Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

Burke, Matthew J.; Kaptchuk, Ted J.; Pascual‐Leone, Álvaro

doi:10.1002/ana.25387

Cited by 69 publications

(74 citation statements)

References 77 publications

(96 reference statements)

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“…Results thus confirm the findings of our pilot study that placebo TENS induces a large placebo effect in experimentally induced nausea (Müller et al, 2016) and further extend them to male volunteers and to a placebo TENS intervention without tactile stimulation. The medical environment, in which the experiment took place – with many factors present that are known to boost placebo effects, such as a room full of sophisticated electrical equipment as well as prolonged interaction with the experimenters (Burke et al, 2019) – may have contributed to this large placebo effect.…”

Section: Discussionmentioning

confidence: 99%

The Role of Tactile Stimulation for Expectation, Perceived Treatment Assignment and the Placebo Effect in an Experimental Nausea Paradigm

et al. 2019

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IntroductionTactile stimulation during a placebo treatment could enhance its credibility and thereby boost positive treatment expectations and the placebo effect. This experimental study aimed to investigate the interplay between tactile stimulation, expectation, and treatment credibility for the placebo effect in nausea.MethodsNinety healthy participants were exposed to a 20-min vection stimulus on two separate days and were randomly allocated to one of three groups on the second day after the baseline period: Placebo transcutaneous electrical nerve stimulation (TENS) with tactile stimulation (n = 30), placebo TENS without tactile stimulation (n = 30), or no intervention (n = 30). Placebo TENS was performed for 20 min at a dummy acupuncture point on both forearms. Expected and perceived nausea severity and further symptoms of motion sickness were assessed at baseline and during the evaluation period. At the end of the experiment, participants in the placebo groups guessed whether they had received active or placebo treatment.ResultsExpected nausea decreased significantly more in the placebo groups as compared to the no treatment control group (interaction day × group, F = 6.60, p = 0.003, partial η2 = 0.20), with equal reductions in the two placebo groups (p = 1.0). Reduced expectation went along with a significant placebo effect on nausea (interaction day × group, F = 22.2, p < 0.001, partial η2 = 0.35) with no difference between the two placebo groups (p = 1.0). Twenty-three out of 29 participants in the tactile placebo group (79%) but only 14 out of 30 participants (47%) in the non-tactile placebo group believed that they had received the active intervention (p = 0.015). Bang’s blinding index (BI) indicated random guessing in the non-tactile placebo group (BI = 0; 95% CI, −0.35 to 0.35) and non-random guessing in the direction of an “opposite guess” in the tactile placebo group (BI = −0.52; 95% CI, −0.81 to −0.22).ConclusionTactile stimulation during placebo TENS did not further enhance positive treatment expectations and the placebo effect in nausea but increased the credibility of the intervention. Further trials should investigate the interaction between perceived treatment assignment, expectation, and the placebo effect during the course of a trial.

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Section: Discussionmentioning

confidence: 99%

The Role of Tactile Stimulation for Expectation, Perceived Treatment Assignment and the Placebo Effect in an Experimental Nausea Paradigm

et al. 2019

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“…Outside of lab environments, people report nocebo effects from various technologies such as electromagnetic fields (58) or wind turbines (59). When artificially increasing the perceived complexity of placebo procedures, or when using inherently complex procedures such as brain stimulation (25), researchers should take care to minimise potential nocebo effects (60,61).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the perceived complexity of the procedure may be irrelevant if participants believe it is only scanning their brain; presumably few patients experience symptom relief from an MRI alone. Alternatively, studies could replace the machine component with an inert pill, to compare simple and complex interventions while holding the other contextual factors constant (7,25).…”

Section: Discussionmentioning

confidence: 99%

“…The control groups of brain-based intervention trials may resemble top-down placebo studies. For example, the transcranial magnetic stimulation procedure contains "almost all conceivable factors that might enhance placebo effects", including complex scientific machinery, medical paraphernalia, interactions with experts, a credible institution, and plentiful media attention (25). We propose that mock neuroscience equipment, such as defunct MRI scanners, may serve as similarly potent placebos (26).…”

Section: Introductionmentioning

confidence: 99%

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Super placebos: A feasibility study combining contextual factors to promote placebo effects

