Influences of the second motion probing gradient b-value and T2 relaxation time on magnetic resonance diffusion-derived ‘vessel density’ (DDVD) calculation: the examples of liver, spleen, and liver simple cyst

Introduction

Our exploration of diffusion-weighted imaging (DWI) in liver fibrosis evaluation revealed that diffusion-derived ‘vessel density’ (DDVD) could potentially reflect microvascular perfusion. For spin-echo type echo-planar sequence, the second motion probing gradient after the 180-degree radiofrequencey pulse cannot fully re-focus the flowing spins in vessel and micro-vessels after being de-phased by the first motion probing gradient before the 180-degree RF pulse. Therefore, liver blood vessels including sub-pixel microvessels show high signal when there is no motion probing gradient (b=0 s/mm²) and low signal when even very low b-values (such as b=1, b=2 s/mm²) are applied (Figure 1) (1). Thus, the signal difference between images when the motion probing gradient is ‘off’ and ‘on’ reflects the extent of tissue vessel density in physiological sense, and we term this as DDVD. DDVD [unit: arbitrary unit (au)/pixel] is derived from the Eq. [1]:

DDVDb0b2=Sb0/ROIarea0−Sb2/ROIarea2[1]

Figure 1 1.5 T liver diffusion weighted images with b-value of 0 (A), 1 (B), 2 (C), 15 s/mm² (D). Dummy scan (C) was scanned ahead of b=0 image (A). The signal difference between b=0 s/mm² image and b=1 or 2 s/mm² images is dramatic, particularly the vessels show high signal when the motion probing gradient is ‘off’ while showing dark signal when the motion probing gradient is ‘on’ even at b=1 s/mm². The high intensity of the vasculature seen on b=0 s/mm² image led to the naming of diffusion derived ‘vessel density’.

where ROI_area0 and ROI_area2 refer to the number of pixels in the selected region-of-interest (ROI) on b=0 and b=2 s/mm² DWI, respectively. S_b0 refers to the measured sum signal intensity within the ROI when b=0, and S_b2 refers to the measured sum signal intensity within the ROI when b=2 s/mm², thus S_b/ROI_area equates to the mean signal intensity within the ROI. S_b2 and ROI_area2 can also be approximated by other low b-values (such as b=10 s/mm²) DWI. In our initial testing (1), with 20 healthy livers, 11 stage-1 fibrotic livers, and 5 stage-4 fibrotic livers, mean DDVD was 26.5 for healthy livers, 21.8 for stage-1 fibrotic livers, and 12.1 for stage-4 fibrotic livers (1) (approach shown on Figure 1). If we consider a pixel to be an individual ROI, DDVD pixelwise map can be constructed pixel-by-pixel with this same principle (2).

The analysis of DDVD requires only two b-values (with one being b=0 s/mm² and the other being non-zero low b-value), with a significantly shorter scanning time than contrast enhanced computed tomography (CT)/magnetic resonance imaging (MRI) while without the need of a contrast agent injection. DDVD is conceptually as simple as the apparent diffusion coefficient (ADC). DDVD measure based on this simple principle appears to be useful as a straightforward imaging biomarker in diverse clinical scenarios. Huang et al. (3) showed that DDVD analysis demonstrates liver parenchyma has an age-dependent decrease of micro-perfusion in healthy women. This agrees with the known physiological age-dependent reduction in liver blood flow which has been well documented using a variety of technical methods including histology, dye dilution, indicator clearance. DDVD is a useful parameter for distinguishing livers with and without fibrosis, and livers with more severe fibrosis tend to have even lower DDVD measurements than those with milder liver fibrosis (1,4,5). With DDVD analysis, Zheng et al. (6) demonstrated that per unit micro-circulation of spleen is decreased in viral hepatitis-B liver fibrosis patients, and this reduction in micro-circulation is associated with the severity of liver fibrosis. This is consistent with earlier radioisotope imaging or CT perfusion studies where splenic blood flow (unit in mL/min/mL) was decreased in liver fibrosis patients (7-10), though total splenic blood flow, calculated multiplying specific splenic flow by spleen volume, was increased. He et al. (11) and Li et al. (12) reported that placenta DDVD as a perfusion biomarker allows excellent separation of normal and early pre-eclampsia pregnancies. Lu et al. (13) reported that placenta regional DDVD is significantly higher in pregnant women with placenta accreta spectrum disorders than women with normal placenta, and especially higher in patients with placenta percreta. Hu et al. (14) described that liver hemangiomas can be mostly differentiated from liver mass-forming lesions [hepatocellular carcinomas (HCCs) and focal nodular hyperplasia] solely based on DDVD map. Chen et al. (15) described a proof-of-concept study that a combination of DDVD map and high b-value DWI identifies the exitance and the size of penumbras.

