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Quantitative MRI (qMRI) has been shown to be clinically useful for numerous applications in the brain and body. The development of rapid, accurate, and reproducible qMRI techniques offers access to new multiparametric data, which can provide a comprehensive view of tissue pathology. This work introduces a multiparametric qMRI protocol along with full postprocessing pipelines, optimized for brain imaging at 3 Tesla and using state-of-the-art qMRI tools. The total scan time is under 50 minutes and includes eight pulse-sequences, which produce range of quantitative maps including T1, T2, and T2* relaxation times, magnetic susceptibility, water and macromolecular tissue fractions, mean diffusivity and fractional anisotropy, magnetization transfer ratio (MTR), and inhomogeneous MTR. Practical tips and limitations of using the protocol are also provided and discussed. Application of the protocol is presented on a cohort of 28 healthy volunteers and 12 brain regions-of-interest (ROIs). Quantitative values agreed with previously reported values. Statistical analysis revealed low variability of qMRI parameters across subjects, which, compared to intra-ROI variability, was x4.1 ± 0.9 times higher on average. Significant and positive linear relationship was found between right and left hemispheres' values for all parameters and ROIs with Pearson correlation coefficients of r>0.89 (P<0.001), and mean slope of 0.95 ± 0.04. Finally, scan-rescan stability demonstrated high reproducibility of the measured parameters across ROIs and volunteers, with close-to-zero mean difference and without correlation between the mean and difference values (across map types, mean P value was 0.48 ± 0.27). The entire quantitative data and postprocessing scripts described in the manuscript are publicly available under dedicated GitHub and Figshare repositories. The quantitative maps produced by the presented protocol can promote longitudinal and multi-center studies, and improve the biological interpretability of qMRI by integrating multiple metrics that can reveal information, which is not apparent when examined using only a single contrast mechanism., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Radunsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To demonstrate the bias in quantitative MT (qMT) measures introduced by the presence of dipolar order and on-resonance saturation (ONRS) effects using magnetization transfer (MT) spoiled gradient-recalled (SPGR) acquisitions, and propose changes to the acquisition and analysis strategies to remove these biases., Methods: The proposed framework consists of SPGR sequences prepared with simultaneous dual-offset frequency-saturation pulses to cancel out dipolar order and associated relaxation (T 1D ) effects in Z-spectrum acquisitions, and a matched quantitative MT (qMT) mathematical model that includes ONRS effects of readout pulses. Variable flip angle and MT data were fitted jointly to simultaneously estimate qMT parameters (macromolecular proton fraction [MPF], T 2,f , T 2,b , R, and free pool T 1 ). This framework is compared with standard qMT and investigated in terms of reproducibility, and then further developed to follow a joint single-point qMT methodology for combined estimation of MPF and T 1 ., Results: Bland-Altman analyses demonstrated a systematic underestimation of MPF (-2.5% and -1.3%, on average, in white and gray matter, respectively) and overestimation of T 1 (47.1 ms and 38.6 ms, on average, in white and gray matter, respectively) if both ONRS and dipolar order effects are ignored. Reproducibility of the proposed framework is excellent (ΔMPF = -0.03% and ΔT 1  = -19.0 ms). The single-point methodology yielded consistent MPF and T 1 values with respective maximum relative average bias of -0.15% and -3.5 ms found in white matter., Conclusion: The influence of acquisition strategy and matched mathematical model with regard to ONRS and dipolar order effects in qMT-SPGR frameworks has been investigated. The proposed framework holds promise for improved accuracy with reproducibility., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Off-resonance radio frequency irradiation can induce the ordering of proton spins in the dipolar fields of their neighbors, in molecules with restricted mobility. This dipolar order decays with a characteristic relaxation time, T 1D , that is very different from the T 1 and T 2 relaxation of the nuclear alignment with the main magnetic field. Inhomogeneous magnetization transfer (ihMT) imaging is a refinement of magnetization transfer (MT) imaging that isolates the MT signal dependence on dipolar order relaxation times within motion-constrained molecules. Because T 1D relaxation is a unique contrast mechanism, ihMT may enable improved characterization of tissue. Initial work has stressed the high correlation between ihMT signal and myelin density. Dipolar order relaxation appears to be much longer in membrane lipids than other molecules. Recent work has shown, however, that ihMT acquisitions may also be adjusted to emphasize different ranges of T 1D . These newer approaches may be sensitive to other microstructural components of tissue. Here, we review the concepts and history of ihMT and outline the requirements for further development to realize its full potential., (© 2022 John Wiley & Sons Ltd.)

