A pilot study of bladder voiding with real-time MRI and computational fluid dynamics.

Lower urinary track symptoms (LUTS) affect many older adults. Multi-channel urodynamic studies provide information about bladder pressure and urinary flow but offer little insight into changes in bladder anatomy and detrusor muscle function. Here we present a novel method for real time MRI during bladder voiding. This was performed in a small cohort of healthy men and men with benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) to demonstrate proof of principle; The MRI urodynamic protocol was successfully implemented, and bladder wall displacement and urine flow dynamics were calculated. Displacement analysis on healthy controls showed the greatest bladder wall displacement in the dome of the bladder while men with BPH/LUTS exhibited decreased and asymmetric bladder wall motion. Computational fluid dynamics of voiding showed men with BPH/LUTS had larger recirculation regions in the bladder. This study demonstrates the feasibility of performing MRI voiding studies and their potential to provide new insight into lower urinary tract function in health and disease.

Introduction

Lower urinary track symptoms (LUTS) and changes in bladder function occur frequently as individuals age [1-3]. Studies have evaluated the anatomical and functional changes of the bladder in patients with LUTS [4, 5]; however, the biomechanical characteristics of the lower urogenital tract, and how these are altered in patients with LUTS, are not fully understood. There is a compelling need to better delineate the anatomic and functional changes of the lower urinary tract in individual patients to improve diagnostic precision and allow for individualized treatment.

Lower urinary tract function is commonly assessed through multi-channel urodynamic studies that determine bladder pressure and flow during voiding. These studies can be performed in combination with fluoroscopic imaging to visualize the urine flow during voiding. However, these studies are invasive and provide little insight into the changes in bladder anatomy and detrusor muscle function that occur with aging and lower urinary tract obstruction [6]. Use of non-invasive methods for the study of lower urinary tract anatomy and function has been limited. Image based patient specific computational models have been extensively used for cardiovascular evaluation and personalized treatment planning [7-10]. We envision a comparable approach for the evaluation of patients with LUTS. In this pilot study, we describe a magnetic resonance imaging (MRI) urodynamics method, as well as a patient specific MRI-based computational fluid dynamics (CFD) simulation of bladder voiding. These methods were applied to a small cohort of healthy men and men with benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) to demonstrate proof of principle.

Materials and methods

This study was approved by the University of Wisconsin Health Sciences IRB (approval number 2017-1373-CP006). Three men with BPH/LUTS were recruited from the University of Wisconsin Urology clinic (ages 73, 71, and 54). The inclusion criteria were adult men recently diagnosed with BPH. Three control subjects were recruited from a database of healthy controls maintained by the MR research group at UW-Madison (ages 66, 42, and 44). Inclusion criteria were healthy adult men not experiencing any symptoms consistent with BPH. Exclusion criteria for both groups were contraindication to MRI (e.g. pacemaker, contraindicated metallic implants, claustrophobia, etc) and patients who have undergone prostatectomy. MRI was performed on a clinical 3T scanner (Premier, GE Healthcare, Waukesha, WI) using a high-density flexible surface coil array (AIR Coil, GE Healthcare). An MRI urodynamics protocol was implemented which involved a fluid challenge and voiding during MRI. Three-dimensional ‘Fast-spin echo’ (FSE) T2-weighted acquisitions were performed immediately before and after voiding. A sagittal plane 2D spoiled gradient echo (SGRE) dynamic real-time imaging (RTI) acquisition was performed during voiding. The MRI protocol timeline is shown in Fig 1. The bladder was segmented from pre- and post- voiding 3D images of the bladder, while bladder cross-sectional area change during voiding was calculated from the 2D RTI. Measurements from both the 3D and 2D images were incorporated in a patient specific simulation of bladder voiding. Further details on the fluid challenge, 3D FSE MRI, 2D RTI MRI, post-processing and computational fluid dynamics are in the subsequent sub-sections.

Fig 1

MRI protocol.

Fluid challenge

The subject was instructed to fast for 4 hrs. prior to arrival to the MRI session. Upon arrival, the subject was asked to empty his bladder and to drink approximately 1 L of a water and electrolyte beverage (Gatorade G2, The Gatorade Company, Chicago, IL) 30 minutes before MRI scanning, and an additional 100 ml every 10 minutes until scanning (total of approximately 1.3 L). Before the imaging session started, the subject was equipped with a condom catheter system that allowed him to void supine in the scanner. The condom catheter was connected to a container through a flexible plastic tube.

