Myelin Mapping Research Articles

A human brain atlas of χ-separation for normative iron and myelin distributions.

Iron and myelin are primary susceptibility sources in the human brain. These substances are essential for a healthy brain, and their abnormalities are often related to various neurological disorders. Recently, an advanced susceptibility mapping technique, which is referred to as χ-separation (pronounced as "chi"-separation), has been proposed, successfully disentangling paramagnetic iron from diamagnetic myelin. This method provided a new opportunity for generating high-resolution iron and myelin maps of the brain. Utilizing this technique, this study constructs a normative χ-separation atlas from 106 healthy human brains. The resulting atlas provides detailed anatomical structures associated with the distributions of iron and myelin, clearly delineating subcortical nuclei, thalamic nuclei, and white matter fiber bundles. Additionally, susceptibility values in a number of regions of interest are reported along with age-dependent changes. This atlas may have direct applications such as localization of subcortical structures for deep brain stimulation or high-intensity focused ultrasound and also serve as a valuable resource for future research.

Q‐Space Myelin Map: A new myelin‐specific imaging technique for treatment monitoring of multiple sclerosis

AbstractObjectivesIn multiple sclerosis (MS) patients, hyperintense signals on T2‐weighted images by magnetic resonance imaging are signs of demyelination; however, T2 signals lack specificity and fail to detect remyelination. For more precise monitoring of MS, a new magnetic resonance imaging technique, q‐space Myelin Map (qMM), which specifically identifies myelin, has been developed. This study aimed to explore clinical factors associated with remyelination for different disease‐modifying drugs, and to examine the utility and feasibility of qMM in clinical practice.MethodsData from sequential patients with relapsing–remitting MS initiating disease‐modifying drugs at our center were collected. After treatment initiation, qMM was carried out at 6‐month intervals and the resulting images analyzed for evidence of remyelination.ResultsA total of 48 patients with relapsing–remitting MS were included: 22 with dimethyl fumarate, 14 with fingolimod, four with glatiramer acetate and eight with natalizumab. qMM showed qMM‐remyelination in 22 patients (45.8%). In natalizumab patients, baseline ages were 33.6 ± 6.9 years (n = 5) and 47.3 ± 5.8 years (n = 3) in patients with or without qMM remyelination, respectively. In dimethyl fumarate patients, the proportion of women was 100% (n = 10) and 50% (n = 12) in patients with or without qMM myelination, respectively.ConclusionsThis exploratory study suggested the potential clinical utility of qMM for visualizing remyelination in MS patients and fine‐tuning their pharmacotherapy. Two potential clinical factors promoting qMM‐remyelination were identified: female sex with dimethyl fumarate and younger baseline age with natalizumab; a larger prospective study is warranted to confirm these results.

Multiparametric Characterization and Spatial Distribution of Different MS Lesion Phenotypes.