As absolute magnetic resonance (MR) signal intensity is influenced by various factors, including B0/B1 spatial inhomogeneity, coil loading, receiver gain, etc., we use the ratio of a lesion to its adjacent native tissue (such as the ratio of HCC’s DDVD to liver DDVD) to minimize these scaling factors. Li et al. (16) applied DDVD to assess the perfusion of HCC. DDVD results (ratio of HCC DDVD to background liver DDVD) approximately agree with other dynamic contrast enhanced CT/MRI literature data (17-19). Lu et al. (20) reported earlier clinical grades rectal carcinoma had a higher DDVD ratio (tumor to tumor-free rectal wall) than those of the advanced clinical grades. This is consistent with the biological behaviors of rectal carcinoma (21). In one study, we used DDVD ratio (DDVDr) to evaluate 24 pleomorphic adenomas (PAs), 14 malignant tumors, and 16 Warthin’s tumors. DDVDr was DDVD of the tumor divided by DDVD of tumor free parotid gland tissue. A systematic literature search was conducted for parotid gland tumor perfusion imaging and histology microvessel density studies. Perfusion parameters of PAs, malignant tumors, and Warthin’s tumors were further normalized by PA’ measure (thus the normalized measure for PA is 1). The ratio results of malignant tumor DDVD and Warthin’s tumors DDVDr were compared with literature results. In the cases of parotid gland tumors, DDVD appears to offer more consistent and comparable results (comparable to CT and histology microvessel density results) than arial spin labeling and intravoxel incoherent motion (IVIM) [briefly summarized in (15)].

In clinical practice, it is highly likely that DDVD protocol users in different MRI scanner settings will select different second non-zero low b-value. Most of the Philips scanners allow the selection of b=1, b=2 s/mm², etc., while some other scanners only allow the lowest non-zero b-value to be 10, or 20 s/mm². To facilitate the comparison of at least relative DDVD values (relative DDVD means absolute DDVD of one tissue is normalized by absolute DDVD of another reference tissue) cross different MRI scanners, taking the cases of liver, spleen, liver simple cyst as examples, this study measures DDVD with the second non-zero low b-values ranging from 1 to 30 s/mm². Healthy liver and spleen are two large solid organs in the upper abdomen with similar amounts of blood perfusion as shown in Table 1 (3,9,10,21-34) and Table 2 (3,19,34-39) (liver perfusion being the sum of hepatic arterial perfusion and portal veinous perfusion), though it is likely that the liver has slightly higher blood volume (unit in mL/100 mL) due to the blood supply of portal vein and spleen has slightly higher blood flow (unit in mL/min/mL) due to the pure blood supply of the splenic artery. Compared with the liver, the spleen has longer T2 with higher contact of free water (23-25,40), thus DDVD data of the liver and the spleen allow us to study how DDVD measure is affected by T2. One of the perceived advantages of DDVD over ADC and IVIM imaging is that, when we use DWI images of b=0 and a non-zero very low b-value to calculate DDVD, DDVD is minimally affected by T2. On the other hand, both diffusion metrics of IVIM and ADC are heavily contributed by T2 (34,41-44). Conventional IVIM-perfusion fraction (PF) is known to be affected by tissue’s T2 time, with longer T2 time leading to a ‘depressed’ PF measure (16,43). For example, Li et al. (16) showed most HCCs have higher DDVD (calculated from b=0 and b=2 mm²/s DWI or calculated from b=0 and b=10 mm²/s DWI) which is consistent with histology and CT/MRI results. However, most IVIM reports described a lower PF for HCC than for adjacent liver parenchyma (16,43). DDVD results (calculated from b=0 and b=2 mm²/s DWI) show the liver and spleen have very similar perfusion (6), while most IVIM reports described spleen PF is only half of that of the liver (45). While ADC is a composite biomarker influenced by many factors, ADC measure is more affected by T2 than by diffusion (42,43,46). For example (46), abscess liquid (pus) has a very low ADC of around 0.65×10⁻³ mm²/s due to its T2 being 80 ms; articular cartilage has a high ADC of around 1.5×10⁻³ mm²/s due to its short T2 (around 40 ms at 3.0T), chondrosarcoma has a high ADC of around 2.3×10⁻³ mm² due to its long T2 time (around e.g., 120 ms). These values are not reasonable for a metric expected to reflect in vivo diffusion (46).

