Can TMS-evoked potentials act as biomarkers of long-term potentiation or long-term depression induced by paired associative stimulation?
Neurophysiological correlates of plasticity induced by paired associative stimulation (PAS) targeting the motor cortex: a TMS-EEG registered report
Recommendation: posted 12 January 2024, validated 15 January 2024
Edwards, G. (2024) Can TMS-evoked potentials act as biomarkers of long-term potentiation or long-term depression induced by paired associative stimulation?. Peer Community in Registered Reports, . https://rr.peercommunityin.org/articles/rec?id=533
Level of bias control achieved: Level 6. No part of the data or evidence that will be used to answer the research question yet exists and no part will be generated until after IPA.
List of eligible PCI RR-friendly journals:
- Brain and Neuroscience Advances
- Imaging Neuroscience
- NeuroImage: Reports
- Peer Community Journal
- Royal Society Open Science
1. Arrigoni, E., Bolognini, N., Pisoni, A. & Guidali, G. (2024). Neurophysiological correlates of plasticity induced by paired associative stimulation (PAS) targeting the motor cortex: a TMS-EEG registered report. In principle acceptance of Version 3 by Peer Community in Registered Reports. https://osf.io/detjc
The recommender in charge of the evaluation of the article and the reviewers declared that they have no conflict of interest (as defined in the code of conduct of PCI) with the authors or with the content of the article.
Evaluation round #2
DOI or URL of the report: https://osf.io/48fh3/?view_only=df553c39c5d246d5b8f1ce509f5f2e16
Version of the report: REV1
Author's Reply, 10 Jan 2024
Decision by Grace Edwards, posted 08 Dec 2023, validated 08 Dec 2023
Dear Dr. Guidali,
Thank you for your thorough reply to the reviewers and recommender. I have received positive responses from all three of our reviewers and ask you reply to the few remaining comments. Please reply with a point-by-point response to the reviewers and recommender, accompanied by a track-changes updated manuscript.
Our anonymous reviewer requests you revisit Dr Oberman’s suggestion of extending your inter-pulse interval and asks you explicitly state that the MEPs will be recorded with the EEG cap on using the same conditions as was used for the TEPs.
With regard to your response to my comments, I have a few minor issues I’d like to be addressed:
I appreciate that power analyses have been performed on concrete hypotheses, and that the more exploratory analyses have been removed from your Stage 1. However, there are multiple mentions of connectivity in the abstract and introduction which may be confusing to the reader as there are no planned connectivity analyses in the Stage 1. These should also be removed, and the connectivity only discussed in the Stage 2 if exploratory analyses are performed. The only reason we allow the mention of exploratory analyses in a Stage 1 is if there is a particular design component which is only selected to support an exploratory analysis, therefore requiring an explanation for readability. Along these lines, the analysis examining the modulation of the N100 following PASLTP should also only be mentioned in the Stage 2.
Could you also outline the conclusions you could draw if your hypotheses are not upheld in the final column of the Study Table? You have most of this information in the “Interpretation given different outcomes” column. For example, for H0, what does it mean to the field if you are unable to replicate typical impact of PASLTP and PASLTD protocols on MEP? Investigation of TEPs in this case is highly interesting as modulation impact may be more obvious in this measure.
Finally, please also define TEP (i.e. TMS evoked potentials) in the abstract prior to the first use of the acronym.
As you are already aware, there is a December 2023 submission closure until 10th January 2024. Looking forward to hearing from you in the New Year.
