Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum

Previously, we tested the prediction that axonal damage results in decreased axial diffusivity (λ_∥) while demyelination leads to increased radial diffusivity (λ_?). Cuprizone treatment of C57BL/6 mice was a highly reproducible model of CNS white matter demyelination and remyelination affecting the corpus callosum (CC). In the present study, six C57BL/6 male mice were fed 0.2% cuprizone for 12 weeks followed by 12 weeks of recovery on normal chow. The control mice were fed normal chow and imaged in parallel. Biweekly in vivo DTI examinations showed transient decrease of λ_∥ in CC at 2–6 weeks of cuprizone treatment. Immunostaining for nonphosphorylated neurofilaments demonstrated corresponding axonal damage at 4 weeks of treatment. Significant demyelination was evident from loss of Luxol fast blue staining at 6–12 weeks of cuprizone ingestion and was paralleled by increased λ_? values, followed by partial normalization during the remyelination phase. The sensitivity of λ_? to detect demyelination may be modulated in the presence of axonal damage during the early stage of demyelination at 4 weeks of cuprizone treatment. Our results suggest that λ_∥ and λ_? may be useful in vivo surrogate markers of axonal and myelin damage in mouse CNS white matter. Magn Reson Med, 2006. Published 2006 Wiley‐Liss, Inc.     

Preferential occult injury of corpus callosum in multiple sclerosis measured by diffusion tensor imaging

PURPOSE: To investigate the feasibility of diffusion tensor imaging (DTI) assessment of microscopic fiber tract injury in the corpus callosum (CC) and other normal-appearing white matter (NAWM) in patients with early multiple sclerosis (MS). MATERIALS AND METHODS: DTI was performed in 12 healthy volunteers and 15 patients who have relatively short disease duration (mean = 2.7 years). Both fractional anisotropy (FA) and mean diffusivity (MD) were obtained in different regions of normal-appearing CC (NACC) and NAWM in frontal and occipital regions. RESULTS: The data showed significantly lower FA (P < 0.001) and higher MD (P < 0.04) for NACC regions, but not for frontal and occipital NAWM regions, in patients than in those in healthy volunteers after Bonferroni adjustment. The increase of MD in the entire NACC regions was correlated with the total cerebral lesion volume (r = 0.75, P = 0.001) in patients. CONCLUSION: The water diffusion changes indicate that in the early phase of disease there is a preferential occult injury of CC, which is likely due to the Wallerian degeneration from distant lesions.     

In vivo assessment of peripheral nerve regeneration by diffusion tensor imaging

Purpose

To evaluate the sensitivity of diffusion tensor imaging (DTI) in assessing peripheral nerve regeneration in vivo. We assessed the changes in the DTI parameters and histological analyses after nerve injury to examine degeneration and regeneration in the rat sciatic nerves.

Materials and Methods

For magnetic resonance imaging (MRI), 16 rats were randomly divided into two groups: group P (permanently crushed; n = 7) and group T (temporally crushed; n = 9). Serial MRI of the right leg was performed before the operation, and then performed at the timepoints of 1, 2, 3, and 4 weeks after the crush injury. The changes in fractional anisotropy (FA), axial diffusivity (λ_∥), and radial diffusivity (λ_?) were quantified. For histological analyses, the number of axons and the myelinated axon areas were quantified.

Results

Decreased FA and increased λ_? were observed in the degenerative phase, and increased FA and decreased λ_? were observed in the regenerative phase. The changes in FA and λ_? were strongly correlated with histological changes, including axonal and myelin regeneration.

Conclusion

DTI parameters, especially λ_?, can be good indicators for peripheral nerve regeneration and can be applied as noninvasive diagnostic tools for a variety of neurological diseases. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.

     

In vivo generalized diffusion tensor imaging (GDTI) using higher‐order tensors (HOT)

Generalized diffusion tensor imaging (GDTI) using higher‐order tensor (HOT) statistics generalizes the technique of diffusion tensor imaging by including the effect of nongaussian diffusion on the signal of MRI. In GDTI‐HOT, the effect of nongaussian diffusion is characterized by higher‐order tensor statistics (i.e., the cumulant tensors or the moment tensors), such as the covariance matrix (the second‐order cumulant tensor), the skewness tensor (the third‐order cumulant tensor), and the kurtosis tensor (the fourth‐order cumulant tensor). Previously, Monte Carlo simulations have been applied to verify the validity of this technique in reconstructing complicated fiber structures. However, no in vivo implementation of GDTI‐HOT has been reported. The primary goal of this study is to establish GDTI‐HOT as a feasible in vivo technique for imaging nongaussian diffusion. We show that probability distribution function of the molecular diffusion process can be measured in vivo with GDTI‐HOT and be visualized with three‐dimensional glyphs. By comparing GDTI‐HOT to fiber structures that are revealed by the highest resolution diffusion‐weighted imaging (DWI) possible in vivo, we show that the GDTI‐HOT can accurately predict multiple fiber orientations within one white matter voxel. Furthermore, through bootstrap analysis we demonstrate that in vivo measurement of HOT elements is reproducible, with a small statistical variation that is similar to that of diffusion tensor imaging. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.     

In vivo diffusion tensor imaging of the human prostate.

This study demonstrates the feasibility of in vivo prostate diffusion tensor imaging (DTI) in human subjects. We implemented an EPI-based diffusion-weighted (DW) sequence with seven-direction diffusion gradient sensitization, and acquired DT images from six subjects using cardiac gating with a phased-array prostate surface coil operating in a linear mode. We calculated two indices to quantify diffusion anisotropy. The direction of the eigenvector corresponding to the leading eigenvalue was displayed by means of a color-coding scheme. The average diffusion values of the prostate peripheral zone (PZ) and central gland (CG) were 1.95 +/- 0.08 x 10(-3) mm2 s and 1.53 +/- 0.34 x 10(-3) mm2 s, respectively. The average fractional anisotropy (FA) values for the PZ and CG were 0.46 +/- 0.04 and 0.40 +/- 0.08, respectively. The diffusion ellipsoid in prostate tissue was anisotropic and approximated a prolate model, as shown in the color maps of the anisotropy. Consistent with the tissue architecture, the prostate fiber orientations were predominantly in the superior-inferior (SI) direction for both the PZ and CG. This study shows the feasibility of in vivo DTI and establishes normative DT values for six subjects.     

Analysis of new diffusion tensor imaging anisotropy measures in the three‐phase plot

Purpose:

To evaluate diffusion anisotropy from diffusion tensor imaging using new measures derived from Hellinger divergences and from compositional data distances.

Materials and Methods:

New anisotropy measures obtained from the diffusion tensor imaging were measured and compared with classic ones such as fractional anisotropy (FA) and relative anisotropy (RA). The evaluation was done using the three‐phase plot (3P‐plot). The measures were compared with regard to their sensitivity to detect white and gray matter changes on human DTI data acquired from five normal volunteers. For each volunteer, different volumes of interest located in white matter (WM) and gray matter (GM) were considered.

Results:

The proposed Compositional Kullback‐Leibler (KLA) and the classic FA had a similar behavior, although KLA detected better the transitions between white and gray matter. Moreover, KLA showed a better discrimination in areas with great confluence of fibers.

Conclusion:

KLA detects better than FA the difference between WM and GM. This leads KLA to be a good measure for segmenting WM from GM. J. Magn. Reson. Imaging 2010;31:1435–1444. © 2010 Wiley‐Liss, Inc.     

Three‐dimensional diffusion tensor microimaging for anatomical characterization of the mouse brain

Diffusion tensor imaging is gaining increasing importance for anatomical imaging of the developing mouse brain. However, the application of diffusion tensor imaging to mouse brain imaging at microscopic levels is hindered by the limitation on achievable spatial resolution. In this study, fast diffusion tensor microimaging of the mouse brain, based on a diffusion‐weighted gradient and spin echo technique with twin‐navigator echo phase correction, is presented. Compared to echo planar and spin echo acquisition, the diffusion‐weighted gradient and spin echo acquisition resulted in significant reduction in scan time and had minimal image distortion, thereby allowing acquisition at higher spatial resolution. In this study, three‐dimensional diffusion tensor microimaging of the mouse brains at spatial resolutions of 50‐60 μm revealed unprecedented anatomical details. Thin fiber bundles in the adult striatum and white matter tracts in the embryonic day 12 mouse brains were visualized for the first time. The study demonstrated that data acquired using the diffusion tensor microimaging technique allow three‐dimensional mapping of gene expression data and can serve as a platform to study gene expression patterns in the context of neuroanatomy in the developing mouse brain. Magn Reson Med 64:249–261, 2010. © 2010 Wiley‐Liss, Inc.     

