Rapid and quantitative CEST-MRI sequence using water presaturation.

PURPOSE: Despite the significant potential for in vivo metabolic imaging in preclinical and clinical applications, CEST MRI suffers from long scan time and inaccurate quantification. This study aims to suppress the contaminations among signals under different frequencies, which could shorten the TR and thereby facilitate CEST imaging acceleration and quantification. METHODS: A novel sequence is proposed by applying a water-presaturation (WPS) module at the beginning of each TR. WPS CEST quickly knocks down the residual signal from previous TRs so that the magnetization of all TRs recovers from zero, which aligns well with the formula of quasi-steady-state theorem and enables accurate quantification within shorter TR. WPS CEST was assessed by simulations, creatine phantom, and healthy human brain scans at 3 T. RESULTS: In simulation and phantom experiment, WPS CEST allows accurate estimation of exchange rate (ksw) using omega plot and using shorter delay time (Td) and saturation time (Ts) (e.g., 1 s/1 s) compared with the conventional CEST. Simulations further showed that WPS CEST could obtain consistent spin-lock relaxation (R1ρ) values over varied Tds and Tss. Six human scans indicated that R1ρ collected from conventional sequences showed significant differences between two groups with Td and Ts of (1 s/1 s) and (2 s/2 s) (amide: 1.721 ± 0.051 s-1 vs. 1.622 ± 0.050 s-1, p = 0.001; nuclear Overhauser enhancement: 1.792 ± 0.046 s-1 vs. 1.687 ± 0.053 s-1, p = 0.004), whereas WPS CEST scans using these 2 Td/Ts values obtained the same mean R1ρ (amide: 1.616 ± 0.053 s-1 vs. 1.616 ± 0.048 s-1, p = 0.862; nuclear Overhauser enhancement: 1.688 ± 0.064 s-1 vs. 1.684 ± 0.054 s-1, p = 0.544). CONCLUSION: WPS CEST demonstrated accurate quantitation within shorter TR compared with conventional sequences, and thereby may allow rapid quantitative CEST scans in various situations.

Adjustment of rotation and saturation effects (AROSE) for CEST imaging.

PURPOSE: Endogenous CEST signal usually has low specificity due to contaminations from the magnetization transfer contrast (MTC) and other labile protons with overlapping or close Larmor frequencies. We propose to improve CEST signal specificity with adjustment of rotation and saturation effects (AROSE). METHODS: The AROSE approach measures the difference between CEST signals acquired with the same average irradiation power but largely different duty cycles, for example, a continuous wave or a high duty cycle pulse train versus a low duty cycle pulse train with a flip angle φ. Simulation, phantom, and in vivo rodent studies were performed to evaluate the characteristics of the AROSEφ signal. RESULTS: Simulation and experimental results show that AROSE2π is a low-pass filter that can suppress fast exchanging processes (e.g., >3000 s-1 ), whereas AROSEπ is a band-pass filter suppressing both fast and slow exchange (e.g., <30 s-1 ) rates. For other φ angles, the sensitivity and the exchange-rate filtering effect of AROSEφ falls between AROSEπ and AROSE2π . AROSE can also minimize MTC and improve the Larmor frequency selectivity of the CEST signal. The linewidth of the AROSE1.5π spectrum is about 60% to 65% when compared to the CEST spectrum measured by continuous wave. Depending on the needs of an application, the sensitivity, exchange-rate filtering, and Larmor frequency selectivity can be adjusted by varying the flip angle, duty cycle, and average irradiation power. CONCLUSION: Compared to conventional CEST signals, AROSE can minimize MTC and improve exchange rate filtering and Larmor frequency specificity.

Whole-cerebrum guanidino and amide CEST mapping at 3 T by a 3D stack-of-spirals gradient echo acquisition.

