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Published in final edited form as: Gynecol Obstet Invest. 2015 Aug 26;81(3):193–201. doi: 10.1159/000431223

Longitudinal changes in placental MRI relaxation parameter in murine pregnancy: compartmental analysis

Uday Krishnamurthy 1,2, Gabor Szalai 3, Yimin Shen 1, Zhonghui Xu 3, Brijesh Kumar Yadav 1,2, Adi Laurentiu Tarca 3,6, Tinnakorn Chaiworapongsa 3,4, Edgar Hernandez-Andrade 3,4, Nandor Gabor Than 3,4,5, Ewart Mark Haacke 1,2, Roberto Romero; D Med Sci3,7,8,*, Jaladhar Neelavalli 1,2,*
PMCID: PMC4769121  NIHMSID: NIHMS694833  PMID: 26336923

Abstract

Objective

To quantify gestation-dependent longitudinal changes in the magnetic resonance transverse relaxation parameter (T2) of the major constituent regions of the mouse placenta and evaluate their relative contributions to changes in overall placental T2.

Methods

Timed-pregnant CD-1 mice underwent magnetic resonance imaging (MRI) at 7.0 Tesla field strength, on gestational days (GD) 13, 15 and 17. T2 of placenta and its constituent high blood perfusion and low blood perfusion regions were quantified. A linear mixed-effects model was used to fit the T2 across gestation, and significance of coefficients was tested.

Results

A decrease in the T2 values of the placenta and its constituent regions was observed across gestation. Temporal change in T2 was estimated to be -1.85 msec/GD (p<0.0001) for the placenta, -1.00 msec/GD (p<0.001) for the high, and -1.66 msec/GD (p<0.0001) for the low perfusion zones.

Conclusion

T2 of the constituent zones of the murine placenta decreases with advancing gestation. While the T2 of the low perfusion zone is smaller than the high perfusion zone, there is no difference in their decrease rate relative to that of the whole placenta (p=0.24). The results suggest increased role of constituent volume fractions in affecting overall gestation-dependent placental T2 decrease in mice.

Keywords: Mouse, Relaxation rate, Spin-spin relaxation, Junctional zone, Labyrinth zone, Relative contribution, High perfusion zone, Low perfusion zone

Introduction

Ultrasound (US) is the preferred modality for diagnostic fetal imaging. However, the role of magnetic resonance imaging (MRI) in fetal diagnostic evaluation is increasing in part due to its exquisite soft tissue contrast and potential to perform quantitative functional imaging [1-4]. US has traditionally been used for fetal screening and assessment mainly due to its ease of operation, high temporal and spatial resolution and adaptability to motion. The choice of prenatal diagnostic imaging (US vs. MRI) is subject to clinical indications [5]. During pregnancy, the placenta plays an important role in the exchange of oxygen and nutrients between the maternal and fetal circulations. Any decline/alteration of this exchange within the placenta is associated with conditions like intrauterine growth restriction (IUGR) [6, 7]. Experimental studies performed in lamb fetuses have shown that reduced placental blood flow is associated with an increased risk of fetal death and acidosis [8-10]. In human fetuses, increased vascular resistance in the uterine arteries is associated with a higher risk of IUGR and preeclampsia [11, 12]. Hence placental in vivo assessment plays a crucial role in accessing the health of the fetus. Using MRI it is possible to quantitatively assess the functional and morpohological status of the placenta non-invasively [13, 14].

Murine models of pregnancy are extensively used to study placental development due to the anatomical, functional and cellular similarities of the murine and human placentas [15-18]. The mouse placenta consists of three major regions, namely the labyrinth zone, the junctional zone and the decidua. While it is known that the labyrinth zone (analogous to the villous placenta in humans) is the site for materno-fetal gas, nutrient and waste exchange, the development of the fetus also depends on the proper functioning of the junctional zone and the decidua [19]. Along with the developing fetus, the placenta shows marked and proportional changes with increasing gestational age (GA), and the different regions of the placenta show differential development [20, 21]. The placenta is subject to continuous structural, morphological and functional changes with advancing gestation. Due to these physiological changes seen across gestation, the quantitative parameters such as volume, capillary density, mass and blood flow are susceptible to normal variation [20, 22, 23]. Hence, characterization of these GA dependent changes using the non-invasive methods is important.