MS lesions exhibit varying degrees of axonal and myelin damage. A comprehensive description of lesion phenotypes could contribute to an improved radiologic evaluation of smoldering inflammation and remyelination processes. This study aimed to identify in vivo distinct MS lesion types using quantitative susceptibility mapping and susceptibility mapping-weighted imaging and to characterize them through T1-relaxometry, myelin mapping, and diffusion MR imaging. The spatial distribution of lesion phenotypes in relation to ventricular CSF was investigated. MS lesions of 53 individuals were categorized into iso- or hypointense lesions, hyperintense lesions, and paramagnetic rim lesions, on the basis of their appearance on quantitative susceptibility mapping alone, according to published criteria, and with the additional support of susceptibility mapping-weighted imaging. Susceptibility values, T1-relaxation times, myelin and free water fractions, intracellular volume fraction, and the orientation dispersion index were compared among lesion phenotypes. The distance of the geometric center of each lesion from the ventricular CSF was calculated. Eight hundred ninety-six MS lesions underwent the categorization process using quantitative susceptibility mapping and susceptibility mapping-weighted imaging. The novel use of susceptibility mapping-weighted images, which revealed additional microvasculature details, led us to re-allocate several lesions to different categories, resulting in a 35.6% decrease in the number of paramagnetic rim lesions, a 22.5% decrease in hyperintense lesions, and a 17.2% increase in iso- or hypointense lesions, with respect to the categorization based on quantitative susceptibility mapping only. The outcome of the categorization based on the joint use of quantitative susceptibility mapping and susceptibility mapping-weighted imaging was that 44.4% of lesions were iso- or hypointense lesions, 47.9% were hyperintense lesions, and 7.7% were paramagnetic rim lesions. A worsening gradient was observed from iso- or hypointense lesions to hyperintense lesions to paramagnetic rim lesions in T1-relaxation times, myelin water fraction, free water fraction, and intracellular volume fraction. Paramagnetic rim lesions were located closer to ventricular CSF than iso- or hypointense lesions. The volume of hyperintense lesions was associated with a more severe disease course. Quantitative susceptibility mapping and susceptibility mapping-weighted imaging allow in vivo classification of MS lesions into different phenotypes, characterized by different levels of axonal and myelin loss and spatial distribution. Hyperintense lesions and paramagnetic rim lesions, which have the most severe microstructural damage, were more often observed in the periventricular WM and were associated with a more severe disease course.

Intracortical Myelin in Youths at Risk for Depression

BackgroundMajor depressive disorder (MDD) is a leading cause of disability. To understand why depression develops, it is important to distinguish between early neural markers of vulnerability that precede the onset of MDD and features that develop during depression. Recent neuroimaging findings suggest that reduced global and regional intracortical myelination (ICM), especially in the lateral prefrontal cortex, may be associated with depression, but it is unknown whether it is a precursor or a consequence of MDD. The study of offspring of affected parents offers the opportunity to distinguish between precursors and consequences by examining individuals who carry high risk at a time when they have not experienced depression. MethodsWe acquired 129 T1-weighted and T2-weighted scans from 56 (25 female) unaffected offspring of parents with depression and 114 scans from 63 (34 female) unaffected offspring of parents without a history of depression (ages 9 to 16 years). To assess scan quality, we calculated test-retest reliability. We used the scan ratios to calculate myelin maps for 68 cortical regions. We analyzed data using mixed-effects modeling. ResultsICM did not differ between high and low familial risk youths in global (B = 0.06, SE = 0.03, p = .06) or regional (B = 0.05, SE = 0.03, p = .08) analyses. Our pediatric sample had high ICM reliability (intraclass correlation coefficient = 0.79; 95% CI, 0.55–0.88). ConclusionsBased on our results, reduced ICM does not appear to be a precursor of MDD. Future studies should examine ICM in familial high-risk youths across a broad developmental period.

Role of hierarchical heterogeneity in shaping seizure onset dynamics: Insights from structurally-based whole-brain dynamical network models

The brain is a highly complex network system exhibiting nonlinear dynamics, and alterations in brain structure may give rise to pathological brain dynamics such as seizures. Recent efforts in whole-brain network modeling have provided a framework of integrating subject data with nonlinear dynamical models for reproducing empirically observed phenomenon. A question remaining largely unexplored is how the structure of brain network system support and affect seizure-like dynamics. In this paper, we simulate seizures using a structurally-based whole-brain dynamical model of coupled oscillators operating in the bistable regime, and seizure onset likelihood is quantified by the escape time for nodes to transit from background to oscillatory seizure state. Based on this model, the effect of spatial heterogeneity in brain regions on seizure onset dynamics is explored. Specifically, magnetic resonance imaging derived T1w/T2w myelin map is used to parameterize the model with biologically-relevant spatial heterogeneity that approximates structural hierarchy in the human cortex. The unique shaping effect of hierarchical heterogeneity on seizure onset dynamics is demonstrated through comparisons with surrogate models where the spatial order of heterogeneity is altered. We find that hierarchical heterogeneity could most effectively impede the propagation of excitation across brain networks. It may also improve the model’s capacity to better characterize latent seizure focus as observed clinically and to personalize for epilepsy patients. The robustness of results is demonstrated using an alternative way of representing spatial heterogeneity and a higher resolution of representing brain regions. Our findings highlight the significant role of hierarchical heterogeneity as a relevant mechanism of ictogenesis and its importance to be considered in the workflow of whole-brain modeling for epilepsy patients, which are fundamental to understanding the dynamical nature of the brain system and developing personalized treatments for epilepsy patients.