3D MRI of the lower urinary tract

2D fast-spin echo (FSE) T2-weighted axial acquisitions are currently used for clinical evaluation of patients with bladder or prostate-related diseases [11, 12]. Even though these images provide relevant information for clinical diagnosis, they are limited by their slice thickness (~7mm), demanding additional assumptions when performing volumetric measurements. Anatomical changes of the bladder can be spatially heterogeneous, requiring a volumetric (three-dimensional) evaluation. As an alternative, and in order to improve the spatial resolution for the current study, a single-slab 3D FSE T2-weighted imaging sequence was used [13]. This methodology utilizes parallel imaging–simultaneous acceleration in two directions–allowing the acquisition of additional and thinner slices, producing voxels with the same size in the slice and in-plane directions (isotropic resolution), contrary to conventional axial FSE acquisitions (anisotropic resolution, i.e.: slice thickness larger than in-plane pixel size).

Dynamic imaging of the bladder

Advanced MRI sequence development has allowed for dynamic real-time acquisition of data for anatomical and functional assessment. Dynamic anatomical MRI has been used extensively for heart function assessment, where balanced steady-state-free precession (bSSFP) images have been shown to provide sufficient contrast to separate the myocardium and the blood pool [14]. bSSFP has previously been used to determine the bladder motion during voiding in healthy volunteers [15]. We endeavored to reproduce this protocol and obtain bSSFP images in a healthy volunteer during voiding. However, the volunteer expressed significant abdominal discomfort due to peripheral nerve stimulation during the real time MR acquisition. This made this approach untenable for use in our study. To circumvent this road block, we used an MRI sequence that consists of a series of parallel sagittal 2D spoiled gradient echo (SGRE) dynamic real-time images capturing the bladder neck and urethra as well as other regions of the bladder. In this protocol, images are constantly acquired for four minutes allowing complete capture of voiding mechanics during bladder voiding without inducing any discomfort. Dynamic images were segmented to measure the relative displacement of the bladder wall during voiding. Only one control subject underwent the real-time imaging protocol. The other two control subjects were imaged prior to the real-time imaging being added to the IRB protocol and instead were asked to step out of the scanner and void in the bathroom after the 3D MRI was performed. Immediately after voiding the subject was asked to return to the MRI scanner and the 3D MRI was repeated.

MRI post-processing

Using 3D FSE T2-weighted images the bladder was segmented (Mimics, Materialise, Leuven, Belgium) for both pre and post voiding. The pre and post voiding bladder volumes were then exported as stereolithography (STL) files. From 2D RTI data during voiding, the area of a sagittal plane through the bladder was measured over time.

To estimate the motion of the bladder wall during voiding a spherical coordinate system was defined for the bladder, similar to previous motion estimation algorithms used in cardiac chambers [16, 17]. The coordinate system origin was set to be the center of the post voiding bladder volume. In general, the bladder wall displacement () is a three dimensional vector that has spatial and time dependence.

Based on prior work in cardiac chambers, we simplify the complete description of bladder wall motion by assuming the bladder wall only moves radially (d = d = 0) and the spatial and time dependence of the wall motion can be separated as where d0(θ,ϕ) is the total displacement from the pre to post void anatomies and α(t) is the time dependence function that varies from 0 at the start of voiding to 1 at the end of voiding. For wall displacement analysis, the bladder wall was divided into anterior-posterior, dome-base, and left-right regions (Fig 2) and an asymmetry ratio was calculated based on the difference between the median displacement of the left and right bladder wall regions.

Fig 2

Schematic of the bladder wall divided into anterior-posterior, dome-base, and left-right regions for regional displacement and asymmetry analysis.

Different colors represent different regions (anterior–aqua, posterior–yellow, dome–navy blue, base–royal blue, left–red, right–not shown).

For each point on the bladder surface d0 the distance between the pre and post voiding anatomies was calculated using a fast, minimum storage ray-triangle intersection algorithm [18] implemented in MATLAB. The time dependence function α(t) can be calculated from real time measurements of bladder area during voiding, where A(t) is the bladder area, t0 is the time at the start of voiding and t is the time at the end of voiding. Bladder area measurements from the real time sagittal MR images showed a sigmoidal behavior (Fig 3). Based on that behavior, α(t) was chosen to be a square root of cosine function.