While most of the placental developmental and structural changes have been studied using stereology or other methods (after euthanizing the fetus) [20, 22], the in vivo assessment of functional development and remodeling of the placenta using non-invasive methods like MRI has been limited. Non-invasive placental blood supply is usually evaluated with Doppler velocimetry (in the uterine arteries), and the placental blood perfusion by calculating three dimensional power ultrasound indices [24-26]. US can also provide information on the size, volume, and echogenicity of the placenta [27-29]. Nevertheless placental physiological and functional assessment using US is limited [30, 31]. Of importance, it has been shown that reduced placental volume is accounted by increased placental efficiency, indicating that functional changes, which often accompany morphological changes, are more physiologically relevant [19, 21]. MRI provides a non-invasive quantitative alternative to functional placental imaging. MRI transverse relaxation time (T2) parameter has been shown to correlate with micro-vascular perfusion status of the tissue and is sensitive to changes in perfusion and tissue morphology [32-35]. Quantitative MRI of the placenta, particularly T2, has been shown to be a potential noninvasive biomarker for IUGR in both humans and animal models [36-38]. Conversely, due to normal physiologic changes that occur with aging placenta, the T2 parameter may also progressively change with advancing GA [23, 39]. Establishing the trajectory of these normal variations using non-invasive MRI-based methods allows for further use of such methods to recognize changes that occur due to various pathological processes. Furthermore, understanding the normal progression of the T2 of the placenta as a function of gestation could better inform future MRI based studies for appropriate timing of investigation.

Studies using dynamic contrast enhanced (DCE) MRI and contrast enhanced US have reported distinct functional (perfusion) compartments of the placenta [40, 41]. Placental oxygenation studied using BOLD MRI under conditions of maternal hyperoxia in humans also suggests distinct compartments [42]. Hence it is imperative to study them independently. These distinct functional compartments of the placenta, the high blood perfusion (HPZ) and low blood perfusion zones (LPZ) roughly correspond to the labyrinth and the junctional zones. Previous studies have shown that T2 value of the overall placenta decreases with gestation [23] and that at a given gestation, the T2 values of the constituent placental zones are different [38]. However, it is not clear how the T2 of constitute zones of the placenta changes with gestation and how they contribute to the GA-dependent decrease of overall placental T2. Therefore, in this longitudinal study we evaluated the changes in the T2 of the murine placenta and its constituent regions (HPZ and LPZ) at three different time points along the gestational period axis: on GD13, GD15 and GD17 (full term duration - 19 to 21 days). Analysis was carried out to evaluate the differential contribution of the individual compartments to the temporal changes in the whole placental T2.

Materials and Methods

Animal care and handling

The study protocol (A#11-03-11) was approved by the Institutional Animal Care and Use Committee (IACUC) of Wayne State University (Detroit, MI, USA). Animal care and handling followed the standards set forth by the National Research Council of the National Academies [43] and those published in our previous study [44]. Timed-pregnant CD-1 mice (n=9) were obtained from Charles River Laboratories (Wilmington, MA, USA). Pregnancy was confirmed by manual examination on GD12. Mice were kept separately in filter top rodent cages and fed with ad libitum water and food. A regular 12:12 hour dark-light cycle, constant temperature (24±1° C) and humidity (50±5%) was maintained in the animal room, and mice were monitored for food and water intake, vital signs, behavior and activity. MR imaging was performed on GD13, GD15 and GD17 for each of the nine pregnant mice.

Imaging procedure

All MRI studies were performed on a 7.0T, 20 cm bore superconducting magnet (ClinScan, Bruker, Karlsruhe, Germany) interfaced with a Siemens console. Prior to image acquisition, anesthesia was induced by isoflurane to sedate the animals (4% v/v via induction chamber and then 2% v/v maintenance). Mice were kept under anesthesia throughout the acquisition time. The animals were first subjected to a series of localization scans, following which T2 weighted turbo spin echo data (TSE) were acquired for anatomical assessment of the fetus and high resolution visualization of the corresponding placentae. A fat saturated, multi echo T2 weighted spin echo sequence was used for T2 measurement, which was acquired using the following sequence parameters (Table 1): matrix size of 320×512; relaxation time (TR) of 2840 msec; slice thickness of 0.8mm; an in-plane resolution of 0.08×0.08 mm2 and pixel bandwidth of 150 Hz/pixel. A total of 6 echoes at the echo times (TE) of 10.8, 21.6, 32.4, 43.2, 54, 64.8 msec were acquired, and T2 maps were generated using a custom code written in Matlab (The MathWorks Inc., Natick, MA, USA) for linear least-squares fitting to the mono-exponential signal decay equation [45]:

Table 1. MRI parameters used for multi echo spin echo T2 weighted imaging sequence.