In Vivo Myelin Water Quantification Using Diffusion–Relaxation Correlation MRI: A Comparison of 1D and 2D Methods

Multidimensional Magnetic Resonance Imaging (MRI) is a versatile tool for microstructure mapping. We use a diffusion weighted inversion recovery spin echo (DW-IR-SE) sequence with spiral readouts at ultra-strong gradients to acquire a rich diffusion–relaxation data set with sensitivity to myelin water. We reconstruct 1D and 2D spectra with a two-step convex optimization approach and investigate a variety of multidimensional MRI methods, including 1D multi-component relaxometry, 1D multi-component diffusometry, 2D relaxation correlation imaging, and 2D diffusion-relaxation correlation spectroscopic imaging (DR-CSI), in terms of their potential to quantify tissue microstructure, including the myelin water fraction (MWF). We observe a distinct spectral peak that we attribute to myelin water in multi-component T1 relaxometry, T1-T2 correlation, T1-D correlation, and T2-D correlation imaging. Due to lower achievable echo times compared to diffusometry, MWF maps from relaxometry have higher quality. Whilst 1D multi-component T1 data allows much faster myelin mapping, 2D approaches could offer unique insights into tissue microstructure and especially myelin diffusion.

Physical activity and the brain myelin content in humans.

New imaging sequences and biophysical models allow adopting magnetic resonance imaging (MRI) for in vivo myelin mapping in humans. Understanding myelination and remyelination processes in the brain is fundamental from the perspective of proper design of physical exercise and rehabilitation schemes that aim to slow down demyelination in the aging population and to induce remyelination in patients with neurodegenerative diseases. Therefore, in this review we strive to provide a state-of-the art summary of the existing MRI studies in humans focused on the effects of physical activity on myelination/remyelination. We present and discuss four cross-sectional and four longitudinal studies and one case report. Physical activity and an active lifestyle have a beneficial effect on the myelin content in humans. Myelin expansion can be induced in humans throughout the entire lifespan by intensive aerobic exercise. Additional research is needed to determine (1) what exercise intensity (and cognitive novelty, which is embedded in the exercise scheme) is the most beneficial for patients with neurodegenerative diseases, (2) the relationship between cardiorespiratory fitness and myelination, and (3) how exercise-induced myelination affect cognitive abilities.

Myelin Density in Normal-Appearing White Matter in Measurements by q-Space Diffusional MRI Correlates with Clinical Disability in Multiple Sclerosis (P10-3.005)

Myelin Density in Normal-Appearing White Matter in Measurements by q-Space Diffusional MRI Correlates with Clinical Disability in Multiple Sclerosis (P10-3.005)

294. Cortical Myelin Mapping in Antipsychotic Medication-Naïve First-Episode Psychosis Patients Who Do or Do Not Display Clinical Features of the Deficit Syndrome

294. Cortical Myelin Mapping in Antipsychotic Medication-Naïve First-Episode Psychosis Patients Who Do or Do Not Display Clinical Features of the Deficit Syndrome

The intracortical myelin content of impulsive choices: results from T1- and T2-weighted MRI myelin mapping.

