Nikola Stikov

Quantifying the local tissue volume and composition in individual brains with magnetic resonance imaging

Here, we describe a quantitative neuroimaging method to estimate the macromolecular tissue volume (MTV), a fundamental measure of brain anatomy. By making measurements over a range of field strengths and scan parameters, we tested the key assumptions and the robustness of the method. The measurements confirm that a consistent quantitative estimate of MTV can be obtained across a range of scanners. MTV estimates are sufficiently precise to enable a comparison between data obtained from an individual subject with control population data. We describe two applications. First, we show that MTV estimates can be combined with T1 and diffusion measurements to augment our understanding of the tissue properties. Second, we show that MTV provides a sensitive measure of disease status in individual patients with multiple sclerosis. The MTV maps are obtained using short clinically appropriate scans that can reveal how tissue changes influence behavior and cognition.

Bound pool fractions complement diffusion measures to describe white matter micro and macrostructure

Diffusion imaging and bound pool fraction (BPF) mapping are two quantitative magnetic resonance imaging techniques that measure microstructural features of the white matter of the brain. Diffusion imaging provides a quantitative measure of the diffusivity of water in tissue. BPF mapping is a quantitative magnetization transfer (qMT) technique that estimates the proportion of exchanging protons bound to macromolecules, such as those found in myelin, and is thus a more direct measure of myelin content than diffusion. In this work, we combined BPF estimates of macromolecular content with measurements of diffusivity within human white matter tracts. Within the white matter, the correlation between BPFs and diffusivity measures such as fractional anisotropy and radial diffusivity was modest, suggesting that diffusion tensor imaging and bound pool fractions are complementary techniques. We found that several major tracts have high BPF, suggesting a higher density of myelin in these tracts. We interpret these results in the context of a quantitative tissue model.

In vivo histology of the myelin g-ratio with magnetic resonance imaging

The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the macaque, the g-ratio was relatively constant across the corpus callosum, as measured by both MRI and electron microscopy. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment.

A robust methodology for in vivo T1 mapping

In this article, a robust methodology for in vivo T1 mapping is presented. The approach combines a gold standard scanning procedure with a novel fitting procedure. Fitting complex data to a five‐parameter model ensures accuracy and precision of the T1 estimation. A reduced‐dimension nonlinear least squares method is proposed. This method turns the complicated multi‐parameter minimization into a straightforward one‐dimensional search. As the range of possible T1 values is known, a global grid search can be used, ensuring that a global optimal solution is found. When only magnitude data are available, the algorithm is adapted to concurrently restore polarity. The performance of the new algorithm is demonstrated in simulations and phantom experiments. The new algorithm is as accurate and precise as the conventionally used Levenberg‐Marquardt algorithm but much faster. This gain in speed makes the use of the five‐parameter model viable. In addition, the new algorithm does not require initialization of the search parameters. Finally, the methodology is applied in vivo to conventional brain imaging and to skin imaging. T1 values are estimated for white matter and gray matter at 1.5 T and for dermis, hypodermis, and muscle at 1.5 T, 3 T, and 7 T. Magn Reson Med, 2010.

Practical medical applications of quantitative MR relaxometry.

Conventional MR images are qualitative, and their signal intensity is dependent on several complementary contrast mechanisms that are manipulated by the MR hardware and software. In the absence of a quantitative metric for absolute interpretation of pixel signal intensities, one that is independent of scanner hardware and sequences, it is difficult to perform comparisons of MR images across subjects or longitudinally in the same subject. Quantitative relaxometry isolates the contributions of individual MR contrast mechanisms (T1, T2, T2*) and provides maps, which are independent of the MR protocol and have a physical interpretation often expressed in absolute units. In addition to providing an unbiased metric for comparing MR scans, quantitative relaxometry uses the relationship between MR maps and physiology to provide a noninvasive surrogate for biopsy and histology. This study provides an overview of some promising clinical applications of quantitative relaxometry, followed by a description of the methods and challenges of acquiring accurate and precise quantitative MR maps. It concludes with three case studies of quantitative relaxometry applied to studying multiple sclerosis, liver iron, and acute myocardial infarction. J. Magn. Reson. Imaging 2012;36:805–824.

On the accuracy of T1 mapping: searching for common ground.

There are many T1 mapping methods available, each of them validated in phantoms and reporting excellent agreement with literature. However, values in literature vary greatly, with T1 in white matter ranging from 690 to 1100 ms at 3 Tesla. This brings into question the accuracy of one of the most fundamental measurements in quantitative MRI. Our goal was to explain these variations and look into ways of mitigating them.

