Continuous Real-Time Neuropsychological Testing during Resection Phase in Left and Right Prefrontal Brain Tumors

Round 1

Reviewer 1 Report

-Overall, the paper seems interesting, but it is really hard to read in its current form. The authors should concentrate more on the language and the style of writing. The use of terminology should be more clear since the reader gets confused about what executive functions are, what cognitive functions are, and what is tested. The focus in the Introduction is on “executive functions as multicomponetial construct, but in the Abstract, we can find “cognitive status.” Also, it is quite hard to understand what is the aim of the study, to develop or to choose several neuropsychological tests that are often used in pre and post-surgery in the context of intraoperative surgery, or it is the aim to test RH and LH patients on different neuropsychological measures intraop, pre and post-surgery? Also, the reader gets the impression, the more tests are better?! This is not quite understandable since the authors did not compare the results with DES, but only concluded that DES has some time constraints (is the conclusion based on their results from Skrap et al.J Neurosurg 125:877–887, 2016?). It is not quite sure how the sensitivity of chosen neuropsychological tests is validated  (Skrap et al.J Neurosurg 125:877–887, 2016?) to be used in everyday surgery in other neurosurgical settings. When to use DES and without DES, meaning using only neuropsychological tests? Can the authors explain if the participants from the submitted paper are those from the paper published by Skrap et al.?

-the terminology and grammatic should be checked by professional English speakers as well as the whole manuscript. For example, “intra-operatory monitoring” is not the grammatically right term to use in “intraoperative neurophysiology”. Instead, “intraoperative monitoring technique” is the right term. Please check the entire manuscript with this terminology.

- The grammatic is a bit problematic in the whole manuscript and should be checked carefully by the professional (for example: “detecting some any possible deterioration”). Also, the sentences are a bit long in many places, redundant and repeating, and currently, the manuscript is hard to read due to grammatical and semantic issues, due to no professional English checking before submission.

-The use of acronyms vs full terms should be consistent in the whole manuscript (i.e. SDMT versus symbol-digit modality test (raw 329 full terms, but previously the acronym was introduced, etc; the full terms again used in the Discussion paragraph compared to previous paragraphs were acronyms were used). The consistency in the use of acronyms vs full terms should be present in the whole manuscript.

-raw 112-116, plus the whole Introduction should be more understandable in defining executive functions and the aim of the study.  So the aim of the study was to investigate executive functions. Which ones? How executive functions can be categorized in a way when measuring different constructs? The reader only gets the impression from the introduction's last paragraph that the executive function is a multi-componential construct. Please be more concrete and try to connect the constructs you are measuring intraop, pre and post-op when defining the aim of the study.

-raw 64-66 – please insert the reference for the sentence..”They used..” or rewrite to be more understandable.

-raw-83-84-please rewrite the sentence to be more understandable “We are in effect speaking about negative mapping”

-85-89 – the last two sentences of this paragraph can be rewritten together to be more understandable, right now the sentences are similar and somehow repeating.

-raw 93, sentence “RTNT allows the administration of many tests”. This sentence is somehow weird, and the positioning is not understandable.

-raw 102-104 – Please rewrite these sentences to be understandable in one sentence. “It is also up to the neuropsychologist to assess whether the decrease is due to the resection or other variables. Deterioration occurs gradually, and sometimes it depends  on the handling and procedure itself.”

-raw 105 – it is advisable to remove sentence construction such as “here we tried”, since it is colloquial, and to remove parts with “WE selected test”.. and try to use fewer constructions with “we” (i.e. raw 123, 124..); “our” approach (i.e., raw 172); “we measured” (Table 1), “we designed”, “we tested (raw 341) etc.

-If this is only the “our approach”, meaning from the authors, how can we be sure that this list of tests is accurate, is properly validated by other research groups?

