Assessing regional intracortical myelination in schizophrenia spectrum and bipolar disorders using the optimized T1w/T2w-ratio.

BACKGROUND: Dysmyelination could be part of the pathophysiology of schizophrenia spectrum (SCZ) and bipolar disorders (BPD), yet few studies have examined myelination of the cerebral cortex. The ratio of T1- and T2-weighted magnetic resonance images (MRI) correlates with intracortical myelin. We investigated the T1w/T2w-ratio and its age trajectories in patients and healthy controls (CTR) and explored associations with antipsychotic medication use and psychotic symptoms. METHODS: Patients with SCZ (n = 64; mean age = 30.4 years, s.d. = 9.8), BPD (n = 91; mean age 31.0 years, s.d. = 10.2), and CTR (n = 155; mean age = 31.9 years, s.d. = 9.1) who participated in the TOP study (NORMENT, University of Oslo, Norway) were clinically assessed and scanned using a General Electric 3 T MRI system. T1w/T2w-ratio images were computed using an optimized pipeline with intensity normalization and field inhomogeneity correction. Vertex-wise regression models were used to compare groups and examine group × age interactions. In regions showing significant differences, we explored associations with antipsychotic medication use and psychotic symptoms. RESULTS: No main effect of diagnosis was found. However, age slopes of the T1w/T2w-ratio differed significantly between SCZ and CTR, predominantly in frontal and temporal lobe regions: Lower T1w/T2w-ratio values with higher age were found in CTR, but not in SCZ. Follow-up analyses revealed a more positive age slope in patients who were using antipsychotics and patients using higher chlorpromazine-equivalent doses. CONCLUSIONS: While we found no evidence of reduced intracortical myelin in SCZ or BPD relative to CTR, different regional age trajectories in SCZ may suggest a promyelinating effect of antipsychotic medication.

Non-Invasive High-Resolution Imaging of In Vivo Human Myelinated Axons.

This work aims to reveal the microscopic (2-3 micrometer resolution) appearance of human myelinated nerve fibers in vivo for the first time. We analyzed the myelinated retinal nerve fibers of a male patient without other neurological disorders in a non-invasive way using the transscleral optical phase imaging method with adaptive optics. We also analyzed the fellow eye with non-myelinated nerve fibers and compared the results with traditional ocular imaging methods such as optical coherence tomography. We documented the microscopic appearance of human myelin and myelinated axons in vivo. This method allowed us to obtain better details than through traditional ocular imaging methods. We hope these findings will be useful to the scientific community to evaluate neuro-retinal structures through new imaging techniques and more accurately document nerve anatomy and the pathophysiology of this disease.

miR-34a/TAN1/CREB Axis Engages in Alleviating Oligodendrocyte Trophic Factor-Induced Myelin Repair Function and Astrocyte-Dependent Neuroinflammation in the Early Stages of Alzheimer's Disease: The Anti-Neurodegenerative Effect of Treadmill Exercise.

Reduced myelin stability observed in the early stages of Alzheimer's disease leads to spatial learning and memory impairment. Exercise has been shown to protect nerves, reduce the risk of Alzheimer's disease, and strengthen synaptic connectivity. However, the underlying mechanisms of how exercise can promote myelin repair and coordinate inflammation and proliferation are still uncertain. In this study, we conducted histological and biochemical assays of cortical lysates after behavioral testing to detect pathological changes, myelin sheath thickness, and mRNA and protein levels. It is notable that D-galactose model mice exhibited elevated miRNA-34a levels, overactive astrocytes, decreased myelin staining scores, increased apoptosis, and decreased synaptic plasticity in the brain. Significantly, after eight weeks of exercise, we observed improvements in LFB scores, NeuN( +) neuron counts, and myelin basic protein (MBP) expression. Additionally, exercise promoted the expression of oligodendrocyte markers Olig2 and PDFGR-α associated with brain proliferation, and improved spatial cognitive function. Furthermore, it decreased the inflammation caused by astrocyte secretions (TNF-α, Cox-2, CXCL2). Interestingly, we also observed downregulation of miR-34a and activation of the TAN1/PI3K/CREB signaling pathway. Our data shed light on a previously unsuspected mechanism by which exercise reduces miR-34a levels and protects neuronal function and survival by preventing excessive demyelination and inflammatory infiltration in the CNS.