Sequence TE (in msec) TR (in msec) BW (in Hz/pixel) In plane isotropic voxel size (in mm) Slice thickness (in mm)
Multi echo spin echo 10.8, 21.6, 32.4, 43.2, 54, 64.8 2840 150 0.08×0.08 0.8
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TE - echo time, TR - repetition time, BW – bandwidth, Hz – hertz.

T2=−TEi−TE0lnsis0

In this equation Si refers to the magnitude signal intensity at the given TEi with i =2,3,4,5,6 and S0 and TE0 refer to the signal and the TE of the first echo respectively. The data from the six echoes is fitted to this linear equation to estimate the T2 value. All the images were acquired in axial orientation relative to the magnet coordinate system, which was also axial relative to the imaged pregnant mice.

Image processing

The T2 maps were generated using the multi echo spin echo data by fitting the signal to a mono exponential function on a pixel by pixel basis. Pixels with poor fit or those which resulted in negative values were thresholded to zero. A central slice through the placental cross-section, where the constituent HPZ and LPZ were visualized, was chosen for the quantitative T2 measurements. A total of three free hand drawn region of interests (ROIs) were used to map (a) the whole placenta, (b) the HPZ and (c) the LPZ from which the T2 values were recorded. The manual segmentation of the regions was performed considering the spin echo T2 weighted images at different TEs, primarily the data at TEs of 32.4 msec, 43.2 msec and 54 msec as they are closest to placental T2 values previously reported [23], providing good T2 contrast. The ROIs for the HPZ and LPZ were drawn conservatively to avoid partial volume voxels at the boundaries of these regions. The whole-placenta ROI was drawn to include the high and low perfusion regions along with the boundary regions that could not be definitively classified into either of these two regions. A minimum of 40 voxels were included in the ROIs to ensure low standard error in the mean T2 measurement. The decidua was not included in the whole-placental ROI. Longitudinal changes in the placental T2 values were then statistically compared for differences. Since maternal systemic blood pressure and the heart rate increase during pregnancy in murine pregnancies [46], such systemic differences in maternal physiology due to advancement in pregnancy could act as a confounding factor influencing the placental T2 measure. Systemic changes in maternal cardiovascular physiology are expected to affect T2 values of maternal organs like muscle. Therefore, the changes in T2 value of maternal muscle tissue, specifically the lateral group of muscles of the hind limb, as a function of GA were statistically evaluated.

Statistical analysis

The T2 measurements from different placentas in a given mice at a given GD were averaged. The averaged T2 values were evaluated for possible changes due to advancing gestation. The linear temporal patterns across GA for T2 measurements were fitted using a linear mixed effects (LME) model. The fixed effects included GD as a continuous variable, T2 measurements from a given compartment (total placenta, HPZ, and LPZ), and the interaction between these two variables, and a random intercept was exercised for each mouse. Furthermore, the presence or absence of systematic changes in maternal physiology was ascertained by statistically evaluating changes in T2 value of the reference maternal muscle tissue as a function of GA using a repeated measures analysis of variance test. All visualization and analysis were performed within the R computing environment [47], and the LME model was built using R package “nlme” [48].

Results

T2 relaxation times

The placental T2 relaxation times decreased with advancing gestation (Table 2). A total of nine mice were followed longitudinally. T2 values were measured from a total of 35 placentas on GD13, from 36 placentas on GD15 and from 35 placentas on GD17. The T2 weighted images showed the clear distinction of the constituent regions of the placenta (Figure 1). The average whole placental T2 relaxation time, measured across all placentas, was 46.23±4.2 msec (mean ± standard deviation) on GD13, 42.19±6.60 msec on GD15 and 39.08±1.67 msec on GD17 (Figure 2). Here, the standard deviations represent the variation of the measured T2 value from one placenta to another. The standard error in individual T2 measures from a given ROI did not exceed more than 0.3 msec across all placentas evaluated. The average T2 value for the HPZ, measured across all placentas, was 60.76±4.07 msec on GD13, 59.85±5.77 msec on GD15 and 56.50±3.68 ms on GD17. Corresponding average T2 value for the LPZ was 40.67±3.74 msec on GD13, 37.13±5.67 msec on GD15 and 34.12±1.99 msec on GD17.

