Oscillating Gradient Spin-echo Sequences Research Articles

Impact of tissue properties on time-dependent alterations in apparent diffusion coefficient: a phantom study using oscillating-gradient spin-echo and pulsed-gradient spin-echo sequences

PurposeThe purpose of this study was to investigate whether the changes in apparent diffusion coefficients (ADCs) due to differences in diffusion time reflect tissue properties in actual measurements of phantoms.Materials and methodsVarious n-alkane phantoms and sucrose/collagen phantoms with various collagen densities were set up with and without polyvinyl alcohol (PVA) foam with an average pore diameter of 300 μm. Thus, n-alkanes or sucrose/collagen represented substrate viscosity and the presence of PVA foam represented tissue structure with septum. Diffusion-weighted images with various diffusion times (7.71–60 ms) were acquired using pulsed-gradient spin-echo (PGSE) and oscillating-gradient spin-echo (OGSE) sequences. The ADCs of the phantoms with and without PVA foam were calculated.ResultsThe ADCs of some of the phantoms without PVA decreased with diffusion times decreased. In the n-alkane phantoms, only C8H18 showed significantly different ADCs depending on the use of PVA foam in the OGSE sequence. On the other hand, sucrose/collagen phantoms showed significant differences according to diffusion time. The ADCs of the phantoms decreased as the molecular size of the n-alkanes or collagen density of the sucrose/collagen phantom increased. Compared to phantoms without PVA foam, the ADC of the phantoms with PVA foam decreased as the diffusion time increased.ConclusionChanges in ADCs due to differences in diffusion time reflect tissue properties in actual measurements of phantoms. These changes in ADCs can be used for tissue characterization in vivo.

Diffusion Tensor Imaging of Skeletal Muscle Contraction Using Oscillating Gradient Spin Echo.

Diffusion tensor imaging (DTI) measures water diffusion in skeletal muscle tissue and allows for muscle assessment in a broad range of neuromuscular diseases. However, current DTI measurements, typically performed using pulsed gradient spin echo (PGSE) diffusion encoding, are limited to the assessment of non-contracted musculature, therefore providing limited insight into muscle contraction mechanisms and contraction abnormalities. In this study, we propose the use of an oscillating gradient spin echo (OGSE) diffusion encoding strategy for DTI measurements to mitigate the effect of signal voids in contracted muscle and to obtain reliable diffusivity values. Two OGSE sequences with encoding frequencies of 25 and 50 Hz were tested in the lower leg of five healthy volunteers with relaxed musculature and during active dorsiflexion and plantarflexion, and compared with a conventional PGSE approach. A significant reduction of areas of signal voids using OGSE compared with PGSE was observed in the tibialis anterior for the scans obtained in active dorsiflexion and in the soleus during active plantarflexion. The use of PGSE sequences led to unrealistically elevated axial diffusivity values in the tibialis anterior during dorsiflexion and in the soleus during plantarflexion, while the corresponding values obtained using the OGSE sequences were significantly reduced. Similar findings were seen for radial diffusivity, with significantly higher diffusivity measured in plantarflexion in the soleus muscle using the PGSE sequence. Our preliminary results indicate that DTI with OGSE diffusion encoding is feasible in human musculature and allows to quantitatively assess diffusion properties in actively contracting skeletal muscle. OGSE holds great potential to assess microstructural changes occurring in the skeletal muscle during contraction, and for non-invasive assessment of contraction abnormalities in patients with muscle diseases.

Improved gradient waveforms for oscillating gradient spin-echo (OGSE) diffusion tensor imaging.