Efficacy and Safety of the Natural Killer T Cell-Stimulatory Glycolipid OCH-NCNP1 for Patients With Relapsing Multiple Sclerosis: Protocol for a Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. OBJECTIVE: This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. METHODS: This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica-immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). RESULTS: We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. CONCLUSIONS: This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46709.

Fluorescence and magnetic resonance imaging of ONL-93 cells in a rat model of ischemic.

OBJECTIVES: The current methods for detecting myelin changes in ischemic stroke are indirect and cannot accurately reflect their status. This study aimed to develop a novel fluorescent-magnetic resonance dual-modal molecular imaging probe for direct imaging of myelin. METHODS: Compounds 7a and 7b were synthesized by linking the MeDAS group and Gadolinium (III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. Compound 7a was selected for characterization and further study. Cell uptake, cytotoxicity, and magnetic resonance imaging scans were performed on cells. In vitro experiments on frozen brain sections from 7-day-old, 8-week-old, and ischemic stroke rats were compared with commercially available Luxol Fast Blue staining. After HPLC and MR scanning, brain tissue was soaked in 7a and scanned using T1WI and T1maps sequences. RESULTS: Spectrophotometer results showed that compounds 7a and 7b had fluorescent properties. MR scans indicated that the compounds had contrast agent properties. Cells could uptake 7a and exhibited high signals in imaging scans. Compound 7a brain tissue staining showed more fluorescence in myelin-rich regions and identified injury sites in ischemic stroke rats. MR scanning of brain sections provided clear myelin contrast. CONCLUSION: A novel fluorescent-magnetic resonance dual-modal molecular imaging probe for direct imaging of myelin was successfully developed and tested in rats with ischemic stroke. These findings provide new insights for the clinical diagnosis of demyelinating diseases.

The Effects and Mechanism of Scutellaria baicalensis Georgi Stems and Leaves Flavonoids on Myelin Sheath Degeneration Induced by Composite Aß in Rats.

BACKGROUND: Alzheimer's disease is a degenerative disease of the central nervous system, and its characteristic pathological changes are closely associated with Aß deposition and neurofibrillary tangles. Many studies have found that malignant changes in the myelin sheath and oligodendrocyte (OL) are accompanied by the occurrence and development of AD. Therefore, any method that can resist myelin sheath and OL disorders may be a potential strategy for AD. OBJECTIVE: To investigate the effects and mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on the myelin sheath degeneration induced by Aß25-35 combined with AlC13 and RHTGF-ß1 (composite Aß) in rats. METHODS: A rat AD model was established by intracerebroventricular injection of composite Aß. The Morris water maze was used to screen the memory impairment rat model. The successful model rats were divided into the model group and the 35, 70, and 140 mg/kg SSFS groups. The myelin sheath changes in the cerebral cortex were observed with an electron microscope. The expression of the oligodendrocyte- specific protein claudin 11 was detected with immunohistochemistry. The protein expression levels of myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG) and myelin basic protein (MBP), sphingomyelin synthase-1 (SMS1), and sphingomyelinase-2 (SMPD2) were assayed by Western blotting. RESULTS: The intracerebroventricular injection of composite Aß caused degeneration of the myelin sheath structure and was accompanied by the decreased claudin 11, MOG, MAG, MBP, and SMS1, and increased SMPD2 protein expression in the cerebral cortex. However, 35, 70, and 140 mg/kg SSFs can differentially ameliorate the above abnormal changes induced by composite Aß. CONCLUSION: SSFs can alleviate myelin sheath degeneration and increase the protein expression of claudin 11, MOG, MAG, and MBP, and the effective mechanism may be related to the positive regulation of SMS1 and SMPD2 activities.

