Detection of microscopic diffusion anisotropy in human cortical gray matter in vivo with double diffusion encoding.

PURPOSE: To detect microscopic diffusion anisotropy in human cortical gray matter in vivo with double diffusion encoding experiments. METHODS: Double diffusion encoding experiments were performed on a 3 T whole-body MR system using echo-planar imaging. Angular double diffusion encoding measurements were acquired with 8 × 8 and 12 × 12 planar direction combinations and were analyzed in three regions of interest containing white matter, mostly cortical gray matter, and one having significant contributions from cerebrospinal fluid. Inversion with variable recovery times served to estimate and eliminate white matter partial volume effects. To investigate the influence of magnetic field inhomogeneities, experiments with gradient offsets and cross-term compensated diffusion weightings were performed. The MA index, a rotationally invariant measure of the microscopic diffusion anisotropy, was determined from measurements with 96 direction combinations. RESULTS: The angular signal modulation in the gray matter region of interest has two components, one being consistent, inter alia, with cross terms with field inhomogeneities while the other represents a signal difference between parallel/antiparallel and orthogonal direction combinations, ie, the fingerprint of microscopic diffusion anisotropy. Based on the amplitudes and their dependency on the inversion time, white matter partial volumes can be excluded as the sole source for this modulation, providing strong evidence for the detection of microscopic diffusion anisotropy in cortical gray matter. MA maps of healthy volunteers show considerably lower values in cortical gray matter compared with white matter. CONCLUSION: Microscopic diffusion anisotropy can be measured in human cortical brain matter, which could help to characterize the microstructure of healthy and pathological tissue.

Microscopic diffusion anisotropy in the human brain: Age-related changes.

The fractional anisotropy (FA) that can be derived from diffusion tensor imaging (DTI), is ambiguous because it not only depends on the tissue microstructure but also on the axon or fiber orientation distribution within a voxel. Measures of the microscopic diffusion anisotropy, like the microscopic anisotropy index (MA) that can be determined with so-called double-wave-vector (DWV) or double diffusion encoding (DDE) imaging, are independent of this orientation distribution and, thus, offer a more direct and undisguised access to the tissue structure on a cellular or microscopic scale. In this study, FA and MA measurements were performed in a group of aged (>60y), healthy volunteers and compared to the data obtained recently for a group of young (<33y), healthy volunteers to reveal age-related differences. The coefficients-of-variation (CV) determined for the aged group were considerably lower for MA than for FA in average and in most of the 16 ROIs analyzed due to lower between-subject variations of MA. FA differences between the young and the aged group were in line with previous DTI studies. MA was also decreased in the aged group but in more of the 16 ROIs and with a higher significance. Furthermore, MA differences were also observed in frontal brain regions containing fiber crossings that did not reveal significant FA differences, i.e. MA seems to provide a better sensitivity to detect microstructural changes in such regions. In some non-cortical gray matter structures like the putamen, FA was increased but MA was decreased in the aged group which could indicate a coherent fiber orientation in the aged group related to the loss of crossing or fanning fibers. In conclusion, MA not only could improve the detectability of differences of the tissue microstructure but, in conjunction with FA, could also help to identify the underlying changes.

Conventions and nomenclature for double diffusion encoding NMR and MRI.

Stejskal and Tanner's ingenious pulsed field gradient design from 1965 has made diffusion NMR and MRI the mainstay of most studies seeking to resolve microstructural information in porous systems in general and biological systems in particular. Methods extending beyond Stejskal and Tanner's design, such as double diffusion encoding (DDE) NMR and MRI, may provide novel quantifiable metrics that are less easily inferred from conventional diffusion acquisitions. Despite the growing interest on the topic, the terminology for the pulse sequences, their parameters, and the metrics that can be derived from them remains inconsistent and disparate among groups active in DDE. Here, we present a consensus of those groups on terminology for DDE sequences and associated concepts. Furthermore, the regimes in which DDE metrics appear to provide microstructural information that cannot be achieved using more conventional counterparts (in a model-free fashion) are elucidated. We highlight in particular DDE's potential for determining microscopic diffusion anisotropy and microscopic fractional anisotropy, which offer metrics of microscopic features independent of orientation dispersion and thus provide information complementary to the standard, macroscopic, fractional anisotropy conventionally obtained by diffusion MR. Finally, we discuss future vistas and perspectives for DDE.

