So You Want to Image Myelin Using MRI: An Overview and Practical Guide for Myelin Water Imaging.

Myelin water imaging (MWI) is an MRI imaging biomarker for myelin. This method can generate an in vivo whole-brain myelin water fraction map in approximately 10 minutes. It has been applied in various applications including neurodegenerative disease, neurodevelopmental, and neuroplasticity studies. In this review we start with a brief introduction of myelin biology and discuss the contributions of myelin in conventional MRI contrasts. Then the MRI properties of myelin water and four different MWI methods, which are categorized as T2 -, T2 *-, T1 -, and steady-state-based MWI, are summarized. After that, we cover more practical issues such as availability, interpretation, and validation of these methods. To illustrate the utility of MWI as a clinical research tool, MWI studies for two diseases, multiple sclerosis and neuromyelitis optica, are introduced. Additional topics about imaging myelin in gray matter and non-MWI methods for myelin imaging are also included. Although technical and physiological limitations exist, MWI is a potent surrogate biomarker of myelin that carries valuable and useful information of myelin. Evidence Level: 5 Technical Efficacy: 1 J. MAGN. RESON. IMAGING 2021;53:360-373.

Quantitative age-dependent differences in human brainstem myelination assessed using high-resolution magnetic resonance mapping.

Previous in-vivo magnetic resonance imaging (MRI)-based studies of age-related differences in the human brainstem have focused on volumetric morphometry. These investigations have provided pivotal insights into regional brainstem atrophy but have not addressed microstructural age differences. However, growing evidence indicates the sensitivity of quantitative MRI to microstructural tissue changes in the brain. These studies have largely focused on the cerebrum, with very few MR investigations addressing age-dependent differences in the brainstem, in spite of its central role in the regulation of vital functions. Several studies indicate early brainstem alterations in a myriad of neurodegenerative diseases and dementias. The paucity of MR-focused investigations is likely due in part to the challenges imposed by the small structural scale of the brainstem itself as well as of substructures within, requiring accurate high spatial resolution imaging studies. In this work, we applied our recently developed approach to high-resolution myelin water fraction (MWF) mapping, a proxy for myelin content, to investigate myelin differences with normal aging within the brainstem. In this cross-sectional investigation, we studied a large cohort (n = 125) of cognitively unimpaired participants spanning a wide age range (21-94 years) and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. We believe that this study is the first investigation of MWF differences with normative aging in the adult brainstem. Further, our results provide reference MWF values.

Nonlinear associations of neurite density and myelin content with age revealed using multicomponent diffusion and relaxometry magnetic resonance imaging.

Most magnetic resonance imaging (MRI) studies investigating the relationship between regional brain myelination or axonal density and aging have relied upon nonspecific methods to probe myelin and axonal content, including diffusion tensor imaging and relaxation time mapping. While these studies have provided pivotal insights into changes in cerebral architecture with aging and pathology, details of the underlying microstructural alterations have not been fully elucidated. In the current study, we used the BMC-mcDESPOT analysis, a direct and specific multicomponent relaxometry method for imaging of myelin water fraction (MWF), a marker of myelin content, and NODDI, an emerging multicomponent diffusion technique, for neurite density index (NDI) imaging, a proxy of axonal density. We investigated age-related differences in MWF and NDI in several white matter brain regions in a cohort of cognitively unimpaired participants over a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by a decrease at older ages, in agreement with previous work. We found a similarly complex regional association between NDI and age, with several cerebral structures also exhibiting a quadratic, inverted U-shape, relationship. This novel observation suggests an increase in axonal density until the fourth decade of age followed by a rapid loss at older ages. We also observed that these age-related differences in MWF and NDI vary across different brain regions, as expected. Finally, our study indicates no significant association between MWF and NDI in most cerebral structures investigated, although this association approached significance in a limited number of brain regions, indicating the complementary nature of their information and encouraging further investigation. Overall, we find evidence of nonlinear associations between age and myelin or axonal density in a sample of well-characterized adults, using direct myelin and axonal content imaging methods.