The dependence of the diffusion tensor on frequency is of great interest in studies of tissue microstructure because it reveals restrictions to the Brownian motion of water molecules caused by cell membranes. Oscillating gradient spin-echo (OGSE) sequences can sample this dependence with gradient shapes for which the power spectrum of the zeroth moment is focused at a target frequency. In order to maintain the total spectral power (ie the b-value), oscillating gradient amplitudes must grow with the frequency squared. For this reason, OGSE applications on clinical MRI scanners are limited to low frequencies, for which it is difficult to obtain a narrow frequency bandwidth of the gradient moment in a useful echo time. In particular, the commonly used pair of single-period trapezoidal-cosine pulses separated by a half-period produces significant side lobes away from the target frequency. To mitigate this effect, improved OGSE waveforms are proposed, which reduce the gap between the two gradient pulses to the minimum duration required for the refocusing RF pulse. Additionally, a slight deviation from the periodicity of the waveforms is proposed in order to permit using the maximum slew rate of the gradient system for all lobes of trapezoidal waveforms while maintaining advantageous spectral properties, which is not the case for the currently used OGSE sequences. Numerical calculations validate these changes, showing that both modifications significantly narrow the gradient moment power spectrum and increase the contribution of its main lobe to the b-value, thus improving the specificity of the measurement. The utility of the new shapes is demonstrated by diffusion tensor measurements of human white matter in vivo over the range of 30-75 Hz with a b-value of nearly 1000 s/mm2 , using a high-performance gradient insert. However, the improvement should increase the sampling precision of OGSE experiments for all gradient systems.

Magnetic resonance spectroscopy extended by oscillating diffusion gradients: Cell-specific anomalous diffusion as a probe for tissue microstructure in human brain

PurposeTo demonstrate that oscillating gradient spin-echo sequences can be combined with diffusion-weighted magnetic resonance spectroscopy even on clinical MR systems to study human brain at short diffusion times to provide apparent diffusion coefficients (ADCs) sensitive to a narrower cellular length scale than pulsed gradient spin-echo sequences at long diffusion time. MethodsMeasurements were performed on a 3T MR system using a semiLaser sequence with diffusion-weighting realized by oscillating and pulsed gradient modules, encoding diffusion times <10 ms and >50 ms, respectively. Metabolite-cycling was included to measure metabolites and water simultaneously. The sequence was tested in a phantom and in a parieto-occipital cerebral region of interest with mixed gray/white matter content of 6 subjects. The water reference was used for phase, frequency, and eddy-current correction as well as motion compensation. ADCs were estimated by 1D sequential and 2D simultaneous fitting. ResultsMeasurements in the phantom established that both sequences yield equal ADCs, independent of diffusion time, as expected for free diffusion. In contrast, averaged metabolite diffusion in vivo was found to be 1.9 times faster at short (8.3 ms) than at long (155 ms) diffusion times. The difference in ADC was found to be statistically significant for the creatines, cholines, N-acetylaspartate, myo-inositol, and glutamate. The water ADC was measured to be 1.3 times larger at short than at long diffusion time. ConclusionIt is demonstrated that application of oscillating gradients in diffusion-weighted MRS is feasible on clinical MR systems to establish the dependence of ADCs on diffusion times in humans. The initial results largely confirm earlier reports for mice’ and rats’ brain at short and long diffusion times. ADCs representing diffusion at short and ultra-short diffusion times are of interest to probe cellular or subcellular changes in disease. The presented methodology may thus open the door for investigation of pathophysiological changes in cell-specific microstructures in human cohorts.

Changes in the ADC of diffusion-weighted MRI with the oscillating gradient spin-echo (OGSE) sequence due to differences in substrate viscosities.

Compared with the conventional pulsed gradient spin-echo (PGSE) sequence, diffusion-weighted imaging (DWI) with the oscillating gradient spin-echo (OGSE) sequence can shorten the diffusion time by changing the frequency. The purpose was to investigate whether n-alkanes are suitable as isotropic phantoms for estimating the diffusion coefficient with the OGSE sequence. We investigated changes in the apparent diffusion coefficient (ADC) due to differences in the viscosities of nine n-alkane phantoms with different numbers of carbon atoms from C8H18 to C16H34 using OGSE and PGSE sequences at 21°C. Effective diffusion times of 4.3, 5.1, 6.5, 9.3, 20, 40, and 60ms were used. The T2 relaxation times of each n-alkane phantom were measured using quantitative synthetic magnetic resonance imaging (MRI). Circular regions of interest were placed manually within the alkane phantoms on ADC and T2 maps. In each alkane phantom, changes in mean ADC values were almost constant with changes in diffusion times. Viscosities and ADC values showed inverse proportionality, as expected theoretically. The ADC values of alkanes do not depend on diffusion times. The n-alkanes can be useful phantoms for assessing the accuracy of clinical protocols of DWI with the OGSE sequence.

