Moreover, they can be regarded prerequisites for activating the implicit self because they create the personal climate for self-expression. Expressing one’s personal feeling is one of the most basic components of self-function and strongly contributes to emotional coping [91,93]. Roger’s three components of beneficial personal interaction alleviate clinical symptoms as demonstrated in numerous studies [94,95]. Enhancing them has been shown to improve patients’ motivation and adherence as well as patients’ self-regulatory competencies [90]. At their very core, they increase the meaning of an intervention as well as self-regulatory competence, and hence, may also amplify placebo effects. In light of the empirical evidence for the effectiveness of the three criteria for the quality of the therapist-patient relationship, our understanding of the mechanisms mediating beneficial effects of relationship quality is still very limited: Why does a patient who feels accepted, felt for and listened to develop improved self-regulatory skills? The three Rogerian criteria can help physicians activate their patients’ self. Evidence for this notion comes from research on empathy. Recent studies show that the same brain structures activated by pain are also engaged when a helper observes someone else in pain. Furthermore, these empathy-related responses are modulated as a function of the affective link between the two [96,97]. Hence, empathy is more than emotional contagion, sympathy, or compassion because it involves feelings that are isomorphic to those of the other person. Decety and Lamm [98] proposed a model in which bottom-up (i.e., direct matching between perception and action) and top-down information processes (i.e., regulation, contextual appraisal, and control) are intertwined in the generation of empathy [99]. According to this approach,

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bottom-up processes comprise direct emotion sharing automatically activated by perceptual input. This component of empathy is similar to emotional contagion mediated by intuitive behavior control, according to PSI-theory. Top-down processes on the other hand, are executive functions implemented in the (right) prefrontal and cingulate cortex. They serve to regulate both cognition and emotion through selective attention and self-regulation. Thus, top-down regulation modulates lower levels, thereby rendering individuals less dependent on external cues. Most importantly, whether one is empathic depends on the contextual appraisal of a situation as well as the ability of perspective taking. This is another example for high-level cognition affecting emotional reactivity. For example, in studies in which the meaning of the context is changed, e.g., when biopsy needle is inserted into an anesthetized hand, empathic responses of the observer fail to show [100]. Furthermore, when an observer perceives another person as unauthentic, he/she does not empathize [101]. In sum, empathy may either involve inhibition or amplification of representations activated through sensory channels and mechanisms. It is generated by high-level control mechanisms, for example, by means of imagination or anticipation of the other’s state (even when minimal sensory information about the other person is available). Under such circumstances, context information is required as well as affective memory, and self-to-other projections to infer the other person’s affective condition. It may be concluded that the doctor’s empathy facilitates the activation of high-level selfrepresentations in the patient which facilitate placebo effects. The second component of Roger’s interactional characteristics, acceptance, also depends on the activation of EM: According to a widely known principle, a biological system ceases to be active unless it is needed. Lasting inactivity results in degeneration. Examples range from muscle atrophy as a result of prolonged disuse [102] to degeneration of brain networks that are not activated for some time [103]. In light of the evidence describing brain systems supporting self-representational functions [59,60], we may conclude that when a person does not feel accepted as a ‘‘person’’, the system representing the person, is shut off. This seems plausible because if the self enables someone to understand and accept another person, it should be deactivated when a person does not feel understood or accepted. If this happens repeatedly, the neural basis of self-representation may deteriorate. Activation of the self is needed when recognition of a patient as a whole person is required: a person with a particular past, with current needs and concerns, etc. A recent study, for example, has found a link between doctors’ impersonal attitude and their perceiving patients as ‘‘difficult’’ [104]. In this study ‘‘difficult’’ patients had a heightened sensitivity for interpersonal rejection, a personal history of problematic medical relationships, and therefore high expectations of medical services. Consequently, they were often disappointed due to the absence of substantial personal understanding and so-

cial support from their clinicians. Many felt that the clinicians did not show genuine interest, and hence they did not feel fully recognized. In a study by Schmid Mast, Kindlimann and Langewitz [105], patients exposed to a patient-centered communication style (as opposed to a disease- or merely emotion-centered one), in which the physician conveyed bad news empathically and according to the patient’s needs and his understanding of the provided information, the physician was perceived as most emotional, least dominant, most appropriate, and most expressive of hope. The third and fourth component of the therapist-patient interaction, authenticity and personal presence, are characteristics which have intensively been investigated by communication psychologists. For example, Schulz von Thun [106] breaks down the ‘‘anatomy’’ of a message into four components. According to this account, any message exchanged between two interaction partners consists of: 1. 2. 3. 4.

its content its appeal its relational implication the self-disclosure of the sender.

This anatomy of communication is quite universal. Hence, messages not only serve to inform, but they carry with them expectations, requests, or questions not explicitly expressed but implicitly intended. Furthermore, they may convey information about how the sender views himself/herself and how he/she appraises the relationship with the partner. In the clinical realm, for a doctor to be both authentic and present, he/she needs to be made sure that all four aspects align. Let us take, as an example, a patient who needs to be given a worrisome diagnosis (e.g., diabetes mellitus type 2). In addition to the actual content of the message, i.e., the diagnosis, the message may implicitly convey the therapist’s concern about the patient’s health (self-disclosure component). The message may as well be intended to enjoin the patient to consider his life style (appeal) or it may signal that the doctor regards help as indispensable and that the patient is dependent on him/her (relationship component). Fig. 1 depicts this scenario. For the doctor to be authentic (or congruent) all four components of a message need to be clearly expressed. Should this not be the case (e.g., when the doctor nonverbally disapproves of the patient’s life style but verbally soothes him/her), the quality of the relationship may suffer, thereby attenuating factors which optimize the meaningfulness of the relationship. Likewise, doctors who primarily heed the content of the patient’s messages may fail to fully capture the implicitly intended message. To fully grasp the meaning of the patient’s behavior, the physician must ‘‘read between the lines’’ and discern the patient’s implicit request to be helped (appeal) and acknowledging the patient unwillingness to self-disclose or show his autonomy (relationship).

