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Purpose: To compare the performance of fat fraction quantification using single-R(2)* and dual-R(2)* correction methods in patients with fatty liver, using MR spectroscopy (MRS) as the reference standard.Materials and Methods: From a group of 97 patients, 32 patients with hepatic fat fraction greater than 5%, as measured by MRS, were identified. In these patients, chemical shift encoded fat-water imaging was performed, covering the entire liver in a single breathhold. Fat fraction was measured from the imaging data by postprocessing using 6 different models: single- and dual-R(2)* correction, each performed with complex fitting, magnitude fitting, and mixed magnitude/complex fitting to compare the effects of phase error correction. Fat fraction measurements were compared with co-registered spectroscopy measurements using linear regression.Results: Linear regression demonstrated higher agreement with MRS using single-R(2)* correction compared with dual-R(2)* correction. Among single-R(2)* models, all 3 fittings methods performed similarly well (slope = 1.0 ± 0.06, r(2) = 0.89-0.91).Conclusion: Single-R(2)* modeling is more accurate than dual-R(2)* modeling for hepatic fat quantification in patients, even in those with high hepatic fat concentrations. [ABSTRACT FROM AUTHOR]

Purpose: To determine the precision and accuracy of hepatic fat-fraction measured with a chemical shift-based MRI fat-water separation method, using single-voxel MR spectroscopy (MRS) as a reference standard.Materials and Methods: In 42 patients, two repeated measurements were made using a T(1) -independent, T 2*-corrected chemical shift-based fat-water separation method with multi-peak spectral modeling of fat, and T(2) -corrected single voxel MR spectroscopy. Precision was assessed through calculation of Bland-Altman plots and concordance correlation intervals. Accuracy was assessed through linear regression between MRI and MRS. Sensitivity and specificity of MRI fat-fractions for diagnosis of steatosis using MRS as a reference standard were also calculated.Results: Statistical analysis demonstrated excellent precision of MRI and MRS fat-fractions, indicated by 95% confidence intervals (units of absolute percent) of [-2.66%,2.64%] for single MRI ROI measurements, [-0.81%,0.80%] for averaged MRI ROI, and [-2.70%,2.87%] for single-voxel MRS. Linear regression between MRI and MRS indicated that the MRI method is highly accurate. Sensitivity and specificity for detection of steatosis using averaged MRI ROI were 100% and 94%, respectively. The relationship between hepatic fat-fraction and body mass index was examined.Conclusion: Fat-fraction measured with T(1) -independent T 2*-corrected MRI and multi-peak spectral modeling of fat is a highly precise and accurate method of quantifying hepatic steatosis. [ABSTRACT FROM AUTHOR]

Noninvasive biomarkers of intracellular accumulation of fat within the liver (hepatic steatosis) are urgently needed for detection and quantitative grading of nonalcoholic fatty liver disease, the most common cause of chronic liver disease in the United States. Accurate quantification of fat with MRI is challenging due the presence of several confounding factors, including T*2 decay. The specific purpose of this work is to quantify the impact of T*2 decay and develop a multiexponential T*2 correction method for improved accuracy of fat quantification, relaxing assumptions made by previous T*2 correction methods. A modified Gauss-Newton algorithm is used to estimate the T*2 for water and fat independently. Improved quantification of fat is demonstrated, with independent estimation of T*2 for water and fat using phantom experiments. The tradeoffs in algorithm stability and accuracy between multiexponential and single exponential techniques are discussed. Magn Reson Med 63:849-857, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Purpose: To validate a T(1)-independent, T(2)*-corrected fat quantification technique that uses accurate spectral modeling of fat using a homogeneous fat-water-SPIO phantom over physiologically expected ranges of fat percentage and T(2)* decay in the presence of iron overload.Materials and Methods: A homogeneous gel phantom consisting of vials with known fat-fractions and iron concentrations is described. Fat-fraction imaging was performed using a multiecho chemical shift-based fat-water separation method (IDEAL), and various reconstructions were performed to determine the impact of T(2)* correction and accurate spectral modeling. Conventional two-point Dixon (in-phase/out-of-phase) imaging and MR spectroscopy were performed for comparison with known fat-fractions.Results: The best agreement with known fat-fractions over the full range of iron concentrations was found when T(2)* correction and accurate spectral modeling were used. Conventional two-point Dixon imaging grossly underestimated fat-fraction for all T(2)* values, but particularly at higher iron concentrations.Conclusion: This work demonstrates the necessity of T(2)* correction and accurate spectral modeling of fat to accurately quantify fat using MRI. [ABSTRACT FROM AUTHOR]

