Towards in vivo g-ratio mapping using MRI: unifying myelin and diffusion imaging

The g-ratio, quantifying the comparative thickness of the myelin sheath encasing an axon, is a geometrical invariant that has high functional relevance because of its importance in determining neuronal conduction velocity. Advances in MRI data acquisition and signal modelling have put in vivo mapping of the g-ratio, across the entire white matter, within our reach. This capacity would greatly increase our knowledge of the nervous system: how it functions, and how it is impacted by disease. This is the second review on the topic of g-ratio mapping using MRI. As such, it summarizes the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches. Using simulations based on recently published data, this review demonstrates the relevance of the calibration step for three myelin-markers (macromolecular tissue volume, myelin water fraction, and bound pool fraction). It highlights the need to estimate both the slope and offset of the relationship between these MRI-based markers and the true myelin volume fraction if we are really to achieve the goal of precise, high sensitivity g-ratio mapping in vivo. Other challenges discussed in this review further evidence the need for gold standard measurements of human brain tissue from ex vivo histology. We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the potential of many novel techniques yet to be investigated.Comment: Will be published as a review article in Journal of Neuroscience Methods as parf of the Special Issue with Hu Cheng and Vince Calhoun as Guest Editor

Axon diameters and myelin content modulate microscopic fractional anisotropy at short diffusion times in fixed rat spinal cord

Mapping tissue microstructure accurately and noninvasively is one of the frontiers of biomedical imaging. Diffusion Magnetic Resonance Imaging (MRI) is at the forefront of such efforts, as it is capable of reporting on microscopic structures orders of magnitude smaller than the voxel size by probing restricted diffusion. Double Diffusion Encoding (DDE) and Double Oscillating Diffusion Encoding (DODE) in particular, are highly promising for their ability to report on microscopic fractional anisotropy ({\mu}FA), a measure of the pore anisotropy in its own eigenframe, irrespective of orientation distribution. However, the underlying correlates of {\mu}FA have insofar not been studied. Here, we extract {\mu}FA from DDE and DODE measurements at ultrahigh magnetic field of 16.4T in the aim to probe fixed rat spinal cord microstructure. We further endeavor to correlate {\mu}FA with Myelin Water Fraction (MWF) derived from multiexponential T2 relaxometry, as well as with literature-based spatially varying axonal diameters. In addition, a simple new method is presented for extracting unbiased {\mu}FA from three measurements at different b-values. Our findings reveal strong anticorrelations between {\mu}FA (derived from DODE) and axon diameter in the distinct spinal cord tracts; a moderate correlation was also observed between {\mu}FA derived from DODE and MWF. These findings suggest that axonal membranes strongly modulate {\mu}FA, which - owing to its robustness towards orientation dispersion effects - reflects axon diameter much better than its typical FA counterpart. The {\mu}FA exhibited modulations when measured via oscillating or blocked gradients, suggesting selective probing of different parallel path lengths and providing insight into how those modulate {\mu}FA metrics. Our findings thus shed light into the underlying microstructural correlates of {\mu}FA and are (...

Magnetic susceptibility anisotropy of myocardium imaged by cardiovascular magnetic resonance reflects the anisotropy of myocardial filament α-helix polypeptide bonds.

BackgroundA key component of evaluating myocardial tissue function is the assessment of myofiber organization and structure. Studies suggest that striated muscle fibers are magnetically anisotropic, which, if measurable in the heart, may provide a tool to assess myocardial microstructure and function.MethodsTo determine whether this weak anisotropy is observable and spatially quantifiable with cardiovascular magnetic resonance (CMR), both gradient-echo and diffusion-weighted data were collected from intact mouse heart specimens at 9.4 Tesla. Susceptibility anisotropy was experimentally calculated using a voxelwise analysis of myocardial tissue susceptibility as a function of myofiber angle. A myocardial tissue simulation was developed to evaluate the role of the known diamagnetic anisotropy of the peptide bond in the observed susceptibility contrast.ResultsThe CMR data revealed that myocardial tissue fibers that were parallel and perpendicular to the magnetic field direction appeared relatively paramagnetic and diamagnetic, respectively. A linear relationship was found between the magnetic susceptibility of the myocardial tissue and the squared sine of the myofiber angle with respect to the field direction. The multi-filament model simulation yielded susceptibility anisotropy values that reflected those found in the experimental data, and were consistent that this anisotropy decreased as the echo time increased.ConclusionsThough other sources of susceptibility anisotropy in myocardium may exist, the arrangement of peptide bonds in the myofilaments is a significant, and likely the most dominant source of susceptibility anisotropy. This anisotropy can be further exploited to probe the integrity and organization of myofibers in both healthy and diseased heart tissue

Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7T

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in ‘arterial’ and ‘venous’ blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between ‘arterial’ and ‘venous’ contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms

Indirect Detection of Axonal Architecture With Q-Space Imaging

Evaluating axon morphology would provide insights into connectivity, maturation, and disease pathology. Conventional diffusion MRI can provide metrics that are related to axon morphology, but cannot measure specific parameters such as mean axon diameter (MAD) and intracellular fraction (ICF). Q-space imaging (QSI) is an advanced diffusion MRI technique that may be able to provide more information on axon morphology. However, QSI has several limitations that affect its implementation and accuracy. The main objective of this dissertation was to address these limitations and to evaluate the potential of QSI to accurately assess axon morphology. First, a custom-built high-amplitude gradient coil was used to address the limitations in the maximum gradient amplitude available with commercial systems. Second, to understand the relationship between axon morphology and QSI, simulations were used to investigate the effects of the presence of both extracellular and intracellular signals (ECS and ICS) as well as variation in cell size and shape. Third, three QSI-based methods were designed provide specific measures of axon morphology which have not been reported before. The maximum amplitude of the custom gradient coil was 50 T/m that, for the first time, allowed for sub-micron displacement resolution while fulfilling the short gradient approximation. This enabled near-ideal QSI experiments to be performed. QSI experiments on excised mouse spinal cords showed good correlation with histology, but overestimated MAD. Simulations showed that axon morphology was the dominant effect on QSI and suggested that the presence of ECS and ICS signals may complicate interpretation. Three methods were designed to account for signal in ECS and ICS: two relied on a two-compartment model of the displacement probability density function and the echo attenuation at low q-values, and a third varied the gradient duration to differentiate diffusion in ECS from ICS. All three methods provided estimates of MAD and ICF that showed better agreement with histology than QSI. The methods were also evaluated implementation on a clinical scanner. This dissertation demonstrated the sensitivity of QSI to axon morphology and showed the feasibility of three methods to accurately estimate MAD and ICF. Further investigation is warranted to study future applications

Towards in vivo g-ratio mapping using MRI: Unifying myelin and diffusion imaging

BACKGROUND: The g-ratio, quantifying the comparative thickness of the myelin sheath encasing an axon, is a geometrical invariant that has high functional relevance because of its importance in determining neuronal conduction velocity. Advances in MRI data acquisition and signal modelling have put in vivo mapping of the g-ratio, across the entire white matter, within our reach. This capacity would greatly increase our knowledge of the nervous system: how it functions, and how it is impacted by disease. NEW METHOD: This is the second review on the topic of g-ratio mapping using MRI. RESULTS: This review summarizes the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches. COMPARISON WITH EXISTING METHODS: Using simulations based on recently published data, this review reveals caveats to the state-of-the-art calibration methods that have been used for in vivo g-ratio mapping. It highlights the need to estimate both the slope and offset of the relationship between these MRI-based markers and the true myelin volume fraction if we are really to achieve the goal of precise, high sensitivity g-ratio mapping in vivo. Other challenges discussed in this review further evidence the need for gold standard measurements of human brain tissue from ex vivo histology. CONCLUSIONS: We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the full potential of many novel techniques yet to be investigated

Mitigating the impact of flip angle and orientation dependence in single compartment R2* estimates via 2-pool modeling

Purpose: The effective transverse relaxation rate ( R∗2 ) is influenced by biological features that make it a useful means of probing brain microstructure. However, confounding factors such as dependence on flip angle (α) and fiber orientation with respect to the main field ( θ ) complicate interpretation. The α- and θ -dependence stem from the existence of multiple sub-voxel micro-environments (e.g., myelin and non-myelin water compartments). Ordinarily, it is challenging to quantify these sub-compartments; therefore, neuroscientific studies commonly make the simplifying assumption of a mono-exponential decay obtaining a single R∗2 estimate per voxel. In this work, we investigated how the multi-compartment nature of tissue microstructure affects single compartment R∗2 estimates. Methods: We used 2-pool (myelin and non-myelin water) simulations to characterize the bias in single compartment R∗2 estimates. Based on our numeric observations, we introduced a linear model that partitions R∗2 into α-dependent and α-independent components and validated this in vivo at 7T. We investigated the dependence of both components on the sub-compartment properties and assessed their robustness, orientation dependence, and reproducibility empirically. Results: R∗2 increased with myelin water fraction and residency time leading to a linear dependence on α. We observed excellent agreement between our numeric and empirical results. Furthermore, the α-independent component of the proposed linear model was robust to the choice of α and reduced dependence on fiber orientation, although it suffered from marginally higher noise sensitivity. Conclusion: We have demonstrated and validated a simple approach that mitigates flip angle and orientation biases in single-compartment R∗2 estimates

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies