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PURPOSE There has been converging evidence of reliable detections of blood oxygenation level dependent (BOLD) signals evoked by neural stimulation and in a resting state in white matter (WM), within which few studies examined the relationship between BOLD functional signals and tissue metabolism. The purpose of the present study was to explore whether such relationship exists using combined functional MRI and positron emission tomography (PET) measurements of glucose uptake. METHODS Functional and metabolic imaging data from 25 right-handed healthy human adults (aged 18-23 years, 18 females) were analyzed. Measures, including average resting state functional connectivity (FC) with respect to 82 Brodmann areas, fractional amplitude of low-frequency fluctuations (FALFF), and average fluorodeoxyglucose (FDG) uptake by PET, were computed for 48 predefined WM bundles. Pearson correlations across the bundles and 25 subjects studied were calculated among these measures. Linear mixed effects models were used to estimate the variance explainable by a predictor variable in the absence of inter-subject variations. RESULTS Analysis of six separate imaging intervals found that average FC the bundles was significantly correlated with local FDG uptake (r = 0.25, p

PURPOSE: A ratio adjustable power splitter (RAPS) circuit was recently proposed for add-on RF shimming and array-compressed parallel transmission. Here we propose a new RAPS circuit design based on off-the-shelf components for improved performance and manufacturability. THEORY AND METHODS: The original RAPS used a pair of home-built Wilkinson splitter and hybrid coupler connected by a pair of connectorized coaxial cables. Here we propose a new hybrid-pair RAPS (or HP-RAPS) circuit that replaces the home-built circuits with two commercially available hybrid couplers and replaces connectorized cables with interchangeable microstrip lines. We derive the relation between the desired splitting ratio and the required phase shifts for HP-RAPS and investigate how to generate arbitrary splitting ratios using paired meandering and straight lines. Several HP-RAPSs with different splitting ratios were fabricated and tested on the workbench and MRI experiments. RESULTS: The splitting ratio of an HP-RAPS circuit has a tan or cot dependence on the meandering line’s additional length compared to the straight line. The fabricated HP-RAPSs exhibit accurate splitting ratios as expected (

To calculate temperatures from TfMRI is mainly based on long-TE gradient-recalled echo acquisitions that are also suitable for measuring small temperature changes via the PRF shift. A motion- and respiration-robust processing pipeline was developed to calculate temperature changes based on the PRF shift directly from the TThe temperature SD was 0.05°C with the proposed imaging protocol and processing. Statistical analysis showed that the optogenetic stimulation protocol with a 3 s stimulation duration did not result in significant temperature rises. Significant temperature rises up to 0.13°C (p 0. 05) were observed with 6 and 9 s stimulation durations for blue and green light.The proposed processing pipeline can be useful for the design of optogenetic stimulation protocols and for monitoring confounding heating effects.

PURPOSE: To demonstrate the feasibility of 3D multi-shot magnetic resonance imaging acquisitions for stimulus-evoked blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in the human spinal cord in vivo. METHODS: Two fMRI studies were performed at 3 Tesla. The first study was a hypercapnic gas challenge where data were acquired from healthy volunteers using a multi-shot 3D fast field echo (FFE) sequence as well as single-shot multi-slice echo-planar imaging (EPI). In the second study, another cohort of healthy volunteers performed an upper extremity motor task while fMRI data were acquired using a 3D multi-shot acquisition. RESULTS: Both 2D-EPI and 3D-FFE were shown to be sensitive to BOLD signal changes in the cervical spinal cord, and had comparable contrast-to-noise ratios in gray matter. FFE exhibited much less signal drop-out and weaker geometric distortions compared to EPI. In the motor paradigm study, the mean number of active voxels was highest in the ventral gray matter horns ipsilateral to the side of the task and at the spinal level associated with innervation of finger extensors. CONCLUSION: Highly multi-shot acquisition sequences such as 3D-FFE are well suited for stimulus-evoked spinal cord BOLD fMRI.

PURPOSE: This report introduces and validates a new diffusion MRI based method termed MRI-Cytometry that can non-invasively map intravoxel, non-parametric cell size distributions in tissues. METHODS: MRI was used to acquire diffusion-weighted signals with a range of diffusion times and gradient factors, and a model was fit to these data to derive estimates of cell size distributions. We implemented a two-step fitting method to avoid noise-induced artificial peaks and provide reliable estimates of tumor cell size distributions. Computer simulations in silico and experimental measurements on cultured cells in vitro and animal xenografts in vivo were used to validate the accuracy and precision of the method. Tumors in seven patients with breast cancer were also imaged and analyzed using this MRI-Cytometry approach on a clinical 3T MRI scanner. RESULTS: Simulations and experimental results confirm MRI-Cytometry can reliably map intravoxel, non-parametric cell size distributions and has the potential to discriminate smaller and larger cells. The application in breast cancer patients demonstrates the feasibility of direct translation of MRI-Cytometry to clinical applications. CONCLUSION: The proposed MRI-Cytometry method can characterize non-parametric cell size distributions in human tumors, which potentially provides a practical imaging approach to derive specific histopathological information on biological tissues.

PURPOSE: To develop and evaluate a reliable non-invasive means for assessing the severity and progression of fibrosis in kidneys. We employed spin-lock MR imaging with different locking fields to detect and characterize progressive renal fibrosis in an hHB-EGF(Tg/Tg) mouse model. METHODS: Male hHB-EGF(Tg/Tg) mice, a well-established model of progressive fibrosis, and age-matched normal wild type (WT) mice, were imaged at 7T at ages 5–7, 11–13 and 30–40 weeks. Spin-lock relaxation rates R(1ρ) were measured at different locking fields (frequencies) and the resultant dispersion curves were fit to a model of exchanging water pools. The obtained MRI parameters were evaluated as potential indicators of tubulointerstitial fibrosis in kidney. Histological examinations of renal fibrosis were also carried out post-mortem following MRI. RESULTS: Histology detected extensive fibrosis in the hHB-EGF(Tg/Tg) mice, in which collagen deposition and reductions in capillary density were observed in the fibrotic regions of kidneys. R(2) and R(1ρ) values at different spin-lock powers clearly dropped in the fibrotic region as fibrosis progressed. There was less variation in the asymptotic locking field relaxation rate R(1ρ)(∞) between the groups. The exchange parameter S(ρ) and the inflection frequency ω(infl) changed by larger factors. CONCLUSION: Both S(ρ) and ω(infl) depend primarily on the average exchange rate between water and other chemically shifted resonances such as hydroxyls and amides. Spin-lock relaxation rate dispersion, rather than single measurements of relaxation rates, provides more comprehensive and specific information on spatiotemporal changes associated with tubulointerstitial fibrosis in murine kidney.

PURPOSE Cell size is a fundamental characteristic of all tissues, and changes in cell size in cancer reflect tumor status and response to treatments, such as apoptosis and cell-cycle arrest. Unfortunately, cell size can currently be obtained only by pathological evaluation of tumor tissue samples obtained invasively. Previous imaging approaches are limited to preclinical MRI scanners or require relatively long acquisition times that are impractical for clinical imaging. There is a need to develop cell-size imaging for clinical applications. METHODS We propose a clinically feasible IMPULSED (imaging microstructural parameters using limited spectrally edited diffusion) approach that can characterize mean cell sizes in solid tumors. We report the use of a combination of pulse sequences, using different gradient waveforms implemented on clinical MRI scanners and analytical equations based on these waveforms to analyze diffusion-weighted MRI signals and derive specific microstructural parameters such as cell size. We also describe comprehensive validations of this approach using computer simulations, cell experiments in vitro, and animal experiments in vivo and demonstrate applications in preoperative breast cancer patients. RESULTS With fast acquisitions (~7 minutes), IMPULSED can provide high-resolution (1.3 mm in-plane) mapping of mean cell size of human tumors in vivo on clinical 3T MRI scanners. All validations suggest that IMPULSED provides accurate and reliable measurements of mean cell size. CONCLUSION The proposed IMPULSED method can assess cell-size variations in tumors of breast cancer patients, which may have the potential to assess early response to neoadjuvant therapy.

Purpose A new approach to design parallel transmit (pTx) head arrays is proposed that integrates transmit radiofrequency pulse designs with electromagnetic modeling of array coil elements. Theory and methods An approach to design pTx head arrays is proposed that finds optimal groupings of a large number of coils into a small number of channels. An algorithm is proposed to extend array-compressed parallel transmit pulse design by adding the ability to optimally select and prune coil elements, in addition to optimizing compression weights. The performance of the method is demonstrated in simulations of dynamic multislice shimming of the human brain in axial, coronal, and sagittal directions, and of reduced field-of-view excitation targeting the human occipital lobe, with simulated electromagnetic field maps from a group of 5 human head models at 7T. Results For both dynamic multislice shimming and reduced field-of-view excitation, the method successfully designed pTx arrays that simultaneously achieved in general 15% lower mean excitation errors with 20% lower SDs, along with 20% lower mean global averaged specific absorption rate and 50% lower SD than previously reported pTx head array designs. Conclusion With the proposed optimal coil element selection algorithm, the array-compressed parallel transmit pulse design can be extended to design pTx transmit head arrays with joint consideration of the fields within the sample and the radiofrequency pulse. The pTx arrays from such an approach achieved higher transmit excitation accuracy, lower radiofrequency heating in subjects, and more robust performance across subjects compared with previously reported pTx head arrays with the same number of channels.

Purpose Functional magnetic resonance imaging with BOLD contrast is widely used for detecting brain activity in the cortex. Recently, several studies have described anisotropic correlations of resting-state BOLD signals between voxels in white matter (WM). These local WM correlations have been modeled as functional-correlation tensors, are largely consistent with underlying WM fiber orientations derived from diffusion MRI, and appear to change during functional activity. However, functional-correlation tensors have several limitations. The use of only nearest-neighbor voxels makes functional-correlation tensors sensitive to noise. Furthermore, adjacent voxels tend to have higher correlations than diagonal voxels, resulting in orientation-related biases. Finally, the tensor model restricts functional correlations to an ellipsoidal bipolar-symmetric shape, and precludes the ability to detect complex functional orientation distributions (FODs). Methods We introduce high-angular-resolution functional-correlation imaging (HARFI) to address these limitations. In the same way that high-angular-resolution diffusion imaging (HARDI) techniques provide more information than diffusion tensors, we show that the HARFI model is capable of characterizing complex FODs expected to be present in WM. Results We demonstrate that the unique radial and angular sampling strategy eliminates orientation biases present in tensor models. We further show that HARFI FODs are able to reconstruct known WM pathways. Finally, we show that HARFI allows asymmetric "bending" and "fanning" distributions, and propose asymmetric and functional indices which may increase fiber tracking specificity, or highlight boundaries between functional regions. Conclusions The results suggest the HARFI model could be a robust, new way to evaluate anisotropic BOLD signal changes in WM.

Purpose Renal fibrosis is a hallmark of progressive renal disease; however, current clinical tests are insufficient for assessing renal fibrosis. Here we evaluated the utility of quantitative magnetization transfer MRI in detecting renal fibrosis in a murine model of progressive diabetic nephropathy (DN). Methods The db/db eNOS-/- mice, a well-recognized model of progressive DN, and normal wild-type mice were imaged at 7T. The quantitative magnetization transfer data were collected in coronal plane using a 2D magnetization transfer prepared spoiled gradient echo sequence with a Gaussian-shaped presaturation pulse. Parameters were derived using a two-pool fitting model. A normal range of cortical pool size ratio (PSR) was defined as Mean±2SD of wild-type kidneys (N = 20). The cortical regions whose PSR values exceeded this threshold (threshold PSR) were assessed. The correlations between the PSR-based and histological (collagen IV or picrosirius red stain) fibrosis measurements were evaluated. Results Compared with wild-type mice, moderate increases in mean PSR values and scattered clusters of high PSR region were observed in cortex of DN mouse kidneys. Abnormally high PSR regions (% area) that were detected by the threshold PSR were significantly increased in renal cortexes of DN mice. These regions progressively increased on aging and highly correlated with histological fibrosis measures, while the mean PSR values correlated much less. Conclusion Renal fibrosis in DN can be assessed by the quantitative magnetization transfer MRI and threshold analysis. This technique may be used as a novel imaging biomarker for DN and other renal diseases.

Purpose To test the ability of a novel pulse sequence applied in vivo at 3 Tesla to separate the contributions to the water signal from amide proton transfer (APT) and relayed nuclear Overhauser enhancement (rNOE) from background direct water saturation and semisolid magnetization transfer (MT). The lack of such signal source isolation has confounded conventional chemical exchange saturation transfer (CEST) imaging. Methods We quantified APT and rNOE signals using a chemical exchange rotation transfer (CERT) metric, MTRdouble . A range of duty cycles and average irradiation powers were applied, and results were compared with conventional CEST analyses using asymmetry (MTRasym ) and extrapolated magnetization transfer (EMR). Results Our results indicate that MTRdouble is more specific than MTRasym and, because it requires as few as 3 data points, is more rapid than methods requiring a complete Z-spectrum, such as EMR. In white matter, APT (1.5 ± 0.5%) and rNOE (2.1 ± 0.7%) were quantified by using MTRdouble with a 30% duty cycle and a 0.5-µT average power. In addition, our results suggest that MTRdouble is insensitive to B0 inhomogeneity, further magnifying its speed advantage over CEST metrics that require a separate B0 measurement. However, MTRdouble still has nontrivial sensitivity to B1 inhomogeneities. Conclusion We demonstrated that MTRdouble is an alternative metric to evaluate APT and rNOE, which is fast, robust to B0 inhomogeneity, and easy to process.

PURPOSE: To evaluate the ability of spin-lock imaging to detect the uptake of 3-o-methyl-D-glucose (3oMG) in normal brain and brain tumors in animals. METHODS: Measurements of the longitudinal relaxation rate in the rotating frame (R(1ρ)) were made over a range of spin-lock powers in rat brains bearing 9L tumors. The dispersion of R(1ρ) values was quantified by ΔR(1ρ), the difference of R(1ρ) values acquired with low and high locking powers. The glucose analogue 3-o-methyl-D-glucose (3oMG) was administered intravenously and the differences of ΔR(1ρ) values (ΔR(1ρ)(diff)) before and as a function of time after administration were calculated to isolate the contribution of 3oMG to the dispersions, which at high fields mainly reflects chemical exchange effects. In addition, the ratio of image signals from low and high locking fields (the spin-lock ratio, SLR), which requires fewer acquisitions and varies directly with ΔR(1ρ), was computed as an alternative measure of the variation with locking power, and changes in SLR (SLR(diff)) after 3oMG were evaluated. RESULTS: Both ΔR(1ρ)(diff) and SLR(diff) in tumors increased rapidly after injection, whereas intact brain showed a gradual increase up to 1h. ΔR(1ρ)(diff) and SLR(diff) were significantly different between tumors and contralateral normal tissues. CONCLUSION: Spin-lock methods can be used to detect 3oMG in vivo after injection, and appropriate analyses of MRI signals allow tumors to be distinguished from normal brain.

Purpose Numerous studies have adopted resting-state functional MRI methods to infer functional connectivity between cortical regions, but very few have translated them to the spinal cord, despite its critical role in the central nervous system. Resting-state functional connectivity between gray matter horns of the spinal cord has previously been shown to be detectable in humans and nonhuman primates, but it has not been reported previously in rodents. Methods Resting-state functional MRI of the cervical spinal cord of live anesthetized rats was performed at 9.4 T. The quality of the functional images acquired was assessed, and quantitative analyses of functional connectivity in C4-C7 of the spinal cord were derived. Results Robust gray matter horn-to-horn connectivity patterns were found that were statistically significant when compared with adjacent control regions. Specifically, dorsal-dorsal and ventral-ventral connectivity measurements were most prominent, while ipsilateral dorsal-ventral connectivity was also observed but to a lesser extent. Quantitative evaluation of reproducibility also revealed moderate robustness in the bilateral sensory and motor networks that was weaker in the dorsal-ventral connections. Conclusions This study reports the first evidence of resting-state functional circuits within gray matter in the rat spinal cord, and verifies their detectability using resting-state functional MRI at 9.4 T. Magn Reson Med 79:2773-2783, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

PURPOSE Quantitative multi-parametric MRI (mpMRI) methods may allow the assessment of renal injury and function in a sensitive and objective manner. This study aimed to evaluate an array of MRI methods that exploit endogenous contrasts including relaxation rates, pool size ratio (PSR) derived from quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), nuclear Overhauser enhancement (NOE), and apparent diffusion coefficient (ADC) for their sensitivity and specificity in detecting abnormal features associated with kidney disease in a murine model of unilateral ureter obstruction (UUO). METHODS MRI scans were performed in anesthetized C57BL/6N mice 1, 3, or 6 days after UUO at 7T. Paraffin tissue sections were stained with Masson trichrome following MRI. RESULTS Compared to contralateral kidneys, the cortices of UUO kidneys showed decreases of relaxation rates R1 and R2 , PSR, NOE, and ADC. No significant changes in CEST effects were observed for the cortical region of UUO kidneys. The MRI parametric changes in renal cortex are related to tubular cell death, tubular atrophy, tubular dilation, urine retention, and interstitial fibrosis in the cortex of UUO kidneys. CONCLUSION Measurements of multiple MRI parameters provide comprehensive information about the molecular and cellular changes produced by UUO. Magn Reson Med 79:2216-2227, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose Chemical exchange saturation transfer effects at 2 ppm (CEST@2ppm) in brain have previously been interpreted as originating from creatine. However, protein guanidino amine protons may also contribute to CEST@2ppm. This study aims to investigate the molecular origins and specificity of CEST@2ppm in brain. Methods Two experiments were performed: (i) samples containing egg white albumin and creatine were dialyzed using a semipermeable membrane to demonstrate that proteins and creatine can be separated by this method; and (ii) tissue homogenates of rat brain with and without dialysis to remove creatine were studied to measure the relative contributions of proteins and creatine to CEST@2ppm. Results The experiments indicate that dialysis can successfully remove creatine from proteins. Measurements on tissue homogenates show that, with the removal of creatine via dialysis, CEST@2ppm decreases to approximately 34% of its value before dialysis, which indicates that proteins and creatine have comparable contribution to the CEST@2ppm in brain. However, considering the contribution from peptides and amino acids to CEST@2ppm, creatine may have much less contribution to CEST@2ppm. Conclusions The contribution of proteins, peptides, and amino acids to CEST@2ppm cannot be neglected. The CEST@2ppm measurements of creatine in rat brain should be interpreted with caution. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose In principle, MR methods that exploit magnetization transfer (MT) may be used to quantify changes in the molecular composition of tissues after injury. The ability to track such changes in injured spinal cord may allow more precise assessment of the state of neural tissues. Methods Z-Spectra were obtained from the cervical spinal cord before and after a unilateral dorsal column lesion in monkeys at 9.4T. The amplitudes of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects from multiple proton pools, along with nonspecific semisolid MT effects from immobile macromolecules, were quantified using a five-peak Lorenzian fitting of each Z-spectrum. Results Abnormal tissues/cysts that formed around lesion sites exhibited relatively low correlations between their Z-spectra and that of normal gray matter (GM). Compared with normal GM, cysts showed strong CEST but weak semisolid MT and NOE effects after injury. The abnormal tissues around lesion sites were heterogeneous and showed different regional Z-spectra. Different regional correlations between proton pools were observed. Longitudinally, injured spinal cord tissue exhibited remarkable recovery in all subjects. Conclusion Characterization of multiple proton pools from Z-spectra permitted noninvasive, regional, quantitative assessments of changes in tissue composition of injured spinal cord over time. Magn Reson Med 79:1070-1082, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose Some X-ray contrast agents contain exchangeable protons that give rise to exchange-based effects on MRI, including chemical exchange saturation transfer (CEST). However, CEST has poor specificity to explicit exchange parameters. Spin-lock sequences at high field are also sensitive to chemical exchange. Here, we evaluate whether spin-locking techniques can detect the contrast agent iohexol in vivo after intravenous administration, and their potential for measuring changes in tissue pH. Methods Two metrics of contrast based on R1ρ, the spin lattice relaxation rate in the rotating frame, were derived from the behavior of R1ρ at different locking fields. Solutions containing iohexol at different concentrations and pH were used to evaluate the ability of the two metrics to quantify exchange effects. Images were also acquired from rat brains bearing tumors before and after intravenous injections of iohexol to evaluate the potential of spin-lock techniques for detecting the agent and pH variations. Results The two metrics were found to depend separately on either agent concentration or pH. Spin-lock imaging may therefore provide specific quantification of iohexol concentration and the iohexol-water exchange rate, which reports on pH. Conclusions Spin-lock techniques may be used to assess the dynamics of intravenous contrast agents and detect extracellular acidification. Magn Reson Med 79:298–305, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose The goal of this study is to implement a noninvasive method for in vivo mapping of hepatocyte size. This method will have a broad range of clinical and preclinical applications, as pathological changes in hepatocyte sizes are relevant for the accurate diagnosis and assessments of treatment response of liver diseases. Methods Building on the concepts of temporal diffusion spectroscopy in MRI, a clinically feasible imaging protocol named IMPULSED (Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion) has been developed, which is able to report measurements of cell sizes noninvasively. This protocol acquires a selected set of diffusion imaging data and fits them to a model of water compartments in tissues to derive robust estimates of the cellular structures that restrict free diffusion. Here, we adapt and further develop this approach to measure hepatocyte sizes in vivo. We validated IMPULSED in livers of mice and rats and implemented it to image healthy human subjects using a clinical 3T MRI scanner. Results The IMPULSED-derived mean hepatocyte sizes for rats and mice are about 15-20 µm and agree well with histological findings. Maps of mean hepatocyte size for humans can be achieved in less than 15 minutes, a clinically feasible scan time. Conclusion Our results suggest that this method has potential to overcome major limitations of liver biopsy and provide noninvasive mapping of hepatocyte sizes in clinical applications.