PURPOSE: To develop a 3D, high-sensitivity CEST mapping technique based on the 3D stack-of-spirals (SOS) gradient echo readout, the proposed approach was compared with conventional acquisition techniques and evaluated for its efficacy in concurrently mapping of guanidino (Guan) and amide CEST in human brain at 3 T, leveraging the polynomial Lorentzian line-shape fitting (PLOF) method. METHODS: Saturation time and recovery delay were optimized to achieve maximum CEST time efficiency. The 3DSOS method was compared with segmented 3D EPI (3DEPI), turbo spin echo, and gradient- and spin-echo techniques. Image quality, temporal SNR (tSNR), and test-retest reliability were assessed. Maps of Guan and amide CEST derived from 3DSOS were demonstrated on a low-grade glioma patient. RESULTS: The optimized recovery delay/saturation time was determined to be 1.4/2 s for Guan and amide CEST. In addition to nearly doubling the slice number, the gradient echo techniques also outperformed spin echo sequences in tSNR: 3DEPI (193.8 ± 6.6), 3DSOS (173.9 ± 5.6), and GRASE (141.0 ± 2.7). 3DSOS, compared with 3DEPI, demonstrated comparable GuanCEST signal in gray matter (GM) (3DSOS: [2.14%-2.59%] vs. 3DEPI: [2.15%-2.61%]), and white matter (WM) (3DSOS: [1.49%-2.11%] vs. 3DEPI: [1.64%-2.09%]). 3DSOS also achieves significantly higher amideCEST in both GM (3DSOS: [2.29%-3.00%] vs. 3DEPI: [2.06%-2.92%]) and WM (3DSOS: [2.23%-2.66%] vs. 3DEPI: [1.95%-2.57%]). 3DSOS outperforms 3DEPI in terms of scan-rescan reliability (correlation coefficient: 3DSOS: 0.58-0.96 vs. 3DEPI: -0.02 to 0.75) and robustness to motion as well. CONCLUSION: The 3DSOS CEST technique shows promise for whole-cerebrum CEST imaging, offering uniform contrast and robustness against motion artifacts.

Creatine mapping of the brain at 3T by CEST MRI.

PURPOSE: To assess the feasibility of CEST-based creatine (Cr) mapping in brain at 3T using the guanidino (Guan) proton resonance. METHODS: Wild type and knockout mice with guanidinoacetate N-methyltransferase deficiency and low Cr and phosphocreatine (PCr) concentrations in the brain were used to assign the Cr and protein-based arginine contributions to the GuanCEST signal at 2.0 ppm. To quantify the Cr proton exchange rate, two-step Bloch-McConnell fitting was used to fit the extracted CrCEST line-shape and multi-B1 Z-spectral data. The pH response of GuanCEST was simulated to demonstrate its potential for pH mapping. RESULTS: Brain Z-spectra of wild type and guanidinoacetate N-methyltransferase deficiency mice show a clear Guan proton peak at 2.0 ppm at 3T. The CrCEST signal contributes ∼23% to the GuanCEST signal at B1 = 0.8 µT, where a maximum CrCEST effect of 0.007 was detected. An exchange rate range of 200-300 s-1 was estimated for the Cr Guan protons. As revealed by the simulation, an elevated GuanCEST in the brain is observed when B1 is less than 0.4 µT at 3T, when intracellular pH reduces by 0.2. Conversely, the GuanCEST decreases when B1 is greater than 0.4 µT with the same pH drop. CONCLUSIONS: CrCEST mapping is possible at 3T, which has potential for detecting intracellular pH and Cr concentration in brain.

Net O2 exchange rates under dark and light conditions across different stem compartments.

Woody plants display some photosynthetic activity in stems, but the biological role of stem photosynthesis and the specific contributions of bark and wood to carbon uptake and oxygen evolution remain poorly understood. We aimed to elucidate the functional characteristics of chloroplasts in stems of different ages in Fraxinus ornus. Our investigation employed diverse experimental approaches, including microsensor technology to assess oxygen production rates in whole stem, bark, and wood separately. Additionally, we utilized fluorescence lifetime imaging microscopy (FLIM) to characterize the relative abundance of photosystems I and II (PSI : PSII chlorophyll ratio) in bark and wood. Our findings revealed light-induced increases in O2 production in whole stem, bark, and wood. We present the radial profile of O2 production in F. ornus stems, demonstrating the capability of stem chloroplasts to perform light-dependent electron transport. Younger stems exhibited higher light-induced O2 production and dark respiration rates than older ones. While bark emerged as the primary contributor to net O2 production under light conditions, our data underscored that wood chloroplasts are also photosynthetically active. The FLIM analysis unveiled a lower PSI abundance in wood than in bark, suggesting stem chloroplasts are not only active but also acclimate to the spectral composition of light reaching inner compartments.

