Peer review of: A neurovascular high-frequency optical coherence tomography system enables in situ cerebrovas (2020)

Reviewers' comments: 
 
Reviewer #1 (Remarks to the Author): 
 
Current high-resolution cerebrovascular imaging relies on 3-dimensional rotational angiography 
(3DRA) and cone-beam computed tomographic angiography (CB-CTA). These acquisitions require 
significant additional radiation exposure and contrast injection, in addition to the conventional 
digital subtraction imaging. Both 3DRA and CB-CTA are limited in resolution to 50-100 microns 
under optimal conditions, and are often limited by patient movement (both involuntary as well as 
respiration-related and arterial pulsation-related). Since 3DRA and CB-CTA acquisitions require 5-
20 seconds duration for acquisition, they result in time-averaged results, and often a motion-
artifact and noise averaged over the acquisition that limits its utility in sub-optimal conditions. The 
clinical relevance of high-resolution imaging such as afforded by the technique described by the 
authors has become increasingly recognized to be critical to achieve optimal clinical outcomes. One 
example is the need to recognize the exact pathological features of intracranial atherosclerosis, 
another is to determine stent-vessel wall apposition, and yet a third is to obtain additional 
information on embolic material in large vessel occlusion acute stroke cases to better guide 
mechanical thrombectomy attempts. 
 
With that background the authors’ work and the development of HF-OCT comes at an opportune 
time, and provides unsurpassed spatial resolution in a short period of time, that does not require 
additional radiation exposure to the patient. The careful characterization of this new technology by 
the authors should be lauded. It is hoped that future studies from the authors’ group and others 
should further elucidate the advantages of this approach and validate its clinical utility in specific 
sub-conditions, and possible expand its utility to beyond the cerebrovascular system. 
 
Question to the authors: 
 
1-They describe using contrast material to clear the vessel to enable HF-OCT function (line 108); 
did they compare to saline solution infusion or another higher viscosity solution such as Dextran? 
In certain patients with renal insufficiency, it would be desirable to avoid additional contrast 
administration. The authors touch on this point in the Discussion (line 281). 
 
2-Would it be possible to include an elastic compliant proximal balloon for temporary occlusion 
during the injection or at least to slow blood flow down and minimize contrast needed for injection 
to enable HF-OCT functionality? 
 
3-Could the authors comment on how sensitive the accuracy of HF-OCT is to complete clearance of 
the lumen during acquisition? How much does the image deteriorate if the blood clearance is 
imperfect or non-uniform? It is not obvious from the data presented and the readers would 
appreciate a discussion. Although the authors describe it on line 310, the effective clearance 
parameters may be more or less challenging intracranially where laminar flow and streaming may 
provide a radially non-uniform contrast distribution; please discuss. 
 
4-Could you please discuss if any vibration or mechanical forces are exerted by the wire during the 
rotation process and its possible effect on dislodging or disturbing any thrombi that may be 
adherent to the endovascular device or atherosclerotic plaque. 
 
Minor: 
 
1-Spelling line 132, “imaging aith angiography” should be “imaging with angiography” 
 
Adel M. Malek, MD, PhD 
 
  
Reviewer #2 (Remarks to the Author): 
 
The authors report an OCT imaging catheter for acquiring volumetric microscopy data from 
cerebral vascular anatomy. This technique, termed high-frequency optical coherence tomography 
(HF-OCT), provides a clear visualization of the cerebral arterial microstructure. The key technical 
advancement is that the presented device can enter the tortuous cerebrovascular structure. 
Current intravascular OCT, widely used in coronary artery imaging, lacks the flexibility and the size 
is not suitable for cerebral artery imaging. The small size (0.016-inch wire-like catheter) and the 
flexibility overcome the existing limitations. The images of ex vivo and in vivo models of 
cerebrovascular arteries with neuroendovascular devices are promising. Here are my comments 
and questions: 
 
1. Several references, which are original or relevant, should be included. Here are some 
suggestions: 
-Yun et al., Comprehensive volumetric optical microscopy in vivo, Nature Medicine, 2006 
-Nam et al., Automated detection of vessel lumen and stent struts in intravascular optical 
coherence tomography to evaluate stent apposition and neointimal coverage, Medical Physics, 
2016 
2. Why is this technique is termed high-frequency OCT? What does “high-frequency” mean? 
3. Much more information about the catheter and the system must be added to the manuscript. 
Because the most important technological advancement of the presented work is the 
miniaturization of the catheter and the high-speed imaging system. How is the catheter 
composed? What kind of fiber is used? Was GRIN lens or ball lens used? What is the size of the 
fiber? Was torque coil used? How can the torque be translated with such a small size? What is the 
sheath material and size? A-line rate of the system? How was the large field-of-view obtained? And 
others. 
4. Page 6, does “(angiography)” mean DSA? 
 
 
 
Reviewer #3 (Remarks to the Author): 
 
In this work, the authors present a set of impressive imaging studies using what appears to be a 
company/proprietary product termed HF-OCT for cerebrovascular imaging. The field would find 
value in seeing the current capabilities of the OCT technology in this space, and I congratulate the 
authors on these high-quality imaging results. 
 
However, the work is presented as the introduction of a new imaging platform HF-OCT, yet 
inadequately references and describes prior works demonstrating the use of OCT in this context 
(see list of some of the missing references below), and is entirely vague on the unique features or 
capabilities of the HF-OCT platform. The specific features or advances of HF-OCT are never 
described. 
 
Continuing on this later point, the HF-OCT platform is never described even at a high level. It is 
unclear what HF means, i.e., what is high-frequency. High RF frequency? High rotational 
frequency? The A-line rate is never provided. The imaging range that the system can support is 
not described (yet achieving larger imaging range is claimed). The frame rate is somewhat buried 
in the methods, but pullback speed, frame pitch, etc are undefined. Even the wavelength at which 
the imaging is being done is not described. Is the advance in the OCT portion itself, or in the 
catheter? Or is it both? Given that the central thesis of this work is that prior OCT methods are 
technically inadequate to address the cerebral vasculature, it is required that the technical 
innovations in HF-OCT that overcome these challenges be described. Therefore, I believe that the 
manuscript in its current form, the manuscript lacks clarity and transparency required for 
publication in Nature Communications. It is not acceptable, for example, that after reading the 
manuscript, I cannot point to single technical specification of the HF-OCT that is improved over 
existing OCT methods. 
 
Alternatively, if the manuscript focused instead on demonstrating the use of OCT in 
vessels/sites/applications that had previously been impossible to image, or in clinical settings 
where prior reports were all preclinical, or otherwise was based on the first demonstration of a new 
capability, then these novel demonstrations could serve to differentiate the work from prior reports 
(rather than statements that the HF-OCT platform is superior). However, it is difficult to judge 
from the current manuscript which of the imaging results are entirely novel and enabled (rather 
than enhanced) by the HF-OCT. 
 
Examples of some of the work showing OCT being used for similar applications as described in the 
manuscript but not referenced: 
 
Attizzani GF, Jones MR, Given CA, Brooks WH, Bezerra HG, Costa MA. Frequency-domain optical 
coherence tomography assessment of very late vascular response after carotid stent implantation.J 
Vasc Surg. 2013; 58:201–204 
 
Jones MR, Attizzani GF, Given CA, Brooks WH, Costa MA, Bezerra HG. Intravascular frequency-
domain optical coherence tomography assessment of atherosclerosis and stent-vessel interactions 
in human carotid arteries.AJNR Am J Neuroradiol. 2012