Human White Matter Research Articles

Rationale for the Choice of the Ellipsoidal Reflector Parameters for Biomedical Photometers

Biomedical photometersʼ information-measuring systems with ellipsoidal reflectors have acceptable results in determining of biological tissues optical properties in the visible and near-infrared spectral range. These photometers make it possible to study the optical radiation propagation in turbid media for direct and inverse problems of light-scattering optics. The purpose of this work is to study the influence of the ellipsoidal reflectors design parameters on the results of biomedical photometry when simulating the optical radiation propagation in a system of biological tissue and reflectors in transmitted and reflected light.The paper substantiates the choice of the ellipsoidal reflectors’ focal parameter for efficient registration of forward and backscattered light. The methodology of the process is illustrated by the results of a model experiment using the Monte Carlo simulation for samples of human brain white and gray matter at the visible range of 405 nm, 532 nm, and 650 nm. The total transmittance, diffuse reflectance, and absorption graphs depending on the sample thickness were obtained. Based on the introduced concepts of the ellipsoidal reflector efficiency index and its efficiency factor, the expediency of choosing the ellipsoidal reflectors focal parameter is analyzed to ensure the registration of the maximum amount of scattered light. The graphs of efficiency index in reflected and transmitted light for different thickness samples of white and gray matter and efficiency factors depending on the sample thickness were obtained.The influence of the reflectors ellipticity on the illuminance of various zones of photometric images using the example of an absorbing biological medium – pig liver tissue – at wavelength of 405 nm with a Monte Carlo simulation was analyzed.The optical properties of biological media (scattering and absorption coefficients, scattering anisotropy factor, refractive index) and the samples’ geometric dimensions, particularly the thickness, are predetermined when choosing the ellipsoidal reflectors parameters for registration of the scattered light. Coordinates of the output of photons and their statistical weight obtained in the Monte Carlo simulation of light propagation in biological tissue have a physical effect on a characteristic scattering spot formation in the receiving plane of a biomedical photometer with ellipsoidal reflectors.

The direction-dependence of apparent water exchange rate in human white matter

Transmembrane water exchange is a potential biomarker in the diagnosis and understanding of cancers, brain disorders, and other diseases. Filter-exchange imaging (FEXI), a special case of diffusion exchange spectroscopy adapted for clinical applications, has the potential to reveal different physiological water exchange processes. However, it is still controversial whether modulating the diffusion encoding gradient direction can affect the apparent exchange rate (AXR) measurements of FEXI in white matter (WM) where water diffusion shows strong anisotropy. In this study, we explored the diffusion-encoding direction dependence of FEXI in human brain white matter by performing FEXI with 20 diffusion-encoding directions on a clinical 3T scanner in-vivo. The results show that the AXR values measured when the gradients are perpendicular to the fiber orientation (0.77 ± 0.13 s − 1, mean ± standard deviation of all the subjects) are significantly larger than the AXR estimates when the gradients are parallel to the fiber orientation (0.33 ± 0.14 s − 1, p < 0.001) in WM voxels with coherently-orientated fibers. In addition, no significant correlation is found between AXRs measured along these two directions, indicating that they are measuring different water exchange processes. What's more, only the perpendicular AXR rather than the parallel AXR shows dependence on axonal diameter, indicating that the perpendicular AXR might reflect transmembrane water exchange between intra-axonal and extra-cellular spaces. Further finite difference (FD) simulations having three water compartments (intra-axonal, intra-glial, and extra-cellular spaces) to mimic WM micro-environments also suggest that the perpendicular AXR is more sensitive to the axonal water transmembrane exchange than parallel AXR. Taken together, our results show that AXR measured along different directions could be utilized to probe different water exchange processes in WM.

Human gray and white matter metabolomics to differentiate APOE-dependent metabolic changes in early and late Alzheimer's disease.

