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Background and Purpose Methods Results Conclusion Quantitative susceptibility mapping (QSM), neurite orientation dispersion and density imaging (NODDI), and the g‐ratio have separately shown differences between Parkinson's disease (PD) and healthy controls. The g‐ratio has, however, not been studied in PD in the substantia nigra (SN) and the putamen. A combination of these methods could also potentially be a complementary imaging biomarker for PD. This study aimed to assess the diagnostic performance of QSM, NODDI, the g‐ratio, and a combined QSM‐NODDI imaging marker in the SN and putamen of PD patients.In this prospective study, the diagnostic performance of median region of interest values was compared in a cohort of 15 participants with PD and 14 healthy controls after manual segmentation. The diagnostic performance was assessed using the area under curve (AUC) for the receiving operator characteristic.Median QSM in the contralateral SN identified PD with AUC 0.77, and median isotropic volume fraction identified PD in the ipsilateral SN with AUC 0.68. A combined NODDI‐QSM marker improved diagnostic performance (AUC 0.80). No significant differences were found in the g‐ratio.A combination of median QSM and median isotropic volume fraction improves the differentiation of PD from healthy controls and is a potential biomarker in the diagnostics of PD. This confirms previously reported results indicating that combining QSM and NODDI modestly improves differentiation of PD. [ABSTRACT FROM AUTHOR]

G-ratio is crucial for understanding the nervous system's health and function as it measures the relative myelin thickness around an axon. However, manual measurement is biased and variable, emphasizing the need for an automated and standardized technique. Although deep learning holds promise, current implementations lack clinical relevance and generalizability. This study aimed to develop an automated pipeline for selecting nerve fibers and calculating relevant g-ratio using quality parameters in optical microscopy. Histological sections from the sciatic nerves of 16 female mice were prepared and stained with either p-phenylenediamine (PPD) or toluidine blue (TB). A custom UNet model was trained on a mix of both types of staining to segment the sections based on 7,694 manually delineated nerve fibers. Post-processing excluded nonrelevant nerves. Axon diameter, myelin thickness, and g-ratio were computed from the segmentation results and its reliability was assessed using the intraclass correlation coefficient (ICC). Validation was performed on adjacent cuts of the same nerve. Then, morphometrical analyses of both staining techniques were performed. High agreement with the ground truth was shown by the model, with dice scores of 0.86 (axon) and 0.80 (myelin) and pixel-wise accuracy of 0.98 (axon) and 0.94 (myelin). Good inter-device reliability was observed with ICC at 0.87 (g-ratio) and 0.83 (myelin thickness), and an excellent ICC of 0.99 for axon diameter. Although axon diameter significantly differed from the ground truth (p = 0.006), g-ratio (p = 0.098) and myelin thickness (p = 0.877) showed no significant differences. No statistical differences in morphological parameters (g-ratio, myelin thickness, and axon diameter) were found in adjacent cuts of the same nerve (ANOVA p-values: 0.34, 0.34, and 0.39, respectively). Comparing all animals, staining techniques yielded significant differences in mean g-ratio (PPD: 0.48 ± 0.04, TB: 0.50 ± 0.04), myelin thickness (PPD: 0.83 ± 0.28 μm, TB: 0.60 ± 0.20 μm), and axon diameter (PPD: 1.80 ± 0.63 μm, TB: 1.78 ± 0.63 μm). The proposed pipeline automatically selects relevant nerve fibers for g-ratio calculation in optical microscopy. This provides a reliable measurement method and serves as a potential pre-selection approach for large datasets in the context of healthy tissue. It remains to be demonstrated whether this method is applicable to measure g-ratio related with neurological disorders by comparing healthy and pathological tissue. Additionally, our findings emphasize the need for careful interpretation of inter-staining morphological parameters. [ABSTRACT FROM AUTHOR]

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single-molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation and neurite orientation dispersion and density imaging diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 versus 0.57, difference 0.036, 95% CI: 0.029-0.043, P < 0.001). Lesion volume (Spearman's rho rs= 0.38, P < 0.001) and g-ratio (rs= 0.24, P < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) [11/23 (48%) versus 2/15 (13%), P < 0.05]. These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity and help to identify individuals with a high degree of axonal damage at disease onset.

Abstract Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are unknown. A major feature of lesions is lack of myelin, which increases axonal energy demand and requires adaptation in number and size of mitochondria. Outside lesions, subtle and diffuse alterations are observed in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM), including increased oxidative stress, reduced axon density and changes in myelin composition and morphology. On an ultrastructural level, only limited data is available on alterations in myelinated axons. We generated large scale 2D scanning transmission electron microscopy images (‘nanotomy’) of non-demyelinated brain tissue of control and progressive MS donors, accessible via an open-access online repository. We observed a reduced density of myelinated axons in NAWM, without a decrease in cross-sectional axon area. Small myelinated axons were less frequently and large myelinated axons were more frequently present in NAWM, while the g-ratio was similar. The correlation between axonal mitochondrial radius and g-ratio was lost in NAWM, but not in NAGM. Myelinated axons in control GM and NAGM had a similar g-ratio and radius distribution. We hypothesize that axonal loss in NAWM is likely compensated by swelling of the remaining myelinated axons and subsequent adjustment of myelin thickness to maintain their g-ratio. Failure of axonal mitochondria to adjust their size and fine-tuning of myelin thickness may render NAWM axons and their myelin more susceptible to injury. Graphical Abstract

This article presents the results of a study of the performance characteristics of ceramic grinding wheels during peripheral grinding of flat surfaces carried out using different methods of supplying cooling and lubricating fluid (coolant). In the study, T1 type grinding wheels were used, differing in the type of abrasive used in their construction. The abrasive consisted of mixtures with different volume percentages of: 1) grains of conventional white electro-corundum, 2) grains of submicrocrystalline sintered corundum produced by sol-gel technology, 3) microcrystalline sintered ceramic grains with RECERAMAX™ RT microclasters from RECKEL. Specimens made of 145Cr6 tool steel (60±1 HRC) were ground using coolant feeding by flood method and MQL (Minimum Quantity Lubrication) method. During the study, the components of grinding force (Fn, Ft), radial loss of the grinding wheel and roughness of the ground surface were measured, which made it possible to determine the volumetric wear of the grinding wheel Vs, the total grinding power P, and then calculate the grinding indicators G and Ks. The obtained values of the G index indicate that, regardless of the type of grinding wheel used, a higher relative grinding efficiency was obtained during grinding with the delivery of coolant by the MQL method. The highest values of this index were obtained in the case of the grinding process carried out with a grinding wheel containing RECERAMAX™ RT abrasive. The Ks index confirmed the best performance of the mentioned grinding wheel. Since its value also depends on the total grinding power P and the surface roughness parameter Ra, the grinding process carried out with this grinding wheel is additionally characterized by a better quality of the obtained surface and lower energy consumption.

