Search

Maxwell or concomitant fields imprint additional phases on the transverse magnetization. This concomitant phase may cause severe image artifacts like signal voids or distort the quantitative parameters due to the induced intravoxel dephasing. In particular, double diffusion encoding (DDE) schemes with two pairs of bipolar diffusion-weighting gradients separated by a refocusing radiofrequency (RF) pulse are prone to concomitant field-induced artifacts. In this work, a method for reducing concomitant field effects in these DDE sequences based on additional oscillating gradients is presented. These oscillating gradient pulses obtained by constrained optimization were added to the original gradient waveforms. The modified sequences reduced the accumulated concomitant phase without significant changes in the original sequence characteristics. The proposed method was applied to a DDE acquisition scheme consisting of 60 pairs of diffusion wave vectors. For phantom as well as for in vivo experiments, a considerable increase in the signal-to-noise ratio (SNR) was obtained. For phantom measurements with a diffusion weighting of b = 2000 s/mm2 for each of the gradient pairs, an SNR increase of up to 40% was observed for a transversal slice that had a distance of 5 cm from the isocenter. For equivalent slice parameters, in vivo measurements in the brain of a healthy volunteer exhibited an increase in SNR of up to 35% for b = 750 s/mm2 for each weighting. These findings are supported by corresponding simulations, which also predict a positive effect on the SNR. In summary, the presented method leads to an SNR gain without additional RF refocusing pulses. • Proposes a novel method for concomitant field effect reduction for double diffusion encoding. • Demonstrates a positive effect on the SNR in phantom and in vivo. • Reveals importance for clinical high-amplitude gradient systems. [ABSTRACT FROM AUTHOR]

Water exchange between the different compartments of a heterogeneous specimen can be characterized via diffusion magnetic resonance imaging (dMRI). Many analysis frameworks using dMRI data have been proposed to describe exchange, often using a double diffusion encoding (DDE) stimulated echo sequence. Techniques such as diffusion exchange weighted imaging (DEWI) and the filter exchange and rapid exchange models, use a specific subset of the full space DDE signal. In this work, a general representation of the DDE signal was employed with different sampling schemes (namely constant b1, diagonal and anti-diagonal) from the data reduction models to estimate exchange. A near-uniform sampling scheme was proposed and compared with the other sampling schemes. The filter exchange and rapid exchange models were also applied to estimate exchange with their own subsampling schemes. These subsampling schemes and models were compared on both simulated data and experimental data acquired with a benchtop MR scanner. In synthetic data, the diagonal and near-uniform sampling schemes performed the best due to the consistency of their estimates with the ground truth. In experimental data, the shifted diagonal and near-uniform sampling schemes outperformed the others, yielding the most consistent estimates with the full space estimation. The results suggest the feasibility of measuring exchange using a general representation of the DDE signal along with variable sampling schemes. In future studies, algorithms could be further developed for the optimization of sampling schemes, as well as incorporating additional properties, such as geometry and diffusion anisotropy, into exchange frameworks.

Water exchange between the different compartments of a heterogeneous specimen can be characterized via diffusion magnetic resonance imaging (dMRI). Many analysis frameworks using dMRI data have been proposed to describe exchange, often using a double diffusion encoding (DDE) stimulated echo sequence. Techniques such as diffusion exchange weighted imaging (DEWI) and the filter exchange and rapid exchange models, use a specific subset of the full space DDE signal. In this work, a general representation of the DDE signal was employed with different sampling schemes (namely constant b1, diagonal and anti-diagonal) from the data reduction models to estimate exchange. A near-uniform sampling scheme was proposed and compared with the other sampling schemes. The filter exchange and rapid exchange models were also applied to estimate exchange with their own subsampling schemes. These subsampling schemes and models were compared on both simulated data and experimental data acquired with a benchtop MR scanner. In synthetic data, the diagonal and near-uniform sampling schemes performed the best due to the consistency of their estimates with the ground truth. In experimental data, the shifted diagonal and near-uniform sampling schemes outperformed the others, yielding the most consistent estimates with the full space estimation. The results suggest the feasibility of measuring exchange using a general representation of the DDE signal along with variable sampling schemes. In future studies, algorithms could be further developed for the optimization of sampling schemes, as well as incorporating additional properties, such as geometry and diffusion anisotropy, into exchange frameworks. [ABSTRACT FROM AUTHOR]

Cognitive training-induced neuroplastic brain changes have been reported. This prospective study evaluated whether microscopic fractional anisotropy (μFA) derived from double diffusion encoding (DDE) MRI could detect brain changes following a 4 week cognitive training. Twenty-nine healthy volunteers were recruited and randomly assigned into the training (n = 21) and control (n = 8) groups. Both groups underwent brain MRI including DDE MRI and 3D-T1-weighted imaging twice at an interval of 4–6 weeks, during which the former underwent the training. The training consisted of hour-long dual N-back and attention network tasks conducted five days per week. Training and time-related changes of DDE MRI indices (μFA, fractional anisotropy (FA), and mean diffusivity (MD)) and the gray and white matter volume were evaluated using mixed-design analysis of variance. In addition, any significant imaging indices were tested for correlation with cognitive training-induced task performance changes, using partial correlation analyses. μFA in the left middle frontal gyrus decreased upon the training (53 voxels, uncorrected p < 0.001), which correlated moderately with response time changes in the orienting component of attention (r = −0.521, uncorrected p = 0.032). No significant training and time-related changes were observed for other imaging indices. Thus, μFA can become a sensitive index to detect cognitive training-induced neuroplastic changes.