Table 2. Transverse relaxation, T2 in msec, of the individual compartments of the placenta across different gestational days.

Gestational Day Whole Placenta High Perfusion Zone Low perfusion Zone
Mean SD Mean SD Mean SD
13 46.23 4.20 60.76 4.07 40.67 3.74
15 42.19 6.60 59.85 5.77 37.13 5.67
17 39.08 1.67 56.50 3.68 34.12 1.99
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SD, standard deviation

T2 transverse relaxation time is represented in milliseconds as mean ± standard deviation.

Figure 1. T2 maps of the murine placenta shown across different gestational ages.

Figure 1

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The T2 weighted image of the murine placenta (top row) on GD13 (A), GD15 (B) and GD17 (C). Quantitative T2 map (bottom row) of the corresponding placenta is also shown. Note the contrast between the two constituent regions (High Perfusion Zone – red arrow; Low perfusion Zone – green arrow)

Figure 2. T2 murine placental transverse relaxation times at different gestational ages.

Figure 2

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T2 transverse relaxation times of the murine placenta on gestational day (GD) 13, GD15, and GD17 are represented in msec.

The three T2 values (the whole placenta, HPZ, and LPZ) over all the placentas from a given mouse at a given GD were averaged. Then a global LME model was built for these averaged T2 values with fixed effects including GD as a continuous linear predictor, the T2 values as a factor predictor and their interactions. From this model, the rate of T2 temporal change was estimated to be -1.85 msec/GD (p=4.36×10-6) for the whole placenta, -1.00 msec/GD (p=8.73×10-3) for the HPZ, and -1.66 msec/GD (p=3.12×10-5) for the LPZ (Figure 3). However, overall, there was no significant difference among the three rates (p=0.24). In particular, the difference between the rates of HPZ T2 and placental T2 was 0.85 (p=0.11), and the difference between the rates of LPZ T2 and placental T2 was 0.197 (p=0.71). Though not significant, the linear trend of placental T2 was closer to that of low perfusion zone T2.

Figure 3. Time-course plots of the averaged T2 transverse relaxation time across different regions of the placenta.

Figure 3

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Time course plots of the averaged T2 transverse relaxation time across the whole placenta (left), the high perfusion (middle) and the low perfusion zone (right). Each point corresponds to the average T2 of all placenta of a given mice at a gestational age. The different colors indicate different mice that were longitudinally followed. GA - gestational age.

The influence of maternal systemic changes was evaluated by analyzing the changes in the maternal muscle T2 across the three GDs. A repeated measure single factor analysis of variance (ANOVA) with Greenhouse-Geisser correction showed that the mean T2 values of maternal muscle were similar across the three GDs (p=0.76). This invariance of maternal muscle T2 across different gestation days indicates that the GD dependent change observed in the placental T2 values was not influenced by systemic changes in maternal physiology with advancing gestation.

Discussion

Principal findings of the study

1) Placental T2 values decrease with advancing gestation in normal murine pregnancy; 2) T2 values of both the HPZ and the LPZ decrease with gestation, with T2 value of LPZ lower than that of HPZ; and 3) The slope of linear decrease in T2 with GA for the whole placenta is closer to that of LPZ than the HPZ, although there is no significant difference among the trends for the three (HPZ, LPZ and whole placenta).

Our findings of a longitudinal decrease in the T2 relaxation parameter of the overall placenta with advancing GA are similar to that observed in the human placenta [36, 49]. In murine placenta, while a previous report quantified overall placental T2 in a cross sectional cohort [23], this is the first study reporting longitudinal T2 changes in the constituent zones of the murine placenta. Constituent functional zones of the placenta have been referred to as high and low perfusion regions in this work based on features observed in contrast enhanced studies reported in the mouse placenta [41, 50]. The high perfusion region roughly corresponds to the labyrinth zone and the low perfusion region to the junctional zone [41, 50].