Assessing axonal morphology in vivo opens new avenues for the combined study of brain structure and function. A novel approach has recently been introduced to estimate the morphology of axonal fibers from the combination of magnetic resonance imaging (MRI) data and electroencephalography (EEG) measures of the interhemispheric transfer time (IHTT). In the original study, the IHTT measures were computed from EEG data averaged across a group, leading to bias of the axonal morphology estimates. Here, we seek to estimate axonal morphology from individual measures of IHTT, obtained from EEG data acquired in a visual evoked potential experiment. Subject‐specific IHTTs are computed in a data‐driven framework with minimal a priori constraints, based on the maximal peak of neural responses to visual stimuli within periods of statistically significant evoked activity in the inverse solution space. The subject‐specific IHTT estimates ranged from 8 to 29 ms except for one participant and the between‐session variability was comparable to between‐subject variability. The mean radius of the axonal radius distribution, computed from the IHTT estimates and the MRI data, ranged from 0 to 1.09 μm across subjects. The change in axonal g‐ratio with axonal radius ranged from 0.62 to 0.81 μm−α. The single‐subject measurement of the IHTT yields estimates of axonal morphology that are consistent with histological values. However, improvement of the repeatability of the IHTT estimates is required to improve the specificity of the single‐subject axonal morphology estimates. [ABSTRACT FROM AUTHOR]

G-ratio is crucial for understanding the nervous system’s health and function as it measures the relative myelin thickness around an axon. However, manual measurement is biased and variable, emphasizing the need for an automated and standardized technique. Although deep learning holds promise, current implementations lack clinical relevance and generalizability. This study aimed to develop an automated pipeline for selecting nerve fibers and calculating relevant g-ratio using quality parameters in optical microscopy. Histological sections from the sciatic nerves of 16 female mice were prepared and stained with either p-phenylenediamine (PPD) or toluidine blue (TB). A custom UNet model was trained on a mix of both types of staining to segment the sections based on 7,694 manually delineated nerve fibers. Post-processing excluded non-relevant nerves. Axon diameter, myelin thickness, and g-ratio were computed from the segmentation results and its reliability was assessed using the intraclass correlation coefficient (ICC). Validation was performed on adjacent cuts of the same nerve. Then, morphometrical analyses of both staining techniques were performed. High agreement with the ground truth was shown by the model, with dice scores of 0.86 (axon) and 0.80 (myelin) and pixel-wise accuracy of 0.98 (axon) and 0.94 (myelin). Good inter-device reliability was observed with ICC at 0.87 (g-ratio) and 0.83 (myelin thickness), and an excellent ICC of 0.99 for axon diameter. Although axon diameter significantly differed from the ground truth (p = 0.006), g-ratio (p = 0.098) and myelin thickness (p = 0.877) showed no significant differences. No statistical differences in morphological parameters (g-ratio, myelin thickness, and axon diameter) were found in adjacent cuts of the same nerve (ANOVA p-values: 0.34, 0.34, and 0.39, respectively). Comparing all animals, staining techniques yielded significant differences in mean g-ratio (PPD: 0.48 ± 0.04, TB: 0.50 ± 0.04), myelin thickness (PPD: 0.83 ± 0.28 μm, TB: 0.60 ± 0.20 μm), and axon diameter (PPD: 1.80 ± 0.63 μm, TB: 1.78 ± 0.63 μm). The proposed pipeline automatically selects relevant nerve fibers for g-ratio calculation in optical microscopy. This provides a reliable measurement method and serves as a potential pre-selection approach for large datasets in the context of healthy tissue. It remains to be demonstrated whether this method is applicable to measure g-ratio related with neurological disorders by comparing healthy and pathological tissue. Additionally, our findings emphasize the need for careful interpretation of inter-staining morphological parameters.

Activity-dependent myelination is a fundamental mode of brain plasticity which significantly influences network function. We recently discovered that absence seizures, which occur in multiple forms of generalized epilepsy, can induce activity-dependent myelination, which in turn promotes further progression of epilepsy. Structural alterations of myelin are likely to be widespread, given that absence seizures arise from an extensive thalamocortical network involving frontoparietal regions of the bilateral hemispheres. However, the temporal course and spatial extent of myelin plasticity is unknown, due to limitations of gold-standard histological methods such as electron microscopy (EM). In this study, we leveraged magnetization transfer and diffusion MRI for estimation of g-ratios across major white matter tracts in a mouse model of generalized epilepsy with progressive absence seizures. EM was performed on the same brains after MRI. After seizure progression, we found increased myelination (decreased g-ratios) throughout the anterior portion (genu-to-body) of the corpus callosum but not in the posterior portion (body-splenium) nor in the fornix or the internal capsule. Curves obtained from averaging g-ratio values at every longitudinal point of the corpus callosum were statistically different with p

Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are unknown. A major feature of lesions is lack of myelin, which increases axonal energy demand and requires adaptation in number and size of mitochondria. Outside lesions, subtle and diffuse alterations are observed in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM), including increased oxidative stress, reduced axon density and changes in myelin composition and morphology. On an ultrastructural level, only limited data is available on alterations in myelinated axons. We generated large scale 2D scanning transmission electron microscopy images ('nanotomy') of non-demyelinated brain tissue of control and progressive MS donors, accessible via an open-access online repository. We observed a reduced density of myelinated axons in NAWM, without a decrease in cross-sectional axon area. Small myelinated axons were less frequently and large myelinated axons were more frequently present in NAWM, while the g-ratio was similar. The correlation between axonal mitochondrial radius and g-ratio was lost in NAWM, but not in NAGM. Myelinated axons in control GM and NAGM had a similar g-ratio and radius distribution. We hypothesize that axonal loss in NAWM is likely compensated by swelling of the remaining myelinated axons and subsequent adjustment of myelin thickness to maintain their g-ratio. Failure of axonal mitochondria to adjust their size and fine-tuning of myelin thickness may render NAWM axons and their myelin more susceptible to injury. [ABSTRACT FROM AUTHOR]

Field imagery is an effective way to capture the state of the entire field; yet, current field inspection approaches, when accounting for image resolution and processing speed, using existent imaging systems, do not always enable real-time field inspection. This project involves the innovation of novel technologies by using an FPGA-based image processing (FIP) device that eliminates the technical limitations of the current agricultural imaging services available in the market and will lead to the development of a market-ready service solution. The FIP prototype developed in this study was tested in both a laboratory and outdoor environment by using a digital single-lens reflex (DSLR) camera and web camera, respectively, as the reference system. The FIP system had a high accuracy with a Lin's concordance correlation coefficient of 0.99 and 0.91 for the DLSR and web camera reference system, respectively. The proposed technology has the potential to provide on-the-spot decisions, which in turn, will improve the compatibility and sustainability of different land-based systems. [ABSTRACT FROM AUTHOR]

This article presents the results of a study of the performance characteristics of ceramic grinding wheels during peripheral grinding of flat surfaces carried out using different methods of supplying cooling and lubricating fluid (coolant). In the study, T1 type grinding wheels were used, differing in the type of abrasive used in their construction. The abrasive consisted of mixtures with different volume percentages of: 1) grains of conventional white electro-corundum, 2) grains of submicrocrystalline sintered corundum produced by sol-gel technology, 3) microcrystalline sintered ceramic grains with RECERAMAX™ RT microclasters from RECKEL. Specimens made of 145Cr6 tool steel (60±1 HRC) were ground using coolant feeding by flood method and MQL (Minimum Quantity Lubrication) method. During the study, the components of grinding force (Fn, Ft), radial loss of the grinding wheel and roughness of the ground surface were measured, which made it possible to determine the volumetric wear of the grinding wheel Vs, the total grinding power P, and then calculate the grinding indicators G and Ks. The obtained values of the G index indicate that, regardless of the type of grinding wheel used, a higher relative grinding efficiency was obtained during grinding with the delivery of coolant by the MQL method. The highest values of this index were obtained in the case of the grinding process carried out with a grinding wheel containing RECERAMAX™ RT abrasive. The Ks index confirmed the best performance of the mentioned grinding wheel. Since its value also depends on the total grinding power P and the surface roughness parameter Ra, the grinding process carried out with this grinding wheel is additionally characterized by a better quality of the obtained surface and lower energy consumption. [ABSTRACT FROM AUTHOR]

