Towards higher sensitivity and stability of axon diameter estimation with diffusion‐weighted MRI

Diffusion‐weighted MRI is an important tool for in vivo and non‐invasive axon morphometry. The ActiveAx technique utilises an optimised acquisition protocol to infer orientationally invariant indices of axon diameter and density by fitting a model of white matter to the acquired data. In this study, we investigated the factors that influence the sensitivity to small‐diameter axons, namely the gradient strength of the acquisition protocol and the model fitting routine. Diffusion‐weighted ex. vivo images of the mouse brain were acquired using 16.4‐T MRI with high (G_max of 300 mT/m) and ultra‐high (G_max of 1350 mT/m) gradient strength acquisitions. The estimated axon diameter indices of the mid‐sagittal corpus callosum were validated using electron microscopy. In addition, a dictionary‐based fitting routine was employed and evaluated. Axon diameter indices were closer to electron microscopy measures when higher gradient strengths were employed. Despite the improvement, estimated axon diameter indices (a lower bound of ~ 1.8 μm) remained higher than the measurements obtained using electron microscopy (~1.2 μm). We further observed that limitations of pulsed gradient spin echo (PGSE) acquisition sequences and axonal dispersion could also influence the sensitivity with which axon diameter indices could be estimated. Our results highlight the influence of acquisition protocol, tissue model and model fitting, in addition to gradient strength, on advanced microstructural diffusion‐weighted imaging techniques. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.     

Tract‐specific and age‐related variations of the spinal cord microstructure: a multi‐parametric MRI study using diffusion tensor imaging (DTI) and inhomogeneous magnetization transfer (ihMT)

Being able to finely characterize the spinal cord (SC) microstructure and its alterations is a key point when investigating neural damage mechanisms encountered in different central nervous system (CNS) pathologies, such as multiple sclerosis, amyotrophic lateral sclerosis or myelopathy. Based on novel methods, including inhomogeneous magnetization transfer (ihMT) and dedicated SC probabilistic atlas post‐processing, the present study focuses on the in vivo characterization of the healthy SC tissue in terms of regional microstructure differences between (i) upper and lower cervical vertebral levels and (ii) sensory and motor tracts, as well as differences attributed to normal aging. Forty‐eight healthy volunteers aged from 20 to 70 years old were included in the study and scanned at 3 T using axial high‐resolution T₂*‐w imaging, diffusion tensor imaging (DTI) and ihMT, at two vertebral levels (C2 and C5). A processing pipeline with minimal user intervention, SC segmentation and spatial normalization into a reference space was implemented in order to assess quantitative morphological and structural parameters (cross‐sectional areas, scalar DTI and MT/ihMT metrics) in specific white and gray matter regions of interest. The multi‐parametric MRI metrics collected allowed upper and lower cervical levels to be distinguished, with higher ihMT ratio (ihMTR), higher axial diffusivity (λ_∥) and lower radial diffusivity (λ_⊥) at C2 compared with C5. Significant differences were also observed between white matter fascicles, with higher ihMTR and lower λ_∥ in motor tracts compared with posterior sensory tracts. Finally, aging was found to be associated with significant metric alterations (decreased ihMTR and λ_∥). The methodology proposed here, which can be easily transferred to the clinic, provides new insights for SC characterization. It bears great potential to study focal and diffuse SC damage in neurodegenerative and demyelinating diseases. Copyright © 2016 John Wiley & Sons, Ltd.     

Resolution limit of cylinder diameter estimation by diffusion MRI: The impact of gradient waveform and orientation dispersion

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.     

Time‐dependent diffusion in undulating thin fibers: Impact on axon diameter estimation

Diffusion MRI may enable non‐invasive mapping of axonal microstructure. Most approaches infer axon diameters from effects of time‐dependent diffusion on the diffusion‐weighted MR signal by modeling axons as straight cylinders. Axons do not, however, propagate in straight trajectories, and so far the impact of the axonal trajectory on diameter estimation has been insufficiently investigated. Here, we employ a toy model of axons, which we refer to as the undulating thin fiber model, to analyze the impact of undulating trajectories on the time dependence of diffusion. We study time‐dependent diffusion in the frequency domain and characterize the diffusion spectrum by its height, width, and low‐frequency behavior (power law exponent). Results show that microscopic orientation dispersion of the thin fibers is the main parameter that determines the characteristics of the diffusion spectra. At lower frequencies (longer diffusion times), straight cylinders and undulating thin fibers can have virtually identical spectra. If the straight‐cylinder assumption is used to interpret data from undulating thin axons, the diameter is overestimated by an amount proportional to the undulation amplitude and microscopic orientation dispersion of the fibers. At higher frequencies (shorter diffusion times), spectra from cylinders and undulating thin fibers differ. The low‐frequency behavior of the spectra from the undulating thin fibers may also differ from that of cylinders, because the power law exponent of undulating fibers can reach values below 2 for experimentally relevant frequency ranges. In conclusion, we argue that the non‐straight nature of axonal trajectories should not be overlooked when analyzing and interpreting diffusion MRI data.     