SCT: Spinal Cord Toolbox, an open-source software for processing spinal cord MRI data

Abstract For the past 25 years, the field of neuroimaging has witnessed the development of several software packages for processing multi‐parametric magnetic resonance imaging (mpMRI) to study the brain. These software packages are now routinely used by researchers and clinicians, and have contributed to important breakthroughs for the understanding of brain anatomy and function. However, no software package exists to process mpMRI data of the spinal cord. Despite the numerous clinical needs for such advanced mpMRI protocols (multiple sclerosis, spinal cord injury, cervical spondylotic myelopathy, etc.), researchers have been developing specific tools that, while necessary, do not provide an integrative framework that is compatible with most usages and that is capable of reaching the community at large. This hinders cross‐validation and the possibility to perform multi‐center studies. In this study we introduce the Spinal Cord Toolbox (SCT), a comprehensive software dedicated to the processing of spinal cord MRI data. SCT builds on previously‐validated methods and includes state‐of‐the‐art MRI templates and atlases of the spinal cord, algorithms to segment and register new data to the templates, and motion correction methods for diffusion and functional time series. SCT is tailored towards standardization and automation of the processing pipeline, versatility, modularity, and it follows guidelines of software development and distribution. Preliminary applications of SCT cover a variety of studies, from cross‐sectional area measures in large databases of patients, to the precise quantification of mpMRI metrics in specific spinal pathways. We anticipate that SCT will bring together the spinal cord neuroimaging community by establishing standard templates and analysis procedures. Graphical abstract Figure. No caption available. HighlightsSCT (Spinal Cord Toolbox): Software package for processing spinal cord MRI data.Features Templates & atlases of spinal cord, gray matter and white matter tracts.State‐of‐the‐art segmentation, registration and atlas‐based analysis methods.Open‐source, extensive testing framework, documentation and support via forum.Enables standardized, automatic, robust and reproducible multi‐center studies of large datasets.

g-Ratio weighted imaging of the human spinal cord in vivo.

Abstract The fiber g‐ratio is defined as the ratio of the inner to the outer diameter of the myelin sheath. This ratio provides a measure of the myelin thickness that complements axon morphology (diameter and density) for assessment of demyelination in diseases such as multiple sclerosis. Previous work has shown that an aggregate g‐ratio map can be computed using a formula that combines axon and myelin density measured with quantitative MRI. In this work, we computed g‐ratio weighted maps in the cervical spinal cord of nine healthy subjects. We utilized the 300 mT/m gradients from the CONNECTOM scanner to estimate the fraction of restricted water (fr) with high accuracy, using the CHARMED model. Myelin density was estimated using the lipid and macromolecular tissue volume (MTV) method, derived from normalized proton density (PD) mapping. The variability across spinal level, laterality and subject were assessed using a three‐way ANOVA. The average g‐ratio value obtained in the white matter was 0.76+/−0.03, consistent with previous histology work. Coefficients of variation of fr and MTV were respectively 4.3% and 13.7%. fr and myelin density were significantly different across spinal tracts (p=3×10−7 and 0.004 respectively) and were positively correlated in the white matter (r=0.42), suggesting shared microstructural information. The aggregate g‐ratio did not show significant differences across tracts (p=0.6). This study suggests that fr and myelin density can be measured in vivo with high precision and that they can be combined to produce a g‐ratio‐weighted map robust to free water pool contamination from cerebrospinal fluid or veins. Potential applications include the study of early demyelination in multiple sclerosis, and the quantitative assessment of remyelination drugs. Graphical abstract Figure. No caption available.

Cross-relaxation Imaging of Human Articular Cartilage

In this article, cross‐relaxation imaging is applied to human ex vivo knee cartilage, and correlations of the cross‐relaxation imaging parameters with macromolecular content in articular cartilage are reported. We show that, unlike the more commonly used magnetization transfer ratio, the bound pool fraction, the cross‐relaxation rate (k) and the longitudinal relaxation time (T1) vary with depth and can therefore provide insight into the differences between the top and bottom layers of articular cartilage. Our cross‐relaxation imaging model is more sensitive to macromolecular content in the top layers of cartilage, with bound pool fraction showing moderate correlations with proteoglycan content, and k and T1 exhibiting moderate correlations with collagen. Magn Reson Med, 2011.

Quantitative analysis of the myelin g-ratio from electron microscopy images of the macaque corpus callosum

We provide a detailed morphometric analysis of eight transmission electron micrographs (TEMs) obtained from the corpus callosum of one cynomolgus macaque. The raw TEM images are included in the article, along with the distributions of the axon caliber and the myelin g-ratio in each image. The distributions are analyzed to determine the relationship between axon caliber and g-ratio, and compared against the aggregate metrics (myelin volume fraction, fiber volume fraction, and the aggregate g-ratio), as defined in the accompanying research article entitled ‘In vivo histology of the myelin g-ratio with magnetic resonance imaging’ (Stikov et al., NeuroImage, 2015).