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

Axisymmetric diffusion kurtosis imaging with Rician bias correction: A simulation study

Purpose: To compare the estimation accuracy of axisymmetric diffusion kurtosis imaging (DKI) and standard DKI in combination with Rician bias correction (RBC). Methods: Axisymmetric DKI is more robust against noise-induced variation in the measured signal than standard DKI because of its reduced parameter space. However, its susceptibility to Rician noise bias at low signal-to-noise ratios (SNR) is unknown. Here, we investigate two main questions: first, does RBC improve estimation accuracy of axisymmetric DKI?; second, is estimation accuracy of axisymmetric DKI increased compared to standard DKI? Estimation accuracy was investigated on the five axisymmetric DKI tensor metrics (AxTM): the parallel and perpendicular diffusivity and kurtosis and mean of the kurtosis tensor, using a noise simulation study based on synthetic data of tissues with varying fiber alignment and in-vivo data focusing on white matter. Results: RBC mainly increased accuracy for the parallel AxTM in tissues with highly to moderately aligned fibers. For the perpendicular AxTM, axisymmetric DKI without RBC performed slightly better than with RBC. However, the combination of axisymmetric DKI with RBC was the overall best performing algorithm across all five AxTM in white matter and axisymmetric DKI itself substantially improved accuracy in axisymmetric tissues with low fiber alignment. Conclusion: Combining axisymmetric DKI with RBC facilitates accurate DKI parameter estimation at unprecedented low SNRs ((Formula presented.)) in white matter, possibly making it a valuable tool for neuroscience and clinical research studies where scan time is a limited resource. The tools used here are available in the open-source ACID toolbox for SPM

Adaptive smoothing of multi-shell diffusion-weighted magnetic resonance data by msPOAS

In this article we present a noise reduction method (msPOAS) for multi-shell diffusion-weighted magnetic resonance data. To our knowledge, this is the first smoothing method which allows simultaneous smoothing of all q-shells. It is applied directly to the diffusion weighted data and consequently allows subsequent analysis by any model. Due to its adaptivity, the procedure avoids blurring of the inherent structures and preserves discontinuities. MsPOAS extends the recently developed position-orientation adaptive smoothing (POAS) procedure to multi-shell experiments. At the same time it considerably simplifies and accelerates the calculations. The behavior of the algorithm msPOAS is evaluated on diffusion-weighted data measured on a single shell and on multiple shells

Adaptive smoothing of multi-shell diffusion-weighted magnetic resonance data by msPOAS

In this article we present a noise reduction method (msPOAS) for multi-shell diffusionweighted magnetic resonance data. To our knowledge, this is the first smoothing method which allows simultaneous smoothing of all q-shells. It is applied directly to the diffusion weighted data and consequently allows subsequent analysis by any model. Due to its adaptivity, the procedure avoids blurring of the inherent structures and preserves discontinuities. MsPOAS extends the recently developed positionorientation adaptive smoothing (POAS) procedure to multi-shell experiments. At the same time it considerably simplifies and accelerates the calculations. The behavior of the algorithm msPOAS is evaluated on diffusion-weighted data measured on a single shell and on multiple shells

Conduction velocity along a key white matter tract is associated with autobiographical memory recall ability

Conduction velocity is the speed at which electrical signals travel along axons and is a crucial determinant of neural communication. Inferences about conduction velocity can now be made in vivo in humans using a measure called the magnetic resonance (MR) g-ratio. This is the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it. Here, in the first application to cognition, we found that variations in MR g-ratio, and by inference conduction velocity, of the parahippocampal cingulum bundle were associated with autobiographical memory recall ability in 217 healthy adults. This tract connects the hippocampus with a range of other brain areas. We further observed that the association seemed to be with inner axon diameter rather than myelin content. The extent to which neurites were coherently organised within the parahippocampal cingulum bundle was also linked with autobiographical memory recall ability. Moreover, these findings were specific to autobiographical memory recall and were not apparent for laboratory-based memory tests. Our results offer a new perspective on individual differences in autobiographical memory recall ability, highlighting the possible influence of specific white matter microstructure features on conduction velocity when recalling detailed memories of real-life past experiences

Adaptive smoothing of multi-shell diffusion-weighted magnetic resonance data by msPOAS

In this article we present a noise reduction method (msPOAS) for multi-shell diffusion-weighted magnetic resonance data. To our knowledge, this is the first smoothing method which allows simultaneous smoothing of all q-shells. It is applied directly to the diffusion weighted data and consequently allows subsequent analysis by any model. Due to its adaptivity, the procedure avoids blurring of the inherent structures and preserves discontinuities. MsPOAS extends the recently developed position-orientation adaptive smoothing (POAS) procedure to multi-shell experiments. At the same time it considerably simplifies and accelerates the calculations. The behavior of the algorithm msPOAS is evaluated on diffusion-weighted data measured on a single shell and on multiple shells

From in situ to ex vivo: the effect of autolysis and fixation on quantitative MRI markers for myelin