Fig 3

Real time imaging of voiding in a 66-year-old healthy volunteer.

The curve shows the bladder emptying with respect to time following a sigmoidal behavior. 2D mid sagittal plane images show the bladder deformation at four different time points during the voiding event. Similarly, three-dimensional (3D) maps show bladder contraction (wall displacement) estimated from computational interpolation between pre and post void MRI at four different time points during voiding.

Computational fluid dynamics

The patient-specific bladder anatomies were imported into the computational fluid dynamics (CFD) software CONVERGE v2.4 (Convergent Science Inc, Madison, WI). Bladder wall motion was estimated as described above and imposed with a user-defined function to virtually drive voiding. As only one control subject had real-time MRI the same α(t) function was used for all three control subjects. The urethra wall was assumed to be rigid and the urethra outlet was set to atmospheric pressure. CFD simulations with large boundary motion are typically time-consuming, but this study employed two complementary strategies to enhance simulation speed. First, a cut-cell Cartesian mesh was used as these meshes have advantages in biomedical flows with moving boundaries [19]. Compared to typical boundary fitted meshes, cut-cell grids rapidly re-mesh to handle the moving bladder wall while simultaneously minimizing numerical diffusion from mesh motion. Second, the efficient re-meshing capabilities of cut-cell Cartesian meshes were used by adapting the mesh to the instantaneous flow field, which minimizes simulation time while maintaining accuracy. Results figures were generated with Tecplot 360 (Tecplot, Bellevue, WA). Vorticity, the curl of the velocity field, was averaged over the bladder volume (urethra not included). Dimensionless vorticity was then calculated based on average urethra flow rates and the prostatic urethra diameter for each subject.

Results

The MRI urodynamics protocol was successfully completed in three healthy volunteers and three patients with BPH/LUTS. 2D planes of the bladder during voiding are shown in Fig 3, along with the bladder cross-section area over time. The rate of area change is slowest at the beginning and end of voiding and greatest during the middle of voiding. Three-dimensional plots of the estimated bladder displacement throughout voiding at various time points are shown in Fig 3. The estimated displacement maps show that greatest displacement occurs at the dome of the bladder.

MRI urodynamics was performed on two additional healthy volunteers and three men with BPH/LUTS. The pre and post-voiding anatomies, estimated displacement maps and box plots showing the regional displacement behavior for each subject are shown in Fig 4. The control subjects had large displacements at the bladder dome with little observed asymmetry. The men with BPH/LUTS had smaller displacements and unlike the controls did not exhibit a consistent displacement pattern. These qualitative observations from the displacement maps were confirmed looking at probability functions of the displacement and the left-right asymmetry (Fig 5). Overall the bladder walls of men with BPH/LUTS moved only 25%-50% as much as the control subjects. The control subjects had little left-right asymmetry (4%-14%) while the BPH patients had large left-right asymmetry (40%-160%).

Fig 4

Top row: Pre- and post-voiding bladder anatomies for each subject.

Middle row: Bladder wall displacement maps (in mm) for each subject. Note that the legend scale is much smaller for the men with BPH/LUTS. Bottom row: Box plots showing regional displacement behavior for each subject (C: Control; P: Patient).

Fig 5

Probability density functions of bladder wall displacement show the control subjects bladder move much more during voiding.

Additionally, the men with BPH/LUTS exhibit significant left-right asymmetry that was not observed in the control subjects.

Urodynamics results from computational fluid dynamics (CFD) are shown in Fig 6 for a sagittal plane near the center of the bladder. Control subjects had higher urine velocities in the bladder than men with BPH/LUTS due to their greater bladder wall displacements. Near the initiation of voiding, streamlines (showing the direction of urine flow) for all three control subjects and two men with BPH/LUTS (P1 and P3) were directed toward the bladder neck and prostatic urethra. Patient P2 has a small vortex just above the urethra. Towards the end of the voiding process, control subjects C1 and C3 had small recirculation regions by the anterior bladder wall while the streamlines for C2 were still all directed toward the bladder neck and prostatic urethra. Near the end of voiding patient P1 had a small posterior recirculation region, P2 had a large anterior recirculation region and P3 had large anterior and posterior recirculation regions. Despite the men with BPH/LUTS having larger recirculation regions, they had lower average vorticity (Fig 7) in the bladder due to their slower flow rates and smaller velocities. After making vorticity dimensionless (a normalization to account for differing flow rates between patients), vorticity was similar between healthy controls and men with BPH/LUTS.

