Velocity-selective arterial spin labeling perfusion measurements in 2nd trimester human placenta with varying BMI.

INTRODUCTION: Proper placental development is crucial to fetal health but is challenging to functionally assess non-invasively and is thus poorly characterized in populations. Body mass index (BMI) has been linked with adverse outcomes, but the causative mechanism is uncertain. Velocity-selective arterial spin labeling (VS-ASL) MRI provides a method to non-invasively measure placental perfusion with robustness to confounding transit time delays. In this study, we report on the measurement of perfusion in the human placenta in early pregnancy using velocity-selective arterial spin labeling (VS-ASL) MRI, comparing non-obese and obese participants. METHODS: Participants (N = 97) undergoing routine prenatal care were recruited and imaged with structural and VS-ASL perfusion MRI at 15 and 21 weeks gestation. Resulting perfusion images were analyzed with respect to obesity based on BMI, gestational age, and the presence of adverse outcomes. RESULTS: At 15 weeks gestation BMI was not associated with placental perfusion or perfusion heterogeneity. However, at 21 weeks gestation BMI was associated with higher placental perfusion (p < 0.01) and a decrease in perfusion heterogeneity (p < 0.05). In alignment with past studies, perfusion values were also higher at 21 weeks compared to 15 weeks gestation. In a small cohort of participants with adverse outcomes, at 21 weeks lower perfusion was observed compared to participants with uncomplicated pregnancies. DISCUSSION: These results suggest low placental perfusion in the early second trimester may not be the culpable factor driving associations of obesity with adverse outcomes.

Human prostate MRI at ultrahigh-performance gradient: A feasibility study.

PURPOSE: To demonstrate the technical feasibility and the value of ultrahigh-performance gradient in imaging the prostate in a 3T MRI system. METHODS: In this local institutional review board-approved study, prostate MRI was performed on 4 healthy men. Each subject was scanned in a prototype 3T MRI system with a 42-cm inner-diameter gradient coil that achieves a maximum gradient amplitude of 200 mT/m and slew rate of 500 T/m/s. PI-RADS V2.1-compliant axial T2 -weighted anatomical imaging and single-shot echo planar DWI at standard gradient of 70 mT/m and 150 T/m/s were obtained, followed by DWI at maximum performance (i.e., 200 mT/m and 500 T/m/s). In comparison to state-of-the-art clinical whole-body MRI systems, the high slew rate improved echo spacing from 1020 to 596 µs and, together with a high gradient amplitude for diffusion encoding, TE was reduced from 55 to 36 ms. RESULTS: In all 4 subjects (waist circumference = 81-91 cm, age = 45-65 years), no peripheral nerve stimulation sensation was reported during DWI. Reduced image distortion in the posterior peripheral zone prostate gland and higher signal intensity, such as in the surrounding muscle of high-gradient DWI, were noted. CONCLUSION: Human prostate MRI at simultaneously high gradient amplitude of 200 mT/m and slew rate of 500 T/m/s is feasible, demonstrating that improved gradient performance can address image distortion and T2 decay-induced SNR issues for in vivo prostate imaging.

Diffusion MRI with free gradient waveforms on a high-performance gradient system: Probing restriction and exchange in the human brain.

The dependence of the diffusion MRI signal on the diffusion time carries signatures of restricted diffusion and exchange. Here we seek to highlight these signatures in the human brain by performing experiments using free gradient waveforms designed to be selectively sensitive to the two effects. We examine six healthy volunteers using both strong and ultra-strong gradients (80, 200 and 300 mT/m). In an experiment featuring a large set of 150 gradient waveforms with different sensitivities to restricted diffusion and exchange, our results reveal unique and different time-dependence signatures in grey and white matter. Grey matter was characterised by both restricted diffusion and exchange and white matter predominantly by restricted diffusion. Exchange in grey matter was at least twice as fast as in white matter, across all subjects and all gradient strengths. The cerebellar cortex featured relatively short exchange times (115 ms). Furthermore, we show that gradient waveforms with tailored designs can be used to map exchange in the human brain. We also assessed the feasibility of clinical applications of the method used in this work and found that the exchange-related contrast obtained with a 25-minute protocol at 300 mT/m was preserved in a 4-minute protocol at 300 mT/m and a 10-minute protocol at 80 mT/m. Our work underlines the utility of free waveforms for detecting time dependence signatures due to restricted diffusion and exchange in vivo, which may potentially serve as a tool for studying diseased tissue.

