Optimization of acquisition parameters for cortical inhomogeneous magnetization transfer (ihMT) imaging using a rapid gradient echo readout.

PURPOSE: Imaging biomarkers with increased myelin specificity are needed to better understand the complex progression of neurological disorders. Inhomogeneous magnetization transfer (ihMT) imaging is an emergent technique that has a high degree of specificity for myelin content but suffers from low signal to-noise ratio (SNR). This study used simulations to determine optimal sequence parameters for ihMT imaging for use in high-resolution cortical mapping. METHODS: MT-weighted cortical image intensity and ihMT SNR were simulated using modified Bloch equations for a range of sequence parameters. The acquisition time was limited to 4.5 min/volume. A custom MT-weighted RAGE sequence with center-out k-space encoding was used to enhance SNR at 3 T. Pulsed MT imaging was studied over a range of saturation parameters, and the impact of the turbo factor on the effective ihMT resolution was investigated. 1 mm isotropic ihMTsat maps were generated in 25 healthy adults. RESULTS: Greater SNR was observed for larger number of bursts consisting of 6-8 saturation pulses each, combined with a high readout turbo factor. However, that protocol suffered from a point spread function that was more than twice the nominal resolution. For high-resolution cortical imaging, we selected a protocol with a higher effective resolution at the cost of a lower SNR. We present the first group-average ihMTsat whole-brain map at 1 mm isotropic resolution. CONCLUSION: This study presents the impact of saturation and excitation parameters on ihMTsat SNR and resolution. We demonstrate the feasibility of high-resolution cortical myelin imaging using ihMTsat in less than 20 min.

Inhomogeneous Magnetization Transfer (ihMT) imaging in the acute cuprizone mouse model of demyelination/remyelination.

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 T1D-filters, MPF (Macromolecular Proton Fraction) and R1 (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 T1D-filters, targeted toward long T1D 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 T1D-filter, which isolates short T1D 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 T1D-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 T1D 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 T1D-filter, suggest a sensitivity of the ihMT sequences targeted to short T1Ds 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 T1D components and the variation of each T1D component in pathology.

Orientation dependence of inhomogeneous magnetization transfer and dipolar order relaxation rate in phospholipid bilayers.

Inhomogeneous magnetization transfer (ihMT) is a novel MRI technique used to measure white matter myelination in the brain and spinal cord. In the brain, ihMT has a strong orientation dependence which is likely to arise from the anisotropy of dipolar couplings between protons on oriented lipids in the myelin bilayers. We measured the orientation dependence of the second moment (M2) of the lineshape, dipolar order relaxation rate (R1D), and ihMT ratio (ihMTR) in an oriented phospholipid bilayer at 9.4 T. We found a strong orientation dependence in all three parameters. ihMTR and R1D were maximized when the bilayers were aligned perpendicular to B0 and minimized near the magic angle (∼54.7°). M2 followed an orientation dependence given by the second Legendre polynomial squared as predicted by the form of the secular dipolar Hamiltonian. These results were used to calculate the orientation dependence of R1D and ihMTR in a diffusionless myelin sheath model, which showed ihMTR was maximised for fibers perpendicular to B0 and minimised at 45°, similar to ex-vivo spinal cord with a larger prepulse frequency offset, but in contrast to in vivo brain findings. Adding fiber dispersion to this model smoothed the orientation dependence curve as expected. Our results suggest the importance of the effects of lipid diffusion and prepulse offset frequency on ihMTR.

T1D -weighted ihMT imaging - Part I. Isolation of long- and short-T1D components by T1D -filtering.

PURPOSE: To identify T1D -filtering methods, which can specifically isolate various ranges of T1D components as they may be sensitive to different microstructural properties. METHODS: Modified Bloch-Provotorov equations describing a bi-T1D 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 T1D -filters, which efficiently eliminated the signal from T1D 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 T1D -filter isolating short-T1D components in the 100-µs to 1-ms range. Simulated ihMTR values in central nervous system tissues were confirmed experimentally. CONCLUSION: Long- and short-T1D 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 T1D -range microstructural correlations in in vivo tissues.

T1D -weighted ihMT imaging - Part II. Investigating the long- and short-T1D components correlation with myelin content. Comparison with R1 and the macromolecular proton fraction.