-raw 112- it is unclear what the authors wanted to say with this long sentence (given below). Why RTNT allows more tests to be used and DES does not? Is it related to the time? For DES it is known that tests should be short and sensitive due to the duration of the surgery (the testing should not prolong the surgical procedure), but it is not quite clear why RTNT would allow much more tests. You mean because since no stimulation is applied to brain tissue, the surgeon has “more time” to play around looking for executive functions other than language, speech etc.?“Our hypothesis is that by using more neuropsychological tests (and RTNT allows us to do so, while DES is more time constrained) we increase the probability of detecting some any possible deterioration of cognitive ability, so that we can better monitor the patient’s cognitive status, since executive functions are multi-componential (see above) and one or few tasks do not appear sufficient”

-line 119 ..”We tested” What is this?

-raw 126, it is not quite clear the part in the brackets  please rewrite “(as they perform dedicated RTNT protocols, [22,23])”

-raw 138- how many left-handed patients are in the RH group? It is not quite clear.

-  raw 146 – this is not understandable, please rewrite, “in addition to additional cognitive tests for the LH and the RH”. Please reformulate the sentence so the reader is informed first about the tests used in pre and post surgery for LH and RH group, and what do you mean by additional? Additional to what? Please include the references for each test in the manuscript text.

-Since these patients had glioma in the frontal cortex, why standard DES procedure was not performed in these patients? Or was it performed, but it is not reported here? If DES is performed, this information should also be given.

-The authors reported that the abstract language was tested (raw 110). When inspecting Table 1 the visual object naming task was listed, and this is one of the mostly used tasks during DES for language since there are many studies proving that visual object naming task elicits broader network activated during language processing. Also action verb naming is language task used by authors, also verbaly fluency.It is not quite sure what the author wanted to say with “abstract language processing”. The authors did not test abstract language processing, but rather speech and language processing.

-Did the authors use all the tests from RTNT also in the pre and post-surgery when inspecting LH and RH patients? Paragraph 2.2. and 2.3. , and a supplementary list, should be written to more understandable for the reader. It would be suggested to delineate if the post and pre surgery tests were applied to all LH and RH patients or not. If not, then the supplementary table should be rewritten so that the reader knows which tests were applied to LH and RH patients pre and post-surgery. Also, state clearly what are the tests which are identically used in LH and RH patients intraoperatively vs pre and post-surgery. Also, please in 2.2. paragraph explain better the categorization of the individual test so the reader can figure out which tests are designed as executive functions, cognition, psychological functions, etc.

-The application of the test during intraoperative part should be presented more clearly. It is not quite sure how many times the tests were applied, how long the operation lasted, and how the authors changed the stimuli, for example, if using SDMT (if only one version exists)? How the scoring /analysis was done for the repeated tests during the surgery?

-Figure 1- it does not bring new information, so it can be deleted. The list of tests is given in the manuscript text.

-Table 1 is also a bit redundant, since each test and the domain each test measures can be placed directly into the manuscript text. This paper is not a review paper.

-Table 1,2,3, in the supplementary, need to include also acronyms (Table 1) if used in tables 2 and 3. Why some individual scores are highlighted in Tables 2 and 3? Put the necessary acronym in the table legends.

-The references from the supplementary tables should be introduced in the manuscript reference list.

-Figure 2, where is “C” on the figure? Please check the figure legend properly. The “F” part is of poor resolution, and is it suggested to put the results rather as the text since the list of test used prior and post surgery is given in the supplement file, so the reader would need to go and check in the supplements for the acronyms of the tests presented in the F.

-Terminology “”intra-resection RTNT performance” please rewrite maybe as: simply: “RTNT performance during resection”

-raw 295- “as there is no accuracy but this measure it is expressed as the patients’ span” please rewrite to be more understandable

-raw 341-343-Could the authors explain how these tests were sensitive to the surgical act? Changing the surgeon strategy or? It is known that DES can change the surgical strategy (for example, while mapping Broca’s area and eliciting speech arrest), but how the sensitivity of so many tests can be determined to be valid for intraoperative use?