The MRI relaxation parameter, T2, of a tissue depends on multiple parameters including presence of magnetic field perturbing inclusions like deoxygenated red-blood cells and their volume fraction within the tissue [51]. T2 also depends on diffusion characteristics of tissue water (restricted vs. freely diffusing). The equation that tersely summarizes these dependencies is given by [51-53]:

T2∝1v⋅(Δω)2⋅Da

Here, D is the diffusion coefficient of tissue water content, ν is the tissue volume fraction of the susceptibility inclusions that perturb the magnetic field, like deoxyhemoglobin, (for example - blood volume fraction); Δω is the parameter characterizing the magnitude of field perturbation from the susceptibility inclusions, which inversely relates to blood oxygen saturation. The exponent a depends on the physical nature of water diffusion in the tissue, restricted versus unrestricted [52]. The placenta is a highly vascularized organ containing both oxygenated and deoxygenated blood. A decrease in T2 observed in the whole placenta as well as its constituent functional compartments as a function of GA could be due to a change in one or more of these three tissue characteristics: (a) blood volume fraction (ν), (b) decreased oxygen saturation (i.e., decrease in 1/Δω), or (c) an increase in tissue water diffusion (D). The placental capillary density in mice is known to increase with advancing gestation with corresponding increase in capillary surface area to volume ratio [54, 55], thus increasing ν. This increase in blood volume fraction could lead to a corresponding decrease in T2, assuming that the other parameters of water diffusion (D) and blood oxygenation levels (1/Δω) remain the same. When compared with the literature, however, the % decrease in the T2 values observed in either the HPZ or the overall placenta in this study is much less than the % increase in the placental blood volume fraction reported [20, 55]. For example, an increase of 22% in blood volume fraction of the labyrinth zone was observed at GD17.5 relative to GD15.5 by Rennie et al. [55]. The corresponding % decrease in T2 of the HPZ observed in this study was only 5.6%. This indicates that the change in blood volume fraction may be accompanied with concomitant changes in the other parameters (Δω and D), that affect T2. This is conceivable since the thickness of interhemal membrane, which influences water diffusion between maternal and fetal blood spaces, also decreases with gestation [20, 55], leading to a theoretical increase in diffusion capacity (diffusion coefficient, D) with gestation [20]. Recent MR imaging based reports on the placental apparent diffusion coefficient (ADC), a measure of water diffusion in the whole placenta, however, showed no significant change with advancing gestation in both humans and mice [56, 57]. While these studies use relatively low resolution imaging and pertain to whole placental diffusion, a region-specific study of diffusion characteristics within the placenta, for example labyrinth vs. junctional, could help us in better observing their change trajectory as a function of gestational age. Lastly, how the parameter, 1/Δω, which is proportional to blood oxygenation, changes with advancing gestation within the whole placenta or in its constituent regions is unclear. Interestingly, a recent study in rats showed an increased % change in T2* (a parameter proportional to T2) of the HPZ compared to LPZ under maternal hyperoxygenation [58], indicating different baseline blood oxygenation levels in these compartments. Nevertheless, further studies quantifying blood oxygenation (1/Δω) of the constituent zones and its changes with advancing gestation are required. Quantitative susceptibility mapping techniques may have a role to play in such studies as they allow for non-invasive quantification of in vivo blood oxygenation [59-61].

On all the three GD investigated, we found that the T2 value of the HPZ (labyrinth) is higher than that of LPZ (junctional). The junctional zone (LPZ) in the murine placenta principally consists of spongiotrophoblasts lining the venous sinuses that contain deoxygenated maternal blood draining the labyrinth zone of the placenta [62, 63]. On the other hand, the labyrinth zone (HPZ) is the principal maternal-fetal exchange zone. Thus, while the labyrinth zone (HPZ), contains both oxygenated and deoxygenated blood fractions from the maternal and fetal circulation, the junctional zone (LPZ) predominantly contains predominantly deoxygenated blood. Consequently, the 1/Δω parameter (proportional to blood oxygenation) has a lower value in the junctional zone (LPZ) compared to the labyrinth zone (HPZ). This could explain the shorter T2 observed in the low-perfusion zone, in addition to the presence of glycogen rich cells [64]. Though not significant, the T2 change as a function of GA of the LPZ (-1.66 msec/GD) was closer to that of the whole placenta (-1.85 msec/GD) compared to HPZ (-1.0 msec/GD). The higher slope of the whole placental T2 can be attributed to the differential increase in the volume of the constituent regions [20, 50].

