Timothy M. Shepherd

Resolution of complex tissue microarchitecture using the diffusion orientation transform (DOT)

This article describes an accurate and fast method for fiber orientation mapping using multidirectional diffusion-weighted magnetic resonance (MR) data. This novel approach utilizes the Fourier transform relationship between the water displacement probabilities and diffusion-attenuated MR signal expressed in spherical coordinates. The radial part of the Fourier integral is evaluated analytically under the assumption that MR signal attenuates exponentially. The values of the resulting functions are evaluated at a fixed distance away from the origin. The spherical harmonic transform of these functions yields the Laplace series coefficients of the probabilities on a sphere of fixed radius. Alternatively, probability values can be computed nonparametrically using Legendre polynomials. Orientation maps calculated from excised rat nervous tissue data demonstrate this techniques ability to accurately resolve crossing fibers in anatomical regions such as the optic chiasm. This proposed methodology has a trivial extension to multiexponential diffusion-weighted signal decay. The developed methods will improve the reliability of tractography schemes and may make it possible to correctly identify the neural connections between functionally connected regions of the nervous system.

Aldehyde Fixative Solutions Alter the Water Relaxation and Diffusion Properties of Nervous Tissue

Chemically‐fixed nervous tissues are well‐suited for high‐resolution, time‐intensive MRI acquisitions without motion artifacts, such as those required for brain atlas projects, but the aldehyde fixatives used may significantly alter tissue MRI properties. To test this hypothesis, this study characterized the impact of common aldehyde fixatives on the MRI properties of a rat brain slice model. Rat cortical slices immersion‐fixed in 4% formaldehyde demonstrated 21% and 81% reductions in tissue T1 and T2, respectively (P < 0.001). The T2 reduction was reversed by washing slices with phosphate‐buffered saline (PBS) for 12 h to remove free formaldehyde solution. Diffusion MRI of cortical slices analyzed with a two‐compartment analytical model of water diffusion demonstrated 88% and 30% increases in extracellular apparent diffusion coefficient (ADCEX) and apparent restriction size, respectively, when slices were chemically‐fixed with 4% formaldehyde (P ≤ 0.021). Further, fixation with 4% formaldehyde increased the transmembrane water exchange rate 239% (P < 0.001), indicating increased membrane permeability. Karnovskys and 4% glutaraldehyde fixative solutions also changed the MRI properties of cortical slices, but significant differences were noted between the different fixative treatments (P < 0.05). The observed water relaxation and diffusion changes help better define the validity and limitations of using chemically‐fixed nervous tissue for MRI investigations. Magn Reson Med, 2009.

Effects of temperature and aldehyde fixation on tissue water diffusion properties, studied in an erythrocyte ghost tissue model

Ex vivo biological sample imaging can complement in vivo MRI studies. Since ex vivo studies are typically performed at room temperature, and samples are frequently preserved by fixation, it is important to understand how environmental and chemical changes dictated by ex vivo studies alter the physical and MR properties of a sample. Diffusion and relaxation time measurements were used to assess the effects of temperature change and aldehyde fixation on the biophysical and MR properties of a model biological tissue comprised of erythrocyte ghosts suspended in buffer or agarose gel. Sample temperature was varied between 10°C and 37°C. Diffusion MRI data were analyzed with a biophysically appropriate two‐compartment exchange model. Temperature change resulted in a complex alteration of water diffusion properties due to the compartmental nature of tissues and alteration in membrane permeability. Formaldehyde, Karnovskys solution, and glutaraldehyde all caused statistically significant changes to the biophysical and MR properties of the samples. Fixation caused large decreases in water proton T2, which was restored to near prefixation values by washing free fixative from the samples. Water membrane permeability was also significantly altered by fixation. This study demonstrates that relating in vivo MR data to chemically fixed ex vivo data requires an understanding of the effects of sample preparation. Magn Reson Med, 2006.