Purpose: To evaluate the benefits of fast spin echo (FSE) imaging over rapid gradient-echo (RAGE) for magnetization-prepared inhomogeneous magnetization transfer (ihMT) imaging., Methods: A 3D FSE sequence was modified to include an ihMT preparation (ihMT-FSE) with an optional CSF suppression based on an inversion-recovery (ihMT-FLAIR). After numeric simulations assessing SNR benefits of FSE and the potential impact of an additional inversion-recovery, ihMT-RAGE, ihMT-FSE, and ihMT-FLAIR sequences were compared in a group of six healthy volunteers, evaluating image quality, thermal, and physiological noise as well as quantification using an ihMT saturation (ihMTsat) approach. A preliminary exploration in the cervical spinal cord was also conducted in a group of three healthy volunteers., Results: Several fold improvements in thermal SNR were observed with ihMT-FSE in agreement with numerical simulations. However, we observed significantly higher physiological noise in ihMT-FSE compared to ihMT-RAGE that was mitigated in ihMT-FLAIR, which provided the best total SNR (+74% and +49% compared to ihMT-RAGE in the white and gray matter, P ≤ 0.004). IhMTsat quantification was successful in all cases with strong correlation between all sequences (r 2  > 0.75). Early experiments showed potential for spinal cord imaging., Conclusions: FSE generally offers higher SNR compared to gradient-echo based acquisitions for magnetization-prepared contrasts as illustrated here in the case of ihMT. However, physiological noise has a significant effect, but an inversion-recovery-based CSF suppression was shown to be efficient in mitigating effects of CSF motion., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background: To investigate the association of ihMT (inhom signals with the demyelination and remyelination phases of the acute cuprizone mouse model in comparison with histology, and to assess the extent of tissue damage and repair from MRI data., Methods: Acute demyelination by feeding 0.2% cuprizone for five weeks, followed by a four-week remyelination period was applied on genetically modified plp-GFP mice. Animals were scanned at different time points of the demyelination and remyelination phases of the cuprizone model using a multimodal MRI protocol, including ihMT T 1D -filters, MPF (Macromolecular Proton Fraction) and R 1 (longitudinal relaxation rate). For histology, plp-GFP (proteolipid protein - Green Fluorescent Protein) microscopy and LFB (Luxol Fast Blue) staining were employed as references for the myelin content. Comparison of MRI with histology was performed in the medial corpus callosum (mCC) and cerebral cortex (CTX) at two brain levels whereas ROI-wise and voxel-based analyses of the MRI metrics allowed investigating in vivo the spatial extent of myelin alterations., Results: IhMT high-pass T 1D -filters, targeted toward long T 1D components, showed significant temporal variations in the mCC consistent with the effects induced by the cuprizone toxin. In addition, the corresponding signals correlated strongly and significantly with the myelin content assessed by GFP fluorescence and LFB staining over the demyelination and the remyelination phases. The signal of the band-pass T 1D -filter, which isolates short T 1D components, showed changes over time that were poorly correlated with histology, hence suggesting a sensitivity to pathological processes possibly not related to myelin. Although MPF was also highly correlated to histology, ihMT high-pass T 1D -filters showed better capability to characterize the spatial-temporal patterns during the demyelination and remyelination phases of the acute cuprizone model (e.g., rostro-caudal gradient of demyelination in the mCC previously described in the literature)., Conclusions: IhMT sequences selective for long T 1D components are specific and sensitive in vivo markers of demyelination and remyelination and have successfully captured the spatially heterogeneous pattern of the demyelination and remyelination mechanisms in the cuprizone model. Interestingly, differences in signal variations between the ihMT high-pass and band-pass T 1D -filter, suggest a sensitivity of the ihMT sequences targeted to short T 1D s to alterations other than those of myelin. Future studies will need to further address these differences by examining more closely the origin of the short T 1D components and the variation of each T 1D component in pathology., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: To identify T 1D -filtering methods, which can specifically isolate various ranges of T 1D components as they may be sensitive to different microstructural properties., Methods: Modified Bloch-Provotorov equations describing a bi-T 1D component biophysical model were used to simulate the inhomogeneous magnetization transfer (ihMT) signal from ihMTRAGE sequences at high RF power and low duty-cycle with different switching time values for the dual saturation experiment: Δt = 0.0, 0.8, 1.6, and 3.2 ms. Simulations were compared with experimental signals on the brain gray and white matter tissues of healthy mice at 7T., Results: The lengthening of Δt created ihMT high-pass T 1D -filters, which efficiently eliminated the signal from T 1D components shorter than 1 ms, while partially attenuating that of longer components (≥ 1 ms). Subtraction of ihMTR images obtained with Δt = 0.0 ms and Δt = 0.8 ms generated a new ihMT band-pass T 1D -filter isolating short-T 1D components in the 100-µs to 1-ms range. Simulated ihMTR values in central nervous system tissues were confirmed experimentally., Conclusion: Long- and short-T 1D components were successfully isolated with high RF power and low duty-cycle ihMT filters in the healthy mouse brain. Future studies should investigate the various T 1D -range microstructural correlations in in vivo tissues., (© 2022 International Society for Magnetic Resonance in Medicine.)

Purpose: To investigate the long- and short-T 1D components correlation with myelin content using inhomogeneous magnetization transfer (ihMT) high-pass and band-pass T 1D -filters and to compare ihMT, R 1 , and the macromolecular proton fraction (MPF) for myelin specific imaging., Methods: The 3D ihMT rapid gradient echo (ihMTRAGE) sequences with increasing switching times (Δt) were used to derive ihMT high-pass T 1D -filters with increasing T 1D cutoff values and an ihMT band-pass T 1D -filter for components in the 100 µs to 1 ms range. 3D spoiled gradient echo quantitative MT (SPGR-qMT) protocols were used to derive R 1 and MPF maps. The specificity of R 1 , MPF, and ihMT T 1D -filters was evaluated by comparison with two histological reference techniques for myelin imaging., Results: The higher contribution of long-T 1D s as compared to the short components as Δt got longer led to an increase in the specificity to myelination. In contrast, focusing on the signal originating from a narrow range of short-T 1D s (< 1 ms) as isolated by the band-pass T 1D -filter led to lower specificity. In addition, the significantly lower r 2 correlation coefficient of the band-pass T 1D -filter suggests that the origin of short-T 1D components is mostly associated with non-myelin protons. Also, the important contribution of short-T 1D s to the estimated MPF, explains its low specificity to myelination as compared to the ihMT high-pass T 1D -filters., Conclusion: Long-T 1D components imaging by means of ihMT high-pass T 1D -filters is proposed as an MRI biomarker for myelin content. Future studies should enable the investigation of the sensitivity of ihMT T 1D -filters for demyelinating processes., (© 2022 International Society for Magnetic Resonance in Medicine.)