Delay discounting (DD) refers to a phenomenon that humans tend to choose small-sooner over large-later rewards during intertemporal choices. Steep discounting of delayed outcome is related to a variety of maladaptive behaviors and is considered as a transdiagnostic process across psychiatric disorders. Previous studies have investigated the association between brain structure (e.g. gray matter volume) and DD; however, it is unclear whether the intracortical myelin (ICM) influences DD. Here, based on a sample of 951 healthy young adults drawn from the Human Connectome Project, we examined the relationship between ICM, which was measured by the contrast of T1w and T2w images, and DD and further tested whether the identified associations were mediated by the regional homogeneity (ReHo) of brain spontaneous activity. Vertex-wise regression analyses revealed that steeper DD was significantly associated with lower ICM in the left temporoparietal junction (TPJ) and right middle-posterior cingulate cortex. Region-of-interest analysis revealed that the ReHo values in the left TPJ partially mediated the association of its myelin content with DD. Our findings provide the first evidence that cortical myelination is linked with individual differences in decision impulsivity and suggest that the myelin content affects cognitive performances partially through altered local brain synchrony.

Mapping myelin in white matter with T1-weighted/T2-weighted maps: discrepancy with histology and other myelin MRI measures

The ratio of T1-weighted/T2-weighted magnetic resonance images (T1w/T2w MRI) has been successfully applied at the cortical level since 2011 and is now one of the most used myelin mapping methods. However, no reports have explored the histological validity of T1w/T2w myelin mapping in white matter. Here we compare T1w/T2w with ex vivo postmortem histology and in vivo MRI methods, namely quantitative susceptibility mapping (QSM) and multi-echo T2 myelin water fraction (MWF) mapping techniques. We report a discrepancy between T1w/T2w myelin maps of the human corpus callosum and the histology and analyse the putative causes behind such discrepancy. T1w/T2w does not positively correlate with Luxol Fast Blue (LFB)-Optical Density but shows a weak to moderate, yet significant, negative correlation. On the contrary, MWF is strongly and positively correlated with LFB, whereas T1w/T2w and MWF maps are weakly negatively correlated. The discrepancy between T1w/T2w MRI maps, MWF and histological myelin maps suggests caution in using T1w/T2w as a white matter mapping method at the callosal level. While T1w/T2w imaging may correlate with myelin content at the cortical level, it is not a specific method to map myelin density in white matter.

Mapping the myelin bilayer with short-T2 MRI: Methods validation and reference data for healthy human brain.

To explore the properties of short-T2 signals in human brain, investigate the impact of various experimental procedures on these properties and evaluate the performance of three-component analysis. Eight samples of non-pathological human brain tissue were subjected to different combinations of experimental procedures including D2 O exchange and frozen storage. Short-T2 imaging techniques were employed to acquire multi-TE (33-2067 μs) data, to which a three-component complex model was fitted in two steps to recover the properties of the underlying signal components and produce amplitude maps of each component. For validation of the component amplitude maps, the samples underwent immunohistochemical myelin staining. The signal component representing the myelin bilayer exhibited super-exponential decay with T2,min of 5.48 μs and a chemical shift of 1.07ppm, and its amplitude could be successfully mapped in both white and gray matter in all samples. These myelin maps corresponded well to myelin-stained tissue sections. Gray matter signals exhibited somewhat different components than white matter signals, but both tissue types were well represented by the signal model. Frozen tissue storage did not alter the signal components but influenced component amplitudes. D2 O exchange was necessary to characterize the non-aqueous signal components, but component amplitude mapping could be reliably performed also in the presence of H2 O signals. The myelin mapping approach explored here produced reasonable and stable results for all samples. The extensive tissue and methodological investigations performed in this work form a basis for signal interpretation in future studies both ex vivo and in vivo.

