In JoVE (1)

Other Publications (78)

Articles by Mark D. Does in JoVE

 JoVE Medicine

Quantitative Magnetic Resonance Imaging of Skeletal Muscle Disease

1Institute of Imaging Science, Vanderbilt University, 2Department of Radiology and Radiological Sciences, Vanderbilt University, 3Department of Biomedical Engineering, Vanderbilt University, 4Department of Molecular Physiology and Biophysics, Vanderbilt University, 5Department of Physical Medicine and Rehabilitation, Vanderbilt University, 6Department of Physics and Astronomy, Vanderbilt University

JoVE 52352

Other articles by Mark D. Does on PubMed

Compartmental Study of T(1) and T(2) in Rat Brain and Trigeminal Nerve in Vivo

Magnetic Resonance in Medicine. Feb, 2002  |  Pubmed ID: 11810670

The integrated T(1)-T(2) characteristics of rat brain and trigeminal nerve water were studied in vivo using a rapid method for acquiring a series of images that depend on T(1) and T(2) relaxation times. Gray matter regions showed only one signal component in both the T(1) and T(2) domains. Trigeminal nerve, however, which has been shown previously to exhibit three T(2) components, was found to also exhibit three T(1) components. The correlations between these T(1) and T(2) components were demonstrated by uniquely filtering out each of the three T(2) components using an inversion-recovery preparation, as determined by the component T(1) values. Based on previous works, it is postulated that each of these three signal components is derived from a unique microanatomical region of the nerve. Knowledge of these T(1) components may thus prove valuable in devising novel methods of identifying the presence and quantifying the volume of tissue subtypes such as myelin.

Changes in CBF-BOLD Coupling Detected by MRI During and After Repeated Transient Hypercapnia in Rat

Magnetic Resonance in Medicine. Aug, 2002  |  Pubmed ID: 12210934

The effect of hypercapnia on the cerebral metabolic rate of oxygen consumption (CMRO(2)) remains incompletely understood. This study examined the relationship between susceptibility (blood oxygenation level dependent (BOLD)) and perfusion-weighted (flow-sensitive alternating inversion recovery (FAIR)) MRI techniques both during induction of repeated transient hypercapnia (THC) and after return to normocapnia during whisker barrel functional activation. During induction of THC the FAIR signal became significantly elevated over control after 100 s of hypercapnia (P = 0.039), with a trend of increasing significance to 5 min (P = 0.000008). The FAIR signal in the activated cortex during subsequent normocapnia was significantly increased compared to pre-THC control after each successive period of THC. The mean grouped FAIR signal increased by 81% +/- 63% after one exposure (P = 0.021), by 163% +/- 55% after the second exposure (P = 0.0002), and by 240% +/- 54% after the third exposure (P = 0.000002). The mean grouped BOLD signal trended upward, but did not increase significantly during or after exposure 1, 2, or 3. These data demonstrate increased uncoupling of perfusion-weighted from susceptibility imaging techniques, both in nonactivated cortex during hypercapnia, and with activation after multiple exposures to THC. These results are consistent with saturation of BOLD contrast as well as with increases in CMRO(2) with stimulation after multiple exposures to THC.

Oscillating Gradient Measurements of Water Diffusion in Normal and Globally Ischemic Rat Brain

Magnetic Resonance in Medicine. Feb, 2003  |  Pubmed ID: 12541239

Oscillating gradients were used to probe the diffusion-time/frequency dependence of water diffusion in the gray matter of normal and globally ischemic rat brain. In terms of a conventional definition of diffusion time, the oscillating gradient measurements provided the apparent diffusion coefficient (ADC) of water with diffusion times between 9.75 ms and 375 micros, an order of magnitude shorter than previously studied in vivo. Over this range, ADCs increased as much as 24% in vivo and 50% postmortem, depending on the nature of the oscillating gradient waveform used. Novel waveforms were employed to sample narrow frequency bands of the so-called diffusion spectrum. This spectral description of ADC includes the effects of restriction and/or flow, and is independent of experimental parameters, such as diffusion time. The results in rat brain were found to be consistent with restricted diffusion and the known micro-anatomy of gray matter. Differences between normal and postmortem data were consistent with an increase in water restriction and/or a decrease in flow, and tentatively suggest that physical changes following the onset of ischemia occur on a scale of about 2 microm, similar to a typical cellular dimension in gray matter.

Modified Oscillating Gradient Pulses for Direct Sampling of the Diffusion Spectrum Suitable for Imaging Sequences

Magnetic Resonance Imaging. Apr-May, 2003  |  Pubmed ID: 12850719

A variation of the oscillating gradient spin echo method had been developed, which isolates temporal frequencies of the dephasing spectrum. This allows sampling of the diffusion spectrum, the Fourier transform of the velocity correlation function (VCF). It has been shown that restriction and flow alter this function in ways that can be mathematically characterized, yielding quantitative information on restriction geometry and flow parameters. It is demonstrated that in many systems of interest, dispersion of velocity will produce a peak in the VCF spectrum near omega=0, while restricted diffusion will manifest itself in the spectrum at higher frequencies. The method, therefore, may be useful for decoupling their effects on the apparent diffusion coefficient (ADC), as well as in revealing the physics of both phenomena. This method has been implemented in model systems of packed beads, yielding data consistent with theoretical models of restricted diffusion spectra and data from one previous study. The method may have significant application to biology and medicine, as well as the study of transport phenomena in porous media and complex flow.

Differential Gene Expression in the Kidney of Sickle Cell Transgenic Mice: Upregulated Genes

Blood Cells, Molecules & Diseases. Nov-Dec, 2003  |  Pubmed ID: 14636654

The S+S-Antilles transgenic mouse used in this study has renal defects similar to those seen in sickle cell anemia patients: congested glomeruli, medullary fibrosis, renal enlargement, vasoocclusion, and a urine concentrating defect. We used gene expression microarrays to identify genes highly up-regulated in the kidneys of these mice and validated their expression by real-time PCR. Kidney hypoxia, as demonstrated by the presence of deoxyhemoglobin, was detected by blood oxygen dependent magnetic resonance imaging (BOLD-MRI). Some of the up-regulated genes included cytochrome P450 4a14, glutathione-S-transferase alpha-1, mitochondrial hydroxymethylglutaryl CoA synthase, cytokine inducible SH-2 containing protein, retinol dehydrogenase type III, arginase II, glycolate oxidase, Na/K ATPase, renin-1, and alkaline phosphatase 2. An increase in enzyme activity was also demonstrated for one of the up-regulated genes (arginase II). These genes can be integrated into several different pathophysiological processes: a hypoxia cascade, a replacement cascade, or an ameliorating cascade, one or all of which may explain the phenotype of this disease. We conclude that microarray technology is a powerful tool to identify genes involved in renal disease in sickle cell anemia and that the identification of various metabolic pathways may open new avenues for therapeutic interventions.

Relaxation-selective Magnetization Preparation Based on T1 and T2

Journal of Magnetic Resonance (San Diego, Calif. : 1997). Feb, 2005  |  Pubmed ID: 15649757

A magnetization-preparation scheme is described that combines the spin-echo and inversion-recovery (SEIR) to select spins based on both T1 and T2 characteristics. The inclusion of T2 weighting allows for greater relative suppression of some tissues with respect to others, depending on their respective relaxation times, than does inversion-recovery alone. Formulae describing the observed magnetization following SEIR and double-SEIR (DSEIR) are presented with the corresponding formulae for inversion-recovery (IR) and double-IR (DIR). The formulae are validated with experimental studies on MnCl2 solutions and compared numerically for a variety of possible applications. Results indicate that DSEIR may yield 2x or more signal than DIR in some potential applications.

Selective Excitation of Myelin Water Using Inversion-recovery-based Preparations

Magnetic Resonance in Medicine. Sep, 2005  |  Pubmed ID: 16088884

T1 and T2 relaxation of excised frog sciatic nerve water was characterized at 7 T. Based on these findings, optimal timings for multiple inversion-recovery magnetization preparations were determined to selectively excite the so-called myelin-water T2 component. Subsequent double inversion-recovery and triple inversion-recovery preparations were used in combination with CPMG acquisitions to experimentally determine optimal timings and effect of the preparation. Using double inversion-recovery, optimal timings were found to excite magnetization that is predominantly (approximately 93%) derived from the myelin-water component. Greater selectivity (approximately 96%) was found by extending the preparation to triple inversion-recovery, at the price of decreasing SNR by a factor of approximately 2.

Temporal Diffusion Spectroscopy: Theory and Implementation in Restricted Systems Using Oscillating Gradients

Magnetic Resonance in Medicine. Jan, 2006  |  Pubmed ID: 16342147

The theory of temporal diffusion spectra is reviewed. In contrast to q-space spectroscopy, which measures the displacement spectrum of spins in a spatial domain, the spectral density of the velocity correlation function (VCF) in the temporal domain is considered. It is demonstrated that casting diffusion in this domain may facilitate measurements of microscopic geometry and the decomposition of the diffusion signal into components due to disperse flow and restricted diffusion. An oscillating gradient (OG) method of diffusion spectroscopy was developed and implemented. Microscopic pore sizes, surface-to-volume ratios (S/Vs), and diffusion path tortuosities were extracted from model systems using this method. Cases are discussed in which this type of experiment may allow the characterization of pore geometry when spatial domain experiments fail. OGs may be combined with imaging sequences to map complex patterns of diffusion and flow. Moreover, scalar apparent diffusion coefficient (ADC) measurements in complex biological systems may be subtly dependent on specific pulse sequence parameters. Thus, scalar ADC measurements using gradient pulses with different frequency spectra may give different results. Conversely, the frequency dependence of motion-sensitizing gradient pulses may be exploited to deduce the origin of ADC changes.

