Myelin Water Fraction Measurements Research Articles

Investigating female versus male differences in white matter neuroplasticity associated with complex visuo-motor learning

Magnetic resonance imaging (MRI) has increasingly been used to characterize structure–function relationships during white matter neuroplasticity. Biological sex differences may be an important factor that affects patterns of neuroplasticity, and therefore impacts learning and rehabilitation. The current study examined a participant cohort before and after visuo-motor training to characterize sex differences in microstructural measures. The participants (N = 27) completed a 10-session (4 week) complex visuo-motor training task with their non-dominant hand. All participants significantly improved movement speed and their movement speed variability over the training period. White matter neuroplasticity in females and males was examined using fractional anisotropy (FA) and myelin water fraction (MWF) along the cortico-spinal tract (CST) and the corpus callosum (CC). FA values showed significant differences in the middle portion of the CST tract (nodes 38–51) across the training period. MWF showed a similar cluster in the inferior portion of the tract (nodes 18–29) but did not reach significance. Additionally, at baseline, males showed significantly higher levels of MWF measures in the middle body of the CC. Combining data from females and males would have resulted in reduced sensitivity, making it harder to detect differences in neuroplasticity. These findings offer initial insights into possible female versus male differences in white matter neuroplasticity during motor learning. This warrants investigations into specific patterns of white matter neuroplasticity for females versus males across the lifespan. Understanding biological sex-specific differences in white matter neuroplasticity may have significant implications for the interpretation of change associated with learning or rehabilitation.

Assessing the differential sensitivities of wave-CAIPI ViSTa myelin water fraction and magnetization transfer saturation for efficiently quantifying tissue damage in MS

BackgroundWave-CAIPI Visualization of Short Transverse relaxation time component (ViSTa) is a recently developed, short-T1-sensitized MRI method for fast quantification of myelin water fraction (MWF) in the human brain. It represents a promising technique for the evaluation of subtle, early signals of demyelination in the cerebral white matter of multiple sclerosis (MS) patients. Currently however, few studies exist that robustly assess the utility of ViSTa MWF measures of myelin compared to more conventional MRI measures of myelin in the brain of MS patients. Moreover, there are no previous studies evaluating the sensitivity of ViSTa MWF for the non-invasive detection of subtle tissue damage in both normal-appearing white matter (NAWM) and white matter lesions of MS patients. As a result, a central purpose of this study was to systematically evaluate the relationship between myelin sensitivity of T1-based ViSTa MWF mapping and a more generally recognized metric, Magnetization Transfer Saturation (MTsat), in healthy control and MS brain white matter. MethodsViSTa MWF and MTsat values were evaluated in automatically-classified normal appearing white matter (NAWM), white matter (WM) lesion tissue, cortical gray matter, and deep gray matter of 29 MS patients and 10 healthy controls using 3T MRI. MWF and MT sat were also assessed in a tract-specific manner using the Johns Hopkins University WM atlas. MRI-derived measures of cerebral myelin content were uniquely compared by employing non-normal distribution-specific measures of median, interquartile range and skewness. Separate analyses of variance were applied to test tissue-specific differences in MTsat and ViSTa MWF distribution metrics. Non-parametric tests were utilized when appropriate. All tests were corrected for multiple comparisons using the False Discovery Rate method at the level, α=0.05. ResultsDifferences in whole NAWM MS tissue damage were detected with a higher effect size when using ViSTa MWF (q = 0.0008; ƞ2 = 0.34) compared to MTsat (q = 0.02; ƞ2= 0.24). We also observed that, as a possible measure of WM pathology, ViSTa-derived NAWM MWF voxel distributions of MS subjects were consistently skewed towards lower MWF values, while MTsat voxel distributions showed reduced skewness values. We further identified tract-specific reductions in mean ViSTa MWF of MS patients compared to controls that were not observed with MTsat. However, MTsat (q = 1.4 × 10−21; ƞ2 = 0.88) displayed higher effect sizes when differentiating NAWM and MS lesion tissue. Using regression analysis at the group level, we identified a linear relationship between MTsat and ViSTa MWF in NAWM (R2 = 0.46; p = 7.8 × 10−4) lesions (R2 = 0.30; p = 0.004), and with all tissue types combined (R2 = 0.71; p = 8.4 × 10−45). The linear relationship was also observed in most of the WM tracts we investigated. ViSTa MWF in NAWM of MS patients correlated with both disease duration (p = 0.02; R2 = 0.27) and WM lesion volume (p = 0.002; R2 = 0.34). ConclusionBecause ViSTa MWF and MTsat metrics exhibit differential sensitivities to tissue damage in MS white matter, they can be collected in combination to provide an efficient, comprehensive measure of myelin water and macromolecular pool proton signals. These complementary measures may offer a more sensitive, non-invasive biopsy of early precursor signals in NAWM that occur prior to lesion formation. They may also aid in monitoring the efficacy of remyelination therapies.