Filter-exchange spectroscopy is sensitive to gradual cell membrane degradation.

Transmembrane water permeability changes occur after initialization of necrosis and are a mechanism for early detection of cell death. Filter-exchange spectroscopy (FEXSY) is sensitive to transmembrane water permeability and enables its quantification by magnetic resonance via the apparent exchange rate (AXR). In this study, we investigate AXR changes during necrotic cell death. FEXSY measurements of yeast cells in different necrotic stages were performed and compared with established fluorescence cell death markers and pulsed gradient spin echo measurements. Furthermore, the influence of T2 relaxation on AXR was examined in a two-compartment system. The AXR of yeast cells increased slightly after incubation with 20% isopropanol, whereas it peaked sharply after incubation with 25% isopropanol. At this point, almost all the yeast cells were vital but showed compromised membranes. After incubation with 30% isopropanol, AXR measurements showed high variability, at a point corresponding to a majority of the yeast cells being in late-stage necrosis with disrupted cell membranes. Simulations revealed that, for FEXSY measurements in a two-compartment system, a long filter echo time (TEf), compared with the T2 of the slow-diffusing compartment, filters out a fraction of the slow-diffusing compartment signal and leads to overestimation of apparent diffusion coefficient (ADC) and underestimation of AXR. Our results demonstrate that AXR is sensitive to gradual permeabilization of the cell membrane of living cells in different permeabilization stages without exogenous contrast agents. AXR measurements were sensitive to permeability changes induced by relatively low concentrations of isopropanol, at levels for which no measurable effect was detectable by ADC measurements. TEf may act as a signal filter that affects the estimated AXR value of a system consisting of a variety of local diffusivities and a range of T2 that includes T2 values shorter or comparable with the TEf.

pH Mapping of Gliomas Using Quantitative Chemical Exchange Saturation Transfer MRI: Quasi-Steady-State, Spillover-, and MT-Corrected Omega Plot Analysis.

BACKGROUND: Quantitative in-situ pH mapping of gliomas is important for therapeutic interventions, given its significant association with tumor progression, invasion, and metastasis. Although chemical exchange saturation transfer (CEST) offers a noninvasive way for pH imaging based on the pH-dependent exchange rate (ksw ), the reliable quantification of ksw in glioma remains constrained due to technical challenges. PURPOSE: To quantify the pH of gliomas by measuring the proton exchange rate through optimized omega plot analysis. STUDY TYPE: Prospective. PHANTOMS/ANIMAL MODEL/SUBJECTS: Creatine and murine brain lysates phantoms, six rats with glioma xenograft model, and three patients with World Health Organization grade 2-4 gliomas. FIELD STRENGTH/SEQUENCE: 11.7 T, 7.0 T, CEST imaging, T2 -weighted (T2 W) imaging, and T1 -mapping. ASSESSMENT: Omega plot analysis, quasi-steady-state (QUASS) analysis, multi-pool Lorentzian fitting, amine and amide concentration-independent detection, pH enhanced method with the combination of amide and guanidyl (pHenh ), and magnetization transfer ratio (MTR) were utilized for pH metric quantification. The clinical outcomes were determined through radiologic follow-up and histopathological analysis. STATISTICAL TESTS: Mann-Whitney U test was performed to compare glioma with normal tissue, and Pearson's correlation analysis was used to assess the relationship between ksw and other parameters. RESULTS: In vitro experiments reveal that the determined ksw at 2 ppm increases exponentially with pH (creatine phantoms: ksw = 106 + 0.147 × 10(pH-4.198) ; lysates: ksw = 185.1 + 0.101 × 10(pH-3.914) ). Omega plot analysis exhibits a linear correlation between 1/MTRRex and 1/ω1 2 in the glioma xenografts (R2 > 0.98) and glioma patients (R2 > 0.99). The exchange rate in the rat glioma decreases compared to the contralateral normal tissue (349.46 ± 30.40 s-1 vs. 403.54 ± 51.01 s-1 , P = 0.025), while keeping independence from changes in concentration (r = 0.5037, P = 0.095). Similar pattern was observed in human data. DATA CONCLUSION: Utilizing QUASS-based, spillover-, and MT-corrected omega plot analysis for the measurement of exchange rates, offers a feasible method for quantifying pH within glioma. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 1.

