No Evidence of Cross-Orientation Suppression Differences in Migraine with Aura Compared to Healthy Controls

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The reference number 46 is displayed in italic font.

The introduction is extremely long; it might be worth moving it to the discussion section or shortening it.

The sample size is very low for the conclusions to be considered certain.

 

 

Author Response

The reference number 46 is displayed in italic font.

Thank you, we have amended this.

The introduction is extremely long; it might be worth moving it to the discussion section or shortening it.

Thank you, we have reduced the length of the introduction and moved some of the material to the discussion, please see the tracked changes for full details.

The sample size is very low for the conclusions to be considered certain.

Thank you for your comment, we appreciate that it is of course possible that there is a small effect that we have not been able to detect despite the sensitivity of this study. We have revised the document to further emphasis that this is not a certainty, but it is unlikely that there is a large effect:

“It must be acknowledged that the lack of statistically significant differences in this particular sample does not conclusively demonstrate that there is no possible difference. Importantly, this study was restricted to MA participants recruited from the general population. It may be the case that there would be effects if the participants had a more severe expression of MA, for example recruited from specialist headache clinics rather than the general population.”

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In this manuscript, authors evaluated the cross-orientation suppression task in patients with migraine with aura (MA), thus exploring the interactions between lateral geniculate nuclei and cortex and inhibitory processing. Resting state oscillations and suppression were both studied in a sample of MA patients and healthy controls and no difference was detected between the two groups. 

One of the most relevant aspect of this work is the high power although the small sample size.

However, it would have been interesting to the reader to evaluate any difference during the ictal and interictal phase of migraine cycle.

Moreover, how can you explain the difference between results from your study and other studies evaluating the magnetic suppression of perceptual accuracy (e.g. https://doi.org/10.1111/j.1468-2982.2006.01144.x)? This should be further clarified in the discussion. 

Nevertheless, this is a well-written, clear and well-structured manuscript. There is not an excessive number of self-citations and the experimental design is appropriate to test the hypothesis.

Author Response

In this manuscript, authors evaluated the cross-orientation suppression task in patients with migraine with aura (MA), thus exploring the interactions between lateral geniculate nuclei and cortex and inhibitory processing. Resting state oscillations and suppression were both studied in a sample of MA patients and healthy controls and no difference was detected between the two groups. 

One of the most relevant aspect of this work is the high power although the small sample size.

Thank you for your time and helpful comments.

However, it would have been interesting to the reader to evaluate any difference during the ictal and interictal phase of migraine cycle.

Thank you, we do not have the data on this as this would have required a longitudinal study. We fully agree this would have been an interesting point but did not have the capacity to run this. We have added this to the discussion:

“One limitation of this study is that this was a cross-sectional study aimed at ad-dressing the interictal stage of MA. There have been different effects shown in EEG responses in various perception tasks at the different stages of the migraine cycle, including (Sand et al., 2008, Sand et al., 2009, Judit et al., 2000). A longitudinal study following the migraine cycle would be useful for future research into cross-orientation suppression effects in MA. However, if effects are only seen in the ictal stages, they may be part of the symptom of the attack, rather than any everyday differences that result in the attack triggering.”

 

Moreover, how can you explain the difference between results from your study and other studies evaluating the magnetic suppression of perceptual accuracy (e.g. https://doi.org/10.1111/j.1468-2982.2006.01144.x)? This should be further clarified in the discussion. 

Thank you, this literature has been included in the discussion section, and the difference in methodology has been explained:

“For example, perception of a stimulus can be suppressed by introducing a pulse of TMS stimulation to the cortex shortly after stimulus presentation, indicative of inhibitory pro-cessing. However, this has been shown to be reduced suppression in MA compared to MO and control groups (Chronicle et al., 2006). This kind of suppression is apparent after a delay of around 100ms between stimulus onset and the TMS pulse, and so different from the simultaneous masking in the current study”

Nevertheless, this is a well-written, clear and well-structured manuscript. There is not an excessive number of self-citations and the experimental design is appropriate to test the hypothesis.

Thank you for your time and helpful comments.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This study is interesting, but shows  some limitations.

The first is the very  limited sample characterized from a great heterogenity in disease severity  (frequency of aura attack range from <1/month to 9 attacks/month; in one patient  is also unkown) and age (range 18-64); it is mandatory to exclude that the patients with greater frequency and older did not assume prophylactic therapy for migraine or drugs for other medical condition. Some non  fitting data need to be clarified or revised i.e one patients is reported to present 4-9 attacks  monthly, but the last attack occurs one year before.

 

The second most relevant methodological aspect concern the timing of EEG acquisition; the authors report, indeed , that registration is rescheduled if attack occurs in the previous  48 hours, but no data are reported concerning the occurrence of subsequent attacks; this kind of data need to be reported in the paper  since it might affect results. Several  literature evidence support , indeed,  a correlation between different electrophysiological data and the  days to the next headache attack. A cyclic pattern of activation in migraine has been shown in sensorimotor and visual cortices by both electrophysiological and neuroimaging studies with  peculiar pattern of activation related to the distance from the successive migraine attack.

