Is an “Epigenetic Diet” for Migraines Justified? The Case of Folate and DNA Methylation
Round 1
Reviewer 1 Report
General:
The authors have provided a detailed review of epigenetics in regulating gene expression, epigenetics in relation to migraine, epigenetics in relation to diet, and the cross-over of the two. It is an interesting area of expansion in the diet and migraine space, but there are several areas of concern in the paper which require attention before the paper would be acceptable for publication. The description of migraine pathophysiology is mostly consistent with current science, yet the paper makes connections and assertions that go a step beyond current science. (See comments regarding cortical spreading depression in the specific comments.) Additionally, the description of dietary influence on migraine does not capture current scientific opinion on food triggers of migraine. (See specific comments.) And the authors’ labeling the elimination diet as not being risky (in the conclusion section) underestimates the risks of malnutrition and psychological load of following such a strict and poorly evidenced diet. Perhaps more importantly, the paper expends significant details to describe individual concepts and studies, but in doing so, loses sight of its overall message. It is not clear what the reader should be taking away from reading the whole paper, that was not evidenced in the abstract. (i.e., The epigenetic diet is a ‘promising avenue’ for prevention/treatment of migraine, but more research is needed.)
I would encourage the authors to consider the following topics in revisions: What would be the advantages of an epigenetic diet for migraine, versus drugs that can be more controlled and potentially more specific? The authors clearly state that “it is difficult to find a diet that would not affect epigenetic profile”, so it is not entirely clear what and how a diet could theoretically be modified to influence migraine. How would/should future research studies be designed to isolate the impact of these dietary modifications? Also, since much space is dedicated to the folate example: can you elucidate any mechanisms connecting the MTHFR polymorphism and the migraine pathophysiology described in section 4? (i.e., CGRP, CSD, trigger theory, etc.)
Also, the paper would benefit from revisions by a native English-speaker. This is a highly nuanced subject (actually, it is three highly nuanced subjects overlapping: migraine, diet, and epigenetics). Some of the nuance is being lost in the language. Some individual occurrences of language questions are included in the specific comments below.
Specifics:
Line 50 “certain recommended diet” seems oddly phrased.
Line 52 “as beneficiary”, beneficial is the word perhaps?
Line 68 “asses the”, assess.
Line 119 “may undergone”, have is missing?
Line 225 source of this prevalence statistic? Please cite.
Line 232-237 (figure 3 caption) and text lines 238-243. Re-evaluate for accuracy and certainty of the science. The exact mechanisms whereby CSD is initiated are not yet elucidated, nor precisely how CSD initiates subsequent phases of a migraine, nor precisely how suspected triggers exert their influence. The specific order of events presented here is therefore not substantiated.
Lines 242-243: This line should be re-phrased in light of the recent pharmaceuticals approved for migraine treatment and prevention (approved for use in the U.S.). Are treatment options still anticipated to be insufficient even given these new treatments?
Lines 244-246 (Figure 4): The caption needs to be rephrased to convey that these are *suspected* triggers or *reported* triggers. Recent research suggests that many believed food triggers are actually food cravings experienced as the first phase of migraine before pain onset. Past research which relied primarily on self-reported food triggers is no longer reliable.
Line 253 “another”, other?
Line 261 “Some are described in the further text.” It is not clear what is the purpose of this sentence. Some other genes? By ‘further text’, do you mean this article?
Line 271 “higher extent that their sequence”, confusing, seems cut off.
Line 283-285 According to the cited reference, the only meta-analysis was related to magnesium treatment for migraine, and even that was intravenous magnesium for acute treatment of migraine, not supplement magnesium. This reference is inadequate to support the assertion that “results of several meta-analyses suggest” these supplements are effective. To my knowledge, these meta-analyses do not exist, but other citations could prove me wrong.
291-292 Given that this was a large population level, cross-sectional study [ref 68], the results should be interpreted more cautiously. These differences in macronutrient intake were observed (albeit very small in magnitude), and further research is necessary to explain them.
#70 mixed headache and migraine patients.
#71 all relevant differently methylated regions results were located in genes involved in drug addiction and mechanisms and neuropsychiatric illness; also larger sample was needed. Only one gene in study related to migraine.
#74 medications can alter methylation pathways, no medication information was collected upon intake.
#75 this was done in leukocytes, not CNS, there is tissue-specificity in DNA methylation.
#76 I had no access to.