PURPOSE: To investigate the long- and short-T1D components correlation with myelin content using inhomogeneous magnetization transfer (ihMT) high-pass and band-pass T1D -filters and to compare ihMT, R1 , 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 T1D -filters with increasing T1D cutoff values and an ihMT band-pass T1D -filter for components in the 100 µs to 1 ms range. 3D spoiled gradient echo quantitative MT (SPGR-qMT) protocols were used to derive R1 and MPF maps. The specificity of R1 , MPF, and ihMT T1D -filters was evaluated by comparison with two histological reference techniques for myelin imaging. RESULTS: The higher contribution of long-T1D 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-T1D s (< 1 ms) as isolated by the band-pass T1D -filter led to lower specificity. In addition, the significantly lower r2 correlation coefficient of the band-pass T1D -filter suggests that the origin of short-T1D components is mostly associated with non-myelin protons. Also, the important contribution of short-T1D s to the estimated MPF, explains its low specificity to myelination as compared to the ihMT high-pass T1D -filters. CONCLUSION: Long-T1D components imaging by means of ihMT high-pass T1D -filters is proposed as an MRI biomarker for myelin content. Future studies should enable the investigation of the sensitivity of ihMT T1D -filters for demyelinating processes.

An MR fingerprinting approach for quantitative inhomogeneous magnetization transfer imaging.

PURPOSE: Magnetization transfer (MT) and inhomogeneous MT (ihMT) contrasts are used in MRI to provide information about macromolecular tissue content. In particular, MT is sensitive to macromolecules, and ihMT appears to be specific to myelinated tissue. This study proposes a technique to characterize MT and ihMT properties from a single acquisition, producing both semiquantitative contrast ratios and quantitative parameter maps. THEORY AND METHODS: Building on previous work that uses multiband RF pulses to efficiently generate ihMT contrast, we propose a cyclic steady-state approach that cycles between multiband and single-band pulses to boost the achieved contrast. Resultant time-variable signals are reminiscent of an MR fingerprinting acquisition, except that the signal fluctuations are entirely mediated by MT effects. A dictionary-based low-rank inversion method is used to reconstruct the resulting images and to produce both semiquantitative MT ratio and ihMT ratio maps, as well as quantitative parameter estimates corresponding to an ihMT tissue model. RESULTS: Phantom and in vivo brain data acquired at 1.5 Tesla demonstrate the expected contrast trends, with ihMT ratio maps showing contrast more specific to white matter, as has been reported by others. Quantitative estimation of semisolid fraction and dipolar T1 was also possible and yielded measurements consistent with literature values in the brain. CONCLUSION: By cycling between multiband and single-band pulses, an entirely MT-mediated fingerprinting method was demonstrated. This proof-of-concept approach can be used to generate semiquantitative maps and quantitatively estimate some macromolecular-specific tissue parameters.

A strategy to reduce the sensitivity of inhomogeneous magnetization transfer (ihMT) imaging to radiofrequency transmit field variations at 3 T.

PURPOSE: To minimize the sensitivity of inhomogeneous magnetization transfer gradient-echo (ihMT-GRE) imaging to radiofrequency (RF) transmit field ( B1+ ) 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 B1+ variations was investigated by comparing measurements obtained at nominal transmitter adjustments and following a 20% global B1+ drop. The resulting relative variations (δihMTR ) were evaluated voxelwise as a function of the local B1+ distribution. The reproducibility of the protocol providing minimal B1+ 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 B1+ 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 δihMTR 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 B1+ variations and allows for clinical-ready ihMT imaging at 3 T. This feature is of particular interest for high and ultra-high field applications.

A model-based framework for correcting B1+ inhomogeneity effects in magnetization transfer saturation and inhomogeneous magnetization transfer saturation maps.