Microscopic diffusion anisotropy in the human brain: reproducibility, normal values, and comparison with the fractional anisotropy.

Human neuroimaging of tissue microstructure, such as axonal density and integrity, is key in clinical and neuroscience research. Most studies rely on diffusion tensor imaging (DTI) and the measures derived from it, most prominently fractional anisotropy (FA). However, FA also depends on fiber orientation distribution, a more macroscopic tissue property. Recently introduced measures of so-called microscopic diffusion anisotropy, diffusion anisotropy on a cellular or microscopic level, overcome this limitation because they are independent of the orientation distributions of axons and fibers. In this study, we evaluate the feasibility of two measures of microscopic diffusion anisotropy I(MA) and MA indices, for human neuroscience and clinical research. Both indices reflect the eccentricity of the cells but while I(MA) also depends on the cell size, MA is independent of the cell size and, like FA, scaled between 0 and 1. In whole-brain measurements of a group of 19 healthy volunteers, we measured average values and variability, evaluated their reproducibility, both within and between sessions, and compared MA to FA values in selected regions-of-interest (ROIs). The within- and between-session comparison did not show substantial differences but the reproducibility was much better for the MA than I(MA) (coefficient of variation between sessions 10.5% vs. 28.9%). The reproducibility was less for MA than FA overall, but comparable in the defined ROIs and the average group sizes required for between-group comparisons was similar (about 60 participants for a relative difference of 5%). Group-averaged values of MA index were generally larger and showed less variation across white-matter brain ROIs than FA (mean ± standard deviation of seven ROIs 0.83 ± 0.10 vs. 0.58 ± 0.13). Even in some gray-matter ROIs, MA values comparable to those of white matter ROIs were observed. Furthermore, the within-group variation of the values in white matter ROIs was lower for the MA compared to the FA (mean standard deviation over volunteers 0.038 vs. 0.049) which could be due to significant variability in the distribution of fiber orientation contributing to FA. These results indicate that MA (i) should be preferred to I(MA), (ii) has a reproducibility and group-size requirements comparable to those of FA; (iii) is less sensitive to the fiber orientation distribution than FA; and (iv) could be more sensitive to differences or changes of the tissue microstructure than FA. R1.1.

Mapping measures of microscopic diffusion anisotropy in human brain white matter in vivo with double-wave-vector diffusion-weighted imaging.

PURPOSE: To demonstrate that rotationally invariant measures of the diffusion anisotropy on a microscopic scale can be mapped in human brain white matter in vivo. METHODS: Echo-planar imaging experiments (resolution 3.0 × 3.0 × 3.0 mm(3) ) involving two diffusion-weighting periods (δ = 22 ms, Δ = 25 ms) in the same acquisition, so-called double-wave-vector or double-pulsed-field-gradient diffusion-weighting experiments, were performed on a 3 T whole-body magnetic resonance system with a long mixing time ( τm=45 ms) between the two diffusion weightings. RESULTS: The disturbing influences of background gradient fields, eddy currents, and the finite mixing time can be minimized using 84 direction combinations based on nine directions and their antipodes. In healthy volunteers, measures of the microscopic diffusion anisotropy ( IMA and MA indexes) could be mapped in white matter across the human brain. The measures were independent (i) of the absolute orientation of the head and of the diffusion directions and (ii) of the predominant fiber orientation. Compared to the fractional anisotropy derived from the conventional diffusion tensor, the double-wave-vector indexes exhibit a narrower distribution, which could reflect their independence of the fiber orientation distribution. CONCLUSIONS: Mapping measures of the microscopic diffusion anisotropy in human brain white matter is feasible in vivo and could help to characterize tissue microstructure in the healthy and pathological brain.

Double-wave-vector diffusion-weighted imaging reveals microscopic diffusion anisotropy in the living human brain.

