Characterization of Prostate Microstructure Using Water Diffusion and NMR Relaxation

For many pathologies, early structural tissue changes occur at the cellular level, on the scale of micrometers or tens of micrometers. Magnetic resonance imaging (MRI) is a powerful non-invasive imaging tool used for medical diagnosis, but its clinical hardware is incapable of reaching the cellular length scale directly. In spite of this limitation, microscopic tissue changes in pathology can potentially be captured indirectly, from macroscopic imaging characteristics, by studying water diffusion. Here we focus on water diffusion and NMR relaxation in the human prostate, a highly heterogeneous organ at the cellular level. We present a physical picture of water diffusion and NMR relaxation in the prostate tissue, that is comprised of a densely-packed cellular compartment (composed of stroma and epithelium), and a luminal compartment with almost unrestricted water diffusion. Transverse NMR relaxation is used to identify fast and slow T2 components, corresponding to these tissue compartments, and to disentangle the luminal and cellular compartment contributions to the temporal evolution of the overall water diffusion coefficient. Diffusion in the luminal compartment falls into the short-time surface-to-volume (S/V) limit, indicating that only a small fraction of water molecules has time to encounter the luminal walls of healthy tissue; from the S/V ratio, the average lumen diameter averaged over three young healthy subjects is measured to be 217.7 ± 188.7 μm. Conversely, the diffusion in the cellular compartment is highly restricted and anisotropic, consistent with the fibrous character of the stromal tissue. Diffusion transverse to these fibers is well described by the random permeable barrier model (RPBM), as confirmed by the dynamical exponent ϑ = 1/2 for approaching the long-time limit of diffusion, and the corresponding structural exponent p = −1 in histology. The RPBM-derived fiber diameter and membrane permeability were 19.8 ± 8.1 μm and 0.044 ± 0.045 μm/ms, respectively, in agreement with known values from tissue histology and membrane biophysics. Lastly, we revisited 38 prostate cancer cases from a recently published study, and found the same dynamical exponent ϑ = 1/2 of diffusion in tumors and benign regions. Our results suggest that a multi-parametric MRI acquisition combined with biophysical modeling may be a powerful non-invasive complement to prostate cancer grading, reducing the need for biopsies

Universal Sampling Denoising (USD) for noise mapping and noise removal of non-Cartesian MRI

Random matrix theory (RMT) combined with principal component analysis has resulted in a widely used MPPCA noise mapping and denoising algorithm, that utilizes the redundancy in multiple acquisitions and in local image patches. RMT-based denoising relies on the uncorrelated identically distributed noise. This assumption breaks down after regridding of non-Cartesian sampling. Here we propose a Universal Sampling Denoising (USD) pipeline to homogenize the noise level and decorrelate the noise in non-Cartesian sampled k-space data after resampling to a Cartesian grid. In this way, the RMT approaches become applicable to MRI of any non-Cartesian k-space sampling. We demonstrate the denoising pipeline on MRI data acquired using radial trajectories, including diffusion MRI of a numerical phantom and ex vivo mouse brains, as well as in vivo $T_2$ MRI of a healthy subject. The proposed pipeline robustly estimates noise level, performs noise removal, and corrects bias in parametric maps, such as diffusivity and kurtosis metrics, and $T_2$ relaxation time. USD stabilizes the variance, decorrelates the noise, and thereby enables the application of RMT-based denoising approaches to MR images reconstructed from any non-Cartesian data. In addition to MRI, USD may also apply to other medical imaging techniques involving non-Cartesian acquisition, such as PET, CT, and SPECT

Time-Dependent Diffusion in the Body

Hardware and physiology impose stringent constraints on the millimeter-scale resolution limits of Magnetic Resonance Imaging (MRI). Diffusion MRI is a technique that can effectively surpass the resolution limit by deriving contrast from micrometer restrictions to water diffusion. This thesis studies time dependence of the diffusion coefficient, D(t), in the body [muscle and prostate], where the specificity towards tissue microanatomy is unlocked through biophysical modeling. Unlike the brain, muscle and prostate have a broad range of length scales facilitating the measurement of a dynamic range of D(t). Chapter 1 introduces the physical description of the MRI signal and D(t). Chapter 2 considers the practical/engineering considerations of measuring D(t) on MRI systems. Chapter 3 demonstrates the measurement of temporal diffusion limits on a fiber phantom. Chapter 4 measures and models D(t) in muscle tissue, revealing the myofiber diameter, which is a biomarker shown to be sensitive towards both atrophy and hypertrophy. Chapter 5 measures and models D(t) in prostate cancer, thus revealing stromal cell and luminal diameters. Furthermore, evidence is provided that considerations of D(t) allows for the separation of various prostate cancer grades using MRI. Chapter 6 reviews the findings of this thesis and considers the potential clinical implications from this work