Decreased water exchange rate across blood-brain barrier in hereditary cerebral small vessel disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood-brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there is BBB damage in the two types of hereditary CSVD, especially in heterozygous HTRA1 mutation-related CSVD. In this study, a case-control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation-related CSVD (n = 9) and healthy controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (kw). Correlation and multiple linear regression analyses were used to examine the association between kw and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients (Bonferroni-corrected P < 0.007). In the CADASIL group, decreased kw in the whole brain (ß = -0.634, P = 0.001), normal-appearing white matter (ß = -0.599, P = 0.002) and temporal lobe (ß = -0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (ß = 0.458, P = 0.001; ß = 0.884, P = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients, suggesting a common pathophysiological mechanism underlying the two types of hereditary CSVD. These results highlight the potential use of kw for monitoring the course of CADASIL and heterozygous HTRA1 mutation-related CSVD, a possibility which should be tested in future research.

Low-cost interventions to improve ventilation in long-term care facilities.

Residents of long-term care facilities are particularly vulnerable to communicable diseases. Low-cost interventions to increase air exchange rates (AERs) may be useful in reducing the transmission of airborne communicable diseases between long-term care residents and staff. In this study, carbon dioxide gas was used as a tracer to evaluate the AER associated with the implementation of low-cost ventilation interventions. Under baseline conditions with the room's door closed, the mean AER was 0.67 ACH; while baseline conditions with the door open had a significantly higher mean AER of 3.87 ACH (p < 0.001). Subsequently opening a window with the door open increased mean AER by 1.49 ACH (p = 0.012) and adding a fan in the window further increased mean AER by 1.87 ACH (p < 0.001). Regression analyses indicated that the flow rate of air entering through the window, both passively and through the use of a fan, was significantly associated with an increase in AER (p < 0.001). These results indicate that low-cost interventions that pull outside air into resident rooms were effective in improving the air exchange rates in these facilities. While implementation of these interventions is dependent on facility rules and isolation requirements of residents with airborne communicable diseases, these interventions remain viable options for long-term care facilities to improve resident room ventilation without requiring costly ventilation system upgrades.

Weighted Signed Networks Reveal Interactions between US Foreign Exchange Rates.

Correlations between exchange rates are valuable for illuminating the dynamics of international trade and the financial dynamics of countries. This paper explores the changing interactions of the US foreign exchange market based on detrended cross-correlation analysis. First, we propose an objective way to choose a time scale parameter appropriate for comparing different samples by maximizing the summed magnitude of all DCCA coefficients. We then build weighted signed networks under this optimized time scale, which can clearly display the complex relationships between different exchange rates. Our study shows negative cross-correlations have become pyramidally rare in the past three decades. Both the number and strength of positive cross-correlations have grown, paralleling the increase in global interconnectivity. The balanced strong triads are identified subsequently after the network centrality analysis. Generally, while the strong development links revealed by foreign exchange have begun to spread to Asia since 2010, Europe is still the center of world finance, with the euro and Danish krone consistently maintaining the closest balanced development relationship. Finally, we propose a fluctuation propagation algorithm to investigate the propagation pattern of fluctuations in the inferred exchange rate networks. The results show that, over time, fluctuation propagation patterns have become simpler and more predictable.

Average saturation efficiency filter ASEF-CEST MRI of stroke rodents.