Cognitive training-induced neuroplastic brain changes have been reported. This prospective study evaluated whether microscopic fractional anisotropy (μFA) derived from double diffusion encoding (DDE) MRI could detect brain changes following a 4 week cognitive training. Twenty-nine healthy volunteers were recruited and randomly assigned into the training (n = 21) and control (n = 8) groups. Both groups underwent brain MRI including DDE MRI and 3D-T1-weighted imaging twice at an interval of 4–6 weeks, during which the former underwent the training. The training consisted of hour-long dual N-back and attention network tasks conducted five days per week. Training and time-related changes of DDE MRI indices (μFA, fractional anisotropy (FA), and mean diffusivity (MD)) and the gray and white matter volume were evaluated using mixed-design analysis of variance. In addition, any significant imaging indices were tested for correlation with cognitive training-induced task performance changes, using partial correlation analyses. μFA in the left middle frontal gyrus decreased upon the training (53 voxels, uncorrected p < 0.001), which correlated moderately with response time changes in the orienting component of attention (r = −0.521, uncorrected p = 0.032). No significant training and time-related changes were observed for other imaging indices. Thus, μFA can become a sensitive index to detect cognitive training-induced neuroplastic changes. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) has been established its usefulness in evaluating normal-appearing white matter (NAWM) and other lesions that are difficult to evaluate with routine clinical MRI in the evaluation of the brain and spinal cord lesions in multiple sclerosis (MS), a demyelinating disease. With the recent advances in the software and hardware of MRI systems, increasingly complex and sophisticated MRI and analysis methods, such as q-space imaging, diffusional kurtosis imaging, neurite orientation dispersion and density imaging, white matter tract integrity, and multiple diffusion encoding, referred to as advanced diffusion MRI, have been proposed. These are capable of capturing in vivo microstructural changes in the brain and spinal cord in normal and pathological states in greater detail than DTI.This paper reviews the current status of recent advanced diffusion MRI for assessing MS in vivo as part of an issue celebrating two decades of magnetic resonance in medical sciences (MRMS), an official journal of the Japanese Society of Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]

Diffusion exchange spectroscopy (DEXSY) is a multidimensional NMR technique that can reveal how water molecules exchange between compartments within heterogeneous media, such as biological tissue. Data from DEXSY experiments is typically processed using numerical inverse Laplace transforms (ILTs) to produce a diffusion-diffusion spectrum. A tacit assumption of this ILT approach is that the signal behavior is Gaussian—i.e., the spin echo intensity decays exponentially with the degree of diffusion weighting. The assumptions that underlie Gaussian signal behavior may be violated, however, depending on the gradient strength applied and the sample under study. We argue that non-Gaussian signal behavior due to restrictions is to be expected in the study of biological tissue using diffusion NMR. Further, we argue that this signal behavior can produce confounding features in the diffusion-diffusion spectra obtained from numerical ILTs of DEXSY data—entangling the effects of restriction and exchange. Specifically, restricted signal behavior can result in broadening of peaks and in the appearance of illusory exchanging compartments with distributed diffusivities, which pearl into multiple peaks if not highly regularized. We demonstrate these effects on simulated data. That said, we suggest the use of features in the signal acquisition domain that can be used to rapidly probe exchange without employing an ILT. We also propose a means to characterize the non-Gaussian signal behavior due to restrictions within a sample using DEXSY measurements with a near zero mixing time or storage interval. We propose a combined acquisition scheme to independently characterize restriction and exchange with various DEXSY measurements, which we term Restriction and Exchange from Equally-weighted Double and Single Diffusion Encodings (REEDS-DE). We test this method on ex vivo neonatal mouse spinal cord—a sample consisting primarily of gray matter—using a low-field, static gradient NMR system. In sum, we highlight critical shortcomings of prevailing DEXSY analysis methods that conflate the effects of restriction and exchange, and suggest a viable experimental approach to disentangle them.

Purpose: The impact of microscopic diffusional kurtosis (µK), arising from restricted diffusion and/or structural disorder, remains a controversial issue in contemporary diffusion MRI (dMRI). Recently, correlation tensor imaging (CTI) was introduced to disentangle the sources contributing to diffusional kurtosis, without relying on a‐priori multi‐gaussian component (MGC) or other microstructural assumptions. Here, we investigated µK in in vivo rat brains and assessed its impact on state‐of‐the‐art methods ignoring µK. Theory and Methods: CTI harnesses double diffusion encoding (DDE) experiments, which were here improved for speed and minimal bias using four different sets of acquisition parameters. The robustness of the improved CTI protocol was assessed via simulations. In vivo CTI acquisitions were performed in healthy rat brains using a 9.4T pre‐clinical scanner equipped with a cryogenic coil, and targeted the estimation of µK, anisotropic kurtosis, and isotropic kurtosis. Results: The improved CTI acquisition scheme substantially reduces scan time and importantly, also minimizes higher‐order‐term biases, thus enabling robust µK estimation, alongside Kaniso and Kiso metrics. Our CTI experiments revealed positive µK both in white and gray matter of the rat brain in vivo; µK is the dominant kurtosis source in healthy gray matter tissue. The non‐negligible µK substantially were found to bias prior MGC analyses of Kiso and Kaniso. Conclusions: Correlation Tensor MRI offers a more accurate and robust characterization of kurtosis sources than its predecessors. µK is non‐negligible in vivo in healthy white and gray matter tissues and could be an important biomarker for future studies. Our findings thus have both theoretical and practical implications for future dMRI research. [ABSTRACT FROM AUTHOR]