PURPOSE: In this work, we propose that Δ B1+ -induced errors in magnetization transfer (MT) saturation (MTsat ) maps can be corrected with use of an R1 and B1+ map and through numerical simulations of the sequence. THEORY AND METHODS: One healthy subject was scanned at 3.0T using a partial quantitative MT protocol to estimate the relationship between observed R1 (R1,obs ) and apparent bound pool size ( M0,appB ) in the brain. MTsat values were simulated for a range of B1+ , R1,obs , and M0,appB . An equation was fit to the simulated MTsat , then a linear relationship between R1,obs and M0,appB was generated. These results were used to generate correction factor maps for the MTsat acquired from single-point data. The proposed correction was compared to an empirical correction factor with different MT-preparation schemes. RESULTS: M0,appB was highly correlated with R1,obs (r > 0.96), permitting the use of R1,obs to estimate M0,appB for B1+ correction. All B1+ corrected MTsat maps displayed a decreased correlation with B1+ compared to uncorrected MTsat and MTsat corrected with an empirical factor in the corpus callosum. There was good agreement between the proposed approach and the empirical correction with radiofrequency saturation at 2 kHz, with larger deviations seen when using saturation pulses further off-resonance and in inhomogeneous (ih) MTsat maps. CONCLUSION: The proposed correction decreases the dependence of MTsat on B1+ inhomogeneities. Furthermore, this flexible framework permits the use of different saturation protocols, making it useful for correcting B1+ inhomogeneities in ihMT.

Combining inhomogeneous magnetization transfer and multipoint Dixon acquisition: Potential utility and evaluation.

PURPOSE: The recently introduced inhomogeneous magnetization transfer (ihMT) method has predominantly been applied for imaging the central nervous system. Future applications of ihMT, such as in peripheral nerves and muscles, will involve imaging in the vicinity of adipose tissues. This work aims to systematically investigate the partial volume effect of fat on the ihMT signal and to propose an efficient fat-separation method that does not interfere with ihMT measurements. METHODS: First, the influence of fat on ihMT signal was studied using simulations. Next, the ihMT sequence was combined with a multi-echo Dixon acquisition for fat separation. The sequence was tested in 9 healthy volunteers using a 3T human scanner. The ihMT ratio (ihMTR) values were calculated in regions of interest in the brain and the spinal cord using standard acquisition (no fat saturation), water-only, in-phase, and out-of-phase reconstructions. The values obtained were compared with a standard fat suppression method, spectral presaturation with inversion recovery. RESULTS: Simulations showed variations in the ihMTR values in the presence of fat, depending on the TEs used. The IhMTR values in the brain and spinal cord derived from the water-only ihMT multi-echo Dixon images were in good agreement with values from the unsuppressed sequence. The ihMT-spectral presaturation with inversion recovery combination resulted in 24%-35% lower ihMTR values compared with the standard non-fat-suppressed acquisition. CONCLUSION: The presence of fat within a voxel affects the ihMTR calculations. The IhMT multi-echo Dixon method does not compromise the observable ihMT effect and can potentially be used to remove fat influence in ihMT.

Silent myelin-weighted magnetic resonance imaging.

Background: Inhomogeneous Magnetization Transfer (ihMT) is an emerging, uniquely myelin-specific magnetic resonance imaging (MRI) contrast. Current ihMT acquisitions utilise fast Gradient Echo sequences which are among the most acoustically noisy MRI sequences, reducing patient comfort during acquisition. We sought to address this by modifying a near silent MRI sequence to include ihMT contrast. Methods: A Magnetization Transfer preparation module was incorporated into a radial Zero Echo-Time sequence. Repeatability of the ihMT ratio and inverse ihMT ratio were assessed in a cohort of healthy subjects. We also investigated how head orientation affects ihMT across subjects, as a previous study in a single subject suggests this as a potential confound. Results: We demonstrated that ihMT ratios comparable to existing, acoustically loud, implementations could be obtained with the silent sequence. We observed a small but significant effect of head orientation on inverse ihMTR. Conclusions: Silent ihMT imaging is a comparable alternative to conventional, noisy, alternatives. For all future ihMT studies we recommend careful positioning of the subject within the scanner.

A comparison study of inhomogeneous magnetization transfer (ihMT) and magnetization transfer (MT) in multiple sclerosis based on whole brain acquisition at 3.0 T.