Frequency-dependent diffusion kurtosis imaging in the human brain using an oscillating gradient spin echo sequence and a high-performance head-only gradient.

Measuring the time/frequency dependence of diffusion MRI is a promising approach to distinguish between the effects of different tissue microenvironments, such as membrane restriction, tissue heterogeneity, and compartmental water exchange. In this study, we measure the frequency dependence of diffusivity (D) and kurtosis (K) with oscillating gradient diffusion encoding waveforms and a diffusion kurtosis imaging (DKI) model in human brains using a high-performance, head-only MAGNUS gradient system, with a combination of b-values, oscillating frequencies (f), and echo time that has not been achieved in human studies before. Frequency dependence of diffusivity and kurtosis are observed in both global and local white matter (WM) and gray matter (GM) regions and characterized with a power-law model ∼Λ*fθ. The frequency dependences of diffusivity and kurtosis (including changes between fmin and fmax, Λ, and θ) vary over different WM and GM regions, indicating potential microstructural differences between regions. A trend of decreasing kurtosis over frequency in the short-time limit is successfully captured for in vivo human brains. The effects of gradient nonlinearity (GNL) on frequency-dependent diffusivity and kurtosis measurements are investigated and corrected. Our results show that the GNL has prominent scaling effects on the measured diffusivity values (3.5∼5.5% difference in the global WM and 6∼8% difference in the global cortex) and subsequently affects the corresponding power-law parameters (Λ, θ) while having a marginal influence on the measured kurtosis values (<0.05% difference) and power-law parameters (Λ, θ). This study expands previous OGSE studies and further demonstrates the translatability of frequency-dependent diffusivity and kurtosis measurements to human brains, which may provide new opportunities to probe human brain microstructure in health and disease.

Revealing tumor microstructure with oscillating diffusion encoding MRI in pre-surgical and post-treatment glioma patients.

PURPOSE: We hypothesized that the time-dependent diffusivity at short diffusion times, as measured by oscillating gradient spin echo (OGSE) diffusion MRI, can characterize tissue microstructures in glioma patients. THEORY AND METHODS: Five adult patients with known diffuse glioma, including two pre-surgical and three with new enhancing lesions after treatment for high-grade glioma, were scanned in an ultra-high-performance gradient 3.0T MRI system. OGSE diffusion MRI at 30-100 Hz and pulsed gradient spin echo diffusion imaging (approximated as 0 Hz) were obtained. The ADC and trace-diffusion-weighted image at each acquired frequency were calculated, that is, ADC (f) and TraceDWI (f). RESULTS: In pre-surgical patients, biopsy-confirmed solid enhancing tumor in a high-grade glioblastoma showed higher ADC ( f ) ADC ( 0 Hz ) $$ \frac{\mathrm{ADC}\ (f)}{\mathrm{ADC}\ \left(0\ \mathrm{Hz}\right)} $$ and lower TraceDWI ( f ) TraceDWI ( 0 Hz ) $$ \frac{\mathrm{TraceDWI}\ (f)}{\mathrm{TraceDWI}\ \left(0\ \mathrm{Hz}\right)} $$ , compared to that at same OGSE frequency in a low-grade astrocytoma. In post-treatment patients, the enhancing lesions of two patients who were diagnosed with tumor progression contained more voxels with high ADC ( f ) ADC ( 0 Hz ) $$ \frac{\mathrm{ADC}\ (f)}{\mathrm{ADC}\ \left(0\ \mathrm{Hz}\right)} $$ and low TraceDWI ( f ) TraceDWI ( 0 Hz ) $$ \frac{\mathrm{TraceDWI}\left(\mathrm{f}\right)}{\mathrm{TraceDWI}\left(0\ \mathrm{Hz}\right)} $$ , compared to the enhancing lesions of a patient who was diagnosed with treatment effect. Non-enhancing T2 signal abnormality lesions in both the pre-surgical high-grade glioblastoma and post-treatment tumor progressions showed regions with high ADC ( f ) ADC ( 0 Hz ) $$ \frac{\mathrm{ADC}\ (f)}{\mathrm{ADC}\ \left(0\ \mathrm{Hz}\right)} $$ and low TraceDWI ( f ) TraceDWI ( 0 Hz ) $$ \frac{\mathrm{TraceDWI}\ \left(\mathrm{f}\right)}{\mathrm{TraceDWI}\ \left(0\ \mathrm{Hz}\right)} $$ , consistent with infiltrative tumor. The solid tumor of the glioblastoma, the enhancing lesions of post-treatment tumor progressions, and the suspected infiltrative tumors showed high diffusion time-dependency from 30 to 100 Hz, consistent with high intra-tumoral volume fraction (cellular density). CONCLUSION: Different characteristics of OGSE-based time-dependent diffusivity can reveal heterogenous tissue microstructures that indicate cellular density in glioma patients.

