Beyond Broca’s and Wernicke’s: Functional Mapping of Ancillary Language Centers Prior to Brain Tumor Surgery

Round 1

Reviewer 1 Report

Abstract: Well written. Doesn’t have to be limited to patients with glial tumors. Language laterality also requested for epilepsy cases of dysplasia or cortical and vascular malformations.

Introduction: Could potentially add the limitations of awake cortical mapping such as: extended operating room times and resources, some patients cannot tolerate awake mapping, and intraoperative seizures. This is why pre op and noninvasive fMRI has a vital complementary role for surgical planning.

Discussion:

LI = Laterality Index. Should add that counted voxels should be in known language areas to determine hemispheric dominance (ie don’t include active voxels in visual cortex of occipital lobes). Also should discuss the effect of being too liberal with the LI, statistical threshold could result in misinterpretation with the concept of pseudo-reorganization in tumor cases.

Activation distance: Border of lesion to the center of activation is commonly accepted. Must keep in mind that these distances are not static. The distances change, move and shift as head position changes, craniotomy happens with CSF loss and tumor debulking.

SMA: Would be nice to include an additional image for SMA with a case where the pre- or language SMA is shown anterior to the motor component of the SMA task. Include that a line drawn from AC to SMA orthogonally from the AC-PC line bisects the language and motor components of the SMA.

Add an interpretation/pitfalls section:

1)      Age: Should include how age is a factor in hemisphere lateralization. Younger patients (less than 12 yo) tend to have lower LI scores and bilateral or atypical language lateralization. As they age and brain matures lateralization happens. Should keep this in mind for young fMRI cases.

2)      Atypical language and Handedness: Should include when to anticipate a higher chance of atypical language lateralization. Such as young age, long standing epilepsy, autism, ambidextrous and familial left handedness. This can be anticipated with good history taking at task coaching prior to fMRI and also with the Edinburgh Handedness Inventory.

3)      Neurovascular uncoupling. From carotid stenosis, language center near AVM or tumor or near the peritumoral edema. Could include role of breathhold task.

4)      Use Combined Activation Display of language tasks to increase confidence. For example it is easier to interpret language lateralization when all language tasks are superimposed rather than one task at a time. See Ref: A Gore et al Combined task activation display as an effective method to teach introductory fMRI users. Clin Imaging. 2019

Add a section on how to protocol/logistics/post processing:

1)      Which language tasks do you use for a lesion in the frontal lobe vs a lesion in the temporal or parietal lobes? Does it change?

2)      Edinburgh Handedness Inventory (EHI) should be included to raise radiology interpretation confidence and for when to anticipate atypical language results.

3)      Which recons to you send to PACS and the OR navigation software? Only axials? Often language centers are best shown on Sagittal recons.

4)      Which LI thresholds do you use? Is there a range? Maybe present a representative case and show steps of fMRI task selection, image processing and interpretation. Show how you would teach all this to a neuro fellow. 

Figures: I like the color images. They are nice. Would include these new figures for more real clinical examples: 

1. SMA addition as stated above for language and motor SMA relationship.

2. Images with a tumor and distances measured to activation centers. Show how you would measure!

3. Representative case with a tumor and language centers primary and secondary and show how you would interpret the case for laterality 

4. There is only one image currently with a tumor. Could consider adding more. For example for each language center section show a normal anatomy case and next to it show one with a lesion where the language center is shifted or involved somehow. Get creative!

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

I enjoyed reading this review manuscript. It is very well written and easy to follow.

Main concerns:

1. The authors, rightful so, brought up the concept of brain networks associated with language production and language comprehension. Therefore, it would make the MS better to mention the research that introduces the concept of brain networks (both task-related and non-task-related, i.w., resting-state). 

2. To build on my last comment, the authors have.a great opportunity to insert resting-state brain network research on Page 3, Lines 120-128; Page 3, Lines 141 - 145; Page 4, Lines 176 - 180; and Page 4, Lines 189 - 197, for example. 