Olfactory adaptation, characterized by attenuation of response to repeated odor stimulations or continuous odor exposure, is an intrinsic feature of olfactory processing. Adaptation can be induced by either "synaptic depression" due to depletion of neurotransmitters, or "enhanced inhibition" onto principle neurons by local inhibitory interneurons in olfactory structures. It is not clear which mechanism plays a major role in olfactory adaptation. More importantly, molecular sources of enhanced inhibition have not been identified. In this study, olfactory responses to either repeated 40-s stimulations with interstimulus intervals (ISI) of 140-s or 30-min, or a single prolonged 200-s stimulus were measured by fMRI in different naïve rats. Olfactory adaptations in the olfactory bulb (OB), anterior olfactory nucleus (AON), and piriform cortex (PC) were observed only with repeated 40-s odor stimulations, and no olfactory adaptations were detected during the prolonged 200-s stimulation. Interestingly, in responses to repeated 40-s odor stimulations in the PC, the first odor stimulation induced positive activations, and odor stimulations under adapted condition induced negative activations. The negative activations suggest that "sparse coding" and "global inhibition" are the characteristics of olfactory processing in PC, and the global inhibition manifests only under an adapted condition, not a naïve condition. Further, we found that these adaptations were NMDA receptor dependent; an NMDA receptor antagonist (MK801) blocked the adaptations. Based on the mechanism that glutamate NMDA receptor plays a role in the inhibition onto principle neurons by interneurons, our data suggest that the olfactory adaptations are caused by enhanced inhibition from interneurons. Combined with the necessity of the interruption of odor stimulation to observe the adaptations, the molecular source for the enhanced inhibition is most likely an increased glutamate release from presynaptic terminals due to glutamate over-replenishment during the interruption of odor stimulation. Furthermore, with blockage of the adaptations, the data reveal that orbital, medial & prefrontal, and cingulate cortices (OmPFC) are involved in the olfactory processing. [ABSTRACT FROM AUTHOR]

Analysis of the spatial distribution of metals, metalloids, and non-metals in biological tissues is of significant interest in the life sciences, helping to illuminate the function and roles these elements play within various biological pathways. Chemical imaging methods are commonly employed to address biological questions and reveal individual spatial distributions of analytes of interest. Elucidation of these spatial distributions can help determine key elemental and molecular information within the respective biological specimens. However, traditionally utilized imaging methods prove challenging for certain biological tissue analysis, especially with respect to applications that require high spatial resolution or depth profiling. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been shown to be effective for direct elemental analysis of solid materials with high levels of precision. In this work, chemical imaging using LA-ICP-MS has been applied as a powerful analytical methodology for the analysis of liver tissue samples. The proposed analytical methodology successfully produced both qualitative and quantitative information regarding specific elemental distributions within images of thin tissue sections with high levels of sensitivity and spatial resolution. The spatial resolution of the analytical methodology was innovatively enhanced, helping to broaden applicability of this technique to applications requiring significantly high spatial resolutions. This information can be used to further understand the role these elements play within biological systems and impacts dysregulation may have., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild-type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small-animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol -1 s -1 ) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well-known bias in gadoxetate rate constants. This will promote the clinical translation of MR-based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies., (© 2020 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Functional magnetic resonance imaging (fMRI) is a valuable tool for studying neural activations in the central