PURPOSE: The average saturation efficiency filter (ASEF) is a novel method of improving the specificity of CEST; however, there is a mismatch between the magnetization transfer (MT) effect under high-duty cycle and low-duty cycle pulse trains. We explore measures of mitigation and the sensitivity and potential of ASEF imaging in phantoms and stroke rats. METHODS: Simulation and nicotinamide phantoms in denatured protein were used to investigate the effect of different average saturation powers and MT pool parameters on matching coefficients used for correction as well as the ASEF ratio signal and baseline. Then, in vivo studies were performed in stroke rodents to further investigate the sensitivity and fidelity of ASEF ratio spectra. RESULTS: Simulation and studies of nicotinamide phantoms show that the matching coefficient needed to correct the baseline MT mismatch is strongly dependent on the average saturation power. In vivo studies in stroke rodents show that the matching coefficient required to correct the baseline MT mismatch is different for normal versus ischemic tissue. Thus, a baseline correction was performed to further suppress the residue MT mismatch. After correction of the mismatch, ASEF ratio achieved comparable contrast at 3.6 ppm between normal and ischemic tissue when compared to the apparent amide proton transfer (APT*) approach. Moreover, contrasts for 2.0 and 2.6 ppm were also ascertainable from the same spectra. CONCLUSION: ASEF can improve the CEST signal specificity of slow exchange labile protons such as amide and guanidyl, with small loss to sensitivity. It has strong potential in the CEST imaging of various diseases.

Quantification of blood-brain barrier water exchange and permeability with multidelay diffusion-weighted pseudo-continuous arterial spin labeling.

PURPOSE: To present a pulse sequence and mathematical models for quantification of blood-brain barrier water exchange and permeability. METHODS: Motion-compensated diffusion-weighted (MCDW) gradient-and-spin echo (GRASE) pseudo-continuous arterial spin labeling (pCASL) sequence was proposed to acquire intravascular/extravascular perfusion signals from five postlabeling delays (PLDs, 1590-2790 ms). Experiments were performed on 11 healthy subjects at 3 T. A comprehensive set of perfusion and permeability parameters including cerebral blood flow (CBF), capillary transit time (τc ), and water exchange rate (kw ) were quantified, and permeability surface area product (PSw ), total extraction fraction (Ew ), and capillary volume (Vc ) were derived simultaneously by a three-compartment single-pass approximation (SPA) model on group-averaged data. With information (i.e., Vc and τc ) obtained from three-compartment SPA modeling, a simplified linear regression of logarithm (LRL) approach was proposed for individual kw quantification, and Ew and PSw can be estimated from long PLD (2490/2790 ms) signals. MCDW-pCASL was compared with a previously developed diffusion-prepared (DP) pCASL sequence, which calculates kw by a two-compartment SPA model from PLD = 1800 ms signals, to evaluate the improvements. RESULTS: Using three-compartment SPA modeling, group-averaged CBF = 51.5/36.8 ml/100 g/min, kw = 126.3/106.7 min-1 , PSw = 151.6/93.8 ml/100 g/min, Ew = 94.7/92.2%, τc = 1409.2/1431.8 ms, and Vc = 1.2/0.9 ml/100 g in gray/white matter, respectively. Temporal SNR of MCDW-pCASL perfusion signals increased 3-fold, and individual kw maps calculated by the LRL method achieved higher spatial resolution (3.5 mm3 isotropic) as compared with DP pCASL (3.5 × 3.5 × 8 mm3 ). CONCLUSION: MCDW-pCASL allows visualization of intravascular/extravascular ASL signals across multiple PLDs. The three-compartment SPA model provides a comprehensive measurement of blood-brain barrier water dynamics from group-averaged data, and a simplified LRL method was proposed for individual kw quantification.

Isolation of amide proton transfer effect and relayed nuclear Overhauser enhancement effect at -3.5ppm using CEST with double saturation powers.