Ex vivo histology remains the gold standard against which MRI biophysical models, e.g. the MR g-ratio which characterises the fraction of a fibre’s diameter that is myelinated, are evaluated. The MR g-ratio model requires a measure of myelin density, for which magnetization transfer saturation (MT) has been used as a biomarker. However, changes occurring post mortem, e.g. autolysis, temperature changes and fixation, significantly alter the MRI signal. Here we investigate how these changes impact MT. We found that MT decreased post mortem but greatlyincreased upon fixation. These effects are similar to reported changes of other established MRI myelin-markers

Fiber-orientation independent component of R2* obtained from single-orientation MRI measurements in simulations and a post-mortem human optic chiasm

The effective transverse relaxation rate (R2*) is sensitive to the microstructure of the human brain like the g-ratio which characterises the relative myelination of axons. However, the fibre-orientation dependence of R2* degrades its reproducibility and any microstructural derivative measure. To estimate its orientation-independent part (R2,iso*) from single multi-echo gradient-recalled-echo (meGRE) measurements at arbitrary orientations, a second-order polynomial in time model (hereafter M2) can be used. Its linear time-dependent parameter, β1, can be biophysically related to R2,iso* when neglecting the myelin water (MW) signal in the hollow cylinder fibre model (HCFM). Here, we examined the performance of M2 using experimental and simulated data with variable g-ratio and fibre dispersion. We found that the fitted β1 can estimate R2,iso* using meGRE with long maximum-echo time (TEmax ≈ 54 ms), but not accurately captures its microscopic dependence on the g-ratio (error 84%). We proposed a new heuristic expression for β1 that reduced the error to 12% for ex vivo compartmental R2 values. Using the new expression, we could estimate an MW fraction of 0.14 for fibres with negligible dispersion in a fixed human optic chiasm for the ex vivo compartmental R2 values but not for the in vivo values. M2 and the HCFM-based simulations failed to explain the measured R2*-orientation-dependence around the magic angle for a typical in vivo meGRE protocol (with TEmax ≈ 18 ms). In conclusion, further validation and the development of movement-robust in vivo meGRE protocols with TEmax ≈ 54 ms are required before M2 can be used to estimate R2,iso* in subjects

Simultaneous adaptive smoothing of relaxometry and quantitative magnetization transfer mapping

Attempts for in-vivo histology require a high spatial resolution that comes with the price of a decreased signal-to-noise ratio. We present a novel iterative and multi-scale smoothing method for quantitative Magnetic Resonance Imaging (MRI) data that yield proton density, apparent transverse and longitudinal relaxation, and magnetization transfer maps. The method is based on the propagation-separation approach. The adaptivity of the procedure avoids the inherent bias from blurring subtle features in the calculated maps that is common for non-adaptive smoothing approaches. The characteristics of the methods were evaluated on a high-resolution data set (500 μ isotropic) from a single subject and quantified on data from a multi-subject study. The results show that the adaptive method is able to increase the signal-to-noise ratio in the calculated quantitative maps while largely avoiding the bias that is otherwise introduced by spatially blurring values across tissue borders. As a consequence, it preserves the intensity contrast between white and gray matter and the thin cortical ribbon

Finding the best clearing approach - Towards 3D wide-scale multimodal imaging of aged human brain tissue

The accessibility of new wide-scale multimodal imaging techniques led to numerous clearing techniques emerging over the last decade. However, clearing mesoscopic-sized blocks of aged human brain tissue remains an extremely challenging task. Homogenizing refractive indices and reducing light absorption and scattering are the foundation of tissue clearing. Due to its dense and highly myelinated nature, especially in white matter, the human brain poses particular challenges to clearing techniques. Here, we present a comparative study of seven tissue clearing approaches and their impact on aged human brain tissue blocks (> 5 mm). The goal was to identify the most practical and efficient method in regards to macroscopic transparency, brief clearing time, compatibility with immunohistochemical processing and wide-scale multimodal microscopic imaging. We successfully cleared 26 × 26 × 5 mm3-sized human brain samples with two hydrophilic and two hydrophobic clearing techniques. Optical properties as well as light and antibody penetration depths highly vary between these methods. In addition to finding the best clearing approach, we compared three microscopic imaging setups (the Zeiss Laser Scanning Microscope (LSM) 880 , the Miltenyi Biotec Ultramicroscope ll (UM ll) and the 3i Marianas LightSheet microscope) regarding optimal imaging of large-scale tissue samples. We demonstrate that combining the CLARITY technique (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging compatible Tissue hYdrogel) with the Zeiss LSM 880 and combining the iDISCO technique (immunolabeling-enabled three-dimensional imaging of solvent-cleared organs) with the Miltenyi Biotec UM ll are the most practical and efficient approaches to sufficiently clear aged human brain tissue and generate 3D microscopic images. Our results point out challenges that arise from seven clearing and three imaging techniques applied to non-standardized tissue samples such as aged human brain tissue