Tensor Splines for Interpolation and Approximation of DT-MRI With Applications to Segmentation of Isolated Rat Hippocampi

In this paper, we present novel algorithms for statistically robust interpolation and approximation of diffusion tensors-which are symmetric positive definite (SPD) matrices-and use them in developing a significant extension to an existing probabilistic algorithm for scalar field segmentation, in order to segment diffusion tensor magnetic resonance imaging (DT-MRI) datasets. Using the Riemannian metric on the space of SPD matrices, we present a novel and robust higher order (cubic) continuous tensor product of -splines algorithm to approximate the SPD diffusion tensor fields. The resulting approximations are appropriately dubbed tensor splines. Next, we segment the diffusion tensor field by jointly estimating the label (assigned to each voxel) field, which is modeled by a Gauss Markov measure field (GMMF) and the parameters of each smooth tensor spline model representing the labeled regions. Results of interpolation, approximation, and segmentation are presented for synthetic data and real diffusion tensor fields from an isolated rat hippocampus, along with validation. We also present comparisons of our algorithms with existing methods and show significantly improved results in the presence of noise as well as outliers.

Symmetric positive 4th order tensors & their estimation from diffusion weighted MRI

In Diffusion Weighted Magnetic Resonance Image (DW-MRI) processing a 2nd order tensor has been commonly used to approximate the diffusivity function at each lattice point of the DW-MRI data. It is now well known that this 2nd-order approximation fails to approximate complex local tissue structures, such as fibers crossings. In this paper we employ a 4th order symmetric positive semi-definite (PSD) tensor approximation to represent the diffusivity function and present a novel technique to estimate these tensors from the DW-MRI data guaranteeing the PSD property. There have been several published articles in literature on higher order tensor approximations of the diffusivity function but none of them guarantee the positive semi-definite constraint, which is a fundamental constraint since negative values of the diffusivity coefficients are not meaningful. In our methods, we parameterize the 4th order tensors as a sum of squares of quadratic forms by using the so called Gram matrix method from linear algebra and its relation to the Hilberts theorem on ternary quartics. This parametric representation is then used in a nonlinear-least squares formulation to estimate the PSD tensors of order 4 from the data. We define a metric for the higher-order tensors and employ it for regularization across the lattice. Finally, performance of this model is depicted on synthetic data as well as real DW-MRI from an isolated rat hippocampus.

Structural insights from high-resolution diffusion tensor imaging and tractography of the isolated rat hippocampus

The hippocampus is a critical structure for learning and memory formation injured by diverse neuropathologies such as epilepsy or Alzheimers disease. Recently, clinical investigations have attempted to use diffusion tensor MRI as a more specific surrogate marker for hippocampal damage. To first better understand the tissue architecture of healthy hippocampal regions, this study characterized 10 rat hippocampi with diffusion tensor imaging (DTI) at 50-microm in-plane image resolution using a 14.1-T magnet. Chemical fixation of the dissected and straightened rat hippocampus provided a simple, effective way to reduce partial volume effects when segmenting hippocampal regions and improved mean signal-to-noise per unit time (e.g. 50.6+/-4.4 at b=1250 s/mm2 in 27 min). Contrary to previous reports that water diffusion is homogeneous throughout the nervous system, statistically different mean diffusivities were observed (e.g. 0.238+/-0.054 and 0.318+/-0.084 microm2/ms for the molecular and granule cell layers respectively) (ANOVA, P<0.05). Different hippocampal subregions had lower fractional anisotropy than uniformly fibrous structures like corpus callosum because of their complex architecture. DTI-derived color fiber orientation maps and tractography demonstrated most components of the trisynaptic intrahippocampal pathway (e.g. orientations in stratum lacunosum-moleculare were dominated by perforant and Schaffer fibers) and also permitted some assessment of connectivity in the rat hippocampus.

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy.

There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6weeks) and chronic (12weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p<0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p=0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ=0.66; p=0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ=0.48; p=0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter.

Silent Intralesional Microhemorrhage as a Risk Factor for Brain Arteriovenous Malformation Rupture