Fig 6

CFD results showing velocity contours and streamlines on a sagittal plane at the center of the bladder for each subject.

Time points are displayed both near the initiation and termination voiding.

Fig 7

Bladder vorticity was lower for the men with BPH/LUTS due to their lower flowrates and urine velocities.

After making vorticity dimensionless (a normalization to account for different flow rates between subjects), vorticity was similar for both groups.

Discussion

This study demonstrates the feasibility of MRI bladder voiding studies to provide new insight into lower urinary tract function in health and disease, and to generate patient-specific simulations of voiding. Additionally, our studies have revealed a previously unsuspected aspect of bladder voiding. Is has been generally assumed that the sphere-shaped full bladder contracted with relatively uniform displacement. Yet, the results of this study suggest that this is not the case: Displacement analysis of voiding in healthy controls revealed a much greater displacement of the bladder dome than the other regions of the bladder (Fig 3). This is a simple, but profoundly startling, observation that may influence understanding of the contractile function of the bladder during voiding after further study. There is increasing appreciation for the role of impaired bladder contractility and its effects on treatment outcomes [20-24]. All of the men with BPH/LUTS in this study exhibited decreased bladder contractility on traditional multichannel urodynamic evaluation (data not shown). The limitation of standard urodynamic evaluation is that it provides only an indirect assessment of bladder contractility calculated from voiding pressure and flow at a single point in the voiding effort (maximum flow). MRI urodynamics, on the other hand, reveals significantly decreased and asymmetric bladder wall motion during voiding.

Although simulations of cardiac flow have incorporated wall motion going back to the 1970s [25, 26], this is to our knowledge the first MRI urodynamic-based simulation of bladder wall motion during voiding. Prior CFD studies have set the bladder wall to be an inlet [27, 28] or used the ureters to drive voiding [29]. The CFD methodology presented here represents a significant step towards improving the physical and physiological realism of urodynamic simulations. As expected based on smaller bladder wall displacements, our simulation results showed that men with BPH/LTUS had lower urine velocities. More interestingly, the men with BPH/LUTS had larger recirculation regions in the bladder which could increase the energy demands of voiding.

In summary, this study demonstrated the feasibility of MRI bladder voiding studies to non-invasively investigate bladder function. Results from displacement analysis showed men with BPH/LUTS had decreased and asymmetric bladder wall motion compared to healthy male controls and fluid dynamic analysis of voiding showed them to have larger recirculation regions in the bladder.

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4 May 2020

PONE-D-20-10274

MRI Based Patient Specific Urinary Flow Dynamics Simulation

PLOS ONE

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Additional Editor Comments (if provided):

As editor, I concur completely with the review as presented. At present it is a case report. In order for this to be useful to the field, additional data need to be obtained. I also feel comfortable with a single review, given that the paper is premature at this point. Some difficulties in obtaining reviewers was experienced due to the highly technical nature of the methodology. Most urologists are unfamiliar with the technical details of MRI, and I did not wish to cause further delays in returning the manuscript. I do not see an additional review changing my assessment of the manuscript.

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Reviewer #1: Yes

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Reviewer #1: No

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Reviewer #1: This is an interesting paper that has applied cardiac wall movement analysis using MRI to assess bladder voiding. The data presented is a bit premature, as the technique was only assessed on one healthy volunteer. There is no statistical analyses to support their hypothesis that most of the bladder wall movement occurs in the dome region. Although the application of the MRI methodology is new for bladder voiding, the approach to measure cardiac wall movement is well documented. I applaud the investigators for attempting to use the methodology in the bladder, which requires such approaches to non-invasively assess its function. Although, the approach is not entirely non-invasive, as the placement of the catheter and voiding approach described seems like it would be cumbersome for patients with bladder disorders.

At the very least, this method needs to be assessed in multiple individuals to support the outcome that there are regional differences in bladder wall movement during voiding. Individuals with bladder voiding issues should have also been included, which would have been more relevant to the urology community.

**********

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12 Aug 2020

We thank the reviewer and editor for their consideration and feedback regarding our manuscript. Based on reviewer and editor comments we have expanded our manuscript from a case report of one healthy subject to a small cohort of three healthy subjects and three subjects with lower urinary tract symptoms. As the manuscript has been entirely rewritten changes to the manuscript are not marked. Point by point responses to reviewer comments follow.