Many have suggested that irregularities in metabolism play an underlying role in the progression of Alzheimer's Disease (AD). A detailed knowledge of the biochemical composition of AD brain tissue vs normal brain tissue will be key in understanding the metabolic processes underlying AD, especially as they relate to APOE genotype. Here we perform a metabolomics analysis on the brain tissue of a large cohort of community-based participants in the UK-ADC brain bank to characterize the biochemical profiles of brains with and without Alzheimer's disease and other mixed pathologies based on APOE genotype and disease stage. The global biochemical profiles of post-mortem human brain tissue from the gray matter of Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 158 community-based older adult volunteers was analyzed. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch's two-sample t-test to approximate fold change of metabolites between disease stage and APOE genotype. Random forest was used to rank metabolites in order of importance for predicting AD presence in tissue. Late stage disease in the APOE E4 genotype has decreases in lysophospholipids, long chain polyunsaturated fatty acids, endocannabinoids, and branched fatty acids as well as N-acetylserine in the gray matter. Late stage disease in the APOE E4 genotype has increases in phospholipid metabolism and decreases in amino acid metabolism and Vitamin B6. The APOE E4 genotype is associated with increases in gamma-glutamyl amino acids, lysophospholipid, and amino acid metabolism and decreases in urea cycle, sterol, stachydrine, and benzoate metabolism during early stages of disease, but that there are few metabolic differences between genotypes in later disease. Alzheimer's disease has increases in phospholipid metabolism and decreases in amino acid metabolism compared to normal. Early stage disease showed many metabolic differences between genotypes and late stage tissues looked remarkably similar across genotype. This suggests there may be metabolically distinct pathways that each genotype takes to produce a tissue with common endpoint of disease characterized by an AD biochemical profile. Further studies are needed to examine whether these metabolites are consistently altered in Alzheimer's disease.

Imaging functional neuroplasticity in human white matter tracts

Magnetic resonance imaging (MRI) studies are sensitive to biological mechanisms of neuroplasticity in white matter (WM). In particular, diffusion tensor imaging (DTI) has been used to investigate structural changes. Historically, functional MRI (fMRI) neuroplasticity studies have been restricted to gray matter, as fMRI studies have only recently expanded to WM. The current study evaluated WM neuroplasticity pre–post motor training in healthy adults, focusing on motor learning in the non-dominant hand. Neuroplasticity changes were evaluated in two established WM regions-of-interest: the internal capsule and the corpus callosum. Behavioral improvements following training were greater for the non-dominant hand, which corresponded with MRI-based neuroplasticity changes in the internal capsule for DTI fractional anisotropy, fMRI hemodynamic response functions, and low-frequency oscillations (LFOs). In the corpus callosum, MRI-based neuroplasticity changes were detected in LFOs, DTI, and functional correlation tensors (FCT). Taken together, the LFO results converged as significant amplitude reductions, implicating a common underlying mechanism of optimized transmission through altered myelination. The structural and functional neuroplasticity findings open new avenues for direct WM investigations into mapping connectomes and advancing MRI clinical applications.

Insights into human cerebral white matter maturation and degeneration across the adult lifespan

White matter (WM) microstructural properties change across the adult lifespan and with neuronal diseases. Understanding microstructural changes due to aging is paramount to distinguish them from neuropathological changes. Conducted on a large cohort of 147 cognitively unimpaired subjects, spanning a wide age range of 21 to 94 years, our study evaluated sex- and age-related differences in WM microstructure. Specifically, we used diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) indices, sensitive measures of myelin and axonal density in WM, and myelin water fraction (MWF), a measure of the fraction of the signal of water trapped within the myelin sheets, to probe these differences. Furthermore, we examined regional correlations between MWF and DTI indices to evaluate whether the DTI metrics provide information complementary to MWF. While sexual dimorphism was, overall, nonsignificant, we observed region-dependent differences in MWF, that is, myelin content, and axonal density with age and found that both exhibit nonlinear, but distinct, associations with age. Furthermore, DTI indices were moderately correlated with MWF, indicating their good sensitivity to myelin content as well as to other constituents of WM tissue such as axonal density. The microstructural differences captured by our MRI metrics, along with their weak to moderate associations with MWF, strongly indicate the potential value of combining these outcome measures in a multiparametric approach. Furthermore, our results support the last-in-first-out and the gain-predicts-loss hypotheses of WM maturation and degeneration. Indeed, our results indicate that the posterior WM regions are spared from neurodegeneration as compared to anterior regions, while WM myelination follows a temporally symmetric time course across the adult life span.

Evaluating the Reliability of Human Brain White Matter Tractometry.

The validity of research results depends on the reliability of analysis methods. In recent years, there have been concerns about the validity of research that uses diffusion-weighted MRI (dMRI) to understand human brain white matter connections in vivo, in part based on the reliability of analysis methods used in this field. We defined and assessed three dimensions of reliability in dMRI-based tractometry, an analysis technique that assesses the physical properties of white matter pathways: (1) reproducibility, (2) test-retest reliability, and (3) robustness. To facilitate reproducibility, we provide software that automates tractometry (https://yeatmanlab.github.io/pyAFQ). In measurements from the Human Connectome Project, as well as clinical-grade measurements, we find that tractometry has high test-retest reliability that is comparable to most standardized clinical assessment tools. We find that tractometry is also robust: showing high reliability with different choices of analysis algorithms. Taken together, our results suggest that tractometry is a reliable approach to analysis of white matter connections. The overall approach taken here both demonstrates the specific trustworthiness of tractometry analysis and outlines what researchers can do to establish the reliability of computational analysis pipelines in neuroimaging.

Cerebral white matter vasculature: still uncharted?

White matter vasculature plays a major role in the pathophysiology of permanent neurological deficits following a stroke or progressive cognitive alteration related to small vessel disease. Thus, knowledge of the complex vascularization and functional aspects of the deep white matter territories is paramount to comprehend clinical manifestations of brain ischaemia. This review provides a structured presentation of the existing knowledge of the vascularization of the human cerebral white matter from seminal historical studies to the current literature. First, we revisit the highlights of prenatal development of the endoparenchymal telencephalic vascular system that are crucial for the understanding of vessel organization in the adult. Second, we reveal the tangled history of debates on the existence, clinical significance and physiological role of leptomeningeal anastomoses. Then, we present how conceptions on white matter vascularization transitioned from the mixed ventriculopetal/ventriculofugal theory, in which a low-flow area was interposed in between concurrent arterial flows, to the purely ventriculopetal theory. The latter model explains variable white matter sensitivity to ischaemia by various organizations of ventriculopetal vessel terminals having different origin/length properties and interconnection patterns. Next, arteries supplying primarily the white matter are described according to their length and overall structure. Furthermore, the known distribution territories, to date, are studied in relation to primary anatomical structures of the human cerebral white matter, emphasizing the sparsity of the 'ground truth' data available in the literature. Finally, the implications for both large vessel occlusion and chronic small vessel disease are discussed, as well as the insights from neuroimaging. All things considered, we identify the need for further research on deep white matter vascularization, especially regarding the arterial supply of white matter fibre tracts.

THE INFLUENCE OF SPATIAL RESOLUTION AND FIBER DENSITY ON THE FRACTAL DIMENSION OF CEREBRAL FIBER TRACTS

The determination of the generalized fractal dimensions (FDs) from MRI tractograms is affected by image resolution and the number of fiber tracts. In this work, we demonstrate that only certain combinations of image resolution, number of fiber tracts and exponent of the generalized dimensions are able to capture structural changes in human cerebral white matter. MRI tractography was carried out for a different number of fiber tracts and was discretized on different grid sizes. Generalized FDs were evaluated for two groups of healthy subjects with different age distribution. For the box-counting dimension ([Formula: see text]) the highest difference between two age groups was found for a matrix size of 20483 pixel with a strong dependence on the number of fiber tracts. The correlation dimension found the highest differences for a resolution of 10243 pixel, largely independent of the number of fiber tracts. The correlation dimension evaluated for tractograms discretized on a 10243 grid is a robust measurement to capture structural changes in human cerebral white matter by means of FD.

Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation

Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following exvivo and invivo demyelinating injury.