Improving the Realism of White Matter Numerical Phantoms: A Step toward a Better Understanding of the Influence of Structural Disorders in Diffusion MRI

White matter is composed of irregularly packed axons leading to a structural disorder in the extra-axonal space. Diffusion MRI experiments using oscillating gradient spin echo sequences have shown that the diffusivity transverse to axons in this extra-axonal space is dependent on the frequency of the employed sequence. In this study, we observe the same frequency-dependence using 3D simulations of the diffusion process in disordered media. We design a novel white matter numerical phantom generation algorithm which constructs biomimicking geometric configurations with few design parameters, and enables to control the level of disorder of the generated phantoms. The influence of various geometrical parameters present in white matter, such as global angular dispersion, tortuosity, presence of Ranvier nodes, beading, on the extra-cellular perpendicular diffusivity frequency dependence was investigated by simulating the diffusion process in numerical phantoms of increasing complexity and fitting the resulting simulated diffusion MR signal attenuation with an adequate analytical model designed for trapezoidal OGSE sequences. This work suggests that angular dispersion and especially beading have non-negligible effects on this extracellular diffusion metrics that may be measured using standard OGSE DW-MRI clinical protocols.

Low frequency oscillating gradient spin-echo sequences improve sensitivity to axon diameter: An experimental study in viable nerve tissue

Mapping axon diameters within the central and peripheral nervous system could play an important role in our understanding of nerve pathways, and help diagnose and monitor an array of neurological disorders. Numerous diffusion MRI methods have been proposed for imaging axon diameters, most of which use conventional single diffusion encoding (SDE) spin echo sequences. However, a growing number of studies show that oscillating gradient spin echo (OGSE) sequences can provide additional advantages over conventional SDE sequences. Recent theoretical results suggest that this is especially the case in realistic scenarios, such as when fibres have unknown or dispersed orientation. In the present study, we adopt the ActiveAx approach to experimentally investigate the extent of these advantages by comparing the performances of SDE and trapezoidal OGSE in viable nerve tissue. We optimise SDE and OGSE ActiveAx protocols for a rat peripheral nerve tissue and test their performance using Monte Carlo simulations and a 800 mT/m gradient strength pre-clinical imaging experiment. The imaging experiment uses excised sciatic nerve from a rat's leg placed in a MRI compatible viable isolated tissue (VIT) maintenance chamber, which keeps the tissue in a viable physiological state that preserves the structural complexity of the nerve and enables lengthy scan times. We compare model estimates to histology, which we perform on the nerve post scanning. Optimisation produces a three-shell SDE and OGSE ActiveAx protocol, with the OGSE protocol consisting of one SDE sequence and two low-frequency oscillating gradient waveform sequences. Both simulation and imaging results show that the OGSE ActiveAx estimates of the axon diameter index have a higher accuracy and a higher precision compared to those from SDE. Histology estimates of the axon diameter index in our nerve tissue samples are 4–5.8 μm and these are excellently matched with the OGSE estimates 4.2–6.5 μm, while SDE overestimates at 5.2–8 μm for the same sample. We found OGSE estimates to be more precise with on average a 0.5 μm standard deviation compared to the SDE estimates which have a 2 μm standard deviation. When testing the robustness of the estimates when the number of the diffusion gradient directions reduces, we found that both OGSE and SDE estimates are affected, however OGSE is more robust to these changes than the SDE. Overall, these results suggest, quantitatively and in in vivo conditions, that low-frequency OGSE sequences may provide improved accuracy of axon diameter mapping compared to standard SDE sequences.

New insights about time-varying diffusivity and its estimation from diffusion MRI.

Characterizing the relation between the applied gradient sequences and the measured diffusion MRI signal is important for estimating the time-dependent diffusivity, which provides important information about the microscopic tissue structure. In this article, we extend the classical theory of Stepišnik for measuring time-dependent diffusivity under the Gaussian phase approximation. In particular, we derive three novel expressions which represent the diffusion MRI signal in terms of the mean-squared displacement, the instantaneous diffusivity, and the velocity autocorrelation function. We present the explicit signal expressions for the case of single diffusion encoding and oscillating gradient spin-echo sequences. Additionally, we also propose three different models to represent time-varying diffusivity and test them using Monte-Carlo simulations and in vivo human brain data. The time-varying diffusivities are able to distinguish the synthetic structures in the Monte-Carlo simulations. There is also strong statistical evidence about time-varying diffusivity from the in vivo human data set. The proposed theory provides new insights into our understanding of the time-varying diffusivity using different gradient sequences. The proposed models for representing time-varying diffusivity can be utilized to study time-varying diffusivity using in vivo human brain diffusion MRI data. Magn Reson Med 78:763-774, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Assessing the accuracy of using oscillating gradient spin echo sequences with AxCaliber to infer micron-sized axon diameters.