Reviewed by Lindsay Oberman, 07 Nov 2023
Reviewed by anonymous reviewer 1, 08 Dec 2023
Reviewed by Domenica Veniero, 21 Nov 2023
Evaluation round #1
DOI or URL of the report: https://osf.io/78up2?view_only=df553c39c5d246d5b8f1ce509f5f2e16
Version of the report: 1
Author's Reply, 03 Nov 2023
Decision by Grace Edwards, posted 05 Oct 2023, validated 05 Oct 2023
Dear Dr. Guidali,
Thank you for your Stage 1 submission. I have received three insightful reviews on your proposed study. The reviewers see merit in the scientific question, and the design of the study to target the associated hypotheses, however there are some concerns about the theoretical support behind some of the hypotheses. To highlight some of the critical concerns:
Our anonymous reviewer requests you provide additional empirical and theoretical support for your hypotheses. For example, you already cite a few articles to support why the modulation of P30 and P60 align with empirical studies suggesting they are a valid marker for PAS-induced modulation, I suggest you expand on these citations and potentially add more to further support this hypothesis. Equally, the other hypotheses would benefit from further motivation. The anonymous reviewer and Dr. Veniero request clarity on the connectivity analysis and how it will result in evidence of connectivity modulation rather than change in cortical excitability. Finally, the anonymous reviewer highlighted that hypothesis 5 could simply result from subthreshold stimulation at 90% resting motor threshold. It is my interpretation that you hypothesize a modulation of the P60, with no impact on P30 – this would suggest 90% rMT is sufficient to activate the corticospinal tract. If that is the case, interpretation of a P60 modulation for H5 should be contingent on a lack of P30 modulation to preclude insufficient stimulation. A significant repeated measures ANOVA does not control for the lack of P30 modulation.
Dr. Oberman is concerned about the heterogeneity of your sample in producing expected PAS-LTP and PAS-LTD MEP effects. Dr. Oberman suggests a pre-test to include participants which show the expected potentiation and depreciation MEPs. I share Dr. Oberman’s concern and request that you consider this pre-test, finally including the number of participants necessary to power the expected results. Alternatively, you should write a contingency plan: How will you interpret your TEP results (hypotheses H1-H5) if the MEP analysis (H0) shows no significant difference between the PAS-LTP and PAS-LTD MEPs? Along these lines, please could the authors complete the final column of the study design table. It may be more relevant to consider this final column as the alternatives to the hypothesized outcome which can elucidate the best approach for future analyses.
Dr. Veniero and Dr. Oberman highlight that you plan to collect the MEP and TEP data in serial rather than concurrently. As the MEP analysis acts as a positive control for following analyses on the TEP data, it seems sensible to consider collecting the data concurrently. Dr. Veniero also noted that the language surrounding the hypotheses should be more direct, which is the standard for registered reports. Wording like “we could speculate…” on page 5, should be replaced by “we hypothesize”, and each hypothesis should be supported with the relevant empirical literature. Any hypotheses which seem more exploratory will need to be removed from the Stage 1 – please see my further comments on this below. Of course, this does not preclude these analyses from being performed in an exploratory section of the Stage 2.
From my position as a recommender, I have a few notes regarding the registered reports formatting:
Hypothesis three is currently not strongly formulated, making targeted analyses, and the powering of these analyses very difficult. Please evidence your hypothesis for a particular connectivity effect following PAS. If there are multiple avenues to examine, you may want to consider running connectivity analyses in a more exploratory manner, reserved only for Stage 2. The same could be said for hypothesis four. As is currently written in the manuscript, you say effects could remain or disappear (page. 9) and that you could not state a priori how these profiles would progress over time for each stimulation protocol (page 6). For a registered report, a more solid hypothesis is critical, especially for powering your expected effect size.
For hypotheses H2 - H5 the authors indicate there are no prior studies which provide evidence for a hypothesized effect size. This is an understandable and common concern when running power analyses. At PCIRR, we recommend that the authors examine the literature for effects sizes which align with their effect of interest, for example regarding H2: TEP modulation for N100 with LTD like stimulation protocols (e.g. Casula et al., 2014). The same can be said for effect sizes associated with H3 to H5. Assuming a medium effect size for these hypotheses is risky and may mean you will not have the power to examine the effects of interest. Using an assumed small effect size would reduce this risk. Alternatively, if you believe there is no way to predict the effect size of interest for these hypotheses, these analyses become more exploratory in nature. In which case these four sets of analyses should be removed from the registration.
Please specify exactly where the EOG channels will be placed to pick up the blink and saccade artifacts, i.e. vertical and horizontal EOG.
With revisions following the suggestions from our three reviewers, I believe your manuscript has potential for in-principle acceptance. I would therefore request a revision and resubmission with a point-by-point reply to the reviewers and myself.