This paper investigates the impact of cell body (namely soma) size and branching of cellular projections on diffusion MR imaging (dMRI) and spectroscopy (dMRS) signals for both standard single diffusion encoding (SDE) and more advanced double diffusion encoding (DDE) measurements using numerical simulations. The aim is to investigate the ability of dMRI/dMRS to characterize the complex morphology of brain cells focusing on these two distinctive features of brain grey matter.To this end, we employ a recently developed computational framework to create three dimensional meshes of neuron-like structures for Monte Carlo simulations, using diffusion coefficients typical of water and brain metabolites. Modelling the cellular structure as realistically connected spherical soma and cylindrical cellular projections, we cover a wide range of combinations of sphere radii and branching order of cellular projections, characteristic of various grey matter cells. We assess the impact of spherical soma size and branching order on the b-value dependence of the SDE signal as well as the time dependence of the mean diffusivity (MD) and mean kurtosis (MK). Moreover, we also assess the impact of spherical soma size and branching order on the angular modulation of DDE signal at different mixing times, together with the mixing time dependence of the apparent microscopic anisotropy (μA), a promising contrast derived from DDE measurements.The SDE results show that spherical soma size has a measurable impact on both the b-value dependence of the SDE signal and the MD and MK diffusion time dependence for both water and metabolites. On the other hand, we show that branching order has little impact on either, especially for water. In contrast, the DDE results show that spherical soma size has a measurable impact on the DDE signal's angular modulation at short mixing times and the branching order of cellular projections significantly impacts the mixing time dependence of the DDE signal's angular modulation as well as of the derived μA, for both water and metabolites.Our results confirm that SDE based techniques may be sensitive to spherical soma size, and most importantly, show for the first time that DDE measurements may be more sensitive to the dendritic tree complexity (as parametrized by the branching order of cellular projections), paving the way for new ways of characterizing grey matter morphology, non-invasively using dMRS and potentially dMRI.

Double diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side water and metabolite DDE spectroscopic (DDES) experiments provides complementary measures from which intracellular and extracellular microscopic fractional anisotropies (μFA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular μFA and diffusivities of specific cell types. By contrast, water DDES measurements allow examination of the separate contributions to water μFA and diffusivity from the intra- and extracellular spaces, by using a wide range of b values to gradually eliminate the extracellular contribution. Here, we aimed to estimate tissue and compartment specific human brain microstructure by combining water and metabolites DDES experiments. We performed our DDES measurements in two brain regions that contain widely different amounts of white matter (WM) and gray matter (GM): parietal white matter (PWM) and occipital gray matter (OGM) in a total of 20 healthy volunteers at 7 Tesla. Metabolite DDES measurements were performed at b = 7199 s/mm2, while water DDES measurements were performed with a range of b values from 918 to 7199 s/mm2. The experimental framework we employed here resulted in a set of insights pertaining to the morphology of the intracellular and extracellular spaces in both gray and white matter. Results of the metabolite DDES experiments in both PWM and OGM suggest a highly anisotropic intracellular space within neurons and glia, with the possible exception of gray matter glia. The water μFA obtained from the DDES results at high b values in both regions converged with that of the metabolite DDES, suggesting that the signal from the extracellular space is indeed effectively suppressed at the highest b value. The μFA measured in the OGM significantly decreased at lower b values, suggesting a considerably lower anisotropy of the extracellular space in GM compared to WM. In PWM, the water μFA remained high even at the lowest b value, indicating a high degree of organization in the interstitial space in WM. Tortuosity values in the cytoplasm for water and tNAA, obtained with correlation analysis of microscopic parallel diffusivity with respect to GM/WM tissue fraction in the volume of interest, are remarkably similar for both molecules, while exhibiting a clear difference between gray and white matter, suggesting a more crowded cytoplasm and more complex cytomorphology of neuronal cell bodies and dendrites in GM than those found in long-range axons in WM.

Brain water and some critically important energy metabolites, such as lactate or glucose, are present in both intracellular and extracellular spaces (ICS/ECS) at significant levels. This ubiquitous nature makes diffusion MRI/MRS data sometimes difficult to interpret and model. While it is possible to glean information on the diffusion properties in ICS by measuring the diffusion of purely intracellular endogenous metabolites (such as NAA), the absence of endogenous markers specific to ECS hampers similar analyses in this compartment. In past experiments, exogenous probes have therefore been injected into the brain to assess their apparent diffusion coefficient (ADC) and thus estimate tortuosity in ECS. Here, we use a similar approach in mice by injecting sucrose, a well‐known ECS marker, in either the lateral ventricles or directly in the prefrontal cortex. For the first time, we propose a thorough characterization of ECS diffusion properties encompassing (1) short‐range restriction by looking at signal attenuation at high b values, (2) tortuosity and long‐range restriction by measuring ADC time‐dependence at long diffusion times and (3) microscopic anisotropy by performing double diffusion encoding (DDE) measurements. Overall, sucrose diffusion behavior is strikingly different from that of intracellular metabolites. Acquisitions at high b values not only reveal faster sucrose diffusion but also some sensitivity to restriction, suggesting that the diffusion in ECS is not fully Gaussian at high b. The time evolution of the ADC at long diffusion times shows that the tortuosity regime is not reached yet in the case of sucrose, while DDE experiments suggest that it is not trapped in elongated structures. No major difference in sucrose diffusion properties is reported between the two investigated routes of injection and brain regions. These original experimental insights should be useful to better interpret and model the diffusion signal of molecules that are distributed between ICS and ECS compartments. [ABSTRACT FROM AUTHOR]

We developed a Monte Carlo simulator for diffusion-weighted imaging sequences which displays the motion of water molecules and computes the dynamic phase dispersion due to the applied motion probing gradients. This simulator can be used to validate the analytical equations of diffusion models and understand their limitations due to their approximations. Here, we introduce the software and some specific use cases. The software can be downloaded from the following website: https://www.nirs.qst.go.jp/amr_diag. [ABSTRACT FROM AUTHOR]

Microstructure imaging by means of multidimensional diffusion encoding is increasingly applied in clinical research, with expectations that it yields a parameter that better correlates with clinical disability than current methods based on single diffusion encoding. Under the assumption that diffusion within a voxel can be well described by a collection of diffusion tensors, several parameters of this diffusion tensor distribution can be derived, including mean size, variance of sizes, orientational dispersion, and microscopic anisotropy. The information provided by multidimensional diffusion encoding also enables us to decompose the sources of the conventional fractional anisotropy and mean kurtosis. In this study, we explored the utility of the diffusion tensor distribution approach for characterizing white-matter degeneration in aging and in Parkinson disease by using double diffusion encoding. Data from 23 healthy older subjects and 27 patients with Parkinson disease were analyzed. Advanced age was associated with greater mean size and size variances, as well as smaller microscopic anisotropy. By analyzing the parameters underlying diffusion kurtosis, we found that the reductions of kurtosis in aging and Parkinson disease reported in the literature are likely driven by the reduction in microscopic anisotropy. Furthermore, microscopic anisotropy correlated with the severity of motor impairment in the patients with Parkinson disease. The present results support the use of multidimensional diffusion encoding in clinical studies and are encouraging for its future clinical implementation.