nervous system of animals due to its wide spatial coverage and non-invasive nature. However, the advantages of fMRI have not been fully realized in functional studies in mice, especially in the olfactory system, possibly due to the lack of suitable anesthesia protocols with spontaneous breathing. Since mice are widely used in biomedical research, it is desirable to evaluate different anesthesia protocols for olfactory fMRI studies in mice. Dexmedetomidine (DEX) as a sedative/anesthetic has been introduced to fMRI studies in mice, but it has a limited anesthesia duration. To extend the anesthesia duration, DEX has been combined with a low dose of isoflurane (ISO) or ketamine (KET) in previous functional studies in mice. In this report, olfactory fMRI studies were performed under three anesthesia protocols (DEX alone, DEX/ISO, and DEX/KET) in three different groups of mice. Isoamyl-acetate was used as an odorant, and the odorant-induced neural activations were measured by blood oxygenation-level dependent (BOLD) fMRI. BOLD fMRI responses were observed in the olfactory bulb (OB), anterior olfactory nuclei (AON), and piriform cortex (Pir). Interestingly, BOLD fMRI activations were also observed in the prefrontal cortical region (PFC), which are most likely caused by the draining vein effect. The response in the OB showed no adaptation to either repeated odor stimulations or continuous odor exposure, but the response in the Pir showed adaptation during the continuous odor exposure. The data also shows that ISO suppresses the olfactory response in the OB and AON, while KET enhances the olfactory response in the Pir. Thus, DEX/KET should be an attractive anesthesia for olfactory fMRI in mice., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R 1 , but evidence for between-site reproducibility of R 1 in small-animal MRI is lacking., Objective: To assess R 1 repeatability and multi-site reproducibility in phantoms for preclinical MRI., Methods: R 1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R 1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured., Results: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R 1 -based MR biomarkers were found to be quite sensitive even to such small errors in R 1 , notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni 2+ in 2% agarose varied between 0.66 s -1  mM -1 at 3 T and 0.94 s -1  mM -1 at 11.7T., Interpretation: While several factors affect the reproducibility of R 1 -based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R 1 -reproducibility., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Olfactory adaptation, characterized by attenuation of response to repeated odor stimulations or continuous odor exposure, is an intrinsic feature of olfactory processing. Adaptation can be induced by either "synaptic depression" due to depletion of neurotransmitters, or "enhanced inhibition" onto principle neurons by local inhibitory interneurons in olfactory structures. It is not clear which mechanism plays a major role in olfactory adaptation. More importantly, molecular sources of enhanced inhibition have not been identified. In this study, olfactory responses to either repeated 40-s stimulations with interstimulus intervals (ISI) of 140-s or 30-min, or a single prolonged 200-s stimulus were measured by fMRI in different naïve rats. Olfactory adaptations in the olfactory bulb (OB), anterior olfactory nucleus (AON), and piriform cortex (PC) were observed only with repeated 40-s odor stimulations, and no olfactory adaptations were detected during the prolonged 200-s stimulation. Interestingly, in responses to repeated 40-s odor stimulations in the PC, the first odor stimulation induced positive activations, and odor stimulations under adapted condition induced negative activations. The negative activations suggest that "sparse coding" and "global inhibition" are the characteristics of olfactory processing in PC, and the global inhibition manifests only under an adapted condition, not a naïve condition. Further, we found that these adaptations were NMDA receptor dependent; an NMDA receptor antagonist (MK801) blocked the adaptations. Based on the mechanism that glutamate NMDA receptor plays a role in the inhibition onto principle neurons by interneurons, our data suggest that the olfactory adaptations are caused by enhanced inhibition from interneurons. Combined with the necessity of the interruption of odor stimulation to observe the adaptations, the molecular source for the enhanced inhibition is most likely an increased glutamate release from presynaptic terminals due to glutamate over-replenishment during the interruption of odor stimulation. Furthermore, with blockage of the adaptations, the data reveal that orbital, medial & prefrontal, and cingulate cortices (OmPFC) are involved in the