Diffusion of Myelin Water

Magnetic Resonance in Medicine. Aug, 2006  |  Pubmed ID: 16767712

We studied compartmentally specific characteristics of water diffusion in excised frog sciatic nerve by combining T1 or T2 selective acquisitions with pulse-gradient spin-echo (PGSE) diffusion weighting, with the specific objective of characterizing myelin water diffusion. Combining a PGSE with a Carr-Purcell-Meiboom-Gill (CPMG) acquisition provided apparent diffusion coefficients (ADCs) for each of the three T2 components found in nerve, including the short-lived component believed to be derived from myelin water. Double-inversion-recovery (DIR) preparation provided an alternate means of discriminating myelin water, and in combination with PGSE provided somewhat different measures of ADC. The DIR measures yielded myelin water ADCs of 0.37 microm2/ms (parallel to nerve) and 0.13 microm2/ms (perpendicular to nerve). These ADC estimates were postulated to be more accurate than those based on T2 discrimination, although the difference between the two findings is not clear.

Aqueous Urea As a Model System for Bi-exponential Relaxation

Magma (New York, N.Y.). Feb, 2007  |  Pubmed ID: 17260153

To evaluate the utility of aqueous urea, doped inner- and outer-sphere relaxation agents, as an adjustable two-component model system.

Multicomponent T2 Analysis of Dithiocarbamate-mediated Peripheral Nerve Demyelination

Neurotoxicology. May, 2007  |  Pubmed ID: 17350098

Standard light microscope histological evaluation of peripheral nerve lesions has been used routinely to assess peripheral nerve demyelination; however, the development of magnetic resonance (MR) methodology for assessing peripheral nerve may provide complementary information, with less expense and in less time than nerve histology methods. In this study, the utility of multicomponent NMR T(2) relaxation analysis for assessing myelin injury in toxicology studies was examined using two dithiocarbamates, N,N-diethyldithiocarbamate (DEDC) and pyrrolidine dithiocarbamate (PDTC), known to produce myelin injury and elevate copper in the nervous system. T(2) analysis was used in conjunction with standard histological methods to assess myelin injury and determine if dithiocarbamate-mediated copper accumulation in peripheral nerve was associated with more severe myelin lesions. Male Sprague-Dawley rats were administered i.p. DEDC for 8 weeks and maintained on either a diet containing normal (13 ppm) or elevated (200 ppm) copper. Another group of male Sprague-Dawley rats was administered oral PDTC and a 200 ppm copper diet, with controls given only the 200 ppm copper diet, for 47 weeks. Following exposures, the morphology of sciatic nerve was evaluated using light microscopy and multicomponent T(2) analysis of excised fixed nerves; and copper levels in sciatic nerve were determined using ICP-AES. Light microscopy demonstrated the presence of a primary myelinopathy in dithiocarbamate-exposed rats characterized by intramyelinic edema, demyelination, and secondary axonal degeneration. Both the nerve copper level and number of degenerated axons, as ascertained by ICP-AES and microscopy, respectively, were augmented by dietary copper supplementation in conjunction with administration of DEDC or PDTC. T(2) analysis revealed a decreased contribution from the shortest T(2) component in multicomponent T(2) spectra obtained from animals administered DEDC or PDTC, consistent with decreased myelin content; and the decrease of the myelin water component was inversely correlated to the levels of nerve copper and myelin lesion counts. Also, the T(2) analysis showed reduced variability compared to histological assessment. These studies support multicomponent T(2) analysis as a complementary method to light microscopic evaluations that may also be applicable to in vivo assessments.

Numerical Study of Water Diffusion in Biological Tissues Using an Improved Finite Difference Method

Physics in Medicine and Biology. Apr, 2007  |  Pubmed ID: 17374905

An improved finite difference (FD) method has been developed in order to calculate the behaviour of the nuclear magnetic resonance signal variations caused by water diffusion in biological tissues more accurately and efficiently. The algorithm converts the conventional image-based finite difference method into a convenient matrix-based approach and includes a revised periodic boundary condition which eliminates the edge effects caused by artificial boundaries in conventional FD methods. Simulated results for some modelled tissues are consistent with analytical solutions for commonly used diffusion-weighted pulse sequences, whereas the improved FD method shows improved efficiency and accuracy. A tightly coupled parallel computing approach was also developed to implement the FD methods to enable large-scale simulations of realistic biological tissues. The potential applications of the improved FD method for understanding diffusion in tissues are also discussed.

Dipeptidyl Peptidase IV Deficiency Increases Susceptibility to Angiotensin-converting Enzyme Inhibitor-induced Peritracheal Edema

The Journal of Allergy and Clinical Immunology. Aug, 2007  |  Pubmed ID: 17531305

Serum dipeptidyl peptidase IV (DPPIV) activity is decreased in some individuals with ACE inhibitor-associated angioedema. ACE and DPPIV degrade substance P, an edema-forming peptide. The contribution of impaired degradation of substance P by DPPIV to the pathogenesis of ACE inhibitor-associated angioedema is unknown.

2D Arbitrary Shape-selective Excitation Summed Spectroscopy (ASSESS)

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. Jul, 2007  |  Pubmed ID: 17659614

Conventional single-voxel localization for MR spectroscopy (MRS) is restricted to selecting only rectangular-shaped regions of interest (ROIs). The complexity of tissue shapes of interest and the desire to maximize the signal-to-noise ratio (SNR) while minimizing partial-volume effects require more sophisticated localization techniques. A group of spatially selective RF pulses are proposed in this work for the measurement of spectra from regions of arbitrary shape based on using a radial trajectory in k-space. Utilizing a single k-line per excitation results in a broad spectroscopic bandwidth. However, spatial localization accuracy is compromised for nutation angles > 10 degrees because of the small-tip-angle approximation of the Bloch equations. By interleaving multiple radial k-lines per excitation with nonselective refocusing pulses, one can achieve accurate localization for nutation angles up to 90 degrees while simultaneously maintaining the spectral bandwidth. The technique is described and compared with existing localization methods, and in vivo results are demonstrated.

Temporal DeltaB0 and Relaxation in the Rat Heart

Magnetic Resonance in Medicine. Nov, 2007  |  Pubmed ID: 17969107

Field maps of the induced main magnetic field offset (DeltaB(0)) were measured in the rat heart at various points in the cardiac cycle for the purpose of identifying their effects on relaxation measurements. The mean DeltaB(0) of the left ventricle averaged across rats was found to be 0.11 +/- 0.35 ppm and 0.19 +/- 0.39 ppm at the onset of systole and diastole, respectively. The root mean square (RMS) variation in resonant frequency of the left ventricle averaged across rats was found to be 0.09 +/- 0.05 ppm and 0.06 +/- 0.04 ppm during systole and diastole, respectively. Temporal variations in DeltaB(0) could substantially affect quantitative MRI measurements. To assess this, transverse relaxation rates (R(2) and R(2)(*)) were measured at different points in the cardiac cycle, and the effects of DeltaB(0) were estimated using measured field map data. For a given region of the left ventricle, DeltaB(0) induced a mean error across rats of < or =3.9% for R(2) and < or =9.6% for R(2)(*). For R(2)(*) measurements, the static component of the field inhomogeneity was found to be responsible for most of the error induced.

Quantitative T2 Measurement of a Single Voxel with Arbitrary Shape Using Pinwheel Excitation and CPMG Acquisition

Magma (New York, N.Y.). Dec, 2007  |  Pubmed ID: 17999101

The aim of this study is to present a new approach for making quantitative single-voxel T (2) measurements from an arbitrarily shaped region of interest (ROI), where the advantage of the signal-to-noise ratio (SNR) per unit time of the single-voxel approach over conventional imaging approach can be achieved.

Compartmental Relaxation and Diffusion Tensor Imaging Measurements in Vivo in Lambda-carrageenan-induced Edema in Rat Skeletal Muscle

NMR in Biomedicine. Jul, 2008  |  Pubmed ID: 18041804

Integrated diffusion tensor T(2) measurements were made on normal and edematous rat muscle, and the data were fitted with one- and two-compartment models, respectively. Edematous muscle exhibited a short-lived component (T(2) = 28 +/- 6 ms), with diffusion characteristics similar to that of normal muscle, and a long-lived component (T(2) = 96 +/- 27 ms), with greater mean apparent diffusion coefficient (ADC) and lower fractional anisotropy (FA). With this two-component description of diffusion and relaxation, values of ADC and FA estimated with a conventional pulsed-gradient spin-echo sequence will depend on the echo time, relative fraction of short-lived and long-lived water signals, and the intrinsic ADC and FA values within the tissue. On the basis of the relative differences in water diffusion properties between long-lived and short-lived water signals, as well as the similarities between the short-lived component and normal tissue, it is postulated that these two signal components largely reflect intracellular and extracellular water.

New Insights into Tumor Microstructure Using Temporal Diffusion Spectroscopy

Cancer Research. Jul, 2008  |  Pubmed ID: 18632649

Magnetic resonance images (MRI) that depict rates of water diffusion in tissues can be used to characterize the cellularity of tumors and are valuable in assessing their early response to treatment. Water diffusion rates are sensitive to the cellular and molecular content of tissues and are affected by local microstructural changes associated with tumor development. However, conventional maps of water diffusion reflect the integrated effects of restrictions to free diffusion at multiple scales up to a specific limiting spatial dimension, typically several micrometers. Such measurements cannot distinguish effects caused by structural variations at a smaller scale. Variations in diffusion rates then largely reflect variations in the density of cells, and no information is available about changes on a subcellular scale. We report here our experiences using a new approach based on Oscillating Gradient Spin-Echo (OGSE) MRI methods that can differentiate the influence on water diffusion of structural changes on scales much smaller than the diameter of a single cell. MRIs of glioblastomas in rat brain in vivo show an increased contrast and spatial heterogeneity when diffusion measurements are selectively sensitized to shorter distance scales. These results show the benefit of OGSE methods for revealing microscopic variations in tumors in vivo and confirm that diffusion measurements depend on factors other than cellularity.

Optimal Echo Spacing for Multi-echo Imaging Measurements of Bi-exponential T2 Relaxation

Journal of Magnetic Resonance (San Diego, Calif. : 1997). Feb, 2009  |  Pubmed ID: 19028432

Calculations, analytical solutions, and simulations were used to investigate the trade-off of echo spacing and receiver bandwidth for the characterization of bi-exponential transverse relaxation using a multi-echo imaging pulse sequence. The Cramer-Rao lower bound of the standard deviation of the four parameters of a two-pool model was computed for a wide range of component T(2) values and echo spacing. The results demonstrate that optimal echo spacing (TE(opt)) is not generally the minimal available given other pulse sequence constraints. The TE(opt) increases with increasing value of the short T(2) time constant and decreases as the ratio of the long and short time constant decreases. A simple model of TE(opt) as a function of the two T(2) time constants and four empirically derived scalars is presented.