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

Introduction: Quantitative and non-invasive measures of brain myelination and maturation during development are of great importance to both clinical and translational research communities. While the metrics derived from diffusion tensor imaging, are sensitive to developmental changes and some pathologies, they remain difficult to relate to the actual microstructure of the brain tissue. The advent of advanced model-based microstructural metrics requires histological validation. The purpose of the study was to validate novel, model-based MRI techniques, such as macromolecular proton fraction mapping (MPF) and neurite orientation and dispersion indexing (NODDI), against histologically derived indexes of myelination and microstructural maturation at various stages of development. Methods: New Zealand White rabbit kits underwent serial in-vivo MRI examination at postnatal days 1, 5, 11, 18, and 25, and as adults. Multi-shell, diffusion-weighted experiments were processed to fit NODDI model to obtain estimates, intracellular volume fraction (ICVF) and orientation dispersion index (ODI). Macromolecular proton fraction (MPF) maps were obtained from three source (MT-, PD-, and T1-weighted) images. After MRI sessions, a subset of animals was euthanized and regional samples of gray and white matter were taken for western blot analysis, to determine myelin basic protein (MBP), and electron microscopy, to estimate axonal, myelin fractions and g-ratio. Results: MPF of white matter regions showed a period of fast growth between P5 and P11 in the internal capsule, with a later onset in the corpus callosum. This MPF trajectory was in agreement with levels of myelination in the corresponding brain region, as assessed by western blot and electron microscopy. In the cortex, the greatest increase of MPF occurred between P18 and P26. In contrast, myelin, according to MBP western blot, saw the largest hike between P5 and P11 in the sensorimotor cortex and between P11 and P18 in the frontal cortex, which then seemingly plateaued after P11 and P18 respectively.G-ratio by MRI markers decreased with age in the white matter. However, electron microscopy suggest a relatively stable g-ratio throughout development. Conclusion: Developmental trajectories of MPF accurately reflected regional differences of myelination rate in different cortical regions and white matter tracts. MRI-derived estimation of g-ratio was inaccurate during early development, likely due to the overestimation of axonal volume fraction by NODDI due to the presence of a large proportion of unmyelinated axons.

The physical principle of myelin development is obtained from our previous study by explaining Peter's quadrant mystery: an externally applied negative and positive E-field can promote and inhibit the growth of the inner tongue of the myelin sheath, respectively. In this study, this principle is considered as a fundamental hypothesis, named Hypothesis-E, to explain more phenomena about myelin development systematically. Specifically, the g-ratio and the fate of the Schwann cell's differentiation are explained in terms of the E-field. Moreover, an experiment is proposed to validate this theory. [ABSTRACT FROM AUTHOR]

Myelination and the formation of nodes of Ranvier are essential for the rapid conduction of nerve impulses along axons in the peripheral nervous system (PNS). While many animal-based and serum-containing models of peripheral myelination have been developed, these have limited ability when it comes to studying genetic disorders affecting peripheral myelination. We report a fully induced pluripotent stem cell (iPSC)-derived human model of peripheral myelination using Schwann cells (SCs) and motoneurons, cultured in a serum-free medium on patterned and nonpatterned surfaces. Results demonstrated iPSC-derived SC-expressed early growth response protein 2 (Egr2), a key transcription factor for myelination, and after ∼30 days in coculture, hallmark features of myelination, including myelin segment and node of Ranvier formation, were observed. Myelin segments were stained for the myelin basic protein, which surrounded neurofilament-stained motoneuron axons. Clusters of voltage-gated sodium channels flanked by paranodal protein contactin-associated protein 1, indicating node of Ranvier formation, were also observed. High-resolution confocal microscopy allowed for 3D reconstruction and measurement of myelin g-ratios of myelin segments, with an average g-ratio of 0.67, consistent with reported values in the literature, indicating mature myelin segment formation. This iPSC-based model of peripheral myelination provides a platform to investigate numerous PNS diseases, including Charcot-Marie Tooth disorder, Guillian-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and antimyelin-associated glycoprotein peripheral neuropathy, with the potential for greater translatability to humans for improving the applicability for drug-screening programs.

Experimental autoimmune encephalomyelitis (EAE) is a basic and reliable model used to study clinical and pathological hallmarks of multiple sclerosis (MS) in rodents. Several studies suggest neural precursor cells (NPCs) as a significant research tool while reporting that transplanted NPCs are a promising therapeutic approach to treating neurological disorders, such as MS. The main objective was to approach a preclinical, in vivo scenario of oligodendrogenesis with NPCs, targeting the main chronic demyelinated lumbosacral milieu of EAE, via the least invasive delivery method which is lumbar puncture. We utilized MOG35‐55 peptide to induce EAE in C57BL/6 mice and prior to the acute relapse, we intervened with either the traceable GFP+ cellular therapy or saline solution in the intrathecal space of their lumbar spine. A BrdU injection, which enabled us to monitor endogenous proliferation, marked the endpoint 50 days post‐induction (50 dpi). Neuropathology with high‐throughput, triple immunofluorescent, and transmission electron microscopy (TEM) data were extracted and analyzed. The experimental treatment attenuated the chronic phase of EAE (50 dpi; score <1) following an acute, clinical relapse. Myelination and axonal integrity were rescued in the NPC‐treated animals along with suppressed immune populations. The differentiation profile of the exogenous NPCs and endogenous BrdU+ cells was location‐dependent where GFP+‐rich areas drove undifferentiated phenotypes toward the oligodendrocyte lineage. In situ oligodendrocyte enrichment was demonstrated through increased (p < 0.001) gap junction channels of Cx32 and Cx47, reliable markers for proliferative oligodendroglia syncytium. TEM morphometric analysis ultimately manifested an increased g‐ratio in lumbosacral fibers of the recovered animals (p < 0.001). Herein, we suggest that a single, lumbar intrathecal administration of NPCs capacitated a viable cellular load and resulted in clinical and pathological amelioration, stimulating resident OPCs to overcome the remyelination failure in EAE demyelinating locale. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. Magnetic resonance imaging (MRI) can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. This paper provides an overview of MRI data acquisition, management and processing in FutureMS. FutureMS is registered with the Integrated Research Application System (IRAS, UK) under reference number 169955. Methods and analysis: MRI is performed at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures. Conclusions: FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression in a large population of RRMS patients in Scotland.

Axonal demyelination is a cardinal feature of aging and age-related diseases. The g -ratio, mathematically defined as the inner-to-outer diameter of a myelinated axon, is used as a structural index of optimal axonal myelination and has been shown to represent a sensitive imaging biomarker of microstructural integrity. Several magnetic resonance imaging (MRI) methods for whole-brain mapping of aggregate g -ratio have been introduced. Computation of the aggerate g -ratio requires estimates of the myelin volume fraction (MVF) and the axonal volume fraction (AVF). While accurate determinations of MVF and AVF can be obtained through multicomponent relaxometry or diffusion analyses, respectively, these methods require lengthy acquisition times making their implementation challenging in a clinical context. Therefore, any attempt to overcome this drawback is needed. Expanding on our previous work, we introduced a new MRI method for whole-brain mapping of aggregate g -ratio. This new approach is based on the use of a single-shell diffusion for AVF determination, reducing the acquisition time by approximately ~10 min from our recently introduced approach, while offering the possibility to investigate g -ratio differences in previous studies with existing data for MVF mapping and single-shell diffusion data for AVF mapping. Our comparison analysis indicates that our newly derived aggregate g -ratio values were similar to those derived from our previous method, which requires a longer acquisition time. Further, in agreement with our previous observations, we found quadratic U-shaped relationships between aggregate g -ratio and age in this much larger study cohort. However, our results show that sexual dimorphism in g -ratio was not significant in any brain region investigated. [ABSTRACT FROM AUTHOR]