- raw 343-350- the sentence should be rewritten to be more understandable. How were tests “changed more”? What does this mean? Do you mean the performance score on a particular test changed during the resection regarding starting of the incision to the end? The sentences are formulated strangely, and it is hard to follow the author's logic.

 "In particular, for the RH patients, a visuospatial attention test (Milner Landmark test) and emotion induction test (International Affective picture stimuli) were those who changed more in terms of median performance while in terms of patients’ minimum values also the metaphor comprehension test changed more. For the LH patients a task monitoring selective attention and working memory (digit symbol modality test), the Stroop and short term memory and working memory were those who changed more in terms of median performance and in the patients’ minimum values."

-raw 352 – This sentence starting with “this is” sounds strange and should be rewritten. “This is the aim of RTNT, that is  monitoring functions and early detecting changes [20].

-raw 361 – please rewrite these two sentences or join them since they sound strange and parcellated. How can resection be “high”, you mean large, or extended…? The last sentence is somehow not positioned well, and the reading is not smooth.“The resection in these parts of the brain has been very high. On average was 95.76% ± 6.17% .The neuropsychological literature shows that the maintenance of executive functions is relevant to ascertain the patients’ good quality of life [1, 26].”

-374-375, the reference is missing. Which studies are consistent with the reported manuscript?

-What is the definition of narrative language in the context of frontal brain surgeries?

-  It is not quite understood why the focus is on “more tasks” for intraop neuropsychological monitoring. Firstly, the sensitivity of each neuropsychological test should be verified by many research groups and an indication of when to use each group of tests. The take-home message here should be rewritten.“The frontal RTNT protocol could contribute, by proposing an approach allowing the introduction in intra-operative neuropsychological monitoring of more tasks. The RTNT allows using many more test than those who can be associated to DES (due to time constraints). In particular we acknowledge that visuo-spatial planning and cognitive estimation can be adapted to the operatory room and included in the monitoring (as post-surgery they are among the task changing more). This view supports the use of the mapping and monitoring also to in case of right hemisphere resections [12]."

-Conclusion should be written concerning the results of the study.

Author Response

Comments and Suggestions for Authors

-Overall, the paper seems interesting, but it is really hard to read in its current form. The authors should concentrate more on the language and the style of writing. The use of terminology should be more clear since the reader gets confused about what executive functions are, what cognitive functions are, and what is tested.

1. We thank the Reviewer for her/his suggestions, which helped us to improve our manuscript. We addressed below all the point she/he raised.

The focus in the Introduction is on “executive functions as multicomponetial construct, but in the Abstract, we can find “cognitive status.”

1. The Reviewer is right and we changed accordingly to “the patients’ performance at several tasks measuring components of the executive functions”

Also, it is quite hard to understand what is the aim of the study, to develop or to choose several neuropsychological tests that are often used in pre and post-surgery in the context of intraoperative surgery, or it is the aim to test RH and LH patients on different neuropsychological measures intraop, pre and post-surgery?

1. We confirm that the aim of the present study was to choose several neuropsychological tests that are often used in pre and post-surgery in the context of intraoperative surgery. We clarified this now.

Also, the reader gets the impression, the more tests are better?! This is not quite understandable since the authors did not compare the results with DES, but only concluded that DES has some time constraints (is the conclusion based on their results from Skrap et al.J Neurosurg 125:877–887, 2016?).

1. The literature shows that the Stroop test was used during DES applied during frontal lobe resection; the Stroop test measure inhibition of cognitive interference that occurs during automatic processing, which is one of the executive functions. The RTNT includes tests measuring also other executive functions e.g., verbal short term memory, attention, working memory, verbal monitoring. We anyway deleted the sentence “Administering a limited number of tests during resection would not cover the full variety of executive functions.” that could give the idea -more is better-. We also tried to better explain the RTNT (see also our response to your point below on the timing”).

It is not quite sure how the sensitivity of chosen neuropsychological tests is validated  (Skrap et al.J Neurosurg 125:877–887, 2016?) to be used in everyday surgery in other neurosurgical settings.