Minor Concerns:

1. Page 1, Line 10: Start Abstract with "Functional MRI", not "fMRI".

2. Page 1, Line 32: I do not understand what "baselining" means in the context of the MS. Please clarify.

3. Page 2, Line 56: What does "LI" refer to? Laterality Index? If yes, please include it in the MS, e.g., Laterality Index (LI).

4. Page 3, Line 113: Riley and colleagues (2022). There does not seem to be a reference citation (and number) associated with this paper.

5. Page 3, Line 130: Insert acronym, i.e., "inferior frontal gyrus (IFG)".

6. Page 3, Line 135-136: missing year for "Gajardo-Vidal and colleagues" reference.

7. Page 3, Line 142: sentence structure. Maybe include a colon , e.g., "involve two functional distinct areas: a language...".

8. Page 4, Line 153: Citation 35 refers to an association of task-free and task-related activations. Doesn't seem like an appropriate citation for this sentence.

9. Page 4, Line 154: Change "functional MRI" to "fMRI".

10. Page 6, Figure 1: Unclear whether the activations portrayed in the figure is a group average or an individual's brain activity. Please clarify (this and the following figures!).

10. Page 6, Figure 1: Unclear whether this is the left hemisphere (I assume it is but it should be indicated). Also, the legend should be adjusted so that no words are cut off (make more concise).

11. Page 6, Line 264: change "brain behavior" to "brain-behavior".

12. Page 7, Line 307: replace "SLF" with "superior longitudinal fasciculus (SLF)".

13. Page 7, Line 309: Replace "fMRI" with "Functional MRI". Paragraphs should not begin with an acronym.

14. Page 8, Figure 2: Indicate hemisphere side. Where is the legend? Why are the BOLD activations of word generation indicated by outlines and not filled in blobs? Please be consistent across figures.

15. Page 8, Figure 2 caption: change "DLPFC, GMFA, and the Frontal Eye Fields. Sagittal view of nodes of BOLD activation for word generation (green) and verb generation (purple) tasks. Overlapping nodes of activation are visible for both language tasks in each of the dorsolateral prefrontal cortex (DLPFC), graphemic motor frontal area (GMFA), and the Frontal Eye Fields" to "dorsolateral prefrontal cortex (DLPFC) , graphemic motor frontal area (GMFA), and the Frontal Eye Fields (FEFs). Sagittal view of nodes of BOLD activation for word generation (green) and verb generation (purple) tasks. Overlapping nodes of activation are visible for both language tasks in each of the DLPFC, GMFA, and the FEFs".

16. Page 8, Line 337: Remove "who have undergone". Sentence does not make sense with that wording.

17. Page 8, Line 341. Missing period after [72] reference.

18. Page 8, Line 341: Year missing after "Scarone and colleagues".

19. Page 8, Line 344: Change "SMA" to "supplementary motor area (SMA)".

20. Page 9, Line 357: Year missing after "Benjamin and colleagues". 

21. Page 9, Line 363, 366, 370, : change "Frontal Eyes Field(s)" to "FEF(s)".

22. Page 9, Line 369: change "Brodmann areas 6, 8, and 977" to "Brodmann areas 6, 8, and 9[77]".

23. Page 9, Line 378: Authors mention "one case" but no reference is provided.

24. Page 10, Line 431: Change "Activation on fMRI in language SMA" to "Functional MRI activation in language SMA".

25. Page 10, Line 434: Citation for "Hertrich et al., 2016" not in reference list.

26. Page 10, Line 436-437: Change to "Lesions in unilateral SMA were associated with greater fMRI activation on the contralateral side, and reduced fMRI activation on the side of the lesion"

27. Page 11, Figure 3: Please be consistent with using blobs vs. outlines across all figures. Please indicate which side is the right vs left. Legend is missing.