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Agree.

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Given the small sample sizes (n=3 and n=3 for both groups) we did not perform statistical analysis. The purpose of this study was to demonstrate a novel technique to assess bladder function so we feel this is appropriate. Additionally, we have added “pilot study” to the manuscript title per the editors advice and given our small sample size.

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Reviewer #1: No

The data points used to create the figures are now included in a supplementary excel file.

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Agree.

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an interesting paper that has applied cardiac wall movement analysis using MRI to assess bladder voiding. The data presented is a bit premature, as the technique was only assessed on one healthy volunteer. There is no statistical analyses to support their hypothesis that most of the bladder wall movement occurs in the dome region. Although the application of the MRI methodology is new for bladder voiding, the approach to measure cardiac wall movement is well documented. I applaud the investigators for attempting to use the methodology in the bladder, which requires such approaches to non-invasively assess its function. Although, the approach is not entirely non-invasive, as the placement of the catheter and voiding approach described seems like it would be cumbersome for patients with bladder disorders.

At the very least, this method needs to be assessed in multiple individuals to support the outcome that there are regional differences in bladder wall movement during voiding. Individuals with bladder voiding issues should have also been included, which would have been more relevant to the urology community.

We have expanded our manuscript from a case report of one healthy subject to a small cohort of three healthy subjects and three subjects with lower urinary tract symptoms. Given the small sample size we did not perform statistical analysis.

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We do not wish to make the peer review history public.

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14 Oct 2020

PONE-D-20-10274R1

A Pilot Study of Bladder Voiding with Real-Time MRI and Computational Fluid Dynamics

PLOS ONE

Dear Dr. Roldán-Alzate,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Please carefully address the issues raised by Reviewer 2.

==============================

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Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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Reviewer #2: Partly

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Reviewer #1: N/A

Reviewer #2: N/A

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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6. Review Comments to the Author

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Reviewer #1: The authors have expanded the study, which has improved the overall quality of the study. Although it would have been ideal to include more patients and conduct statistical analyses, I think the study still warrants being considered for publication.

Reviewer #2: Methods:

1. Authors should include how they documented patients in control group were asymptomatic (e.g. International Prostate Symptom Score or AUA symptom score).

2. How were the 3 BPH/LUTS patients selected from the urology clinic? (Randomly?, IPSS?, Traditional Urodynamics?)

3. Patient selection did not specifically exclude those with neurologic diseases that are known to effect bladder function, such as, diabetes, parkinsonism, etc., even though the control group showed no symptoms. The group with BPH/LUTS could also have complicating neurologic disorders. Therefore, I suggest that the authors specifically state that there were no histories of such diseases.

4. It would have been nice to have Total Prostatic Volumes and Transition zone volumes on at least the BPH/LUTS group.

5. Examination with patients in the supine position in not very physiologic and represents a distinct limitation of the experiment. (Unlike with cardiac CFD.) The potential effect of positioning should be brought up in the DISCUSSION section.

6. The models rely on many assumptions, some of which the authors accurately report

Results:

1. P9,line1 Statement should insert the words “may be” before “due” or amend to say “there is an association between wall displacement and increased flow velocity in the bladder”, since they have not done a large cohort to provide proof.

2. Fig. 6 Caption The authors might have provided more information on how to interpret “streaming lines” and “time points.” Engineers may be familiar with these concepts, but urologists, radiologists imagers and other readers probably need assistance. Also, “velocity magnitude” should be defined here or in the text of the manuscript.

3. Fig. 7 Caption Insert “likely” before “due”.

Discussion:

1. P10,line 3 The authors are “profoundly startled” by dome movement, but I would expect that because the base of the inferior detrusor is limited in movement by the thicker and stiffer stiffer overlying trigone. This would be expected to be exaggerated by gravity if the subject voids in the usual upright posture. A few examples of this are listed below:

[Assessment of movements of the different anatomic portions of the bladder, implications for image-guided radiation therapy for bladder cancer]. [French]

Evaluation des mouvements des differentes portions anatomiques de la vessie, implications pour la radiotherapie guidee par l'image pour les cancers de vessie.

Pan Q; Thariat J; Bogalhas F; Lagrange JL.

Cancer Radiotherapie. 16(3):167-78, 2012 May.

[Journal Article]

UI: 22365260

Authors Full Name

Pan, Q; Thariat, J; Bogalhas, F; Lagrange, J-L.