1. All the test are task published and normed (not by us but by authors who run norming studies on lasge sample of subjects) for the Italian population and currently used in neuropsychological testing of executive functions. Nobody doubt on the validity of these tests. We only adapted them to the surgical setting. The study was an attempt to test the sensitivity of the chosen neuropsychological tests to detect intra surgery decreases of performance. We showed that patient performance decreased in some of them, and not in other, and that there was a correspondence in test decrease between intraop and post-surgery scores.

When to use DES and without DES, meaning using only neuropsychological tests?

1. This was never argued in our manuscript. We recognize that DES is the gold standard and should be used. We argue that RTNT is complementary to DES and could be used together with DES to increase the amount of information. We clarified this issue now.

Can the authors explain if the participants from the submitted paper are those from the paper published by Skrap et al.?

1. The patients included in the present study were not from the paper published by Skrap et al. We clarified this issue.

-the terminology and grammatic should be checked by professional English speakers as well as the whole manuscript. For example, “intra-operatory monitoring” is not the grammatically right term to use in “intraoperative neurophysiology”. Instead, “intraoperative monitoring technique” is the right term. Please check the entire manuscript with this terminology.

1. We changed accordingly in the whole manuscript.

- The grammatic is a bit problematic in the whole manuscript and should be checked carefully by the professional (for example: “detecting some any possible deterioration”). Also, the sentences are a bit long in many places, redundant and repeating, and currently, the manuscript is hard to read due to grammatical and semantic issues, due to no professional English checking before submission.

1. A professional English speaker checked the whole manuscript.

-The use of acronyms vs full terms should be consistent in the whole manuscript (i.e. SDMT versus symbol-digit modality test (raw 329 full terms, but previously the acronym was introduced, etc; the full terms again used in the Discussion paragraph compared to previous paragraphs were acronyms were used). The consistency in the use of acronyms vs full terms should be present in the whole manuscript.

1. We changed accordingly in the whole manuscript.

-raw 112-116, plus the whole Introduction should be more understandable in defining executive functions and the aim of the study.  So the aim of the study was to investigate executive functions. Which ones? How executive functions can be categorized in a way when measuring different constructs? The reader only gets the impression from the introduction's last paragraph that the executive function is a multi-componential construct. Please be more concrete and try to connect the constructs you are measuring intraop, pre and post-op when defining the aim of the study.

1. We agree with the Reviewer and we rephrased the paragraph by adding that “The RTNT includes test assessing the use of strategies (fluency test), abstraction (metaphor comprehension test), inhibition (Stroop test), attention allocation and maintenance (Attentional Matrices), emotional processing (IAPS) memory (short term memory and working memory), social cognition (Theory of mind test), selective attention (Symbol Digit Modalities Test).” We also better explained the aim of the study that was “ The aim was to choose several neuropsychological tests that are often used in pre- and post-surgery in the context of intraoperative surgery.”

-raw 64-66 – please insert the reference for the sentence..”They used..” or rewrite to be more understandable.

1. We corrected accordingly.

-raw-83-84-please rewrite the sentence to be more understandable “We are in effect speaking about negative mapping”

1. We corrected accordingly.

-85-89 – the last two sentences of this paragraph can be rewritten together to be more understandable, right now the sentences are similar and somehow repeating.

1. We changed accordingly.

-raw 93, sentence “RTNT allows the administration of many tests”. This sentence is somehow weird, and the positioning is not understandable.

1. We changed accordingly.

-raw 102-104 – Please rewrite these sentences to be understandable in one sentence. “It is also up to the neuropsychologist to assess whether the decrease is due to the resection or other variables. Deterioration occurs gradually, and sometimes it depends  on the handling and procedure itself.”

1. We changed accordingly.

-raw 105 – it is advisable to remove sentence construction such as “here we tried”, since it is colloquial, and to remove parts with “WE selected test”.. and try to use fewer constructions with “we” (i.e. raw 123, 124..); “our” approach (i.e., raw 172); “we measured” (Table 1), “we designed”, “we tested (raw 341) etc.