olfactory processing., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to compare dual-energy computed tomography (DECT) and magnetic resonance imaging (MRI) for fat quantification using tissue triglyceride concentration and histology as references in an animal model of hepatic steatosis., Materials and Methods: This animal study was approved by our institution's Research Animal Resource Center. After validation of DECT and MRI using a phantom consisting of different triglyceride concentrations, a leptin-deficient obese mouse model (ob/ob) was used for this study. Twenty mice were divided into 3 groups based on expected levels of hepatic steatosis: low (n = 6), medium (n = 7), and high (n = 7) fat. After MRI at 3 T, a DECT scan was immediately performed. The caudate lobe of the liver was harvested and analyzed for triglyceride concentration using a colorimetric assay. The left lateral lobe was also extracted for histology. Magnetic resonance imaging fat-fraction (FF) and DECT measurements (attenuation, fat density, and effective atomic number) were compared with triglycerides and histology., Results: Phantom results demonstrated excellent correlation between triglyceride content and each of the MRI and DECT measurements (r(2) ≥ 0.96, P ≤ 0.003). In vivo, however, excellent triglyceride correlation was observed only with attenuation (r(2) = 0.89, P < 0.001) and MRI-FF (r(2) = 0.92, P < 0.001). Strong correlation existed between attenuation and MRI-FF (r(2) = 0.86, P < 0.001). Nonlinear correlation with histology was also excellent for attenuation and MRI-FF., Conclusions: Dual-energy computed tomography (CT) data generated by the current Gemstone Spectral Imaging analysis tool do not improve the accuracy of fat quantification in the liver beyond what CT attenuation can already provide. Furthermore, MRI may provide an excellent reference standard for liver fat quantification when validating new CT or DECT methods in human subjects.

Purpose: To validate the utility and performance of a T 2 correction method for hepatic fat quantification in an animal model of both steatosis and iron overload., Materials and Methods: Mice with low (n = 6), medium (n = 6), and high (n = 8) levels of steatosis were sedated and imaged using a chemical shift-based fat-water separation method to obtain magnetic resonance imaging (MRI) fat-fraction measurements. Imaging was performed before and after each of two superparamagnetic iron oxide (SPIO) injections to create hepatic iron overload. Fat-fraction maps were reconstructed with and without T 2 correction. Fat-fraction with and without T 2 correction and T 2 measurements were compared after each injection. Liver tissue was harvested and imaging results were compared to triglyceride extraction and histology grading., Results: Excellent correlation was seen between MRI fat-fraction and tissue-based fat quantification. Injections of SPIOs led to increases in R 2 (=1/T 2). Measured fat-fraction was unaffected by the presence of iron when T 2 correction was used, whereas measured fat-fraction dramatically increased without T 2 correction., Conclusion: Hepatic fat-fraction measured using a T 2-corrected chemical shift-based fat-water separation method was validated in an animal model of steatosis and iron overload. T 2 correction enables robust fat-fraction estimation in both the presence and absence of iron, and is necessary for accurate hepatic fat quantification., (Copyright © 2011 Wiley Periodicals, Inc.)

Purpose: The purpose was to compare T(2)* relaxation times and proton density fat-fraction (PDFF) values between brown (BAT) and white (WAT) adipose tissue in lean and ob/ob mice., Materials and Methods: A group of lean male mice (n=6) and two groups of ob/ob male mice placed on similar 4-week (n=6) and 8-week (n=8) ad libitum diets were utilized. The animals were imaged at 3 T using a T(2)*-corrected chemical-shift-based water-fat magnetic resonance imaging (MRI) method that provides simultaneous estimation of T(2)* and PDFF on a voxel-wise basis. Regions of interest were drawn within the interscapular BAT and gonadal WAT depots on co-registered T(2)* and PDFF maps. Measurements were assessed using analysis of variance, Bonferroni-adjusted t test for multigroup comparisons and the Tukey post hoc test., Results: Significant differences (P<.01) in BAT T(2)* and PDFF were observed between the lean and ob/ob groups. The ob/ob animals exhibited longer BAT T(2)* and greater PDFF than lean animals. However, only BAT PDFF was significantly different (P<.01) between the two ob/ob groups. When comparing BAT to WAT within each group, T(2)* and PDFF values were consistently lower in BAT than WAT (P<.01). The difference was most prominent in the lean animals. In both ob/ob groups, BAT exhibited very WAT-like appearances and