Purpose: To minimize the sensitivity of inhomogeneous magnetization transfer gradient-echo (ihMT-GRE) imaging to radiofrequency (RF) transmit field ( B 1 + ) inhomogeneities at 3 T., Methods: The ihMT-GRE sequence was optimized by varying the concentration of the RF saturation energy over time, obtained by increasing the saturation pulse power while extending the sequence repetition time (TR). Different protocols were tested using numerical simulations and human in vivo experiments in the brain white matter (WM) of healthy subjects at 3 T. The sensitivity of the ihMT ratio (ihMTR) to B 1 + variations was investigated by comparing measurements obtained at nominal transmitter adjustments and following a 20% global B 1 + drop. The resulting relative variations (δ ihMTR ) were evaluated voxelwise as a function of the local B 1 + distribution. The reproducibility of the protocol providing minimal B 1 + bias was assessed in a test-retest experiment., Results: In line with simulations, ihMT-GRE experiments conducted at high concentration of the RF energy over time demonstrated strong reduction of the B 1 + inhomogeneity effects in the human WM. Under the optimal conditions of 350-ms TR and 3-µT root mean square (RMS) saturation power, 73% of all WM voxels presented δ ihMTR below 10%. Reproducibility analysis yielded a close-to-zero systematic bias (ΔihMTR = -0.081%) and a high correlation (ρ² = 0.977) between test and retest experiments., Conclusion: Concentrating RF saturation energy in ihMT-GRE sequences mitigates the sensitivity of the ihMTR to B 1 + variations and allows for clinical-ready ihMT imaging at 3 T. This feature is of particular interest for high and ultra-high field applications., (© 2021 International Society for Magnetic Resonance in Medicine.)

Rugby players are subject to multiple impacts to their head and neck that could have adverse neurological effects and put them at increased risk of neurodegeneration. Previous studies demonstrated altered default mode network and diffusion metrics on brain, as well as more foraminal stenosis, disc protrusion and neck pain among players of contact sports as compared to healthy controls. However, the long-term effects of practice and repetitive impacts on brain and cervical spinal cord (cSC) of the rugby players have never been systematically investigated. In this study, 15 retired professional and amateur rugby players (R) and 15 age-matched healthy controls (HC) (all males; mean age R: 46.8 ± 7.6; and HC: 48.6 ± 9.5) were recruited both to investigate cord impairments and further characterize brain structure damage. Medical questionnaires including modified Japanese Orthopedic Association scale (mJOA) and Neck Disability Index (NDI) were filled by all participants. A 3 T multi-parametric MR protocol including conventional qualitative techniques such as T 1 -, T 2 -, and T 2 *-weighted sequences, as well as state-of-the art quantitative techniques including MP2RAGE T 1 mapping and 3D ihMTRAGE, was used on both brain and cSC. Normalized brain WM and GM volumes, spine Overall Stenosis Score, cord cross-sectional area and regional T 1 and ihMT metrics were derived from these acquisitions. Rugby players showed significantly higher NDI scores, as well as a faster decline of normalized brain GM volume with age as compared to HC. Moreover, higher T 1 values on cSC suggestive of structural degeneration, together with higher T 1 and lower ihMTsat on brain WM suggestive of demyelination, were observed in retired rugby players as compared to age-matched controls, which may suggest cumulative effects of long-term impacts on the tissues. Metrics also suggest early aging and different aging processes on brain tissue in the players. These preliminary observations provide new insights in the domain, which should now be further investigated on larger cohorts and multicentric longitudinal studies, and further correlated to the likelihood of neurodegenerative diseases and risk factors., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