1. We changed accordingly.

-If this is only the “our approach”, meaning from the authors, how can we be sure that this list of tests is accurate, is properly validated by other research groups?

1. We changed a accordingly, by not using “our” and “we” as suggested by the Reviewer in another point she/he raised. The frontal RTNT is not validated by other neurosurgery teams. Indeed with our manuscript we aim at presenting it. The present data are hardly comparable to those of other neurosurgery teams because, as mentioned in the introduction section, awake surgery in frontal areas is not so common, and because literature shows that the tasks used are limited to one or two. As to the task used, there is one exception, meaning the Stroop test, that is used by few neurosurgery teams during DES and in the RTNT and we have already compared our and their (similar) results in the Discussion session.

-raw 112- it is unclear what the authors wanted to say with this long sentence (given below). Why RTNT allows more tests to be used and DES does not? Is it related to the time? For DES it is known that tests should be short and sensitive due to the duration of the surgery (the testing should not prolong the surgical procedure), but it is not quite clear why RTNT would allow much more tests. You mean because since no stimulation is applied to brain tissue, the surgeon has “more time” to play around looking for executive functions other than language, speech etc.?“Our hypothesis is that by using more neuropsychological tests (and RTNT allows us to do so, while DES is more time constrained) we increase the probability of detecting some any possible deterioration of cognitive ability, so that we can better monitor the patient’s cognitive status, since executive functions are multi-componential (see above) and one or few tasks do not appear sufficient”

1. We clarified the paragraph. When DES is used the test are done while the excision is paused. Between two consecutive DES, while resection continues, there is an information gap. In these minutes no feedback on cognition is obtained. The RTNT recalls the IONM concept. It is a monitoring technique that is applied continuously during resection. In this way no information gap between two consecutive surgical phases occurs.

-line 119 ..”We tested” What is this?

1. Apologize. It was a refusal. We deleted it now.

-raw 126, it is not quite clear the part in the brackets  please rewrite “(as they perform dedicated RTNT protocols, [22,23])”

1. We rephrased the paragraph

-raw 138- how many left-handed patients are in the RH group? It is not quite clear.

1. We clarified this issue.

-  raw 146 – this is not understandable, please rewrite, “in addition to additional cognitive tests for the LH and the RH”. Please reformulate the sentence so the reader is informed first about the tests used in pre and post surgery for LH and RH group, and what do you mean by additional? Additional to what? Please include the references for each test in the manuscript text.

1. We rephrased the paragraph.

-Since these patients had glioma in the frontal cortex, why standard DES procedure was not performed in these patients? Or was it performed, but it is not reported here? If DES is performed, this information should also be given.

1. We reported the DES mapping.

-The authors reported that the abstract language was tested (raw 110). When inspecting Table 1 the visual object naming task was listed, and this is one of the mostly used tasks during DES for language since there are many studies proving that visual object naming task elicits broader network activated during language processing. Also action verb naming is language task used by authors, also verbaly fluency.It is not quite sure what the author wanted to say with “abstract language processing”. The authors did not test abstract language processing, but rather speech and language processing.

1. Abstract language processing was tested by means of metaphor comprehension.

-Did the authors use all the tests from RTNT also in the pre and post-surgery when inspecting LH and RH patients? Paragraph 2.2. and 2.3. , and a supplementary list, should be written to more understandable for the reader. It would be suggested to delineate if the post and pre surgery tests were applied to all LH and RH patients or not. If not, then the supplementary table should be rewritten so that the reader knows which tests were applied to LH and RH patients pre and post-surgery. Also, state clearly what are the tests which are identically used in LH and RH patients intraoperatively vs pre and post-surgery. Also, please in 2.2. paragraph explain better the categorization of the individual test so the reader can figure out which tests are designed as executive functions, cognition, psychological functions, etc.