Cite My Projects Annotate

AB PURPOSE: To assess interfraction and intrafraction bladder wall movements in the different anatomic portions of the bladder. PATIENTS AND METHODS: Six patients were treated for prostate cancer with conformal irradiation. Daily online cone beam computed tomography was performed for repositioning and an additional one was performed following irradiation once weekly. Four craniocaudal levels were defined to calculate movements amplitudes compared to the scanner tracking: level 1 at the bladder neck, level 2 at mid-height of the bladder, level 3 at mid-height of the dome, level 4 at the apex in a distended bladder. Bladder height was also measured. RESULTS: On 198 daily cone beam computed tomographies, radial bladder right/left/anterior/posterior wall displacements at level 2 were 0.08 +/- 0.24, 0.11 +/- 0.33, 0.16 +/- 0.45 and 0.14 +/- 0.50 cm and at level 3 0.07 +/- 0.78, 0.18 +/- 0.98, 0.43 +/- 0.94 and 0.04 +/- 1.02 cm. Dome and neck displacements were 0.08 +/- 1.41 cm and 0.08 +/- 0.64 cm. Seventeen cone beam computed tomographies were done following irradiation. Radial bladder right/left/anterior/halfway up the trine wall displacements at level 2 before and after irradiation were 0.02+/-0.18, 0.01+/-0.30, 0.09 +/- 0.32 and 0.22 +/- 0.42 cm and at level 3 0.27 +/- 0.60, 0.37 +/- 1.15, 0.18 +/- 0.87 and 0.54 +/- 1.68 cm. CONCLUSION: Significant bladder wall displacements were observed on the anterior wall and upper portion of the bladder. Isotropic margins may not be sufficient to account for inter- and intrafraction bladder wall displacements at the latter levels. Tailored bladder anatomy-based anisotropic margins may be necessary to optimally spare the small intestine and to guaranty proper tumour coverage in case of bladder cancer. For upper bladder tumours, margins of over 2 cm would be necessary, which make them less adequate for external beam irradiation.

Assessment of Bladder Motion for Clinical Radiotherapy Practice Using Cine–Magnetic Resonance Imaging

Catherine A McBain;Vincent S Khoo;David L Buckley;Jonathan S Sykes;Melanie M Green;Richard A Cowan;Charles E Hutchinson;Christopher J Moore;Patricia M Price

ISSN: 0360-3016; DOI: 10.1016/j.ijrobp.2008.11.040

International journal of radiation oncology, biology, physics. , 2009, Vol.75(3),

2. p10 line 7 “thatt” typo

3. p10,l para 7 The authors might consider that CFD may also show vesicoureteral reflux, although it is not demonstrated in this study cohort.

REFERENCES: There are several incomplete or mistaken references

#13 Busse R incomplete reference

#28 Turkiye “Klinikleri” J Med Sci

SUMMARY

Pilot feasibility studies require a lesser level of evidence than more determinative research. The authors conceive of an image-based non-invasive technique that may substitute for traditional multichannel urodynamics. I would offer that their studies may provide different information rather than fully replace pressure-flow studies. The results of this study can make no conclusions other than proof of concept which it adequately does. I would recommend the authors re-phrase the final paragraph to say that the findings “in men with BPH/LUTS “suggest asymmetric bladder wall motion compared to healthy men…….”

**********

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Reviewer #1: No

Reviewer #2: No

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Submitted filename: Review PLOSone Article.docx

Click here for additional data file.

16 Oct 2020

We thank the reviewers for their consideration of our manuscript and for their expert advice on how to best improve our manuscript. Changes to the manuscript are tracked and point-by-point responses to reviewer comments are below.

Methods:

1. Authors should include how they documented patients in control group were asymptomatic (e.g. International Prostate Symptom Score or AUA symptom score).

Healthy controls were recruited from a database in the department of Radiology. At time of consenting patients were asked about LUT symptoms.

“At the time of consenting it was confirmed that patients were not experiencing LUT symptoms.”

2. How were the 3 BPH/LUTS patients selected from the urology clinic? (Randomly?, IPSS?, Traditional Urodynamics?)

Patients with known BPH/LUTS and scheduled for surgical treatment were recruited for the study.