Virtual histology of multi-modal magnetic resonance imaging of cerebral cortex in young men.

Neurobiology underlying inter-regional variations - across the human cerebral cortex - in measures derived with multi-modal magnetic resonance imaging (MRI) is poorly understood. Here, we characterize inter-regional variations in a large number of such measures, including T1 and T2 relaxation times, myelin water fraction (MWF), T1w/T2w ratio, mean diffusivity (MD), fractional anisotropy (FA), magnetization transfer ratio (MTR) and cortical thickness. We then employ a virtual-histology approach and relate these inter-regional profiles to those in cell-specific gene expression. Virtual histology revealed that most MRI-derived measures, including T1, T2 relaxation time, MWF, T1w/T2w ratio, MTR, FA and cortical thickness, are associated with expression profiles of genes specific to CA1 pyramidal cells; these genes are enriched in biological processes related to dendritic arborisation. In addition, T2 relaxation time, MWF and T1w/T2w ratio are associated with oligodendrocyte-specific gene-expression profiles, supporting their use as measures sensitive to intra-cortical myelin. MWF contributes more variance than T1w/T2w ratio to the mean oligodendrocyte expression profile, suggesting greater sensitivity to myelin. These cell-specific MRI associations may help provide a framework for determining which MRI sequences to acquire in studies with specific neurobiological hypotheses.

Longitudinal white matter and cognitive development in pediatric carriers of the apolipoprotein ε4 allele.

We have previously demonstrated cross-sectional differences in magnetic resonance imaging (MRI) measurements of white matter myelin and gray matter in infants with or without the apolipoprotein ε4 allele, a major genetic risk factor for late-onset Alzheimer's disease (AD). In this study, we sought to compare longitudinal MRI white matter myelin and cognitive-behavioral changes in infants and young children with and without this allele. Serial MRI and cognitive tests were obtained on 223 infants and young children, including 74 ε4 carriers and 149 non-carriers, 2-68 months of age, matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated brain mapping algorithms and non-linear mixed models were used to characterize and compare trajectories of white matter myelin and cognitive-behavioral test scores. The APOE ε4 carriers had statistically significant differences in white matter myelin development, in the uncinate fasciculus, temporal lobe, internal capsule and occipital lobe. Additionally, ε4 carriers had a slightly greater rate of development in early learning composite a surrogate measure of IQ representative of expressive language, receptive language, fine motor, and visual skills, but displayed slightly lower non verbal development quotient scores a composite measure of fine motor and visual skills across the entire age range. This study supports the possibility that ε4 carriers have slightly altered rates of white matter and cognitive development in childhood. It continues to raise questions about the role of APOE in human brain development and the relevance of these developmental differences to the predisposition to AD.

Inherent and unpredictable bias in multi-component DESPOT myelin water fraction estimation.

Multicomponent driven equilibrium steady-state observation of T1 and T2 (mcDESPOT) aims to quantify the Myelin Water Fraction (MWF) using a two-pool microstructural model. The MWF has been used to track neurodevelopment and neurodegeneration and has been histologically correlated to myelin content. mcDESPOT has a clinically feasible acquisition time and high signal-to-noise ratio (SNR) relative to other MWF techniques. However, disagreement exists in the literature between experimental studies that show MWF maps with plausible grey matter-white matter (GM-WM) contrast and theoretical work that questions the accuracy and precision of mcDESPOT. We demonstrate that mcDESPOT parameter estimation is inaccurate and imprecise if intercompartmental exchange is included in the microstructural model, but that significant bias results if exchange is neglected. The source of apparent MWF contrast is likely due to the complex convergence behaviour of the Stochastic Region Contraction (SRC) method commonly used to fit the mcDESPOT model. mcDESPOT-derived parameter estimates are hence not directly relatable to the underlying microstructural model and are only comparable to others using similar acquisition schemes and fitting constraints.

A comparison of inhomogeneous magnetization transfer, myelin volume fraction, and diffusion tensor imaging measures in healthy children.