Characteristics of Patients Diagnosed With Guillain-Barré Syndrome at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, From 2000 to 2018.

BACKGROUND: Guillain-Barré syndrome (GBS) is the leading cause of non-polio acute flaccid paralysis worldwide, emphasizing the importance of epidemiological studies on this condition. Therefore, well-designed epidemiological studies in different populations can provide a better understanding of the characteristics of patients with GBS and the nature of the disease. To our knowledge, no previous study has attempted to describe the characteristics of patients with GBS in Kingdom of Saudi Arabia (KSA) based on disease subtypes and clinical features in both adult and pediatric patients. This study aimed to assess the frequencies of GBS subtypes and their relationships with patient characteristics and clinical data in a tertiary hospital in Jeddah, KSA. METHODS: This was a retrospective review of patients diagnosed with GBS between January 2000 and January 2018 at King Abdulaziz University Hospital (KAUH), a tertiary center in Jeddah, KSA. RESULTS: In total, 47 patients with GBS (median age: seven years for pediatric and 36 years for adult patients) were included in the current study. There were six male and three female pediatric patients and 19 male and 19 female adult patients. Among patients with GBS who were classified into a specific electrophysiological subtype (n = 28), 13 (46.2%) had acute inflammatory demyelinating polyneuropathy (AIDP), 11 (39%) had an axonal subtype, and four (14%) had Miller Fisher syndrome (MFS). Patients required prolonged hospitalization of approximately 20 ± 22 days (2.83 ± 3.11 weeks). Patients with MFS were more likely to have higher cytoalbuminologic dissociation than those with other subtypes. CONCLUSION: AIDP was the most frequent type of GBS, followed by the axonal type. Patients required prolonged hospitalization of approximately 20 ± 22 days (2.83 ± 3.11 weeks). Patients with MFS were more likely to have higher cytoalbuminologic dissociation than those with other subtypes. GBS type did not show a relationship with ICU admission or mechanical ventilation use. There was no association between specific therapies and different GBS subtypes and no significant difference in outcomes between different patterns of clinical presentation. Intravenous immunoglobulin (IVIg) and plasma exchange (PE) treatments both had the same efficacy in relation to outcomes for patients with GBS.

P2Y12 receptor mediates apoptosis and demyelination to affect functional recovery in mice with spinal cord injury.

Among diseases of the central nervous system (CNS), spinal cord injury (SCI) has a high fatality rate. It has been proven that P2Y G protein-coupled purinergic receptors have a neuroprotective role in apoptosis and regeneration inside the damaged spinal cord. The P2Y12 receptor (P2Y12R) has recently been linked to peripheral neuropathy and stroke. However, the role of P2Y12R after SCI remains unclear. Our study randomly divided C57BL/6J female mice into 3 groups: Sham+DMSO, SCI+DMSO, and SCI+MRS2395. MRS2395 as a P2Y12R inhibitor was intraperitoneally injected at a dose of 1.5 mg/kg once daily for 7 days. We showed that the P2Y12R was markedly activated after injury, and it was double labeled with the microglial and neuron. Behavioral tests were employed to assess motor function recovery. By using immunofluorescence staining, the NeuN expression level was detected. The morphology of neurons was observed by hematoxylin-eosin and Nissl staining. P2Y12R, Bax, GFAP, PCNA and calbindin expression levels were detected using Western blot. Meanwhile, mitochondria and myelin sheath were observed by transmission electron microscopy (TEM). Our findings demonstrated that MRS2395 significantly enhanced motor function induced by SCI and that was used to alleviate apoptosis and astrocyte scarring. NeuN positive cells in the SCI group were lower than in the therapy group, although Bax, GFAP, PCNA and calbindin expression levels were considerably higher. Moreover, following MRS2395 therapy, the histological damage was reversed. A notable improvement in myelin sheath and mitochondrial morphology was seen in the therapy group. Together, our findings indicate that activation of P2Y12R in damaged spinal cord may be a critical event and suggest that inhibition of P2Y12R might be a feasible therapeutic strategy for treating SCI.