You have diabetes mellitus type 2! (content)

I am worried about your health! (self-disclosure)

Doctor’s message

You need to stick to strict dietary habits! (appeal)

Without my medical help you won’t be cured! (relationship) Fig. 1. The four universal components of a message. Note: Although only the content of the actual message is verbally given, the three other aspects are implicitly conveyed.

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Fig. 2. Systems conditioning in a medical context.

So far, such hidden cues are generally underresearched, especially in medical encounters. Yet, the clinical communication patterns are significant for the treatment outcome. In one study [107], for example, patients provided less medical information, spoke less, and agreed more when they interacted with a highly dominant as opposed to a less dominant physician. They openedup, however, when interacting with a high-caring doctor. In another study, affilliative nonverbal behavior (e.g., eye gaze and proximity) of the physician was related to higher patient satisfaction [108]. In sum, from the rather scant literature on the importance of communicative factors for treatment outcomes it can be concluded that both physician and patient should ascribe meaning to the interaction. The more self-aspects are involved the more personal meaning is created (i.e., on an emotional, cognitive, and self-regulatory level of human functioning). From a functional account, meaning is more than consciously accessible personal episodes. According to PSI theory, personal meaning activates one special cognitive-affective system, that is, extension memory, which is best suited to warrant a meaningful clinical relationship. It integrates an almost unlimited number of ambient clues, behavioral patterns and episodic information which allows the therapist to holistically respond to the patient’s needs (both medical and psychological). A final question relates to the development of affect regulation: According to PSI theory, not only does the integrative self support affect regulation (especially self-motivation and self-relaxation), but affect regulation in turn facilitates self access (recall that excessive negative affect inhibits self-access). Therefore, any progress made during therapy towards strengthening the patient’s ability to regulate emotions will facilitate self-access and, as a result, support placebo effects. How does the brain acquire the capacity to ‘‘self-regulate’’ affective states? ‘‘Self-regulation’’ of affect requires the self to have an impact on emotional and somatic states which in turn should depend on the connectivity between the self and the autonomic nervous system. According to the classical conditioning paradigm, new connections are acquired among two stimuli or subsystems when the two entities to be connected are activated simultaneously or in close succession [109]. When the connectivity between the self and affect-generating subsystems is to be strengthened (as a prerequisite for the self to regulate affect), the self should be activated simultaneously (or in close succession) with brain structures related to affect (e.g., relevant parts of the limbic system). According to the ‘‘systems conditioning model’’ developed in the context of PSI theory, this temporal contiguity between self-activation and affect regulation typically happens when a caregiver succeeds in regulating the patient’s emotion in a personally meaningful situation (i.e., while the patient’s self is active). For example, when a doctor restores positive mood through encouragement, the connection between the patient’s self system and affect-regulatory mechanisms (e.g., within the limbic system) will be strengthened, provided the patient’s self is active, that is,

when he/she feels understood and accepted as a person. Successful encouragement will be only short-lived when it occurs in a situation in which the receiving person’s self is not activated. This mechanism is shown in Fig. 2. Conclusion According to the herein introduced view, the clinician’s intervention and behavior is most effective in terms of engaging nonspecific and overall treatment effects when his/her self is activated. This is the case when the doctor responds in a way that best meets both his/her and the patient’s needs (in other words, he/she needs to be authentic). Pain, for example, is one of the most reliable medical conditions where strong and reliable placebo effects are found. Pain claims the patient’s awareness because it is highly adverse (i.e., it is introspectively accessible and can vicariously be experienced). It is also easily communicated (both verbally and nonverbally) and allows the doctor to appropriately respond to the patient’s needs (even if only a placebo is administered). Hence, placebo effects are the more probable the more self-aspects of both patient and clinician are activated. According to the systems conditioning assumption of PSI theory, individuals may develop different effective self-regulatory strategies for different situations. The most important condition for placebo effects to occur is a personal (as opposed to superficial or impersonal) encounter between helper and helpee. Conflict of interest statement The authors declare no conflict of interest. References [1] Kaptchuk TJ. Powerful placebo: the dark side of the randomised controlled trial. Lancet 1998;351:1722–7. [2] Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. J Intern Med 2004;256:91–100. [3] Schneider R. The psychology of the placebo effect: exploring meaning from a functional account. J Mind Behav 2007;18:11–7. [4] Miller FG, Colloca L, Kaptchuk TJ. The placebo effect: illness and interpersonal healing. Perspect Biol Med 2009;52:518–39. [5] Aslaksen PM, Flaten MA. The roles of physiological and subjective stress in the effectiveness of a placebo on experimentally induced pain. Psychosom Med 2008;70:811–8. [6] Bingel U, Wanigasekera V, Wiech et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 2011;3:70ra15. [7] Brown CA, Seymor B, El-Deredy W, Jones AKP. Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula. Pain 2008;139:324–32. [8] Charron J, Rainville P, Marchand S. Direct comparison of placebo effects on clinical and experimental pain. Clin J Pain 2006;22:204–11. [9] Eippert F, Bingel U, Schoell E, Yacubian J, Büchel C. Blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans. J Neurosci 2008;28:5465–72.

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