Abstract Background Bisphosphonates (BPs) are forceful inhibitors of osteoclast-mediated bone resorption. Long-term BP use is associated with multiple rare but severe adverse effects. The objective of this study was to investigate the possible effects of BPs in the structure of femoral nerve. Specimens from the femoral nerve of ten female 12-month old Wistar rats were used as control group and ten female 12-month old Wistar rats to which Alendronate (Fosamax, Merck) was administered per os for 13 weeks, were used as research group. Samples were observed under a Transmission Electron Microscope. G ratio measurements and statistical analysis with SPSS program were also performed. Results The control group showed no major changes of the nerve’s histologic image, with the exception of some spots of thickness of the nerve myelin sheath. The research group showed major morphological changes which varied from partial disorganization or thickening of the myelin to severe myelin thickening and axon strangulation. A statistically significant difference of the G ratio between the two groups was observed. Conclusions The reported values (found in literature) for the morphologic measurements of the femoral nerve in Wistar rats are not complying with the ones we found in our study. There was a significant reduction of all three variables (the mean axon like diameter, the myelin thickness, G ratio) studied in the femoral nerve of the research group in contrast to control group. Our study demonstrates a possible correlation between alendronate administration and femoral nerve’s function, nevertheless due to the small specimen further research is needed.

Introduction: Quantitative microstructural MRI, such as myelin-sensitive magnetisation transfer ratio (MTR) or saturation (MTsat), axon-sensitive water diffusion Neurite Orientation Dispersion and Density Imaging (NODDI), and the aggregate g-ratio, may provide more specific markers of white matter integrity than conventional MRI for early patient stratification in relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to determine the sensitivity of such markers to longitudinal pathological change within cerebral white matter lesions (WML) and normal-appearing white matter (NAWM) in recently diagnosed RRMS. Methods: Seventy-nine people with recently diagnosed RRMS, from the FutureMS longitudinal cohort, were recruited to an extended MRI protocol at baseline and one year later. Twelve healthy volunteers received the same MRI protocol, repeated within two weeks. Ethics approval and written informed consent were obtained.3T MRI included magnetisation transfer, and multi-shell diffusion-weighted imaging. NAWM and whole brain were segmented from 3D T1-weighted MPRAGE, and WML from T2-weighted FLAIR. MTR, MTsat, NODDI isotropic (ISOVF) and intracellular (ICVF) volume fractions, and g-ratio (calculated from MTsat and NODDI data) were measured within WML and NAWM. Brain parenchymal fraction (BPF) was also calculated.Longitudinal change in BPF and microstructural metrics was assessed with paired t-tests (α = 0.05) and linear mixed models, adjusted for confounding factors with False Discovery Rate (FDR) correction for multiple comparisons. Longitudinal changes were compared with test-retest Bland-Altman limits of agreement from healthy control white matter. The influence of longitudinal change on g-ratio was explored through post-hoc analysis in silico by computing g-ratio with realistic simulated MTsat and NODDI values. Results: In NAWM, g-ratio and ICVF increased, and MTsat decreased over one year (adjusted mean difference = 0.007, 0.005, and −0.057 respectively, all FDR-corrected p

Rapid development in mobile phone technologies increase the average mobile phone usage duration. This increase also triggers exposure to radiofrequency radiation (RF), which is a risk factor for the health. In this study, it was aimed to investigate the effect of mobile phone working with LTE-Advanced Pro (4.5 G) mobile network on the optic nerve, which is responsible for the transmission of visual information. Thirty-two rats divided into two groups as control (no RF, sham exposure) and experimental (RF exposure using a mobile phone with LTE-Advanced Pro network; 2 hours/day, 6 weeks). The visual evoked potential (VEP) was recorded and determined amplitudes and latencies of VEP waves. Optic nerve malondialdehyde level, catalase and superoxide dismutase activities were determined. Furthermore, ultrastructural and morphometric changes of optic nerve were evaluated. In VEP recordings, the mean VEP amplitudes of experimental group were significantly lower than control group. In ultrastructural evaluation, myelinated nerve fibres and glial cells were observed in normal histologic appearance both in sham and experimental group. However, by performing morphometric analysis, in the experimental group, axonal diameter and myelin thickness were shown to be lower and the G-ratio was higher than in the sham group. In the experimental group, malondialdehyde level was significantly higher and superoxide dismutase and catalase activities were significantly lower than sham group. There was a high correlation between VEP wave amplitudes and oxidative stress markers. Findings obtained in this study support optic nerve damage. These results point out an important risk that may decrease the quality of life. [ABSTRACT FROM AUTHOR]

Many histological techniques are used to identify and characterize myelin in the mammalian nervous system. Due to the high content of lipids in myelin sheaths, coherent anti-stokes Raman scattering (CARS) microscopy is a label-free method that allows identifying myelin within tissues. CARS excites the CH2 vibrational mode at 2845 cm−1 and CH2 bonds are found in lipids. In this study, we have used CARS for a new biological application in the field of spinal cord analysis. We have indeed compared several parameters of spinal cord myelin sheath in three different species, i.e., mouse, lemur, and human using a label-free method. In all species, we analyzed the dorsal and the lateral funiculi of the adult thoracic spinal cord. We identified g-ratio differences between species. Indeed, in both funiculi, g-ratio was higher in mice than in the two primate species, and the myelin g-ratio in lemurs was higher than in humans. We also detected a difference in g-ratio between the dorsal and the lateral funiculi only in humans. Furthermore, species differences between axon and fiber diameters as well as myelin thickness were observed. These data may reflect species specificities of conduction velocity of myelin fibers. A comparison of data obtained by CARS imaging and fluoromyelin staining, a method that, similar to CARS, does not require resin embedding and dehydration, displays similar results. CARS is, therefore, a label-free alternative to other microscopy techniques to characterize myelin in healthy and neurological disorders affecting the spinal cord.

Objective: To evaluate: (a) the specific effect that the demyelination and axonal loss have on the DW signal, and (b) the impact of the sequence parameters on the sensitivity to damage of two clinically feasible DWI techniques, i.e. DKI and NODDI. Methods: We performed a Monte Carlo simulation of water diffusion inside a novel synthetic model of white matter in the presence of axonal loss and demyelination, with three compartments with permeable boundaries between them. We compared DKI and NODDI in their ability to detect and assess the damage, using several acquisition protocols. We used the F test statistic as an index of the sensitivity for each DWI parameter to axonal loss and demyelination, respectively. Results: DKI parameters significantly changed with increasing axonal loss, but, in most cases, not with demyelination; all the NODDI parameters showed sensitivity to both the damage processes (at p < 0.01). However, the acquisition protocol strongly affected the sensitivity to damage of both the DKI and NODDI parameters and, especially for NODDI, the parameter absolute values also. Discussion: This work is expected to impact future choices for investigating white matter microstructure in focusing on specific stages of the disease, and for selecting the appropriate experimental framework to obtain optimal data quality given the purpose of the experiment. [ABSTRACT FROM AUTHOR]

