Reviewer's report
Title:The study of visceral hypersensitivity and psychological stress in
gastroesophageal reflux disease
Version: 1Date:23 December 2010
Reviewer: Daniel Sifrim
Reviewer's report:
Major Compulsory Revisions
1. The aims are not well defined in the context of the study, or of the title. If the
aim was to assess differences in cerebral responses to intra-oesophageal acid
and psychological stimuli, why was so much time spent assessing the
psychological profile of 176 GERD patient? Or was an (undeclared) aim of the
study to assess psychological comorbidity in GERD subgroups? If so perhaps it
detracts from the study focus to present it in the same paper.
2. The authors should clarify their recruitment and selection process. It is not
clear how 39 subjects were chosen for fMRI studies from the 176 recruited. How
this group compares with the lager group of 176 patients?
3. I doubt that the NERD- SI- group truly are a GERD subgroup. It is highly likely
that they represent a group with functional heartburn. This would be compatible
with the well-documented increased psychological comorbidity in this group.
4. The “psychological stimulus” is a weak aspect of the study as presented. The
running title and aim of the study imply a desire to test brain responses to stress
in GERD. Do the authors have data to show that the stimulus used did indeed
alter stress levels? This could easily have been tested using scores (e.g. VAS)
during the course of the experiment. Demonstration of higher stress levels after
the stimulus is essential to answer the study questions. It is possible that the
stimulus used could be testing the subjects’ suggestibility, not response to
stress?
5. The focus of the discussion regarding the fMRI studies appears to be
misplaced. The authors appear keen to discuss differences between the NERD
subgroups, whereas in fact little differences are present. Where differences are
found, they do not follow a logical pattern (e.g. in response to acid stimulus the
IC region was activated in RE, NERD- SI+ and NERD- SI- groups, but not in the
NERD+ group) and no attempt was made to explain these differences. In fact,
the study does appear to show differences between controls and GERD (taken
as a whole), and this may be something the authors wish to explore further.
6. The discussion states that "cerebral activation response to acid stimulus in RE
and NERD+ patients are more intensive than the other subgroups". This is a
false statement that is not borne out in the results. The max stimulation seen in
the RE group was only significantly more intense than one other group
(remarkably it was the NERD+ group).
7. I believe that discussion of visceral hypersensitivity with respect to these
results is potentially misleading. The study only supposes (but does not
demonstrate) that activation of certain brain regions in the study setting are
associated with visceral hypersensitivity. It should also be noted that very few
subjects were actually able to perceive the acid stimulus.
8. The fact that acid perfusion provoked a more intense FMRI activation than
psychological stimulus does not mean that hypersensitivity to acid is peripheral
rather than central!!!
9. I believe it is wrong to suggest that NERD- SI- patients have an "acid sensitive
esophagus with visceral hypersensitivity". By definition they do not show acid
sensitivity. Their SI is negative.
10. The discussion regarding high CRH levels in NERD- SI- patients does not
allow for the fact that they were no higher than in the other GERD subgroups.
11. The authors' concluding sentence is that "these results have important
implications for improved understanding of the pathogenesis of NERD-, and for
the development of more effective therapeutic approaches". Unfortunately, other
than demonstrating higher psychological morbidity in NERD- SI- patients (not
surprising, and not the stated aim of the study) the study as reported here does
not appear to reveal key differences between the GERD subgroups with regards
to fMRI (or at least any differences are not clearly explained or interpreted).
Minor Compulsory Revisions
1. There are many spelling and grammatical errors throughout the manuscript.
As it stands the manuscript cannot be published without major editing.
2. The authors’ discussion on strengths and limitations of the study is not
included.
3. The NERD-SI- group is now called functional heartburn. The authors should
explain why they used different classification
4. Did the NERD patients received earlier PPI during the last month or they were
naive to PPI treatment.
5. The authors enrolled only the NERD-SI- responsive to PPI but they did not
check the PPI response in the other NERD groups.
6. Was there any difference in the SCL-90 between responders and not
responders?
Discretionary Revisions
1. The symptom associated probability (SAP) is a more accurate tool than
symptom index (SI) in assessment of symptom-reflux correlation. Perhaps the
authors could define their subgroups more accurately using SAP rather than SI
(or both).
2. The methodology for acid infusion could be more robust. The same sequence
was followed in all cases (which does not control for changes which could
conceivably be produced by the subjects’ acclimatization to the study conditions,
changes in stress levels over the course of the study etc.). A variation in
sequence order and repetition of infusions would lead to more reliable data.
Recommendation
• This is an interesting study. It requires major revision before acceptance for
publication.
Level of interest
• The article has a significant level of interest
Quality of written English
• Not suitable for publication unless extensively edited.
Statistical review
• No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests
• I declare that I have no competing interests.