Multi‐compartmental diffusion characterization of the human cervical spinal cord in vivo using the spherical mean technique

The purpose of this work was to evaluate the feasibility and reproducibility of the spherical mean technique (SMT), a multi‐compartmental diffusion model, in the spinal cord of healthy controls, and to assess its ability to improve spinal cord characterization in multiple sclerosis (MS) patients at 3 T. SMT was applied in the cervical spinal cord of eight controls and six relapsing‐remitting MS patients. SMT provides an elegant framework to model the apparent axonal volume fraction v_ax, intrinsic diffusivity D_ax, and extra‐axonal transverse diffusivity D_{ex_perp} (which is estimated as a function of v_ax and D_ax) without confounds related to complex fiber orientation distribution that reside in diffusion MRI modeling. SMT's reproducibility was assessed with two different scans within a month, and SMT‐derived indices in healthy and MS cohorts were compared. The influence of acquisition scheme on SMT was also evaluated. SMT's v_ax, D_ax, and D_{ex_perp} measurements all showed high reproducibility. A decrease in v_ax was observed at the site of lesions and normal appearing white matter (p < 0.05), and trends towards a decreased D_ax and increased D_{ex_perp} were seen. Importantly, a twofold reduction in acquisition yielded similarly high accuracy with SMT. SMT provides a fast, reproducible, and accurate method to improve characterization of the cervical spinal cord, and may have clinical potential for MS patients.     

Blood–spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast‐enhanced MRI

After a primary traumatic injury, spinal cord tissue undergoes a series of pathobiological changes, including compromised blood–spinal cord barrier (BSCB) integrity. These vascular changes occur over both time and space. In an experimental model of spinal cord injury (SCI), longitudinal dynamic contrast‐enhanced MRI (DCE‐MRI) studies were performed up to 56 days after SCI to quantify spatial and temporal changes in the BSCB permeability in tissue that did not show any visible enhancement on the post‐contrast MRI (non‐enhancing tissue). DCE‐MRI data were analyzed using a two‐compartment pharmacokinetic model. These studies demonstrate gradual restoration of BSCB with post‐SCI time. However, on the basis of DCE‐MRI, and confirmed by immunohistochemistry, the BSCB remained compromised even at 56 days after SCI. In addition, open‐field locomotion was evaluated using the 21‐point Basso–Beattie–Bresnahan scale. A significant correlation between decreased BSCB permeability and improved locomotor recovery was observed. Copyright © 2008 John Wiley & Sons, Ltd.     

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis

Diffusion magnetic resonance imaging (MRI) exhibits contrast that identifies macro‐ and microstructural changes in neurodegenerative diseases. Previous studies have shown that MR diffusion tensor imaging (DTI) can observe changes in spinal cord white matter in animals and humans affected with symptomatic amyotrophic lateral sclerosis (ALS). The goal of this preclinical work was to investigate the sensitivity of DTI for the detection of signs of tissue damage before symptoms appear. High‐field MRI data were acquired using a 9.4‐T animal scanner to examine the spinal cord of an ALS mouse model at pre‐ and post‐symptomatic stages (days 80 and 120, respectively). The MRI results were validated using yellow fluorescent protein (YFP) via optical microscopy of spinal cord tissue slices collected from the YFP,G93A‐SOD1 mouse strain. DTI maps of diffusion‐weighted imaging (DWI) signal intensity, mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were computed for axial slices of the lumbar region of the spinal cord. Significant changes were observed in FA (6.7% decrease, p < 0.01), AD (19.5% decrease, p < 0.01) and RD (16.1% increase, p < 0.001) at postnatal day 80 (P80). These differences were correlated with changes in axonal fluorescence intensity and membrane cellular markers. This study demonstrates the value of DTI as a potential tool to detect the underlying pathological progression associated with ALS, and may accelerate the discovery of therapeutic strategies for patients with this disease.     