Tacrolimus, a widely used immunosuppressive drug for preventing graft rejection following organ transplantation, was reported to develop neurotoxic side effects ranging from mild to severe symptoms in the literature. Rats were randomly divided into three groups as control and 2-week and 3-week treatment groups and received a 2 mg/kg/day tacrolimus by oral gavage. Animals were sacrificed and sciatic nerves obtained from all groups were fixed and processed for light and electron microscopic investigations. The myelinated fiber diameter, axon diameter, G-ratio (axon diameter/myelinated fiber diameter), and myelin thickness were also determined. The data obtained in the control and tacrolimus-treated groups were compared. The control group sciatic nerve fascicles showed normal morphology with myelinated and unmyelinated fibers. Experimental groups exhibited axonal dilatation, irregularly thickened and vacuolated myelin sheaths with separation of myelin layers. The morphometric analysis showed that the myelinated fibers of the 2-week tacrolimus-treated group displayed a moderate increase in the myelin thickness and axon and fiber diameter in comparison with the control and 3-week tacrolimus-treated groups. The G-ratio was found to be in normal range in all groups and there were no statistically significant difference. The present study indicates that the treatment with tacrolimus may produce a mild degenerative change but prolonged drug administration for 3 weeks led to improvement in morphometric and morphologic data and the normal G-ratio values, suggesting that the regeneration capacity of the myelinated fibers maintains their normal function to transmit nerve impulses. [ABSTRACT FROM AUTHOR]

Treatment for peripheral nerve injury remains limited. The inherent differences between motor and sensory nerve fibers in peripheral nerves should be considered to improve the effects of clinical treatment of peripheral nerve injury. In this study, we investigated the differences in protein expression and ultrastructure between the cutaneous and muscular branches of the femoral nerve in rats. Our results suggest that the cutaneous branch of the femoral nerve mainly contains sensory nerve fibers and few motor nerve fibers; Correspondingly, many motor nerve fibers and few sensory nerve fibers were observed in the muscular branch of the femoral nerve, which indicate that two branches of femoral nerve are mixed nerve. The mean thickness of the myelin sheath and basement membrane of the medullated fibers in the muscular branch of the femoral nerve was greater than that of the cutaneous branch of the femoral nerve. However, the cutaneous branch has a larger G-ratio. Gene Ontology enrichment analysis revealed that the cellular component term extracellular space was the most highly enriched, and more genes were upregulated in the muscular branch of the femoral nerve. Meanwhile, the expression of key proteins were validated by Western Blot, and immunofluorescence targets the expression of key proteins, which is consistent with the enrichment analysis of Gene Ontology. In conclusion, inherent differences in protein expression and ultrastructure were observed between the cutaneous and muscular branches of the femoral nerve in rats, which should be considered in future studies on the treatment of peripheral nerve injuries.

Due to limitations of human in vivo studies, detailed computational models enable understanding the neural signaling in the degenerated auditory system and cochlear implants (CIs). Four human cochleae were used to quantify hearing levels depending on dendritic changes in diameter and myelination thickness from type I of the auditory nerve fibers (ANFs). Type I neurons transmit the auditory information as spiking pattern from the inner hair cells (IHCs) to the cochlear nucleus. The impact of dendrite diameter and degree of myelination on neural signal transmission was simulated for (1) synaptic excitation via IHCs and (2) stimulation from CI electrodes. An accurate three-dimensional human cochlear geometry, along with 30 auditory pathways, mimicked the CI environment. The excitation properties of electrical potential distribution induced by two CI were analyzed. Main findings: (1) The unimodal distribution of control dendrite diameters becomes multimodal for hearing loss cases; a group of thin dendrites with diameters between 0.3 and 1 μm with a peak at 0.5 μm appeared. (2) Postsynaptic currents from IHCs excite such thin dendrites easier and earlier than under control conditions. However, this advantage is lost as their conduction velocity decreases proportionally with the diameter and causes increased spike latency and jitter in soma and axon. Firing probability reduces through the soma passage due to the low intracellular current flow in thin dendrites during spiking. (3) Compared with dendrite diameter, variations in myelin thickness have a small impact on spiking performance. (4) Contrary to synaptic excitation, CIs cause several spike initiation sites in dendrite, soma region, and axon; moreover, fiber excitability reduces with fiber diameter. In a few cases, where weak stimuli elicit spikes of a target neuron (TN) in the axon, dendrite diameter reduction has no effect. However, in many cases, a spike in a TN is first initiated in the dendrite, and consequently, dendrite degeneration demands an increase in threshold currents. (5) Threshold currents of a TN and co-stimulation of degenerated ANFs in other frequency regions depend on the electrode position, including its distance to the outer wall, the cochlear turn, and the three-dimensional pathway of the TN. [ABSTRACT FROM AUTHOR]

Treatment for peripheral nerve injury remains limited. The inherent differences between motor and sensory nerve fibers in peripheral nerves should be considered to improve the effects of clinical treatment of peripheral nerve injury. In this study, we investigated the differences in protein expression and ultrastructure between the cutaneous and muscular branches of the femoral nerve in rats. Our results suggest that the cutaneous branch of the femoral nerve mainly contains sensory nerve fibers and few motor nerve fibers; Correspondingly, many motor nerve fibers and few sensory nerve fibers were observed in the muscular branch of the femoral nerve, which indicate that two branches of femoral nerve are mixed nerve. The mean thickness of the myelin sheath and basement membrane of the medullated fibers in the muscular branch of the femoral nerve was greater than that of the cutaneous branch of the femoral nerve. However, the cutaneous branch has a larger G-ratio. Gene Ontology enrichment analysis revealed that the cellular component term extracellular space was the most highly enriched, and more genes were upregulated in the muscular branch of the femoral nerve. Meanwhile, the expression of key proteins were validated by Western Blot, and immunofluorescence targets the expression of key proteins, which is consistent with the enrichment analysis of Gene Ontology. In conclusion, inherent differences in protein expression and ultrastructure were observed between the cutaneous and muscular branches of the femoral nerve in rats, which should be considered in future studies on the treatment of peripheral nerve injuries. [ABSTRACT FROM AUTHOR]

Aim: Experimental studies have shown that the progesterone metabolite, allopregnanolone, is endowed with promyelinating effects. The mechanisms underlying these promyelinating effects are not well understood. Therefore, we explored the impact of allopregnanolone's synthetic analogue, ganaxolone, on remyelination and microglial activation following focal demyelination in the corpus callosum of ovariectomized rats. Methods: Ovariectomized adult Sprague Dawley rats received a stereotaxic injection of 2 µL of 1% lysolecithin solution in the corpus callosum followed by daily injections of either ganaxolone (intraperitoneal injection [i.p.], 2.5 mg/kg) or vehicle. The demyelination lesion was assessed 3 and 7 days postdemyelination insult using Luxol fast blue staining and transmission electron microscopy. The expression levels of myelin proteins (MBP, MAG, MOG, CNPase) were explored using Western blot. The inflammatory response and clearance of damaged myelin were evaluated using immunofluorescent staining (Iba1, dMBP, GFAP) and multiplex enzyme‐linked immunosorbent assay (IL‐1β, TNF‐α, IL‐4, IL‐10, IL‐6). Results: Systemic administration of ganaxolone promoted remyelination of lysolecithin‐induced demyelination, upregulated the expression of major myelin proteins, and enhanced microglial clearance of damaged myelin. Astrocytosis, as well as locally produced pro‐ and antiinflammatory cytokines, was not affected by ganaxolone treatment. Conclusion: Ganaxolone promotes remyelination in response to focal demyelination of the corpus callosum of ovariectomized rats. This effect is, at least in part, mediated by enhancing microglial clearance of myelin debris, which creates a conducive environment for a successful remyelination process. [ABSTRACT FROM AUTHOR]

Grinding is the main manufacturing process used in finishing operations. Center-less grinding is widely used in the production of auto parts e.g. roller bearings, valve stem and stem of shock absorbers. Center-less grinding is used in large-scale production due to shorter time and higher flexibility. However, the set-up of the grinder is complex and slow, and depends on the operators’ ability. The choice of the best parameters in the process is important to define exactly the cutting strategy and to optimize the process. Current study analyzes the input parameters: feed rate and type of materials on the responses G-ratio, surface roughness, and roundness. Thus, stems of shock absorbers were used as work pieces on the shop floor. Cutting speed and grinding wheel type were constant. The input parameters comprised feed rate and type of materials (1025 and 1045). Responses were surface roughness, roundness error and G-ratio. Results demonstrated that the kinds of tested material was the parameter that most influenced G-ratio and surface roughness. Moreover, feed rate had little influence on the quality of the work pieces, mainly on roundness error.