Comparative analysis of signal models for microscopic fractional anisotropy estimation using q-space trajectory encoding

Microscopic diffusion anisotropy imaging using diffusion-weighted MRI and multidimensional diffusion encoding is a promising method for quantifying clinically and scientifically relevant microstructural properties of neural tissue. Several methods for estimating microscopic fractional anisotropy (µFA), a normalized measure of microscopic diffusion anisotropy, have been introduced but the differences between the methods have received little attention thus far. In this study, the accuracy and precision of µFA estimation using q-space trajectory encoding and different signal models were assessed using imaging experiments and simulations. Three healthy volunteers and a microfibre phantom were imaged with five non-zero b-values and gradient waveforms encoding linear and spherical b-tensors. Since the ground-truth µFA was unknown in the imaging experiments, Monte Carlo random walk simulations were performed using axon-mimicking fibres for which the ground truth was known. Furthermore, parameter bias due to time-dependent diffusion was quantified by repeating the simulations with tuned waveforms, which have similar power spectra, and with triple diffusion encoding, which, unlike q-space trajectory encoding, is not based on the assumption of time-independent diffusion. The truncated cumulant expansion of the powder-averaged signal, gamma-distributed diffusivities assumption, and q-space trajectory imaging, a generalization of the truncated cumulant expansion to individual signals, were used to estimate µFA. The gamma-distributed diffusivities assumption consistently resulted in greater µFA values than the second order cumulant expansion, 0.1 greater when averaged over the whole brain. In the simulations, the generalized cumulant expansion provided the most accurate estimates. Importantly, although time-dependent diffusion caused significant overestimation of µFA using all the studied methods, the simulations suggest that the resulting bias in µFA is less than 0.1 in human white matter.

Age-Related Variations in Regional White Matter Volumetry and Microstructure During the Post-adolescence Period: A Cross-Sectional Study of a Cohort of 1,713 University Students.

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilized to study white matter changes during development and aging. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18–26. We assessed the age and sex dependence of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterized by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. These findings emphasize the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood.

Detection of human white matter activation and evaluation of its function in movement decoding using stereo-electroencephalography (SEEG)

Objective. White matter tissue takes up approximately 50% of the human brain volume and it is widely known as a messenger conducting information between areas of the central nervous system. However, the characteristics of white matter neural activity and whether white matter neural recordings can contribute to movement decoding are often ignored and still remain largely unknown. In this work, we make quantitative analyses to investigate these two important questions using invasive neural recordings. Approach. We recorded stereo-electroencephalography (SEEG) data from 32 human subjects during a visually-cued motor task, where SEEG recordings can tap into gray and white matter electrical activity simultaneously. Using the proximal tissue density method, we identified the location (i.e. gray or white matter) of each SEEG contact. Focusing on alpha oscillatory and high gamma activities, we compared the activation patterns between gray matter and white matter. Then, we evaluated the performance of such white matter activation in movement decoding. Main results. The results show that white matter also presents activation under the task, in a similar way with the gray matter but at a significantly lower amplitude. Additionally, this work also demonstrates that combing white matter neural activities together with that of gray matter significantly promotes the movement decoding accuracy than using gray matter signals only. Significance. Taking advantage of SEEG recordings from a large number of subjects, we reveal the response characteristics of white matter neural signals under the task and demonstrate its enhancing function in movement decoding. This study highlights the importance of taking white matter activities into consideration in further scientific research and translational applications.

Relating quantitative 7T MRI across cortical depths to cytoarchitectonics, gene expression and connectomics.

Ultra‐high field MRI across the depth of the cortex has the potential to provide anatomically precise biomarkers and mechanistic insights into neurodegenerative disease like Huntington's disease that show layer‐selective vulnerability. Here we compare multi‐parametric mapping (MPM) measures across cortical depths for a 7T 500 μm whole brain acquisition to (a) layer‐specific cell measures from the von Economo histology atlas, (b) layer‐specific gene expression, using the Allen Human Brain atlas and (c) white matter connections using high‐fidelity diffusion tractography, at a 1.3 mm isotropic voxel resolution, from a 300mT/m Connectom MRI system. We show that R2*, but not R1, across cortical depths is highly correlated with layer‐specific cell number and layer‐specific gene expression. R1‐ and R2*‐weighted connectivity strength of cortico‐striatal and intra‐hemispheric cortical white matter connections was highly correlated with grey matter R1 and R2* across cortical depths. Limitations of the layer‐specific relationships demonstrated are at least in part related to the high cross‐correlations of von Economo atlas cell counts and layer‐specific gene expression across cortical layers. These findings demonstrate the potential and limitations of combining 7T MPMs, gene expression and white matter connections to provide an anatomically precise framework for tracking neurodegenerative disease.