Microstructure imaging by means of multidimensional diffusion encoding is increasingly applied in clinical research, with expectations that it yields a parameter that better correlates with clinical disability than current methods based on single diffusion encoding. Under the assumption that diffusion within a voxel can be well described by a collection of diffusion tensors, several parameters of this diffusion tensor distribution can be derived, including mean size, variance of sizes, orientational dispersion, and microscopic anisotropy. The information provided by multidimensional diffusion encoding also enables us to decompose the sources of the conventional fractional anisotropy and mean kurtosis. In this study, we explored the utility of the diffusion tensor distribution approach for characterizing white-matter degeneration in aging and in Parkinson disease by using double diffusion encoding. Data from 23 healthy older subjects and 27 patients with Parkinson disease were analyzed. Advanced age was associated with greater mean size and size variances, as well as smaller microscopic anisotropy. By analyzing the parameters underlying diffusion kurtosis, we found that the reductions of kurtosis in aging and Parkinson disease reported in the literature are likely driven by the reduction in microscopic anisotropy. Furthermore, microscopic anisotropy correlated with the severity of motor impairment in the patients with Parkinson disease. The present results support the use of multidimensional diffusion encoding in clinical studies and are encouraging for its future clinical implementation. [ABSTRACT FROM AUTHOR]

Purpose: Double diffusion encoding (DDE) MRI enables the estimation of microscopic diffusion anisotropy, yielding valuable information on tissue microstructure. A recent study proposed that the acquisition of rotationally invariant DDE metrics, typically obtained using a spherical "5‐design," could be greatly simplified by assuming Gaussian diffusion, facilitating reduced acquisition times that are more compatible with clinical settings. Here, we aim to validate the new minimal acquisition scheme against the standard DDE 5‐design, and to quantify the proposed method's noise robustness to facilitate future clinical use. Theory and Methods: DDE MRI experiments were performed on both ex vivo and in vivo rat brains at 9.4 T using the 5‐design and the proposed minimal design and taking into account the difference in the number of acquisitions. The ensuing microscopic fractional anisotropy (μFA) maps were compared over a range of b‐values up to 5000 s/mm2. Noise robustness was studied using analytical calculations and numerical simulations. Results: The minimal protocol quantified μFA at an accuracy comparable to the estimates obtained by means of the more theoretically robust DDE 5‐design. μFA's sensitivity to noise was found to strongly depend on compartment anisotropy and tensor magnitude in a nonlinear manner. When μFA < 0.75 or when mean diffusivity is particularly low, very high signal‐to‐noise ratio is required for precise quantification of µFA. Conclusion: Our work supports using DDE for quantifying microscopic diffusion anisotropy in clinical settings but raises hitherto overlooked precision issues when measuring μFA with DDE and typical clinical signal‐to‐noise ratio. [ABSTRACT FROM AUTHOR]

Purpose: To present a double diffusion encoding MRI sequence on a clinical scanner to analyze micro‐structure and micro‐vasculature of tumors. Methods: The sequence was tested on phantoms, asparaguses, and 2 tumors allografts in a rodent. Results were analyzed using an adapted VERDICT model to estimate microstructural parameters. The technical feasibility of the sequence on a 3T clinical system was assessed on a water phantom. The accuracy of cell size estimation was assessed on asparaguses by comparison with light microscopy. Cell size estimations were also validated when limiting relative angles of diffusion encodings to 0 and 180°. Sensitivities to restricted diffusion and incoherent flow from the vasculature were investigated in experimental tumor models. Values of microstructural parameters in viable and decaying tumor tissue were compared with those obtained from histological analysis. Results: Measurements on the water phantom revealed no significant sequence artifacts and accurate apparent diffusion coefficient values within a 4% relative error. In asparaguses, quartiles and medians of pore size distributions typically deviated less than 6% from light microscopy regardless of whether the full or reduced set of relative angles was used. Signal analyses in tumors showed mixed effects of both blood flow and diffusion restriction. Microstructural parameter estimations in tumors were consistent with histology and allowed clear and histology‐proven distinctions between decaying and viable tumor tissue. Conclusions: Double diffusion encoding with clinical gradients and scan times allows characterization of restricted diffusion and micro‐circulation flow in tumors. Our estimated microstructural parameters are promising for further investigations in assessing microstructural evolutions in tumors. [ABSTRACT FROM AUTHOR]

Double diffusion encoding is a magnetic resonance technique with applications in measuring microstructure. In many tissues, cell size (which is of a few micrometers) is an important biological parameter. Estimating an arbitrary pore size distribution from a diffusion attenuated signal usually relies on varying a single experimental setting. This inversion process is numerically unstable. Numerical simulations are presented, where multiple experimental settings are varied concomitantly. The inversion’s results show good agreement with ground truth.