PURPOSE: Quantifications of amide proton transfer (APT) and nuclear Overhauser enhancement (rNOE(-3.5)) mediated saturation transfer with high specificity are challenging because their signals measured in a Z-spectrum are overlapped with confounding signals from direct water saturation (DS), semi-solid magnetization transfer (MT), and CEST of fast-exchange pools. In this study, based on two canonical CEST acquisitions with double saturation powers (DSP), a new data-postprocessing method is proposed to specifically quantify the effects of APT and rNOE. METHODS: For CEST imaging with relatively low saturation powers ( ω 1 2 $$ {\upomega}_1^2 $$ ), both the fast-exchange CEST effect and the semi-solid MT effect roughly depend on ω 1 2 $$ {\upomega}_1^2 $$ , whereas the slow-exchange APT/rNOE(-3.5) effect do not, which is exploited to isolate a part of the APT and rNOE effects from the confounding signals in this study. After a mathematical derivation for the establishment of the proposed method, numerical simulations based on Bloch equations are then performed to demonstrate its specificity to detections of the APT and rNOE effects. Finally, an in vivo validation of the proposed method is conducted using an animal tumor model at a 4.7 T MRI scanner. RESULTS: The simulations show that DSP-CEST can quantify the effects of APT and rNOE and substantially eliminate the confounding signals. The in vivo experiments demonstrate that the proposed DSP-CEST method is feasible for the imaging of tumors. CONCLUSION: The data-postprocessing method proposed in this study can quantify the APT and rNOE effects with considerably increased specificities and a reduced cost of imaging time.

CEST MR fingerprinting (CEST-MRF) for brain tumor quantification using EPI readout and deep learning reconstruction.

PURPOSE: To develop a clinical CEST MR fingerprinting (CEST-MRF) method for brain tumor quantification using EPI acquisition and deep learning reconstruction. METHODS: A CEST-MRF pulse sequence originally designed for animal imaging was modified to conform to hardware limits on clinical scanners while keeping scan time under 2 min. Quantitative MRF reconstruction was performed using a deep reconstruction network (DRONE) to yield the water relaxation and chemical exchange parameters. The feasibility of the six parameter DRONE reconstruction was tested in simulations using a digital brain phantom. A healthy subject was scanned with the CEST-MRF sequence, conventional MRF and CEST sequences for comparison. Reproducibility was assessed via test-retest experiments and the concordance correlation coefficient calculated for white matter and gray matter. The clinical utility of CEST-MRF was demonstrated on four patients with brain metastases in comparison to standard clinical imaging sequences. Tumors were segmented into edema, solid core, and necrotic core regions and the CEST-MRF values compared to the contra-lateral side. RESULTS: DRONE reconstruction of the digital phantom yielded a normalized RMS error of ≤7% for all parameters. The CEST-MRF parameters were in good agreement with those from conventional MRF and CEST sequences and previous studies. The mean concordance correlation coefficient for all six parameters was 0.98 ± 0.01 in white matter and 0.98 ± 0.02 in gray matter. The CEST-MRF values in nearly all tumor regions were significantly different (P = 0.05) from each other and the contra-lateral side. CONCLUSION: Combination of EPI readout and deep learning reconstruction enabled fast, accurate and reproducible CEST-MRF in brain tumors.

The exchange rate of creatine CEST in mouse brain.

PURPOSE: To estimate the exchange rate of creatine (Cr) CEST and to evaluate the pH sensitivity of guanidinium (Guan) CEST in the mouse brain. METHODS: Polynomial and Lorentzian line-shape fitting (PLOF) were implemented to extract the amine, amide, and Guan CEST signals from the brain Z-spectrum at 11.7T. Wild-type (WT) and knockout mice with the guanidinoacetate N-methyltransferase deficiency (GAMT-/- ) that have low Cr and phosphocreatine (PCr) concentrations in the brain were used to extract the CrCEST signal. To quantify the CrCEST exchange rate, a two-step Bloch-McConnell (BM) fitting was used to fit the CrCEST line-shape, B1 -dependent CrCEST, and the pH response with different B1 values. The pH in the brain cells was altered by hypercapnia to measure the pH sensitivity of GuanCEST. RESULTS: Comparison between the Z-spectra of WT and GAMT-/- mice suggest that the CrCEST is between 20% and 25% of the GuanCEST in the Z-spectrum at 1.95 ppm between B1 = 0.8 and 2 µT. The CrCEST exchange rate was found to be around 240-480 s-1 in the mouse brain, which is significantly lower than that in solutions (∼1000 s-1 ). The hypercapnia study on the mouse brain revealed that CrCEST at B1 = 2 µT and amineCEST at B1 = 0.8 µT are highly sensitive to pH change in the WT mouse brain. CONCLUSIONS: The in vivo CrCEST exchange rate is slow, and the acquisition parameters for the CrCEST should be adjusted accordingly. CrCEST is the major contribution to the opposite pH-dependence of GuanCEST signal under different conditions of B1 in the brain.