Myelin water imaging from multi-echo [formula omitted] MR relaxometry data using a joint sparsity constraint

Demyelination is the key pathological process in multiple sclerosis (MS). The extent of demyelination can be quantified with magnetic resonance imaging by assessing the myelin water fraction (MWF). However, long computation times and high noise sensitivity hinder the translation of MWF imaging to clinical practice. In this work, we introduce a more efficient and noise robust method to determine the MWF using a joint sparsity constraint and a pre-computed B1+-T2 dictionary.A single component analysis with this dictionary is used in an initial step to obtain a B1+ map. The T2 distribution is then determined from a reduced dictionary corresponding to the estimated B1+ map using a combination of a non-negativity and a joint sparsity constraint.The non-negativity constraint ensures that a feasible solution with non-negative contribution of each T2 component is obtained. The joint sparsity constraint restricts the T2 distribution to a small set of T2 relaxation times shared between all voxels and reduces the noise sensitivity.The applied Sparsity Promoting Iterative Joint NNLS (SPIJN) algorithm can be implemented efficiently, reducing the computation time by a factor of 50 compared to the commonly used regularized non-negative least squares algorithm. The proposed method was validated in simulations and in 8 healthy subjects with a 3D multi-echo gradient- and spin echo scan at 3 ​T. In simulations, the absolute error in the MWF decreased from 0.031 to 0.013 compared to the regularized NNLS algorithm for SNR ​= ​250. The in vivo results were consistent with values reported in literature and improved MWF-quantification was obtained especially in the frontal white matter. The maximum standard deviation in mean MWF in different regions of interest between subjects was smaller for the proposed method (0.0193) compared to the regularized NNLS algorithm (0.0266). In conclusion, the proposed method for MWF estimation is less computationally expensive and less susceptible to noise compared to state of the art methods. These improvements might be an important step towards clinical translation of MWF measurements.

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T2 decay data.

Multi-compartment T2 mapping has gained particular relevance for the study of myelin water in the brain. As a facilitator of rapid saltatory axonal signal transmission, myelin is a cornerstone indicator of white matter development and function. Regularized non-negative least squares fitting of multi-echo T2 data has been widely employed for the computation of the myelin water fraction (MWF), and the obtained MWF maps have been histopathologically validated. MWF measurements depend upon the quality of the data acquisition, B1+ homogeneity and a range of fitting parameters. In this special issue article, we discuss the relevance of these factors for the accurate computation of multi-compartment T2 and MWF maps. We generated multi-echo spin-echo T2 decay curves following the Carr-Purcell-Meiboom-Gill approach for various myelin concentrations and myelin T2 scenarios by simulating the evolution of the magnetization vector between echoes based on the Bloch equations. We demonstrated that noise and imperfect refocusing flip angles yield systematic underestimations in MWF and intra-/extracellular water geometric mean T2 (gmT2 ). MWF estimates were more stable than myelin water gmT2 time across different settings of the T2 analysis. We observed that the lower limit of the T2 distribution grid should be slightly shorter than TE1 . Both TE1 and the acquisition echo spacing also have to be sufficiently short to capture the rapidly decaying myelin water T2 signal. Among all parameters of interest, the estimated MWF and intra-/extracellular water gmT2 differed by approximately 0.13-4 percentage points and 3-4 ms, respectively, from the true values, with larger deviations observed in the presence of greater B1+ inhomogeneities and at lower signal-to-noise ratio. Tailoring acquisition strategies may allow us to better characterize the T2 distribution, including the myelin water, in vivo.