In vivo diffusion tensor imaging of the human calf muscle

PURPOSE: To demonstrate the feasibility of in vivo calf muscle fiber tracking in human subjects. MATERIALS AND METHODS: An EPI-based diffusion tensor imaging (DTI) sequence with six-direction diffusion gradient sensitization was implemented, and DT images were acquired at 3 Tesla on five subjects using an extremity coil. The mean diffusivity, fractional anisotropy (FA), and fiber angle (with respect to the magnet z-axis) were measured in different muscles, and fibers were tracked from several regions of interest (ROIs). RESULTS: The fiber orientations in the current DTI studies agree well with those determined in previous spectroscopic studies. The orientation angles ranged from 13.4 degrees in the lateral gastrocnemius to 48.5 degrees in the medial soleus. The diffusion ellipsoid in muscle tissue is anisotropic and approximates a prolate model, as shown by color maps of the anisotropy. Fibers were tracked from the different muscle regions, and the unipennate and bipennate structure of muscle fibers was visualized. CONCLUSION: The study clearly shows that in vivo fiber tracking of muscle fibers is feasible and could potentially be applied to study muscle structure function relationships.     

创伤性脑白质损伤的扩散张量成像研究

目的:评价扩散张量成像(DTI)在创伤性脑白质损伤(WMI)中的应用价值。方法:16例创伤性脑外伤后经临床诊断有WMI的患者通过Philips 1.5TIntera Achieva MR扫描仪行常规MRI和DTI。后处理获得部分各向异性指数(FA)、表观弥散系数(ADC)和纤维示踪成像三维图。根据T2WI及T2快速场回波图像,分别于WMI区域、同侧同名或对侧同名纤维束正常区域取感兴趣区,测量FA值和ADC值并进行比较。结果:脑外伤患者损伤脑白质中挫伤和出血、仅挫伤和仅出血区域三者之间的FA值(F=0.68,P>0.05)和ADC值(F=0.53,P>0.05)均未见明显不同。除仅出血区域的ADC值与对照区域相比差异无统计学意义(t=1.36,P>0.05),挫伤和出血(t=9.72,P<0.05)、仅挫伤(t=8.28,P<0.05)和仅出血(t=5.44,P<0.05)区域的FA值较正常对照区域明显降低,挫伤和出血(t=4.71,P<0.05)、仅挫伤(t=4.81,P<0.05)的ADC值较正常对照明显增高,纤维示踪成像显示损伤区域脑白质较正常区域稀疏、分离、缺失。结论:DTI技术能够显示患者WMI区域的异常改变,但ADC值对出血的判断有局限性。     

Noise removal in magnetic resonance diffusion tensor imaging.

Although promising for visualizing the structure of ordered tissues, MR diffusion tensor imaging (DTI) has been hampered by long acquisition time and low spatial resolution associated with its inherently low signal-to-noise ratio (SNR). Moreover, the uncertainty in the DTI measurements has a direct impact on the accuracy of structural renderings such as fiber streamline tracking. Noise removal techniques can be used to improve the SNR of DTI without requiring additional acquisitions, albeit most low-pass filtering methods are accompanied by undesirable image blurring. In the present study, a modified vector-based partial-differential-equation (PDE) filtering formalism was implemented for smoothing DTI vector fields. Using an image residual-energy criterion to equate the degree of smoothing and error metrics empirically derived from DTI data to quantify the relative performances, the effectiveness in denoising DTI data is compared among image-based and vector-based PDE and fixed and adaptive low-pass k-space filtering. The results demonstrate that the edge-preservation feature of the PDE approach can be highly advantageous in enhancing DTI measurements, particularly for vector-based PDE filtering in applications relying on DTI directional information. These findings suggest a potential role for the postprocessing enhancement technique to improve the practical utility of DTI.     

Investigation of anomalous estimates of tensor-derived quantities in diffusion tensor imaging.

The diffusion tensor is typically assumed to be positive definite. However, noise in the measurements may cause the eigenvalues of the tensor estimate to be negative, thereby violating this assumption. Negative eigenvalues in diffusion tensor imaging (DTI) data occur predominately in regions of high anisotropy and may cause the fractional anisotropy (FA) to exceed unity. Two constrained least squares methods for eliminating negative eigenvalues are explored. These methods, the constrained linear least squares method (CLLS) and the constrained nonlinear least squares method (CNLS), are compared with other commonly used algebraic constrained methods. The CLLS tensor estimator can be shown to be equivalent to the linear least squares (LLS) tensor estimator when the LLS tensor estimate is positive definite. Similarly, the CNLS tensor estimator can be shown to be equivalent to the nonlinear least squares (NLS) tensor estimator when the NLS tensor estimate is positive definite. The constrained least squares methods for eliminating negative eigenvalues are evaluated with both simulations and in vivo human brain DTI data. Simulation results show that the CNLS method is, in terms of mean squared error for estimating trace and FA, the most effective method for correcting negative eigenvalues.     