Validation of surface-to-volume ratio measurements derived from oscillating gradient spin echo on a clinical scanner using anisotropic fiber phantoms

A diffusion measurement in the short-time surface-to-volume ratio (S/V) limit (Mitra et al., Phys Rev Lett. 1992;68:3555) can disentangle the free diffusion coefficient from geometric restrictions to diffusion. Biophysical parameters, such as the S/V of tissue membranes, can be used to estimate microscopic length scales non-invasively. However, due to gradient strength limitations on clinical MRI scanners, pulsed gradient spin echo (PGSE) measurements are impractical for probing the S/V limit. To achieve this limit on clinical systems, an oscillating gradient spin echo (OGSE) sequence was developed. Two phantoms containing 10 fiber bundles, each consisting of impermeable aligned fibers with different packing densities, were constructed to achieve a range of S/V values. The frequency-dependent diffusion coefficient, D(ω), was measured in each fiber bundle using OGSE with different gradient waveforms (cosine, stretched cosine, and trapezoidal), while D(t) was measured from PGSE and stimulated-echo measurements. The S/V values derived from the universal high-frequency behavior of D(ω) were compared against those derived from quantitative proton density measurements using single spin echo (SE) with varying echo times, and from magnetic resonance fingerprinting (MRF). S/V estimates derived from different OGSE waveforms were similar and demonstrated excellent correlation with both SE- and MRF-derived S/V measures (ρ  ≥  0.99). Furthermore, there was a smoother transition between OGSE frequency f and PGSE diffusion time when using teffS/V=9/64f, rather than the commonly used t  = 1/(4f), validating the specific frequency/diffusion time conversion for this regime. Our well-characterized fiber phantom can be used for the calibration of OGSE and diffusion modeling techniques, as the S/V ratio can be measured independently using other MR modalities. Moreover, our calibration experiment offers an exciting perspective of mapping tissue S/V on clinical systems

In vivo observation and biophysical interpretation of time-dependent diffusion in human white matter

The presence of micrometer-level restrictions leads to a decrease of diffusion coefficient with diffusion time. Here we investigate this effect in human white matter in vivo. We focus on a broad range of diffusion times, up to 600 ms, covering diffusion length scales up to about 30 microns. We perform stimulated echo diffusion tensor imaging on 5 healthy volunteers and observe a relatively weak time-dependence in diffusion transverse to major fiber tracts. Remarkably, we also find notable time-dependence in the longitudinal direction. Comparing models of diffusion in ordered, confined and disordered media, we argue that the time-dependence in both directions can arise due to structural disorder, such as axonal beads in the longitudinal direction, and the random packing geometry of fibers within a bundle in the transverse direction. These time-dependent effects extend beyond a simple picture of Gaussian compartments, and may lead to novel markers that are specific to neuronal fiber geometry at the micrometer scale

Time-dependent diffusivity and kurtosis in phantoms and patients with head and neck cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175204/1/mrm29457.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175204/2/mrm29457_am.pd

Combined diffusion-relaxometry microstructure imaging : Current status and future prospects

Microstructure imaging seeks to noninvasively measure and map microscopic tissue features by pairing mathematical modeling with tailored MRI protocols. This article reviews an emerging paradigm that has the potential to provide a more detailed assessment of tissue microstructure—combined diffusion-relaxometry imaging. Combined diffusion-relaxometry acquisitions vary multiple MR contrast encodings—such as b-value, gradient direction, inversion time, and echo time—in a multidimensional acquisition space. When paired with suitable analysis techniques, this enables quantification of correlations and coupling between multiple MR parameters—such as diffusivity, (Formula presented.), (Formula presented.), and (Formula presented.). This opens the possibility of disentangling multiple tissue compartments (within voxels) that are indistinguishable with single-contrast scans, enabling a new generation of microstructural maps with improved biological sensitivity and specificity