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Mark D. Does

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11 papers
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11

YNIMG Journal 2020 Journal Article

Diffusion time dependency along the human corpus callosum and exploration of age and sex differences as assessed by oscillating gradient spin-echo diffusion tensor imaging

  • Pascal Tétreault
  • Kevin D. Harkins
  • Corey A. Baron
  • Rob Stobbe
  • Mark D. Does
  • Christian Beaulieu

Conventional diffusion imaging uses pulsed gradient spin echo (PGSE) waveforms with diffusion times of tens of milliseconds (ms) to infer differences of white matter microstructure. The combined use of these long diffusion times with short diffusion times (<10 ​ms) enabled by oscillating gradient spin echo (OGSE) waveforms can enable more sensitivity to changes of restrictive boundaries on the scale of white matter microstructure (e. g. membranes reflecting the axon diameters). Here, PGSE and OGSE images were acquired at 4. 7 ​T from 20 healthy volunteers aged 20–73 years (10 males). Mean, radial, and axial diffusivity, as well as fractional anisotropy were calculated in the genu, body and splenium of the corpus callosum (CC). Monte Carlo simulations were also conducted to examine the relationship of intra- and extra-axonal radial diffusivity with diffusion time over a range of axon diameters and distributions. The results showed elevated diffusivities with OGSE relative to PGSE in the genu and splenium (but not the body) in both males and females, but the OGSE-PGSE difference was greater in the genu for males. Females showed positive correlations of OGSE-PGSE diffusivity difference with age across the CC, whereas there were no such age correlations in males. Simulations of radial diffusion demonstrated that for axon sizes in human brain both OGSE and PGSE diffusivities were dominated by extra-axonal water, but the OGSE-PGSE difference nonetheless increased with area-weighted outer-axon diameter. Therefore, the lack of OGSE-PGSE difference in the body is not entirely consistent with literature that suggests it is composed predominantly of axons with large diameter. The greater OGSE-PGSE difference in the genu of males could reflect larger axon diameters than females. The OGSE-PGSE difference correlation with age in females could reflect loss of smaller axons at older ages. The use of OGSE with short diffusion times to sample the microstructural scale of restriction implies regional differences of axon diameters along the corpus callosum with preliminary results suggesting a dependence on age and sex.

YNIMG Journal 2018 Journal Article

Evaluating g-ratio weighted changes in the corpus callosum as a function of age and sex

  • Shai Berman
  • Kathryn L. West
  • Mark D. Does
  • Jason D. Yeatman
  • Aviv A. Mezer

Recent years have seen a growing interest in relating MRI measurements to the structural-biophysical properties of white matter fibers. The fiber g-ratio, defined as the ratio between the inner and outer radii of the axon myelin sheath, is an important structural property of white matter, affecting signal conduction. Recently proposed modeling methods that use a combination of quantitative-MRI signals, enable a measurement of the fiber g-ratio in vivo. Here we use an MRI-based g-ratio estimation to observe the variance of the g-ratio within the corpus callosum, and evaluate sex and age related differences. To estimate the g-ratio we used a model (Stikov et al. , 2011; Duval et al. , 2017) based on two different WM microstructure parameters: the relative amounts of myelin (myelin volume fraction, MVF) and fibers (fiber volume fraction, FVF) in a voxel. We derived the FVF from the fractional anisotropy (FA), and estimated the MVF by using the lipid and macromolecular tissue volume (MTV), calculated from the proton density (Mezer et al. , 2013). In comparison to other methods of estimating the MVF, MTV represents a stable parameter with a straightforward route of acquisition. To establish our model, we first compared histological MVF measurements (West et al. , 2016) with the MRI derived MTV. We then implemented our model on a large database of 92 subjects (44 males), aged 7 to 81, in order to evaluate age and sex related changes within the corpus callosum. Our results show that the MTV provides a good estimation of MVF for calculating g-ratio, and produced values from the corpus callosum that correspond to those found in animals ex vivo and are close to the theoretical optimum, as well as to published in vivo data. Our results demonstrate that the MTV derived g-ratio provides a simple and reliable in vivo g-ratio-weighted (GR*) measurement in humans. In agreement with theoretical predictions, and unlike other tissue parameters measured with MRI, the g-ratio estimations were found to be relatively stable with age, and we found no support for a significant sexual dimorphism with age.

YNIMG Journal 2018 Journal Article

Experimental studies of g-ratio MRI in ex vivo mouse brain

  • Kathryn L. West
  • Nathaniel D. Kelm
  • Robert P. Carson
  • Daniel C. Alexander
  • Daniel F. Gochberg
  • Mark D. Does

This study aimed to experimentally evaluate a previously proposed MRI method for mapping axonal g-ratio (ratio of axon diameters, measured to the inner and outer boundary of myelin). MRI and electron microscopy were used to study excised and fixed brains of control mice and three mouse models of abnormal white matter. The results showed that g-ratio measured with MRI correlated with histological measures of myelinated axon g-ratio, but with a bias that is likely due to the presence of non-myelinated axons. The results also pointed to cases where the MRI g-ratio model simplifies to be primarily a function of total myelin content.