#77 study in rat cells, if migraine has “neurogenic inflammation and components of the immune system” being implicated in it, then is this study capable of inducing the methylation of the CALCA gene that they’re looking for? Specifically, do cell cultures have the ability to answer this question fully? Or is an animal model more appropriate?
Line 333 CGRP, not CGPR
Line 349 “is a generic term for a type B vitamin”. Re-phrase.
#86 effects of unmetabolized folic acid on intracellular folate metabolism is the issue. They state folate supplementation, but the issue is the unmetabolized FA in the blood plasma due to lack of 5,10-methylene tetrahydrofolate reductase being adequately active. This mixes studies which supplement with FA versus supplementation of folate.
#94 I have no access
#95 this was a meta-analysis. Also, sig. correlation was in the TT type but not in the Caucasian population. Asian decent was significant for TT and MA in one study.
Line 416 “a lower levels”
Line 421 “557T allele of the MTHFR gene”, I could not find reference to this in text, do they mean C677T?
Line 432 “is conceptually simpler that”
Line 433 “exert beneficiary effect”, beneficial?
Line 434 “that predisposes to a dietary”
Line 456 “may active demethylate”
Line 457 “what is superior”
Line 461 “VA-fortifying”
Line 477 “a folate-rich diet as epigenetic diet effective”
Author Response
Comment: The authors have provided a detailed review of epigenetics in regulating gene expression, epigenetics in relation to migraine, epigenetics in relation to diet, and the cross-over of the two. It is an interesting area of expansion in the diet and migraine space, but there are several areas of concern in the paper which require attention before the paper would be acceptable for publication. The description of migraine pathophysiology is mostly consistent with current science, yet the paper makes connections and assertions that go a step beyond current science. (See comments regarding cortical spreading depression in the specific comments.) Additionally, the description of dietary influence on migraine does not capture current scientific opinion on food triggers of migraine. (See specific comments.)
Answer: We have addressed the above remarks in the replies to specific comments.
Comment: And the authors’ labeling the elimination diet as not being risky (in the conclusion section) underestimates the risks of malnutrition and psychological load of following such a strict and poorly evidenced diet.
Answer: We have added the following sentences to the “Conclusion and Perspectives section”:
“However, a long-term elimination diet can result in undernutrition, a form of malnutrition, which is characterized as the inadequate intake of protein, energy, and micronutrients, that and may results in disorders, including psychological loads or infection [110]. An easy and quick tool to evaluate the risk of malnutrition resulting from an elimination diet is the Malnutrition Universal Screening Tool (MUST) that can be used to determine nutritional risk [111].“
with two new references:
Meijers, J.M.; van Bokhorst-de van der Schueren, M.A.; Schols, J.M.; Soeters, P.B.; Halfens, R.J. Defining malnutrition: mission or mission impossible? Nutrition (Burbank, Los Angeles County, Calif.) 2010, 26, 432-440, doi:10.1016/j.nut.2009.06.012. Stratton, R.J.; Hackston, A.; Longmore, D.; Dixon, R.; Price, S.; Stroud, M.; King, C.; Elia, M. Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the 'malnutrition universal screening tool' ('MUST') for adults. The British journal of nutrition 2004, 92, 799-808, doi:10.1079/bjn20041258.
Comment: Perhaps more importantly, the paper expends significant details to describe individual concepts and studies, but in doing so, loses sight of its overall message. It is not clear what the reader should be taking away from reading the whole paper, that was not evidenced in the abstract. (i.e., The epigenetic diet is a ‘promising avenue’ for prevention/treatment of migraine, but more research is needed.)
Answer: We have changed the sentence (Abstract):
“Therefore, epigenetic diet in migraine might be a “promising avenue” in prevention and treatment of migraine, but it requires further studies that could involve the fortification of folate-rich diet with valproic acid, another modifier of epigenetic profile effective in migraine prophylaxis.”
into the following fragment:
“Results obtained so far do not warrant recommendation of any epigenetic diet as effective in migraine prevention and therapy. Further studies, including a folate-rich diet fortified with valproic acid, may help to clarify this issue.”
We have added the following sentence at the end of the “2. Epigenetic Regulation of Gene Expression” section:
“In summary, the epigenetic profile is dynamically regulated by several objects that interact with each other. Not all these interactions are known or can be predicted, which is why any epigenetic intervention can be associated with a relatively high degree of uncertainty.”
We have added the following sentence at the end of the “3. The Epigenetic Diet – Does It Really Exist?” section:
“In summary, the use of the term “epigenetic diet” is, at present, not fully justified and it should not be understood like other relatively well established kinds of the diets, including the Mediterranean diet or ketogenic diet.”