INTRODUCTION: Multiple sclerosis (MS) is a central nervous system disorder that may eventually affect its function. The clinical standard for MS severity is based on a clinical scale, which lacks lesion specific information. Magnetic resonance imaging of MS faces the challenge of myelin specificity, and in this work a new method inhomogeneous magnetization transfer (ihMT) is investigated as new biomarker of demyelination in MS. METHODS: Local ethics committee approved this study and written informed consents were obtained. Between Oct 2017 to May 2018, eighteen patients with relapsing-remitting MS (RRMS) (6 males, 12 females, mean age 31.2) and sixteen healthy volunteers (6 males, 10 females, mean age 30.4 years) were enrolled in this prospective study. All subjects underwent MRI exams including MT and ihMT imaging as well as the Expanded Disability Status Scale (EDSS) assessments. Independent sample t-test were used to compare the difference of ihMT parameters between healthy white matter (HWM) and normal appearing white matter (NAWM) and between HWM and MS lesions, respectively. Spearman correlation were used to analyze the correlation between ihMT parameters of MS lesions and EDSS score. RESULTS: The ihMTR and qihMT demonstrate significant differences between WHM and NAWM groups, while no significant differences are observed for MTR and qMT. All parameters show significant differences between HWM and MS groups (p < 0.05). There was moderate negative correlation between MTR, qMT and EDSS score (-0.440 and -0.572), while there was a strong negative correlation between ihMTR and qihMT and EDSS score (-0.704 and -0.739). CONCLUSION: Based on whole brain analysis at 3.0 T, ihMT showed better correlation with EDSS compared to magnetization transfer imaging, and may be a potentially valuable biomarker for demyelination in MS.

Steady-state imaging with inhomogeneous magnetization transfer contrast using multiband radiofrequency pulses.

PURPOSE: Inhomogeneous magnetization transfer (ihMT) is an emerging form of MRI contrast that may offer high specificity for myelinated tissue. Existing ihMT and pulsed MT sequences often use separate radiofrequency pulses for saturation and signal excitation. This study investigates the use of nonselective multiband radiofrequency pulses for simultaneous off-resonance saturation and on-resonance excitation specifically for generation of ihMT contrast within rapid steady-state pulse sequences. THEORY AND METHODS: A matrix-based signal modeling approach was developed and applied for both balanced steady state free precession and spoiled gradient echo sequences, accounting specifically for multiband pulses. Phantom experiments were performed using a combination of balanced steady state free precession and spoiled gradient echo sequences, and compared with model fits. A human brain imaging exam was performed using balanced steady state free precession sequences to demonstrate the achieved contrast. RESULTS: A simple signal model derived assuming instantaneous radiofrequency pulses was shown to agree well with full integration of the governing equations and provided fits to phantom data for materials with strong ihMT contrast (PL161 root mean square error = 0.9%, and hair conditioner root mean square error = 2.4%). In vivo ihMT ratio images showed the expected white matter contrast that has been seen by other ihMT investigations, and the observed ihMT ratios corresponded well with predictions. CONCLUSIONS: ihMT contrast can be generated by integrating multiband radiofrequency pulses directly into both spoiled gradient echo and balanced steady state free precession sequences, and the presented signal modeling approach can be used to understand the acquired signals.

MRI assessment of multiple dipolar relaxation time (T1D) components in biological tissues interpreted with a generalized inhomogeneous magnetization transfer (ihMT) model.

T1D, the relaxation time of dipolar order, is sensitive to slow motional processes. Thus T1D 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 T1D model associated with a modified ihMT sequence was previously proposed for in vivo evaluation of T1D with MRI. However, experiments have suggested that myelinated tissues exhibit multiple T1D components probably due to a heterogeneous molecular mobility. A bi-component T1D 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 T1Ds 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 T1D model.

Imaging molecules.

Molecular imaging using MRI is gaining momentum. While sensitivity of MR is limited compared to other molecular imaging modalities, the molecular specificity is high in comparison. Moreover, MRI offers contrast based on multitude of processes and scales, from intramolecular relaxation pathways to water diffusion. Living tissue offers abundance of potential molecular targets of interest in biology and medicine. In this short perspective we focus on some direct and indirect methods to visualize endogenous molecules. We briefly discuss Spectroscopic Imaging (MRSI), Chemical Exchange Saturation Transfer (CEST) and Magnetization Transfer Contrast (MTC). Imaging molecules with MRI is part of the larger universe of imaging methods. Moreover, it is part of ever increasing pool of data combining imaging with other modalities, biology and patient outcomes.