YNIMG Journal 2018 Journal Article

Inferring brain tissue composition and microstructure via MR relaxometry

  • Mark D. Does

MRI relaxometry is sensitive to a variety of tissue characteristics in a complex manner, which makes it both attractive and challenging for characterizing tissue. This article reviews the most common water proton relaxometry measures, T 1, T 2, and T 2 *, and reports on their development and current potential to probe the composition and microstructure of brain tissue. The development of these relaxometry measures is challenged by the need for suitably accurate tissue models, as well as robust acquisition and analysis methodologies. MRI relaxometry has been established as a tool for characterizing neural tissue, particular with respect to myelination, and the potential for further development exists.

YNIMG Journal 2018 Journal Article

Myelin volume fraction imaging with MRI

  • Kathryn L. West
  • Nathaniel D. Kelm
  • Robert P. Carson
  • Daniel F. Gochberg
  • Kevin C. Ess
  • Mark D. Does

MRI is a valuable tool to assess myelin during development and demyelinating disease processes. While multiexponential T 2 and quantitative magnetization transfer measures correlate with myelin content, neither provides the total myelin volume fraction. In many cases correlative measures are adequate; but to assess microstructure of myelin, (e. g. calculate the g-ratio using MRI), an accurate measure of myelin volume fraction is imperative. Using a volumetric model of white matter, we relate MRI measures of myelin to absolute measures of myelin volume fraction and compare them to quantitative histology. We assess our approach in control mice along with two models of hypomyelination and one model of hypermyelination and find strong agreement between MRI and histology amongst models. This work investigates the sensitivities of MRI myelin measures to changes in axon geometry and displays promise for estimating g-ratio from MRI.

YNIMG Journal 2016 Journal Article

A revised model for estimating g-ratio from MRI

  • Kathryn L. West
  • Nathaniel D. Kelm
  • Robert P. Carson
  • Mark D. Does

A key measure of white matter health is the g-ratio, which is defined as the ratio between the inner axon radius and the outer, myelinated, axon radius. Recent methods have been proposed to measure the g-ratio non-invasively using the relationship between two magnetic resonance imaging (MRI) measures. While this relationship is intuitive, it predicates on the simplifying assumption that g-ratio is constant across axons. Here, we extend the model to account for a distribution of g-ratio values within an imaging voxel, and evaluate this model with quantitative histology from normal and hypomyelinated mouse brains.

YNIMG Journal 2016 Journal Article

Evaluation of diffusion kurtosis imaging in ex vivo hypomyelinated mouse brains

  • Nathaniel D. Kelm
  • Kathryn L. West
  • Robert P. Carson
  • Daniel F. Gochberg
  • Kevin C. Ess
  • Mark D. Does

Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and DKI-derived white matter tract integrity metrics (WMTI) were experimentally evaluated ex vivo through comparisons to histological measurements and established magnetic resonance imaging (MRI) measures of myelin in two knockout mouse models with varying degrees of hypomyelination. DKI metrics of mean and radial kurtosis were found to be better indicators of myelin content than conventional DTI metrics. The biophysical WMTI model based on the DKI framework reported on axon water fraction with good accuracy in cases with near normal axon density, but did not provide additional specificity to myelination. Overall, DKI provided additional information regarding white matter microstructure compared with DTI, making it an attractive method for future assessments of white matter development and pathology.

YNIMG Journal 2016 Journal Article

Multi-compartment microscopic diffusion imaging

  • Enrico Kaden
  • Nathaniel D. Kelm
  • Robert P. Carson
  • Mark D. Does
  • Daniel C. Alexander

This paper introduces a multi-compartment model for microscopic diffusion anisotropy imaging. The aim is to estimate microscopic features specific to the intra- and extra-neurite compartments in nervous tissue unconfounded by the effects of fibre crossings and orientation dispersion, which are ubiquitous in the brain. The proposed MRI method is based on the Spherical Mean Technique (SMT), which factors out the neurite orientation distribution and thus provides direct estimates of the microscopic tissue structure. This technique can be immediately used in the clinic for the assessment of various neurological conditions, as it requires only a widely available off-the-shelf sequence with two b-shells and high-angular gradient resolution achievable within clinically feasible scan times. To demonstrate the developed method, we use high-quality diffusion data acquired with a bespoke scanner system from the Human Connectome Project. This study establishes the normative values of the new biomarkers for a large cohort of healthy young adults, which may then support clinical diagnostics in patients. Moreover, we show that the microscopic diffusion indices offer direct sensitivity to pathological tissue alterations, exemplified in a preclinical animal model of Tuberous Sclerosis Complex (TSC), a genetic multi-organ disorder which impacts brain microstructure and hence may lead to neurological manifestations such as autism, epilepsy and developmental delay.