Purpose: Biophysical tissue models are increasingly used in the interpretation of diffusion MRI (dMRI) data, with the potential to provide specific biomarkers of brain microstructural changes. However, it has been shown recently that, in the general Standard Model, parameter estimation from dMRI data is ill‐conditioned even when very high b‐values are applied. We analyze this issue for the Neurite Orientation Dispersion and Density Imaging with Diffusivity Assessment (NODDIDA) model and demonstrate that its extension from single diffusion encoding (SDE) to double diffusion encoding (DDE) resolves the ill‐posedness for intermediate diffusion weightings, producing an increase in accuracy and precision of the parameter estimation. Methods: We analyze theoretically the cumulant expansion up to fourth order in b of SDE and DDE signals. Additionally, we perform in silico experiments to compare SDE and DDE capabilities under similar noise conditions. Results: We prove analytically that DDE provides invariant information non‐accessible from SDE, which makes the NODDIDA parameter estimation injective. The in silico experiments show that DDE reduces the bias and mean square error of the estimation along the whole feasible region of 5D model parameter space. Conclusions: DDE adds additional information for estimating the model parameters, unexplored by SDE. We show, as an example, that this is sufficient to solve the previously reported degeneracies in the NODDIDA model parameter estimation. [ABSTRACT FROM AUTHOR]

Purpose: It is known that white matter modeling based on commonly used linear diffusion encoding is an ill‐posed problem. We analyze the additional information gained from a double pulsed diffusion encoding. Methods: Zeroth (spherical means) and second‐order (harmonic powers) rotation invariant signal features are used to factor micro‐ and mesoscopic contributions. The b‐value dependency up to second‐order of the features form 6 nonlinear equations, which are analyzed. Results: The 6 derived equations can be uniquely solved for all relevant biophysical parameters. No assumptions about the form of the mesoscopic contribution (fiber dispersion) is necessary. Under certain conditions the solution still shows a certain degeneracy which is inherent to model. It is further shown that a combination of second‐order information from single and spherical diffusion encoding is not enough to solve the problem. Conclusions: A combination of single and double pulsed diffusion encodings is sufficient to solve the full 3 compartment white matter model uniquely. [ABSTRACT FROM AUTHOR]

Purpose: Microscopic fractional anisotropy (µFA) can disentangle microstructural information from orientation dispersion. While double diffusion encoding (DDE) MRI methods are widely used to extract accurate µFA, it has only recently been proposed that powder‐averaged single diffusion encoding (SDE) signals, when coupled with the diffusion standard model (SM) and a set of constraints, could be used for µFA estimation. This study aims to evaluate µFA as derived from the spherical mean technique (SMT) set of constraints, as well as more generally for powder‐averaged SM signals. Methods: SDE experiments were performed at 16.4 T on an ex vivo mouse brain (Δ/δ = 12/1.5 ms). The µFA maps obtained from powder‐averaged SDE signals were then compared to maps obtained from DDE‐MRI experiments (Δ/τ/δ = 12/12/1.5 ms), which allow a model‐free estimation of µFA. Theory and simulations that consider different types of heterogeneity are presented for corroborating the experimental findings. Results: µFA, as well as other estimates derived from powder‐averaged SDE signals produced large deviations from the ground truth in both gray and white matter. Simulations revealed that these misestimations are likely a consequence of factors not considered by the underlying microstructural models (such as intercomponent and intracompartmental kurtosis). Conclusion: Powder‐averaged SMT and (2‐component) SM are unable to accurately report µFA and other microstructural parameters in ex vivo tissues. Improper model assumptions and constraints can significantly compromise parameter specificity. Further developments and validations are required prior to implementation of these models in clinical or preclinical research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Diffusional kurtosis imaging (DKI) measures the deviation of the displacement probability from a normal distribution, complementing the data commonly acquired by diffusion MRI. It is important to elucidate the sources of kurtosis contrast, particularly in biological tissues where microscopic kurtosis (intrinsic kurtosis) and diffusional heterogeneity may co‐exist. Methods: We have developed a technique for microscopic kurtosis MRI, dubbed microscopic diffusional kurtosis imaging (µDKI), using a symmetrized double diffusion encoding (s‐DDE) EPI sequence. We compared this newly developed µDKI to conventional DKI methods in both a triple compartment phantom and in vivo. Results: Our results showed that whereas conventional DKI and µDKI provided similar measurements in a compartment of monosphere beads, kurtosis measured by µDKI was significantly less than that measured by conventional DKI in a compartment of mixed Gaussian pools. For in vivo brain imaging, µDKI showed small yet significantly lower kurtosis measurement in regions of the cortex, CSF, and internal capsule compared to the conventional DKI approach. Conclusions: Our study showed that µDKI is less susceptible than conventional DKI to sub‐voxel diffusional heterogeneity. Our study also provided important preliminary demonstration of our technique in vivo, warranting future studies to investigate its diagnostic use in examining neurological disorders. [ABSTRACT FROM AUTHOR]

Abstract Microscopic diffusion anisotropy (μA) has been recently gaining increasing attention for its ability to decouple the average compartment anisotropy from orientation dispersion. Advanced diffusion MRI sequences, such as double diffusion encoding (DDE) and double oscillating diffusion encoding (DODE) have been used for mapping μA, usually using measurements from a single b shell. However, the accuracy of μA estimation vis-à-vis different b-values was not assessed. Moreover, the time-dependence of this metric, which could offer additional insights into tissue microstructure, has not been studied so far. Here, we investigate both these concepts using theory, simulation, and experiments performed at 16.4T in the mouse brain, ex-vivo. In the first part, simulations and experimental results show that the conventional estimation of microscopic anisotropy from the difference of D(O)DE sequences with parallel and orthogonal gradient directions yields values that highly depend on the choice of b-value. To mitigate this undesirable bias, we propose a multi-shell approach that harnesses a polynomial fit of the signal difference up to third order terms in b-value. In simulations, this approach yields more accurate μA metrics, which are similar to the ground-truth values. The second part of this work uses the proposed multi-shell method to estimate the time/frequency dependence of μA. The data shows either an increase or no change in μA with frequency depending on the region of interest, both in white and gray matter. When comparing the experimental results with simulations, it emerges that simple geometric models such as infinite cylinders with either negligible or finite radii cannot replicate the measured trend, and more complex models, which, for example, incorporate structure along the fibre direction are required. Thus, measuring the time dependence of microscopic anisotropy can provide valuable information for characterizing tissue microstructure. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) is a promising biomarker of spinal cord injury (SCI). In the acute aftermath, DTI in SCI animal models consistently demonstrates high sensitivity and prognostic performance, yet translation of DTI to acute human SCI has been limited. In addition to technical challenges, interpretation of the resulting metrics is ambiguous, with contributions in the acute setting from both axonal injury and edema. Novel diffusion MRI acquisition strategies such as double diffusion encoding (DDE) have recently enabled detection of features not available with DTI or similar methods. In this work, we perform a systematic optimization of DDE using simulations and an in vivo rat model of SCI and subsequently implement the protocol to the healthy human spinal cord. First, two complementary DDE approaches were evaluated using an orientationally invariant or a filter-probe diffusion encoding approach. While the two methods were similar in their ability to detect acute SCI, the filter-probe DDE approach had greater predictive power for functional outcomes. Next, the filter-probe DDE was compared to an analogous single diffusion encoding (SDE) approach, with the results indicating that in the spinal cord, SDE provides similar contrast with improved signal to noise. In the SCI rat model, the filter-probe SDE scheme was coupled with a reduced field of view (rFOV) excitation, and the results demonstrate high quality maps of the spinal cord without contamination from edema and cerebrospinal fluid, thereby providing high sensitivity to injury severity. The optimized protocol was demonstrated in the healthy human spinal cord using the commercially-available diffusion MRI sequence with modifications only to the diffusion encoding directions. Maps of axial diffusivity devoid of CSF partial volume effects were obtained in a clinically feasible imaging time with a straightforward analysis and variability comparable to axial diffusivity derived from DTI. Overall, the results and optimizations describe a protocol that mitigates several difficulties with DTI of the spinal cord. Detection of acute axonal damage in the injured or diseased spinal cord will benefit the optimized filter-probe diffusion MRI protocol outlined here.