Olson¹,

Lifshitz²,

Raz³

et al. 2020

Preprint

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Ample evidence demonstrates that placebo effects are modulated by contextual factors. Few interventions, however, attempt to combine a broad range of these factors. Here, we explore the therapeutic power of placebos by leveraging factors including social proof, positive suggestion, and social learning. This study aimed to test the feasibility of an elaborate "super placebo" intervention to reduce symptoms of various disorders in a pediatric population. In a single-arm qualitative study, participants entered an inactive MRI scanner which they were told could help their brain heal itself through the power of suggestion. The sample included 11 children (6-13 years old) diagnosed with disorders known to be receptive to placebos and suggestion (Attention Deficit Hyperactivity Disorder, Tourette Syndrome, chronic skin picking, and migraines). The children were given positive suggestions before entering the scanner for 2 to 4 sessions over the span of approximately one month. We assessed open-ended treatment outcomes via recorded interviews and home visits. The procedure was feasible and no adverse events occurred. Ten of the eleven parents reported improvements in their children after the intervention, ranging from minor transient changes to long-term reductions in subjective and objective symptoms (e.g., migraines and skin lesions). These preliminary findings demonstrate the feasibility and promise of combining a broad range of contextual factors in placebo studies. Future research is needed to assess the causal effects of such interventions.

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“…The former is related to behavioral and cognitive changes (including certain expectations) that result from a person’s belief that their brain is being stimulated, while the latter is related to somatosensory effects (e.g., muscle twitches), peripheral nerve stimulation, and auditory effects (perception of a clicking sound). The sham approach might induce placebo effects of different magnitude (Burke et al, 2019 ). The mismatch between active TMS and the sensory effects of control TMS can form participants’ beliefs about the effectiveness of brain stimulation.…”

Section: Rtms Control Conditionsmentioning

confidence: 99%

Causal Inferences in Repetitive Transcranial Magnetic Stimulation Research: Challenges and Perspectives

Hobot

Klincewicz

Sandberg

et al. 2021

Front. Hum. Neurosci.

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Transcranial magnetic stimulation (TMS) is used to make inferences about relationships between brain areas and their functions because, in contrast to neuroimaging tools, it modulates neuronal activity. The central aim of this article is to critically evaluate to what extent it is possible to draw causal inferences from repetitive TMS (rTMS) data. To that end, we describe the logical limitations of inferences based on rTMS experiments. The presented analysis suggests that rTMS alone does not provide the sort of premises that are sufficient to warrant strong inferences about the direct causal properties of targeted brain structures. Overcoming these limitations demands a close look at the designs of rTMS studies, especially the methodological and theoretical conditions which are necessary for the functional decomposition of the relations between brain areas and cognitive functions. The main points of this article are that TMS-based inferences are limited in that stimulation-related causal effects are not equivalent to structure-related causal effects due to TMS side effects, the electric field distribution, and the sensitivity of neuroimaging and behavioral methods in detecting structure-related effects and disentangling them from confounds. Moreover, the postulated causal effects can be based on indirect (network) effects. A few suggestions on how to manage some of these limitations are presented. We discuss the benefits of combining rTMS with neuroimaging in experimental reasoning and we address the restrictions and requirements of rTMS control conditions. The use of neuroimaging and control conditions allows stronger inferences to be gained, but the strength of the inferences that can be drawn depends on the individual experiment’s designs. Moreover, in some cases, TMS might not be an appropriate method of answering causality-related questions or the hypotheses have to account for the limitations of this technique. We hope this summary and formalization of the reasoning behind rTMS research can be of use not only for scientists and clinicians who intend to interpret rTMS results causally but also for philosophers interested in causal inferences based on brain stimulation research.

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Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

Cited by 69 publications

References 77 publications

The Role of Tactile Stimulation for Expectation, Perceived Treatment Assignment and the Placebo Effect in an Experimental Nausea Paradigm

The Role of Tactile Stimulation for Expectation, Perceived Treatment Assignment and the Placebo Effect in an Experimental Nausea Paradigm

Super placebos: A feasibility study combining contextual factors to promote placebo effects

Causal Inferences in Repetitive Transcranial Magnetic Stimulation Research: Challenges and Perspectives

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