Methods

This is a restrospective analysis of previously prospectively acquired liver IVIM data. All IVIM data were acquired with institutional ethical approval and with informed consent obtained from individual participants (14,47). Data acquisition protocols are listed in the Appendix 1. 1.5T IVIM DWI data included 26 healthy volunteers (14 males, 12 females, mean age: 24 years old; range, 20–41 years old) and two liver fibrosis patients (2 males, aged 45 years and 49 years respectively). 3.0T IVIM DWI data included 19 healthy volunteers (10 males, 9 females, mean age: 33 years old; range, 22–65 years old) and 2 liver fibrosis patients (1 male aged 60 years and 1 female, aged 47 years).

All image processing was implemented in a custom program developed on MATLAB (Mathworks, Natick, MA, USA). DWI data with b-values of 0, 1, 2, 15, 20, 30 s/mm² were used for 1.5T MRI, and DWI data with b-values of 0, 2, 4, 7, 10, 15, 20, 30 s/mm² were used for 3.0T MRI. On each DW image for the liver and spleen, ROIs were drawn to cover a large portion of the right liver parenchyma and spleen parenchyma while avoiding large vessels and artifacts. Based on Eq. [1], DDVD_b0b1, DDVD_b0b2, DDVD_b0b4, DDVD_b0b7, DDVDb_0b10, DDVD_b0b15, DDVD_b0b20, and DDVD_b0b30 were calculated from b=0 and b=1 images, b=0 and b=2 images, b=0 and b=4 images, b=0 and b=7 images, b=0 and b=10 images, b=0 and b=15 images, b=0 and b=20 images, b=0 and b=30 s/mm² images, respectively. For each study subject, the mean signal intensity of each ROI was weighted by the number of pixels included in each ROI relative to total ROI area in a subject, then the sum of the weighted DDVDs was calculated to obtain the value for each liver and spleen. For liver simple cysts (from the two liver fibrosis patients scanned at 1.5T), only two cysts (size =26.8 and 36.3 mm) totaling six slices were available for DDVD measurement.

Influences of the second b-value on DDVD were compared for liver, spleen, and liver simple cyst, and compared between 1.5T results and 3.0T results. Data are presented graphically.

Results

For 1.5T data, the plotted data between the second b-values for DDVD calculation and liver, spleen, or cyst DDVD values are shown in Figures 2,3. It is noted that, when the second b-value was 1 s/mm², DDVD_spleen value was slightly higher than DDVD_liver value; when the second b-value was 2 s/mm², DDVD_liver value was slightly higher than DDVD_spleen value. After that, the absolute difference between DDVD_liver value and DDVD_spleen value became increasingly larger, with DDVD_liver value being consistently higher. DDVD_cyst showed a value close to 0 when the second b-value was 1 s/mm², and a low value when the second b-value was 2 s/mm². When the second b-value was 20 or 30 s/mm², DDVD_cyst values were higher than the DDVD_liver value.

Figure 2 Fitted data of 1.5T liver and spleen DDVD median values over second b-values, data of 28 subjects (16 males, 12 females) among them two male cases were with liver fibrosis. DDVD, diffusion derived ‘vessel density’.

Figure 3 Fitted data of 1.5T liver, spleen, and liver cyst DDVD median values over second b-values. Liver and spleen data are from 28 subjects. Liver cyst data are based on two cysts totaling six slices from two male patients with liver fibrosis. DDVD, diffusion derived ‘vessel density’.

The relationship between the second b-values and the DDVD_liver values at 1.5T was fitted by

1.5TDDVDliver=5.654∗ln(2ndb)+8.915[2]

The relationship between the second b-values and spleen DDVD_spleen values at 1.5T was fitted by

1.5TDDVDspleen=4.270∗ln(2ndb)+9.225[3]

The relationship between the second b-values and liver cyst DDVD values at 1.5T was linearly fitted by (48):

1.5TDDVDcyst=DDVD=2.009∗(2ndb)−2.982[4]

DDVD pixelwise maps of two cases of liver simple cysts at 1.5T are shown in Figure 4.

Figure 4 DDVD appearance of liver cysts (arrow) at 1.5T. b=0 diffusion-weighted imaging (A1,B1) and DDVD pixelwise maps with the second b-value being 1 (A2,B2), 2 (A3,B3), 15 (A4,B4), 20 (A5,B5), and 30 s/mm² (A6,B6), respectively. Due to the T2 contribution to DDVD values and together with possible misalignment between b=0 image and the second b-value image, typical DDVD appears is lost when second b-value is >15 s/mm². The cysts were marked with region-of-interest of red color on b=0 diffusion weighted image. DDVD, diffusion derived ‘vessel density’.