YNIMG Journal 2014 Journal Article

Mapping mean axon diameter and axonal volume fraction by MRI using temporal diffusion spectroscopy

  • Junzhong Xu
  • Hua Li
  • Kevin D. Harkins
  • Xiaoyu Jiang
  • Jingping Xie
  • Hakmook Kang
  • Mark D. Does
  • John C. Gore

Mapping mean axon diameter and intra-axonal volume fraction may have significant clinical potential because nerve conduction velocity is directly dependent on axon diameter, and several neurodegenerative diseases affect axons of specific sizes and alter axon counts. Diffusion-weighted MRI methods based on the pulsed gradient spin echo (PGSE) sequence have been reported to be able to assess axon diameter and volume fraction non-invasively. However, due to the relatively long diffusion times used, e. g. >20ms, the sensitivity to small axons (diameter<2μm) is low, and the derived mean axon diameter has been reported to be overestimated. In the current study, oscillating gradient spin echo (OGSE) diffusion sequences with variable frequency gradients were used to assess rat spinal white matter tracts with relatively short effective diffusion times (1–5ms). In contrast to previous PGSE-based methods, the extra-axonal diffusion cannot be modeled as hindered (Gaussian) diffusion when short diffusion times are used. Appropriate frequency-dependent rates are therefore incorporated into our analysis and validated by histology-based computer simulation of water diffusion. OGSE data were analyzed to derive mean axon diameters and intra-axonal volume fractions of rat spinal white matter tracts (mean axon diameter of ~1. 27–5. 54μm). The estimated values were in good agreement with histology, including the small axon diameters (<2. 5μm). This study establishes a framework for the quantification of nerve morphology using the OGSE method with high sensitivity to small axons.

YNICL Journal 2013 Journal Article

In-vivo multi-exponential T2, magnetization transfer and quantitative histology in a rat model of intramyelinic edema

  • Kevin D. Harkins
  • William M. Valentine
  • Daniel F. Gochberg
  • Mark D. Does

Two MRI methods, multi-exponential analysis of transverse relaxation (MET2) and quantitative magnetization transfer (qMT), were used along with quantitative evaluation of histology in a study of intra-myelinic edema in rat spinal white matter. The results showed a strong linear correlation between a distinct long-T2 signal from MET2 analysis and the edema water volume fraction as measured by histology, although this analysis overestimated the edema water content by ≈ 100% relative to quantitative histological measurements. This overestimation was reasoned to result from the effects of inter-compartmental water exchange on observed transverse relaxation. Commonly studied MRI markers for myelin, the myelin water fraction (from MET2 analysis) and the macromolecular pool size ratio (from qMT analysis) produced results that could not be explained purely by changes in myelin content. The results demonstrate the potential for MET2 analysis as well as the limits of putative myelin markers for characterizing white matter abnormalities involving intra-myelinic edema.

YNIMG Journal 2013 Journal Article

The radial diffusivity and magnetization transfer pool size ratio are sensitive markers for demyelination in a rat model of type III multiple sclerosis (MS) lesions

  • Vaibhav A. Janve
  • Zhongliang Zu
  • Song-Yi Yao
  • Ke Li
  • Fang Lin Zhang
  • Kevin J. Wilson
  • Xiawei Ou
  • Mark D. Does

Determining biophysical sensitivity and specificity of quantitative magnetic resonance imaging is essential to develop effective imaging metrics of neurodegeneration. Among these metrics, apparent pool size ratio (PSR) from quantitative magnetization transfer (qMT) imaging and radial diffusivity (RD) from diffusion tensor imaging (DTI) are both known to relate to histological measure of myelin density and integrity. However their relative sensitivities towards quantitative myelin detection are unknown. In this study, we correlated high-resolution quantitative magnetic resonance imaging measures of subvoxel tissue structures with corresponding quantitative myelin histology in a lipopolysaccharide (LPS) mediated animal model of MS. Specifically, we acquired quantitative magnetization transfer (qMT) and diffusion tensor imaging (DTI) metrics (on the same tissue sample) in an animal model system of type III oligodendrogliopathy which lacked prominent lymphocytic infiltration, a system that had not been previously examined with quantitative MRI. We find that the qMT measured apparent pool size ratio (PSR) showed the strongest correlation with a histological measure of myelin content. DTI measured RD showed the next strongest correlation, and other DTI and relaxation parameters (such as the longitudinal relaxation rate (R1f) or fractional anisotropy (FA)) showed considerably weaker correlations with myelin content.

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