PURPOSE: Previous studies have shown that diffusion of water through intrinsic susceptibility gradients produces a dispersion of the spin-lattice relaxation rate in the rotating frame (R(1)) over a low range of spin-locking amplitudes (0 < ω(1) < 100 Hz), whereas at higher ω(1) and high magnetic fields a second dispersion arises due to chemical exchange. Here, we separated these different effects and evaluated their contributions in tumors. METHODS: Maps of R(1ρ) and its changes with locking field were acquired on intracranial 9L tumor models. R(1ρ) changes due to diffusion (R(1ρ)(Diff)) were calculated by subtracting maps of R(1ρ) at 100 Hz (R(1ρ)(100Hz)) from those at 0 Hz (R(1ρ)(0Hz)). R(1ρ) changes due to exchange (R(1ρ)(Ex)) were calculated by subtracting maps of R(1ρ) at 5620 Hz (R(1ρ)(5620Hz)) from those of R(1ρ) at 100 Hz (R(1ρ)(100Hz)). Measurements of vascular dimensions and spacing were performed ex vivo using three-dimensional confocal microscopy. RESULTS: R(1ρ) changes at low ω(1) in tumors (5.24±1.78s(−1)) are substantially (p=3.7e-06) greater than those in normal tissues (1.36±0.70s(−1)), which we suggest is due to greater contributions from diffusion through susceptibility gradients. Tumor vessels were larger and spaced less closely compared to normal brain, which may be one factor contributing the susceptibility within 9L tumors. The contrast between tumor and normal tissues for R(1ρ)(Diff) is larger than for R(1ρ)(Ex) and for the apparent R(2w). CONCLUSION: Images sensitive to the variations of spin-lock relaxation rates at low ω(1) provide a novel form of contrast that reflects the heterogeneous nature of intrinsic variations within tumors.

Purpose To detect, map, and quantify a novel nuclear Overhauser enhancement (NOE)-mediated magnetization transfer (MT) with water at approximately −1.6 ppm [NOE(−1.6)] in rat brain using MRI. Methods Continuous wave MT sequences with a variety of radiofrequency irradiation powers were optimized to achieve the maximum contrast of this NOE(−1.6) effect at 9.4 T. The distribution of effect magnitudes, resonance frequency offsets, and line widths in healthy rat brains and the differences of the effect between tumors and contralateral normal brains were imaged and quantified using a multi-Lorentzian fitting method. MR measurements on reconstituted model phospholipids as well as two cell lines (HEK293 and 9L) were also performed to investigate the possible molecular origin of this NOE. Results Our results suggest that the NOE(−1.6) effect can be detected reliably in rat brain. Pixel-wise fittings demonstrated the regional variations of the effect. Measurements in a rodent tumor model showed that the amplitude of NOE(−1.6) in brain tumor was significantly diminished compared with that in normal brain tissue. Measurements of reconstituted phospholipids suggest that this effect may originate from choline phospholipids. Conclusion NOE(−1.6) could be used as a new biomarker for the detection of brain tumor. Magn Reson Med 78:588–597, 2017. © 2016 International Society for Magnetic Resonance in Medicine

Purpose A temporal diffusion MRI spectroscopy based approach has been developed to quantify cancer cell size and density in vivo. Methods A novel imaging microstructural parameters using limited spectrally edited diffusion (IMPULSED) method selects a specific limited diffusion spectral window for an accurate quantification of cell sizes ranging from 10 to 20 μm in common solid tumors. In practice, it is achieved by a combination of a single long diffusion time pulsed gradient spin echo (PGSE) and three low-frequency oscillating gradient spin echo (OGSE) acquisitions. To validate our approach, hematoxylin and eosin staining and immunostaining of cell membranes, in concert with whole slide imaging, were used to visualize nuclei and cell boundaries, and hence, enabled accurate estimates of cell size and cellularity. Results Based on a two compartment model (incorporating intra- and extracellular spaces), accurate estimates of cell sizes were obtained in vivo for three types of human colon cancers. The IMPULSED-derived apparent cellularities showed a stronger correlation (r = 0.81; P