MR fingerprinting for semisolid magnetization transfer and chemical exchange saturation transfer quantification.

Chemical exchange saturation transfer (CEST) MRI has positioned itself as a promising contrast mechanism, capable of providing molecular information at sufficient resolution and amplified sensitivity. However, it has not yet become a routinely employed clinical technique, due to a variety of confounding factors affecting its contrast-weighted image interpretation and the inherently long scan time. CEST MR fingerprinting (MRF) is a novel approach for addressing these challenges, allowing simultaneous quantitation of several proton exchange parameters using rapid acquisition schemes. Recently, a number of deep-learning algorithms have been developed to further boost the performance and speed of CEST and semi-solid macromolecule magnetization transfer (MT) MRF. This review article describes the fundamental theory behind semisolid MT/CEST-MRF and its main applications. It then details supervised and unsupervised learning approaches for MRF image reconstruction and describes artificial intelligence (AI)-based pipelines for protocol optimization. Finally, practical considerations are discussed, and future perspectives are given, accompanied by basic demonstration code and data.

Repeatability and reproducibility of apparent exchange rate measurements in yeast cell phantoms using filter-exchange imaging.

OBJECTIVES: Development of a protocol for validation and quality assurance of filter-exchange imaging (FEXI) pulse sequences with well-defined and reproducible phantoms. MATERIALS AND METHODS: A FEXI pulse sequence was implemented on a 7 T preclinical MRI scanner. Six experiments in three different test categories were established for sequence validation, demonstration of the reproducibility of phantoms and the measurement of induced changes in the apparent exchange rate (AXR). First, an ice-water phantom was used to investigate the consistency of apparent diffusion coefficient (ADC) measurements with different diffusion filters. Second, yeast cell phantoms were utilized to validate the determination of the AXR in terms of repeatability (same phantom and session), reproducibility (separate but comparable phantoms in different sessions) and directionality of diffusion encodings. Third, the yeast cell phantoms were, furthermore, used to assess potential AXR bias because of altered cell density and temperature. In addition, a treatment experiment with aquaporin inhibitors was performed to evaluate the influence of these compounds on the cell membrane permeability in yeast cells. RESULTS: FEXI-based ADC measurements of an ice-water phantom were performed for three different filter strengths, showed good agreement with the literature value of 1.099 × 10-3 mm2/s and had a maximum coefficient of variation (CV) of 0.55% within the individual filter strengths. AXR estimation in a single yeast cell phantom and imaging session with five repetitions resulted in an overall mean value of (1.49 ± 0.05) s-1 and a CV of 3.4% between the chosen regions of interest. For three separately prepared phantoms, AXR measurements resulted in a mean value of (1.50 ± 0.04) s-1 and a CV of 2.7% across the three phantoms, demonstrating high reproducibility. Across three orthogonal diffusion directions, a mean value of (1.57 ± 0.03) s-1 with a CV of 1.9% was detected, consistent with isotropy of AXR in yeast cells. Temperature and AXR were linearly correlated (R2 = 0.99) and an activation energy EA of 37.7 kJ/mol was determined by Arrhenius plot. Furthermore, a negative correlation was found between cell density (as determined by the reference ADC/fe) and AXR (R2 = 0.95). The treatment experiment resulted in significantly decreased AXR values at different temperatures in the treated sample compared to the untreated control indicating an inhibiting effect. CONCLUSIONS: Using ice-water and yeast cell-based phantoms, a protocol for the validation of FEXI pulse sequences was established for the assessment of stability, repeatability, reproducibility and directionality. In addition, a strong dependence of AXR on cell density and temperature was shown. As AXR is an emerging novel imaging biomarker, the suggested protocol will be useful for quality assurance of AXR measurements within a study and potentially across multiple sites.