Mechanical Responses of a Single Myelin Layer: A Molecular Simulation Study.

The myelin sheath provides insulation to the brain's neuron cells, which aids in signal transmission and communication with the body. Degenerated myelin hampers the connection between the glial cells, which are the front row responders during traumatic brain injury mitigation. Thus, the structural integrity of the myelin layer is critical for protecting the brain tissue from traumatic injury. At the molecular level, myelin consists of a lipid bilayer, myelin basic proteins (MBP), proteolipid proteins (PLP), water and ions. Structurally, the myelin sheath is formed by repeatedly wrapping forty or more myelin layers around an axon. Here, we have used molecular dynamic simulations to model and capture the tensile response of a single myelin layer. An openly available molecular dynamic solver, LAMMPS, was used to conduct the simulations. The interatomic potentials for the interacting atoms and molecules were defined using CHARMM force fields. Following a standard equilibration process, the molecular model was stretched uniaxially at a deformation rate of 5 Å/ps. We observed that, at around 10% applied strain, the myelin started to cohesively fail via flaw formation inside the bilayers. Further stretching led to a continued expansion of the defect inside the bilayer, both radially and transversely. This study provides the cellular-level mechanisms of myelin damage due to mechanical load.

Aerobic exercise attenuates abnormal myelination and oligodendrocyte differentiation in 3xTg-AD mice.

Pathological features of Alzheimer's Disease (AD) include alterations in the structure and function of neurons as well as of myelin sheaths. Accumulated evidence shows that aerobic type of exercise can enhance neuroplasticity in mouse models of AD. However, whether and how aerobic exercise can affect myelin sheath repair and neuroprotection in the AD models remains unclear. In this study we tested the hypotheses that 1) myelin structural alterations in 3xTg-AD mice would be related to abnormalities in oligodendrocyte lineage cells, resulting in impaired learning and memory, and 2) a 6-month aerobic exercise intervention would have beneficial effects on such alterations. Two-month-old male 3xTg-AD mice were randomly assigned to a control (AC) or an exercise (AE) group, and age-matched male C57BL/6;129 mice were also randomly assigned to a normal control (NC) or an exercise (NE) group, with n = 12 in each group. Mice in the exercise groups were trained on a motor-drive treadmill, 60 min per day, 5 days per week for 6 months. Cognitive function was assessed at the end of the intervention period. Then, brain specimens were obtained for assessments of morphological and oligodendrocyte lineage cell changes. The results of electron microscopy showed that myelin ultrastructure demonstrated a higher percentage of loose and granulated myelin sheath around axons in the temporal lobe in the AC, as compared with the NC group, along with greater cognitive dysfunction at 8-months of age. These differences were accompanied by significantly greater myelin basic protein (MBP) expression and less neuron-glial antigen-2 (NG2) protein and mRNA levels in the AC, compared to the NC. However, there were no significant between-group differences in the G-ratio (the ratio of axon diameter to axon plus myelin sheath diameter) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) protein and mRNA levels. The aerobic exercise ameliorated cognitive deterioration and appeared to keep components of myelin sheath and oligodendrocyte precursor cells stabilized, resulting in a decrease in the percentage of loose and granulated myelin sheath and MBP protein, and an increase in NG2 protein and mRNA levels in the AE group. Therefore, the 6-month exercise intervention demonstrated beneficial effects on myelin lesions, abnormal differentiation of oligodendrocytes and general brain function in the 3xTg-AD mice, providing further insights into the role of aerobic exercise in management of neurodegeneration in AD by maintaining intact myelination.

Radiation-dependent demyelination in normal appearing white matter in glioma patients, determined using quantitative magnetic resonance imaging.

