Behavioral conditioning of immunosuppression is possible in humans

Goebel, Marion U.; Trebst, Almuth Elisabeth; Steiner, Jan; Xie, Yu; Exton, Michael S.; Frede, Stilla; Canbay, Ali; Michel, Martin C.; Heemann, Uwe; Schedlowski, Manfred

doi:10.1096/fj.02-0389com

Cited by 212 publications

(161 citation statements)

References 19 publications

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“…Our study is clearly distinguished from previous studies because it focuses on the nonconscious activation of placebo/nocebo responses and demonstrates that placebo/nocebo can be activated even if the conditioned stimulus is not consciously perceived. In traditional placebo studies, conditioning is often used by pairing the administration of an unconditioned stimulus (e.g., effective analgesic pill, cream, or injection) with a conditioned stimulus (e.g., inert placebo pill, cream, or injection), thus producing placebo responses through "associative learning" (27)(28)(29)(30). Even if associative learning in such studies has been described in terms of a "nonconscious" mechanism (in which cognition may be an epiphenomenon, rather than part of a causal chain), the activation of the conditioned response has always been obtained by a perceptible conditioned stimulus.…”

Section: Discussionmentioning

confidence: 99%

Nonconscious activation of placebo and nocebo pain responses

Jensen

Kaptchuk

Kirsch

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

250

215

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The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we performed two experiments in which the responses to thermal pain stimuli were assessed. The first experiment assessed whether a conditioning paradigm, using clearly visible cues for high and low pain, could induce placebo and nocebo responses. The second experiment, in a separate group of subjects, assessed whether conditioned placebo and nocebo responses could be triggered in response to nonconscious (masked) exposures to the same cues. A total of 40 healthy volunteers (24 female, mean age 23 y) were investigated in a laboratory setting. Participants rated each pain stimulus on a numeric response scale, ranging from 0 = no pain to 100 = worst imaginable pain. Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. This is a unique experimental verification of the influence of nonconscious conditioned stimuli on placebo/nocebo effects and the results challenge the exclusive role of awareness and conscious cognitions in placebo responses.analgesia | hyperalgesia | consciousness P lacebo and nocebo effects are critical components of medical practice and clinical research. Placebo analgesia and nocebo hyperalgesia are the most robust and well studied of these effects. Learning is known to play an important role in placebo and nocebo effects and the dominant theories invoke classical conditioning and expectancies as explanatory tools (1). Both rely on a notion that the conscious perception of sensory or social stimuli, such as the cue that triggers expectancy or the conditioned stimulus in classical conditioning, are needed to obtain placebo responses. In some circumstances, conditioning may be an automatic nonconscious process, but in most cases, it seems to involve the formation of expectations (2-4). However, it is not known whether conscious perception of a conditioned stimulus is needed to elicit a conditioned response.There is a large literature suggesting that behavior can be motivated by stimuli that are not consciously perceived, because they are presented at low intensities or masked from conscious awareness (5, 6), sometimes referred to as subliminal stimuli. Nonconscious operations are considered a fundamental feature of human cognition, for example in reward processing (7,8), fear learning (9, 10), and social behavior (11,12). Furthermore, evidence suggests that conditioned responses may be acquired outside of conscious awareness (13-15). Neuroimaging studies of the human brain suggest that certain structures, such as the striatum and ...

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Section: Discussionmentioning

confidence: 99%

Nonconscious activation of placebo and nocebo pain responses

Jensen

Kaptchuk

Kirsch

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

250

215

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“…For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-␥ (IFN-␥) mRNA expression, in vitro release of IL-2 and IFN-␥, as well as lymphocyte proliferation (Goebel et al, 2002). This study supports a conditioning mechanism in immunosuppressive placebo responses and is in keeping with the effects of sumatriptan conditioning on GH and cortisol secretion .…”

Section: The Pharmacological Approachmentioning

confidence: 99%

Neurobiological Mechanisms of the Placebo Effect

Benedetti¹,

Mayberg²,

Wager³

et al. 2005

J. Neurosci.

608

388

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“…It has been shown, for example, that associating a flavored drink with cyclosporin A leads to conditioned immunosuppression in human subjects. 23 Patient-subjects in neurosurgical trials, such as those for PD, have potentially experienced repeated clinical treatments or research trial interventions. 24 These individuals may be conditioned to respond therapeutically to procedures included in a clinical trial, or conversely, they may harbor lowered expectations for any future interventions, however novel.…”

Section: Methodological Justificationmentioning

confidence: 99%

Placebo-Controlled Procedural Trials for Neurological Conditions

Horng

Miller

2007

Neurotherapeutics

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Summary:Neurological disease has been a central focus in the ongoing ethical debate over the use of invasive placebo controls, especially sham surgery. The risk to research subjects and necessary use of deception involved in these procedures must be balanced against the methodological need to control for bias and the placebo effect. We review a framework formulated for the ethical assessment of sham surgery in the context of research evaluating novel procedures for neurological conditions. Special issues raised include the growing evidence of expectation and conditioning effects in a number of neurological diseases, the escalating scale of risk from different types of invasive placebo interventions, and the increasing use of cross-over designs, which allow a switch from placebo to active intervention without additional procedures.

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Behavioral conditioning of immunosuppression is possible in humans

Cited by 212 publications

References 19 publications

Nonconscious activation of placebo and nocebo pain responses

Nonconscious activation of placebo and nocebo pain responses

Neurobiological Mechanisms of the Placebo Effect

Placebo-Controlled Procedural Trials for Neurological Conditions

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