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.

Quantitative magnetization transfer MRI unbiased by on-resonance saturation and dipolar order contributions.

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 (T1D ) 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], T2,f , T2,b , R, and free pool T1 ). 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 T1 . 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 T1 (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 ΔT1 = -19.0 ms). The single-point methodology yielded consistent MPF and T1 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.

Inhomogeneous magnetization transfer imaging: Concepts and directions for further development.

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, T1D , that is very different from the T1 and T2 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 T1D 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 T1D . 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.

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.

Protonation tuned dipolar order mediated 1H→13C cross-polarization for dissolution-dynamic nuclear polarization experiments.

A strategy of dipolar order mediated nuclear spin polarization transfer has recently been combined with dissolution-dynamic nuclear polarization (dDNP) and improved by employing optimized shaped radiofrequency pulses and suitable molecular modifications. In the context of dDNP experiments, this offers a promising means of transferring polarization from high-gamma 1H spins to insensitive 13C spins with lower peak power and lower energy compared with state-of-the-art cross-polarization schemes. The role of local molecular groups and the glassing matrix protonation level are both postulated to play a key role in the polarization transfer pathway via an intermediary reservoir of dipolar spin order. To gain appreciation of the mechanisms involved in the dipolar order mediated polarization transfer under dDNP conditions, we investigate herein the influence of the pivotal characteristics of the sample makeup: (i) revising the protonation level for the constituents of the DNP glass; and (ii) utilizing deuterated molecular derivatives. Experimental demonstrations are presented for the case of [1-13C]sodium acetate. We find that the proton sample molarity has a large impact on both the optimal parameters and the performance of the dipolar order mediated cross-polarization sequence, with the 13C signal build-up time drastically shortened in the case of high solvent protonation levels. In the case of a deuterated molecular derivative, we observe that the nearby 2H substituted methyl group is deleterious to the 1H→13C transfer phenomenon (particularly at low levels of sample protonation). Overall, increased solvent protonation makes the dipolar order governed polarization transfer significantly faster and more efficient. This study sheds light on the influential sample formulation traits which govern the dipolar order-controlled transfer of polarization and indicates that the polarization transfer efficiencies of deuterated molecules can be boosted and reach high performances simply by adequate solvent protonation.

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.

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.

Minimizing the effects of magnetization transfer asymmetry on inhomogeneous magnetization transfer (ihMT) at ultra-high magnetic field (11.75 T).

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 %.

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.

Dipolar nuclear polarization via the spin diffusion of a dipole order.

We propose transfer of the paramagnetic impurity (PI) polarization to nuclei in bulk, outside the diffusion barrier, by using dipolar system of the nuclear spins. The transfer can overcome influence of the diffusion barrier and is proposed to be implemented in four stages. At the first stage, transition of the Zeeman PI order to the Zeeman order of nuclear spins inside the spin-diffusion barrier is occurred. During the second stage the Zeeman order of both the nuclear spins inside the barrier and the nuclear spins in bulk is transferred into the nuclear dipolar spin order. As a result, the nuclear dipolar spin reservoir inside the barrier acquires a lower spin temperature, and thus a gradient of the spin temperature of the nuclear dipolar spin system is created. Since the external magnetic field and the magnetic field created by PIs do not effect on the dipole-dipole interaction between the nuclear spins, the dipolar reservoir is common for all nuclear spins, both inside and outside the diffusion barrier. Restriction of the diffusion barrier is removed and the spin diffusion of the dipole energy and transfer of the spin dipolar order to bulk spins occurs without obstacles (the third stage). At the last stage, to register an NMR signal, the dipolar order of the bulk spins is transferred into the Zeeman order of these spins. Estimations show that enhancement of the polarization can reaches in the case of a 1H nuclear spin, ~220, for 13C ~850, and for 15N ~2130.

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.

Magnetization transfer in a partly deuterated lyotropic liquid crystal by single- and dual-frequency RF irradiations.

The mechanism of magnetization transfer (MT) in a lyotropic liquid crystal made of sodium dodecyl sulfate, decanol, and water molecules is investigated by using deuterated molecules and single- and dual-frequency RF irradiations. The resulting Z-spectra suggest that the decanol molecules are mainly responsible for the MT effects in this system, through proton exchange to water. This is further confirmed by monitoring the relaxation of dipolar order, which allows one to estimate the transfer rate of magnetization from decanol to water. The potential benefits of using dual-frequency RF irradiation for inducing MT effects are explored through numerical solutions to a MT model based on Provotorov's partial saturation theory.