In vivo diffusion tensor imaging of the rat spinal cord at 9.4T

PURPOSE: To determine differences in diffusion measurements in white matter (WM) and gray matter (GM) regions of the rat cervical, thoracic, and cauda equina spinal cord using in vivo diffusion tensor imaging (DTI) with a 9.4T MR scanner. MATERIALS AND METHODS: DTI was performed on seven rats in three slices at the cervical, thoracic, and cauda equina regions of the spinal cord using a 9.4T magnet. Axial diffusion weighted images (DWIs) were collected at a b-value of 1000 seconds/mm(2) in six directions. Regions of interest were identified via T2-weighted images for the lateral, dorsal, and ventral funiculi, along with GM regions. RESULTS: Analysis of variance (ANOVA) results indicated significant differences between every WM funiculus compared to GM for longitudinal apparent diffusion coefficient (lADC), transverse apparent diffusion coefficient (tADC), fractional anisotropy (FA), measured longitudinal anisotropy (MA1), and anisotropy index (AI). A significant difference in mean diffusivity (MD) between regions of the spinal cord was not found. Diffusion measurements were significantly different at each spinal level. In general, GM regions were significantly different than WM regions; however, there were few significant differences between individual WM regions. CONCLUSION: In vivo DTI of the rat spinal cord at 9.4T appears sensitive to the architecture of neural structures in the rat spinal cord and may be a useful tool in studying trauma and pathologies in the spinal cord.     

Using diffusion tensor imaging and immunofluorescent assay to evaluate the pathology of multiple sclerosis

Purpose:

To determine the ability of the principal diffusion tensor imaging (DTI) indices to predict the underlying histopathology evaluated with immunofluorescent assay (IFA).

Materials and Methods:

Conventional T2 and 3D multishot‐diffusion weighted echoplanar imaging (3D ms‐DWEPI) was performed on a fixed, ex vivo human cervical spinal cord (CSC) from a patient with a history of multiple sclerosis (MS). In all, 170 regions of interest (ROIs) were selected within the white matter and categorized as a high intensity lesion (HIL), low intensity lesion (LIL), and normal‐appearing white matter (NAWM). The longitudinal diffusivity (λl), radial diffusivity (λr), and fractional anisotropy (FA) were obtained from each ROI. The underlying histopathology was then evaluated using immunofluorescent assay with antibodies directed to myelin and neurofilament staining.

Results:

The mean values for λl and λr were significantly elevated within HIL relative to NAWM and LIL. IFA analysis of HIL demonstrated significant demyelination, without significant if any axon loss. The FA values were significantly reduced in HIL and LILs. FA values were also reduced in lesions with increased λl and λr values relative to normal.

Conclusion:

Aberrant λl, λr, and FA relative to normal values are strong indicators of demyelination. DTI indices are not specific for axon loss. IFA analysis is a reliable method to demonstrate myelin and axon pathology within the ex vivo setting. J. Magn. Reson. Imaging 2011;33:557–564. © 2011 Wiley‐Liss, Inc.     

In vivo diffusion tensor MRI of the human heart: Reproducibility of breath‐hold and navigator‐based approaches

The aim of this study was to implement a quantitative in vivo cardiac diffusion tensor imaging (DTI) technique that was robust, reproducible, and feasible to perform in patients with cardiovascular disease. A stimulated‐echo single‐shot echo‐planar imaging (EPI) sequence with zonal excitation and parallel imaging was implemented, together with a novel modification of the prospective navigator (NAV) technique combined with a biofeedback mechanism. Ten volunteers were scanned on two different days, each time with both multiple breath‐hold (MBH) and NAV multislice protocols. Fractional anisotropy (FA), mean diffusivity (MD), and helix angle (HA) fiber maps were created. Comparison of initial and repeat scans showed good reproducibility for both MBH and NAV techniques for FA (P > 0.22), MD (P > 0.15), and HA (P > 0.28). Comparison of MBH and NAV FA (FA_MBHday1 = 0.60 ± 0.04, FA_NAVday1 = 0.60 ± 0.03, P = 0.57) and MD (MD_MBHday1 = 0.8 ± 0.2 × 10^?3 mm²/s, MD_NAVday1 = 0.9 ± 0.2 × 10^?3 mm²/s, P = 0.07) values showed no significant differences, while HA values (HA_MBHday1Endo = 22 ± 10°, HA_{MBHday1Mid‐Endo} = 20 ± 6°, HA_{MBHday1Mid‐Epi} = ?1 ± 6°, HA_MBHday1Epi = ?17 ± 6°, HA_NAVday1Endo = 7 ± 7°, HA_{NAVday1Mid‐Endo} = 13 ± 8°, HA_{NAVday1Mid‐Epi} = ?2 ± 7°, HA_NAVday1Epi = ?14 ± 6°) were significantly different. The scan duration was 20% longer with the NAV approach. Currently, the MBH approach is the more robust in normal volunteers. While the NAV technique still requires resolution of some bulk motion sensitivity issues, these preliminary experiments show its potential for in vivo clinical cardiac diffusion tensor imaging and for delivering high‐resolution in vivo 3D DTI tractography of the heart. Magn Reson Med 70:454–465, 2013. © 2012 Wiley Periodicals, Inc.     