Diffusion MRI with free gradient waveforms on a high-performance gradient system: Probing restriction and exchange in the human brain.

The dependence of the diffusion MRI signal on the diffusion time carries signatures of restricted diffusion and exchange. Here we seek to highlight these signatures in the human brain by performing experiments using free gradient waveforms that are selectively sensitive to the two effects. We examine six healthy volunteers using both strong and ultra-strong gradients (80, 200 and 300 mT/m). In an experiment featuring a large set of gradient waveforms with different sensitivities to restricted diffusion and exchange (150 samples), our results reveal unique time-dependence signatures in grey and white matter, where the former is characterised by both restricted diffusion and exchange and the latter predominantly exhibits restricted diffusion. Furthermore, we show that gradient waveforms with independently varying sensitivities to restricted diffusion and exchange can be used to map exchange in the human brain. We consistently find that exchange in grey matter is at least twice as fast as in white matter, across all subjects and all gradient strengths. The shortest exchange times observed in this study were in the cerebellar cortex (115 ms). We also assess the feasibility of future clinical applications of the method used in this work, where we find that the grey-white matter exchange contrast obtained with a 25-minute 300 mT/m protocol is preserved by a 4-minute 300 mT/m and a 10-minute 80 mT/m protocol. Our work underlines the utility of free waveforms for detecting time-dependence signatures due to restricted diffusion and exchange in vivo, which may potentially serve as a tool for studying diseased tissue.

Ferumoxytol dynamic contrast enhanced magnetic resonance imaging identifies altered placental cotyledon perfusion in rhesus macaques†.

Identification of placental dysfunction in early pregnancy with noninvasive imaging could be a valuable tool for assessing maternal and fetal risk. Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) can be a powerful tool for interrogating placenta health. After inoculation with Zika virus or sham inoculation at gestation age (GA) 45 or 55 days, animals were imaged up to three times at GA65, GA100, and GA145. DCE MRI images were acquired at all imaging sessions using ferumoxytol, an iron nanoparticle-based contrast agent, and analyzed for placental intervillous blood flow, number of perfusion domains, and perfusion domain volume. Cesarean section was performed at GA155, and the placenta was photographed and dissected for histopathology. Photographs were used to align cotyledons with estimated perfusion domains from MRI, allowing comparison of estimated cotyledon volume to pathology. Monkeys were separated into high and low pathology groups based on the average number of pathologies present in the placenta. Perfusion domain flow, volume, and number increased through gestation, and total blood flow increased with gestation for both low pathology and high pathology groups. A statistically significant decrease in perfusion domain volume associated with pathology was detected at all gestational ages. Individual perfusion domain flow comparisons demonstrated a statistically significant decrease with pathology at GA100 and GA145, but not GA65. Since ferumoxytol is currently used to treat anemia during human pregnancy and as an off-label MRI contrast agent, future transition of this work to human pregnancy may be possible.

Free-breathing liver fat and R2∗ quantification using motion-corrected averaging based on a nonlocal means algorithm.

PURPOSE: To propose a motion-robust chemical shift-encoded (CSE) method with high signal-to-noise (SNR) for accurate quantification of liver proton density fat fraction (PDFF) and R2∗ . METHODS: A free-breathing multi-repetition 2D CSE acquisition with motion-corrected averaging using nonlocal means (NLM) was proposed. PDFF and R2∗ quantified with 2D CSE-NLM were compared to two alternative 2D techniques: direct averaging and single acquisition (2D 1ave) in a digital phantom. Further, 2D NLM was compared in patients to 3D techniques (standard breath-hold, free-breathing and navigated), and the alternative 2D techniques. A reader study and quantitative analysis (Bland-Altman, correlation analysis, paired Student's t-test) were performed to evaluate the image quality and assess PDFF and R2∗ measurements in regions of interest. RESULTS: In simulations, 2D NLM resulted in lower standard deviations (STDs) of PDFF (2.7%) and R2∗ (8.2  s-1 ) compared to direct averaging (PDFF: 3.1%, R2∗ : 13.6  s-1 ) and 2D 1ave (PDFF: 8.7%, R2∗ : 33.2  s-1 ). In patients, 2D NLM resulted in fewer motion artifacts than 3D free-breathing and 3D navigated, less signal loss than 2D direct averaging, and higher SNR than 2D 1ave. Quantitatively, the STDs of PDFF and R2∗ of 2D NLM were comparable to those of 2D direct averaging (p>0.05). 2D NLM reduced bias, particularly in R2∗ (-5.73 to -0.36  s-1 ) that arises in direct averaging (-3.96 to 11.22  s-1 ) in the presence of motion. CONCLUSIONS: 2D CSE-NLM enables accurate mapping of PDFF and R2∗ in the liver during free-breathing.