We have added the following sentences at the end of the “6. Folate and Its Role in DNA Methylation and Migraine Pathogenesis” section:
“In summary, folate is essential for DNA methylation and its presence in the diet was reported to exert a beneficial effect on migraines. However, these profitable effects of dietary folate have not been attributed to changes in DNA methylation or other alterations in epigenetic profile.”
In addition, we have introduced some minor changes and modifications throughout the entire text to strengthen our view that epigenetic diet in general and its application in migraines in particular, are not fully justified at present.
Comment: I would encourage the authors to consider the following topics in revisions: What would be the advantages of an epigenetic diet for migraine, versus drugs that can be more controlled and potentially more specific?
Answer: We have added the following fragment to the final section:
“Considering the application of an epigenetic diet for migraines we should determine its advantages over epigenetic drugs than can be administrated in a more controlled way with a potentially more specific action. Our answer is: There are no advantages. The only possible advantage is that a drug with known epigenetic action may not act effectively on migraines when administrated alone, but it may prove to be efficient when given in a combination with dietary components. However, this is rather illusory advantage as the similar an ineffective, but generally neutral, effect of a drug may change into an adverse effect when added as a diet supplement.”
Comment: The authors clearly state that “it is difficult to find a diet that would not affect epigenetic profile”, so it is not entirely clear what and how a diet could theoretically be modified to influence migraine.
Answer: This is exactly what we think and have tried to present in this manuscript.
Comment: How would/should future research studies be designed to isolate the impact of these dietary modifications?
Answer: We have added the following fragment to the final section:
“On the other hand, attempts to isolate the impact of targeted dietary modifications may make little, if any, sense as they might lead to the replacement of a diet with a drug.”
Comment: Also, since much space is dedicated to the folate example: can you elucidate any mechanisms connecting the MTHFR polymorphism and the migraine pathophysiology described in section 4? (i.e., CGRP, CSD, trigger theory, etc.)
Answer: We have added the following fragment to the “5. Folate and Its Role in DNA Methylation and Migraine Pathogenesis” section:
“Although the exact mechanism connecting the 677C>T polymorphism of the MTHFR gene with migraine pathophysiology is not completely known, some pathways can be considered. The C → T transition at 677 leads to the substitution of alanine to valine, thereby resulting in a reduced activity of the MTHFR enzyme compared with to its wild-type counterpart [101]. Consequently, individuals homozygous for the T variant have higher homocysteine levels than the C homozygotes [102]. As stated previously, an excess of homocysteine can be destructive for vessels and play a role in migraine pathogenesis, especially in migraines with aura [103]. However, the direct link between homocysteine level and migraines is still the a matter of debate, especially since only one study so far has evaluated the level of homocysteine in the cerebral fluid of migraineurs [104]. Nevertheless, elevated homocysteine may cause injury to endothelial cells, reduced flexibility of the vessels, and changes in hemostasis, which may contribute to headaches and the many associated effects and even vascular comorbidity of migraines, especially MA [105]. Homocysteine and its related compounds may act as excitatory agonists of the NMDA subtype of glutamate receptors, which are important for the cortical spreading depression [106, 107]. Other potential aspects of the significance of the 677T>C polymorphisms in the MTHFR gene, such as its association with calcitonin gene related peptide or migraine triggers, have not been investigated so far and require further research.”
with new references:
Liew, S.C.; Gupta, E.D. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015, 58, 1-10. McNulty, H.; Dowey le, R.C.; Strain, J.J.; Dunne, A.; Ward, M.; Molloy, A.M.; McAnena, L.B.; Hughes, J.P.; Hannon-Fletcher, M.; Scott, J.M. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation. 2006 Jan 3;113(1):74-80. Isobe, C.; Terayama, Y. A remarkable increase in total homocysteine concentrations in the CSF of migraine patients with aura. Headache 2010, 50, 1561-1569, doi:10.1111/j.1526-4610.2010.01713.x. Sadeghi, O.; Maghsoudi, Z.; Askari, G.; Khorvash, F.; Feizi, A. Association between serum levels of homocysteine with characteristics of migraine attacks in migraine with aura. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences 2014, 19, 1041-1045. Ho, P.I.; Ortiz, D.; Rogers, E.; Shea, T.B. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. Journal of neuroscience research 2002, 70, 694-702, doi:10.1002/jnr.10416. Kruman, II; Culmsee, C.; Chan, S.L.; Kruman, Y.; Guo, Z.; Penix, L.; Mattson, M.P. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000, 20, 6920-6926.