Sensitive and specific biomarkers of myelin can help define baseline brain health and development, identify and monitor disease pathology, and evaluate response to treatment where myelin content is affected. Diffusion measures such as radial diffusivity (RD) are commonly used to assess myelin content, but are not specific to myelin. Inhomogeneous magnetization transfer (ihMT) and multicomponent driven equilibrium single-pulse observation of T1 and T2 (mcDESPOT) offer quantitative parameters (qihMT and myelin volume fraction/VFm, respectively) which are suggested to have improved sensitivity to myelin. We compared RD, qihMT, and VFm in a cohort of 23 healthy children aged 8-13 years to evaluate the similarities and differences across these measures. All 3 measures were significantly related across brain voxels, but VFm and qihMT were significantly more strongly correlated (qihMT-VFm r = 0.89) than either measure was with RD (RD-qihMT r = -0.66, RD-VFm r = -0.74; all p < 0.001). Mean parameters differed in several regions, especially in subcortical gray matter. These differences can likely be explained by unique sensitivities of each measure to non-myelin factors, such as crossing fiber geometry, axonal packing, fiber orientation, glial density, or magnetization transfer effects in a voxel. We also observed an orientation dependence of qihMT in white matter, such that qihMT decreased as fiber orientation went from parallel to perpendicular to B0. All measures appear to be sensitive to myelin content, though qihMT and VFm appear to be more specific to it than RD. Scan time, noise tolerance, and resolution requirements may inform researchers of the appropriate measure to choose for a specific application.

Improved determination of the myelin water fraction in human brain using magnetic resonance imaging through Bayesian analysis of mcDESPOT.

Myelin water fraction (MWF) mapping with magnetic resonance imaging has led to the ability to directly observe myelination and demyelination in both the developing brain and in disease. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) has been proposed as a rapid approach for multicomponent relaxometry and has been applied to map MWF in the human brain. However, even for the simplest two-pool signal model consisting of myelin-associated and non-myelin-associated water, the dimensionality of the parameter space for obtaining MWF estimates remains high. This renders parameter estimation difficult, especially at low-to-moderate signal-to-noise ratios (SNRs), due to the presence of local minima and the flatness of the fit residual energy surface used for parameter determination using conventional nonlinear least squares (NLLS)-based algorithms. In this study, we introduce three Bayesian approaches for analysis of the mcDESPOT signal model to determine MWF. Given the high-dimensional nature of the mcDESPOT signal model, and, therefore the high-dimensional marginalizations over nuisance parameters needed to derive the posterior probability distribution of the MWF, the Bayesian analyses introduced here use different approaches to reduce the dimensionality of the parameter space. The first approach uses normalization by average signal amplitude, and assumes that noise can be accurately estimated from signal-free regions of the image. The second approach likewise uses average amplitude normalization, but incorporates a full treatment of noise as an unknown variable through marginalization. The third approach does not use amplitude normalization and incorporates marginalization over both noise and signal amplitude. Through extensive Monte Carlo numerical simulations and analysis of in vivo human brain datasets exhibiting a range of SNR and spatial resolution, we demonstrated markedly improved accuracy and precision in the estimation of MWF using these Bayesian methods as compared to the stochastic region contraction (SRC) implementation of NLLS.

Analysis of mcDESPOT- and CPMG-derived parameter estimates for two-component nonexchanging systems.

