Yaniv Assaf

Diffusion Tensor Imaging (DTI)-based White Matter Mapping in Brain Research: A Review

Diffusion tensor imaging (DTI) has become one of the most popular MRI techniques in brain research, as well as in clinical practice. The number of brain studies with DTI is growing steadily and, over the last decade, has produced more than 700 publications. Diffusion tensor imaging enables visualization and characterization of white matter fascicli in two and three dimensions. Since the introduction of this methodology in 1994, it has been used to study the white matter architecture and integrity of the normal and diseased brains (multiple sclerosis, stroke, aging, dementia, schizophrenia, etc.). Although it provided image contrast that was not available with routine MR techniques, unique information on white matter and 3D visualization of neuronal pathways, many questions were raised regarding the origin of the DTI signal. Diffusion tensor imaging is constantly validated, challenged, and developed in terms of acquisition scheme, image processing, analysis, and interpretation. While DTI offers a powerful tool to study and visualize white matter, it suffers from inherent artifacts and limitations. The partial volume effect and the inability of the model to cope with non-Gaussian diffusion are its two main drawbacks. Nevertheless, when combined with functional brain mapping, DTI provides an efficient tool for comprehensive, noninvasive, functional anatomy mapping of the human brain. This review summarizes the development of DTI in the last decade with respect to the specificity and utility of the technique in radiology and anatomy studies.

Axcaliber: A method for measuring axon diameter distribution from diffusion MRI

The diameter of a myelinated nerve axon is directly proportional to its conduction velocity, so the axon diameter distribution helps determine the channel capacity of nervous transmission along fascicles in the central (CNS) and peripheral nervous systems (PNS). Previously, this histological information could only be obtained using invasive tissue biopsies. Here we propose a new NMR‐based approach that employs a model of water diffusion within “restricted” cylindrical axons to estimate their diameter distribution within a nerve bundle. This approach can be combined with MRI to furnish an estimate of the axon diameter distribution within each voxel. This method is validated by comparing the diameter distributions measured using the NMR and histological techniques on sciatic and optic nerve tissue specimens. The axon diameter distribution measured in each voxel of porcine spinal cord using MRI and using histological methods were similar. Applications are expected in longitudinal studies designed to follow nerve growth in normal and abnormal development, as well as in diagnosing disorders and diseases affecting specific populations of axons in the CNS and PNS. Magn Reson Med 59:1347–1354, 2008.

Composite hindered and restricted model of diffusion (CHARMED) MR imaging of the human brain

High b value diffusion-weighted images sampled at high angular resolution were analyzed using a composite hindered and restricted model of diffusion (CHARMED). Measurements and simulations of diffusion in white matter using CHARMED provide an unbiased estimate of fiber orientation with consistently smaller angular uncertainty than when calculated using a DTI model or with a dual tensor model for any given signal-to-noise level. Images based on the population fraction of the restricted compartment provide a new contrast mechanism that enhances white matter like DTI. Nevertheless, it is assumed that these images might be more sensitive than DTI to white matter disorders. We also provide here an experimental design and analysis framework to implement CHARMED MRI that is feasible on human clinical scanners.

New modeling and experimental framework to characterize hindered and restricted water diffusion in brain white matter

To characterize anisotropic water diffusion in brain white matter, a theoretical framework is proposed that combines hindered and restricted models of water diffusion (CHARMED) and an experimental methodology that embodies features of diffusion tensor and q‐space MRI. This model contains a hindered extra‐axonal compartment, whose diffusion properties are characterized by an effective diffusion tensor, and an intra‐axonal compartment, whose diffusion properties are characterized by a restricted model of diffusion within cylinders. The hindered model primarily explains the Gaussian signal attenuation observed at low b values; the restricted non‐Gaussian model does so at high b. Both high and low b data obtained along different directions are required to estimate various microstructural parameters of the composite model, such as the nerve fiber orientation(s), the T2‐weighted extra‐ and intra‐axonal volume fractions, and principal diffusivities. The proposed model provides a description of restricted diffusion in 3D given by a 3D probability distribution (average propagator), which is obtained by 3D Fourier transformation of the estimated signal attenuation profile. The new model is tested using synthetic phantoms and validated on excised spinal cord tissue. This framework shows promise in determining the orientations of two or more fiber compartments more precisely and accurately than with diffusion tensor imaging. Magn Reson Med 52:965–978, 2004. Published 2004 Wiley‐Liss, Inc.