2. The list of test administered to LH and RH patient pre and post-surgery is now reported in Table 1 (LH/RH protocol) as well as in Table 2. We also state clearly what are the tests which are identically used in LH and RH patients intraoperatively vs pre and post-surgery by adding a column in Table 2.

-The application of the test during intraoperative part should be presented more clearly. It is not quite sure how many times the tests were applied, how long the operation lasted, and how the authors changed the stimuli, for example, if using SDMT (if only one version exists)? How the scoring /analysis was done for the repeated tests during the surgery?

1. We now clarified this issue.

-Figure 1- it does not bring new information, so it can be deleted. The list of tests is given in the manuscript text.

1. We deleted Figure 1.

-Table 1 is also a bit redundant, since each test and the domain each test measures can be placed directly into the manuscript text. This paper is not a review paper.

1. We inserted Table 1 in the main text, and shortened the paragraph so that we do not present redundant information now.

-Table 1,2,3, in the supplementary, need to include also acronyms (Table 1) if used in tables 2 and 3. Why some individual scores are highlighted in Tables 2 and 3? Put the necessary acronym in the table legends.

1. We included now the acronyms, and explained that highlighted scores denote pathological performance.

-The references from the supplementary tables should be introduced in the manuscript reference list.

1. We included now the references from the supplementary tables in the manuscript reference list.

-Figure 2, where is “C” on the figure? Please check the figure legend properly. The “F” part is of poor resolution, and is it suggested to put the results rather as the text since the list of test used prior and post surgery is given in the supplement file, so the reader would need to go and check in the supplements for the acronyms of the tests presented in the F.

1. Apologize for the error. We included now “C” in the Figure (now Figure 1). As to the plots presented in “F” we increased now the resolution. We prefer showing the plot instead of presenting the results in the main text since it would require adding a very long list of scores (39 scores (x2)=78). We added in the figure legend the list of acronyms.

-Terminology “”intra-resection RTNT performance” please rewrite maybe as: simply: “RTNT performance during resection”

1. We changed it now.

-raw 295- “as there is no accuracy but this measure it is expressed as the patients’ span” please rewrite to be more understandable

1. We rephrased the sentence now.

-raw 341-343-Could the authors explain how these tests were sensitive to the surgical act? Changing the surgeon strategy or? It is known that DES can change the surgical strategy (for example, while mapping Broca’s area and eliciting speech arrest), but how the sensitivity of so many tests can be determined to be valid for intraoperative use?

1. We thank the Reviewer for this question. The comparison is legitimate; however it is known that DES is very reliable for relatively simple functional areas such as sensory and motor regions, or language areas. For other areas the risk of negativity in the responses by using DES increases; nonetheless a negative response, i.e. DES not eliciting any effects, can turn into an immediate postoperative deficit. By using RTNT we increased the amount of information on the patient’s cognition even in areas such as the frontal areas. Following our methodological approach of monitoring cognitive functions, and working on many patients in awake surgery, when possible, we use this method also with resections in the frontal lobe. In this way, we acquire more data and experience and we are more confident in evaluating extra-total excisions. We evaluate global performance, many test in few minutes, meaning that we would not terminate in this case resection of a frontal tumor if only the Stroop or Comprehension of metaphors test worsen during resection. Sometimes, due to the possibility that it is just a reversible worsening of the performance, before deciding that it is a definitive value, we move surgery to another area and returning to proceed with surgery in the same area only in case the patient has recovered. In conclusion, we use RTNT for a greater guarantee in light of the enlargement of the excision that as we know, correlates with a better prognosis.

Author Response File: Author Response.doc

Reviewer 2 Report

The reviewed paper describes neuropsychological test battery for frontal lobe mapping for left and right hemisphere. The introduction is comprehensive, methods and results correspond to the study design. Only one thing that can be improved - the lack of conclusion. Please extend it with rationale of usage so huge tests amount that can prolonged the duration of surgery.