Center-out EPI (COEPI): A fast single-shot imaging technique with a short TE.

PURPOSE: To develop a center-out echo planar imaging (COEPI) acquisition technique to increase SNR through minimizing the TE. METHODS: In single-shot COEPI, the phase-encoding starts from the center (ky = 0) toward both sides of k-space to substantially shorten the TE compared to the conventional single-shot EPI. The phase-encoding gradient waveform is partially overlapped with the frequency-encoding gradient waveform to keep the echo spacing constant during the echo train readout. A reconstruction pipeline was developed to correct for phase and off-resonance errors in COEPI. Gradient-recalled echo (GRE), spin echo (SE), and DWI COEPI were obtained in phantoms and healthy brains at 1.5 tesla (T) and 3.0T. The SNR in COEPI and single-shot partial ky EPI was compared. RESULTS: Acquisition matrix of 128 × 80 (16 overscan lines) was obtained in both COEPI and EPI. At 1.5T/3.0T, a minimum TE of 3 ms/4 ms in GRE-COEPI, 11 ms/12 ms in SE-COEPI, and 40 ms in DWI-COEPI (3.0T only, maximum b value = 2000 s/mm2 ) was achieved, compared to a minimum TE of 18 ms/16 ms in GRE-EPI, 37 ms/34 ms in SE-EPI, and 66 ms in DWI-EPI, respectively. Image blurring and Nyquist ghost appear in COEPI and were substantially reduced after corrections. At 1.5T/3.0T, a SNR increase of 27.7% ± 6.9%/20.7% ± 7.0% in GRE-COEPI and 37.7% ± 5.7%/28.2% ± 1.3% in SE-COEPI was observed in white matter of human brains, compared to GRE-EPI and SE-EPI, respectively. At 3.0T, a SNR increase of 41.2% ± 4.1% in DWI-COEPI was observed in white matter of 5 subjects at 5 b values (0~2000 s/mm2 ), compared to DWI-EPI. CONCLUSION: The feasibility of COEPI and its SNR benefit were demonstrated in this study.

Impact of ferumoxytol magnetic resonance imaging on the rhesus macaque maternal-fetal interface†.

Ferumoxytol is a superparamagnetic iron oxide nanoparticle used off-label as an intravascular magnetic resonance imaging (MRI) contrast agent. Additionally, ferumoxytol-uptake by macrophages facilitates detection of inflammatory sites by MRI through ferumoxytol-induced image contrast changes. Therefore, ferumoxytol-enhanced MRI holds great potential for assessing vascular function and inflammatory response, critical to determine placental health in pregnancy. This study sought to assess the fetoplacental unit and selected maternal tissues, pregnancy outcomes, and fetal well-being after ferumoxytol administration. In initial developmental studies, seven pregnant rhesus macaques were imaged with or without ferumoxytol administration. Pregnancies went to term with vaginal delivery and infants showed normal growth rates compared to control animals born the same year that did not undergo MRI. To determine the impact of ferumoxytol on the maternal-fetal interface (MFI), fetal well-being, and pregnancy outcome, four pregnant rhesus macaques at ~100 gestational day underwent MRI before and after ferumoxytol administration. Collection of the fetoplacental unit and selected maternal tissues was performed 2-3 days following ferumoxytol administration. A control group that did not receive ferumoxytol or MRI was used for comparison. Iron levels in fetal and MFI tissues did not differ between groups, and there was no significant difference in tissue histopathology with or without exposure to ferumoxytol, and no effect on placental hormone secretion. Together, these results suggest that the use of ferumoxytol and MRI in pregnant rhesus macaques does not negatively impact the MFI and can be a valuable experimental tool in research with this important animal model.