Comment: Also, the paper would benefit from revisions by a native English-speaker. This is a highly nuanced subject (actually, it is three highly nuanced subjects overlapping: migraine, diet, and epigenetics). Some of the nuance is being lost in the language. Some individual occurrences of language questions are included in the specific comments below.
Answer: We have had our manuscript checked by the MDPI English editing service.
Specifics:
Comment: Line 50 “certain recommended diet” seems oddly phrased.
Answer: We have decided to remove the sentence: “However, certain recommended diet seems to have a general character, addressing objects or effects that are responsible for a wide spectrum of phenotypic features.” – it is not only oddly phrased, but does not fit general context of the manuscript.
Comment: Line 52 “as beneficiary”, beneficial is the word perhaps? Line 68 “asses the”, assess. Line 119 “may undergone”, have is missing?
Answer: We have changed accordingly (may undergone → may undergo).
Comment: Line 225 source of this prevalence statistic? Please cite.
Answer: We have added additional information on the year and the reference:
Steiner, T.J.; Stovner, L.J.; Birbeck, G.L. Migraine: the seventh disabler. J Headache Pain 2013, 14, (1), 1.
Comment: Line 232-237 (figure 3 caption) and text lines 238-243. Re-evaluate for accuracy and certainty of the science. The exact mechanisms whereby CSD is initiated are not yet elucidated, nor precisely how CSD initiates subsequent phases of a migraine, nor precisely how suspected triggers exert their influence. The specific order of events presented here is therefore not substantiated.
Answer: We have added the title to the Figure 3 caption – A putative mechanism for migraine headaches induced by a trigger. Furthermore, we have added the note at the end of the caption: “The specific order of events presented here is hypothetical and requires validation.” Moreover, we have changed the following sentence:
“The aura may include several visual and mental syndromes and is believed to relate to cortical spreading depression (CSD), an important effect in migraine induced by its trigger that leads to activation of the trigeminal nerve and the headache phase (Figure 3) [49].
into:
“The aura may include several visual and mental syndromes and is believed to relate to cortical spreading depression (CSD), an important effect in migraines. However, the exact mechanism whereby CSD is initiated is not exactly known, nor is it known how CSD initiates the subsequent phases of migraines. Some possible mechanism including the activation of the trigeminal nerve and the induction of neurogenic inflammation, are presented in Figure 3 [50]. “
Comment: Lines 242-243: This line should be re-phrased in light of the recent pharmaceuticals approved for migraine treatment and prevention (approved for use in the U.S.). Are treatment options still anticipated to be insufficient even given these new treatments?
Answer: We have changed the sentence:
“Current prevention and treatment options are ineffective in more than half of migraine-affected patients, so new prophylactic and therapeutic targets need to be identified [51].”
into:
“Although the prevention and treatment of migraines remain challenging [52], migraine drugs approved by the FDA have lately produced hope for a breakthrough (https://www.accessdata.fda.gov/scripts/cder/daf/). These drugs include erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality), which are all monoclonal antibodies and GRPC antagonists. It is too early to draw a definite conclusion on the general role these drugs may play in migraine treatment, but the first observations are prospective despite the relatively high cost of therapy with these drugs, estimated at about $575 per month (https://www.health.harvard.edu/diseases-and-conditions/are-the-new-migraine-medications-working).”
Comment: Lines 244-246 (Figure 4): The caption needs to be rephrased to convey that these are *suspected* triggers or *reported* triggers. Recent research suggests that many believed food triggers are actually food cravings experienced as the first phase of migraine before pain onset. Past research which relied primarily on self-reported food triggers is no longer reliable.
Answer: It is really difficult and I am afraid that we are not able to make a definite, non-overlapping categorization of migraine triggers into “suspected” and “reported” and decide whether these “reported” are reliable or not. On the other hand, all triggers we presented have been somehow “reported”, no matter whether they have been actually reported in large clinical trials or in research on small samples or self-reports. That is why we have changed the Fig. 4 legend into:
“Main migraine triggers. Some are well established and confirmed by reports on large cohorts, but others are problematic and require further research. Recent research suggests that some food triggers are actually food cravings experienced as the first phase of a migraine before pain onset. Their action and threshold can be modulated by several environmental and genetic factors that act synergistically.”