Transverse Relaxation and Magnetization Transfer in Skeletal Muscle: Effect of PH

Magnetic Resonance in Medicine. Mar, 2009  |  Pubmed ID: 19097244

Exercise increases the intracellular T(2) (T(2,i)) of contracting muscles. The mechanism(s) for the T(2,i) increase have not been fully described, and may include increased intracellular free water and acidification. These changes may alter chemical exchange processes between intracellular free water and proteins. In this study, the hypotheses were tested that (a) pH changes T(2,i) by affecting the rate of magnetization transfer (MT) between free intracellular water and intracellular proteins, and (b) the magnitude of the T(2,i) effect depends on acquisition mode (localized or nonlocalized) and echo spacing. Frog gastrocnemius muscles were excised and their intracellular pH was either kept at physiological pH (7.0) or modified to model exercising muscle (pH 6.5). The intracellular transverse relaxation rate (R(2,i) = 1/T(2,i)) always decreased in the acidic muscles, but the changes were greater when measured using more rapid refocusing rates. The MT rate from the macromolecular proton pool to the free water proton pool, its reverse rate, and the spin-lattice relaxation rate of water decreased in acidic muscles. It is concluded that intracellular acidification alters the R(2,i) of muscle water in a refocusing rate-dependent manner, and that the R(2,i) changes are correlated with changes in the MT rate between macromolecules and free intracellular water.

Sensitivity of MR Diffusion Measurements to Variations in Intracellular Structure: Effects of Nuclear Size

Magnetic Resonance in Medicine. Apr, 2009  |  Pubmed ID: 19205020

Magnetic resonance imaging measurements of the apparent rate of water diffusion in tumors are sensitive to variations in tissue cellularity, which have been shown useful for characterizing tumors and their responses to treatments. However, because of technical limitations on most MRI systems, conventional pulse gradient spin echo (PGSE) methods measure relatively long time scales, during which water molecules may encounter diffusion barriers at multiple spatial scales, including those much greater than typical cell dimensions. As such they cannot distinguish changes on subcellular scales from gross changes in cell density. Oscillating gradient spin echo (OGSE) methods have the potential to distinguish effects on restriction at much shorter time and length scales. Both PGSE and OGSE methods have been studied numerically by simulating diffusion in a three-dimensional, multicompartment tissue model. The results show that conventional measurements with the PGSE method cannot selectively probe variations over short length scales and, therefore, are relatively insensitive to intracellular structure, whereas results using OGSE methods at moderate gradient frequencies are affected by variations in cell nuclear sizes and can distinguish tissues that differ only over subcellular length scales. This additional sensitivity suggests that OGSE imaging may have significant advantages over conventional PGSE methods for characterizing tumors.

Evidence of Multiexponential T2 in Rat Glioblastoma

NMR in Biomedicine. Jul, 2009  |  Pubmed ID: 19267385

The aim of this study was to characterize multiexponential T(2) (MET(2)) relaxation in a rat C6 glioblastoma tumor model. To do this, rats (n = 11) were inoculated with the C6 cells via stereotaxic injection into the brain. Ten days later, MET(2) measurements were performed in vivo using a single-slice, multi-echo spin-echo sequence at 7.0 T. Tumor signal was biexponential in eight animals with a short-lived T(2) component (T(2) = 20.7 +/- 5.4 ms across samples) representing 6.8 +/- 6.2% of the total signal and a long-lived T(2) component (T(2) = 76.4 +/- 9.3 ms) representing the remaining signal fraction. In contrast, signal from contralateral grey matter was consistently monoexponential (T(2) = 48.8 +/- 2.3 ms). Additional ex vivo studies (n = 3) and Monte Carlo simulations showed that the in vivo results were not significantly corrupted by partial volume averaging or noise. The underlying physiological origin of the observed MET(2) components is unknown; however, MET(2) analysis may hold promise as a non-invasive tool for characterizing tumor microenvironment in vivo on a sub-voxel scale.

N,N-diethyldithiocarbamate Promotes Oxidative Stress Prior to Myelin Structural Changes and Increases Myelin Copper Content

Toxicology and Applied Pharmacology. Aug, 2009  |  Pubmed ID: 19467251

Dithiocarbamates are a commercially important class of compounds that can produce peripheral neuropathy in humans and experimental animals. Previous studies have supported a requirement for copper accumulation and enhanced lipid peroxidation in dithiocarbamate-mediated myelinopathy. The study presented here extends previous investigations in two areas. Firstly, although total copper levels have been shown to increase within the nerve it has not been determined whether copper is increased within the myelin compartment, the primary site of lesion development. Therefore, the distribution of copper in sciatic nerve was characterized using synchrotron X-ray fluorescence microscopy to determine whether the neurotoxic dithiocarbamate, N,N-diethyldithiocarbamate, increases copper levels in myelin. Secondly, because lipid peroxidation is an ongoing process in normal nerve and the levels of lipid peroxidation products produced by dithiocarbamate exposure demonstrated an unusual cumulative dose response in previous studies the biological impact of dithiocarbamate-mediated lipid peroxidation was evaluated. Experiments were performed to determine whether dithiocarbamate-mediated lipid peroxidation products elicit an antioxidant response through measuring the protein expression levels of three enzymes, superoxide dismutase 1, heme oxygenase 1, and glutathione transferase alpha, that are linked to the antioxidant response element promoter. To establish the potential of oxidative injury to contribute to myelin injury the temporal relationship of the antioxidant response to myelin injury was determined. Myelin structure in peripheral nerve was assessed using multi-exponential transverse relaxation measurements (MET(2)) as a function of exposure duration, and the temporal relationship of protein expression changes relative to the onset of changes in myelin integrity were determined. Initial assessments were also performed to explore the potential contribution of dithiocarbamate-mediated inhibition of proteasome function and inhibition of cuproenzyme activity to neurotoxicity, and also to assess the potential of dithiocarbamates to promote oxidative stress and injury within the central nervous system. These evaluations were performed using an established model for dithiocarbamate-mediated demyelination in the rat utilizing sciatic nerve, spinal cord and brain samples obtained from rats exposed to N,N-diethyldithiocarbamate (DEDC) by intra-abdominal pumps for periods of 2, 4, and 8 weeks and from non exposed controls. The data supported the ability of DEDC to increase copper within myelin and to enhance oxidative stress prior to structural changes detectable by MET(2). Evidence was also obtained that the excess copper produced by DEDC in the central nervous system is redox active and promotes oxidative injury.

Quantitative Characterization of Tissue Microstructure with Temporal Diffusion Spectroscopy

Journal of Magnetic Resonance (San Diego, Calif. : 1997). Oct, 2009  |  Pubmed ID: 19616979

The signals recorded by diffusion-weighted magnetic resonance imaging (DWI) are dependent on the micro-structural properties of biological tissues, so it is possible to obtain quantitative structural information non-invasively from such measurements. Oscillating gradient spin echo (OGSE) methods have the ability to probe the behavior of water diffusion over different time scales and the potential to detect variations in intracellular structure. To assist in the interpretation of OGSE data, analytical expressions have been derived for diffusion-weighted signals with OGSE methods for restricted diffusion in some typical structures, including parallel planes, cylinders and spheres, using the theory of temporal diffusion spectroscopy. These analytical predictions have been confirmed with computer simulations. These expressions suggest how OGSE signals from biological tissues should be analyzed to characterize tissue microstructure, including how to estimate cell nuclear sizes. This approach provides a model to interpret diffusion data obtained from OGSE measurements that can be used for applications such as monitoring tumor response to treatment in vivo.

Multiexponential T2, Magnetization Transfer, and Quantitative Histology in White Matter Tracts of Rat Spinal Cord

Magnetic Resonance in Medicine. Apr, 2010  |  Pubmed ID: 20373391

Quantitative MRI measures of multiexponential T(2) relaxation and magnetization transfer were acquired from six samples of excised and fixed rat spinal cord and compared with quantitative histology. MRI and histology data were analyzed from six white matter tracts, each of which possessed unique microanatomic characteristics (axon diameter and myelin thickness, in particular) but a relatively constant volume fraction of myelin. The results indicated that multiexponential T(2) relaxation characteristics varied substantially with variation of microanatomy, while the magnetization transfer characteristics remained close to constant. The most-often-cited multiexponential T(2) relaxation metric, myelin water fraction, varied by almost a factor of 2 between two regions with myelin volume fractions that differed by only approximately 12%. Based on the quantitative histology, the proposed explanation for this variation was intercompartmental water exchange, which caused the underestimation of myelin water fraction and T(2) values and is, presumably, a greater factor in white matter regions where axons are small and myelin is thin. In contrast to the multiexponential T(2) relaxation observations, magnetization transfer metrics were relatively constant across white matter tracts and concluded to be relatively insensitive to intercompartmental water exchange.

Optimized Inversion Recovery Sequences for Quantitative T1 and Magnetization Transfer Imaging

Magnetic Resonance in Medicine. Aug, 2010  |  Pubmed ID: 20665793

Inversion recovery sequences that vary the inversion time (t(i)) have been employed to determine T(1) and, more recently, quantitative magnetization transfer parameters. Specifically, in previous work, the inversion recovery pulse sequences varied t(i) only while maintaining a constant delay (t(d)) between repetitions. T(1) values were determined by fitting to a single exponential function, and quantitative magnetization transfer parameters were then determined by fitting to a biexponential function with an approximate solution. In the current study, new protocols are employed, which vary both t(i) and t(d) and fit the data with minimal approximations. Cramer-Rao lower bounds are calculated to search for acquisition schemes that will maximize the precision efficiencies of T(1) and quantitative magnetization transfer parameters. This approach is supported by Monte Carlo simulations. The optimal T(1) schemes are verified by measurements on MnCl(2) samples. The optimal quantitative magnetization transfer schemes are confirmed by measurements on a series of cross-linked bovine serum albumin phantoms of varying concentrations. The effects of varying the number of sampling data points are also explored, and a rapid acquisition scheme is demonstrated in vivo. These new optimized quantitative imaging methods provide an improved means for determining T(1) and magnetization transfer parameter values compared to previous inversion recovery based methods.