Level of interest: An article of importance in its field
Quality of written English: Not suitable for publication unless extensively edited
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Reviewer's report
Title:The study of visceral hypersensitivity and psychological stress in
gastroesophageal reflux disease
Version: 1Date:23 December 2010
Reviewer: Daniel Sifrim
Reviewer's report:
Major Compulsory Revisions
1. The aims are not well defined in the context of the study, or of the title. If the
aim was to assess differences in cerebral responses to intra-oesophageal acid
and psychological stimuli, why was so much time spent assessing the
psychological profile of 176 GERD patient? Or was an (undeclared) aim of the
study to assess psychological comorbidity in GERD subgroups? If so perhaps it
detracts from the study focus to present it in the same paper.
2. The authors should clarify their recruitment and selection process. It is not
clear how 39 subjects were chosen for fMRI studies from the 176 recruited. How
this group compares with the lager group of 176 patients?
3. I doubt that the NERD- SI- group truly are a GERD subgroup. It is highly likely
that they represent a group with functional heartburn. This would be compatible
with the well-documented increased psychological comorbidity in this group.
4. The “psychological stimulus” is a weak aspect of the study as presented. The
running title and aim of the study imply a desire to test brain responses to stress
in GERD. Do the authors have data to show that the stimulus used did indeed
alter stress levels? This could easily have been tested using scores (e.g. VAS)
during the course of the experiment. Demonstration of higher stress levels after
the stimulus is essential to answer the study questions. It is possible that the
stimulus used could be testing the subjects’ suggestibility, not response to
stress?
5. The focus of the discussion regarding the fMRI studies appears to be
misplaced. The authors appear keen to discuss differences between the NERD
subgroups, whereas in fact little differences are present. Where differences are
found, they do not follow a logical pattern (e.g. in response to acid stimulus the
IC region was activated in RE, NERD- SI+ and NERD- SI- groups, but not in the
NERD+ group) and no attempt was made to explain these differences. In fact,
the study does appear to show differences between controls and GERD (taken
as a whole), and this may be something the authors wish to explore further.
6. The discussion states that "cerebral activation response to acid stimulus in RE
and NERD+ patients are more intensive than the other subgroups". This is a
false statement that is not borne out in the results. The max stimulation seen in
the RE group was only significantly more intense than one other group
(remarkably it was the NERD+ group).
7. I believe that discussion of visceral hypersensitivity with respect to these
results is potentially misleading. The study only supposes (but does not
demonstrate) that activation of certain brain regions in the study setting are
associated with visceral hypersensitivity. It should also be noted that very few
subjects were actually able to perceive the acid stimulus.
8. The fact that acid perfusion provoked a more intense FMRI activation than
psychological stimulus does not mean that hypersensitivity to acid is peripheral
rather than central!!!
9. I believe it is wrong to suggest that NERD- SI- patients have an "acid sensitive
esophagus with visceral hypersensitivity". By definition they do not show acid
sensitivity. Their SI is negative.
10. The discussion regarding high CRH levels in NERD- SI- patients does not
allow for the fact that they were no higher than in the other GERD subgroups.
11. The authors' concluding sentence is that "these results have important
implications for improved understanding of the pathogenesis of NERD-, and for
the development of more effective therapeutic approaches". Unfortunately, other
than demonstrating higher psychological morbidity in NERD- SI- patients (not
surprising, and not the stated aim of the study) the study as reported here does
not appear to reveal key differences between the GERD subgroups with regards
to fMRI (or at least any differences are not clearly explained or interpreted).
Minor Compulsory Revisions
1. There are many spelling and grammatical errors throughout the manuscript.
As it stands the manuscript cannot be published without major editing.
2. The authors’ discussion on strengths and limitations of the study is not
included.
3. The NERD-SI- group is now called functional heartburn. The authors should
explain why they used different classification
4. Did the NERD patients received earlier PPI during the last month or they were
naive to PPI treatment.
5. The authors enrolled only the NERD-SI- responsive to PPI but they did not
check the PPI response in the other NERD groups.
6. Was there any difference in the SCL-90 between responders and not
responders?
Discretionary Revisions
1. The symptom associated probability (SAP) is a more accurate tool than
symptom index (SI) in assessment of symptom-reflux correlation. Perhaps the
authors could define their subgroups more accurately using SAP rather than SI
(or both).
2. The methodology for acid infusion could be more robust. The same sequence
was followed in all cases (which does not control for changes which could
conceivably be produced by the subjects’ acclimatization to the study conditions,
changes in stress levels over the course of the study etc.). A variation in
sequence order and repetition of infusions would lead to more reliable data.
Recommendation
• This is an interesting study. It requires major revision before acceptance for
publication.
Level of interest
• The article has a significant level of interest
Quality of written English
• Not suitable for publication unless extensively edited.
Statistical review
• No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests
• I declare that I have no competing interests.