Validating the sensitivity of inhomogeneous magnetization transfer (ihMT) MRI to myelin with fluorescence microscopy.

Inhomogeneous Magnetization Transfer (ihMT) is a development from the MT MRI technique. IhMT can be considered as a dipolar order relaxation time (T1D) 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 T1D-filtering and radiofrequency power temporal distributions, were used for comparison with fluorescence microscopy. Strong and significant linear relationships (r2 (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 (r2 (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. T1D-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 T1D than myelin. Overall, these results strongly support the sensitivity of ihMT to myelin content.

Reproducibility of inhomogeneous magnetization transfer (ihMT): A test-retest, multi-site study.

BACKGROUND: Inhomogeneous magnetization transfer (ihMT) has been reported to feature superior sensitivity and specificity for myelin imaging. However, the reproducibility on ihMT has yet been rarely investigated up to date. The purpose of the present study is to assess the multi-center reproducibility and test-retest variability of ihMT in central nervous system. METHODS: 5 volunteers were recruited and scanned twice on three 3.0 T magnetic resonance imaging (MRI) scanners using ihMT with identical scan parameters. The maps of quantitative ihMT (qihMT) and ihMT ratio (ihMTR) for each scan were calculated. Voxel based analysis then was performed to generate qihMT and ihMTR values for major white matter fibers. The intra- and inter-scanner reliability and reproducibility was assessed with intraclass correlation coefficients (ICCs). Bland-Altman method was used to show the level of agreement between two measurement types. Paired t-test and one-way ANOVA test were also used to compare the difference between inter- and intra-scanner, respectively. RESULTS: In the 10 major white matter tracts areas, the ICCs indicated high intra- and inter-scanner measurement reliability and reproducibility. The Bland-Altman plots together with 95% confidence interval (CI) across all ROIs in the five volunteers also demonstrated good repeatability. No significant inter- and intra-scanner differences were found in Paired t-test and one-way ANOVA tests. CONCLUSION: Good inter- and intra-scanner reliability and reproducibility of ihMT measurements were observed in this study. These findings support the use of ihMT measurements as biomarkers in multicenter and/or longitudinal studies.

Low duty-cycle pulsed irradiation reduces magnetization transfer and increases the inhomogeneous magnetization transfer effect.

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.

Microstructural correlates of 3D steady-state inhomogeneous magnetization transfer (ihMT) in the human brain white matter assessed by myelin water imaging and diffusion tensor imaging.

PURPOSE: To compare the recently introduced inhomogeneous magnetization transfer (ihMT) technique with more established MRI techniques including myelin water imaging (MWI) and diffusion tensor imaging (DTI), and to evaluate the microstructural attributes correlating with this new contrast method in the human brain white matter. METHODS: Eight adult healthy volunteers underwent T1 -weighted, ihMT, MWI, and DTI imaging on a 3T human scanner. The ihMT ratio (ihMTR), myelin water fraction (MWF), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) values were calculated from different white matter tracts. The angle ( θ ) between the directions of the principal eigenvector, as measured by DTI, and the main magnetic field was calculated for all voxels from various fiber tracts. The ihMTR was correlated with MWF and DTI metrics. RESULTS: A strong correlation was found between ihMTR and MWF (ρ = 0.77, P < 0.0001). This was followed by moderate to weak correlations between ihMTR and DTI metrics: RD (ρ = -0.30, P < 0.0001), FA (ρ = 0.20, P < 0.0001), MD (ρ = -0.19, P < 0.0001), AD (ρ = 0.02, P < 0.0001). A strong correlation was found between ihMTR and θ (ρ = -0.541, P < 0.0001). CONCLUSION: The strong correlation with myelin water imaging and its low coefficient of variation suggest that ihMT has the potential to become a new structural imaging marker of myelin. The substantial orientational dependence of ihMT should be taken into account when evaluating and quantitatively interpreting ihMT results.

Whole brain inhomogeneous magnetization transfer (ihMT) imaging: Sensitivity enhancement within a steady-state gradient echo sequence.

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.

Optimization of inhomogeneous magnetization transfer (ihMT) MRI contrast for preclinical studies using dipolar relaxation time (T1D ) filtering.

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 (T1D ) 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 T1D 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 T1D 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 T1D 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.