The impact of early life nutrition on myelin development is of interest given that cognitive and behavioral function depends on proper myelination. Evidence shows that myelination can be altered by dietary lipid, but most of these studies have been performed in the context of disease or impairment. Here, we assessed the effects of lipid blends containing various levels of a hydrolyzed fat (HF) system on myelination in healthy piglets. Piglets were sow-reared, fed a control diet, or a diet containing 12%, 25%, or 53% HF consisting of cholesterol, fatty acids, monoglycerides, and phospholipid from lecithin. At postnatal day 28/29, magnetic resonance imaging (MRI) was performed to assess changes to brain development, followed by brain collection for microscopic analyses of myelin in targeted regions using CLARITY tissue clearing, immunohistochemistry, and electron microscopy techniques. Sow-reared piglets exhibited the highest overall brain white matter volume by MRI. However, a 25% HF diet resulted in the greatest total myelin density in the prefrontal cortex based on 3D modeling analysis of myelinated filaments. Nodal gap length and g-ratio were inversely correlated with percentage of HF in the corpus callosum, as well as in the PFC and internal capsule for g-ratio, indicating that a 53% HF diet resulted in the thickest myelin per axon and a 0% HF control diet the thinnest in specific brain regions. These findings indicate that HF promoted myelination in the neonatal piglet in a region- and concentration-dependent manner., (© 2023 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Spinal cord injury (SCI) results from penetrating or compressive traumatic injury to the spine in humans or by the surgical compression of the spinal cord in experimental animals. In this study, the neuroprotective potential of Spirulina platensis was investigated on ultrastructural and functional recovery of the spinal cord following surgical-induced injury. Twenty-four Sprague-Dawley rats were divided into three groups; sham group, control (trauma) group, and experimental (S. platensis) group (180 mg/kg) of eight rats each. For each group, the rats were then subdivided into two groups to allow measurement at two different timepoints (day 14 and 28) for the microscopic analysis. Rats in the control and experimental S. platensis groups were subjected to partial crush injury at the level of T12 with Inox number 2 modified forceps by compressing on the spinal cord for 30 s. Pairwise comparisons of ultrastructural grading mean scores difference between the control and experimental S. platensis groups reveals that there were significant differences on the axonal ultrastructure, myelin sheath and BBB Score on Day 28; these correlate with the functional locomotor recovery at this timepoint. The results suggest that supplementation with S. platensis induces functional recovery and effective preservation of the spinal cord ultrastructure after SCI. These findings will open new potential avenue for further research into the mechanism of S. platensis-mediated spinal cord repair. [ABSTRACT FROM AUTHOR]

Tissue microstructure modeling of diffusion MRI signal is an active research area striving to bridge the gap between macroscopic MRI resolution and cellular-level tissue architecture. Such modeling in neuronal tissue relies on a number of assumptions about the microstructural features of axonal fiber bundles, such as the axonal shape (e.g., perfect cylinders) and the fiber orientation dispersion. However, these assumptions have not yet been validated by sufficiently high-resolution 3-dimensional histology. Here, we reconstructed sequential scanning electron microscopy images in mouse brain corpus callosum, and introduced a random-walker (RaW)-based algorithm to rapidly segment individual intra-axonal spaces and myelin sheaths of myelinated axons. Confirmed by a segmentation based on human annotations initiated with conventional machine-learning-based carving, our semi-automatic algorithm is reliable and less time-consuming. Based on the segmentation, we calculated MRI-relevant estimates of size-related parameters (inner axonal diameter, its distribution, along-axon variation, and myelin g-ratio), and orientation-related parameters (fiber orientation distribution and its rotational invariants; dispersion angle). The reported dispersion angle is consistent with previous 2-dimensional histology studies and diffusion MRI measurements, while the reported diameter exceeds those in other mouse brain studies. Furthermore, we calculated how these quantities would evolve in actual diffusion MRI experiments as a function of diffusion time, thereby providing a coarse-graining window on the microstructure, and showed that the orientation-related metrics have negligible diffusion time-dependence over clinical and pre-clinical diffusion time ranges. However, the MRI-measured inner axonal diameters, dominated by the widest cross sections, effectively decrease with diffusion time by ~ 17% due to the coarse-graining over axonal caliber variations. Furthermore, our 3d measurement showed that there is significant variation of the diameter along the axon. Hence, fiber orientation dispersion estimated from MRI should be relatively stable, while the "apparent" inner axonal diameters are sensitive to experimental settings, and cannot be modeled by perfectly cylindrical axons. [ABSTRACT FROM AUTHOR]

Abstract Application of cutting fluids in grinding disc cutting process (GDCP) plays a significant role in minimizing production cost and energy. However, GDCP is significantly different from the grinding wheel grinding process (GWGP) with its very thin disc (3.5 mm), large diameter (400 mm), large cutting depth (several and even ten of millimeters) and no cutting fluids, which lead to a lot of environmental pollution such as sparking, chips splashing, smoke, dust and so on. In this regard, atomization application of water-based cutting fluids is good choice due to less environmental threat in addition to high thermal conductivity and supreme cooling/lubricating efficiency. Besides some eco-friendly properties of additives such as surfactant and graphene, application of such additives eliminates the need for toxic additives used frequently in the industry. Hence, in this study, four types of environmentally friendly water-based cutting fluids (W, W-S, W-G, W-G-S) are prepared by ultrasonic stirring of water, surfactant (sodium alcohol ether sulfate, SAES) and graphene, then their atomization applications are assessed in GDCP of AISI 1045, as one of the most common and representative material in industry application. To optimize these cutting fluids, G-ratio, F x -F y and cutting tilt are compared with those of dry cutting using joint analysis of specific heat, viscosity, wettability, permeability and two-direction force. Also, agglomeration of graphene is proposed to reveal the unexpected reduction in lubrication performance and finally a cutting fluid is developed for minimizing the loss of grinding disc. The obtained results of four types of cutting fluids manifest that the proposed W-S can maximally improve G-ratio by amount of 77.6%, reduce line span by amount of 34.5% and cutting tilt by amount of 14.8% compared with conventional dry cutting. [ABSTRACT FROM AUTHOR]

Electron microscopy (EM) studies of the postmortem human brain provide a level of resolution essential for understanding brain function in both normal and disease states. However, processes associated with death can impair the cellular and organelle ultrastructural preservation required for quantitative EM studies. Although postmortem interval (PMI), the time between death and preservation of tissue, is thought to be the most influential factor of ultrastructural quality, numerous other factors may also influence tissue preservation. The goal of the present study was to assess the effects of pre- and postmortem factors on multiple components of ultrastructure in the postmortem human prefrontal cortex. Tissue samples from 30 subjects were processed using standard EM histochemistry. The primary dependent measure was number of identifiable neuronal profiles, and secondary measures included presence and/or integrity of synapses, mitochondria, and myelinated axonal fibers. Number of identifiable neuronal profiles was most strongly affected by the interaction of PMI and pH, such that short PMIs and neutral pH values predicted the best preservation. Secondary measures were largely unaffected by pre- and postmortem factors. Together, these data indicate that distinct components of the neuropil are differentially affected by PMI and pH in postmortem human brain. [ABSTRACT FROM AUTHOR]