Purpose To investigate the influence of transcytolemmal water exchange on estimates of tissue microstructural parameters derived from diffusion MRI using conventional PGSE and IMPULSED methods. Methods Computer simulations were performed to incorporate a broad range of intracellular water life times τin (50–∞ ms), cell diameters d (5–15 μm), and intrinsic diffusion coefficient Din (0.6–2 μm2/ms) for different values of signal-to-noise ratio (SNR) (10 to 50). For experiments, murine erythroleukemia (MEL) cancer cells were cultured and treated with saponin to selectively change cell membrane permeability. All fitted microstructural parameters from simulations and experiments in vitro were compared with ground-truth values. Results Simulations showed that, for both PGSE and IMPULSED methods, cell diameter d can be reliably fit with sufficient SNR (≥ 50), whereas intracellular volume fraction fin is intrinsically underestimated due to transcytolemmal water exchange. Din can be reliably fit only with sufficient SNR and using the IMPULSED method with short diffusion times. These results were confirmed with those obtained in the cell culture experiments in vitro. Conclusion For the sequences and models considered in this study, transcytolemmal water exchange has minor effects on the fittings of d and Din with physiologically relevant membrane permeabilities if the SNR is sufficient (> 50), but fin is intrinsically underestimated. Magn Reson Med 77:2239–2249, 2017. © 2016 International Society for Magnetic Resonance in Medicine

Purpose Several studies have shown strong correlations between myelin content and T1 within the brain, and have even suggested that T1 can be used to estimate myelin content. However, other micro-anatomical features such as compartment size are known to affect longitudinal relaxation rates, similar to compartment size effects in porous media. Methods T1 measurements were compared with measured or otherwise published axon size measurements in white matter tracts of the rat spinal cord, rat brain, and human brain. Results In both ex vivo and in vivo studies, correlations were present between the relaxation rate 1/T1 and axon size across regions of rat spinal cord with nearly equal myelin content. Conclusion While myelination is likely the dominant determinant of T1 in white matter, variations in white matter microstructure, independent of myelin volume fraction, may also be reflected in T1 differences between regions or subjects. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

PURPOSE Diabetic nephropathy (DN) is the leading cause of renal failure; however, current clinical tests are insufficient for assessing this disease. DN is associated with changes in renal metabolites, so we evaluated the utility of chemical exchange saturation transfer (CEST) imaging to detect changes characteristic of this disease. METHODS Sensitivity of CEST imaging at 7 Tesla to DN was evaluated by imaging diabetic mice [db/db, db/db endothelial nitric oxide synthase (eNOS)-/-] that show different levels of nephropathy as well as by longitudinal imaging (8 to 24 weeks). Nondiabetic (db/m) mice were used as controls. RESULTS Compared with nondiabetic mice, the CEST contrasts of hydroxyl metabolites that correspond to glucose and glycogen were significantly increased in papilla (P), inner medulla (IM), and outer medulla (OM) in db/db and db/db eNOS-/- kidneys at 16 weeks. The db/db eNOS-/- mice that showed advanced nephropathy exhibited greater CEST effects in OM and significant CEST contrasts were also observed in cortex. Longitudinally, db/db mice exhibited progressive increases in hydroxyl signals in IM+P and OM from 12 to 24 weeks and an increase was also observed in cortex at 24 weeks. CONCLUSION CEST MRI can be used to measure changes of hydroxyl metabolites in kidney during progression of DN. Magn Reson Med 76:1531-1541, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Purpose The goal of this study was to investigate the influence of water compartmentation and heterogeneous relaxation properties on quantitative magnetization transfer (qMT) imaging in tissues, and in particular whether a two-pool model is sufficient to describe qMT data in brain tumors. Methods Computer simulations and in vivo experiments with a series of qMT measurements before and after injection of Gd-DTPA were performed. Both off-resonance pulsed saturation (pulsed) and on-resonance selective inversion recovery (SIR) qMT methods were used, and all data were fit with a two-pool model only. Results Simulations indicated that a two-pool fitting of four-pool data yielded accurate measures of pool size ratio (PSR) of macromolecular versus free water protons when there were fast transcytolemmal exchange and slow R1 recovery. The fitted in vivo PSR of both pulsed and SIR qMT methods showed no dependence on R1 variations caused by different concentrations of Gd-DTPA during wash-out, whereas the fitted kex (magnetization transfer exchange rate) changed significantly with R1. Conclusion A two-pool model provides reproducible estimates of PSR in brain tumors independent of relaxation properties in the presence of relatively fast transcytolemmal exchange, whereas estimates of kex are biased by relaxation variations. In addition, estimates of PSR in brain tumors using the pulsed and SIR qMT methods agree well with one another. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Purpose To investigate the influence of cell membrane permeability on diffusion measurements over a broad range of diffusion times. Methods Human myelogenous leukemia K562 cells were cultured and treated with saponin to selectively alter cell membrane permeability, resulting in a broad physiologically relevant range of 0.011–0.044 μm/ms. Apparent diffusion coefficient (ADC) values were acquired with the effective diffusion time (Δeff) ranging from 0.42 to 3000 ms. Cosine-modulated oscillating gradient spin echo (OGSE) measurements were performed to achieve short Δeff from 0.42 to 5 ms, while stimulated echo acquisitions were used to achieve long Δeff from 11 to 2999 ms. Computer simulations were also performed to support the experimental results. Results Both computer simulations and experiments in vitro showed that the influence of membrane permeability on diffusion MR measurements is highly dependent on the choice of diffusion time, and it is negligible only when the diffusion time is at least one order of magnitude smaller than the intracellular exchange lifetime. Conclusion The influence of cell membrane permeability on the measured ADCs is negligible in OGSE measurements at moderately high frequencies. By contrast, cell membrane permeability has a significant influence on ADC and quantitative diffusion measurements at low frequencies such as those sampled using conventional pulsed gradient methods. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Purpose This study aimed to evaluate the reproducibility and specificity of quantitative magnetization transfer (qMT) imaging for monitoring spinal cord injuries (SCIs). Methods MRI scans were performed in anesthetized monkeys at 9.4T, before and serially after a unilateral lesion of the cervical spinal cord. A two-pool fitting model was used to derive qMT parameters. Results qMT measures were reproducible across normal subjects, with an average pool size ratio (PSR) of 0.086 ± 0.003 (mean ± SD) for gray matter, and 0.120 ± 0.005 for white matter, respectively. Compared with normal gray matter, the PSR of abnormal tissues rostral and caudal to the injury site decreased by 19.5% (P