Diffusion-tensor imaging is widely used to characterize diffusion in biological tissue, however, the derived anisotropy information, e.g., the fractional anisotropy, is ambiguous. For instance, low values of the diffusion anisotropy in brain white matter voxels may reflect a reduced axon density, i.e., a loss of fibers, or a lower fiber coherence within the voxel, e.g., more crossing fibers. This ambiguity can be avoided with experiments involving two diffusion-weighting periods applied successively in a single acquisition, so-called double-wave-vector or double-pulsed-field-gradient experiments. For a long mixing time between the two periods such experiments are sensitive to the cells' eccentricity, i.e., the diffusion anisotropy present on a microscopic scale. In this study, it is shown that this microscopic diffusion anisotropy can be detected in white matter in the living human brain, even in a macroscopically isotropic region-of-interest (fractional anisotropy = 0). The underlying signal difference between parallel and orthogonal wave vector orientations does not show up in standard diffusion-weighting experiments but is specific to the double-wave-vector experiment. Furthermore, the modulation amplitude observed is very similar for regions-of-interest with different fractional anisotrpy values. Thus, double-wave-vector experiments may provide a direct and reliable access to white matter integrity independent of the actual fiber orientation distribution within the voxel.

Detection of microscopic diffusion anisotropy on a whole-body MR system with double wave vector imaging.

Double-wave-vector diffusion-weighting experiments can detect diffusion anisotropy on a microscopic level which, e.g., could distinguish lower fiber densities from reduced fiber coherence. The underlying signal difference between parallel and orthogonal wave vector orientations has been observed on vertical-bore MR systems (≥500 mT m(-1) ); however, numerical simulations reveal that it is expected to be considerably reduced for typical whole-body MR gradient pulse durations. Here, pig spinal cord tissue and a reference fluid phantom were investigated on a 3 T clinical MR system (40 mT m(-1) ). By averaging over different absolute wave vector orientations, signal variations caused by experimental imperfections like background gradient fields and eddy currents were minimized and a rotationally invariant anisotropy measure could be assessed. A significant microscopic anisotropy was observed in gray and white matter tissue even in the plane perpendicular to the cord which is consistent with previous vertical-bore experiments. Thus, it is demonstrated that double-wave-vector experiments can investigate the microscopic anisotropy on whole-body MR systems.

Double-wave-vector diffusion-weighting experiments with multiple concatenations at long mixing times.

MR sequences where two diffusion-weighting periods are applied successively in a single acquisition seem to be a promising tool for the investigation of tissue structure on a microscopic level such as the characterization of the compartment size or eccentricity measures of pores. However, the application of such double-wave-vector (DWV) experiments on whole-body MR systems is hampered by the long gradient pulses required that have been shown to reduce the signal modulation. In this work, it is demonstrated that involving multiple concatenations of the two diffusion-weighting periods can ameliorate this problem in experiments with long mixing times between the two wave vectors. The recently presented tensor equation is extended to multiple concatenations. As confirmed by Monte-Carlo simulations, this model shows a good approximation of the signals observed for typical whole-body gradient pulse durations and the derived anisotropy measures are obtained with good accuracy. Most importantly, the signal modulation is increased with multiple concatenations because shorter gradient pulses can be used to achieve the desired diffusion-weighting. Thus, the multiple concatenation approach may help to improve the applicability and reliability of DWV measurements with long mixing times on standard whole-body MR systems.

A tensor model and measures of microscopic anisotropy for double-wave-vector diffusion-weighting experiments with long mixing times.

Experiments with two diffusion-weighting periods applied successively in a single experiment, so-called double-wave-vector (DWV) diffusion-weighting experiments, are a promising tool for the investigation of material or tissue structure on a microscopic level, e.g. to determine cell or compartment sizes or to detect pore or cell anisotropy. However, the theoretical descriptions presented so far for experiments that aim to investigate the microscopic anisotropy with a long mixing time between the two diffusion weightings, are limited to certain wave vector orientations, specific pore shapes, and macroscopically isotropic samples. Here, the signal equations for fully restricted diffusion are re-investigated in more detail. A general description of the signal behavior for arbitrary wave vector directions, pore or cell shapes, and orientation distributions of the pores or cells is obtained that involves a fourth-order tensor approach. From these equations, a rotationally invariant measure of the microscopic anisotropy, termed MA, is derived that yields information complementary to that of the (macroscopic) anisotropy measures of standard diffusion-tensor acquisitions. Furthermore, the detailed angular modulation for arbitrary cell shapes with an isotropic orientation distribution is derived. Numerical simulations of the MR signal with a Monte-Carlo algorithms confirm the theoretical considerations. The extended theoretical description and the introduction of a reliable measure of the microscopic anisotropy may help to improve the applicability and reliability of corresponding experiments.