Comment: Line 253 “another”, other?
Answer: We have changed into “other”.
Comment: Line 261 “Some are described in the further text.” It is not clear what is the purpose of this sentence. Some other genes? By ‘further text’, do you mean this article?
Answer: I understand this sentence should be rather removed. We have done so.
Comment: Line 271 “higher extent that their sequence”, confusing, seems cut off.
Answer: We have changed the sentence:
“Epigenetic profile of genes can be changed by nutrition in higher extent that their sequence [64].”
into:
“The cellular epigenetic profile is more prone to nutritional modifications than corresponding DNA sequence [65].”
Comment: Line 283-285 According to the cited reference, the only meta-analysis was related to magnesium treatment for migraine, and even that was intravenous magnesium for acute treatment of migraine, not supplement magnesium. This reference is inadequate to support the assertion that “results of several meta-analyses suggest” these supplements are effective. To my knowledge, these meta-analyses do not exist, but other citations could prove me wrong.
Answer: We have decided to remove this paragraph as it is misleading and actually weakly related to the subject of this manuscript.
Comment: 291-292 Given that this was a large population level, cross-sectional study [ref 68], the results should be interpreted more cautiously. These differences in macronutrient intake were observed (albeit very small in magnitude), and further research is necessary to explain them.
Answer: We have changed the following sentence in the last paragraph in the “4. Migraine in the diet” section:
“This study suggests that gender-specific difference in nutrition consumption may contribute to the difference in migraine prevalence between men and women.”
into:
“These results indicate a gender-specific difference in the consumption of macronutrients among migraineurs. However, whether this difference contributes to a different prevalence of migraine between men and women should be confirmed by further research as the difference observed in these large cross-sectional studies were not very pronounced.”
Comment: #70 mixed headache and migraine patients.
Answer: We have included that information.
Comment: #71 all relevant differently methylated regions results were located in genes involved in drug addiction and mechanisms and neuropsychiatric illness; also larger sample was needed. Only one gene in study related to migraine.
Answer: As we included information on the involvement of the genes and underlined that only one of them was correlated with migraine, we have the following sentence at the end of that paragraph:
“These results require confirmation in larger samples.”
Comment: #74 medications can alter methylation pathways, no medication information was collected upon intake.
Answer: We have added the following sentence:
“As many drugs can influence the epigenetic profile this study suffers from the drawback that no medication information was collected.”
Comment: #75 this was done in leukocytes, not CNS, there is tissue-specificity in DNA methylation.
Answer: We have added the following sentence:
“However, these studies were performed on peripheral blood leukocytes, but DNA methylation is tissue-specific as it is involved in tissue-specific gene expression.”
Comment: #76 I had no access to.
No answer
Comment: #77 study in rat cells, if migraine has “neurogenic inflammation and components of the immune system” being implicated in it, then is this study capable of inducing the methylation of the CALCA gene that they’re looking for? Specifically, do cell cultures have the ability to answer this question fully? Or is an animal model more appropriate?
Answer: We have changed the sentence:
“The CGRP gene is normally inactive in trigeminal glia, but epigenetic modifications may result in its activation that may play a role in migraine pathogenesis [77].”
into:
“The CGRP gene is normally inactive in trigeminal glia, but it was shown that epigenetic modifications resulted in its activation in rat cells in vitro [78]. Whether or not this observation is related to migraine pathogenesis should be further established as there are several questions associated with that study, for example, can an in vitro study on rat cells be associated with human migraines?”
Comment: Line 333 CGRP, not CGPR
Answer: We have corrected that.
Comment: Line 349 “is a generic term for a type B vitamin”. Re-phrase.
Answer: We have changed the sentence:
“Folate (folacin, vitamin B9) is a generic term for a type B vitamin that is an essential micronutrients playing a critical role in one-carbon cellular metabolism [79, 80].”
into:
“Folate (folacin, vitamin B9) is one of the B vitamins and an essential micronutrient that plays a critical role in one-carbon cellular metabolism [79, 80].”
Comment: #86 effects of unmetabolized folic acid on intracellular folate metabolism is the issue. They state folate supplementation, but the issue is the unmetabolized FA in the blood plasma due to lack of 5,10-methylene tetrahydrofolate reductase being adequately active. This mixes studies which supplement with FA versus supplementation of folate.
Answer: We have added the following sentence to that fragment:
“This review summarized studies with the supplementation of both folate and folic acid, which were not adequate due to inter-individual variability in the activity of 5,10-methylene THF reductase.”
