Preclinical Research on Focused Ultrasound-Mediated Blood–Brain Barrier Opening for Neurological Disorders: A Review
Round 1
Reviewer 1 Report
The manuscript of preclinical research on focused ultrasound-mediated blood-brain barrier opening for neurological disorder is a well-written and comprehensive review in this field. The references are up-to-date and appropriate. This review will contribute significantly to the hot research field.
The description of BBB requires a bit more detailed information, as well as low-intensity focused ultrasound information. The other point which needs clarification is in line 147 about brain tumors, the whole paragraph describes all about glioblastomas. However, the last sentence states that trastuzumab is used to treat breast cancer brain metastases. It is okay to include this here, but a few sentences should be added to document the treatment of brain metastases.
Overall, this is a well-organized review, which reads well.
Author Response
[Reviewer 1]
The manuscript of preclinical research on focused ultrasound-mediated blood-brain barrier opening for neurological disorder is a well-written and comprehensive review in this field. The references are up-to-date and appropriate. This review will contribute significantly to the hot research field.
Reviewer 1.1) The description of BBB requires a bit more detailed information, as well as low-intensity focused ultrasound information.
Response 1.1) Thank you for the comment. According to the comment, we have modified the description in the manuscript as follows:
[Page 01, Lines 30-36]
The BBB separates the lumen of cerebral blood vessels from the brain parenchyma and selectively restricts permeation through tight junctions between vascular endothelial cells. Each of these tight junctions is composed of a protein complex of various trans-membrane proteins, such as junctional adhesion molecules (JAM), occludin and claudin (Fig. 1). Outside of the BBB, it forms a structure with astrocytes and pericytes. In particular, the astrocytic endfeet establish connections between neurons and blood flux and regulate the formation of the BBB [1].
Reviewer 1.2) The other point which needs clarification is in line 147 about brain tumors, the whole paragraph describes all about glioblastomas. However, the last sentence states that trastuzumab is used to treat breast cancer brain metastases. It is okay to include this here, but a few sentences should be added to document the treatment of brain metastases.
Response 1.2) Thank you for the comment. We deleted trastuzumab from that sentence. And we further described metastatic brain tumors as follows:
[Page 08, Lines 211-220]
Brain metastasis represents an important predictor of mortality for various non-brain cancers such as breast cancer. Like primary brain tumors, brain metastases do not have an intact BBB, but most therapeutics still have lower intra-tumoral bioavaila-bility than non-brain tumors [84]. FUS studies have continued to treat metastatic brain tumors as well as primary brain tumors. In 2012, there was a study confirming the therapeutic effect by delivering Trastuzumab based on FUS-BBB opening in a breast cancer brain metastases model [85]. Additional research reported in 2016 demonstrated that administration of trastuzumab and pertuzumab in a brain metastasis mouse model of breast cancer inhibited the growth of brain metastasis when used with FUS, com-pared to chemotherapy alone [86].
Whether it is a primary brain tumor or a metastatic brain tumor, the critical factor in the tumor microenvironment is to what extent the anticancer drugs could be delivered into the target region.
Reviewer 2 Report
In this review, the authors discuss latest trends in focused ultrasound mediated blood brain barrier opening, centering on studies related to some of the common neurological disorders and the secondary biological effects. The review has been written comprehensively and provides ample information on advancements in the field. The contents of this review seem suitable for the scope of this journal and will be interesting to the readers. However, the review needs to be modified to include further relevant reports, expand on discussing bioeffects/limitations and fix few minor concerns before being accepted. I have several suggestions and recommendations for the authors as listed below.
1. Although it was briefly discussed under ‘brain tumor’ section, the authors need to dwell a little bit more about ‘efflux transporters’ in the introduction.
2. Under introduction, it will be helpful if disadvantages of ‘invasive’ procedures can be mentioned briefly to make a point that non-invasive FUS method is preferable.
3. The text size needs to be increased in both the figures.
4. In line 74, they have wrongly cited figure 1 instead of 2.
5. As the review discusses biological effects, it makes sense to include other brain cells in the figure. They can include cells that have been shown to be part of neurovascular units which actively participate in BBB functioning and neuroinflammation (such as pericytes, microglia and neuros).
6. Will it be helpful to readers if a brain MRI image showing FUS-mediated enhanced permeability is shown (optional, only if it is easy to use from a publication after permission).
7. In line 90, expand AD before parenthesis.
8. Under section 2.1 I would recommend that authors discuss failure of some of AD drugs in trials.
9. In Tables, will it help if 1st column is reduced to just the Reference number and moved to the end? This is an optional suggestion, only if authors also feel this will increase space for text in the table.
10. In line 138, a-synuclein appears without prior introduction.
11. The lines 167-168 need to be rephrased. Currently it is hard to comprehend.
12. Under section 2.3 I strongly recommend that authors include studies on brain metastases (in addition to gliomas) which have become a very big challenge recently.
13. Line 243: period missing after 24 hours.
14. As one of the major focus of this review is biological effects, I would strongly request authors dwell on bioeffects further (under section 3). For example, microglial activation and has not been mentioned at all!
15. Conclusions and future directions can be expanded a little, to summarize current limitations and promising future avenues.
Author Response
Please see the attachment
Author Response File: 
Author Response.pdf
Round 2
Reviewer 2 Report
The authors have addressed all of my concerns satisfactorily. However, minor English grammar check might be necessary, especiay in the new text that was added.