PURPOSE: To optimize a selective inversion recovery (SIR) sequence for macromolecular content mapping in the human brain at 3.0 T. METHODS: SIR is a quantitative method for measuring magnetization transfer (qMT) that employs a low-power, on-resonance inversion pulse. This results in a biexponential recovery of free water signal that can be sampled at various inversion/predelay times (t(I)/t(D)) to estimate a subset of qMT parameters, including the macromolecular-to-free pool-size-ratio (PSR), the R(1) of free water (R(1f)), and the rate of MT exchange (k(mf)). The adoption of SIR has been limited by long acquisition times (≈4 mins/slice). Here, we use Cramér-Rao Lower Bound theory and data reduction strategies to select optimal t(I)/t(D) combinations to reduce imaging times. The schemes were experimentally validated in phantoms, and tested in healthy volunteers (N=4) and a multiple sclerosis patient. RESULTS: Two optimal sampling schemes were determined: i) a 5-point scheme (k(mf) estimated) and ii) a 4-point scheme (k(mf) assumed). In phantoms, the 5/4-point schemes yielded parameter estimates with similar signal-to-noise ratios as our previous 16-point scheme, but with 4.1/6.1-fold shorter scan times. Pair-wise comparisons between schemes did not detect significant differences for any scheme/parameter. In humans, parameter values were consistent with published values, and similar levels of precision were obtained from all schemes. Furthermore, fixing k(mf) reduced the sensitivity of PSR to partial-volume averaging, yielding more consistent estimates throughout the brain. CONCLUSIONS: qMT parameters can be robustly estimated in ≤1 min/slice (without independent measures of ΔB(0), B(1)(+), and T(1)) when optimized t(I)−t(D) combinations are selected.

Purpose To monitor the spontaneous recovery of cervical spinal cord injury (SCI) using longitudinal multiparametric MRI methods. Methods Quantitative MRI imaging including diffusion tensor imaging, magnetization transfer (MT), and chemical exchange saturation transfer (CEST) were conducted in anesthetized squirrel monkeys at 9.4T. The structural, cellular, and molecular features of the spinal cord were examined before and at different time points after a dorsal column lesion in each monkey. Results Images with MT contrast enhanced visualization of the gray and white matter boundaries and the lesion and permitted differentiation of core and rim compartments within an abnormal volume (AV). In the early weeks after SCI, both core and rim exhibited low cellular density and low protein content, with high levels of exchanging hydroxyl, amine, and amide protons, as evidenced by increased apparent diffusion coefficient, decreased fractional anisotropy, decreased MT ratio, decreased nuclear Overhauser effect, and large CEST effects. Over time, cellular density and fiber density increased, whereas amide, amine, and hydroxyl levels dropped significantly, but at differing rates. Histology confirmed the nature of the AV to be a cyst. Conclusion Multiparametric MRI offers a novel method to quantify the spontaneous changes in structure and cellular and molecular compositions of SC during spontaneous recovery from injury. Magn Reson Med 74:1125–1137, 2015. © 2014 Wiley Periodicals, Inc.

Purpose A diffusion-weighted multishot echo-planar imaging approach combined with SENSE and a two-dimensional (2D) navigated motion correction was investigated as an alternative to conventional single-shot counterpart to obtain optic nerve images at higher spatial resolution with reduced artifacts. Methods Fifteen healthy subjects were enrolled in the study. Six of these subjects underwent a repeated acquisition at least 2 weeks after the initial scan session to address reproducibility. Both single-shot and multishot diffusion tensor imaging studies of the human optic nerve were performed with matched scan time. Effect of subject motions were corrected using 2D phase navigator during multishot image reconstruction. Tensor-derived indices from proposed multishot were compared against conventional single-shot approach. Image resolution difference, right–left optic nerve asymmetry, and test–retest reproducibility were also assessed. Results In vivo results of acquired multishot images and quantitative maps of diffusion properties of the optic nerve showed significantly reduced image artifacts (e.g., distortions and blurring), and the derived diffusion indices were comparable to those from other studies. Single-shot scans presented larger variability between right and left optic nerves than multishot scans. Multishot scans also presented smaller variations across scans at different time points when compared with single-shot counterparts. Conclusion The multishot technique has considerable potential for providing improved information on optic nerve pathology and may also be translated to higher fields. Magn Reson Med 74:953–963, 2015. © 2014 Wiley Periodicals, Inc.

Purpose This study investigates amide proton transfer (APT) and nuclear overhauser enhancement (NOE) in phantoms and 9L tumors in rat brains at 9.4 Tesla, using a recently developed method that can isolate different contributions to exchange. Methods Chemical exchange rotation transfer (CERT) was used to quantify APT and NOEs through subtraction of signals acquired at two irradiation flip angles, but with the same average irradiation power. Results CERT separates and quantifies specific APT and NOE signals without contamination from other proton pools, and thus overcomes a key shortcoming of conventional CEST asymmetry approaches. CERT thus has increased specificity, though at the cost of decreased signal strength. In vivo experiments show that the APT effect acquired with CERT in 9L rat tumors (3.1%) is relatively greater than that in normal tissue (2.5%), which is consistent with previous CEST asymmetry analysis. The NOE effect centered at −1.6 ppm shows substantial image contrast within the tumor and between the tumor and the surrounding tissue, while the NOE effect centered at −3.5 ppm shows little contrast. Conclusion CERT provides an image contrast that is more specific to chemical exchange than conventional APT by means of asymmetric CEST Z-spectra analysis. Magn Reson Med 72:471–476, 2014. © 2013 Wiley Periodicals, Inc.

Purpose Head motion continues to be a major source of artifacts and data quality degradation in MRI. The goal of this work was to develop and demonstrate a novel technique for prospective, 6 degrees of freedom (6DOF) rigid body motion estimation and real-time motion correction using inductively coupled wireless nuclear magnetic resonance (NMR) probe markers. Methods Three wireless probes that are inductively coupled with the scanner's RF setup serve as fiducials on the subject's head. A 12-ms linear navigator module is interleaved with the imaging sequence for head position estimation, and scan geometry is updated in real time for motion compensation. Flip angle amplification in the markers allows the use of extremely small navigator flip angles (∼1°). A novel algorithm is presented to identify marker positions in the absence of marker specific receive channels. Motion correction is demonstrated in high resolution 2D and 3D gradient recalled echo experiments in a phantom and humans. Results Significant improvement of image quality is demonstrated in phantoms and human volunteers under different motion conditions. Conclusion A novel real-time 6DOF head motion correction technique based on wireless NMR probes is demonstrated in high resolution imaging at 7 Tesla. Magn Reson Med 72:971–985, 2014. © 2013 Wiley Periodicals, Inc.