We present a new consensus atlas of deep grey nuclei obtained by shape-based averaging of manual segmentation of two experienced neuroradiologists and optimized from 7T MP2RAGE images acquired at (.6 mm) 3 in 60 healthy subjects. A group-wise normalization method was used to build a high-contrast and high-resolution T 1 -weighted brain template (.5 mm) 3 using data from 30 out of the 60 controls. Delineation of 24 deep grey nuclei per hemisphere, including the claustrum and 12 thalamic nuclei, was then performed by two expert neuroradiologists and reviewed by a third neuroradiologist according to tissue contrast and external references based on the Morel atlas. Corresponding deep grey matter structures were also extracted from the Morel and CIT168 atlases. The data-derived, Morel and CIT168 atlases were all applied at the individual level using non-linear registration to fit the subject reference and to extract absolute mean quantitative T 1 values derived from the 3D-MP2RAGE volumes, after correction for residual B 1 + biases. Three metrics (the Dice and the volumetric similarity coefficients and a novel Hausdorff distance) were used to estimate the inter-rater agreement of manual MRI segmentation and inter-atlas variability, and these metrics were measured to quantify biases due to image registration, and their impact on the measurements of the quantitative T 1 values was highlighted. This represents a fully automated segmentation process permitting the extraction of unbiased normative T 1 values in a population of young healthy controls as a reference for characterizing subtle structural alterations of deep grey nuclei relevant to a range of neurological diseases., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objectives: Ultra-high field magnetic resonance imaging (MRI) (≥7 T) is a unique opportunity to improve the clinical diagnosis of brain pathologies, such as multiple sclerosis or focal epilepsy. However, several shortcomings of 7 T MRI, such as radiofrequency field inhomogeneities, could degrade image quality and hinder radiological interpretation. To address these challenges, an original synthetic MRI method based on T1 mapping achieved with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence was developed. The radiological quality of on-demand T1-based contrasts generated by this technique was evaluated in multiple sclerosis and focal epilepsy imaging at 7 T., Materials and Methods: This retrospective study was carried out from October 2017 to September 2019 and included 21 patients with different phenotypes of multiple sclerosis and 35 patients with focal epilepsy who underwent MRI brain examinations using a whole-body investigative 7 T magnetic resonance system. The quality of 2 proposed synthetic contrast images were assessed and compared with conventional images acquired at 7 T using the MP2RAGE sequence by 4 radiologists, evaluating 3 qualitative criteria: signal homogeneity, contrast intensity, and lesion visualization. Statistical analyses were performed on reported quality scores using Wilcoxon rank tests and further multiple comparisons tests. Intraobserver and interobserver reliabilities were calculated as well., Results: Radiological quality scores were reported higher for synthetic images when compared with original images, regardless of contrast, pathologies, or raters considered, with significant differences found for all 3 criteria (P < 0.0001, Wilcoxon rank test). None of the 4 radiologists ever rated a synthetic image "markedly worse" than an original image. Synthetic images were rated slightly less satisfying for only 3 epileptic patients, without precluding lesion identification., Conclusion: T1-based synthetic MRI with the MP2RAGE sequence provided on-demand contrasts and high-quality images to the radiologist, facilitating lesion visualization in multiple sclerosis and focal epilepsy, while reducing the magnetic resonance examination total duration by removing an additional sequence., Competing Interests: Conflicts of interest and sources of funding: This study was supported by the following funding sources: 7T-AMI ANR-11-EQPX-0001, A*MIDEX-EI-13-07-130115-08.38-7T-AMISTART, Fondation ARSEP (Fondation pour l'Aide à la recherche sur la Sclérose en Plaques), and CNRS (Centre National de la Recherche Scientifique). Dr Massire is an employee of Siemens Healthcare SAS since September 2019. Dr Troalen is currently an employee of Siemens Healthcare SAS. Dr Kober is a current employee and shareholder of Siemens Healthcare AG and holds patents filed by Siemens Healthcare. For the remaining authors, no relevant relationships are declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To demonstrate the feasibility of integrating the magnetization transfer (MT) preparations required for inhomogeneous MT (ihMT) within an MPRAGE-style acquisition. Such a sequence allows for reduced power deposition and easy inclusion of other modules., Methods: An ihMT MPRAGE-style sequence (ihMTRAGE) was initially simulated to investigate acquisition of the 3D ihMT data sequentially, or in an interleaved manner. The ihMTRAGE sequence was implemented on a 3T clinical scanner to acquire ihMT data from the brain and spine., Results: Both simulations and in vivo data provided an ihMT signal that was significantly greater using a sequential ihMTRAGE acquisition, compared with an interleaved implementation. Comparison with a steady-state ihMT acquisition (defined as having one MT RF pulse between successive acquisition modules) demonstrated how ihMTRAGE allows for a reduction in average power deposition, or greater ihMT signal at equal average power deposition. Inclusion of a prospective motion-correction module did not significantly affect the ihMT signal obtained from regions of interest in the brain. The ihMTRAGE acquisition allowed combination with a spatial saturation module to reduce phase wrap artifacts in a cervical spinal cord acquisition., Conclusions: Use of preparations necessary for ihMT experiments within an MPRAGE-style sequence provides a useful alternative for acquiring 3D ihMT data. Compared with our steady-state implementation, ihMTRAGE provided reduced power deposition, while allowing use of the maximum intensity from off-resonance RF pulses. The 3D ihMTRAGE acquisition allowed combination of other modules with the preparation necessary for ihMT experiments, specifically motion compensation and spatial saturation modules., (© 2020 International Society for Magnetic Resonance in Medicine.)

T 1D , the relaxation time of dipolar order, is sensitive to slow motional processes. Thus T 1D is a probe for membrane dynamics and organization that could be used to characterize myelin, the lipid-rich membrane of axonal fibers. A mono-component T 1D model associated with a modified ihMT sequence was previously proposed for in vivo evaluation of T 1D with MRI. However, experiments have suggested that myelinated tissues exhibit multiple T 1D components probably due to a heterogeneous molecular mobility. A bi-component T 1D model is proposed and implemented. ihMT images of ex-vivo, fixed rat spinal cord were acquired with multiple frequency alternation rate. Fits to data yielded two T 1D s of about 500 μs and 10 ms. The proposed model seems to further explore the complexity of myelin organization compared to the previously reported mono-component T 1D model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Inhomogeneous Magnetization Transfer (ihMT) is a development from the MT MRI technique. IhMT can be considered as a dipolar order relaxation time (T 1D ) weighted imaging modality whose signal has shown an enhanced selectivity for myelin-rich structures. However, a formal validation of the ihMT sensitivity relative to a gold standard myelin density measurement has not yet been reported. To address this need, we compared ihMT MRI with green fluorescence protein (GFP) microscopy, in a study performed on genetically-modified plp-GFP mice, considered as a reference technique for myelin-content assessment. Various ihMT protocols consisting of variable T 1D -filtering and radiofrequency power temporal distributions, were used for comparison with fluorescence microscopy. Strong and significant linear relationships (r 2 (0.87-0.96), p < 0.0001) were found between GFP and ihMT ratio signals across brain regions for all tested protocol variants. Conventional MT ratios showed weaker correlations (r 2 (0.24-0.78), p ≤ 0.02) and a much larger signal fraction unrelated to myelin, hence corresponding to a much lower specificity for myelin. T 1D -filtering reduced the ihMT signal fraction not attributed to myelin by almost twofold relative to zero filtering suggesting that at least half of the unrelated signal has a substantially shorter T 1D than myelin. Overall, these results strongly support the sensitivity of ihMT to myelin content., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intense off-resonant RF irradiation can lead to saturation of the macromolecular pool magnetization and enhance bound pool dipolar order responsible for the inhomogeneous magnetization transfer (ihMT) effect, but the intensity of RF power in human imaging studies is limited by safety constraints on RF heating. High RF intensities can still be achieved if applied in short pulses with low duty-cycle. Here we investigate the benefits of low duty-cycle irradiation for MT and ihMT studies with both theoretical and experimental methods. Solutions for pulsed irradiation of a two-pool model including dipolar order effects were implemented. Experiments were conducted at 3 T in the brain and through the calf of healthy human subjects. 2D echo planar images were acquired following a preparation of RF irradiation with a 2 s train of 5 ms pulses repeated from between 10 to 100 ms for duty-cycles (DCs) of 50% to 5%, and at varying offset frequencies, and time averaged RF powers. MT and ihMT data were measured in regions of interest within gray matter, white matter and muscle, and fit to the model. RF irradiation effects on signal intensity were reduced at 5% relative to 50% DCs. This reduced RF effect was much larger for single than dual frequency irradiation. 5% DC irradiation reduced single and dual frequency MT ratios but increased ihMT ratios up to 3 fold in brain tissues. Muscle ihMT increased by an even larger factor, depending on the frequency and applied power. The model predicted these changes with duty-cycle. The model fit the data well and constrained model parameters. Low duty-cycle pulsed irradiation reduces MT effects and markedly increases dipolar order effects. This approach is an attractive method to enhance ihMT signal-to-noise ratio and demonstrates a measurable ihMT effect in muscle tissue at 3 T under acceptable specific absorption rates. The effects of duty-cycle changes demonstrated in a separate MT/ihMT preparation provide a route for new applications in magnetization-prepared MRI sequences., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To implement, characterize, and optimize an interleaved inhomogeneous magnetization transfer (ihMT) gradient echo sequence allowing for whole-brain imaging within a clinically compatible scan time., Theory and Methods: A general framework for ihMT modelling was developed based on the Provotorov theory of radiofrequency saturation, which accounts for the dipolar order underpinning the ihMT effect. Experimental studies and numerical simulations were performed to characterize and optimize the ihMT-gradient echo dependency with sequence timings, saturation power, and offset frequency. The protocol was optimized in terms of maximum signal intensity and the reproducibility assessed for a nominal resolution of 1.5 mm isotropic. All experiments were performed on healthy volunteers at 1.5T., Results: An important mechanism driving signal optimization and leading to strong ihMT signal enhancement that relies on the dynamics of radiofrequency energy deposition has been identified. By taking advantage of the delay allowed for readout between ihMT pulse bursts, it was possible to boost the ihMT signal by almost 2-fold compared to previous implementation. Reproducibility of the optimal protocol was very good, with an intra-individual error < 2%., Conclusion: The proposed sensitivity-boosted and time-efficient steady-state ihMT-gradient echo sequence, implemented and optimized at 1.5T, allowed robust high-resolution 3D ihMT imaging of the whole brain within a clinically compatible scan time. Magn Reson Med 79:2607-2619, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