Spillovers and connectedness in foreign exchange markets: The role of trade policy uncertainty.

This paper analyses the directional spillover effects and connectedness for both return and volatility of nine US dollar exchange rates of globally most traded currencies under the influence of trade policy uncertainty. We find two interesting results over the study period ranging from December 1993 to July 2019. First, there exists asymmetric spillovers and connectedness among the considered exchange rates when trade policy uncertainty is present. Second, the volatility spillover is stronger than the return connectedness between exchange rate and trade policy uncertainty. These findings are robust to the presence of economic policy uncertainty effects. Concomitantly, the trade policy uncertainty patterns are also found to be useful for predicting currency market dynamics. Our findings contribute to the debate on the impact of trade policy uncertainty on the global economy and financial sector.

The direction-dependence of apparent water exchange rate in human white matter.

Transmembrane water exchange is a potential biomarker in the diagnosis and understanding of cancers, brain disorders, and other diseases. Filter-exchange imaging (FEXI), a special case of diffusion exchange spectroscopy adapted for clinical applications, has the potential to reveal different physiological water exchange processes. However, it is still controversial whether modulating the diffusion encoding gradient direction can affect the apparent exchange rate (AXR) measurements of FEXI in white matter (WM) where water diffusion shows strong anisotropy. In this study, we explored the diffusion-encoding direction dependence of FEXI in human brain white matter by performing FEXI with 20 diffusion-encoding directions on a clinical 3T scanner in-vivo. The results show that the AXR values measured when the gradients are perpendicular to the fiber orientation (0.77 ± 0.13 s - 1, mean ± standard deviation of all the subjects) are significantly larger than the AXR estimates when the gradients are parallel to the fiber orientation (0.33 ± 0.14 s - 1, p < 0.001) in WM voxels with coherently-orientated fibers. In addition, no significant correlation is found between AXRs measured along these two directions, indicating that they are measuring different water exchange processes. What's more, only the perpendicular AXR rather than the parallel AXR shows dependence on axonal diameter, indicating that the perpendicular AXR might reflect transmembrane water exchange between intra-axonal and extra-cellular spaces. Further finite difference (FD) simulations having three water compartments (intra-axonal, intra-glial, and extra-cellular spaces) to mimic WM micro-environments also suggest that the perpendicular AXR is more sensitive to the axonal water transmembrane exchange than parallel AXR. Taken together, our results show that AXR measured along different directions could be utilized to probe different water exchange processes in WM.

Average saturation efficiency filter (ASEF) for CEST imaging.

PURPOSE: Endogenous CEST signal usually has low specificity due to contamination from the magnetization transfer effect and from fast exchanging labile protons with close Larmor frequencies. We propose to improve CEST signal specificity with an average saturation efficiency filter (ASEF). METHODS: ASEF measures the difference between CEST signals acquired with similar average irradiation power but largely different duty cycles (DC), for example, a continuous wave or a high DC pulse train versus a low DC one. Simulation and Cr phantom studies were performed to evaluate the characteristics of ASEF for CEST. RESULTS: Theoretical and simulation studies show that ASEF can suppress fast exchanging processes, with only a small loss of chemical exchange contrast for slow-to-intermediate exchange rates if the difference in DC is large. In the RF offset range of 2 to 5 ppm with an averaged saturation power of 0.8 and 1.6 microteslas, there is a mismatch of ∼0.1% to 2% in the magnetization transfer signal between saturation by continuous wave and a pulse train with DC = 15% and pulse duration of 24 ms, respectively. This mismatch can be minimized by careful selection of saturation power, pulse duration, and DC differences or by applying a small fudge factor between the 2 irradiation powers. Phantom studies of Cr confirmed that ASEF can minimize the magnetization transfer effect and reduce sensitivity to fast exchange processes. CONCLUSION: ASEF can improve the specificity of slow-to-intermediate exchanging CEST signal with a relatively small loss of sensitivity.