The ratio of the absolute T2 of high to low perfusion zones (T2high-perfusion/T2low-perfusion corresponding to T2labyrinth/T2junctional) at GD17 is found to be 1.7 in our study. In comparison, a cross-sectional study in mice reported this ratio to be 2.5 (at GD 17.5) [38]. This difference could largely be attributed to the magnetic strength at which imaging was carried out (7.0T in our study vs. 11.74T). Other factors leading to this difference could include the different strain of the mice studied (CD1 in our study vs. C57BL/6JArc) and differences in imaging resolution (i.e. effect of partial voluming). Furthermore, the T2 of blood decreases quadratically with magnetic field strength [65, 66] which in-turn could differentially affect the T2 value of placental tissue depending on the extent of its vascular density and oxygen saturation.

Systemic maternal cardiovascular factors could, in principle, influence the T2 values measured in the placenta. However, no significant change in maternal muscle tissue as a function of GA was observed in this study, indicating that maternal physiology did not change with GA, and our observations on alterations in T2 were due to placental developmental changes. Due to the functional dependence of T2 relaxation on parameters like blood oxygenation status, vascular density, volume and water diffusion in tissue [37, 52], it is found to be a significant parameter for the diagnosis of preeclampsia and IUGR [49]. However, the role of each of these functional parameters and their natural progression across gestation continues to be an active area of research. In pregnancies complicated by preeclampsia and IUGR, studies have demonstrated shorter placental T2 relaxation times [49, 67]. In this context, it becomes important to understand the physiological decrease in the relaxation time that can be attributed to GA. The results presented in this study quantify this change. Different regions of the placenta show differential development with progressing gestation [19] and thus might be affected differently when there is placental pathology. Hence, regional analysis of the T2 parameter was carried out in this study.

There are a few limitations in this study. The LME model used for the analysis assumes a linear relation between the T2 parameter and GA, the use of a non-linear model with a greater sample size across many gestational days might increase the sensitivity of the quantitative MR parameter. T2 measurements from the central slices of the placenta were used in this study with conservative ROI placements within constituent placental regions. During longitudinal scans of the same pregnant mice, identifications of the same set of placentas and fetuses between different GDs were not possible and remain a practical challenge [68]. Hence, the average data from a group of placentas, evaluated longitudinally, is presented. Nevertheless, this aspect should not affect the conclusions of this study because, despite some placenta-to-placenta variation of the measured T2 parameter, the changes with GA in both the placenta and its constituent regions were found to be significant.

Conclusions

Placental T2 relaxation times decrease with advancing gestation in murine pregnancy. Significant decrease in T2 values of the constituent high and low perfusion zones of the placenta is also observed and T2 value of low perfusion zone is smaller than that of the high perfusion zone across gestation. The absolute T2 value of low perfusion zone is closer to that of the whole placenta. Furthermore, while not statistically significant, the slope of the T2 vs. GA curve for the low perfusion zone (as opposed to the high perfusion zone) was closer to that observed in the whole placenta. These results indicate the increased role of the respective volume fractiosns of these constituent zones influencing the overall placental T2 vs. GA trajectory.

Acknowledgments

This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS); and, in part, with Federal funds from NICHD (NIH, DHHS) under Contract No. HHSN275201300006C. The authors are grateful to Dr. Theodore Price (Perinatology Research Branch), Dr. Lisa J. Brossia-Root, Laura Lee McIntyre, and all personal involved in the Division of Laboratory Animal Resources (Wayne State University). This research and writing of the manuscript was also supported in part by a Small Business Technology Transfer (STTR) grant from the National Heart, Lung, and Blood Institute (NHLBI, NIH, DHHS; 1R42HL112580-01A1), by Wayne State University's Perinatal Research Initiative and Perinatology Virtual Discovery Grant to J.N. (made possible by the W.K. Kellogg Foundation award P3018205). U.K. was a recipient of Thomas C. Rumble fellowship from Wayne State University. N.G.T. is the recipient of the Hungarian Academy of Sciences Momentum Grant (#LP2014-7/2014).

Parts of the data reported in this paper were presented as a poster at the “Joint Annual Meeting of the International Society of Magnetic Resonance in Medicine and European Society of Magnetic Resonance in Medicine and Biology” in Milan, Italy, May10-16, 2014

Footnotes

Disclosure/Conflicts of Interest: The authors have no conflicts of interest.

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