For 3.0T data, the plotted data between the second b-values for DDVD calculation and liver or spleen DDVD values are shown in Figure 5. When the second b-value was 2 s/mm², DDVD_liver was already higher than DDVD_spleen. After that, the absolute difference between DDVD_liver value and spleen DDVD_spleen value became increasingly larger.

Figure 5 Fitted data of liver and spleen DDVD median values over second b-value, 1.5T and 3.0T data. 1.5T data are of 28 subjects (16 males, 12 females), among them two male cases were with liver fibrosis. 3.0T data are of 21 subjects (11 males, 10 females), among them one male case and one female case were with liver fibrosis. DDVD, diffusion derived ‘vessel density’.

The relationship between the second b-values and the DDVD_liver values at 3.0T was fitted by

3.0TDDVDliver=10.082∗ln(2ndb)+28.859[5]

The relationship between the second b-values and spleen DDVD_spleen values at 3.0T was fitted by

3.0TDDVDspleen=5.863∗ln(2ndb)+30.494[6]

Measured DDVD values are also shown in Table 3, and the ratios of DDVD_spleen to DDVD_liver are shown in Figure 6. A comparison of 1.5T data and 3.0T data shows the absolute DDVD values measured higher at 3.0T than at 1.5T, and the absolute DDVD difference between the liver and spleen was greater at 3.0T than at 1.5T, even when the second b-value was 2 s/mm². However, the ratios of DDVD_spleen to DDVD_liver did not apparently differ between 1.5T and 3.0T. From the second b-value being 2 s/mm² onward, an increasingly larger second b-value was associated with a trend of slow decreasing of the ratio of DDVD_spleen to DDVD_liver. For 3T data, DDVD_spleen to DDVD_liver ratio was 0.790 when the second b-value was 30 s/mm².

Figure 6 Ratios of DDVD_spleen to DDVD_liver over increasing second b-values, and ratio of spleen ADC to liver ADC from a literature report by Kim et al. (49). From second b-value being 2 s/mm² onward, an increasingly larger second b-value is associated with a slow decreasing trend of the ratio of DDVD_spleen to DDVD_liver. Typical ADC data are from Kim et al. (spleen ADC 0.79, liver ADC 1.07×10⁻³ mm²/s, measured at 3.0 T with b-value of 0, 800 s/mm²). The ratio of spleen ADC to liver ADC appears to be in line with the ratio of DDVD_spleen to DDVD_liver. DDVD, diffusion derived ‘vessel density’; ADC, apparent diffusion coefficient.

Discussion

In our earlier studies, we used various second b-values for DDVD calculation. In some studies, we used historical IVIM imaging data, thus the available lowest second b-value was utilized for DDVD calculation. In some prospective studies, the second b-value was constrained by the MRI scanners, as many MRI scanners do not allow the second b-value to be less than 10 s/mm². Since the perfusion status and T2 relaxation times of liver, spleen, and liver simple cysts are very well characterized, using the examples of liver, spleen, and liver cyst, this study aims to understand the impact of the second b-value for DDVD calculation, which we assume it is mainly moderated by T2. Figure 2 shows, when the second b-value was 1, or 2 s/mm², the impact of T2 on DDVD was minimal, though that longer T2 (of the spleen relative to the liver) is associated with smaller DDVD could be noted even at very low second b-values (such as b=2 s/mm²). From the second b-value being 2 s/mm² onward, an increasingly larger second b-value was associated with a slowly increasing contribution from T2, reflected by the slow decreasing trend of the ratio of DDVD_spleen to DDVD_liver. It is interesting to note that, the ratio of spleen ADC to liver ADC appears to be in line with the ratio of DDVD_spleen to DDVD_liver. Figures 5,6 suggest the ‘fast diffusion’ (i.e., perfusion) difference between liver and spleen may be modulated by T2. The ratio of spleen ADC to liver ADC appears to be in line with the ratio of DDVD_spleen to liver DDVD_liver suggests the possibility that the difference between the spleen ADC and liver ADC is also modulated by T2 (41,42). In other words, if the difference between spleen ADC and liver ADC is modulated by other factor(s), then the ratio of spleen ADC to liver ADC would more likely differ from the ratio of DDVD_spleen to DDVD_liver.