Purpose A method is described for characterizing magnetically inhomogeneous media and the spatial scales of intrinsic susceptibility variations within samples. The rate of spin-lattice relaxation in the rotating frame, R1ρ, is affected by diffusion effects to a degree that depends on the magnitude of an applied spin-locking field. Appropriate analysis of the dispersion of R1ρ with locking field may be used to characterize susceptibility variations in inhomogeneous tissues. Theory and Methods The contribution of diffusion to R1ρ is quantified by an analytic expression derived by analyzing of the effects of diffusion through periodic variations of magnetic susceptibility and is used to predict the effects of inhomogeneities in simple phantoms. The theory is further applied to imaging to derive parametric images that portray the dimensions of susceptibility inhomogeneities independent of their magnitude. Results Significant dispersion of R1ρ with locking field was predicted and measured experimentally for suspensions of microspheres ranging from 1 to 90 μm in diameter. For scales of practical interest, these dispersion effects occur at much lower locking fields than the range in which chemical exchange effects cause similar dispersion. Conclusion There is good agreement between theory and experiment, and the method has potential for quantitative tissue characterization and functional imaging. Magn Reson Med 71:1906–1911, 2014. © 2013 Wiley Periodicals, Inc.

To investigate the influence of transcytolemmal water exchange on estimates of tissue microstructural parameters derived from diffusion MRI using conventional PGSE and IMPULSED methods.Computer simulations were performed to incorporate a broad range of intracellular water life times τSimulations showed that, for both PGSE and IMPULSED methods, cell diameter d can be reliably fit with sufficient SNR (≥ 50), whereas intracellular volume fraction fFor the sequences and models considered in this study, transcytolemmal water exchange has minor effects on the fittings of d and D

Variations in local magnetic susceptibility may induce magnetic field gradients that affect the signals acquired for MR imaging. Under appropriate diffusion conditions, such fields produce effects similar to slow chemical exchange. These effects may also be found in combination with other chemical exchange processes at multiple time scales. We investigate these effects with simulations and measurements to determine their contributions to rotating frame (R1ρ ) relaxation in model systems. Simulations of diffusive and chemical exchange effects on R1ρ dispersion were performed using the Bloch equations. Additionally, R1ρ dispersion was measured in suspensions of Sephadex and latex beads with varying spin locking fields at 9.4 T. A novel analysis method was used to iteratively fit for apparent chemical and diffusive exchange rates with a model by Chopra et al. Single- and double-inflection points in R1ρ dispersion profiles were observed, respectively, in simulations of slow diffusive exchange alone and when combined with rapid chemical exchange. These simulations were consistent with measurements of R1ρ in latex bead suspensions and small-diameter Sephadex beads that showed single- and double-inflection points, respectively. These observations, along with measurements following changes in temperature and pH, are consistent with the combined effects of slow diffusion and rapid -OH exchange processes.

The combination of parallel imaging with partial Fourier acquisition has greatly improved the performance of diffusion-weighted single-shot EPI and is the preferred method for acquisitions at low to medium magnetic field strength such as 1.5 or 3 T. Increased off-resonance effects and reduced transverse relaxation times at 7 T, however, generate more significant artifacts than at lower magnetic field strength and limit data acquisition. Additional acceleration of k-space traversal using a multishot approach, which acquires a subset of k-space data after each excitation, reduces these artifacts relative to conventional single-shot acquisitions. However, corrections for motion-induced phase errors are not straightforward in accelerated, diffusion-weighted multishot EPI because of phase aliasing. In this study, we introduce a simple acquisition and corresponding reconstruction method for diffusion-weighted multishot EPI with parallel imaging suitable for use at high field. The reconstruction uses a simple modification of the standard sensitivity-encoding (SENSE) algorithm to account for shot-to-shot phase errors; the method is called image reconstruction using image-space sampling function (IRIS). Using this approach, reconstruction from highly aliased in vivo image data using 2-D navigator phase information is demonstrated for human diffusion-weighted imaging studies at 7 T. The final reconstructed images show submillimeter in-plane resolution with no ghosts and much reduced blurring and off-resonance artifacts.

In this study, we introduce a new method for amide proton transfer imaging based on chemical exchange rotation transfer. It avoids several artifacts that plague conventional chemical exchange saturation transfer approaches by creating label and reference scans based on varying the irradiation pulse rotation angle (π and 2π radians) instead of the frequency offset (3.5 and −3.5 ppm). Specifically, conventional analysis is sensitive to confounding contributions from magnetic field (B0) inhomogeneities and, more problematically, inherently asymmetric macromolecular resonances. In addition, the lipid resonance at −3.5 ppm complicates the interpretation of the reference scan and decreases the resulting contrast. Finally, partial overlap of the amide signal by nearby amines and hydroxyls obscure the results. By avoiding these issues, our new method is a promising approach for imaging endogenous protein and peptide content and mapping pH.

Amide proton transfer imaging, a specific form of chemical exchange saturation transfer imaging, has previously been applied to studies of acute ischemic acidosis, stroke, and cancer. However, interpreting the resulting contrast is complicated by its dependence on the exchange rate between amides and water, the amide concentration, amide and water relaxation, and macromolecular magnetization transfer. Hence, conventional chemical exchange saturation transfer contrast is not specific to changes such as reductions in pH due to tissue acidosis. In this article, a multi-angle ratiometric approach based on several pulsed-chemical exchange saturation transfer scans at different irradiation flip angles is proposed to specifically reflect exchange rates only. This separation of exchange effects in pulsed-chemical exchange saturation transfer experiments is based on isolating rotation vs. saturation contributions, and such methods form a new subclass of chemical exchange rotation transfer (CERT) experiments. Simulations and measurements of creatine/agar phantoms indicate that a newly proposed imaging metric isolates the effects of exchange rate changes, independent of other sample parameters.

By fitting dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data to an appropriate pharmacokinetic model, quantitative physiological parameters can be estimated. In this study, we compare four different models by applying four statistical measures to assess their ability to describe DCE-MRI data obtained in 28 human breast cancer patient sets: the chi-square test (χ2), Durbin-Watson statistic (DW), Akaike Information Criteria (AIC), and Bayesian Information Criterion (BIC). The pharmacokinetic models include: the fast exchange limit model with (FXL_vp) and without (FXL) a plasma component, and the fast and slow exchange regime models (FXR and SXR, respectively). The results show that the FXL_vp and FXR models yielded the smallest χ2 in 45.64% and 47.53% of the voxels, respectively; they also had the smallest number of voxels showing serial correlation with 0.71% and 2.33%, respectively. The AIC indicated that the FXL_vp and FXR models were preferred in 42.84% and 46.59% of the voxels, respectively. The BIC also indicated the FXL_vp and FXR models were preferred in 39.39% and 45.25% of the voxels, respectively. Thus, these four metrics indicate that the FXL_vp and the FXR models provide the most complete statistical description of DCE-MRI time courses for the patients selected in this study.