PURPOSE: To compare the reliability and stability of the multicomponent-driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) and Carl-Purcell-Meiboom-Gill (CPMG) approaches to parameter estimation. METHODS: The stability and reliability of mcDESPOT and CPMG-derived parameter estimates were compared through examination of energy surfaces, evaluation of model sloppiness, and Monte Carlo simulations. Comparisons were performed on an equal time basis and assuming a two-component system. Parameter estimation bias, reflecting accuracy, and dispersion, reflecting precision, were derived for a range of signal-to-noise ratios (SNRs) and relaxation parameters. RESULTS: The energy surfaces for parameters incorporated into the mcDESPOT signal model exhibit flatness, a complex structure of local minima, and instability to noise to a much greater extent than the corresponding surfaces for CPMG. Although both mcDESPOT and CPMG performed well at high SNR, the CPMG approach yielded parameter estimates of considerably greater accuracy and precision at lower SNR. CONCLUSION: mcDESPOT and CPMG both permit high-quality parameter estimates under SNR that are clinically achievable under many circumstances, depending upon available hardware and resolution and acquisition time constraints. At moderate to high SNR, the mcDESPOT approach incorporating two-step phase increments can yield accurate parameter estimates while providing values for longitudinal relaxation times that are not available through CPMG. However, at low SNR, the CPMG approach is more stable and provides superior parameter estimates. Magn Reson Med 75:2406-2420, 2016. © 2015 Wiley Periodicals, Inc.

Advanced neuroimaging to quantify myelin in vivo: Application to mild TBI.

BACKGROUND: Difficulty providing accurate diagnosis and prognosis, especially after mild forms of traumatic brain injury (TBI), has increased efforts to detect changes in white matter microstructure using advanced neuroimaging techniques. Although methods such as diffusion tensor imaging (DTI) have greatly increased knowledge of white matter changes resulting from TBI, several shortcomings limit the utility of these techniques particularly when applied to populations with mild TBI (mTBI) history. In vivo imaging of myelin may be particularly well suited to detect changes in white matter microstructure resulting from mTBI. REVIEW: This manuscript will briefly review the animal and histological data supporting the important role of myelin following TBI, contributions and shortcomings of the use of diffusion tensor imaging (DTI) in mild TBI and the utility of multi-component relaxometry (MCR) techniques as a method for improved visualizing of white matter microstructural integrity in myelin. CONCLUSION: The use of MCR-based techniques has potential as a clinical and research tool to assess and track changes in myelin as well as the common behavioural changes such as slowed processing speed following TBI.

Incorporation of nonzero echo times in the SPGR and bSSFP signal models used in mcDESPOT.

PURPOSE: To analyze the effect of neglecting nonzero echo times (TEs) in the conventional model of multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). THEORY AND METHODS: Formulations of the two-component spoiled gradient recalled echo (SPGR) and balanced steady state free precession (bSSFP) models that incorporate nonzero TE effects are presented in the context of mcDESPOT and compared with the conventionally used SPGR and bSSFP models which ignore nonzero TEs. Relative errors in derived parameter estimates from conventional mcDESPOT, omitting TE effects, are assessed using simulations over a wide range of experimental and sample parameters. RESULTS: The neglect of nonzero TE leads to an overestimate of the SPGR signal and an underestimate of the bSSFP signal. These effects can introduce large errors in parameter estimates derived from conventional mcDESPOT under realistic imaging conditions. CONCLUSION: SPGR and bSSFP signal models accounting for nonzero TE effects should be incorporated into quantitative mcDESPOT analyses.

Comparison of myelin water fraction from multiecho T2 decay curve and steady-state methods.

PURPOSE: Myelin water fraction is conventionally measured from the T2 decay curve. Recently, a steady-state approach entitled multicomponent-driven equilibrium single pulse observation of T1 /T2 (mcDESPOT) was employed for myelin water fraction mapping. However, no direct comparison between the established multiecho T2 relaxation method and mcDESPOT has been performed. METHODS: Gradient and spin echo (GRASE) acquired T2 decay curve and mcDESPOT measurements were acquired from 10 healthy volunteers using a 3T MRI. We compared myelin water fraction, transmit radio frequency field (B1 ), and T2 's of intra- and extracellular water obtained from both methods. RESULTS: For all brain regions examined, myelin water fractions from mcDESPOT were significantly higher than those from multiecho GRASE. B1 maps were qualitatively similar between GRASE and mcDESPOT, but multicomponent T2 times were significantly different. To investigate the effect of exchange, mcDESPOT data were analyzed with and without exchange. When exchange was turned off, intra- and extracellular T2 times from mcDESPOT were roughly consistent with GRASE results; however, myelin water fractions derived from mcDESPOT were still significantly higher than those derived from GRASE. CONCLUSION: Myelin water fraction values derived from mcDESPOT cannot be considered to be equivalent to those derived from T2 decay curve approaches.