Multidimensional analysis and detection of informative features in human brain white matter.

The white matter contains long-range connections between different brain regions and the organization of these connections holds important implications for brain function in health and disease. Tractometry uses diffusion-weighted magnetic resonance imaging (dMRI) to quantify tissue properties along the trajectories of these connections. Statistical inference from tractometry usually either averages these quantities along the length of each fiber bundle or computes regression models separately for each point along every one of the bundles. These approaches are limited in their sensitivity, in the former case, or in their statistical power, in the latter. We developed a method based on the sparse group lasso (SGL) that takes into account tissue properties along all of the bundles and selects informative features by enforcing both global and bundle-level sparsity. We demonstrate the performance of the method in two settings: i) in a classification setting, patients with amyotrophic lateral sclerosis (ALS) are accurately distinguished from matched controls. Furthermore, SGL identifies the corticospinal tract as important for this classification, correctly finding the parts of the white matter known to be affected by the disease. ii) In a regression setting, SGL accurately predicts "brain age." In this case, the weights are distributed throughout the white matter indicating that many different regions of the white matter change over the lifespan. Thus, SGL leverages the multivariate relationships between diffusion properties in multiple bundles to make accurate phenotypic predictions while simultaneously discovering the most relevant features of the white matter.

White matter plasticity in healthy older adults: The effects of aerobic exercise

White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer's disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60–79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions resulted in positive changes in the T1w/T2w signal in late-myelinating regions, as compared to widespread decreases in the T1w/T2w signal in the active control. Notably, in the aerobic walking group, positive change in the T1w/T2w signal correlated with improved episodic memory performance. Lastly, intervention-induced increases in cardiorespiratory fitness did not correlate with change in the T1w/T2w signal. Together, our findings suggest that white matter regions that are vulnerable to aging retain some degree of plasticity that can be induced by aerobic exercise training. In addition, we provided evidence that the T1w/T2w signal may be a useful and broadly accessible measure for studying short-term within-person plasticity and deterioration in the adult human white matter.

Ultrastructural Characterization of Human Oligodendrocytes and Their Progenitor Cells by Pre-embedding Immunogold.

Oligodendrocytes are the myelinating cells of the central nervous system. They provide trophic, metabolic, and structural support to neurons. In several pathologies such as multiple sclerosis (MS), these cells are severely affected and fail to remyelinate, thereby leading to neuronal death. The gold standard for studying remyelination is the g-ratio, which is measured by means of transmission electron microscopy (TEM). Therefore, studying the fine structure of the oligodendrocyte population in the human brain at different stages through TEM is a key feature in this field of study. Here we study the ultrastructure of oligodendrocytes, its progenitors, and myelin in 10 samples of human white matter using nine different markers of the oligodendrocyte lineage (NG2, PDGFRα, A2B5, Sox10, Olig2, BCAS1, APC-(CC1), MAG, and MBP). Our findings show that human oligodendrocytes constitute a very heterogeneous population within the human white matter and that its stages of differentiation present characteristic features that can be used to identify them by TEM. This study sheds light on how these cells interact with other cells within the human brain and clarify their fine characteristics from other glial cell types.

Sex Chromosome Dosage Effects on White Matter Structure in the Human Brain.

Sex chromosome aneuploidies, a group of neurogenetic conditions characterized by aberrant sex chromosome dosage (SCD), are associated with increased risks for psychopathology as well as alterations in gray matter structure. However, we still lack a comprehensive understanding of potential SCD-associated changes in white matter structure, or knowledge of how these changes might relate to known alterations in gray matter anatomy. Thus, here, we use voxel-based morphometry on structural neuroimaging data to provide the first comprehensive maps of regional white matter volume (WMV) changes across individuals with varying SCD (n = 306). We show that mounting X- and Y-chromosome dosage are both associated with widespread WMV decreases, including in cortical, subcortical, and cerebellar tracts, as well as WMV increases in the genu of the corpus callosum and posterior thalamic radiation. We also correlate X- and Y-chromosome-linked WMV changes in certain regions to measures of internalizing and externalizing psychopathology. Finally, we demonstrate that SCD-driven WMV changes show a coordinated coupling with SCD-driven gray matter volume changes. These findings represent the most complete maps of X- and Y-chromosome effects on human white matter to date, and show how such changes connect to psychopathological symptoms and gray matter anatomy.

