How to Study Placebo Responses in Motion Sickness with a Rotation Chair Paradigm in Healthy Participants

The overall goal of the described methodology is the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm in healthy participants.

Placebo effects and responses play a role in every medical intervention when patients or participants expect to get an effective treatment to relieve symptoms in everyday medical practice or in clinical trials ¹. In the latter, placebo groups are included to control for placebo effects and all unspecific effects that could occur during the study, such as the natural course of disease (spontaneous remission, fluctuation of symptoms, regression to the mean, habituation), observer and patient biases (scaling biases, social desirability, conditioned answers), or “real” placebo responses ². Placebo responses are symptom improvements in individuals that occur only because of patients’ or participants’ expectancy or learned responses to a specific treatment. While learning is multi-faceted, it is assumed that all aspects of learning result in an expectancy concerning the treatment – whether by conscious expectations or unconscious conditioned reactions ^1,3.

Studies with the primary aim to investigate placebo responses have to include additional groups to control for the above mentioned unspecific effects in comparison to the pure placebo response. For example, a group with positive expectancy concerning the treatment is compared with a group with no expectancy concerning the treatment while both groups receive the same inert substance. One possible study design is the so-called balanced placebo design (Table 1) in which half of the participants receive the real drug and the other half receives a placebo, and half of the participants of each drug group receive the correct information and the other half receives the wrong information about the drug received. Participants will be randomly assigned to one of the four groups to assess the differential effects of the drug received and the information given in a between-groups design. Therefore, the four groups are real drug/drug information, real drug/placebo information, placebo/drug information, placebo/placebo information ⁴.

A further question in placebo research is whether patients or participants “only” feel better subjectively or whether there is an objectively measurable change in physiology ^5,6. Imaging studies, especially in experimental pain studies, have shown repeatedly that placebo responses are associated with changes in neural activity, e.g. in the somatosensory cortex ⁷ or in the rostral anterior cingulated cortex (rACC) that is also involved in opioid analgesia ^8,9. Therefore, it is clear that placebo responses are not only subjective response biases by participants. However, there is the remaining question whether placebo responses also occur in the target organ such as the stomach in motion sickness. To investigate this question it is necessary not only to ask for subjective symptom reports but also to assess objective organ specific measures.

Inducing motion sickness in a rotation chair paradigm in healthy subjects is a useful and easy to establish methodology to investigate placebo responses in a multivariate way. According to the neural mismatch theory ^10,11, motion sickness occurs because of a mismatch between actual and expected perceptions from different sensory systems such as the vestibular and the visual system. This mismatch leads to a series of vegetative symptoms like nausea, vertigo, sweating, or tiredness but also to changes in gastric myoelectrical activity ^12,13, and can be evoked in most healthy participants depending on the strength of the stimulus ¹⁴. We have already repeatedly employed this rotation chair paradigm to induce motion sickness to investigate mediators ¹⁵ and placebo and nocebo responses ^16-18. In this paradigm, healthy participants are seated in a rotating chair, have to wear an eye mask and earphones to reduce the ability to orientate themselves during the rotation procedure, and to move their head slowly up and down. Particularly, the head movements induce the so-called Coriolis effect, the experience of an illusionary tumbling movement that leads to symptoms of nausea ¹¹. Participants can be asked to rate a list of subjective symptoms that typically occur during motion sickness, behavioral measures such as the number of head movements and the total rotation time tolerated can be assessed, and gastric myoelectrical activity can be objectively recorded with electrogastrography (EGG).

To record EGG data, three cutaneous electrodes are placed on the skin above the stomach and connected to a recording device ^19,20. As myoelectrical signals of the stomach are weaker than those from the heart, it is recommended to use an active electrodes technique that amplifies signals directly at the electrodes’ side before sending them to the recording device. Although the EGG is sensitive to movement artifacts by speaking or deep breathing, it provides the advantage that it is a non-invasive technique and does not affect the studied physiological reactions of the stomach. In comparison, techniques such as implanted serosal electrodes ²¹ or fluoroscopies ²² are more invasive and could affect the studied behavior in an unforeseen way. To analyze EGG data, the data are screened visually for artifacts and are analyzed with a time series analysis such as a Fast Fourier Transformation (FFT). A predominance of the frequency range around three cycles per min (cpm) is regarded as normal gastric activity (normogastria) and a range from 4 to 10 cpm as tachygastria. A shift from normogastria in a baseline assessment to tachygastria has repeatedly been associated with nausea induced by rotation chair or vection drum ^19,23,24.

There are only a few studies that have investigated placebo responses in motion sickness by manipulating expectations only, but these have lacked successful induction of a placebo response in any outcome measure ^25,26. When participants were exposed to a motion sickness inducing stimulus after being given a placebo pill along with the information that it will either: decrease symptoms (placebo information); increase symptoms (nocebo information); or have no effect; participants who received the nocebo information reported fewer symptoms and showed less tachygastria compared to the other groups ²⁶. A possible explanation by the authors was that participants who were given the positive information were disappointed that they had strong symptoms although they received the drug, but participants who were given the negative information were surprised that the procedure was not as strong as they expected. In a study by our own group, only male participants who were told that an orally delivered medication would increase symptoms (nocebo effect) compared to participants who did not receive any information showed lowered rotation tolerance without an effect on symptom ratings ¹⁶.

In conclusion, placebo responses through positive information given along with a placebo treatment have not been demonstrated on motion sickness with a rotation chair paradigm, except latter studies of our own group ¹⁸ (Weimer, K., Horing, B., Klosterhalfen, S., & Enck, P., 2012). Furthermore, placebo responses have rarely been investigated with multiple outcome measures in one study. The focus of this article is, therefore, to describe a methodology to assess placebo responses in a multivariate way by subjective, behavioral and objective outcome measures in an experimental paradigm for studying motion sickness.