 

Comments on the Quality of English Language

Minor editings are required

Author Response

This study is interesting, but shows  some limitations.

The first is the very  limited sample characterized from a great heterogenity in disease severity  (frequency of aura attack range from <1/month to 9 attacks/month; in one patient  is also unkown) and age (range 18-64); it is mandatory to exclude that the patients with greater frequency and older did not assume prophylactic therapy for migraine or drugs for other medical condition. Some non  fitting data need to be clarified or revised i.e one patients is reported to present 4-9 attacks  monthly, but the last attack occurs one year before.

 Thank you for your comment, we did ask all our participants if they were currently taking any medication and can confirm none of our participants were taking any medication. We have added this to the manuscript.

“None of the MA participants reported taking any medication”.

We appreciate these are quite a low-severity sample of migraine, with most participants reporting relatively few attacks. This was deliberately to collect a sample from the community, rather than referred from a headache clinic, as this is more representative of the level of episodic migraine seen in the general population. It may be the case that effects would be seen in participants with more severe expressions of migraine recruited from headache clinics. We have included this in the discussion:

“It must be acknowledged that the lack of statistically significant differences in this particular sample does not conclusively demonstrate that there is no possible difference. Importantly, this study was restricted to MA participants recruited from the general population. It may be the case that there would be effects if the participants had a more severe expression of MA, for example recruited from specialist headache clinics rather than the general population.”

We agree, there is some inconsistency in the reporting from the MA participants. We have checked with the participants involved. There was a period of very frequent migraine that resulted in the diagnosis of migraine, however the last attack was a while ago, so we have revised this to less than 1 per month currently, and explained in further detail in the manuscript, in the footnotes of Table 1.

“This participant had much more frequent migraines , around 4-9 per month, around one year ago.”

We have also recruited two more observers to replace these ones. The re-analysis can be seen in the Supplementary Information. This has made no substantial difference to the overall result.

All of this has been combined in the discussion section:

“. Finally, some of the participants had not experienced an attack for a while. There is evidence that migraine has a variable course across the lifespan, but there are no agreed criteria for remission of the disease, although some authors suggest this to be longer than a year (for a discussion see Rattanawong et al., 2022). In which case, we have re-analyzed our results removing the two individuals who had not experienced migraine for a while, this made no difference to the overall pattern of results. This analysis can be seen in the Appendix C. However, it may be that different results would be found in individuals currently experiencing more severe and frequent migraine attacks. This remains for future work”

The second most relevant methodological aspect concern the timing of EEG acquisition; the authors report, indeed , that registration is rescheduled if attack occurs in the previous  48 hours, but no data are reported concerning the occurrence of subsequent attacks; this kind of data need to be reported in the paper  since it might affect results. Several  literature evidence support , indeed,  a correlation between different electrophysiological data and the  days to the next headache attack. A cyclic pattern of activation in migraine has been shown in sensorimotor and visual cortices by both electrophysiological and neuroimaging studies with  peculiar pattern of activation related to the distance from the successive migraine attack.

Thank you, we agree with your comments. We have clarified that our participants did not anticipate a migraine attack after the testing session in the manuscript:

“Our participants were specifically asked if they felt they may experience a migraine attack in the next three days, all of them reported that they did not.”

 We also agree with your comment and the comments of some of the other reviewers that information about the migraine cycle would have greatly added to this paper, however we did not have capacity to run this longitudinal study, therefore we have added this to the discussion.

“One limitation of this study is that this was a cross-sectional study aimed at addressing the interictal stage of MA. There have been different effects shown in EEG responses in various perception tasks at the different stages of the migraine cycle, including (Sand et al., 2008, Sand et al., 2009, Judit et al., 2000). A longitudinal study following the migraine cycle would be useful for future research into cross-orientation suppression effects in MA. However, if effects are only seen in the ictal stages, they may be part of the symptom of the attack, rather than any everyday differences that result in the attack triggering.”

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors "No evidence of cross-orientation suppression differences in migraine-with-aura compared to healthy controls" is an interesting study of cross-orientation suppression. Although only cases of migraine with aura were compared to controls it is interesting to see that there were no inter-group differences. I have no objections regarding publication of the manuscript.

 

Author Response

"No evidence of cross-orientation suppression differences in migraine-with-aura compared to healthy controls" is an interesting study of cross-orientation suppression. Although only cases of migraine with aura were compared to controls it is interesting to see that there were no inter-group differences. I have no objections regarding publication of the manuscript.

 

Thank you for your time in reviewing the manuscript, and for your positive feedback.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

On the basis of the Author's replies I support the publication of the manuscript in its current form.

Author Response

Thank you for your time in reviewing this manuscript, it is much appreciated.

Reviewer 3 Report

Comments and Suggestions for Authors

The paper has now achieved significant imptovement. I suggest however to include some of the data in a supplementary material.

Comments on the Quality of English Language

necessary minor editing, especially in the new added parts of this version of the paper

Author Response

Thank you for your helpful comments. We have edited the manuscript, with special focus on the sections that are new. The data and accompanying analysis scripts are available at the Open Science Framework: https://osf.io/4ycju/ We have clarified this in the manuscript under the data availability statement.