MR fingerprinting enables quantitative measures of brain tissue relaxation times and myelin water fraction in the first five years of life

Quantitative assessments of normative brain development using MRI are of critical importance to gain insights into healthy neurodevelopment. However, quantitative MR imaging poses significant technical challenges and requires prohibitively long acquisition times, making it impractical for pediatric imaging. This is particularly relevant for healthy subjects, where imaging under sedation is not clinically indicated. MR Fingerprinting (MRF), a novel MR imaging framework, provides rapid, efficient, and simultaneous quantification of multiple tissue properties. In this study, a 2D MR Fingerprinting method was developed that achieves a spatial resolution of 1 × 1 × 3 mm3 with rapid and simultaneous quantification of T1, T2 and myelin water fraction (MWF). Phantom experiments demonstrated that accurate measurements of T1 and T2 relaxation times were achieved over a wide range of T1 and T2 values. MRF images were acquired cross-sectionally from 28 typically developing children, 0 to five years old, who were enrolled in the UNC/UMN Baby Connectome Project. Differences associated with age of R1 (=1/T1), R2 (=1/T2) and MWF were obtained from several predefined white matter regions. Both R1 and R2 exhibit a marked increase until ∼20 months of age, followed by a slower increase for all WM regions. In contrast, the MWF remains at a negligible level until ∼6 months of age for all predefined ROIs and gradually increases afterwards. Depending on the brain region, rapid increases are observed between 6 and 12 months to 6–18 months, followed by a slower pace of increase in MWF. Neither relaxivities nor MWF were significantly different between the left and right hemispheres. However, regional differences in age-related R1 and MWF measures were observed across different white matter regions. In conclusion, our results demonstrate that the MRF technique holds great potential for multi-parametric assessments of normative brain development in early childhood.

Inter-Vendor Reproducibility of Myelin Water Imaging Using a 3D Gradient and Spin Echo Sequence.

Myelin water imaging can be achieved using multicomponent T2 relaxation analysis to quantify in vivo measurement of myelin content, termed the myelin water fraction (MWF). Therefore, myelin water imaging can be a valuable tool to better understand the underlying white matter pathology in demyelinating diseases, such as multiple sclerosis. To apply myelin water imaging in multisite studies and clinical applications, it must be acquired in a clinically feasible scan time (less than 15 min) and be reproducible across sites and scanner vendors. Here, we assessed the reproducibility of MWF measurements in regional and global white matter in 10 healthy human brains across two sites with two different 3 T magnetic resonance imaging scanner vendors (Philips and Siemens), using a 32-echo gradient and spin echo (GRASE) sequence. A strong correlation was found between the MWF measurements in the global white matter (Pearson’s r = 0.91; p < 0.001) for all participants across the two sites. The mean intersite MWF coefficient of variation across participants was 2.77% in the global white matter and ranged from 4.47% (splenium of the corpus callosum) to 17.89% (genu of the corpus callosum) in white matter regions of interest. Bland-Altman analysis showed a good agreement in MWF measurements between the two sites with small bias of 0.002. Overall, MWF estimates were in good agreement across the two sites and scanner vendors. Our findings support the use of quantitative multi-echo T2 relaxation metrics, such as the MWF, in multicenter studies and clinical trials to gain deeper understanding about the pathological processes resulting from the underlying disease progression in neurodegenerative diseases.

Quantitative Ex Vivo MRI Changes due to Progressive Formalin Fixation in Whole Human Brain Specimens: Longitudinal Characterization of Diffusion, Relaxometry, and Myelin Water Fraction Measurements at 3T.