Breastfeeding and early white matter development: A cross-sectional study.

Does breastfeeding alter early brain development? The prevailing consensus from large epidemiological studies posits that early exclusive breastfeeding is associated with improved measures of IQ and cognitive functioning in later childhood and adolescence. Prior morphometric brain imaging studies support these findings, revealing increased white matter and sub-cortical gray matter volume, and parietal lobe cortical thickness, associated with IQ, in adolescents who were breastfed as infants compared to those who were exclusively formula-fed. Yet it remains unknown when these structural differences first manifest and when developmental differences that predict later performance improvements can be detected. In this study, we used quiet magnetic resonance imaging (MRI) scans to compare measures of white matter microstructure (mcDESPOT measures of myelin water fraction) in 133 healthy children from 10 months through 4 years of age, who were either exclusively breastfed a minimum of 3 months; exclusively formula-fed; or received a mixture of breast milk and formula. We also examined the relationship between breastfeeding duration and white matter microstructure. Breastfed children exhibited increased white matter development in later maturing frontal and association brain regions. Positive relationships between white matter microstructure and breastfeeding duration are also exhibited in several brain regions, that are anatomically consistent with observed improvements in cognitive and behavioral performance measures. While the mechanisms underlying these structural differences remains unclear, our findings provide new insight into the earliest developmental advantages associated with breastfeeding, and support the hypothesis that breast milk constituents promote healthy neural growth and white matter development.

Accelerating MR parameter mapping using sparsity-promoting regularization in parametric dimension.

MR parameter mapping requires sampling along additional (parametric) dimension, which often limits its clinical appeal due to a several-fold increase in scan times compared to conventional anatomic imaging. Data undersampling combined with parallel imaging is an attractive way to reduce scan time in such applications. However, inherent SNR penalties of parallel MRI due to noise amplification often limit its utility even at moderate acceleration factors, requiring regularization by prior knowledge. In this work, we propose a novel regularization strategy, which uses smoothness of signal evolution in the parametric dimension within compressed sensing framework (p-CS) to provide accurate and precise estimation of parametric maps from undersampled data. The performance of the method was demonstrated with variable flip angle T1 mapping and compared favorably to two representative reconstruction approaches, image space-based total variation regularization and an analytical model-based reconstruction. The proposed p-CS regularization was found to provide efficient suppression of noise amplification and preservation of parameter mapping accuracy without explicit utilization of analytical signal models. The developed method may facilitate acceleration of quantitative MRI techniques that are not suitable to model-based reconstruction because of complex signal models or when signal deviations from the expected analytical model exist.

REUSED: A deep neural network method for rapid whole-brain high-resolution myelin water fraction mapping from extremely under-sampled MRI.

Changes in myelination are a cardinal feature of brain development and the pathophysiology of several central nervous system diseases, including multiple sclerosis and dementias. Advanced magnetic resonance imaging (MRI) methods have been developed to probe myelin content through the measurement of myelin water fraction (MWF). However, the prolonged data acquisition and post-processing times of current MWF mapping methods pose substantial hurdles to their clinical implementation. Recently, fast steady-state MRI sequences have been implemented to produce high-spatial resolution whole-brain MWF mapping within ∼20 min. Despite the subsequent significant advances in the inversion algorithm to derive MWF maps from steady-state MRI, the high-dimensional nature of such inversion does not permit further reduction of the acquisition time by data under-sampling. In this work, we present an unprecedented reduction in the computation (∼30 s) and the acquisition time (∼7 min) required for whole-brain high-resolution MWF mapping through a new Neural Network (NN)-based approach, named NN-Relaxometry of Extremely Under-SamplEd Data (NN-REUSED). Our analyses demonstrate virtually similar accuracy and precision in derived MWF values using NN-REUSED compared to results derived from the fully sampled reference method. The reduction in the acquisition and computation times represents a breakthrough toward clinically practical MWF mapping.