Author Response

Reviewer#2

Comments and Suggestions for Authors

The reviewed paper describes neuropsychological test battery for frontal lobe mapping for left and right hemisphere. The introduction is comprehensive, methods and results correspond to the study design. Only one thing that can be improved - the lack of conclusion. Please extend it with rationale of usage so huge tests amount that can prolonged the duration of surgery.

1. We thank the Reviewer#2 for her/his positive evaluation of the present study. Closely following her/his suggestions, we added a conclusion as follows:

“Monitoring aspects of executive functions in the frontal lobe is less frequently used, as compared to language and motor mapping, and few neurosurgical teams use awake surgery in this case [8-14]. However, evidence for post-surgery neuropsychological deficits after frontal resections are reported [13,16,46]. In this view, we monitored aspects of executive functions by using the RTNT approach. RTNT allows the use of many test, without prolonging the duration of surgery. RTNT does not lengthen surgery time, as the neuropsychologist uses the resection time to administer tests: it is performed while the surgeon proceeds with the excision, and lasts as soon as the resection is finished. On the contrary, the RTNT taught us that achieving resection in the shortest time is of utmost importance. Since the surgeon has more feedback on the patients’ cognitive status the resection time is shorter as there is more confidence [20] in carrying it on.”

Author Response File: Author Response.doc

Round 2

Reviewer 1 Report

Please check the two supplementary documents uploaded under ” Download supplementary file(s)” and "Download Non-published Material”.

In the first doc Table 1 and Table 2 refer to pre anad post surgical neuropsychological scores of patients.

In the second doc Table S1 refers to Pre-and post-surgery neuropsychological assessment, and Table S2 and Table S3 refer to pre anad post surgical neuropsychological scores of patients.

It seems that Table 1 and Table 2 from the first doc is identical to Table S2 and Table S3.

Please verify and correct accordingly in the manuscript file when referencing to the tables from the “two” version of supplementary document uploaded.

-Table 2 “boldings in the table can be removed, especially bolding of the reference numbers

- The references of the neuropsychological tests in the manuscript are not the same as in the supplementary table. Please correct accordingly. (for example Oldfied id [24] in the manuscript and in the supplementary table list is [1]. We believe the authors need to correct which version of the supplementary doc is the right which will be published with the manuscript and which one is the oldier version. “Table 2. RTNT protocols for LH and RH frontal resections. See Supplementary Table S1 for a

complete list of references” Here the reader gets confused? What references, probably this is the oldier version?

Author Response

Please check the two supplementary documents uploaded under ” Download supplementary file(s)” and "Download Non-published Material”. In the first doc Table 1 and Table 2 refer to pre and post surgical neuropsychological scores of patients.In the second doc Table S1 refers to Pre-and post-surgery neuropsychological assessment, and Table S2 and Table S3 refer to pre anad post surgical neuropsychological scores of patients. It seems that Table 1 and Table 2 from the first doc is identical to Table S2 and Table S3. Please verify and correct accordingly in the manuscript file when referencing to the tables from the “two” version of supplementary document uploaded.

1. Apologize for this error. We confirm the correct display is S1 Pre-surgery neuropsychological assessment and S2 Post-surgery neuropsychological assessment. We revised in the text now.

-Table 2 “boldings in the table can be removed, especially bolding of the reference numbers

2. We removed the bolding in table 2.

- The references of the neuropsychological tests in the manuscript are not the same as in the supplementary table. Please correct accordingly. (for example Oldfied id [24] in the manuscript and in the supplementary table list is [1]. We believe the authors need to correct which version of the supplementary doc is the right which will be published with the manuscript and which one is the oldier version. “Table 2. RTNT protocols for LH and RH frontal resections. See Supplementary Table S1 for a complete list of references” Here the reader gets confused? What references, probably this is the oldier version?

1. Apologize for this error. The reference to the list in Table S1 was a refusal from our previous revision. Now we removed this reference as all the citations are reported in the Reference list in the main text.

Author Response File: Author Response.doc