Postmortem MRI can be used to reveal important pathologies and establish radiology-pathology correlations. However, quantitative MRI values are altered by tissue fixation. Therefore, the purpose of this study was to investigate time-dependent effects of formalin fixation on MRI relaxometry (T1 and T2), diffusion tensor imaging (fractional anisotropy, FA; and mean diffusivity, MD), and myelin water fraction (MWF) measurements throughout intact human brain specimens. Two whole, neurologically-healthy human brains were immersed in 10% formalin solution and scanned at 13 time points between 0 and 1,032 h. Whole-brain maps of longitudinal (T1) and transverse (T2) relaxation times, FA, MD, and MWF were generated at each time point to illustrate spatiotemporal changes, and region-of-interest analyses were then performed in eight brain structures to quantify temporal changes with progressive fixation. Although neither of the diffusion measures (FA nor MD) showed significant changes as a function of formalin fixation time, both T1 and T2-relaxation times significantly decreased, and MWF estimates significantly increased with progressive fixation until (and likely beyond) our final measurements were taken at 1,032 h. These results suggest that T1-relaxation, T2-relaxation and MWF estimates must be performed quite early in the fixation process to avoid formalin-induced changes compared to in vivo values; and furthermore, that different ex vivo scans within an experiment must be acquired at consistent (albeit still early) fixation intervals to avoid fixative-related differences between samples. Conversely, ex vivo diffusion measures (FA and MD) appear to depend more on other factors (e.g., pulse sequence optimization, sample temperature, etc.).

Validating myelin water imaging with transmission electron microscopy in a rat spinal cord injury model

Myelin content is an important marker for neuropathology and MRI generated myelin water fraction (MWF) has been shown to correlate well with myelin content. However, because MWF is based on the amount of signal from myelin water, that is, the water trapped between the myelin lipid bilayers, the reading may depend heavily on myelin morphology. This is of special concern when there is a mix of intact myelin and myelin debris, as in the case of injury. To investigate what MWF measures in the presence of debris, we compared MWF to transmission electron microscopy (TEM) derived myelin fraction that measures the amount of compact appearing myelin. A rat spinal cord injury model was used with time points at normal (normal myelin), 3 weeks post-injury (myelin debris), and 8 weeks post-injury (myelin debris, partially cleared). The myelin period between normal and 3 or 8 weeks post-injury cords did not differ significantly, suggesting that as long as the bilayer structure is intact, myelin debris has the same water content as intact myelin. The MWF also correlated strongly with the TEM-derived myelin fraction, suggesting that MWF measures the amount of compact appearing myelin in both intact myelin and myelin debris. From the TEM images, it appears that as myelin degenerates, it tends to form large watery spaces within the myelin sheaths that are not classified as myelin water. The results presented in this study improve our understanding and allows for better interpretation of MWF in the presence of myelin debris.

Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping

The elaboration of the myelinated white matter is essential for normal neurodevelopment, establishing and mediating rapid communication pathways throughout the brain. These pathways facilitate the synchronized communication required for higher order behavioral and cognitive functioning. Altered neural messaging (or ‘disconnectivity’) arising from abnormal white matter and myelin development may underlie a number of neurodevelopmental psychiatric disorders. Despite the vital role myelin plays, few imaging studies have specifically examined its maturation throughout early infancy and childhood. Thus, direct investigations of the relationship(s) between evolving behavioral and cognitive functions and the myelination of the supporting neural systems have been sparse. Further, without knowledge of the ‘normative’ developmental time-course, identification of early abnormalities associated with developmental disorders remains challenging. In this work, we examined the use of longitudinal (T1) and transverse (T2) relaxation time mapping, and myelin water fraction (MWF) imaging to investigate white matter and myelin development in 153 healthy male and female children, 3 months through 60 months in age. Optimized age-specific acquisition protocols were developed using the DESPOT and mcDESPOT imaging techniques; and mean T1, T2 and MWF trajectories were determined for frontal, temporal, occipital, parietal and cerebellar white matter, and genu, body and splenium of the corpus callosum. MWF results provided a spatio-temporal pattern in-line with prior histological studies of myelination. Comparison of T1, T2 and MWF measurements demonstrates dissimilar sensitivity to tissue changes associated with neurodevelopment, with each providing differential but complementary information.