28. Page 11, Figure 3 caption: Change to "Language tasks eliciting BOLD activation in pre-supplementary motor area (SMA). Axial view of nodes of BOLD activation for word generation (yellow), verb generation (red), and sentence completion (pink) tasks. Overlapping nodes of activation are visible in the pre-SMA/language SMA." Note: is the pre-SMA the same area as language SMA? Please clarify.

29. Page 12, Figure 4: Please include labels in figure to indicate brain hemisphere. Remove any text from figure (I am not sure if it is supposed to be part of the legend). If it is, then please fix. If not, remove and insert a proper legend.

30. Page 12, Figure 4 caption, Line 471: change to "are visible in the IPL".

31. Page 12, Line 491: I am not sure if this was a typo: "rhyming22 [113, 114]". Please fix.

32. Page 12, Line 491: Include year for this citation: "Roux and colleagues".

33. Page 13, Line 509-510: Include year for this citation: "Luders and colleagues". 

34. Page 13, Line 518: Include year for this citation: "Pouratian et al.".

35. Page 13, Line 519: Change to "pre- and post-operative".

36. Page 13, Line 520-521: This sentence is not clear "fMRI suggested language eloquence". What do you mean by "eloquence"? Do you mean "activation"? Please clarify.

37. Page 14, Figure 5: Include labels for Right and Left hemispheres. Include legend.

38. Page 14, Figure 5 caption, Line 553: Change to "visible in the BTLA".

39. Page 14, Line 576: change to: "from aphasia [121].".

40. Page 16, Line 687-688: Is this the correct title for the journal? If not, please correct.

41. Page 18, Line 775: Change to "Stephan TH".         

Author Response

Please see attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Include section on how to protocol/logistics/post processing as previously requested, including: task selection, EHI, recon selection and LI thresholds.

Include additional new images as previously requested: SMA, how to measure distances, how to determine language laterality. More figures with lesions and language centers juxtaposed to figures of normal anatomy and activity centers. 

Author Response

Include section on how to protocol/logistics/post processing as previously requested, including: task selection, EHI, recon selection and LI thresholds.

Within the introduction we have added some additional wording regarding this along with adding a paragraph at the end of our introduction, what our practice is.  It is by no means thought that it should be the standard and setting standards within this paper would exceed the scope of what is trying to be presented.

Include additional new images as previously requested: SMA, how to measure distances, how to determine language laterality. More figures with lesions and language centers juxtaposed to figures of normal anatomy and activity centers. 

We have included more images throughout the paper.

Reviewer 2 Report

After modifications to the manuscript, it has greatly improved.

The authors have made the changes I suggested (as well as suggestions of the other reviewer).

Below is a list of minor suggestions (if these modifications are made, this manuscript it ready for publication):

1. Page 2, Line 69: Change "and Wada" to "and the Wada procedure".

2. Page 2, Lines 78, 85, 89, 94: Change "laterality index" to "LI"; change "laterality indices" to "LIs".

3. Page 3, Lines 98, 102, 120, 129, 130,  132, 146, & 149: Change "laterality index" to "LI"; change "laterality indices" to "LIs".

4. Page 3, Lines 107 to 112: This is a run on sentence and is difficult to understand. Please clarify.

5. Page 3, Line 116: Change "tasks and have been" to "tasks have been".

6. Page 3, Line 117: Change "task based" to "task-based".

7. Page 3, Line 124: Change "with Wada" to "with the Wada procedure".

8. Page 3, Lines 131, 132: Change "ex." to "e.g.,"

9: Page 3, Line 139 to 142: "Approximately 95% of right-handed and 70 to 80% of right-handed individuals..."; well, which is it? Please clarify.

10. Page 4, Lines 157 & 158: Change "boarder" to "border".

11. Page 4, Line 166: change "laterality indices" to "LIs".

12. Page 5, Line 218: include year of publication.

13. Page 9, Line 410: Change "who have undergone has" to "who have undergone surgery has".

14: Page 9, Line 408: change "central SMA" to "central supplementary motor area (SMA)".

Author Response

We have made the minor changes requested and thank you for the input.