The use of two independent diffusion periods between excitation and acquisition, known as double wave vector (DWV) diffusion-weighting or double diffusion encoding, was proven to yield structural information that it is otherwise not easily available in vivo. Comparing the signal difference between relative diffusion gradient orientations, the antiparallel-parallel and the parallel-perpendicular differences yield information on pore size and shape, respectively. However, results in vivo provided larger pore sizes than expected for axons in the corticospinal tract. This study exploits DWV sensitivity to pore shape and aims to obtain information on the extracellular contributions to the DWV pore size results presented here. The in vivo DWV experiments resulted in a positive parallel-perpendicular difference which is consistent with an irregularly shaped pore dominating the origin of the signal.

Purpose: The purpose of this study is to develop double diffusion encoding (DDE) MRI methods for clinical use. Microscopic diffusion anisotropy measurements from DDE promise greater specificity to changes in tissue microstructure compared with conventional diffusion tensor imaging, but implementation of DDE sequences on whole‐body MRI scanners is challenging because of the limited gradient strengths and lengthy acquisition times. Methods: A custom single‐refocused DDE sequence was implemented on a 3T whole‐body scanner. The DDE gradient orientation scheme and sequence parameters were optimized based on a Gaussian diffusion assumption. Using an optimized 5‐min DDE acquisition, microscopic fractional anisotropy (μFA) maps were acquired for the first time in multiple sclerosis patients. Results: Based on simulations and in vivo human measurements, six parallel and six orthogonal diffusion gradient pairs were found to be the minimum number of diffusion gradient pairs necessary to produce a rotationally invariant measurement of μFA. Simulations showed that optimal precision and accuracy of μFA measurements were obtained using b‐values between 1500 and 3000 s/mm2. The μFA maps showed improved delineation of multiple sclerosis lesions compared with conventional fractional anisotropy and distinct contrast from T2‐weighted fluid attenuated inversion recovery and T1‐weighted imaging. Conclusion: The μFA maps can be measured using DDE in a clinical setting and may provide new opportunities for characterizing multiple sclerosis lesions and other types of tissue degeneration. Magn Reson Med 80:507–520, 2018. © 2017 International Society for Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]

Diffusion weighted magnetic resonance imaging (DWI) and related techniques such as diffusion tensor imaging (DTI) are uniquely sensitive to the microstructure of the brain and spinal cord. In the acute aftermath of nervous system injury, for example, DWI reveals changes caused by injury that remains invisible on other MRI contrasts such as T 2 -weighted imaging. This ability has led to a demonstrated clinical utility in cerebral ischemia. However, despite strong promise in preclinical models and research settings, DWI has not been as readily adopted for other acute injuries such as traumatic spinal cord, brain, or peripheral nerve injury. Furthermore, the precise biophysical mechanisms that underlie DWI and DTI changes are not fully understood. In this report, we review the DWI and DTI changes that occur in acute neurological injury of cerebral ischemia, spinal cord injury, traumatic brain injury, and peripheral nerve injury. Their associations with the underlying biology are examined with an emphasis on the role of acute axon and dendrite beading. Lastly, emerging DWI techniques to overcome the limitations of DTI are discussed as these may offer the needed improvements to translate to clinical settings. [ABSTRACT FROM AUTHOR]

As part of an issue celebrating 2 decades of Joseph Ackerman editing the Journal of Magnetic Resonance, this paper reviews recent progress in one of the many areas in which Ackerman and his lab has made significant contributions: NMR measurement of diffusion in biological media, specifically in brain tissue. NMR diffusion signals display exquisite sensitivity to tissue microstructure, and have the potential to offer quantitative and specific information on the cellular scale orders of magnitude below nominal image resolution when combined with biophysical modeling. Here, I offer a personal perspective on some recent advances in diffusion imaging, from diffusion kurtosis imaging to microstructural modeling, and the connection between the two. A new result on the estimation accuracy of axial and radial kurtosis with axially symmetric DKI is presented. I moreover touch upon recently suggested generalized diffusion sequences, promising to offer independent microstructural information. We discuss the need and some methods for validation, and end with an outlook on some promising future directions. [ABSTRACT FROM AUTHOR]