RF Coil Considerations for Short-T2 MRI

Magnetic Resonance in Medicine. Dec, 2010  |  Pubmed ID: 20665825

With continuing hardware and pulse sequence advancements, modern MRI is gaining sensitivity to signals from short-T(2) (1)H species under practical experimental conditions. However, conventional MRI coils are typically not designed for this type of application, as they often contain proton-rich construction materials that may contribute confounding (1)H background signal during short-T(2) measurements. An example of this is shown herein. Separately, a loop-gap style coil was used to compare different coil construction materials and configurations with respect to observed (1)H background signal sizes in a small animal imaging system. Background signal sources were spatially identified and quantified in a number of different coil configurations. It was found that the type and placement of structural coil materials around the loop-gap resonator, as well as the coil's shielding configuration, are critical determinants of the coil's background signal size. Although this study employed a loop-gap resonator design, these findings are directly relevant to standard volume coils commonly used for MRI.

Characterization of Tissue Structure at Varying Length Scales Using Temporal Diffusion Spectroscopy

NMR in Biomedicine. Aug, 2010  |  Pubmed ID: 20677208

The concepts, theoretical behavior and experimental applications of temporal diffusion spectroscopy are reviewed and illustrated. Temporal diffusion spectra are obtained using oscillating-gradient waveforms in diffusion-weighted measurements, and represent the manner in which various spectral components of molecular velocity correlations vary in different geometrical structures that restrict or hinder free movements. Measurements made at different gradient frequencies reveal information on the scale of restrictions or hindrances to free diffusion, and the shape of a spectrum reveals the relative contributions of spatial restrictions at different distance scales. Such spectra differ from other so-called diffusion spectra which depict spatial frequencies and are defined at a fixed diffusion time. Experimentally, oscillating gradients at moderate frequency are more feasible for exploring restrictions at very short distances which, in tissues, correspond to structures smaller than cells. We describe the underlying concepts of temporal diffusion spectra and provide analytical expressions for the behavior of the diffusion coefficient as a function of gradient frequency in simple geometries with different dimensions. Diffusion in more complex model media that mimic tissues has been simulated using numerical methods. Experimental measurements of diffusion spectra have been obtained in suspensions of particles and cells, as well as in vivo in intact animals. An observation of particular interest is the increased contrast and heterogeneity observed in tumors using oscillating gradients at moderate frequency compared with conventional pulse gradient methods, and the potential for detecting changes in tumors early in their response to treatment. Computer simulations suggest that diffusion spectral measurements may be sensitive to intracellular structures, such as nuclear size, and that changes in tissue diffusion properties may be measured before there are changes in cell density.

Characterization of 1H NMR Signal in Human Cortical Bone for Magnetic Resonance Imaging

Magnetic Resonance in Medicine. Sep, 2010  |  Pubmed ID: 20806375

Recent advancements in MRI have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. In human cortical bone, MRI is sensitive to populations of protons ((1)H) partitioned among water and protein sources, which may be differentiated according to intrinsic NMR properties such as chemical shift and transverse and longitudinal relaxation rates. Herein, these NMR properties were assessed in human cortical bone donors from a broad age range, and four distinct (1)H populations were consistently identified and attributed to five microanatomical sources. These findings show that modern human cortical bone MRI contrast will be dominated by collagen-bound water, which can also be exploited to study human cortical bone collagen via magnetization transfer.

Compartment-specific Enhancement of White Matter and Nerve Ex Vivo Using Chromium

Magnetic Resonance in Medicine. Sep, 2010  |  Pubmed ID: 20806376

Chromium--Cr(VI) in the form of potassium dichromate--has been shown to specifically enhance white matter signal. The proposed mechanism for this enhancement is reduction of diamagnetic Cr(VI) to paramagnetic chromium species by oxidizable myelin lipids. The purpose of the study herein was to better understand the microanatomical basis of this enhancement (i.e., the relative enhancement of myelin, intra-axonal, and extra-axonal water). Toward this end, integrated T(1)-T(2) measurements were performed in potassium dichromate loaded (hereafter referred to as chromated) rat brains, rat optic nerve samples, and frog sciatic nerve samples ex vivo. In control optic nerve and white matter, two T(1)-T(2) components were resolved, representing myelin and nonmyelin water (intra- and extra-axonal water). Following chromation, three T(1)-T(2) components were resolved in these same tissues. Results from similar measurements in sciatic nerve-all three components are resolvable in control and chromated samples-and quantitative histologic analysis suggest that this additional T(1)-T(2) component is due to a splitting of the nonmyelin water component into intra- and extra-axonal water components. This compartment-specific enhancement may provide unique contrast for MR histology, as well as allow one to probe the compartmental basis of various contrast mechanisms in neural tissue.

Dependence of Temporal Diffusion Spectra on Microstructural Properties of Biological Tissues

Magnetic Resonance Imaging. Apr, 2011  |  Pubmed ID: 21129880

The apparent diffusion coefficient (ADC) measured using magnetic resonance imaging methods provides information on microstructural properties of biological tissues, and thus has found applications as a useful biomarker for assessing changes such as those that occur in ischemic stroke and cancer. Conventional pulsed gradient spin echo methods are in widespread use and provide information on, for example, variations in cell density. The oscillating gradient spin echo (OGSE) method has the additional ability to probe diffusion behaviors more readily at short diffusion times, and the temporal diffusion spectrum obtained by the OGSE method provides a unique tool for characterizing tissues over different length scales, including structural features of intracellular spaces. It has previously been reported that several tissue properties can affect ADC measurements significantly, and the precise biophysical mechanisms that account for ADC changes in different situations are still unclear. Those factors may vary in importance depending on the time and length scale over which measurements are made. In the present work, a comprehensive numerical simulation is used to investigate the dependence of the temporal diffusion spectra measured by OGSE methods on different microstructural properties of biological tissues, including cell size, cell membrane permeability, intracellular volume fraction, intranucleus and intracytoplasm diffusion coefficients, nuclear size and T(2) relaxation times. Some unique characteristics of the OGSE method at relatively high frequencies are revealed. The results presented in the paper offer a framework for better understanding possible causes of diffusion changes and may be useful to assist the interpretation of diffusion data from OGSE measurements.

Earlier Detection of Tumor Treatment Response Using Magnetic Resonance Diffusion Imaging with Oscillating Gradients

Magnetic Resonance Imaging. Apr, 2011  |  Pubmed ID: 21190804

An improved method for detecting early changes in tumors in response to treatment, based on a modification of diffusion-weighted magnetic resonance imaging, has been demonstrated in an animal model. Early detection of therapeutic response in tumors is important both clinically and in pre-clinical assessments of novel treatments. Noninvasive imaging methods that can detect and assess tumor response early in the course of treatment, and before frank changes in tumor morphology are evident, are of considerable interest as potential biomarkers of treatment efficacy. Diffusion-weighted magnetic resonance imaging is sensitive to changes in water diffusion rates in tissues that result from structural variations in the local cellular environment, but conventional methods mainly reflect changes in tissue cellularity and do not convey information specific to microstructural variations at sub-cellular scales. We implemented a modified imaging technique using oscillating gradients of the magnetic field for evaluating water diffusion rates over very short spatial scales that are more specific for detecting changes in intracellular structure that may precede changes in cellularity. Results from a study of orthotopic 9L gliomas in rat brains indicate that this method can detect changes as early as 24 h following treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea, when conventional approaches do not find significant effects. These studies suggest that diffusion imaging using oscillating gradients may be used to obtain an earlier indication of treatment efficacy than previous magnetic resonance imaging methods.

Non-invasive Predictors of Human Cortical Bone Mechanical Properties: T(2)-discriminated H NMR Compared with High Resolution X-ray

PloS One. Jan, 2011  |  Pubmed ID: 21283693

Recent advancements in magnetic resonance imaging (MRI) have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. To this end, (1)H nuclear magnetic resonance (NMR) and high-resolution X-ray signals from human cortical bone samples were correlated with mechanical properties of bone. Results showed that (1)H NMR signals were better predictors of yield stress, peak stress, and pre-yield toughness than were the X-ray derived signals. These (1)H NMR signals can, in principle, be extracted from clinical MRI, thus offering the potential for improved clinical assessment of fracture risk.

Effects of Intracellular Organelles on the Apparent Diffusion Coefficient of Water Molecules in Cultured Human Embryonic Kidney Cells

Magnetic Resonance in Medicine. Mar, 2011  |  Pubmed ID: 21337411

The apparent diffusion coefficient (ADC) of water in tissues is dependent on the size and spacing of structures in the cellular environment and has been used to characterize pathological changes in stroke and cancer. However, the factors that affect ADC values remain incompletely understood. Measurements of ADC are usually made using relatively long diffusion times; so they reflect the integrated effects of cellular structures over a broad range of spatial scales. We used temporal diffusion spectroscopy to study diffusion in packed cultured human embryonic kidney cells over a range of effective diffusion times following microtubule and actin/cytoskeleton depolymerization and disassembly of the Golgi complex. While Golgi disruption did not change ADC, depolymerization of the microtubule and the actin filament networks caused small decreases in ADC at short diffusion times only. Temporal diffusion spectroscopy provided a novel way to assess intracellular influences on the diffusion properties of tissue water.