properties on the MRI images., Conclusion: T(2)* and PDFF are lower in BAT than WAT. This is likely due to variations in tissue composition. The values were consistently lower in lean mice than in ob/ob mice, suggestive of the former's greater demand for BAT thermogenesis and reflective of leptin hormone deficiencies and diminished BAT metabolic activity in the latter., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To determine the repeatability of stiffness measurements in the liver using MR elastography (MRE) during the fasted and fed states. MRE has gained increased recognition as a noninvasive method to quantify fibrotic changes in the liver. It is well known that eating increases splanchnic blood flow, and fasting status of patients has been recognized as a factor that may affect hepatic stiffness measured with MRE., Materials and Methods: Hepatic MRE stiffness and flow through the superior mesenteric vein (SMV) were measured in 12 healthy subjects in fasted and fed states, and measurements were repeated 5 weeks later. A linear mixed effects model was used to estimate the sources of variability in the data, which included day (exams on different days) and subject. Sources were combined to calculate the overall standard deviation of a single MRE measurement., Results: The total within-subject standard deviation of an MRE exam is 8.5% (standard error [SE] = 1.7%) or 9.0% (SE = 1.8%) for fasted and fed states, respectively. No significant differences between fasted/fed state stiffness and no correlation between hepatic stiffness and SMV flow were observed., Conclusion: As seen in this smaller population, healthy subjects scanned in a known fasted or fed state provide repeatable stiffness estimates with no relationship to SMV flow., (Copyright © 2010 Wiley-Liss, Inc.)

Purpose: To determine the sources of variability of MRE hepatic stiffness measurements using healthy volunteers and patients and to calculate the minimum change required for statistical significance. Hepatic stiffness measured with magnetic resonance elastography (MRE) has demonstrated tremendous potential as a noninvasive surrogate of hepatic fibrosis, although the underlying repeatability of MRE for longitudinal tracking of liver disease has not been documented., Materials and Methods: MRE stiffness measurements from 20 healthy volunteers and 10 patients were obtained twice on the same day, and repeated 2-4 weeks later for volunteers in this institutional review board-approved study. A linear mixed effects model was used to estimate the component sources of variability in the data., Results: The standard deviation of MRE measurements of the same individual on different days is 11.9% (percent of the measured stiffness) using the same reader and 12.0% using different readers. The standard deviation of the difference between two measurements (i.e., longitudinal change in an individual) is 17.4%; the corresponding 95% confidence interval for zero change is (-27.0%, 37.0%)., Conclusion: MRE is a repeatable method for quantifying liver stiffness. Using the described MRE technique, changes greater than 37.0% of the smaller measured stiffness value represent meaningful changes in longitudinal liver stiffness measurements.

Purpose: To develop a chemical-shift-based imaging method for fat quantification that accounts for the complex spectrum of fat, and to compare this method with MR spectroscopy (MRS). Quantitative noninvasive biomarkers of hepatic steatosis are urgently needed for the diagnosis and management of nonalcoholic fatty liver disease (NAFLD)., Materials and Methods: Hepatic steatosis was measured with "fat-fraction" images in 31 patients using a multiecho chemical-shift-based water-fat separation method at 1.5T. Fat-fraction images were reconstructed using a conventional signal model that considers fat as a single peak at -210 Hz relative to water ("single peak" reconstruction). Fat-fraction images were also reconstructed from the same source images using two methods that account for the complex spectrum of fat; precalibrated and self-calibrated "multipeak" reconstruction. Single-voxel MRS that was coregistered with imaging was performed for comparison., Results: Imaging and MRS demonstrated excellent correlation with single peak reconstruction (r(2) = 0.91), precalibrated multipeak reconstruction (r(2) = 0.94), and self-calibrated multipeak reconstruction (r(2) = 0.91). However, precalibrated multipeak reconstruction demonstrated the best agreement with MRS, with a slope statistically equivalent to 1 (0.96 +/- 0.04; P = 0.4), compared to self-calibrated multipeak reconstruction (0.83 +/- 0.05, P = 0.001) and single-peak reconstruction (0.67 +/- 0.04, P < 0.001)., Conclusion: Accurate spectral modeling is necessary for accurate quantification of hepatic steatosis with MRI.