Myelin-weighted imaging derived from quantitative parameter mapping

PurposeWe developed a novel method which is applicable to visualize contrast according to myelin components in the human brain using relaxation time derived from quantitative parameter mapping magnetic resonance imaging (QPM-MRI). Materials and methodsUsing healthy volunteer data (n = 10), we verified that our method demonstrated that the myelin-weighted contrast increased proportionally by products R1 and R2*, i.e., QPM-myelin-weighted image, in which modified T1-weighted/T2-weighted (T1w/T2w) ratio mapping method was applied. We compared measurement values in white matter (WM) and gray matter (GM) regions of the T1w/T2w ratio and R1·R2* product maps of healthy volunteers. Linear regression analysis between each value. Mann Whitney U test between WM and GM signals in each myelin map. In addition, Additionally, QPM-myelin-weighted image was applied to a 32-year-old female MS patient. ResultsLinear regression analysis showed a highly significant correlation between conventional T1w/T2w ratios and R1·R2* products derived from QPM (R = 0.73, P < 0.0001). Moreover, there is a significant difference between WM and GM structures in each myelin images (both, P < 0.0001). Additionally, in a clinical case, MS lesions enabled observation of not only MS plaques but also heterogeneous myelin signal loss associated with demyelination more clearly than T2w image and conventional T1w/T2w ratio image. ConclusionOur myelin-weighted imaging technique using QPM may be useful for myelin visualization and is expected to become independent of measurement conditions due to having quantitative characteristics of QPM itself.

Microstructural imaging and transcriptomics of the basal forebrain in first-episode psychosis

Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n = 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (p > 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

Synthetic MRI in children with tuberous sclerosis complex

ObjectiveThe generation of numerous sequences and quantitative data in a short scanning time is the most potential advantage of Synthetic MRI (SyMRI). We aimed to test detection of the tubers and to determine underlying tissue characteristics, and morphometric alterations in the brain of pediatric tuberous sclerosis complex (TSC) patients, using SyMRI.MethodsConventional brain MRI (cMRI) and SyMRI were prospectively obtained from 10 TSC patients and 18 healthy control subjects (HCs). Two neuroradiologists independently evaluated tubers on both scans. Additionally, automatically segmented volume calculation and myelin quantification, including the subcortical part of the tubers and normal-appearing brain parenchyma (NABP) of patients, were carried out using SyMRI.ResultsThe cMRI and SyMRI comparison showed a very good correlation on the detection of the tubers (k = 0.82–0.94). Automatic segmentation of Non-gray matter/white matter/cerebrospinal fluid (Non), %Non/brain parenchymal volume, and %Non/intracranial volume was significantly higher; however, %Myelin/intracranial volume and %Myelin/brain parenchymal volume were significantly lower in the TSC patients (p < 0.05). The proton density values were significantly increased, and myelin fraction volume and myelin-correlated compound values were significantly decreased in the NABP in TSC patients on myelin maps (p < 0.05). The white-matter volume, myelin and white-matter fractional volume, longitudinal relaxation rate, transverse relaxation rate, and myelin-correlated compound values were significantly decreased in the subcortical part of tubers on quantification maps (p < 0.001) in TSC patients.ConclusionSyMRI enables the detection of cortical tubers and is a developing tool in the quantification of morphometric and tissue alterations in pediatric TSC patients with a rational scanning time.

Individual differences in frontoparietal plasticity in humans

Neuroplasticity, defined as the brain’s potential to change in response to its environment, has been extensively studied at the cellular and molecular levels. Work in animal models suggests that stimulation to the ventral tegmental area (VTA) enhances plasticity, and that myelination constrains plasticity. Little is known, however, about whether proxy measures of these properties in the human brain are associated with learning. Here, we investigated the plasticity of the frontoparietal system by asking whether VTA resting-state functional connectivity and myelin map values (T1w/T2w ratios) predicted learning after short-term training on the adaptive n-back (n = 46, ages 18–25). We found that stronger baseline connectivity between VTA and lateral prefrontal cortex predicted greater improvements in accuracy. Lower myelin map values predicted improvements in response times, but not accuracy. Our findings suggest that proxy markers of neural plasticity can predict learning in humans.