Influence of Cell Cycle Phase on Apparent Diffusion Coefficient in Synchronized Cells Detected Using Temporal Diffusion Spectroscopy

Magnetic Resonance in Medicine. Apr, 2011  |  Pubmed ID: 21413058

The relationship between the apparent diffusion coefficient of tissue water measured by MR methods and the physiological status of cells is of particular relevance for better understanding and interpretation of diffusion-weighted MRI. In addition, there is considerable interest in developing diffusion-dependent imaging methods capable of providing novel information on tissue microstructure, including intracellular changes. To this end, both the conventional pulsed gradient spin-echo methods and the oscillating gradient spin-echo method, which probes diffusion over very short distance (

Optimizing Pulsed-chemical Exchange Saturation Transfer Imaging Sequences

Magnetic Resonance in Medicine. Oct, 2011  |  Pubmed ID: 21432903

Chemical exchange saturation transfer (CEST) provides a new imaging contrast mechanism sensitive to labile proton exchange. Pulsed-CEST imaging is better suited to the hardware constraints on clinical imaging systems when compared with traditional continuous wave-CEST imaging methods. However, designing optimum pulsed-CEST imaging sequences entails complicated and time-consuming numerical integrations. In this work, a simplified and computationally efficient technique is provided to optimize the pulsed-CEST imaging sequence. An analysis was performed of the optimal average irradiation power and the optimal irradiation flip angle as a function of the acquisition parameters and sample properties in both a two-pool model and a three-pool model of endogenous amine exchange. Key simulated and experimental results based on a creatine/agar tissue phantom show that (1) the average irradiation power is a more meaningful sequence metric than is the average irradiation field amplitude, (2) the optimal average powers for continuous wave and pulsed-CEST imaging are approximately equal to each other for a relevant range of solute frequency offsets, exchange rates, and concentrations, (3) an irradiation flip angle of 180° is optimal or near optimal, independent of the other acquisition parameters and the sample properties, and (4) higher duty cycles yield higher CEST contrast.

Origins of the Ultrashort-T2 1H NMR Signals in Myelinated Nerve: a Direct Measure of Myelin Content?

Magnetic Resonance in Medicine. Jul, 2011  |  Pubmed ID: 21574183

Recently developed MRI techniques have enabled clinical imaging of short-lived (1)H NMR signals with T(2) < 1 ms. Using these techniques, novel signal enhancement has been observed in myelinated tissues, although the source of this enhancement has not been identified. Herein, we report studies of the nature and origins of ultrashort T(2) (uT(2)) signals (50 μs < T(2) < 1 ms) from amphibian and mammalian myelinated nerves. NMR measurements and comparisons with myelin phantoms and expected myelin components indicate that these uT(2) signals arise predominantly from methylene (1)H on/in the myelin membranes, which suggests that direct measurement of uT(2) signals can be used as a new means for quantitative myelin mapping.

Effect of Intercompartmental Water Exchange on the Apparent Myelin Water Fraction in Multiexponential T2 Measurements of Rat Spinal Cord

Magnetic Resonance in Medicine. Mar, 2012  |  Pubmed ID: 21713984

The myelin water fraction has been used as a quantitative measure of the amount of myelin present in tissue. However, recent work has suggested that intercompartmental exchange of water between myelin and nonmyelin compartments may cause the myelin water fraction to underestimate the true myelin content of tissue. In this work, multiexponential T(2) experiments were performed in vivo within the rat spinal cord, and a wide variation of the myelin water fraction (10-35%) was measured within four rat spinal cord tracts with similar myelin content. A numerical simulation based upon segmented histology images was used to quantitatively account for T(2) variations between tracts. The model predicts that a difference in exchange between the four spinal cord tracts, mediated by a difference in the average axon radius and myelin thickness, is sufficient to account for the variation in myelin water fraction measured in vivo.

Multi-angle Ratiometric Approach to Measure Chemical Exchange in Amide Proton Transfer Imaging

Magnetic Resonance in Medicine. Sep, 2012  |  Pubmed ID: 22161770

Amide proton transfer imaging, a specific form of chemical exchange saturation transfer imaging, has previously been applied to studies of acute ischemic acidosis, stroke, and cancer. However, interpreting the resulting contrast is complicated by its dependence on the exchange rate between amides and water, the amide concentration, amide and water relaxation, and macromolecular magnetization transfer. Hence, conventional chemical exchange saturation transfer contrast is not specific to changes such as reductions in pH due to tissue acidosis. In this article, a multi-angle ratiometric approach based on several pulsed-chemical exchange saturation transfer scans at different irradiation flip angles is proposed to specifically reflect exchange rates only. This separation of exchange effects in pulsed-chemical exchange saturation transfer experiments is based on isolating rotation vs. saturation contributions, and such methods form a new subclass of chemical exchange rotation transfer (CERT) experiments. Simulations and measurements of creatine/agar phantoms indicate that a newly proposed imaging metric isolates the effects of exchange rate changes, independent of other sample parameters.

Clinically Compatible MRI Strategies for Discriminating Bound and Pore Water in Cortical Bone

Magnetic Resonance in Medicine. Dec, 2012  |  Pubmed ID: 22294340

Advances in modern magnetic resonance imaging (MRI) pulse sequences have enabled clinically practical cortical bone imaging. Human cortical bone is known to contain a distribution of T(1) and T(2) components attributed to bound and pore water, although clinical imaging approaches have yet to discriminate bound from pore water based on their relaxation properties. Herein, two clinically compatible MRI strategies are proposed for selectively imaging either bound or pore water by utilizing differences in their T(1)s and T(2)s. The strategies are validated in a population of ex vivo human cortical bones, and estimates obtained for bound and pore water are compared to bone mechanical properties. Results show that the two MRI strategies provide good estimates of bound and pore water that correlate to bone mechanical properties. As such, the strategies for bound and pore water discrimination shown herein should provide diagnostically useful tools for assessing bone fracture risk, once applied to clinical MRI.

Characterizing Tumor Response to Chemotherapy at Various Length Scales Using Temporal Diffusion Spectroscopy

PloS One. 2012  |  Pubmed ID: 22911846

Measurements of apparent diffusion coefficient (ADC) using magnetic resonance imaging (MRI) have been suggested as potential imaging biomarkers for monitoring tumor response to treatment. However, conventional pulsed-gradient spin echo (PGSE) methods incorporate relatively long diffusion times, and are usually sensitive to changes in cell density and necrosis. Diffusion temporal spectroscopy using the oscillating gradient spin echo (OGSE) sequence is capable of probing short length scales, and may detect significant intracellular microstructural changes independent of gross cell density changes following anti-cancer treatment. To test this hypothesis, SW620 xenografts were treated by barasertib (AZD1152), a selective inhibitor of Aurora B kinase which causes SW620 cancer cells to develop polyploidy and increase in size following treatment, ultimately leading to cell death through apoptosis. Following treatment, the ADC values obtained by both the PGSE and low frequency OGSE methods increased. However, the ADC values at high gradient frequency (i.e. short diffusion times) were significantly lower in treated tumors, consistent with increased intracellular restrictions/hindrances. This suggests that ADC values at long diffusion times are dominated by tumor microstructure at long length scales, and may not convey unambiguous information of subcellular space. While the diffusion temporal spectroscopy provides more comprehensive means to probe tumor microstructure at various length scales. This work is the first study to probe intracellular microstructural variations due to polyploidy following treatment using diffusion MRI in vivo. It is also the first observation of post-treatment ADC changes occurring in opposite directions at short and long diffusion times. The current study suggests that temporal diffusion spectroscopy potentially provides pharmacodynamic biomarkers of tumor early response which distinguish microstructural variations following treatment at both the subcellular and supracellular length scales.

Comparison of Dynamic Contrast-enhanced MRI and Quantitative SPECT in a Rat Glioma Model

Contrast Media & Molecular Imaging. Nov-Dec, 2012  |  Pubmed ID: 22991315

Pharmacokinetic modeling of dynamic contrast-enhanced (DCE) MRI data provides measures of the extracellular-extravascular volume fraction (v(e) ) and the volume transfer constant (K(trans) ) in a given tissue. These parameter estimates may be biased, however, by confounding issues such as contrast agent and tissue water dynamics, or assumptions of vascularization and perfusion made by the commonly used model. In contrast to MRI, radiotracer imaging with SPECT is insensitive to water dynamics. A quantitative dual-isotope SPECT technique was developed to obtain an estimate of v(e) in a rat glioma model for comparison with the corresponding estimates obtained using DCE-MRI with a vascular input function and reference region model. Both DCE-MRI methods produced consistently larger estimates of v(e) in comparison to the SPECT estimates, and several experimental sources were postulated to contribute to these differences.

On the Inherent Precision of McDESPOT

Magnetic Resonance in Medicine. Jan, 2013  |  Pubmed ID: 22411784

A statistical analysis of the mcDESPOT protocol for characterizing two exchanging water proton pools--a seven-dimensional problem that fits to multiple flip angle measurements of both spoiled and refocused gradient echoes--is presented. Theoretical calculations of the Cramér-Rao lower bounds of the variance of fitted model parameters were made using a variety of model system parameters, meant to mimic those expected in human white matter. The results, validated by Monte Carlo simulations, indicated that mcDESPOT signals acquired at feasibly attainable signal-to-noise ratios cannot provide parameter estimates with useful levels of precision. Precision can be greatly improved by constraining solutions with a priori model information, although this will generally lead to biased parameter estimates with less specificity. These results indicate that previous, apparently successful applications of mcDESPOT to human white matter may have used data fitting methods that implicitly constrained parameter solutions, or that the two-pool model of white matter may not be sufficient to describe the observed water proton signal in mcDESPOT acquisitions. In either case, mcDESPOT-derived estimates of two-pool model parameters cannot yet be unambiguously related to specific tissue characteristics.

A New Method for Detecting Exchanging Amide Protons Using Chemical Exchange Rotation Transfer

Magnetic Resonance in Medicine. Mar, 2013  |  Pubmed ID: 22505325

In this study, we introduce a new method for amide proton transfer imaging based on chemical exchange rotation transfer. It avoids several artifacts that plague conventional chemical exchange saturation transfer approaches by creating label and reference scans based on varying the irradiation pulse rotation angle (π and 2π radians) instead of the frequency offset (3.5 and -3.5 ppm). Specifically, conventional analysis is sensitive to confounding contributions from magnetic field (B(0)) inhomogeneities and, more problematically, inherently asymmetric macromolecular resonances. In addition, the lipid resonance at -3.5 ppm complicates the interpretation of the reference scan and decreases the resulting contrast. Finally, partial overlap of the amide signal by nearby amines and hydroxyls obscure the results. By avoiding these issues, our new method is a promising approach for imaging endogenous protein and peptide content and mapping pH.

Characterizing Inter-compartmental Water Exchange in Myelinated Tissue Using Relaxation Exchange Spectroscopy

Magnetic Resonance in Medicine. Nov, 2013  |  Pubmed ID: 23233414

To investigate inter-compartmental water exchange in two model myelinated tissues ex vivo using relaxation exchange spectroscopy.