In this preliminary study, our objective was to investigate the potential of high-resolution anatomical imaging, diffusion tensor imaging (DTI) and conventional/inhomogeneous magnetization transfer imaging [magnetization transfer (MT)/inhomogeneous magnetization transfer (ihMT)] at 3 T, analyzed with template-extracted regions of interest, to measure the atrophy and structural changes of white (WM) and gray (GM) matter spinal cord (SC) occurring in patients with amyotrophic lateral sclerosis (ALS). Ten patients with ALS and 20 age-matched healthy controls were recruited. SC GM and WM areas were automatically segmented using dedicated templates. Atrophy indices were evaluated from T 2 *-weighted images at each vertebral level from cervical C1 to C6. DTI and ihMT metrics were quantified within the corticospinal tract (CST), posterior sensory tract (PST) and anterior GM (aGM) horns at the C2 and C5 levels. Clinical disabilities of patients with ALS were evaluated using the Revised ALS Functional Rating Scale, upper motor neuron (UMN) and Medical Research Council scorings, and correlated with MR metrics. Compared with healthy controls, GM and WM atrophy was observed in patients with ALS, especially at lower cervical levels, where a strong correlation was also observed between GM atrophy and the UMN score (R = -0.75, p = 0.05 at C6). Interestingly, a significant decrease in ihMT ratio was found in all regions of interest (p < 0.0008), fractional anisotropy (FA) and MT ratios decreased significantly in CST, especially at C5 (p < 0.005), and λ // (axial diffusivity) decreased significantly in CST (p = 0.0004) and PST (p = 0.003) at C2. Strong correlations between MRI metrics and clinical scores were also found (0.47 < |R| < 0.87, p < 0.05). Altogether, these preliminary results suggest that high-resolution anatomical imaging and ihMT imaging, in addition to DTI, are valuable for the characterization of SC tissue impairment in ALS. In this study, in addition to an important SC WM demyelination, we also observed, for the first time in ALS, impairments of cervical aGM., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose: This paper describes a technique that can be used in vivo to measure the dipolar relaxation time, T 1D , of macromolecular protons contributing to magnetization transfer (MT) in tissues and to produce quantitative T 1D maps., Theory and Methods: The technique builds upon the inhomogeneous MT (ihMT) technique that is particularly sensitive to tissue components with long T 1D . A standard ihMT experiment was altered to introduce a variable time for switching between positive and negative offset frequencies for RF saturation. A model for the dependence of ihMT was developed and used to fit data acquired in vivo., Results: Application of the method to images from brains of healthy volunteers produced values of T 1D  = (5.9 ± 1.2) ms in gray matter and T 1D  = (6.2 ± 0.4) ms in white matter regions and provided maps of the T 1D parameter., Conclusion: The model and experiments described provide access to a new relaxation characteristic of tissue with potentially unique diagnostic information. Magn Reson Med 78:1362-1372, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