Generalized diffusion tensor imaging and analytical relationships between diffusion tensor imaging and high angular resolution diffusion imaging.

A new method for mapping diffusivity profiles in tissue is presented. The Bloch-Torrey equation is modified to include a diffusion term with an arbitrary rank Cartesian tensor. This equation is solved to give the expression for the generalized Stejskal-Tanner formula quantifying diffusive attenuation in complicated geometries. This makes it possible to calculate the components of higher-rank tensors without using the computationally-difficult spherical harmonic transform. General theoretical relations between the diffusion tensor (DT) components measured by traditional (rank-2) DT imaging (DTI) and 3D distribution of diffusivities, as measured by high angular resolution diffusion imaging (HARDI) methods, are derived. Also, the spherical tensor components from HARDI are related to the rank-2 DT. The relationships between higher- and lower-rank Cartesian DTs are also presented. The inadequacy of the traditional rank-2 tensor model is demonstrated with simulations, and the method is applied to excised rat brain data collected in a spin-echo HARDI experiment.     

In vivo precision of bootstrap algorithms applied to diffusion tensor imaging data

Purpose:

To determine the precision for in vivo applications of model and non–model‐based bootstrap algorithms for estimating the measurement uncertainty of diffusion parameters derived from diffusion tensor imaging data.

Materials and Methods:

Four different bootstrap methods were applied to diffusion datasets acquired during 10 repeated imaging sessions. Measurement uncertainty was derived in eight manually selected regions of interest and in the entire brain white matter and gray matter. The precision of the bootstrap methods was analyzed using coefficients of variation and intra‐class correlation coefficients. Comprehensive simulations were performed to validate the results.

Results:

All bootstrap algorithms showed similar precision which slightly varied in dependence of the selected region of interest. The averaged coefficient of variation in the selected regions of interest was 13.81%, 12.35%, and 17.93% with respect to the apparent diffusion coefficient, the fractional anisotropy value, and the cone of uncertainty, respectively. The repeated measurements showed a very high similarity with intraclass‐correlation coefficients larger than 0.96. The simulations confirmed most of the in vivo findings.

Conclusion:

All investigated bootstrap methods perform with a similar, high precision in deriving the measurement uncertainty of diffusion parameters. Thus, the time‐efficient model‐based bootstrap approaches should be the method of choice in clinical practice. J. Magn. Reson. Imaging 2012;36:979–986. © 2012 Wiley Periodicals, Inc.     

Relative indices of water diffusion anisotropy are equivalent in live and formalin-fixed mouse brains.

Formalin fixation of tissue is a common laboratory practice. A direct comparison of diffusion tensor imaging (DTI) parameters from mouse brains before (in vivo) and after (ex vivo) formalin fixation is reported herein. Five diffusion indices were examined in a cohort of seven mice: relative anisotropy (RA), directional correlation (DC), trace (Tr(D)), trace-normalized axial diffusivity (D(axially)), and radial diffusivity (D(radially)). Seven regions of interest (ROIs), including five in white matter and two in gray matter, were selected for examination. Consistent with previous findings, a significant decrease of Tr(D) was observed for all ROIs after fixation. However, water diffusion anisotropy, as defined by the indices RA, DC, D(axially), and D(radially), remained unchanged after fixation. Thus, fixation does not appear to alter diffusion anisotropy in the mouse brain. This finding supports the utility of diffusion anisotropy analysis of fixed tissue. The combination of DTI measurements and standard histology may shed light on the microstructural determinants of diffusion anisotropy in normal and disease states.