Activity-dependent myelination is a fundamental mode of brain plasticity which significantly influences network function. We recently discovered that absence seizures, which occur in multiple forms of generalized epilepsy, can induce activity-dependent myelination, which in turn promotes further progression of epilepsy. Structural alterations of myelin are likely to be widespread, given that absence seizures arise from an extensive thalamocortical network involving frontoparietal regions of the bilateral hemispheres. However, the temporal course and spatial extent of myelin plasticity is unknown, due to limitations of gold-standard histological methods such as electron microscopy (EM). In this study, we leveraged magnetization transfer and diffusion MRI for estimation of g-ratios across major white matter tracts in a mouse model of generalized epilepsy with progressive absence seizures. EM was performed on the same brains after MRI. After seizure progression, we found increased myelination (decreased g-ratios) throughout the anterior portion (genu-to-body) of the corpus callosum but not in the posterior portion (body-splenium) nor in the fornix or the internal capsule. Curves obtained from averaging g-ratio values at every longitudinal point of the corpus callosum were statistically different with p < 0.001. Seizure-associated myelin differences found in the corpus callosum body with MRI were statistically significant (p = 0.0027) and were concordant with EM in the same region (p = 0.01). Notably, these differences were not detected by diffusion tensor imaging. This study reveals widespread myelin structural change that is specific to the absence seizure network. Furthermore, our findings demonstrate the potential utility and importance of MRI-based g-ratio estimation to non-invasively detect myelin plasticity. • MRI-derived g-ratios detect activity dependent myelination changes. • Widespread but seizure-network specific differences in g-ratio were observed. • G-ratio estimation was more sensitive to myelin changes than DTI alone. [ABSTRACT FROM AUTHOR]

Abstract Quantitative assessment of tissue microstructure is important in studying human brain diseases and disorders in which white matter is implicated, as it has been linked to demyelination, re-myelination, and axonal damage in clinical conditions. Ultra-high field magnetic resonance imaging data obtained using a multi-echo gradient echo sequence has been shown to contain information on myelin, axonal and extracellular compartments in white matter. In this study, we aimed to assess the sensitivity of a three-compartment model to estimate the variation of corresponding compartment parameters (water fraction, relaxation time and frequency shift) of the corpus callosum sub-regions, which are known to have different tissue structure. Additionally, we computed the g-ratio using myelin and axonal water fractions and performed a voxel-by-voxel analysis in the corpus callosum. Based on data acquired for ten participants, we show that the myelin compartment water fraction and T 2 ∗ is consistent across the corpus callosum sub-regions, whilst myelin frequency shift varies. The results show that the variation in water fraction, T 2 ∗ and frequency shift for the myelin signal compartment across the corpus callosum is smaller than for the axonal and extracellular signal compartments. The computed g-ratio was comparable to previously published studies in the corpus callosum. Our study suggests that a multi-echo GRE approach in vivo combined with a complex three-compartment model is sensitive to microstructural parameter variations across the human corpus callosum. Highlights • White matter organisation influences signal compartmentalization. • Myelin water fraction and g-ratio showed similar values across subregions of corpus callosum. • Myelin and axonal frequency shifts vary across the corpus callosum. • Axonal water fraction is higher at the middle of the corpus callosum. [ABSTRACT FROM AUTHOR]

Abstract MR g-ratio, which measures the ratio of the aggregate volume of axons to that of fibers in a voxel, is a potential biomarker for white matter microstructures. In this study, a new approach for acquiring an in-vivo whole human brain g-ratio map is proposed. To estimate the g-ratio, myelin volume fraction and axonal volume fraction are acquired using multi-echo gradient echo myelin water imaging (GRE-MWI) and neurite orientation dispersion and density imaging (NODDI), respectively. In order to translate myelin water fraction measured in GRE-MWI into myelin volume fraction, a new scaling procedure is proposed and validated. This scaling approach utilizes geometric measures of myelin structure and, therefore, provides robustness over previous methods. The resulting g-ratio map reveals an expected range of g-ratios (0.71–0.85 in major fiber bundles) with a small inter-subject coefficient of variance (less than 2%). Additionally, a few fiber bundles (e.g. cortico-spinal tract and optic radiation) show different constituents of myelin volume fraction and axonal volume fraction, indicating potentials to utilize the measures for deciphering fiber tracking. Graphical abstract Image 1 Highlights • A new g-ratio mapping method that combined GRE-MWI with NODDI proposed. • Translation of myelin water fraction into myelin volume fraction developed. • Axonal volume fraction and myelin volume fraction varied among white fiber bundles. [ABSTRACT FROM AUTHOR]

Abstract Microstructural imaging and connectomics are two research areas that hold great potential for investigating brain structure and function. Combining these two approaches can lead to a better and more complete characterization of the brain as a network. The aim of this work is characterizing the connectome from a novel perspective using the myelination measure given by the g-ratio. The g-ratio is the ratio of the inner to the outer diameters of a myelinated axon, whose aggregated value can now be estimated in vivo using MRI. In two different datasets of healthy subjects, we reconstructed the structural connectome and then used the g-ratio estimated from diffusion and magnetization transfer data to characterize the network structure. Significant characteristics of g-ratio weighted graphs emerged. First, the g-ratio distribution across the edges of the graph did not show the power-law distribution observed using the number of streamlines as a weight. Second, connections involving regions related to motor and sensory functions were the highest in myelin content. We also observed significant differences in terms of the hub structure and the rich-club organization suggesting that connections involving hub regions present higher myelination than peripheral connections. Taken together, these findings offer a characterization of g-ratio distribution across the connectome in healthy subjects and lay the foundations for further investigating plasticity and pathology using a similar approach. Highlights • We integrated myelination into the structural connectome using the g-ratio. • The average g-ratio and the number of streamlines follow different patterns. • A myelin blueprint can be observed looking at the hub structure. • The anatomical organization follows patterns consistent with existing literature. [ABSTRACT FROM AUTHOR]

Abstract The fiber g-ratio is the ratio of the inner to the outer diameter of the myelin sheath of a myelinated axon. It has a limited dynamic range in healthy white matter, as it is optimized for speed of signal conduction, cellular energetics, and spatial constraints. In vivo imaging of the g-ratio in health and disease would greatly increase our knowledge of the nervous system and our ability to diagnose, monitor, and treat disease. MRI based g-ratio imaging was first conceived in 2011, and expanded to be feasible in full brain white matter with preliminary results in 2013. This manuscript reviews the growing g-ratio imaging literature and speculates on future applications. It details the methodology for imaging the g-ratio with MRI, and describes the known pitfalls and challenges in doing so. Highlights • This article reviews the recently developed g-ratio imaging framework. • Confounds in the methodology are detailed. • Recent progress and applications are reviewed. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that diet influences the development of autoimmune diseases. However, the influence of diet on axonal damage occurring in EAE (experimental autoimmune encephalomyelitis) has not been examined. In the current study we compared changes in axonal damage and myelin thickness in spinal cords of sham- and MOG (myelin oligodendrocyte glycoprotein) peptide-immunized mice kept on a standard mouse chow (Teklad 7012) versus AIN-93 M chow which was developed for improved animal health. Despite that the development of clinical signs was similar in the 2 groups, there were significant differences in axonal caliber and myelin thickness. Following induction of EAE, axonal caliber was significantly reduced in mice fed Teklad diet, but not those fed the AIN diet. Concomitantly, myelin thickness was decreased by EAE in mice fed Teklad, but not AIN diet. Analysis of g-ratios showed that the increase in g-ratio with increasing axonal size was reduced in mice fed AIN diet. These findings demonstrate that differences in axonal pathology occur in the absence of observable differences in clinical signs, and that inter-study comparisons may be confounded by differences in dietary care. [ABSTRACT FROM AUTHOR]