Current magnetic resonance imaging (MRI) axon diameter measurements rely on the pulsed gradient spin-echo sequence, which is unable to provide diffusion times short enough to measure small axon diameters. This study combines the AxCaliber axon diameter fitting method with data generated from Monte Carlo simulations of oscillating gradient spin-echo sequences (OGSE) to infer micron-sized axon diameters, in order to determine the feasibility of using MRI to infer smaller axon diameters in brain tissue. Monte Carlo computer simulation data were synthesized from tissue geometries of cylinders of different diameters using a range of gradient frequencies in the cosine OGSE sequence . Data were fitted to the AxCaliber method modified to allow the new pulse sequence. Intra- and extra-axonal water were studied separately and together. The simulations revealed the extra-axonal model to be problematic. Rather than change the model, we found that restricting the range of gradient frequencies such that the measured apparent diffusion coefficient was constant over that range resulted in more accurate fitted diameters. Thus a careful selection of frequency ranges is needed for the AxCaliber method to correctly model extra-axonal water, or adaptations to the method are needed. This restriction helped reduce the necessary gradient strengths for measurements that could be performed with parameters feasible for a Bruker BG6 gradient set. For these experiments, the simulations inferred diameters as small as 0.5μm on square-packed and randomly packed cylinders. The accuracy of the inferred diameters was found to be dependent on the signal-to-noise ratio (SNR), with smaller diameters more affected by noise, although all diameter distributions were distinguishable from one another for all SNRs tested. The results of this study indicate the feasibility of using MRI with OGSE on preclinical scanners to infer small axon diameters.

Structural information revealed by the dispersion of ADC with frequency

Diffusion MRI provides a non-invasive means to characterize tissue microstructure at varying length scales. Temporal diffusion spectra reveal how the apparent diffusion coefficient (ADC) varies with frequency. When measured using oscillating gradient spin echo sequences, the manner in which ADC disperses with gradient frequency (which is related to the reciprocal of diffusion time) provides information on the characteristic dimensions of restricting structures within the medium. For example, the dispersion of ADC with oscillating gradient frequency (ΔfADC) has been shown to correlate with axon sizes in white matter and provide novel tissue contrast in images of mouse hippocampus and cerebellum. However, despite increasing interest in applying frequency-dependent ADC to derive novel information on tissue, the interpretations of ADC spectra are not always clear. In this study, the relation between ADC spectra and restricting dimensions are further elucidated and used to derive novel image contrast related to the sizes of intrinsic microstructures.

Systematic changes to the apparent diffusion tensor of in vivo rat brain measured with an oscillating-gradient spin-echo sequence

As the oscillating gradient spin-echo sequence has shown promise as a means to probe tissue microstructure, it was applied here to diffusion-tensor imaging of in vivo rat brain. The apparent diffusion tensor (ADT) was estimated for motion-probing gradient (MPG) frequencies in the range 33.3-133.3 Hz, and regions-of-interest (ROIs) in the corpus callosum (CC), visual cortex (VC), cerebellar white matter (CBWM) and cerebellar grey matter (CBGM) were selected for detailed analysis. There were substantial, approximately linear changes to the ADT with increasing MPG frequency for all four ROIs. All ROIs showed clear increases in mean diffusivity. CBWM had a substantial decrease in fractional anisotropy, whereas the CC and VC had minor increases of the same parameter. All eigenvalues of the ADT tended to increase with frequency for the CBWM, CBGM and VC, but only the principal eigenvalue increased strongly for the CC. On the other hand, there was no evidence that the orientation of the principal eigenvector varied systematically with MPG frequency for any of the ROIs. The relationship between the behaviour of the eigenvalues and the behaviours of the mean diffusivity and fractional anisotropy is investigated in detail. Pixelwise linear fits to the MD from individual animals found elevated changes across the cerebellum. The data acquired for this work encompassed a range of effective diffusion-times from 7.5 ms down to 1.875 ms, and some ideas on how the results might be used to extract quantitative information about brain tissue microstructure are discussed.