A pulsed inhomogeneous magnetization transfer (ihMT)-prepared fast imaging sequence was implemented at 11.75 T for preclinical studies on mouse central nervous system. A strategy based on filtering the ihMT signal originating from short dipolar relaxation time (T 1D ) components is proposed. It involves increasing the repetition time of consecutive radiofrequency (RF) pulses of the dual saturation and allows improved signal specificity for long T 1D myelinated structures. Furthermore, frequency offset, power and timing saturation parameters were adjusted to optimize the ihMT sensitivity. The optimization of the ihMT sensitivity, whilst preserving the strong specificity for the long T 1D component of myelinated tissues, allowed measurements of ihMT ratios on the order of 4-5% in white matter (WM), 2.5% in gray matter (GM) and 1-1.3% in muscle. This led to high relative ihMT contrasts between myelinated tissues and others (~3-4 between WM and muscle, and ≥2 between GM and muscle). Conversely, higher ihMT ratios (~6-7% in WM) could be obtained using minimal T 1D filtering achieved with short saturation pulse repetition time or cosine-modulated pulses for the dual-frequency saturation. This study represents a first stage in the process of validating ihMT as a myelin biomarker by providing optimized ihMT preclinical sequences, directly transposable and applicable to other preclinical magnetic fields and scanners. Finally, ihMT ratios measured in various central nervous system areas are provided for future reference., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose: Inhomogeneous magnetization transfer (ihMT) shows great promise for specific imaging of myelinated tissues. Whereas the ihMT technique has been previously applied in brain applications, the current report presents a strategy for cervical spinal cord (SC) imaging free of cerebrospinal fluid (CSF) pulsatility artifacts., Methods: A pulsed ihMT preparation was combined with a single-shot HASTE readout. Electrocardiogram (ECG) synchronization was used to acquire all images during the quiescent phase of SC motion. However ihMT signal quantification errors may occur when a variable recovery delay is introduced in the sequence as a consequence of variable cardiac cycle. A semiautomatic retrospective correction algorithm, based on repetition time (TR) -matching, is proposed to correct for signal variations of long T 1 -components (e.g., CSF)., Results: The proposed strategy combining ECG synchronization and retrospective data pairing led to clean SC images free of CSF artifacts. Lower variability of the ihMT metrics were obtained with the correction algorithm, and allowed for shorter TR to be used, hence improving signal-to-noise ratio efficiency., Conclusion: The proposed methodology enabled faster acquisitions, while offering robust ihMT quantification and exquisite SC image quality. This opens great perspectives for widening the in vivo characterization of SC physiopathology using MRI, such as studying white matter tracts microstructure or impairment in degenerative pathologies. Magn Reson Med 77:581-591, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objectives: The recently reported inhomogeneous magnetization transfer technique (ihMT) has been proposed for specific imaging of inhomogeneously broadened lines, and has shown great promise for characterizing myelinated tissues. The ihMT contrast is obtained by subtracting magnetization transfer images obtained with simultaneous saturation at positive and negative frequency offsets (dual frequency saturation experiment, MT (+/-)) from those obtained with single frequency saturation (MT (+)) at the same total power. Hence, ihMT may be biased by MT-asymmetry, especially at ultra-high magnetic field. Use of the average of single positive and negative frequency offset saturation MT images, i.e., (MT (+)+MT (-)) has been proposed to correct the ihMT signal from MT-asymmetry signal., Materials and Methods: The efficiency of this correction method was experimentally assessed in this study, performed at 11.75 T on mice. Quantitative corrected ihMT and MT-asymmetry ratios (ihMTR and MTRasym) were measured in mouse brain structures for several MT-asymmetry magnitudes and different saturation parameter sets., Results: Our results indicated a "safe" range of magnitudes (/MTRasym/<4 %) for which MT-asymmetry signal did not bias the corrected ihMT signal. Moreover, experimental evidence of the different natures of both MT-asymmetry and inhomogeneous MT contrasts were provided. In particular, non-zero ihMT ratios were obtained at zero MTRasym values., Conclusion: MTRasym is not a confounding factor for ihMT quantification, even at ultra-high field, as long as MTRasym is restricted to ±4 %.

Being able to finely characterize the spinal cord (SC) microstructure and its alterations is a key point when investigating neural damage mechanisms encountered in different central nervous system (CNS) pathologies, such as multiple sclerosis, amyotrophic lateral sclerosis or myelopathy. Based on novel methods, including inhomogeneous magnetization transfer (ihMT) and dedicated SC probabilistic atlas post-processing, the present study focuses on the in vivo characterization of the healthy SC tissue in terms of regional microstructure differences between (i) upper and lower cervical vertebral levels and (ii) sensory and motor tracts, as well as differences attributed to normal aging. Forty-eight healthy volunteers aged from 20 to 70 years old were included in the study and scanned at 3 T using axial high-resolution T2 *-w imaging, diffusion tensor imaging (DTI) and ihMT, at two vertebral levels (C2 and C5). A processing pipeline with minimal user intervention, SC segmentation and spatial normalization into a reference space was implemented in order to assess quantitative morphological and structural parameters (cross-sectional areas, scalar DTI and MT/ihMT metrics) in specific white and gray matter regions of interest. The multi-parametric MRI metrics collected allowed upper and lower cervical levels to be distinguished, with higher ihMT ratio (ihMTR), higher axial diffusivity (λ∥ ) and lower radial diffusivity (λ⊥ ) at C2 compared with C5. Significant differences were also observed between white matter fascicles, with higher ihMTR and lower λ∥ in motor tracts compared with posterior sensory tracts. Finally, aging was found to be associated with significant metric alterations (decreased ihMTR and λ∥ ). The methodology proposed here, which can be easily transferred to the clinic, provides new insights for SC characterization. It bears great potential to study focal and diffuse SC damage in neurodegenerative and demyelinating diseases. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Comparison of off-resonance saturation with single and dual frequency irradiation indicates a contribution of inhomogeneously broadened lines to magnetization transfer in tissues. This inhomogeneous magnetization transfer (ihMT) phenomenon can be exploited to produce images that highlight tissues containing myelin, in vivo. Here, a model for ihMT is described that includes dipolar order effects from magnetization associated with motion-restricted macromolecules. In this model, equal irradiation at positive and negative frequency offsets eliminates dipolar order and achieves greater saturation than irradiation at a single offset frequency using the same power. Fitting of mouse and human volunteer brain data at different irradiation powers and offset frequencies was performed to assess the relevance of the model and approximate tissue parameters. A key parameter in determining ihMT signal was found to be the relaxation time T1D associated with the dipolar order reservoir and the fraction f of the semi-solid, bound magnetization that possessed a nonzero T1D. Indeed, better fits of myelinated tissue were achieved when assuming f≠1. From such fits, estimated T1Ds of mice in the white matter, (34±14) ms, were much longer than in muscle, T1D=(1±1) ms and the average f from white matter volunteer data was 2.2 times greater than that in grey matter. The combination of f and longer T1Ds was primarily responsible for the much higher ihMT in myelinated tissues, and provided explanation for the species variation. This dipolar order ihMT model should help guide future research, pulse sequence optimization, and clinical applications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: To derive an adapted protocol at ultra high magnetic field for mouse kidney perfusion measurements using pCASL in combination with three widely available fast imaging readouts: segmented SE EPI (sSE EPI), RARE, and TrueFISP., Methods: pCASL sSE EPI, pCASL RARE, and pCASL TrueFISP were used for the acquisition of mouse kidney perfusion images in the axial and coronal planes at 11.75T. Results were compared in terms of perfusion sensitivity, signal-to-noise ratio (SNR), blood flow values, intrasession and intersession repeatability, and image quality (subjectively classified into three grades: good, satisfactory, and unacceptable)., Results: Renal cortex perfusion measurements were performed within 2 min with pCASL RARE/pCASL TrueFISP and 4 min with pCASL sSE EPI. In an axial direction, SNR values of 6.6/5.6/2.8, perfusion sensitivity values of 16.1 ± 3.7/13.6 ± 2.4/13.4 ± 1.0 %, blood flow values of 679 ± 149/466 ± 111/572 ± 46 mL/100 g/min and in-ROI variations values of 192/161/181 mL/100 g/min were obtained with pCASL sSE EPI/pCASL RARE/pCASL TrueFISP. Highest SNR per unit of time (1.8) and highest intra/intersession reliability (92.9% and 95.1%) were obtained with pCASL RARE, which additionally presented highly reproducible satisfactory image quality. In coronal plane, significantly lower SNR, perfusion sensitivity and perfusion values were obtained for all techniques compared with that in the axial plane (P < 0.05) due to magnetization saturation effects., Conclusion: pCASL RARE demonstrated more advantages for longitudinal preclinical kidney perfusion studies at ultra high magnetic field., (© 2015 Wiley Periodicals, Inc.)