Background and Purpose— We investigated whether brain arteriovenous malformation silent intralesional microhemorrhage, that is, asymptomatic bleeding in the nidal compartment, might serve as a marker for increased risk of symptomatic intracranial hemorrhage (ICH). We evaluated 2 markers to assess the occurrence of silent intralesional microhemorrhage: neuroradiological assessment of evidence of old hemorrhage—imaging evidence of bleeding before the outcome events–and hemosiderin positivity in hematoxylin and eosin-stained paraffin block sections. Methods— We identified cases from our brain arteriovenous malformation database with recorded neuroradiological data or available surgical paraffin blocks. Using 2 end points, index ICH or new ICH after diagnosis (censored at treatment, loss to follow-up, or death), we performed logistic or Cox regression to assess evidence of old hemorrhage and hemosiderin positivity adjusting for age, sex, deep-only venous drainage, maximal brain arteriovenous malformation size, deep location, and associated arterial aneurysms. Results— Evidence of old hemorrhage was present in 6.5% (n=975) of patients and highly predictive of index ICH (P<0.001; OR, 3.97; 95% CI, 2.1–7.5) adjusting for other risk factors. In a multivariable model (n=643), evidence of old hemorrhage was an independent predictor of new ICH (hazard ratio, 3.53; 95% CI, 1.35–9.23; P=0.010). Hemosiderin positivity was found in 36.2% (29.6% in unruptured; 47.8% in ruptured; P=0.04) and associated with index ICH in univariate (OR, 2.18; 95% CI, 1.03–4.61; P=0.042; n=127) and multivariable models (OR, 3.64; 95% CI, 1.11–12.00; P=0.034; n=79). Conclusions— The prevalence of silent intralesional microhemorrhage is high and there is evidence for an association with both index and subsequent ICH. Further development of means to detect silent intralesional microhemorrhage during brain arteriovenous malformation evaluation may present an opportunity to improve risk stratification, especially for unruptured brain arteriovenous malformations.

Water diffusion measurements in perfused human hippocampal slices undergoing tonicity changes.

Diffusion MRI has the potential to probe the compartmental origins of MR signals acquired from human nervous tissue. However, current experiments in human subjects require long diffusion times, which may confound data interpretation due to the effects of compartmental exchange. To investigate human nervous tissue at shorter diffusion times, and to determine the relevance of previous diffusion studies in rat hippocampal slices, water diffusion in 20 perfused human hippocampal slices was measured using a wide‐bore 17.6‐T magnet equipped with 1000‐mT/m gradients. These slices were procured from five patients undergoing temporal lobectomy for epilepsy. Tissue viability was confirmed with electrophysiological measurements. Diffusion‐weighted water signal attenuation in the slices was well‐described by a biexponential function (R2 > 0.99). The mean diffusion parameters for slices before osmotic perturbation were 0.686 ± 0.082 for the fraction of fast diffusing water (Ffast), 1.22 ± 0.22 × 10−3 mm2/s for the fast apparent diffusion coefficient (ADC), and 0.06 ± 0.02 × 10−3 mm2/s for the slow ADC. Slice perturbations with 20% hypotonic and 20% hypertonic artificial cerebrospinal fluid led to changes in Ffast of −8.2% and +10.1%, respectively (ANOVA, P < 0.001). These data agree with previous diffusion studies of rat brain slices and human brain in vivo, and should aid the development of working models of water diffusion in nervous tissue, and thus increase the clinical utility of diffusion MRI. Magn Reson Med 49:856–863, 2003.

Reducing Patient Radiation Dose during CT-Guided Procedures: Demonstration in Spinal Injections for Pain

BACKGROUND AND PURPOSE: CT guidance may improve precision for diagnostic and therapeutic spinal injections, but it can increase patient radiation dose. This study examined the impact of reducing tube current on patient radiation exposure and the technical success for these procedures, by using axial acquisitions for short scan lengths and eliminating nonessential imaging. MATERIALS AND METHODS: Our institutional review board approved retrospective analysis of records from 100 consecutive outpatients undergoing spinal injections for pain before and after the CT protocol modification to reduce radiation dose. Data collected included patient age and sex, response to injection, number of sites and spinal levels treated, injection type, performing physician, CT acquisition method, number of imaging series, tube current, scan length, and DLP. RESULTS: Image contrast was reduced with the low-dose protocol, but this did not affect technical success or immediate pain relief. Mean DLP for all procedures decreased from 1458 ± 1022 to 199 ± 101 mGy · cm (P < .001). The range of radiologist-dependent DLP per procedure also was reduced significantly with the modified protocol. Selective nerve root blocks, lumbar injections, multiple injection sites, and the lack of prior imaging were each associated with a slightly higher DLP (<50 mGy · cm). CONCLUSIONS: Radiation to patients undergoing CT-guided spinal injections can be decreased significantly without affecting outcome by reducing tube current, using axial acquisitions for short scan lengths, and eliminating nonessential imaging guidance. These measures also decrease variability in radiation doses between different practitioners and should be useful for other CT-guided procedures in radiology.