Motion‐compensated b‐tensor encoding for in vivo cardiac diffusion‐weighted imaging

Motion is a major confound in diffusion‐weighted imaging (DWI) in the body, and it is a common cause of image artefacts. The effects are particularly severe in cardiac applications, due to the nonrigid cyclical deformation of the myocardium. Spin echo‐based DWI commonly employs gradient moment‐nulling techniques to desensitise the acquisition to velocity and acceleration, ie, nulling gradient moments up to the 2nd order (M2‐nulled). However, current M2‐nulled DWI scans are limited to encode diffusion along a single direction at a time. We propose a method for designing b‐tensors of arbitrary shapes, including planar, spherical, prolate and oblate tensors, while nulling gradient moments up to the 2nd order and beyond. The design strategy comprises initialising the diffusion encoding gradients in two encoding blocks about the refocusing pulse, followed by appropriate scaling and rotation, which further enables nulling undesired effects of concomitant gradients. Proof‐of‐concept assessment of in vivo mean diffusivity (MD) was performed using linear and spherical tensor encoding (LTE and STE, respectively) in the hearts of five healthy volunteers. The results of the M2‐nulled STE showed that (a) the sequence was robust to cardiac motion, and (b) MD was higher than that acquired using standard M2‐nulled LTE, where diffusion‐weighting was applied in three orthogonal directions, which may be attributed to the presence of restricted diffusion and microscopic diffusion anisotropy. Provided adequate signal‐to‐noise ratio, STE could significantly shorten estimation of MD compared with the conventional LTE approach. Importantly, our theoretical analysis and the proposed gradient waveform design may be useful in microstructure imaging beyond diffusion tensor imaging where the effects of motion must be suppressed.     

q‐Space diffusion MRI (QSI) of the disease progression in the spinal cords of the Long Evans shaker: diffusion time and apparent anisotropy

q‐Space diffusion MRI (QSI) was used to study the spinal cords of Long Evans shaker (les) rats, a model of dysmyelination, and their age‐matched controls at different maturation stages. Diffusion was measured parallel and perpendicular to the fibers of the spinal cords of the two groups and at different diffusion times. The results showed that QSI is able to detect the dysmyelination process that occurs in this model in the different stages of the disease. The differences in the diffusion characteristics of the spinal cords of the two groups were found to be larger when the diffusion time was increased from 22 to 100 ms. We found that the radial mean displacement is a much better parameter than the QSI fractional anisotropy (FA) to document the differences between the two groups. We observed that the degree of myelination affects the diffusion characteristics of the tissues, but has a smaller effect on FA. All of the extracted diffusion parameters that are affected by the degree of myelination are affected in a diffusion time‐dependent fashion, suggesting that the terms apparent anisotropy, apparent fractional anisotropy and even apparent root‐mean‐square displacement (rmsD) are more appropriate. Copyright © 2013 John Wiley & Sons, Ltd.     

Histologically derived fiber response functions for diffusion MRI vary across white matter fibers—An ex vivo validation study in the squirrel monkey brain

Understanding the relationship between the diffusion‐weighted MRI signal and the arrangement of white matter fibers is fundamental for accurate voxel‐wise reconstruction of the fiber orientation distribution (FOD) and subsequent fiber tractography. Spherical deconvolution reconstruction techniques model the diffusion signal as the convolution of the FOD with a response function that represents the signal profile of a single fiber orientation. Thus, given the signal and a fiber response function, the FOD can be estimated in every imaging voxel by deconvolution. However, the selection of the appropriate response function remains relatively under‐studied, and requires further validation. In this work, using 3D histologically defined FODs and the corresponding diffusion signal from three ex vivo squirrel monkey brains, we derive the ground truth response functions. We find that the histologically derived response functions differ from those conventionally used. Next, we find that response functions statistically vary across brain regions, which suggests that the practice of using the same kernel throughout the brain is not optimal. We show that different kernels lead to different FOD reconstructions, which in turn can lead to different tractography results depending on algorithmic parameters, with large variations in the accuracy of resulting reconstructions. Together, these results suggest there is room for improvement in estimating and understanding the relationship between the diffusion signal and the underlying FOD.     