Free water elimination and mapping from diffusion MRI

Relating brain tissue properties to diffusion tensor imaging (DTI) is limited when an image voxel contains partial volume of brain tissue with free water, such as cerebrospinal fluid or edema, rendering the DTI indices no longer useful for describing the underlying tissue properties. We propose here a method for separating diffusion properties of brain tissue from surrounding free water while mapping the free water volume. This is achieved by fitting a bi‐tensor model for which a mathematical framework is introduced to stabilize the fitting. Applying the method on datasets from a healthy subject and a patient with edema yielded corrected DTI indices and a more complete tract reconstruction that passed next to the ventricles and through the edema. We were able to segment the edema into areas according to the condition of the underlying tissue. In addition, the volume of free water is suggested as a new quantitative contrast of diffusion MRI. The findings suggest that free water is not limited to the borders of the brain parenchyma; it therefore contributes to the architecture surrounding neuronal bundles and may indicate specific anatomical processes. The analysis requires a conventional DTI acquisition and can be easily merged with existing DTI pipelines. Magn Reson Med, 2009.

In vivo measurement of axon diameter distribution in the corpus callosum of rat brain

Here, we present the first in vivo non-invasive measurement of the axon diameter distribution in the rat corpus callosum. Previously, this measurement was only possible using invasive histological methods. The axon diameter, along with other physical properties, such as the intra-axonal resistance, membrane resistance and capacitance etc. helps determine many important functional properties of nerves, such as their conduction velocity. In this work, we provide a novel magnetic resonance imaging method called AxCaliber, which can resolve the distinct signatures of trapped water molecules diffusing within axons as well as water molecules diffusing freely within the extra-axonal space. Using a series of diffusion weighted magnetic resonance imaging brain scans, we can reliably infer both the distribution of axon diameters and the volume fraction of these axons within each white matter voxel. We were able to verify the known microstructural variation along the corpus callosum of the rat from the anterior (genu) to posterior (splenium) regions. AxCaliber yields a narrow distribution centered approximately 1 microm in the genu and splenium and much broader distributions centered approximately 3 microm in the body of the corpus callosum. The axon diameter distribution found by AxCaliber is generally broader than those usually obtained by histology. One factor contributing to this difference is the significant tissue shrinkage that results from histological preparation. To that end, AxCaliber might provide a better estimate of the in vivo morphology of white matter. Being a magnetic resonance imaging based methodology, AxCaliber has the potential to be used in human scanners for morphological studies of white matter in normal and abnormal development, and white matter related diseases.

High b-Value q-Space Analyzed Diffusion-Weighted MRI: Application to Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affects nearly one million people worldwide, leading to a progressive decline of motor and sensory functions, and permanent disability. High b‐value diffusion‐weighted MR images (b of up to 14000 s/mm2) were acquired from the brains of controls and MS patients. These diffusion MR images, in which signal decay is not monoexponential, were analyzed using the q‐space approach that emphasizes the diffusion characteristics of the slow‐diffusing component. From this analysis, displacement and probability maps were constructed. The computed q‐space analyzed MR images that were compared with conventional T1, T2 (fluid attenuated inversion recovery (FLAIR)), and diffusion tensor imaging (DTI) images were found to be sensitive to the pathophysiological state of white matter. The indices used to construct this q‐space analyzed MR maps, provided a pronounced differentiation between normal tissue and tissues classified as MS plaques by the FLAIR images. More importantly, a pronounced differentiation was also observed between tissues classified by the FLAIR MR images as normal‐appearing white matter (NAWM) in the MS brains, which are known to be abnormal, and the respective control tissues. The potential diagnostic capacity of high b‐value diffusion q‐space analyzed MR images is discussed, and experimental data that explains the consequences of using the q‐space approach once the short pulse gradient approximation is violated are presented. Magn Reson Med 47:115–126, 2002.

