Kevin D. Harkins

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

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.

Effect of intercompartmental water exchange on the apparent myelin water fraction in multiexponential T2 measurements of rat spinal cord

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 T2 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 T2 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. Magn Reson Med, 2012.

Assessment of the effects of cellular tissue properties on ADC measurements by numerical simulation of water diffusion

The apparent diffusion coefficient (ADC), as measured by diffusion‐weighted MRI, has proven useful in the diagnosis and evaluation of ischemic stroke. The ADC of tissue water is reduced by 30‐50% following ischemia and provides excellent contrast between normal and affected tissue. Despite its clinical utility, there is no consensus on the biophysical mechanism underlying the reduction in ADC. In this work, a numerical simulation of water diffusion is used to predict the effects of cellular tissue properties on experimentally measured ADC. The model indicates that the biophysical mechanisms responsible for changes in ADC postischemia depend upon the time over which diffusion is measured. At short diffusion times, the ADC is dependent upon the intrinsic intracellular diffusivity, while at longer, clinically relevant diffusion times, the ADC is highly dependent upon the cell volume fraction. The model also predicts that at clinically relevant diffusion times, the 30‐50% drop in ADC after ischemia can be accounted for by cell swelling alone when intracellular T2 is allowed to be shorter than extracellular T2. Magn Reson Med, 2009.

Validation of quantitative bound- and pore-water imaging in cortical bone.

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.

Characterizing inter-compartmental water exchange in myelinated tissue using relaxation exchange spectroscopy

Purpose: To investigate inter‐compartmental water exchange in two model myelinated tissues ex vivo using relaxation exchange spectroscopy. Methods: Building upon a previously developed theoretical framework, a three‐compartment (myelin, intra‐axonal, and extra‐axonal water) model of the inversion‐recovery prepared relaxation exchange spectroscopy signal was applied in excised rat optic nerve and frog sciatic nerve samples to estimate the water residence time constants in myelin (τmyelin). Results: In the rat optic nerve samples, τmyelin = 138 ± 15 ms (mean ± standard deviation) was estimated. In sciatic nerve, which possesses thicker myelin sheaths than optic nerve, a much longer τmyelin = 2046 ± 140 ms was observed. Conclusion: Consistent with previous studies in rat spinal cord, the extrapolation of exchange rates in optic nerve to in vivo conditions indicates that τmyelin < 100 ms. This suggests that there is a significant effect of inter‐compartmental water exchange on the transverse relaxation of water protons in white matter. The much longer τmyelin values in sciatic nerve supports the postulate that the inter‐compartmental water exchange rate is mediated by myelin thickness. Together, these findings point to the potential for MRI methods to probe variations in myelin thickness in white matter. Magn Reson Med 70:1450–1459, 2013.

The microstructural correlates of T1 in white matter.

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.

Iterative Method for Predistortion of MRI Gradient Waveforms

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.

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

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.

A finite difference method with periodic boundary conditions for simulations of diffusion-weighted magnetic resonance experiments in tissue.

A new finite difference (FD) method for calculating the time evolution of complex transverse magnetization in diffusion-weighted magnetic resonance imaging and spectroscopy experiments is described that incorporates periodic boundary conditions. The new FD method relaxes restrictions on the allowable time step size employed in modeling which can significantly reduce computation time for simulations of large physical extent and allow for more complex, physiologically relevant, geometries to be simulated.

Ischemia‐induced changes of intracellular water diffusion in rat glioma cell cultures

Diffusion‐weighted MRI is commonly used in the diagnosis and evaluation of ischemic stroke because of the rapid decrease observed in the apparent diffusion coefficient (ADC) of tissue water following ischemia. Although this observation has been clinically useful for many years, the biophysical mechanisms underlying the reduction of tissue ADC are still unknown. To help elucidate these mechanisms, we have employed a novel three‐dimensional (3D) hollow‐fiber bioreactor (HFBR) perfused cell culture system that enables cells to be grown to high density and studied via MRI and MRS. By infusing contrast media into the HFBR, signals from intracellular water and extracellular water are spectroscopically resolved and can be investigated individually. Diffusion measurements carried out on C6 glioma HFBR cell cultures indicate that ischemia‐induced cellular swelling results in an increase in the ADC of intracellular water from 0.35 μm2/ms to approximately 0.5 μm2/ms (diffusion time = 25 ms). Magn Reson Med 60:258–264, 2008.