Diffusion MRI microstructure models with in vivo human brain Connectome data: results from a multi‐group comparison

A large number of mathematical models have been proposed to describe the measured signal in diffusion‐weighted (DW) magnetic resonance imaging (MRI). However, model comparison to date focuses only on specific subclasses, e.g. compartment models or signal models, and little or no information is available in the literature on how performance varies among the different types of models. To address this deficiency, we organized the ‘White Matter Modeling Challenge’ during the International Symposium on Biomedical Imaging (ISBI) 2015 conference. This competition aimed to compare a range of different kinds of models in their ability to explain a large range of measurable in vivo DW human brain data. Specifically, we assessed the ability of models to predict the DW signal accurately for new diffusion gradients and b values. We did not evaluate the accuracy of estimated model parameters, as a ground truth is hard to obtain. We used the Connectome scanner at the Massachusetts General Hospital, using gradient strengths of up to 300 mT/m and a broad set of diffusion times. We focused on assessing the DW signal prediction in two regions: the genu in the corpus callosum, where the fibres are relatively straight and parallel, and the fornix, where the configuration of fibres is more complex. The challenge participants had access to three‐quarters of the dataset and their models were ranked on their ability to predict the remaining unseen quarter of the data. The challenge provided a unique opportunity for a quantitative comparison of diverse methods from multiple groups worldwide. The comparison of the challenge entries reveals interesting trends that could potentially influence the next generation of diffusion‐based quantitative MRI techniques. The first is that signal models do not necessarily outperform tissue models; in fact, of those tested, tissue models rank highest on average. The second is that assuming a non‐Gaussian (rather than purely Gaussian) noise model provides little improvement in prediction of unseen data, although it is possible that this may still have a beneficial effect on estimated parameter values. The third is that preprocessing the training data, here by omitting signal outliers, and using signal‐predicting strategies, such as bootstrapping or cross‐validation, could benefit the model fitting. The analysis in this study provides a benchmark for other models and the data remain available to build up a more complete comparison in the future.     

Enhanced delineation of white matter structures of the fixed mouse brain using Gd‐DTPA in microscopic MRI

The purpose of this study was to investigate the effect of gadolinium (III) diethyltriaminepenta‐acetic acid (Gd‐DTPA) mixed with a fixative on the image contrast between the white and gray matter of the perfusion‐fixed mouse brain. A series of microscopic MRI (µMRI) studies using different concentrations of Gd‐DTPA were performed at multiple time points to determine the optimal Gd‐DTPA concentration and fixation time necessary to maximize the contrast‐to‐noise ratio between the white and gray matter with relatively short scan time using a three‐dimensional gradient‐echo pulse sequence. On the basis of the experimental results, high‐resolution (39 µm isotropic) images with excellent contrast‐to‐noise ratio (～50) were acquired in less than 2 h of scan time after the specimen had been soaked in 10 mM Gd‐DTPA for 4 days. Excellent correlation was noted between µMRI and histology in that the µMRI clearly depicted brain regions that were also observed by the Kluver–Barrera stain. The enhanced contrast between the white and gray matter obtained by the proposed µMRI method may facilitate the development of µMRI‐based morphological phenotyping methods for mouse models of neurological disorders. Copyright © 2008 John Wiley & Sons, Ltd.     

Histological and immunocytochemical characterization of neurons located in the white matter of the spinal cord of the pigeon

In the spinal cord of birds a considerable number of neuronal somata is located outside the gray matter. Some of these neurons form segmental marginal nuclei, which lie at the border of the spinal cord near the dentate ligament. In lumbosacral segments these marginal nuclei form accessory lobes which bulge into the vertebral canal. These lobes consist in neurons which are embedded into glia-derived glycogen cells. Furthermore, there are neurons in the white matter near the accessory lobes and numerous paragriseal cells lying in the lateral and ventral funiculus. Glycogen cells are present both in the lobes and in the glycogen body which fills the lumbosacral spinal rhomboid sinus. Immunoreactivity of glial fibrillary acidic protein, a marker of astrocytes, was used to characterize the surrounding of marginal neurons. Astrocytes were numerous in cervical marginal nuclei but rare in accessory lobes. There is cytological (distribution of Nissl substance) and immunocytochemical evidence (immunoreactivity of medium-sized neurofilament, glutamic acid decorboxylase and glutamatergic AMPA receptor subtype GluR2/3) that neurons of the accessory lobes and the nearby white matter are similar, whereas paragriseal cells are different.     