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, which may trigger vascular thrombosis with consecutive infarcts. However, cognitive dysfunctions representing one of the most commonest neuropsychiatric symptoms are frequently present despite the absence of any ischemic brain lesions. Data on the structural and functional basis of the neuropsychiatric symptoms are sparse. To examine the effect of APS on hippocampal neurogenesis and on white matter, we induced experimental APS (eAPS) in adult female Balb/C mice by immunization with β2-glycoprotein 1. To investigate cell proliferation in the dentate gyrus granular cell layer (DG GCL), eAPS and control mice (n = 5, each) were injected with 5-bromo-2′-deoxyuridine (BrdU) once a day for 10 subsequent days. Sixteen weeks after immunization, eAPS resulted in a significant reduction of BrdU-positive cells in the DG GCL compared to control animals. However, double staining with doublecortin and NeuN revealed a largely preserved neurogenesis. Ultrastructural analysis of corpus callosum (CC) axons in eAPS (n = 6) and control mice (n = 7) revealed no significant changes in CC axon diameter or g-ratio. In conclusion, decreased cellular proliferation in the hippocampus of eAPS mice indicates a limited regenerative potential and may represent one neuropathological substrate of cognitive changes in APS while evidence for alterations of white matter integrity is lacking. [ABSTRACT FROM AUTHOR]

This study aimed to experimentally evaluate a previously proposed MRI method for mapping axonal g-ratio (ratio of axon diameters, measured to the inner and outer boundary of myelin). MRI and electron microscopy were used to study excised and fixed brains of control mice and three mouse models of abnormal white matter. The results showed that g-ratio measured with MRI correlated with histological measures of myelinated axon g-ratio, but with a bias that is likely due to the presence of non-myelinated axons. The results also pointed to cases where the MRI g-ratio model simplifies to be primarily a function of total myelin content. [ABSTRACT FROM AUTHOR]

A recent method, denoted in vivo g-ratio-weighted imaging, has related the microscopic g-ratio, only accessible by ex vivo histology, to noninvasive MRI markers for the fiber volume fraction (FVF) and myelin volume fraction (MVF). Different MRI markers have been proposed for g-ratio weighted imaging, leaving open the question which combination of imaging markers is optimal. To address this question, the repeatability and comparability of four g-ratio methods based on different combinations of, respectively, two imaging markers for FVF (tract-fiber density, TFD, and neurite orientation dispersion and density imaging, NODDI) and two imaging markers for MVF (magnetization transfer saturation rate, MT, and, from proton density maps, macromolecular tissue volume, MTV) were tested in a scan-rescan experiment in two groups. Moreover, it was tested how the repeatability and comparability were affected by two key processing steps, namely the masking of unreliable voxels (e.g., due to partial volume effects) at the group level and the calibration value used to link MRI markers to MVF (and FVF). Our data showed that repeatability and comparability depend largely on the marker for the FVF (NODDI outperformed TFD), and that they were improved by masking. Overall, the g-ratio method based on NODDI and MT showed the highest repeatability (90%) and lowest variability between groups (3.5%). Finally, our results indicate that the calibration procedure is crucial, for example, calibration to a lower g-ratio value ( g = 0.6) than the commonly used one ( g = 0.7) can change not only repeatability and comparability but also the reported dependency on the FVF imaging marker. Hum Brain Mapp 39:24-41, 2018. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND: Peripheral nerve injury is a common disease in clinic, which severely affects the patients' quality of life. How to promote peripheral nerve regeneration is an issue of concern. OBJECTIVE: To study the effect of modified rabbit defensin 1 on peripheral nerve regeneration and functional recovery. METHODS: Eighteen Sprague-Dawley rats were randomly divided into three groups. The rat sciatic nerves were transected and bridged by biodegenerated chitin conduits, followed by the injection of neurotrophic factor (group 1), modified rabbit defensin 1 (group 2) and normal saline (control group) into the gluteus, respectively, for consecutive 7 days. RESULTS AND CONCLUSION: The sciatic nerve function index in the groups 1 and 2 was higher than that in the control group at 4 weeks postoperatively. The order of motor nerve conductive velocity was as follows: group 1 > group 2 > control group. The diameter regenerated fibers and axons, and the myelin thickness in the group 2 were less than those in the group 1, but were more than those in the control group. These results indicate that the modified rabbit defensin 1 can promote peripheral nerve regeneration, which may be related with the clearance of residual myelin by macrophages and the improvement in nerve regeneration environment. [ABSTRACT FROM AUTHOR]

We investigated the microscopic structure of transverse sections of the oculomotor, trochlear and abducens nerves of Arabian foals using stereological methods. Bilateral nerve pairs from 2-month-old female Arabian foals were analyzed. The tissues were embedded in plastic blocks, then 1 µm thick sections were cut and stained with osmium tetroxide and methylene blue-azure II. Stereology was performed using light microscopy. Morphometry showed that the right and left pairs of nerves were similar. The transverse sectional areas of the oculomotor, trochlear and abducens nerves were 1.93 ± 0.19 mm2, 0.32 ± 0.06 mm2and 0.70 ± 0.08 mm2, respectively. The oculomotor nerve exhibited a significantly greater number of myelinated axons (16755 ± 1279) and trochlear (2656 ± 494) and the abducens nerves (4468 ± 447). The ratio of the axon diameter to myelinated nerve fiber diameter was 0.58, 0.55 and 0.55 for the oculomotor, trochlear and abducens nerves, respectively. Of the three nerves studied, the abducens nerve exhibited the greatest nerve fiber area, myelin area, nerve and axon diameters, and myelin thickness. The ratio of small myelinated nerve fibers was greatest in the oculomotor nerve. [ABSTRACT FROM AUTHOR]

The fiber g-ratio is defined as the ratio of the inner to the outer diameter of the myelin sheath. This ratio provides a measure of the myelin thickness that complements axon morphology (diameter and density) for assessment of demyelination in diseases such as multiple sclerosis. Previous work has shown that an aggregate g-ratio map can be computed using a formula that combines axon and myelin density measured with quantitative MRI. In this work, we computed g-ratio weighted maps in the cervical spinal cord of nine healthy subjects. We utilized the 300 mT/m gradients from the CONNECTOM scanner to estimate the fraction of restricted water ( fr ) with high accuracy, using the CHARMED model. Myelin density was estimated using the lipid and macromolecular tissue volume (MTV) method, derived from normalized proton density (PD) mapping. The variability across spinal level, laterality and subject were assessed using a three-way ANOVA. The average g-ratio value obtained in the white matter was 0.76+/−0.03, consistent with previous histology work. Coefficients of variation of fr and MTV were respectively 4.3% and 13.7%. fr and myelin density were significantly different across spinal tracts (p=3×10 −7 and 0.004 respectively) and were positively correlated in the white matter (r=0.42), suggesting shared microstructural information. The aggregate g-ratio did not show significant differences across tracts (p=0.6). This study suggests that fr and myelin density can be measured in vivo with high precision and that they can be combined to produce a g-ratio-weighted map robust to free water pool contamination from cerebrospinal fluid or veins. Potential applications include the study of early demyelination in multiple sclerosis, and the quantitative assessment of remyelination drugs. [ABSTRACT FROM AUTHOR]