Oscillating and pulsed gradient diffusion magnetic resonance microscopy over an extendedb‐value range: Implications for the characterization of tissue microstructure

Oscillating gradient spin-echo (OGSE) pulse sequences have been proposed for acquiring diffusion data with very short diffusion times, which probe tissue structure at the subcellular scale. OGSE sequences are an alternative to pulsed gradient spin echo measurements, which typically probe longer diffusion times due to gradient limitations. In this investigation, a high-strength (6600 G/cm) gradient designed for small-sample microscopy was used to acquire OGSE and pulsed gradient spin echo data in a rat hippocampal specimen at microscopic resolution. Measurements covered a broad range of diffusion times (TDeff = 1.2-15.0 ms), frequencies (ω = 67-1000 Hz), and b-values (b = 0-3.2 ms/μm2). Variations in apparent diffusion coefficient with frequency and diffusion time provided microstructural information at a scale much smaller than the imaging resolution. For a more direct comparison of the techniques, OGSE and pulsed gradient spin echo data were acquired with similar effective diffusion times. Measurements with similar TDeff were consistent at low b-value (b < 1 ms/μm(2) ), but diverged at higher b-values. Experimental observations suggest that the effective diffusion time can be helpful in the interpretation of low b-value OGSE data. However, caution is required at higher b, where enhanced sensitivity to restriction and exchange render the effective diffusion time an unsuitable representation. Oscillating and pulsed gradient diffusion techniques offer unique, complementary information. In combination, the two methods provide a powerful tool for characterizing complex diffusion within biological tissues.

Probing mouse brain microstructure using oscillating gradient diffusion MRI

High resolution diffusion tensor images of the mouse brain were acquired using the pulsed gradient spin echo sequence and the oscillating gradient spin echo sequence. The oscillating gradient spin echo tensor images demonstrated frequency-dependent changes in diffusion measurements, including apparent diffusion coefficient and fractional anisotropy, in major brain structures. Maps of the rate of change in apparent diffusion coefficient with oscillating gradient frequency revealed novel tissue contrast in the mouse hippocampus, cerebellum, and cerebral cortex. The observed frequency-dependent contrasts resembled neuronal soma-specific Nissl staining and nuclei-specific 4',6-diamidino-2-phenylindole (DAPI) staining in the mouse brain, which suggests that the contrasts might be related to key features of cytoarchitecture in the brain. In the mouse cuprizone model, oscillating gradient spin echo-based diffusion MRI revealed significantly higher frequency-dependence of perpendicular diffusivity (λ(⊥) ) in the demyelinated caudal corpus callosum at 4 weeks after cuprizone treatment when compared with control mice and mice at 6 weeks after cuprizone treatment. The elevated frequency-dependence of λ(⊥) coincided with the infiltration of activated microglia/macrophages and disruption of axons during acute demyelination in the caudal corpus callosum. The results demonstrate the potential of oscillating gradient spin echo-based diffusion MRI for providing tissue contrasts complimentary to conventional pulsed gradient spin echo-based diffusion MRI.

Determination of a Micron-Scale Restricted Structure in a Perfluorinated Membrane from Time-Dependent Self-Diffusion Measurements

We investigated the 1H time-dependent self-diffusion coefficients, Deff, in perfluorinated membrane with low and high water contents (6% and 24%) at the temperature range from 233 to 323 K. The D(Δeff) was measured as a function of the diffusion time, Δeff, from 1 to 100 ms by field gradient NMR techniques. The oscillating gradient spin-echo sequence (OGSE) and the bipolar pulse longitudinal eddy current delay sequence (BPPLED) were employed to examine the D(Δeff) of the short and long Δeff. The results showed that the 1H self-diffusion coefficients were dependent on Δeff less than 2 ms due to restricted geometry and were constant beyond 3 ms. The tortuosity, α, and surface-to-volume ratio of pore, S/V, for proton diffusion were estimated as geometrical parameters at each temperature. The values of S/V revealed the existence of micron-scale restricted structure compared with well-known nanometer-sized domain in perfluorinated membrane. Activation energy, Ea, of diffusion was also evaluated from the temperature dependence of diffusion at temperature above 263 K. The Ea in the membrane and in the bulk water were almost the same at the temperature range above 263 K while it had some difference at lower temperature.