Expression pattern of Nogo‐A,MAG, and NgR in regenerating urodele spinal cord

Background: The mammalian central nervous system is incapable of substantial axon regeneration after injury partially due to the presence of myelin‐associated inhibitory molecules including Nogo‐A and myelin associated glycoprotein (MAG). In contrast, axolotl salamanders are capable of considerable axon regrowth during spinal cord regeneration. Results: Here, we show that Nogo‐A and MAG, and their receptor, Nogo receptor (NgR), are present in the axolotl genome and are broadly expressed in the central nervous system (CNS) during development, adulthood, and importantly, during regeneration. Furthermore, we show that Nogo‐A and NgR are co‐expressed in Sox2 positive neural progenitor cells. Conclusions: These expression patterns suggest myelin‐associated proteins are permissive for neural development and regeneration in axolotls. Developmental Dynamics 242:847–860, 2013. © 2013 Wiley Periodicals, Inc.     

Fluorescent double‐label study of lateral reticular nucleus projections to the spinal cord and periaqueductal gray in the rat

Following injections of WGA‐HRP into either the spinal cord or periaqueductal gray, labeled neurons were 7observed bilaterally along the periphery of the lateral reticular nucleus (LRN) magnocellular division. The possibility that some of these neurons in the LRN provide collateral axonal branches to both the periaqueductal gray and the spinal cord was investigated in rats using a retrograde double‐labeling method employing two different fluorescent tracers, True Blue and Nuclear Yellow. Following sequential injection of the two fluorescent axonal tracers into the spinal cord and periaqueductal gray in the same animal, a modest number of double‐labeled neurons were observed bilaterally near the medial and dorsal perimeter of the magnocellular division of the LRN. The labeled neurons were distinctly multipolar in shape and measured approximately 15–18 μ in their greatest transverse diameter. No double‐labeled neurons were observed in the parvocellular or subtrigeminal divisions of the LRN. Based upon these observations, it is suggested that collaterals of the LRN‐spinal pathway provide feedback information to the periaqueductal gray that might then be used to modulate the participation of the latter cell group in a variety of pain processing and cardiovascular regulatory functions. Anat Rec 256:91–98, 1999. © 1999 Wiley‐Liss, Inc.     

Region‐specific impairment of the cervical spinal cord (SC) in amyotrophic lateral sclerosis: A preliminary study using SC templates and quantitative MRI (diffusion tensor imaging/inhomogeneous magnetization transfer)

In this preliminary study, our objective was to investigate the potential of high‐resolution anatomical imaging, diffusion tensor imaging (DTI) and conventional/inhomogeneous magnetization transfer imaging [magnetization transfer (MT)/inhomogeneous magnetization transfer (ihMT)] at 3 T, analyzed with template‐extracted regions of interest, to measure the atrophy and structural changes of white (WM) and gray (GM) matter spinal cord (SC) occurring in patients with amyotrophic lateral sclerosis (ALS). Ten patients with ALS and 20 age‐matched healthy controls were recruited. SC GM and WM areas were automatically segmented using dedicated templates. Atrophy indices were evaluated from T ₂*‐weighted images at each vertebral level from cervical C1 to C6. DTI and ihMT metrics were quantified within the corticospinal tract (CST), posterior sensory tract (PST) and anterior GM (aGM) horns at the C2 and C5 levels. Clinical disabilities of patients with ALS were evaluated using the Revised ALS Functional Rating Scale, upper motor neuron (UMN) and Medical Research Council scorings, and correlated with MR metrics. Compared with healthy controls, GM and WM atrophy was observed in patients with ALS, especially at lower cervical levels, where a strong correlation was also observed between GM atrophy and the UMN score (R  = ?0.75, p  = 0.05 at C6). Interestingly, a significant decrease in ihMT ratio was found in all regions of interest (p  < 0.0008), fractional anisotropy (FA) and MT ratios decreased significantly in CST, especially at C5 (p  < 0.005), and λ_// (axial diffusivity) decreased significantly in CST (p  = 0.0004) and PST (p  = 0.003) at C2. Strong correlations between MRI metrics and clinical scores were also found (0.47 < |R | < 0.87, p  < 0.05). Altogether, these preliminary results suggest that high‐resolution anatomical imaging and ihMT imaging, in addition to DTI, are valuable for the characterization of SC tissue impairment in ALS. In this study, in addition to an important SC WM demyelination, we also observed, for the first time in ALS, impairments of cervical aGM.     