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

NeuroImage. Jul, 2013  |  Pubmed ID: 23481461

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.

Partial Removal of Pore and Loosely Bound Water by Low-energy Drying Decreases Cortical Bone Toughness in Young and Old Donors

Journal of the Mechanical Behavior of Biomedical Materials. Jun, 2013  |  Pubmed ID: 23631897

With an ability to quantify matrix-bound and pore water in bone, (1)H nuclear magnetic resonance (NMR) relaxometry can potentially be implemented in clinical imaging to assess the fracture resistance of bone in a way that is independent of current X-ray techniques, which assess bone mineral density as a correlate of bone strength. Working towards that goal, we quantified the effect of partial dehydration in air on the mechanical and NMR properties of human cortical bone in order to understand whether NMR is sensitive to water-bone interactions at low energy and whether such interactions contribute to the age-related difference in the toughness of bone. Cadaveric femurs were collected from male and female donors falling into two age groups: 21-60 years of age (young) and 74-99 years of age (old). After extracting two samples from the medial cortex of the mid-shaft, tensile tests were conducted on Wet specimens and paired, Partially Dry (PtlD) specimens (prepared by low-energy drying in air to remove ∼3% of original mass before testing). Prior analysis by micro-computed tomography found that there were no differences in intra-cortical porosity between the Wet and PtlD specimens nor did an age-related difference in porosity exist. PtlD specimens from young and old donors had significantly less toughness than Wet specimens, primarily due to a dehydration-related decrease in post-yield strain. The low-energy drying protocol did not affect the modulus and yield strength of bone. Subsequent dehydration of the PtlD specimens in a vacuum oven at 62°C and then 103°C, with quantification of water loss at each temperature, revealed an age-related shift from more loosely bound water to more tightly bound water. NMR detected a change in both bound and pore water pools with low-energy air-drying, and both pools were effectively removed when bone was oven-dried at 62°C, irrespective of donor age. Although not strictly significant due to variability in the drying and testing conditions, the absolute difference in toughness between Wet and PtlD tended to be greater for the younger donors that had higher bone toughness and more bound water for the wet condition than did the older donors. With sensitivity to low-energy bone-water interactions, NMR, which underpins magnetic resonance imaging, has potential to assess fracture resistance of bone as it relates to bone toughness.

In-vivo Multi-exponential T2, Magnetization Transfer and Quantitative Histology in a Rat Model of Intramyelinic Edema

NeuroImage. Clinical. 2013  |  Pubmed ID: 24179832

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.

Validation of Quantitative Bound- and Pore-water Imaging in Cortical Bone

Magnetic Resonance in Medicine. Jun, 2014  |  Pubmed ID: 23878027

To implement and validate a previously proposed ultra-short echo time method for measuring collagen-bound- and pore-water concentrations in bone based on their T2 differences.

Imaging Amide Proton Transfer and Nuclear Overhauser Enhancement Using Chemical Exchange Rotation Transfer (CERT)

Magnetic Resonance in Medicine. Aug, 2014  |  Pubmed ID: 24302497

This study investigates amide proton transfer (APT) and nuclear overhauser enhancement (NOE) in phantoms and 9L tumors in rat brains at 9.4 Tesla, using a recently developed method that can isolate different contributions to exchange.

A Comparison of Individual and Population-derived Vascular Input Functions for Quantitative DCE-MRI in Rats

Magnetic Resonance Imaging. May, 2014  |  Pubmed ID: 24556502

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) can quantitatively and qualitatively assess physiological characteristics of tissue. Quantitative DCE-MRI requires an estimate of the time rate of change of the concentration of the contrast agent in the blood plasma, the vascular input function (VIF). Measuring the VIF in small animals is notoriously difficult as it requires high temporal resolution images limiting the achievable number of slices, field-of-view, spatial resolution, and signal-to-noise. Alternatively, a population-averaged VIF could be used to mitigate the acquisition demands in studies aimed to investigate, for example, tumor vascular characteristics. Thus, the overall goal of this manuscript is to determine how the kinetic parameters estimated by a population based VIF differ from those estimated by an individual VIF. Eight rats bearing gliomas were imaged before, during, and after an injection of Gd-DTPA. K(trans), ve, and vp were extracted from signal-time curves of tumor tissue using both individual and population-averaged VIFs. Extended model voxel estimates of K(trans) and ve in all animals had concordance correlation coefficients (CCC) ranging from 0.69 to 0.98 and Pearson correlation coefficients (PCC) ranging from 0.70 to 0.99. Additionally, standard model estimates resulted in CCCs ranging from 0.81 to 0.99 and PCCs ranging from 0.98 to 1.00, supporting the use of a population based VIF if an individual VIF is not available.

|B1(+)|-selective Excitation Pulse Design Using the Shinnar-Le Roux Algorithm

Journal of Magnetic Resonance (San Diego, Calif. : 1997). May, 2014  |  Pubmed ID: 24674887

A new mathematical treatment and algorithm for the design of |B1(+)|-selective RF excitation pulses is presented and validated. The algorithm is based on a rotated Shinnar-Le Roux pulse design algorithm, wherein the pulse's frequency modulation waveform is directly designed by the algorithm, and its amplitude and sign modulation waveform takes the place of the gradient field. A new pulse configuration is described that enables excitation of large tip-angle slice-selective profiles. Experiments were performed to validate the pulses, and simulations were performed to characterize the pulses' sensitivity to off-resonance, and to compare them to adiabatic (BIR-4) pulses.

Multi-parametric MRI Characterization of Inflammation in Murine Skeletal Muscle

NMR in Biomedicine. Jun, 2014  |  Pubmed ID: 24777935

Myopathies often display a common set of complex pathologies that include muscle weakness, inflammation, compromised membrane integrity, fat deposition, and fibrosis. Multi-parametric, quantitative, non-invasive imaging approaches may be able to resolve these individual pathological components. The goal of this study was to use multi-parametric MRI to investigate inflammation as an isolated pathological feature. Proton relaxation, diffusion tensor imaging (DTI), quantitative magnetization transfer (qMT-MRI), and dynamic contrast enhanced (DCE-MRI) parameters were calculated from data acquired in a single imaging session conducted 6-8 hours following the injection of λ-carrageenan, a local inflammatory agent. T2 increased in the inflamed muscle and transitioned to bi-exponential behavior. In diffusion measurements, all three eigenvalues and the apparent diffusion coefficient increased, but λ3 had the largest relative change. Analysis of the qMT data revealed that the T1 of the free pool and the observed T1 both increased in the inflamed tissue, while the ratio of exchanging spins in the solid pool to those in the free water pool (the pool size ratio) significantly decreased. DCE-MRI data also supported observations of an increase in extracellular volume. These findings enriched the understanding of the relation between multiple quantitative MRI parameters and an isolated inflammatory pathology, and may potentially be employed for other single or complex myopathy models.

Iterative Method for Predistortion of MRI Gradient Waveforms

IEEE Transactions on Medical Imaging. Aug, 2014  |  Pubmed ID: 24801945

The purpose of this work is to correct for transient gradient waveform errors in magnetic resonance imaging (MRI), whether from eddy currents, group delay, or gradient amplifier nonlinearities, which are known to affect image quality. An iterative method is proposed to minimize error between desired and measured gradient waveforms, whose success does not depend on accurate knowledge of the gradient system impulse response. The method was applied to half-pulse excitation for 2-D ultra-short echo time (UTE) imaging on a small animal MRI system and to spiral 2-D excitation on a human 7T MRI system. Predistorted gradient waveforms reduced temporal signal variation caused by excitation gradient trajectory errors in 2-D UTE, and improved the quality of excitation patterns produced by spiral excitation pulses. Iterative gradient predistortion is useful for minimizing transient gradient errors without requiring accurate characterization of the gradient system impulse response.

Insights into Reference Point Indentation Involving Human Cortical Bone: Sensitivity to Tissue Anisotropy and Mechanical Behavior

Journal of the Mechanical Behavior of Biomedical Materials. Sep, 2014  |  Pubmed ID: 24929851

Reference point indentation (RPI) is a microindentation technique involving 20 cycles of loading in "force-control" that can directly assess a patient׳s bone tissue properties. Even though preliminary clinical studies indicate a capability for fracture discrimination, little is known about what mechanical behavior the various RPI properties characterize and how these properties relate to traditional mechanical properties of bone. To address this, the present study investigated the sensitivity of RPI properties to anatomical location and tissue organization as well as examined to what extent RPI measurements explain the intrinsic mechanical properties of human cortical bone. Multiple indents with a target force of 10N were done in 2 orthogonal directions (longitudinal and transverse) per quadrant (anterior, medial, posterior, and lateral) of the femoral mid-shaft acquired from 26 donors (25-101 years old). Additional RPI measurements were acquired for 3 orthogonal directions (medial only). Independent of age, most RPI properties did not vary among these locations, but they did exhibit transverse isotropy such that resistance to indentation is greater in the longitudinal (axial) direction than in the transverse direction (radial or circumferential). Next, beam specimens (~2mm×5mm×40mm) were extracted from the medial cortex of femoral mid-shafts, acquired from 34 donors (21-99 years old). After monotonically loading the specimens in three-point bending to failure, RPI properties were acquired from an adjacent region outside the span. Indent direction was orthogonal to the bending axis. A significant inverse relationship was found between resistance to indentation and the apparent-level mechanical properties. Indentation distance increase (IDI) and a linear combination of IDI and the loading slope, averaged over cycles 3 through 20, provided the best explanation of the variance in ultimate stress (r(2)=0.25, p=0.003) and toughness (r(2)=0.35, p=0.004), respectively. With a transverse isotropic behavior akin to tissue hardness and modulus as determined by micro- and nano-indentation and a significant association with toughness, RPI properties are likely influenced by both elastic and plastic behavior of bone tissue.