Evaluation of a motion-robust 2D chemical shift-encoded technique for R2* and field map quantification in ferumoxytol-enhanced MRI of the placenta in pregnant rhesus macaques.

BACKGROUND: 3D chemical shift-encoded (CSE)-MRI techniques enable assessment of ferumoxytol concentration but are unreliable in the presence of motion. PURPOSE: To evaluate a motion-robust 2D-sequential CSE-MRI for R2* and B0 mapping in ferumoxytol-enhanced MRI of the placenta. STUDY TYPE: Prospective. ANIMAL MODEL: Pregnant rhesus macaques. FIELD STRENGTH/SEQUENCE: 3.0T/CSE-MRI. ASSESSMENT: 2D-sequential CSE-MRI was compared with 3D respiratory-gated CSE-MRI in placental imaging of 11 anesthetized animals at multiple timepoints before and after ferumoxytol administration, and in ferumoxytol phantoms (0 µg/mL-440 µg/mL). Motion artifacts of CSE-MRI in 10 pregnant women without ferumoxytol administration were assessed retrospectively by three blinded readers (4-point Likert scale). The repeatability of CSE-MRI in seven pregnant women was also prospectively studied. STATISTICAL TESTS: Placental R2* and boundary B0 field measurements (ΔB0) were compared between 2D-sequential and 3D respiratory-gated CSE-MRI using linear regression and Bland-Altman analysis. RESULTS: In phantoms, a slope of 0.94 (r2 = 0.99, concordance correlation coefficient ρ = 0.99), and bias of -4.8 s-1 (limit of agreement [LOA], -41.4 s-1 , +31.8 s-1 ) in R2*, and a slope of 1.07 (r2 = 1.00, ρ = 0.99) and bias of 11.4 Hz (LOA -12.0 Hz, +34.8 Hz) in ΔB0 were obtained in 2D CSE-MRI compared with 3D CSE-MRI for reference R2* ≤390 s-1 . In animals, a slope of 0.92 (r2 = 0.97, ρ = 0.98) and bias of -2.2 s-1 (LOA -55.6 s-1 , +51.3 s-1 ) in R2*, and a slope of 1.05 (r2 = 0.95, ρ = 0.97) and bias of 0.4 Hz (LOA -9.0 Hz, +9.7 Hz) in ΔB0 were obtained. In humans, motion-impaired R2* maps in 3D CSE-MRI (Reader 1: 1.8 ± 0.6, Reader 2: 1.3 ± 0.7, Reader 3: 1.9 ± 0.6), while 2D CSE-MRI was motion-free (Reader 1: 2.9 ± 0.3, Reader 2: 3.0 ± 0, Reader 3: 3.0 ± 0). A mean difference of 0.66 s-1 and coefficient of repeatability of 9.48 s-1 for placental R2* were observed in the repeated 2D CSE-MRI. DATA CONCLUSION: 2D-sequential CSE-MRI provides accurate R2* and B0 measurements in ferumoxytol-enhanced placental MRI of animals in the presence of respiratory motion, and motion-robustness in human placental imaging. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:580-592.

Quantitative ferumoxytol-enhanced MRI in pregnancy: A feasibility study in the nonhuman primate.

OBJECTIVES: To assess the feasibility of ferumoxytol-enhanced MRI in pregnancy with a nonhuman primate model. MATERIALS AND METHODS: In this prospective study, eleven pregnant rhesus macaques at day 98 ±â€¯5 of gestation were divided into three groups, untreated control (UC) (n = 3), saline control (SC) (n = 4) and interleukin 1 beta (IL-1ß) treated (IT) (n = 4), which were administered with either saline or IL-1ß into the amniotic fluid. All animals were imaged at multiple time points before and after ferumoxytol administration (4 mg/kg). Longitudinal R2* and susceptibility of tissues were obtained using region-of-interest analysis and the longitudinal changes were assessed using linear mixed models and Student's t-test. RESULTS: In fetuses, a slope of 0.3 s-1/day (P = 0.008), 0.00 ppm/day (P = 0.699) and - 0.2 s-1/day (P = 0.023) was observed in liver R2*, liver susceptibility, and lung R2*, respectively. In placentas, R2* and susceptibility increased immediately after ferumoxytol administration (P < 0.001) and decreased to baseline within two days. The mean change from baseline showed no significant difference between the SC group and the IT group at all scan time points. In maternal livers, R2* increased immediately after ferumoxytol administration, further increased at one-day, and then decreased but remained elevated (P < 0.001). The mean change from baseline showed no significant difference between the SC group and the IT group at all scan time points. CONCLUSIONS: This work demonstrates the feasibility of quantitative ferumoxytol-enhanced MRI to measure dynamics of ferumoxytol delivery and washout in the placenta. Stable MRI measurements indicated no evidence of iron deposition in fetal tissues of nonhuman primates after maternal ferumoxytol exposure.