Diffusion-weighted magnetic resonance imaging data obtained early in the course of therapy can be used to estimate tumor proliferation rates, and the estimated rates can be used to predict tumor cellularity at the conclusion of therapy. Six patients underwent diffusion-weighted magnetic resonance imaging immediately before, after one cycle, and after all cycles of neoadjuvant chemotherapy. Apparent diffusion coefficient values were calculated for each voxel and for a whole tumor region of interest. Proliferation rates were estimated using the apparent diffusion coefficient data from the first two time points and then used with the logistic model of tumor growth to predict cellularity after therapy. The predicted number of tumor cells was then correlated to the corresponding experimental data. Pearson's correlation coefficient for the region of interest analysis yielded 0.95 (P = 0.004), and, after applying a 3 × 3 mean filter to the apparent diffusion coefficient data, the voxel-by-voxel analysis yielded a Pearson correlation coefficient of 0.70 ± 0.10 (P0.05).

A challenge to ultra high field functional magnetic resonance imaging (fMRI) is the predominance of noise associated with physiological processes unrelated to tasks of interest. This degradation in data quality may be partially reversed using a series of preprocessing algorithms designed to retrospectively estimate and remove the effects of these noise sources. However, such algorithms are routinely validated only in isolation, and thus consideration of their efficacies within realistic preprocessing pipelines and on different data sets is often overlooked. We investigate the application of eight possible combinations of three pseudo-complementary preprocessing algorithms – phase regression, Stockwell transform filtering, and retrospective image correction (RETROICOR) – to suppress physiological noise in 2D and 3D functional data at 7 Tesla. The performance of each preprocessing pipeline was evaluated using data-driven metrics of reproducibility and prediction. The optimal preprocessing pipeline for both 2D and 3D functional data included phase regression, Stockwell transform filtering, and RETROICOR. This result supports the hypothesis that a complex preprocessing pipeline is preferable to a magnitude-only pipeline, and suggests that fMRI studies should retain complex images and externally monitor subjects’ respiratory and cardiac cycles so that these supplementary data may be used to retrospectively reduce noise and enhance overall data quality.

For quantitative analysis of dynamic contrast enhanced magnetic resonance imaging data, the time course of the concentration of the contrast agent in the blood plasma, or vascular input function (VIF), is required. We compared pharmacokinetic parameters derived using individual and population-based VIFs in mice for two different contrast agents, gadopentetate dimeglumine and P846. Eleven mice with subcutaneous 4T(1) breast cancer xenografts were imaged at 7 T. A precontrast T(1) map was acquired along with dynamic T(1) -weighted gradient echo images before, during, and after a bolus injection of contrast agent delivered via a syringe pump. Each animal's individual VIF and derived population-averaged VIF were used to extract parameters from the signal-time curves of tumor tissue at both the region of interest and voxel level. The results indicate that for both contrast agents, K(trans) values estimated using population-averaged VIF have a high correlation (concordance correlation coefficient > 0.85) with K(trans) values estimated using individual VIF on both a region of interest and voxel level. This work supports the validity of using of a population-based VIF with a stringent injection protocol in preclinical dynamic contrast enhanced magnetic resonance imaging studies.

Quantitative magnetization transfer imaging yields indices describing the interactions between free water protons and immobile, macromolecular protons-including the macromolecular to free pool size ratio (PSR) and the rate of magnetization transfer between pools k(mf) . This study describes the first implementation of the selective inversion recovery quantitative magnetization transfer method on a clinical 3.0-T scanner in human brain in vivo. Selective inversion recovery data were acquired at 16 different inversion times in nine healthy subjects and two patients with relapsing remitting multiple sclerosis. Data were collected using a fast spin-echo readout and reduced repetition time, resulting in an acquisition time of 4 min for a single slice. In healthy subjects, excellent intersubject and intrasubject reproducibilities (assessed via repeated measures) were demonstrated. Furthermore, PSR values in white (mean ± SD = 11.4 ± 1.2%) and gray matter (7.5 ± 0.7%) were consistent with previously reported values, while k(mf) values were approximately 2-fold slower in both white (11 ± 2 s(-1) ) and gray matter (15 ± 6 s(-1) ). In relapsing remitting multiple sclerosis patients, quantitative magnetization transfer indices were sensitive to pathological changes in lesions and in normal appearing white matter.

Recently developed MRI techniques have enabled clinical imaging of short-lived 1H NMR signals with T2 < 1 ms. Using these techniques, novel signal enhancement has been observed in myelinated tissues, although the source of this enhancement has not been identified. Herein, we report studies of the nature and origins of ultrashort T2 (uT2) signals (50 μs < T2 < 1 ms) from amphibian and mammalian myelinated nerves. NMR measurements and comparisons with myelin phantoms and expected myelin components indicate that these uT2 signals arise predominantly from methylene 1H on/in the myelin membranes, which suggests that direct measurement of uT2 signals can be used as a new means for quantitative myelin mapping. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.

Chemical exchange saturation transfer (CEST) MRI is a molecular imaging method that has previously been successful at reporting variations in tissue protein and glycogen contents and pH. We have implemented amide proton transfer (APT), a specific form of chemical exchange saturation transfer imaging, at high field (7 T) and used it to study healthy human subjects and patients with multiple sclerosis. The effects of static field inhomogeneities were mitigated using a water saturation shift referencing method to center each z-spectrum on a voxel-by-voxel basis. Contrary to results obtained at lower fields, APT imaging at 7 T revealed significant contrast between white and gray matters, with a higher APT signal apparent within the white matter. Preliminary studies of multiple sclerosis showed that the APT asymmetry varied with the type of lesion examined. An increase in APT asymmetry relative to healthy tissue was found in some lesions. These results indicate the potential utility of APT at high field as a noninvasive biomarker of white matter pathology, providing complementary information to other MRI methods in current clinical use.

The relationship between the apparent diffusion coefficient of tissue water measured by MR methods and the physiological status of cells is of particular relevance for better understanding and interpretation of diffusion-weighted MRI. In addition, there is considerable interest in developing diffusion-dependent imaging methods capable of providing novel information on tissue microstructure, including intracellular changes. To this end, both the conventional pulsed gradient spin-echo methods and the oscillating gradient spin-echo method, which probes diffusion over very short distance (<

The apparent diffusion coefficient (ADC) of water in tissues is dependent on the size and spacing of structures in the cellular environment and has been used to characterize pathological changes in stroke and cancer. However, the factors that affect ADC values remain incompletely understood. Measurements of ADC are usually made using relatively long diffusion times; so they reflect the integrated effects of cellular structures over a broad range of spatial scales. We used temporal diffusion spectroscopy to study diffusion in packed cultured human embryonic kidney cells over a range of effective diffusion times following microtubule and actin/cytoskeleton depolymerization and disassembly of the Golgi complex. While Golgi disruption did not change ADC, depolymerization of the microtubule and the actin filament networks caused small decreases in ADC at short diffusion times only. Temporal diffusion spectroscopy provided a novel way to assess intracellular influences on the diffusion properties of tissue water.