Adult brain aging investigated using BMC-mcDESPOT-based myelin water fraction imaging.

The relationship between regional brain myelination and aging has been the subject of intense study, with magnetic resonance imaging perhaps the most effective modality for elucidating this. However, most of these studies have used nonspecific methods to probe myelin content, including diffusion tensor imaging, magnetization transfer ratio, and relaxation times. In the present study, we used the BMC-mcDESPOT analysis, a direct and specific method for imaging of myelin water fraction (MWF), a surrogate of myelin content. We investigated age-related differences in MWF in several brain regions in a large cohort of cognitively unimpaired participants, spanning a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by decreases at older ages. We also observed that these age-related differences vary across different brain regions, as expected. Our results provide evidence for nonlinear associations between age and myelin in a large sample of well-characterized adults, using a direct myelin content imaging method.

Multi-component relaxation in clinically isolated syndrome: Lesion myelination may predict multiple sclerosis conversion.

We performed a longitudinal case-control study on patients with clinically isolated syndrome (CIS) with the aid of quantitative whole-brain myelin imaging. The aim was (1) to parse early myelin decay and to break down its distribution pattern, and (2) to identify an imaging biomarker of the conversion into clinically definite Multiple Sclerosis (MS) based on in vivo measurable changes of myelination. Imaging and clinical data were collected immediately after the onset of first neurological symptoms and follow-up explorations were performed after 3, 6, and, 12 months. The multi-component Driven Equilibrium Single Pulse Observation of T1/T2 (mcDESPOT) was applied to obtain the volume fraction of myelin water (MWF) in different white matter (WM) regions at every time-point. This measure was subjected to further voxel-based analysis with the aid of a comparison of the normal distribution of myelination measures with an age and sex matched healthy control group. Both global and focal relative myelination content measures were retrieved. We found that (1) CIS patients at the first clinical episode suggestive of MS can be discriminated from healthy control WM conditions (p < 0.001) and therewith reproduced our earlier findings in late CIS, (2) that deficient myelination in the CIS group increased in T2 lesion depending on the presence of gadolinium enhancement (p < 0.05), and (3) that independently the CIS T2 lesion relative myelin content provided a risk estimate of the conversion to clinically definite MS (Odds Ratio 2.52). We initially hypothesized that normal appearing WM myelin loss may determine the severity of early disease and the subsequent risk of clinically definite MS development. However, in contrast we found that WM lesion myelin loss was pivotal for MS conversion. Regional myelination measures may thus play an important role in future clinical risk stratification.

Traveling Slow Oscillations During Sleep: A Marker of Brain Connectivity in Childhood.

Slow oscillations, a defining characteristic of the nonrapid eye movement sleep electroencephalogram (EEG), proliferate across the scalp in highly reproducible patterns. In adults, the propagation of slow oscillations is a recognized fingerprint of brain connectivity and excitability. In this study, we (1) describe for the first time maturational features of sleep slow oscillation propagation in children (n = 23; 2-13 years) using high-density (hd) EEG and (2) examine associations between sleep slow oscillatory propagation characteristics (ie, distance, traveling speed, cortical involvement) and white matter myelin microstructure as measured with multicomponent Driven Equilibrium Single Pulse Observation of T1 and T2-magnetic resonance imaging (mcDESPOT-MRI). Results showed that with increasing age, slow oscillations propagated across longer distances (average growth of 0.2 cm per year; R(21) = 0.50, p < .05), while traveling speed and cortical involvement (ie, slow oscillation expanse) remained unchanged across childhood. Cortical involvement (R(20) = 0.44) and slow oscillation speed (R(20) = -0.47; both p < .05, corrected for age) were associated with myelin content in the superior longitudinal fascicle, the largest anterior-posterior, intrahemispheric white matter connectivity tract. Furthermore, slow oscillation distance was moderately associated with whole-brain (R(21) = 0.46, p < .05) and interhemispheric myelin content, the latter represented by callosal myelin water fraction (R(21) = 0.54, p < .01, uncorrected). Thus, we demonstrate age-related changes in slow oscillation propagation distance, as well as regional associations between brain activity during sleep and the anatomical connectivity of white matter microstructure. Our findings make an important contribution to knowledge of the brain connectome using a noninvasive and novel analytic approach. These data also have implications for understanding the emergence of neurodevelopmental disorders and the role of sleep in brain maturation trajectories.