Empirical validation of gradient field models for an accurate ADC measured on clinical 3T MR systems in body oncologic applications.

To empirically corroborate vendor-provided gradient nonlinearity (GNL) characteristics and demonstrate efficient GNL bias correction for human brain apparent diffusion coefficient (ADC) across 3T MR systems and spatial locations. Spatial distortion vector fields (DVF) were mapped in 3D using a surface fiducial array phantom for individual gradient channels on three 3T MR platforms from different vendors. Measured DVF were converted into empirical 3D GNL tensors and compared with their theoretical counterparts derived from vendor-provided spherical harmonic (SPH) coefficients. To illustrate spatial impact of GNL on ADC, diffusion weighted imaging using three orthogonal gradient directions was performed on a volunteer brain positioned at isocenter (as a reference) and offset superiorly by 10-17cm (>10% predicted GNL bias). The SPH tensor-based GNL correction was applied to individual DWI gradient directions, and derived ADC was compared with low-bias reference for human brain white matter (WM) ROIs. Empiric and predicted GNL errors were comparable for all three studied 3T MR systems, with <1.0% differences in the median and width of spatial histograms for individual GNL tensor elements. Median (±width) of ADC (10-3mm2/s) histograms measured at isocenter in WM reference ROIs from three MR systems were: 0.73±0.11, 0.71±0.14, 0.74±0.17, and at off-isocenters (before versus after GNL correction) were respectively 0.63±0.14 versus 0.72±0.11, 0.53±0.16 versus 0.74±0.18, and 0.65±0.16 versus 0.76±0.18. The phantom-based spatial distortion measurements validated vendor-provided gradient fields, and accurate WM ADC was recovered regardless of spatial locations and clinical MR platforms using system-specific tensor-based GNL correction for routine DWI.

Characterization of white matter branching in human cerebella: quantitative morphological assessment and fractal analysis of skeletonized MR images

Introduction: The aim of the present study was to investigate branching characteristics of the human cerebellar white matter by the means of findings obtained from the quantitative morphological assessment and fractal analysis of the skeletonized MR images of the human cerebellum.&#x0D; Methods: Thirty individuals with no apparent brain pathology (15 males and 15 females, ranging from 18 - 30 years of age) participated in this study. Their normal T2-weighted MR images of the cerebellar vermis (midsagittal plane) were examined. The skeletonizing procedure and subsequent quantitative morphological assessment of the acquired skeletonized MR images were performed. The following parameters were determined: the number of branches, the number of junctions, the amount of end-point voxels, junction voxels and slab voxels, the average and maximum branch lengths, the longest-shortest patch length, and the number of triple and quadruple points. Additionally, the individual branches of the obtained digital skeletons of the cerebellar white matter were examined and the following parameters were assessed: branch length variability, Euclidean distance, and branch length/Euclidean distance ratio. A fractal analysis was performed using the box counting method prior to and after the MR image skeletonizing procedure. The values of the fractal dimensions (FD) of both skeletonized and non-skeletonized MR images were calculated.&#x0D; Results: It was established that the cerebella, which had the maximum values of the FD, possessed a large number of small branches approximately equal in length and which were connected by numerous junctions, forming numerous endpoints. Those cerebella, which had higher values of the average branch length and greater branch length variability, showed lower values of the FD. The key characteristics of the digital skeleton that determined the values of the FD of the cerebellum and its skeletonized MR images were the number of branches and the number of junctions that had the strongest correlational relationships with the FD of the skeletonized MR images. We submitted a proposition to consider the number of branches and amount of junctions as a diagnostic criterion in the determination of normal values of the FD.&#x0D; Conclusions: The obtained data can be used as diagnostic criteria in assessment of the morphofunctional state of the cerebellum using magnetic resonance imaging (MRI) technique.

Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin’s nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method’s sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.