Purpose: Recently a new MR endogenous contrast mechanism was reported. It allows specifically imaging the magnetization transfer (MT) effect arising from inhomogeneously broadened components of the NMR spectrum, and was hence dubbed ihMT. Such unique NMR lineshape properties are presumably occurring in myelin because of its specifically ordered, multilayered sheath structure. Here, optimization of a pulsed ihMT preparation module is presented to provide guidance for future studies and improve the understanding of underlying contrast mechanisms., Methods: This study was performed at 1.5 Tesla on healthy volunteers. A pulsed ihMT preparation was implemented in combination with a HASTE readout module. The pulse width, interpulse repetition time, total saturation duration and RF saturation power were considered for optimization of the ihMT sensitivity and contrast., Results: An optimal configuration of the preparation module was derived, leading to 10% ihMT signal in internal capsule (relative to unsaturated data) and around 200% signal increase relative to gray matter, i.e., approximately 10-fold superior contrast compared with conventional MT ratios, measured under similar experimental conditions., Conclusion: Overall the ihMT sequence was robust, sensitive and very specific for white matter. These findings suggest great potential for assessing brain myelination and for better characterization of myelin related disorders., (© 2014 Wiley Periodicals, Inc.)

Purpose: To demonstrate the feasibility of a highly sensitive superconducting surface coil for microscopic MRI of the human skin in vivo in a clinical 1.5 Tesla (T) scanner., Materials and Methods: A 12.4-mm high-temperature superconducting coil was used at 1.5T for phantom and in vivo skin imaging. Images were inspected to identify fine anatomical skin structures. Signal-to-noise ratio (SNR) improvement by the high-temperature superconducting (HTS) coil, as compared to a commercial MR microscopy coil was quantified from phantom imaging; the gain over a geometrically identical coil made from copper (cooled or not) was theoretically deduced. Noise sources were identified to evaluate the potential of HTS coils for future studies., Results: In vivo skin images with isotropic 80 μm resolution were demonstrated revealing fine anatomical structures. The HTS coil improved SNR by a factor 32 over the reference coil in a nonloading phantom. For calf imaging, SNR gains of 380% and 30% can be expected over an identical copper coil at room temperature and 77 K, respectively., Conclusion: The high sensitivity of HTS coils allows for microscopic imaging of the skin at 1.5T and could serve as a tool for dermatology in a clinical setting., (© 2013 Wiley Periodicals, Inc.)

Purpose: Quantitative measure of blood flow provides important information regarding renal function, nephropathies and viability of kidney transplantation. Therefore, a method that would allow quantitative and reliable assessment of the renal microvascular perfusion would be very valuable. Arterial spin labeling Magnetic Resonance Imaging has started to be widely used for human studies. For rodents though, despite the increasing number of transgenic mouse models, renal perfusion Magnetic Resonance Imaging has been only sparsely reported. This study investigated the use of FAIR (flow-sensitive alternating inversion recovery) and pseudo-continuous arterial spin labeling (pCASL) for mouse renal blood flow measurements., Methods: FAIR and pCASL were compared in terms of sensitivity, absolute quantification, reproducibility and flexibility of implementation. Multislice and coronal imaging were also investigated. Studies were performed at 11.75 T with volumic transmitter/receiver radiofrequency coils and fast imaging., Results: pCASL demonstrated better experimental flexibility and higher sensitivity compared to FAIR (> +20%). Renal blood flow values in the range of 550-750 mL/100 g/min for the cortex and of 140-230 mL/100 g/min for the medulla, consistent with literature data, were measured., Conclusion: pCASL was successfully applied at very high field for mouse renal blood flow measurements, demonstrating high sensitivity, flexibility and multislice imaging capability. pCASL may be considered as a method of choice for mouse kidney perfusion studies., (Copyright © 2013 Wiley Periodicals, Inc.)