Empirical transmit field bias correction of T1w/T2w myelin maps

T1-weighted divided by T2-weighted (T1w/T2w) myelin maps were initially developed for neuroanatomical analyses such as identifying cortical areas, but they are increasingly used in statistical comparisons across individuals and groups with other variables of interest. Existing T1w/T2w myelin maps contain radiofrequency transmit field (B1+) biases, which may be correlated with these variables of interest, leading to potentially spurious results. Here we propose two empirical methods for correcting these transmit field biases using either explicit measures of the transmit field or alternatively a ‘pseudo-transmit’ approach that is highly correlated with the transmit field at 3T. We find that the resulting corrected T1w/T2w myelin maps are both better neuroanatomical measures (e.g., for use in cross-species comparisons), and more appropriate for statistical comparisons of relative T1w/T2w differences across individuals and groups (e.g., sex, age, or body-mass-index) within a consistently acquired study at 3T. We recommend that investigators who use the T1w/T2w approach for mapping cortical myelin use these B1+ transmit field corrected myelin maps going forward.

Myelin Mapping in Trigeminal Neuralgia: Standardizing Conventional MR Images Enables Quantitative Comparison of Myelin Content (P15-4.003)

Myelin Mapping in Trigeminal Neuralgia: Standardizing Conventional MR Images Enables Quantitative Comparison of Myelin Content (P15-4.003)

Brain virtual histology with X-ray phase-contrast tomography Part I: whole-brain myelin mapping in white-matter injury models.

White-matter injury leads to severe functional loss in many neurological diseases. Myelin staining on histological samples is the most common technique to investigate white-matter fibers. However, tissue processing and sectioning may affect the reliability of 3D volumetric assessments. The purpose of this study was to propose an approach that enables myelin fibers to be mapped in the whole rodent brain with microscopic resolution and without the need for strenuous staining. With this aim, we coupled in-line (propagation-based) X-ray phase-contrast tomography (XPCT) to ethanol-induced brain sample dehydration. We here provide the proof-of-concept that this approach enhances myelinated axons in rodent and human brain tissue. In addition, we demonstrated that white-matter injuries could be detected and quantified with this approach, using three animal models: ischemic stroke, premature birth and multiple sclerosis. Furthermore, in analogy to diffusion tensor imaging (DTI), we retrieved fiber directions and DTI-like diffusion metrics from our XPCT data to quantitatively characterize white-matter microstructure. Finally, we showed that this non-destructive approach was compatible with subsequent complementary brain sample analysis by conventional histology. In-line XPCT might thus become a novel gold-standard for investigating white-matter injury in the intact brain. This is Part I of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part II shows how in-line XPCT enables the whole-brain 3D morphometric analysis of amyloid- (A ) plaques.

Brain virtual histology with X-ray phase-contrast tomography Part II:3D morphologies of amyloid-β plaques in Alzheimer's disease models.

While numerous transgenic mouse strains have been produced to model the formation of amyloid-β (Aβ) plaques in the brain, efficient methods for whole-brain 3D analysis of Aβ deposits have to be validated and standardized. Moreover, routine immunohistochemistry performed on brain slices precludes any shape analysis of Aβ plaques, or require complex procedures for serial acquisition and reconstruction. The present study shows how in-line (propagation-based) X-ray phase-contrast tomography (XPCT) combined with ethanol-induced brain sample dehydration enables hippocampus-wide detection and morphometric analysis of Aβ plaques. Performed in three distinct Alzheimer mouse strains, the proposed workflow identified differences in signal intensity and 3D shape parameters: 3xTg displayed a different type of Aβ plaques, with a larger volume and area, greater elongation, flatness and mean breadth, and more intense average signal than J20 and APP/PS1. As a label-free non-destructive technique, XPCT can be combined with standard immunohistochemistry. XPCT virtual histology could thus become instrumental in quantifying the 3D spreading and the morphological impact of seeding when studying prion-like properties of Aβ aggregates in animal models of Alzheimer's disease. This is Part II of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part I shows how in-line XPCT enables 3D myelin mapping in the whole rodent brain and in human autopsy brain tissue.