Comment: #94 I have no access
No answer
Comment: #95 this was a meta-analysis. Also, sig. correlation was in the TT type but not in the Caucasian population. Asian decent was significant for TT and MA in one study.
Answer: This is what we have written.
Comment: Line 416 “a lower levels”
Answer: We have corrected that.
Comment: Line 421 “557T allele of the MTHFR gene”, I could not find reference to this in text, do they mean C677T?
Answer: Surely, yes. Exactly the 677T allele. We have corrected that.
Commenst: Line 432 “is conceptually simpler that”, Line 433 “exert beneficiary effect”, beneficial?
Answer: We have changed the sentence:
“Avoidance diet, eliminating compounds that are known to exert detrimental effects, is conceptually simpler that comprehensive diet, containing specific compounds that exert beneficiary effects.”
into:
“An avoidance diet, eliminating compounds that are known to exert detrimental effects, is usually easier to apply than comprehensive diet, containing specific compounds that exert beneficial effects.”
Comment: Line 434 “that predisposes to a dietary”
Answer: We have changed the sentences:
“Migraine is a disease that predisposes to dietary interventions as many dietary factors are migraine triggers. Therefore, avoidance diet may be effective in migraine prophylaxis and treatment, if headaches are triggered by a dietary compound.”
into:
“As many dietary factors are known to be putative migraine triggers, an avoidance diet may be effective in migraine prophylaxis and treatment.”
Comment: Line 456 “may active demethylate”
Answer: We have changed into “actively”
Comment: Line 457 “what is superior”
Answer: We have changed the sentence:
“Moreover, it demethylates specific genes what is superior in its therapeutic potential [107].”
into:
“Moreover, VPA demethylates specific genes, thus enhancing its therapeutic potential [117].”
Comment: Line 461 “VA-fortifying”
Answer: We have changed “with VA-fortifying diet” into “on diets fortified with VPA”
Comment: Line 477 “a folate-rich diet as epigenetic diet effective”
Answer: We have changed the sentence:
“There is not substantial evidence to consider a folate-rich diet as epigenetic diet effective in migraine.”
into
“There is not substantial evidence that folate-rich diets are therapeutically effective for migraines.”
Reviewer 2 Report
The review of Fila et al summarizes the literature of a potential link between DNA methylation, nutrients that alter DNA methylation and migraine. The review is in the clear focus of the journal. It is interesting for a broad readership dealing with nutrition, epigenetics or migraine. To my knowledge not many reviews have been published dealing with this topic in this composition. I would like to mention that a perspective article is online for a few month dealing with a similar topic covering some aspects of this review. (CNS Neurol Disord Drug Targets. 2019 Aug 9), nevertheless this review reveals new aspects.
It is written clearly, comprehensive and divided in meaningful subchapters. The review ends with a conclusion briefly summarizing the most important facts.
The authors use high quality figures to illustrate the underlying mechanisms and to summarize the literature. In some cases, the review shifts a little bit to an opinion article, however it is still very balanced and the authors clearly point out that more studies are needed to prove the impact of DNA methylation in migraine.
In summary this is, in my opinion, an excellent review, which is – and this is very rare .
Author Response
The review of Fila et al summarizes the literature of a potential link between DNA methylation, nutrients that alter DNA methylation and migraine. The review is in the clear focus of the journal. It is interesting for a broad readership dealing with nutrition, epigenetics or migraine. To my knowledge not many reviews have been published dealing with this topic in this composition. I would like to mention that a perspective article is online for a few month dealing with a similar topic covering some aspects of this review. (CNS Neurol Disord Drug Targets. 2019 Aug 9), nevertheless this review reveals new aspects.
It is written clearly, comprehensive and divided in meaningful subchapters. The review ends with a conclusion briefly summarizing the most important facts.
The authors use high quality figures to illustrate the underlying mechanisms and to summarize the literature. In some cases, the review shifts a little bit to an opinion article, however it is still very balanced and the authors clearly point out that more studies are needed to prove the impact of DNA methylation in migraine.
In summary this is, in my opinion, an excellent review, which is – and this is very rare .
Answer: All we have to do is thank you.
Round 2
Reviewer 1 Report
The authors have seriously considered my comments and made thoughtful and appropriate revisions to the paper in response. Thank you.
I continue to believe that the use of the English language obscures the authors' subtle points from being thoroughly communicated. However, the authors state the manuscript was reviewed by the MDPI English editing service.