For diffusion MRI quantification of the liver and spleen, due to the longer spleen T2 (60 ms at 3T) than liver T2 (42 ms at 3T), both ADC and IVIM-PF are underestimated for the spleen values relative to the liver values (42,43). This may also cause a relative error for HCC ADC (42). HCC ADC has been traditionally noted to be with restricted diffusion. However, as HCCs are mostly associated with increased arterial blood supply and higher water content (i.e., edema, as shown with higher signal on T2-weighted image), we consider it unlikely that HCC has true lower diffusion, instead the lower HCC ADC is due to the longer T2 of HCC (HCC T2 is estimated to be close to that of spleen being around 60 ms) (42,50-52). On the other hand, measured by DDVD_b0b1 and DDVD_b0b2, the liver and spleen have very similar fast diffusion values. DDVD_b0b2 and DDVD_b0b10 also show higher values for HCC than for liver parenchyma (16). Thus, by minimizing the second b-value, the T2 effect on diffusion metrics can be largely mitigated with DDVD, and this may be an important advantage of DDVD over ADC and IVIM.

This study further demonstrated the practicality of DDVD in diagnosing liver simple cysts. Liver cysts typically show ‘no perfusion’ (Figures 4,7). However, such a ‘no perfusion’ was only observed when a very low second b-value was applied. When the second b-value is higher, for example, >30 s/mm², liver cysts may lose their DDVD characteristics due to the contribution of T2. Note that liver cysts are likely to have a very long T2 being similar to that of gallbladder of 160 ms (53). When the second b-value is high, for example, 30 s/mm², liver cyst may show even higher DDVD signal relative to the liver parenchyma (Figure 8). In addition, as noted earlier (14), the ‘position shift’ between the b=0 image and the second b-value image is a source of quantification error for DDVD calculation of structures inside the liver, as the liver is heavily subject to respiratory motion. One possible way to overcome this difficulty is to scan the DDVD protocol twice (or three) times, and manually select the pair of images with the most similar positions to reconstruct DDVD map. Breath-hold method DDVD data acquisition protocol may be indeed practically feasible (1).

Figure 7 DDVD appearance of liver cysts (arrow) at 3.0T (four liver cysts). b=0 diffusion weighted image (A1,B1,C1) and DDVD pixelwise maps with the second b-value being 2 (A2,B2,C2) or 10 (A3,B3,C3) s/mm², respectively. Liver cysts typically show low DDVD signal. Three cysts were marked with region-of-interest of red color on b=0 diffusion weighted image. DDVD, diffusion derived ‘vessel density’.

Figure 8 DDVD appearance of liver cysts (arrow) at 1.5T. b=0 diffusion weighted imaging (A1,B1) and DDVD pixelwise maps with the second b-value being 1 (A2,B2), 2 (A3,B3), 15 (A4,B4), 20 (A5,B5), and 30 s/mm² (A6,B6), respectively. Together due to the misalignment between b=0 image and the second b-value image and/or the T2 contribution to DDVD values, typical DDVD appearance is lost on A3, A4, A6, B2, B5, B6. DDVD, diffusion derived ‘vessel density’.

There are many limitations to this study. This study used historical IVIM imaging data, and the 1.5T IVIM imaging data did not acquire sufficient data points between b=2 s/m² image and b=15 s/m²; while the 3.0T IVIM imaging data did not acquire b=1 s/m² image. However, we expect the overall trend for the relationship between the second b-values and DDVDs of the liver and spleen would not be affected. Liver cyst data quantitative data were measured only with two cysts with 6 slices at 1.5T. We plan to investigate the observed phenomenon with a larger sample size, more pathological entities, and more second b-values.

In conclusion, this study shows the following points: (I) when the second b-value is very low for DDVD calculation, T2 contribution can be minimized; (II) absolute DDVD values measures higher at 3.0T than at 1.5T and the absolute DDVD difference between liver and spleen is greater at 3.0T than at 1.5T, while the ratios of DDVD_spleen to DDVD_liver do not apparently differ between 1.5T and 3.0T; (III) characteristic liver cyst DDVD signal is only shown with a very low second b-value, and when the second b-value is high, for example, >30 s/mm², liver cysts may show higher DDVD signal relative to liver parenchyma due to the T2 contribution.

Acknowledgments

Funding: This work was supported by a Hong Kong General Research Fund project (No. 14112521) and Shenzhen People’s Hospital Physician Scientist Training “Five Three” Program (No. SYWGSLCYJ202404).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2411/coif). Y.X.J.W. serves as the Editor-in-Chief of Quantitative Imaging in Medicine and Surgery. G.G. serves as an unpaid editorial board member of Quantitative Imaging in Medicine and Surgery.Y.X.J.W. is the founder of Yingran Medicals Ltd., which develops medical image-based diagnostics software. B.H.X. and M.S.Y.Z. contributed to the development of Yingran Medicals Ltd. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study reused historical image data for new analysis. All the diffusion weighed image data were acquired with the institutional ethical approval and with informed consent obtained from individual patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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