Characterizing a short T2 * signal component in the liver using ultrashort TE chemical shift-encoded MRI at 1.5T and 3.0T.

PURPOSE: Recent studies have suggested the presence of short-T2 * signals in the liver, which may confound chemical shift-encoded (CSE) fat quantification when using short echo times (TEs). The purpose of this study was to characterize the liver signal at short echo times and to determine its impact on liver fat quantification. METHODS: An ultrashort echo time (UTE) chemical shift-encoded MRI (CSE-MRI) technique and a multicomponent reconstruction were developed to characterize short-T2 * liver signals. Subsequently, liver fat fraction was quantified using a short-TE (first TE = 0.7 ms) and UTE CSE-MRI acquisitions and compared with a standard CSE-MRI (first TE = 1.2 ms). RESULTS: Short-T2 * signals were consistently observed in the liver of all healthy volunteers imaged at both 1.5T and 3.0T. At 3.0T, short-T2 * signal fractions of 9.6 ± 1.5%, 7.0 ± 1.7%, and 7.4 ± 1.7% with T2 * of 0.23 ± 0.05 ms, 0.20 ± 0.05 ms, and 0.10 ± 0.02 ms were measured in healthy volunteers, patients with liver cirrhotic disease, and patients with hepatic steatosis (but no cirrhosis), respectively. For proton density fat fraction (PDFF) estimation, 1.7% (P < .01) and 3.4% (P < .01) biases were observed in subjects imaged using short-TE CSE-MRI and using UTE CSE-MRI at 1.5T, respectively. The biases were reduced to 0.4% and -0.7%, respectively, by excluding short echoes less than 1 ms. A 3.2% bias (P < .01) was observed in subjects imaged using UTE CSE-MRI at 3.0T, which was reduced to 0.1% by excluding short echoes <1 ms. CONCLUSIONS: A liver short-T2 * signal component was consistently observed and was shown to confound liver fat quantification when short echo times were used with CSE-MRI.

Enantioselective Hydrogenation of Racemic α-Arylamino Lactones to Chiral Amino Diols with Site-Specifically Modified Chiral Spiro Iridium Catalysts.

A protocol for highly enantioselective hydrogenation of racemic α-arylamino lactones with catalysis by site-specifically modified chiral spiro iridium complexes has been developed. With the optimized catalyst, racemic α-arylamino-γ-lactones and α-arylamino-δ-lactones could be hydrogenated to the corresponding chiral 2-amino diols with good to excellent enantioselectivities.

Computation of exact g-factor maps in 3D GRAPPA reconstructions.

PURPOSE: To characterize the noise distributions in 3D-MRI accelerated acquisitions reconstructed with GRAPPA using an exact noise propagation analysis that operates directly in k-space. THEORY AND METHODS: We exploit the extensive symmetries and separability in the reconstruction steps to account for the correlation between all the acquired k-space samples. Monte Carlo simulations and multi-repetition phantom experiments were conducted to test both the accuracy and feasibility of the proposed method; a high-resolution in-vivo experiment was performed to assess the applicability of our method to clinical scenarios. RESULTS: Our theoretical derivation shows that the direct k-space analysis renders an exact noise characterization under the assumptions of stationarity and uncorrelation in the original k-space. Simulations and phantom experiments provide empirical support to the theoretical proof. Finally, the high-resolution in-vivo experiment demonstrates the ability of the proposed method to assess the impact of the sub-sampling pattern on the overall noise behavior. CONCLUSIONS: By operating directly in the k-space, the proposed method is able to provide an exact characterization of noise for any Cartesian pattern sub-sampled along the two phase-encoding directions. Exploitation of the symmetries and separability into independent blocks through the image reconstruction procedure allows us to overcome the computational challenges related to the very large size of the covariance matrices involved.