Increased Sleep Depth in Developing Neural Networks: New Insights from Sleep Restriction in Children.

Brain networks respond to sleep deprivation or restriction with increased sleep depth, which is quantified as slow-wave activity (SWA) in the sleep electroencephalogram (EEG). When adults are sleep deprived, this homeostatic response is most pronounced over prefrontal brain regions. However, it is unknown how children's developing brain networks respond to acute sleep restriction, and whether this response is linked to myelination, an ongoing process in childhood that is critical for brain development and cortical integration. We implemented a bedtime delay protocol in 5- to 12-year-old children to obtain partial sleep restriction (1-night; 50% of their habitual sleep). High-density sleep EEG was assessed during habitual and restricted sleep and brain myelin content was obtained using mcDESPOT magnetic resonance imaging. The effect of sleep restriction was analyzed using statistical non-parametric mapping with supra-threshold cluster analysis. We observed a localized homeostatic SWA response following sleep restriction in a specific parieto-occipital region. The restricted/habitual SWA ratio was negatively associated with myelin water fraction in the optic radiation, a developing fiber bundle. This relationship occurred bilaterally over parieto-temporal areas and was adjacent to, but did not overlap with the parieto-occipital region showing the most pronounced homeostatic SWA response. These results provide evidence for increased sleep need in posterior neural networks in children. Sleep need in parieto-temporal areas is related to myelin content, yet it remains speculative whether age-related myelin growth drives the fading of the posterior homeostatic SWA response during the transition to adulthood. Whether chronic insufficient sleep in the sensitive period of early life alters the anatomical generators of deep sleep slow-waves is an important unanswered question.

Brain and cord myelin water imaging: a progressive multiple sclerosis biomarker.

OBJECTIVES: Conventional magnetic resonance imaging (MRI) is used to diagnose and monitor inflammatory disease in relapsing remitting (RR) multiple sclerosis (MS). In the less common primary progressive (PP) form of MS, in which focal inflammation is less evident, biomarkers are still needed to enable evaluation of novel therapies in clinical trials. Our objective was to characterize the association - across the brain and cervical spinal cord - between clinical disability measures in PPMS and two potential biomarkers (one for myelin, and one for atrophy, both resulting from the same imaging technique). METHODS: Multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) MRI of the brain and cervical spinal cord were obtained for 15 PPMS patients and 11 matched controls. Data were analysed to estimate the signal related to myelin water (VFM), as well as volume measurements. MS disability was assessed using the Multiple Sclerosis Functional Composite score, which includes measures of cognitive processing (Paced Auditory Serial Addition Test), manual dexterity (9-Hole Peg Test) and ambulatory function (Timed 25-Foot Walk); and the Expanded Disability Status Scale. RESULTS: Brain and spinal cord volumes were different in PPMS compared to controls, particularly ventricular (+ 46%, p = 0.0006) and cervical spinal cord volume (- 16%, p = 0.0001). Brain and spinal cord myelin (VFM) were also reduced in PPMS (brain: - 11%, p = 0.01; spine: - 19%, p = 0.000004). Cognitive processing correlated with brain ventricular volume (p = 0.009). Manual dexterity correlated with brain ventricular volume (p = 0.007), and both brain and spinal cord VFM (p = 0.01 and 0.06, respectively). Ambulation correlated with spinal cord volume (p = 0.04) and spinal cord VFM (p = 0.04). INTERPRETATION: In this study we demonstrated that mcDESPOT can be used to measure myelin and atrophy in the brain and spinal cord. Results correlate well with clinical disability scores in PPMS representing cognitive, fine motor and ambulatory disability.