Comments for:

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Transcutaneous auricular vagus nerve stimulation – the essence of the proper control condition

Submitter: Daniel Keszthelyi | daniel.keszthelyi@maastrichtuniversity.nl

Authors: Daniel Keszthelyi, Ali Gholamrezaei, and Bram Beckers

Maastricht University Medical Center

Published June 28, 2021

Dear Editors,

 

We read with interest the paper by Xiaodan Shi et al.(1) on the beneficial effects of transcutaneous auricular vagus nerve stimulation (taVNS) in irritable bowel syndrome (IBS). We commend the authors for paving the way for the exploitation of this novel non-pharmacological intervention for IBS. Treatment of IBS symptoms remains challenging: diverse treatment entities possess limited efficacy and there is no ‘one size fits all’ approach. Patients are best served by treatments that are not only efficacious but devoid of adverse effects and appear attractive to the patient. In respect to the latter, patients with gastrointestinal disorders have been shown to prefer dietary measures and complementary treatments above pharmacological therapy (2). In this sense, taVNS fulfils patients’ needs: it is easy to use, relatively safe and has no known serious side effects (3). Studies such as those by Xiodan Shi et al. are therefore very welcome to substantiate potential therapeutic effects and reinforce both patients’ and health practitioners’ beliefs in its therapeutic efficacy.

 

However, there are important methodological issues with the current study which might have influenced the results. The study is described as single-blinded with patients not being aware of the type of treatment. Therefore, patients’ interactions with study investigators (or clinicians) who were aware of the study type could potentially influence adequacy of blinding and outcome expectancy (4). Moreover, for the control condition, sham stimulation was provided to the forearm. Stimulation at distant locations may not provide similar sensations and may induce different outcome expectancies. Although there is considerable discussion in the literature on the choice of control condition, current consensus considers the earlobe as the most appropriate location for sham stimulation (5). It is also not specified further how patients were instructed on the treatments they are to receive and hence we cannot know what their expectations were. This is also relevant as beliefs on the efficacy of such therapies may have great regional variation (consider Eastern vs Western medicine) and hence impact the generalizability of the findings. Finally, blinding is difficult to achieve given the information via lay media widely available nowadays on the effects of taVNS. 

 

Given the abovementioned, we consider it important to adhere to the recently described reporting standards (5) on studies using taVNS. This will diminish the possibility of the medical-scientific community being dismissive of such therapeutic entities and increasing its acceptance as a legitimate therapeutic option for IBS.

 

References

1.         Shi X, Hu Y, Zhang B, Li W, Chen JD, Liu F. Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation. JCI Insight. 2021.

2.         Yoon SL, Grundmann O, Smith KF, Mason SR. Dietary Supplement and Complementary and Alternative Medicine Use Are Highly Prevalent in Patients with Gastrointestinal Disorders: Results from an Online Survey. J Diet Suppl. 2019;16(6):635-48.

3.         Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R, et al. Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review. Brain Stimul. 2018;11(6):1225-38.

4.         Chen PA, Cheong JH, Jolly E, Elhence H, Wager TD, Chang LJ. Socially transmitted placebo effects. Nat Hum Behav. 2019;3(12):1295-305.

5.         Farmer AD, Strzelczyk A, Finisguerra A, Gourine AV, Gharabaghi A, Hasan A, et al. International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). Front Hum Neurosci. 2020;14:568051.

 

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Reply to "Transcutaneous auricular vagus nerve stimulation – the essence of the proper control condition"

Submitter: Fei Liu | liufeiguo2010@163.com

Authors: Xiaodan Shi, Jiande Chen, and Fei Liu

Published June 28, 2021

Dear Editor,

Thank you very much for giving us an opportunity to submit a reply to "Transcutaneous auricular vagus nerve stimulation – the essence of the proper control condition". We very much appreciate the comments made by the authors and are pleased to discuss the following issues. 

Our study was a single-blinded RCT with patients blinded to the type of treatment. It is known that contextual and psychological factors such as expectations and the characteristics of clinicians themselves could profoundly affect symptom relief (1-3). In this study, the participants in the two different groups were presented with exactly the same information. They were told that they would be enrolled randomly into one of the treatment groups and that the treatment might result in "obvious effect", "a little effect" or "no effect". Patients were not informed that the study was designed to investigate the therapeutic effect of auricular vagal nerve stimulation and therefore were unaware of which points might be the actual treatment points or sham points. Accordingly, the placebo effect and the placebo expectation would be the same for both groups.

During the design of the study, we were fully aware that the earlobe and the superior scapha had been frequently used as sham stimulation points (4-7). However, some publications indicated that there was a vagus nerve distribution in the earlobe (8, 9), and some studies reported that the sham stimulation at the superior scapha also yielded significant improvement (6, 10). In our own practice, transcutaneous electrical stimulation at the earlobe was found effective in reducing pain in patients with migraine (unpublished data). For the use of the superior scapha as the sham stimulation location, we were concerned that electrical stimulation could be propagated to the actual stimulation point since the stimulation current in the transcutaneous method was larger than direct nerve stimulation.

        As to how patients were instructed on the treatments they were to receive, it was arranged as follows: the first treatment session was performed at the hospital by the member of the research team and during that the patient was trained for the localization of the stimulation point and operation of the device as well as the treatment delivery procedure. All subsequent treatments were self-administered by the patient at home. The patient was informed to contact the researcher at any time if they had any problems or discomfort during the treatment at home.

Additionally, blinding was difficult to achieve given the information via lay media widely available nowadays on the effects of taVNS. To avoid this, the information provided to the participant was only about transcutaneous electrical stimulation without the mention of the auricular stimulation.

Once again, the comments made in the E-letter are greatly apricated. We hope that our responses are satisfactory or helpful.

 

 

References

 

1.         Beecher HK. The powerful placebo. J Am Med Assoc. 1955;159(17):1602-1606.

2.         Uhlenhuth EH, et al. The symptomatic relief of anxiety with meprobamate, phenobarbital and placebo. Am J Psychiatry. 1959;115(10):905-910.

3.         Chen PA, et al. Socially transmitted placebo effects. Nat Hum Behav. 2019;3(12):1295-1305.

4.         Giraudier M, et al. Transcutaneous Vagus Nerve Stimulation (tVNS) Improves High-Confidence Recognition Memory but Not Emotional Word Processing. Front Psychol. 2020;11:1276.

5.         Frangos E, et al. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015;8(3):624-636.

6.         Huang F, et al. Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study. BMC Complement Altern Med. 2014;14:203.

7.         Fang J, et al. Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder. Biol Psychiatry. 2016;79(4):266-273.