Characterization of displaced white matter by brain tumors using combined DTI and fMRI.

In vivo white matter tractography by diffusion tensor imaging (DTI) has become a popular tool for investigation of white matter architecture in the normal brain. Despite some unresolved issues regarding the accuracy of DTI, recent studies applied DTI for delineating white matter organization in the vicinity of brain lesions and especially brain tumors. Apart from the intrinsic limitations of DTI, the tracking of fibers in the vicinity or within lesions is further complicated due to changes in diseased tissue such as elevated water content (edema), tissue compression and degeneration. These changes deform the architecture of the white matter and in some cases prevent definite selection of the seed region of interest (ROI) from which fiber tracking begins. We show here that for displaced fiber systems, the use of anatomical approach for seed ROI selection yields insufficient results. Alternatively, we propose to select the seed points based on functional MRI activations which constrain the subjective seed ROI selection. The results are demonstrated on two major fiber systems: the pyramidal tract and the superior longitudinal fasciculus that connect critical motor and language areas, respectively. The fMRI based seed ROI selection approach enabled a more comprehensive mapping of these fiber systems. Furthermore, this procedure enabled the characterization of displaced white matter using the eigenvalue decomposition of DTI. We show that along the compressed fiber system, the diffusivity parallel to the fiber increases, while that perpendicular to the fibers decreases, leading to an overall increase in the fractional anisotropy index reflecting the compression of the fiber bundle. We conclude that definition of the functional network of a subject with deformed white matter should be done carefully. With fMRI, one can more accurately define the seed ROI for DTI based tractography and to provide a more comprehensive, functionally related, white matter mapping, a very important tool used in pre-surgical mapping.

Displacement imaging of spinal cord using q-space diffusion-weighted MRI

Displacement MR images of water in in vitro rat spinal cord were computed from q‐space analysis of high b value diffusion‐weighted MRI data. It is demonstrated that q‐space analysis of heavily diffusion‐weighted MRI (qs‐DWI) provides MR images in which physical parameters of the tissues such as the mean displacement and the probability for zero displacement of the water molecules are used as contrasts. It is shown that these MR images provide structural information surpassing the spatial resolution of conventional MRI by several orders of magnitude. This imaging methodology was used to follow spinal cord maturation in the rat. It was found that changes in the diffusion characteristics of white matter upon maturation are responsible for the emergence of gray/white matter contrast. The mean displacement of water molecules in the white and gray matter of the mature rat spinal cord was found to be 2–3, and 8–10 microns, respectively. The potential and the limitations of this new imaging methodology for early detection of white matter disorders are discussed. Magn Reson Med 44:713–722, 2000.

Assignment of the water slow‐diffusing component in the central nervous system using q‐space diffusion MRS: Implications for fiber tract imaging

Diffusion‐weighted NMR spectroscopy (MRS) was performed on isolated bovine optic nerve and rat brain (in vitro) to characterize the multiexponential water signal decay in diffusion experiments. q‐Space analysis of the diffusion data was used to obtain structural information about the investigated neuronal tissues. This analysis provided displacement distribution profiles of the water in the sample. Two diffusing components were identified from these profiles, thus enabling us to obtain the following information about the slow decaying component: 1) displacement of this component is restricted to a diffusing distance of approximately 2 μm; 2) it has a longer T2 than the rapidly diffusing component; and 3) the population fraction of this component depends on the orientation of the nerve fiber. When the diffusion was measured perpendicular to the long axis of the bovine optic nerve, the weighting of this population was 41 ± 2%, whereas parallel to the long axis of the nerve it was found to be 14 ± 2%. In the randomly oriented brain tissue, the population of this component was only 7 ± 3%. These observations led to the conclusion that the slow‐decaying component originates mainly from restricted water diffusion in the neuronal fibers. In view of these findings, in vitro and in situ diffusion‐weighted images with high b values (with long Δ) were acquired to obtain highly detailed images of white matter fiber tracts in the central nervous system. These images provide detailed information on white matter fiber tract location and allow spinal cord maturation to be followed with high accuracy. Magn Reson Med 43:191–199, 2000.