Multi-parametric MRI Characterization of Healthy Human Thigh Muscles at 3.0 T - Relaxation, Magnetization Transfer, Fat/water, and Diffusion Tensor Imaging

NMR in Biomedicine. Sep, 2014  |  Pubmed ID: 25066274

Muscle diseases commonly have clinical presentations of inflammation, fat infiltration, fibrosis, and atrophy. However, the results of existing laboratory tests and clinical presentations are not well correlated. Advanced quantitative MRI techniques may allow the assessment of myo-pathological changes in a sensitive and objective manner. To progress towards this goal, an array of quantitative MRI protocols was implemented for human thigh muscles; their reproducibility was assessed; and the statistical relationships among parameters were determined. These quantitative methods included fat/water imaging, multiple spin-echo T2 imaging (with and without fat signal suppression, FS), selective inversion recovery for T1 and quantitative magnetization transfer (qMT) imaging (with and without FS), and diffusion tensor imaging. Data were acquired at 3.0 T from nine healthy subjects. To assess the repeatability of each method, the subjects were re-imaged an average of 35 days later. Pre-testing lifestyle restrictions were applied to standardize physiological conditions across scans. Strong between-day intra-class correlations were observed in all quantitative indices except for the macromolecular-to-free water pool size ratio (PSR) with FS, a metric derived from qMT data. Two-way analysis of variance revealed no significant between-day differences in the mean values for any parameter estimate. The repeatability was further assessed with Bland-Altman plots, and low repeatability coefficients were obtained for all parameters. Among-muscle differences in the quantitative MRI indices and inter-class correlations among the parameters were identified. There were inverse relationships between fractional anisotropy (FA) and the second eigenvalue, the third eigenvalue, and the standard deviation of the first eigenvector. The FA was positively related to the PSR, while the other diffusion indices were inversely related to the PSR. These findings support the use of these T1 , T2 , fat/water, and DTI protocols for characterizing skeletal muscle using MRI. Moreover, the data support the existence of a common biophysical mechanism, water content, as a source of variation in these parameters.

Mapping Mean Axon Diameter and Axonal Volume Fraction by MRI Using Temporal Diffusion Spectroscopy

NeuroImage. Dec, 2014  |  Pubmed ID: 25225002

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.

Fast T2 Mapping with Multiple Echo, Caesar Cipher Acquisition and Model-based Reconstruction

Magnetic Resonance in Medicine. Mar, 2015  |  Pubmed ID: 24753216

Fast, quantitative T2 mapping is of value to both clinical and research environments. However, many protocols utilizing fast spin echo (FSE) pulse sequences contain acceleration-induced artifacts that are compounded when fitting parameter maps, especially in the presence of imperfect refocusing. This work presents a B1 -corrected, model-based reconstruction and associated Cartesian FSE phase-encode ordering that provides enhanced accuracy in T2 estimates compared with other common accelerated protocols.

Simple and Robust Saturation-based Slice Selection for Ultrashort Echo Time MRI

Magnetic Resonance in Medicine. Jun, 2015  |  Pubmed ID: 25046136

To present a new method for localizing signal within a two-dimensional (2D) slice suitable for ultrashort echo time (UTE) imaging, called saturation-based UTE (sat-UTE). The new method digitally subtracts two acquisitions that are nonselectively excited with and without selective saturation of the slice of interest.

Identifying Novel Clinical Surrogates to Assess Human Bone Fracture Toughness

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. Jul, 2015  |  Pubmed ID: 25639628

Fracture risk does not solely depend on strength but also on fracture toughness; ie, the ability of bone material to resist crack initiation and propagation. Because resistance to crack growth largely depends on bone properties at the tissue level, including collagen characteristics, current X-ray based assessment tools may not be suitable to identify age-related, disease-related, or treatment-related changes in fracture toughness. To identify useful clinical surrogates that could improve the assessment of fracture resistance, we investigated the potential of (1)H nuclear magnetic resonance spectroscopy (NMR) and reference point indentation (RPI) to explain age-related variance in fracture toughness. Harvested from cadaveric femurs (62 human donors), single-edge notched beam (SENB) specimens of cortical bone underwent fracture toughness testing (R-curve method). NMR-derived bound water showed the strongest correlation with fracture toughness properties (r = 0.63 for crack initiation, r = 0.35 for crack growth, and r = 0.45 for overall fracture toughness; p < 0.01). Multivariate analyses indicated that the age-related decrease in different fracture toughness properties were best explained by a combination of NMR properties including pore water and RPI-derived tissue stiffness with age as a significant covariate (adjusted R(2)  = 53.3%, 23.9%, and 35.2% for crack initiation, crack growth, and overall toughness, respectively; p < 0.001). These findings reflect the existence of many contributors to fracture toughness and emphasize the utility of a multimodal assessment of fracture resistance. Exploring the mechanistic origin of fracture toughness, glycation-mediated nonenzymatic collagen crosslinks and intracortical porosity are possible determinants of bone fracture toughness and could explain the sensitivity of NMR to changes in fracture toughness. Assuming fracture toughness is clinically important to the ability of bone to resist fracture, our results suggest that improvements in fracture risk assessment could potentially be achieved by accounting for water distribution (quantitative ultrashort echo time magnetic resonance imaging) and by a local measure of tissue resistance to indentation, RPI.

The Role of Water Compartments in the Material Properties of Cortical Bone

Calcified Tissue International. Sep, 2015  |  Pubmed ID: 25783011

Comprising ~20% of the volume, water is a key determinant of the mechanical behavior of cortical bone. It essentially exists in two general compartments: within pores and bound to the matrix. The amount of pore water-residing in the vascular-lacunar-canalicular space-primarily reflects intracortical porosity (i.e., open spaces within the matrix largely due to Haversian canals and resorption sites) and as such is inversely proportional to most mechanical properties of bone. Movement of water according to pressure gradients generated during dynamic loading likely confers hydraulic stiffening to the bone as well. Nonetheless, bound water is a primary contributor to the mechanical behavior of bone in that it is responsible for giving collagen the ability to confer ductility or plasticity to bone (i.e., allows deformation to continue once permanent damage begins to form in the matrix) and decreases with age along with fracture resistance. Thus, dehydration by air-drying or by solvents with less hydrogen bonding capacity causes bone to become brittle, but interestingly, it also increases stiffness and strength across the hierarchical levels of organization. Despite the importance of matrix hydration to fracture resistance, little is known about why bound water decreases with age in hydrated human bone. Using (1)H nuclear magnetic resonance (NMR), both bound and pore water concentrations in bone can be measured ex vivo because the proton relaxation times differ between the two water compartments, giving rise to two distinct signals. There are also emerging techniques to measure bound and pore water in vivo with magnetic resonance imaging (MRI). The NMR/MRI-derived bound water concentration is positively correlated with both the strength and toughness of hydrated bone and may become a useful clinical marker of fracture risk.

The Microstructural Correlates of T1 in White Matter

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. Apr, 2015  |  Pubmed ID: 25920491

Several studies have shown strong correlations between myelin content and T1 within the brain, and have even suggested that T1 can be used to estimate myelin content. However, other micro-anatomical features such as compartment size are known to affect longitudinal relaxation rates, similar to compartment size effects in porous media.

In Vivo Quantitative MR Imaging of Bound and Pore Water in Cortical Bone

Radiology. Oct, 2015  |  Pubmed ID: 26020434

To translate and evaluate an in vivo magnetic resonance (MR) imaging protocol for quantitative mapping of collagen-bound and pore water concentrations in cortical bone that involves relaxation-selective ultrashort echo time (UTE) methods.

4.7-T Diffusion Tensor Imaging of Acute Traumatic Peripheral Nerve Injury

Neurosurgical Focus. Sep, 2015  |  Pubmed ID: 26323827

Diagnosis and management of peripheral nerve injury is complicated by the inability to assess microstructural features of injured nerve fibers via clinical examination and electrophysiology. Diffusion tensor imaging (DTI) has been shown to accurately detect nerve injury and regeneration in crush models of peripheral nerve injury, but no prior studies have been conducted on nerve transection, a surgical emergency that can lead to permanent weakness or paralysis. Acute sciatic nerve injuries were performed microsurgically to produce multiple grades of nerve transection in rats that were harvested 1 hour after surgery. High-resolution diffusion tensor images from ex vivo sciatic nerves were obtained using diffusion-weighted spin-echo acquisitions at 4.7 T. Fractional anisotropy was significantly reduced at the injury sites of transected rats compared with sham rats. Additionally, minor eigenvalues and radial diffusivity were profoundly elevated at all injury sites and were negatively correlated to the degree of injury. Diffusion tensor tractography showed discontinuities at all injury sites and significantly reduced continuous tract counts. These findings demonstrate that high-resolution DTI is a promising tool for acute diagnosis and grading of traumatic peripheral nerve injuries.

Quantitative Analysis of Mouse Corpus Callosum from Electron Microscopy Images

Data in Brief. Dec, 2015  |  Pubmed ID: 26504893

This article provides morphometric analysis of 72 electron microscopy images from control (n=4) and hypomyelinated (n=2) mouse corpus callosum. Measures of axon diameter and g-ratio were tabulated across all brains from two regions of the corpus callosum and a non-linear relationship between axon diameter and g-ratio was observed. These data are related to the accompanying research article comparing multiple methods of measuring g-ratio entitled 'A revised model for estimating g-ratio from MRI' (West et al., NeuroImage, 2015).

In Vivo Quantitative MR Imaging of Bound and Pore Water in Cortical Bone

Radiology. Dec, 2015  |  Pubmed ID: 26599934

Hypomyelination Following Deletion of Tsc2 in Oligodendrocyte Precursors

Annals of Clinical and Translational Neurology. Dec, 2015  |  Pubmed ID: 26734657

While abnormalities in myelin in tuberous sclerosis complex (TSC) have been known for some time, recent imaging-based data suggest myelin abnormalities may be independent of the pathognomonic cortical lesions ("tubers"). Multiple mouse models of TSC exhibit myelination deficits, though the cell types responsible and the mechanisms underlying the myelin abnormalities remain unclear.

A Revised Model for Estimating G-ratio from MRI

NeuroImage. Jan, 2016  |  Pubmed ID: 26299793

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.

Evaluation of Diffusion Kurtosis Imaging in Ex Vivo Hypomyelinated Mouse Brains

NeuroImage. Jan, 2016  |  Pubmed ID: 26400013

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.