Purpose: To illustrate the potential bias caused by imaging gradients in correlation MRI sequences using longitudinal magnetization storage (LS) and examine the case of filter exchange imaging (FEXI) yielding maps of the apparent exchange rate (AXR). Methods: The effects of imaging gradients in FEXI were observed on yeast cells. To analyze the AXR bias, signal evolution was calculated by applying matrix exponential operators. Results: A sharp threshold for the slice thickness was identified, below which the AXR is increasingly underestimated. The bias can be understood in terms of an extended low-pass diffusion filtering during the LS interval, which is more pronounced at lower exchange rates. For a total exchange rate constant larger than 1 s−1, the AXR bias is expected to be negligible when slices thicker than 2.5 mm are used. Conclusion: In correlation experiments like FEXI, relying on LS with variable duration, imaging gradients may cause disrupting effects that cannot be easily mitigated and should be carefully considered for unbiased results. In typical clinical applications of FEXI, the imaging gradients are expected to cause a negligible AXR bias. However, the AXR bias may be significant in preclinical settings or whenever thin imaging slices are used. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) is a promising biomarker of spinal cord injury (SCI). In the acute aftermath, DTI in SCI animal models consistently demonstrates high sensitivity and prognostic performance, yet translation of DTI to acute human SCI has been limited. In addition to technical challenges, interpretation of the resulting metrics is ambiguous, with contributions in the acute setting from both axonal injury and edema. Novel diffusion MRI acquisition strategies such as double diffusion encoding (DDE) have recently enabled detection of features not available with DTI or similar methods. In this work, we perform a systematic optimization of DDE using simulations and an in vivo rat model of SCI and subsequently implement the protocol to the healthy human spinal cord. First, two complementary DDE approaches were evaluated using an orientationally invariant or a filter-probe diffusion encoding approach. While the two methods were similar in their ability to detect acute SCI, the filter-probe DDE approach had greater predictive power for functional outcomes. Next, the filter-probe DDE was compared to an analogous single diffusion encoding (SDE) approach, with the results indicating that in the spinal cord, SDE provides similar contrast with improved signal to noise. In the SCI rat model, the filter-probe SDE scheme was coupled with a reduced field of view (rFOV) excitation, and the results demonstrate high quality maps of the spinal cord without contamination from edema and cerebrospinal fluid, thereby providing high sensitivity to injury severity. The optimized protocol was demonstrated in the healthy human spinal cord using the commercially-available diffusion MRI sequence with modifications only to the diffusion encoding directions. Maps of axial diffusivity devoid of CSF partial volume effects were obtained in a clinically feasible imaging time with a straightforward analysis and variability comparable to axial diffusivity derived from DTI. Overall, the results and optimizations describe a protocol that mitigates several difficulties with DTI of the spinal cord. Detection of acute axonal damage in the injured or diseased spinal cord will benefit the optimized filter-probe diffusion MRI protocol outlined here. [ABSTRACT FROM AUTHOR]

Purpose To introduce a novel diffusion pulse sequence, namely double oscillating diffusion encoding (DODE), and to investigate whether it adds sensitivity to microscopic diffusion anisotropy (µA) compared to the well-established double diffusion encoding (DDE) methodology. Methods We simulate measurements from DODE and DDE sequences for different types of microstructures exhibiting restricted diffusion. First, we compare the effect of varying pulse sequence parameters on the DODE and DDE signal. Then, we analyse the sensitivity of the two sequences to the microstructural parameters (pore diameter and length) which determine µA. Finally, we investigate specificity of measurements to particular substrate configurations. Results Simulations show that DODE sequences exhibit similar signal dependence on the relative angle between the two gradients as DDE sequences, however, the effect of varying the mixing time is less pronounced. The sensitivity analysis shows that in substrates with elongated pores and various orientations, DODE sequences increase the sensitivity to pore diameter, while DDE sequences are more sensitive to pore length. Moreover, DDE and DODE sequence parameters can be tailored to enhance/suppress the signal from a particular range of substrates. Conclusions A combination of DODE and DDE sequences maximize sensitivity to µA, compared to using just the DDE method. Magn Reson Med 78:550-564, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. [ABSTRACT FROM AUTHOR]

Double-pulsed diffusional kurtosis imaging (DP-DKI) represents the double diffusion encoding (DDE) MRI signal in terms of six-dimensional (6D) diffusion and kurtosis tensors. Here a method for estimating these tensors from experimental data is described. A standard numerical algorithm for tensor estimation from conventional (i.e. single diffusion encoding) diffusional kurtosis imaging (DKI) data is generalized to DP-DKI. This algorithm is based on a weighted least squares (WLS) fit of the signal model to the data combined with constraints designed to minimize unphysical parameter estimates. The numerical algorithm then takes the form of a quadratic programming problem. The principal change required to adapt the conventional DKI fitting algorithm to DP-DKI is replacing the three-dimensional diffusion and kurtosis tensors with the 6D tensors needed for DP-DKI. In this way, the 6D diffusion and kurtosis tensors for DP-DKI can be conveniently estimated from DDE data by using constrained WLS, providing a practical means for condensing DDE measurements into well-defined mathematical constructs that may be useful for interpreting and applying DDE MRI. Data from healthy volunteers for brain are used to demonstrate the DP-DKI tensor estimation algorithm. In particular, representative parametric maps of selected tensor-derived rotational invariants are presented. [ABSTRACT FROM AUTHOR]

Diffusion MRI has been proposed as a non-invasive technique for axonal diameter mapping. However, accurate estimation of small diameters requires strong gradients, which is a challenge for the transition of the technique from preclinical to clinical MRI scanners, since these have weaker gradients. In this work, we develop a framework to estimate the lower bound for accurate diameter estimation, which we refer to as the resolution limit. We analyse only the contribution from the intra-axonal space and assume that axons can be represented by impermeable cylinders. To address the growing interest in using techniques for diffusion encoding that go beyond the conventional single diffusion encoding (SDE) sequence, we present a generalised analysis capable of predicting the resolution limit regardless of the gradient waveform. Using this framework, waveforms were optimised to minimise the resolution limit. The results show that, for parallel cylinders, the SDE experiment is optimal in terms of yielding the lowest possible resolution limit. In the presence of orientation dispersion, diffusion encoding sequences with square-wave oscillating gradients were optimal. The resolution limit for standard clinical MRI scanners (maximum gradient strength 60-80 mT/m) was found to be between 4 and 8 μm, depending on the noise levels and the level of orientation dispersion. For scanners with a maximum gradient strength of 300 mT/m, the limit was reduced to between 2 and 5 μm. [ABSTRACT FROM AUTHOR]