Reproducibility of tract‐specific magnetization transfer and diffusion tensor imaging in the cervical spinal cord at 3 tesla

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)‐ and magnetization transfer (MT)‐derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column‐specific parallel (λ_||) and perpendicular (λ_?) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT‐weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time‐points separated by more than 1 week. Cross‐sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: λ_||: 2.13 ± 0.14 and 2.14 ± 0.11 μm²/ms; λ_?: 0.67 ± 0.16 and 0.61 ± 0.09 μm²/ms; MD: 1.15 ± 0.15 and 1.12 ± 0.08 μm²/ms; FA: 0.68 ± 0.06 and 0.68 ± 0.05; MTCSF: 0.52 ± 0.05 and 0.50 ± 0.05. We examined the variability and interrater and test‐retest reliability for each metric. These column‐specific MR measurements are expected to enhance understanding of the intimate structure‐function relationship in the cervical spinal cord and may be useful for the assessment of disease progression. Copyright © 2009 John Wiley & Sons, Ltd.     

The impact of edema and fiber crossing on diffusion MRI metrics assessed in an ex vivo nerve phantom: Multi‐tensor model vs. diffusion orientation distribution function

Diffusion tensor imaging (DTI) has been employed for over 2 decades to noninvasively quantify central nervous system diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of coexisting inflammation, edema and crossing nerve fibers. We employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Furthermore, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q‐sampling imaging (GQI), q‐ball imaging (QBI) and neurite orientation dispersion and density imaging to resolve fiber crossing, in reference to the gold standard angles measured from structural images. DTI‐computed diffusivities and fractional anisotropy were significantly confounded by gel‐mimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionally, DBSI accurately and consistently estimated crossing angles in various conditions of gel‐mimicked edema when compared with the gold standard (r² = 0.92, P = 1.9 × 10^?9, bias = 3.9°). Small crossing angles and edema significantly impact the diffusion orientation distribution function, making DKI, GQI and QBI less accurate in detecting and estimating fiber crossing angles. Lastly, we used diffusion tensor ellipsoids to demonstrate that DBSI resolves the confounds of edema and crossing fibers in the peritumoral edema region from a patient with lung cancer metastasis, while DTI failed. In summary, DBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel‐mimicked edema. DBSI also indicated better angular resolution compared with DKI, QBI and GQI.     

Assessment of early docetaxel response in an experimental model of human breast cancer using DCE‐MRI,ex vivo HR MAS,and in vivo 1H MRS

The purpose of this study was to evaluate the use of dynamic contrast‐enhanced (DCE) MRI, in vivo ¹H MRS and ex vivo high resolution magic angle spinning (HR MAS) MRS of tissue samples as methods to detect early treatment effects of docetaxel in a breast cancer xenograft model (MCF‐7) in mice. MCF‐7 cells were implanted subcutaneously in athymic mice and treated with docetaxel (20, 30, and 40 mg/kg) or saline six weeks later. DCE‐MRI and in vivo ¹H MRS were performed on a 7 T MR system three days after treatment. The dynamic images were used as input for a two‐compartment model, yielding the vascular parameters K^trans and v_e. HR MAS MRS, histology, and immunohistochemical staining for proliferation (Ki‐67), apoptosis (M30 cytodeath), and vascular/endothelial cells (CD31) were performed on excised tumor tissue. Both in vivo spectra and HR MAS spectra were used as input for multivariate analysis (principal component analysis (PCA) and partial least squares regression analysis (PLS)) to compare controls to treated tumors. Tumor growth was suppressed in docetaxel‐treated mice compared to the controls. The anti‐tumor effect led to an increase in K^trans and v_e values in all the treated groups. Furthermore, in vivo MRS and HR MAS MRS revealed a significant decrease in choline metabolite levels for the treated groups, in accordance with reduced proliferative index as seen on Ki‐67 stained sections. In this study DCE‐MRI, in vivo MRS and ex vivo HR MAS MRS have been used to demonstrate that docetaxel treatment of a human breast cancer xenograft model results in changes in the vascular dynamics and metabolic profile of the tumors. This indicates that these MR methods could be used to monitor intra‐tumoral treatment effects. Copyright © 2009 John Wiley & Sons, Ltd.