Age-related Changes in the Fracture Resistance of Male Fischer F344 Rat Bone

Bone. Feb, 2016  |  Pubmed ID: 26610688

In addition to the loss in bone volume that occurs with age, there is a decline in material properties. To test new therapies or diagnostic tools that target such properties as material strength and toughness, a pre-clinical model of aging would be useful in which changes in bone are similar to those that occur with aging in humans. Toward that end, we hypothesized that similar to human bone, the estimated toughness and material strength of cortical bone at the apparent-level decreases with age in the male Fischer F344 rat. In addition, we tested whether the known decline in trabecular architecture in rats translated to an age-related decrease in vertebra (VB) strength and whether non-X-ray techniques could quantify tissue changes at micron and sub-micron length scales. Bones were harvested from 6-, 12-, and 24-month (mo.) old rats (n=12 per age). Despite a loss in trabecular bone with age, VB compressive strength was similar among the age groups. Similarly, whole-bone strength (peak force) in bending was maintained (femur) or increased (radius) with aging. There was though an age-related decrease in post-yield toughness (radius) and bending strength (femur). The ability to resist crack initiation was actually higher for the 12-mo. and 24-mo. than for 6-mo. rats (notch femur), but the estimated work to propagate the crack was less for the aged bone. For the femur diaphysis region, porosity increased while bound water decreased with age. For the radius diaphysis, there was an age-related increase in non-enzymatic and mature enzymatic collagen crosslinks. Raman spectroscopy analysis of embedded cross-sections of the tibia mid-shaft detected an increase in carbonate subsitution with advanced aging for both inner and outer tissue.

MRI-derived Bound and Pore Water Concentrations As Predictors of Fracture Resistance

Bone. Jun, 2016  |  Pubmed ID: 26993059

Accurately predicting fracture risk in the clinic is challenging because the determinants are multi-factorial. A common approach to fracture risk assessment is to combine X-ray-based imaging methods such as dual-energy X-ray absorptiometry (DXA) with an online Fracture Risk Assessment Tool (FRAX) that includes additional risk factors such as age, family history, and prior fracture incidents. This approach still does not adequately diagnose many individuals at risk, especially those with certain diseases like type 2 diabetes. As such, this study investigated bound water and pore water concentrations (Cbw and Cpw) from ultra-short echo time (UTE) magnetic resonance imaging (MRI) as new predictors of fracture risk. Ex vivo cadaveric arms were imaged with UTE MRI as well as with DXA and high-resolution micro-computed tomography (μCT), and imaging measures were compared to both whole-bone structural and material properties as determined by three-point bending tests of the distal-third radius. While DXA-derived areal bone mineral density (aBMD) and μCT-derived volumetric BMD correlated well with structural strength, they moderately correlated with the estimate material strength with gender being a significant covariate for aBMD. MRI-derived measures of Cbw and Cpw had a similar predictive ability of material strength as aBMD but did so independently of gender. In addition, Cbw was the only imaging parameter to significantly correlate with toughness, the energy dissipated during fracture. Notably, the strength of the correlations with the material properties of bone tended to be higher when a larger endosteal region was used to determine Cbw and Cpw. These results indicate that MRI measures of Cbw and Cpw have the ability to probe bone material properties independent of bone structure or subject gender. In particular, toughness is a property of fracture resistance that is not explained by X-ray based methods. Thus, these MRI-derived measures of Cbw and Cpw in cortical bone have the potential to be useful in clinical populations for evaluating fracture risk, especially involving diseases that affect material properties of the bone beyond its strength.

Fast and Simplified Mapping of Mean Axon Diameter Using Temporal Diffusion Spectroscopy

NMR in Biomedicine. Apr, 2016  |  Pubmed ID: 27077155

Mapping axon diameter is of interest for the potential diagnosis and monitoring of various neuronal pathologies. Advanced diffusion-weighted MRI methods have been developed to measure mean axon diameters non-invasively, but suffer major drawbacks that prevent their direct translation into clinical practice, such as complex non-linear data fitting and, more importantly, long scanning times that are usually not tolerable for most human subjects. In the current study, temporal diffusion spectroscopy using oscillating diffusion gradients was used to measure mean axon diameters with high sensitivity to small axons in the central nervous system. Axon diameters have been found to be correlated with a novel metric, DDR⊥ (the rate of dispersion of the perpendicular diffusion coefficient with gradient frequency), which is a model-free quantity that does not require complex data analyses and can be obtained from two diffusion coefficient measurements in clinically relevant times with conventional MRI machines. A comprehensive investigation including computer simulations and animal experiments ex vivo showed that measurements of DDR⊥ agree closely with histological data. In humans in vivo, DDR⊥ was also found to correlate well with reported mean axon diameters in human corpus callosum, and the total scan time was only about 8 min. In conclusion, DDR⊥ may have potential to serve as a fast, simple and model-free approach to map the mean axon diameter of white matter in clinics for assessing axon diameter changes.

A Novel Technique Using Hydrophilic Polymers to Promote Axonal Fusion

Neural Regeneration Research. Apr, 2016  |  Pubmed ID: 27212898

The management of traumatic peripheral nerve injury remains a considerable concern for clinicians. With minimal innovations in surgical technique and a limited number of specialists trained to treat peripheral nerve injury, outcomes of surgical intervention have been unpredictable. The inability to manipulate the pathophysiology of nerve injury (i.e., Wallerian degeneration) has left scientists and clinicians depending on the slow and lengthy process of axonal regeneration (~1 mm/day). When axons are severed, the endings undergo calcium-mediated plasmalemmal sealing, which limits the ability of the axon to be primarily repaired. Polythethylene glycol (PEG) in combination with a bioengineered process overcomes the inability to fuse axons. The mechanism for PEG axonal fusion is not clearly understood, but multiple studies have shown that a providing a calcium-free environment is essential to the process known as PEG fusion. The proposed mechanism is PEG-induced lipid bilayer fusion by removing the hydration barrier surrounding the axolemma and reducing the activation energy required for membrane fusion to occur. This review highlights PEG fusion, its past and current studies, and future directions in PEG fusion.

Multi-compartment Microscopic Diffusion Imaging

NeuroImage. Jun, 2016  |  Pubmed ID: 27282476

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.

Differences in Sensitivity to Microstructure Between Cyclic- and Impact-based Microindentation of Human Cortical Bone

Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society. Aug, 2016  |  Pubmed ID: 27513922

Unlike the known relationships between traditional mechanical properties and microstructural features of bone, the factors that influence the mechanical resistance of bone to cyclic reference point microindention (cRPI) and impact microindention (IMI) have yet to be identified. To determine whether cRPI and IMI properties depend on microstructure, we indented the tibia mid-shaft, the distal radius, and the proximal humerus from 10 elderly donors using the BioDent and OsteoProbe (neighboring sites). As the only output measure of IMI, bone material strength index (BMSi) was significantly different across all three anatomical sites being highest for the tibia mid-shaft and lowest for the proximal humerus. Total indentation distance (inverse of BMSi) was higher for the proximal humerus than for the tibia mid-shaft but was not different between other anatomical comparisons. As a possible explanation for the differences in BMSi, pore water, as determined by (1) H nuclear magnetic resonance, was lowest for the tibia and highest for the humerus. Moreover, the local intra-cortical porosity, as determined by micro-computed tomography, was negatively correlated with BMSi for both arm bones. BMSi was also positively correlated with peak bending stress of cortical bone extracted from the tibia mid-shaft. Microstructural correlations with cRPI properties were not significant for any of the bones. The one exception was that average energy dissipated during cRPI was negatively correlated with local tissue mineral density in the tibia mid-shaft. With higher indentation force and larger tip diameter than cRPI, only IMI appears to be sensitive to the underlying porosity of cortical bone. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

A Novel Therapy to Promote Axonal Fusion in Human Digital Nerves

The Journal of Trauma and Acute Care Surgery. Nov, 2016  |  Pubmed ID: 27768666

Peripheral nerve injury can have a devastating impact on our military and veteran population. Current strategies for peripheral nerve repair include techniques such as nerve tubes, nerve grafts, tissue matrices, and nerve growth guides to enhance the number of regenerating axons. Even with such advanced techniques, it takes months to regain function. In animal models, polyethylene glycol (PEG) therapy has shown to improve both physiologic and behavioral outcomes after nerve transection by fusion of a portion of the proximal axons to the distal axon stumps. The objective of this study was to show the efficacy of PEG fusion in humans and to retrospectively compare PEG fusion to standard nerve repair.

Advances in Imaging Approaches to Fracture Risk Evaluation

Translational Research : the Journal of Laboratory and Clinical Medicine. Oct, 2016  |  Pubmed ID: 27816505

Fragility fractures are a growing problem worldwide, and current methods for diagnosing osteoporosis do not always identify individuals who require treatment to prevent a fracture and may misidentify those not a risk. Traditionally, fracture risk is assessed using dual-energy X-ray absorptiometry, which provides measurements of areal bone mineral density at sites prone to fracture. Recent advances in imaging show promise in adding new information that could improve the prediction of fracture risk in the clinic. As reviewed herein, advances in quantitative computed tomography (QCT) predict hip and vertebral body strength; high-resolution HR-peripheral QCT (HR-pQCT) and micromagnetic resonance imaging assess the microarchitecture of trabecular bone; quantitative ultrasound measures the modulus or tissue stiffness of cortical bone; and quantitative ultrashort echo-time MRI methods quantify the concentrations of bound water and pore water in cortical bone, which reflect a variety of mechanical properties of bone. Each of these technologies provides unique characteristics of bone and may improve fracture risk diagnoses and reduce prevalence of fractures by helping to guide treatment decisions.

A Comparative Assessment of Preclinical Chemotherapeutic Response of Tumors Using Quantitative Non-Gaussian Diffusion MRI

Magnetic Resonance Imaging. Dec, 2016  |  Pubmed ID: 27919785

Diffusion-weighted MRI (DWI) signal attenuation is often not mono-exponential (i.e. non-Gaussian diffusion) with stronger diffusion weighting. Several non-Gaussian diffusion models have been developed and may provide new information or higher sensitivity compared with the conventional apparent diffusion coefficient (ADC) method. However the relative merits of these models to detect tumor therapeutic response is not fully clear.

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