Purpose Eddy currents might lead to image distortions in diffusion-weighted echo planar imaging. A method is proposed to reduce their effects on double diffusion encoding (DDE) MRI experiments and the thereby derived microscopic fractional anisotropy (μFA). Methods The twice-refocused spin echo scheme was adapted for DDE measurements. To assess the effect of individual diffusion encodings on the image distortions, measurements of a grid of plastic rods in water were performed. The effect of eddy current compensation on μFA measurements was evaluated in the brains of six healthy volunteers. Results The use of an eddy current compensation reduced the signal variation. As expected, the distortions caused by the second encoding were larger than those of the first encoding, entailing a stronger need to compensate for them. For an optimal result, however, both encodings had to be compensated. The artifact reduction strongly improved the measurement of the μFA in ventricles and gray matter by reducing the overestimation. An effect of the compensation on absolute μFA values in white matter was not observed. Conclusion It is advisable to compensate both encodings in DDE measurements for eddy currents. Magn Reson Med 77:328-335, 2017. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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 (> 60 y), healthy volunteers and compared to the data obtained recently for a group of young (< 33 y), 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. [ABSTRACT FROM AUTHOR]

We report the development of a double diffusion encoding (DDE) MRI method to estimate and map the axon diameter distribution (ADD) within an imaging volume. A variety of biological processes, ranging from development to disease and trauma, may lead to changes in the ADD in the central and peripheral nervous systems. Unlike previously proposed methods, this ADD experimental design and estimation framework employs a more general, nonparametric approach, without a priori assumptions about the underlying form of the ADD, making it suitable to analyze abnormal tissue. In the current study, this framework was used on an ex vivo ferret spinal cord, while emphasizing the way in which the ADD can be weighted by either the number or the volume of the axons. The different weightings, which result in different spatial contrasts, were considered throughout this work. DDE data were analyzed to derive spatially resolved maps of average axon diameter, ADD variance, and extra-axonal volume fraction, along with a novel sub-micron restricted structures map. The morphological information contained in these maps was then used to segment white matter into distinct domains by using a proposed k -means clustering algorithm with spatial contiguity and left–right symmetry constraints, resulting in identifiable white matter tracks. The method was validated by comparing histological measures to the estimated ADDs using a quantitative similarity metric, resulting in good agreement. With further acquisition acceleration and experimental parameters adjustments, this ADD estimation framework could be first used preclinically, and eventually clinically, enabling a wide range of neuroimaging applications for improved understanding of neurodegenerative pathologies and assessing microstructural changes resulting from trauma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diffusion in tissue and porous media is known to be non-Gaussian and has been used for clinical indications of stroke and other tissue pathologies. However, when conventional NMR techniques are applied to biological tissues and other heterogeneous materials, the presence of multiple compartments (pores) with different Gaussian diffusivities will also contribute to the measurement of non-Gaussian behavior. Here we present symmetrized double PFG (sd-PFG), which can separate these two contributions to non-Gaussian signal decay as having distinct angular modulation frequencies. In contrast to prior angular d-PFG methods, sd-PFG can unambiguously extract kurtosis as an oscillation from samples with isotropic or uniformly oriented anisotropic pores, and can generally extract a combination of compartmental anisotropy and kurtosis. The method further fixes its sensitivity with respect to the time dependence of the apparent diffusion coefficient. We experimentally demonstrate the measurement of the fourth cumulant (kurtosis) of diffusion and find it consistent with theoretical predictions. By enabling the unambiguous identification of contributions of compartmental kurtosis to the signal, sd-PFG has the potential to help identify the underlying micro-structural changes corresponding to current kurtosis based diagnostics, and act as a novel source of contrast to better resolve tissue micro-structure. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This paper investigates the impact of cell body (namely soma) size and branching of cellular projections on diffusion MR imaging (dMRI) and spectroscopy (dMRS) signals for both standard single diffusion encoding (SDE) and more advanced double diffusion encoding (DDE) measurements using numerical simulations. The aim is to investigate the ability of dMRI/dMRS to characterize the complex morphology of brain cells focusing on these two distinctive features of brain grey matter. To this end, we employ a recently developed computational framework to create three dimensional meshes of neuron-like structures for Monte Carlo simulations, using diffusion coefficients typical of water and brain metabolites. Modelling the cellular structure as realistically connected spherical soma and cylindrical cellular projections, we cover a wide range of combinations of sphere radii and branching order of cellular projections, characteristic of various grey matter cells. We assess the impact of spherical soma size and branching order on the b-value dependence of the SDE signal as well as the time dependence of the mean diffusivity (MD) and mean kurtosis (MK). Moreover, we also assess the impact of spherical soma size and branching order on the angular modulation of DDE signal at different mixing times, together with the mixing time dependence of the apparent microscopic anisotropy (μA), a promising contrast derived from DDE measurements. The SDE results show that spherical soma size has a measurable impact on both the b-value dependence of the SDE signal and the MD and MK diffusion time dependence for both water and metabolites. On the other hand, we show that branching order has little impact on either, especially for water. In contrast, the DDE results show that spherical soma size has a measurable impact on the DDE signal's angular modulation at short mixing times and the branching order of cellular projections significantly impacts the mixing time dependence of the DDE signal's angular modulation as well as of the derived μA, for both water and metabolites. Our results confirm that SDE based techniques may be sensitive to spherical soma size, and most importantly, show for the first time that DDE measurements may be more sensitive to the dendritic tree complexity (as parametrized by the branching order of cellular projections), paving the way for new ways of characterizing grey matter morphology, non-invasively using dMRS and potentially dMRI. [ABSTRACT FROM AUTHOR]