3. Patient selection did not specifically exclude those with neurologic diseases that are known to effect bladder function, such as, diabetes, parkinsonism, etc., even though the control group showed no symptoms. The group with BPH/LUTS could also have complicating neurologic disorders. Therefore, I suggest that the authors specifically state that there were no histories of such diseases.

None of the patients had a history of neurological disease

“Three men with known BPH/LUTS who were scheduled for surgical treatment were recruited from the University of Wisconsin Urology clinic (ages 73, 71, and 54), none of whom had a history of neurological disease. The inclusion criteria were adult men recently diagnosed with BPH.”

4. It would have been nice to have Total Prostatic Volumes and Transition zone volumes on at least the BPH/LUTS group.

Prostate volumes are now included in the results section.

“Prostate volumes segmented from 3D FSE MRI were larger for BPH/LUTS patients (45, 80, and 106 mL) compared to healthy volunteers (18, 37, and 42 mL).”

5. Examination with patients in the supine position in not very physiologic and represents a distinct limitation of the experiment. (Unlike with cardiac CFD.) The potential effect of positioning should be brought up in the DISCUSSION section.

The potential effects of positioning are now discussed In the manuscript.

“Men normally void either standing or sitting down, and it would be ideal to perform the dynamic studies in a standing position, however, that is not possible due to the patient’s position in the MRI scanner. While multichannel urodynamic evaluation is usually performed with men either standing or sitting, it is often performed in supine position for patients with neurologic disease such as spinal cord injury. Previous studies have demonstrated modest effects of study position on quantitative measures of voiding pressure and urine flow, and ; however, there is no evidence that the anatomy and contractile function of the bladder are significantly altered by position.”

6. The models rely on many assumptions, some of which the authors accurately report

Additional assumptions are now reported.

“The urethra wall was assumed to be rigid and the urethra outlet was set to atmospheric pressure. Additionally, the urine density and viscosity were assumed to be the same for all subjects.”

Results:

1. P9,line1 Statement should insert the words “may be” before “due” or amend to say “there is an association between wall displacement and increased flow velocity in the bladder”, since they have not done a large cohort to provide proof.

“Urodynamics results from computational fluid dynamics (CFD) are shown in Figure 6 for a sagittal plane near the center of the bladder. Control subjects had higher urine velocities in the bladder than men with BPH/LUTS that may be due to their greater bladder wall displacements.”

2. Fig. 6 Caption The authors might have provided more information on how to interpret “streaming lines” and “time points.” Engineers may be familiar with these concepts, but urologists, radiologists imagers and other readers probably need assistance. Also, “velocity magnitude” should be defined here or in the text of the manuscript.

“CFD results showing velocity contours and streamlines on a sagittal plane at the center of the bladder for each subject. Results are displayed for time frames from near both the initiation and termination voiding. Streamlines indicate the direction of urine flow and velocity magnitude is the magnitude of the velocity vector or the overall speed of urine flow.”

3. Fig. 7 Caption Insert “likely” before “due”.

“Bladder vorticity was lower for the men with BPH/LUTS, likely due to their lower flowrates and urine velocities. After making vorticity dimensionless (a normalization to account for different flow rates between subjects), vorticity was similar for both groups.”

Discussion:

1. P10,line 3 The authors are “profoundly startled” by dome movement, but I would expect that because the base of the inferior detrusor is limited in movement by the thicker and stiffer stiffer overlying trigone. This would be expected to be exaggerated by gravity if the subject voids in the usual upright posture. A few examples of this are listed below:

[Assessment of movements of the different anatomic portions of the bladder, implications for image-guided radiation therapy for bladder cancer]. [French]

Evaluation des mouvements des differentes portions anatomiques de la vessie, implications pour la radiotherapie guidee par l'image pour les cancers de vessie.

Pan Q; Thariat J; Bogalhas F; Lagrange JL.

Cancer Radiotherapie. 16(3):167-78, 2012 May.

[Journal Article]

UI: 22365260

Authors Full Name

Pan, Q; Thariat, J; Bogalhas, F; Lagrange, J-L.