Level of interest: An article of importance in its field
Quality of written English: Not suitable for publication unless extensively edited
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Please review this paper.
user
Reviewer's report
Title:The study of visceral hypersensitivity and psychological stress in
gastroesophageal reflux disease
Version: 1Date:23 December 2010
Reviewer: Daniel Sifrim
Reviewer's report:
Major Compulsory Revisions
1. The aims are not well defined in the context of the study, or of the title. If the
aim was to assess differences in cerebral responses to intra-oesophageal acid
and psychological stimuli, why was so much time spent assessing the
psychological profile of 176 GERD patient? Or was an (undeclared) aim of the
study to assess psychological comorbidity in GERD subgroups? If so perhaps it
detracts from the study focus to present it in the same paper.
2. The authors should clarify their recruitment and selection process. It is not
clear how 39 subjects were chosen for fMRI studies from the 176 recruited. How
this group compares with the lager group of 176 patients?
3. I doubt that the NERD- SI- group truly are a GERD subgroup. It is highly likely
that they represent a group with functional heartburn. This would be compatible
with the well-documented increased psychological comorbidity in this group.
4. The “psychological stimulus” is a weak aspect of the study as presented. The
running title and aim of the study imply a desire to test brain responses to stress
in GERD. Do the authors have data to show that the stimulus used did indeed
alter stress levels? This could easily have been tested using scores (e.g. VAS)
during the course of the experiment. Demonstration of higher stress levels after
the stimulus is essential to answer the study questions. It is possible that the
stimulus used could be testing the subjects’ suggestibility, not response to
stress?
5. The focus of the discussion regarding the fMRI studies appears to be
misplaced. The authors appear keen to discuss differences between the NERD
subgroups, whereas in fact little differences are present. Where differences are
found, they do not follow a logical pattern (e.g. in response to acid stimulus the
IC region was activated in RE, NERD- SI+ and NERD- SI- groups, but not in the
NERD+ group) and no attempt was made to explain these differences. In fact,
the study does appear to show differences between controls and GERD (taken
as a whole), and this may be something the authors wish to explore further.
6. The discussion states that "cerebral activation response to acid stimulus in RE
and NERD+ patients are more intensive than the other subgroups". This is a
false statement that is not borne out in the results. The max stimulation seen in
the RE group was only significantly more intense than one other group
(remarkably it was the NERD+ group).
7. I believe that discussion of visceral hypersensitivity with respect to these
results is potentially misleading. The study only supposes (but does not
demonstrate) that activation of certain brain regions in the study setting are
associated with visceral hypersensitivity. It should also be noted that very few
subjects were actually able to perceive the acid stimulus.
8. The fact that acid perfusion provoked a more intense FMRI activation than
psychological stimulus does not mean that hypersensitivity to acid is peripheral
rather than central!!!
9. I believe it is wrong to suggest that NERD- SI- patients have an "acid sensitive
esophagus with visceral hypersensitivity". By definition they do not show acid
sensitivity. Their SI is negative.
10. The discussion regarding high CRH levels in NERD- SI- patients does not
allow for the fact that they were no higher than in the other GERD subgroups.
11. The authors' concluding sentence is that "these results have important
implications for improved understanding of the pathogenesis of NERD-, and for
the development of more effective therapeutic approaches". Unfortunately, other
than demonstrating higher psychological morbidity in NERD- SI- patients (not
surprising, and not the stated aim of the study) the study as reported here does
not appear to reveal key differences between the GERD subgroups with regards
to fMRI (or at least any differences are not clearly explained or interpreted).
Minor Compulsory Revisions
1. There are many spelling and grammatical errors throughout the manuscript.
As it stands the manuscript cannot be published without major editing.
2. The authors’ discussion on strengths and limitations of the study is not
included.
3. The NERD-SI- group is now called functional heartburn. The authors should
explain why they used different classification
4. Did the NERD patients received earlier PPI during the last month or they were
naive to PPI treatment.
5. The authors enrolled only the NERD-SI- responsive to PPI but they did not
check the PPI response in the other NERD groups.
6. Was there any difference in the SCL-90 between responders and not
responders?
Discretionary Revisions
1. The symptom associated probability (SAP) is a more accurate tool than
symptom index (SI) in assessment of symptom-reflux correlation. Perhaps the
authors could define their subgroups more accurately using SAP rather than SI
(or both).
2. The methodology for acid infusion could be more robust. The same sequence
was followed in all cases (which does not control for changes which could
conceivably be produced by the subjects’ acclimatization to the study conditions,
changes in stress levels over the course of the study etc.). A variation in
sequence order and repetition of infusions would lead to more reliable data.
Recommendation
• This is an interesting study. It requires major revision before acceptance for
publication.
Level of interest
• The article has a significant level of interest
Quality of written English
• Not suitable for publication unless extensively edited.
Statistical review
• No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests
• I declare that I have no competing interests.
Level of interest: An article of importance in its field
Quality of written English: Not suitable for publication unless extensively edited
Statistical review: No, the manuscript does not need to be seen by a
statistician.
assistant