This study evaluates the robustness of a magnetic resonance (MR) fat quantification method to changes in R2* caused by an intravenous infusion of superparamagnetic iron oxide (SPIO) contrast agent. The R2* and proton density fat fraction (PDFF) were measured in liver and spine in 14 subjects using an investigational sequence (IDEAL IQ) provided by the MR scanner vendor. Measurements were made before and after SPIO infusion. Results showed SPIO significantly increased R2* in both liver (p=8.8×10(-8)) and spine (p=1.3×10(-2)) but PDFFs were not significantly different in either the liver (p=5.5×10(-1)) or the spine (p=5.6×10(-1)). These results confirm that the IDEAL IQ method of fat quantification is robust to changes in R2*., (Published by Elsevier Inc.)

Iron oxide nanoparticles (IONPs) are widely used as MR contrast agents because of their strong magnetic properties and broad range of applications. The contrast induced by IONPs typically depends on concentration, water accessibility, particle size and heterogeneity of IONP distribution within the microenvironment. Although the latter could be a tool to assess local physiological effects at the molecular level, it renders IONP quantification from relaxation measurements challenging. This study aims to quantify IONP concentration using susceptibility measurements. In addition, further analysis of relaxation data is proposed to extract quantitative information about the IONP spatial distribution. Mesenchymal stem cells were labeled with IONPs and the IONP concentration measured by mass spectroscopy. MR relaxation parameters (T(1), T(2), T(2)*) as well as magnetic susceptibility of cylindrical samples containing serial dilutions of mixtures of free and cell-internalized IONPs were measured and correlated with IONP concentration. Unlike relaxation data, magnetic susceptibility was independent of whether IONPs were free or internalized, making it an excellent candidate for IONP quantification. Using IONP concentration derived from mass spectroscopy and measured relaxation times, free and internalized IONP fractions were accurately calculated. Magnetic susceptibility was shown to be a robust technique to measure IONP concentration in this preliminary study. Novel imaging-based susceptibility mapping techniques could prove to be valuable tools to quantify IONP concentration directly by MRI, for samples of arbitrary shape. Combined with relaxation time mapping techniques, especially T(2) and T(2)*, this could be an efficient way to measure both IONP concentration and the internalized IONP fraction in vivo using MRI, to gain insight into tissue function and molecular imaging paradigms., (Copyright © 2012 John Wiley & Sons, Ltd.)

Antiangiogenic therapy can produce transient tumor regression in glioblastoma (GBM), but no prolongation in patient survival has been achieved. We have constructed a nanosystem targeted to tumor vasculature that incorporates three elements: (i) a tumor-homing peptide that specifically delivers its payload to the mitochondria of tumor endothelial cells and tumor cells, (ii) conjugation of this homing peptide with a proapoptotic peptide that acts on mitochondria, and (iii) multivalent presentation on iron oxide nanoparticles, which enhances the proapoptotic activity. The iron oxide component of the nanoparticles enabled imaging of GBM tumors in mice. Systemic treatment of GBM-bearing mice with the nanoparticles eradicated most tumors in one GBM mouse model and significantly delayed tumor development in another. Coinjecting the nanoparticles with a tumor-penetrating peptide further enhanced the therapeutic effect. Both models used have proven completely resistant to other therapies, suggesting clinical potential of our nanosystem.

Iron oxide nanoparticles (IONPs) are used in various MRI applications as negative contrast agents. A major challenge is to distinguish regions of signal void due to IONPs from those due to low signal tissues or susceptibility artifacts. To overcome this limitation, several positive contrast strategies have been proposed. Relying on IONP T(1) shortening effects to generate positive contrast is a particularly appealing strategy because it should provide additional specificity when associated with the usual negative contrast from effective transverse relaxation time (T(2)*) effects. In this article, ultrashort echo time imaging is shown to be a powerful technique which can take full advantage of both contrast mechanisms. Methods of comparing T(1) and T(2)* contrast efficiency are described and general rules that allow optimizing IONP detection sensitivity are derived. Contrary to conventional wisdom, optimizing T(1) contrast is often a good strategy for imaging IONPs. Under certain conditions, subtraction of a later echo signal from the ultrashort echo time signal not only improves IONP specificity by providing long T(2)* background suppression but also increases detection sensitivity, as it enables a synergistic combination of usually antagonist T(1) and T(2)* contrasts. In vitro experiments support our theory, and a molecular imaging application is demonstrated using tumor-targeted IONPs in vivo., (Copyright © 2010 Wiley-Liss, Inc.)

The tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) specifically homes to tumors by binding to fibrin and fibrin-associated clotted plasma proteins in tumor vessels. Previous results show that CREKA-coated superparamagnetic iron oxide particles can cause additional clotting in tumor vessels, which creates more binding sites for the peptide. We have used this self-amplifying homing system to develop theranostic nanoparticles that simultaneously serve as an imaging agent and inhibit tumor growth by obstructing tumor circulation through blood clotting. The CREKA nanoparticles were combined with nanoparticles coated with another tumor-homing peptide, CRKDKC, and nanoparticles with an elongated shape (nanoworms) were used for improved binding efficacy. The efficacy of the CREKA peptide was then increased by replacing some residues with nonproteinogenic counterparts, which increased the stability of the peptide in the circulation. Treatment of mice bearing orthotopic human prostate cancer tumors with the targeted nanoworms caused extensive clotting in tumor vessels, whereas no clotting was observed in the vessels of normal tissues. Optical and magnetic resonance imaging confirmed tumor-specific targeting of the nanoworms, and ultrasound imaging showed reduced blood flow in tumor vessels. Treatment of mice with prostate cancer with multiple doses of the nanoworms induced tumor necrosis and a highly significant reduction in tumor growth.

Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to alphav integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.