Cite My Projects Annotate

AB PURPOSE: To assess interfraction and intrafraction bladder wall movements in the different anatomic portions of the bladder. PATIENTS AND METHODS: Six patients were treated for prostate cancer with conformal irradiation. Daily online cone beam computed tomography was performed for repositioning and an additional one was performed following irradiation once weekly. Four craniocaudal levels were defined to calculate movements amplitudes compared to the scanner tracking: level 1 at the bladder neck, level 2 at mid-height of the bladder, level 3 at mid-height of the dome, level 4 at the apex in a distended bladder. Bladder height was also measured. RESULTS: On 198 daily cone beam computed tomographies, radial bladder right/left/anterior/posterior wall displacements at level 2 were 0.08 +/- 0.24, 0.11 +/- 0.33, 0.16 +/- 0.45 and 0.14 +/- 0.50 cm and at level 3 0.07 +/- 0.78, 0.18 +/- 0.98, 0.43 +/- 0.94 and 0.04 +/- 1.02 cm. Dome and neck displacements were 0.08 +/- 1.41 cm and 0.08 +/- 0.64 cm. Seventeen cone beam computed tomographies were done following irradiation. Radial bladder right/left/anterior/halfway up the trine wall displacements at level 2 before and after irradiation were 0.02+/-0.18, 0.01+/-0.30, 0.09 +/- 0.32 and 0.22 +/- 0.42 cm and at level 3 0.27 +/- 0.60, 0.37 +/- 1.15, 0.18 +/- 0.87 and 0.54 +/- 1.68 cm. CONCLUSION: Significant bladder wall displacements were observed on the anterior wall and upper portion of the bladder. Isotropic margins may not be sufficient to account for inter- and intrafraction bladder wall displacements at the latter levels. Tailored bladder anatomy-based anisotropic margins may be necessary to optimally spare the small intestine and to guaranty proper tumour coverage in case of bladder cancer. For upper bladder tumours, margins of over 2 cm would be necessary, which make them less adequate for external beam irradiation.

Assessment of Bladder Motion for Clinical Radiotherapy Practice Using Cine–Magnetic Resonance Imaging

Catherine A McBain;Vincent S Khoo;David L Buckley;Jonathan S Sykes;Melanie M Green;Richard A Cowan;Charles E Hutchinson;Christopher J Moore;Patricia M Price

ISSN: 0360-3016; DOI: 10.1016/j.ijrobp.2008.11.040

International journal of radiation oncology, biology, physics. , 2009, Vol.75(3),

This statement has been removed and we these studies are now included in our discussion section.

“Results from daily CTs of bladder cancer patients over the course of a week (presumably at varied levels of bladder filling) similarly show that the bladder wall displacements were greater for the dome of the bladder than the base [20]”

“Asymmetric bladder wall motion has previously been identified in bladder cancer patients during bladder filling [26].”

2. p10 line 7 “thatt” typo

This typo has been corrected.

3. p10,l para 7 The authors might consider that CFD may also show vesicoureteral reflux, although it is not demonstrated in this study cohort.

Investigation of vesicoureteral reflux would require our models to include the ureters. This is now discussed in the manuscript.

“Further improvements to the simulation realism by including the ureters could expand CFD analysis to include phenomena such as vesicoureteral reflux.”

REFERENCES: There are several incomplete or mistaken references

#13 Busse R incomplete reference

#28 Turkiye “Klinikleri” J Med Sci

Reference #13 has been completed. Reference #28 (now #30) has been double checked and it is correct.

SUMMARY

Pilot feasibility studies require a lesser level of evidence than more determinative research. The authors conceive of an image-based non-invasive technique that may substitute for traditional multichannel urodynamics. I would offer that their studies may provide different information rather than fully replace pressure-flow studies. The results of this study can make no conclusions other than proof of concept which it adequately does. I would recommend the authors re-phrase the final paragraph to say that the findings “in men with BPH/LUTS “suggest asymmetric bladder wall motion compared to healthy men…….”

The summary has been rewritten

“In summary, this pilot study demonstrated the feasibility of MRI bladder voiding studies to non-invasively investigate bladder function. Results from displacement analysis suggested that men with BPH/LUTS have decreased and asymmetric bladder wall motion compared to healthy male controls and fluid dynamic analysis of voiding suggested that men with BPH/LUTS have larger recirculation regions in the bladder.”

Submitted filename: Sub3_CFD_Bladder_response.docx

Click here for additional data file.

19 Oct 2020

A Pilot Study of Bladder Voiding with Real-Time MRI and Computational Fluid Dynamics

PONE-D-20-10274R2

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PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

3 Sep 2020

PONE-D-20-10274R1

A Pilot Study of Bladder Voiding with Real-Time MRI and Computational Fluid Dynamics

Dear Dr. Roldán-Alzate:

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