Background and purpose: A brain tumour, especially a glioma, is a rare disease; it is challenging to treat and the prognosis is often poor. Routine care includes surgery and concomitant chemoradiotherapy (CRT). Diagnostic work-up and treatment effects are typically evaluated using magnetic resonance imaging (MRI). Quantitative MRI (qMRI), unlike conventional MRI, has the advantage of providing tissue-specific relaxation rates and proton density. The purpose is to detect changes in normal appearing white matter (NAWM) in brain tumour patients after CRT using qMRI. Materials & methods: NAWM was analysed in 10 patients, in 83 MR examinations performed before and after surgery and after CRT. Relaxation rates R1 and R2, the proton density (PD) and the concentration of myelin (cMy) were calculated from the qMRI scans and analysed in correlation to radiation dose and time after treatment. Results: A significant decrease in cMy between pre-treatment imaging and first follow-up and an increase in PD were observed. For low doses (less than 30 Gy) PD and cMy returned to baseline (=pre-operative status), while for high doses (>30 Gy) the change increased during the full extent of the follow-up period. No difference could be established for R1. For R2 an increase was observed during the first year, which then gradually returned to baseline. For R2, stronger effects were seen as a consequence of higher absorbed doses. Conclusion: In the long-term follow-up for glioma patients, qMRI is a powerful tool for detecting small changes, such as a decrease of myelin concentration, in NAWM after CRT.

Type III NRG-1 plays a regulatory role in the regeneration process of nerves from the beginning of transplantation.

The present study investigated the effect of type III Neuregulin-1 (NRG-1) on changes in the myelin sheath and the recovery of nerve function during the regeneration process following autologous nerve transplantation. Seventy-two Sprague-Dawley rats were divided into a Blank, Model and (antisense oligonucleotide, ASON) group. The Model and ASON groups of SD rats were subjected to autologous nerve transplantation, and the Blank group only had the sciatic nerve exposed. The Model and ASON groups were given local injections of 2 ml PBS buffer solution and 2 ml ASON of Type III NRG-1, respectively, the NRG-1 type III was inhibited by ASON. Changes in the sciatic nerve functional index (SFI) and conduction velocities were observed at different 6 time points. Regeneration of the myelin sheath was observed using transmission electron microscopy. Type III NRG-1 protein was detected using Western blotting and immunohistochemistry, and NRG-1 mRNA was detected using PCR. The SFI of the ASON group was lower than the Model group after transplantation. The conduction velocities of the ASON group on the 14th and 21st days after autologous nerve transplantation were lower than the Model group (P < 0.01). The protein and mRNA expression of type III NRG-1 in the ASON group was lower than the Model group at all 6 time points. The area of medullated nerve fibres was significantly different between the ASON group and the Model group on the 3rd day (P < 0.05), as was the number of medullated nerve fibres per unit area (P < 0.01). The diameter of axons was obviously different between the two groups (P < 0.01). Type III NRG-1 played an important regulatory role in the regeneration process of the nerve from the beginning of transplantation to the 28th day.

Potential role of Schwann cells in neuropathic pain.

Neuropathic pain (NPP) is a common syndrome associated with most forms of disease, which poses a serious threat to human health. NPP may persist even after the nociceptive stimulation is eliminated, and treatment is extremely challenging in such cases. Schwann cells (SCs) form the myelin sheaths around neuronal axons and play a crucial role in neural information transmission. SCs can secrete trophic factors to nourish and protect axons, and can further secrete pain-related factors to induce pain. SCs may be activated by peripheral nerve injury, triggering the transformation of myelinated and non-myelinated SCs into cell phenotypes that specifically promote repair. These differentiated SCs provide necessary signals and spatial clues for survival, axonal regeneration, and nerve regeneration of damaged neurons. They can further change the microenvironment around the regions of nerve injury, and relieve the pain by repairing the injured nerve. Herein, we provide a comprehensive overview of the biological characteristics of SCs, discuss the relationship between SCs and nerve injury, and explore the potential mechanism of SCs and the occurrence of NPP. Moreover, we summarize the feasible strategies of SCs in the treatment of NPP, and attempt to elucidate the deficiencies and defects of SCs in the treatment of NPP.

Structural dynamics of moonlighting intrinsically disordered proteins - A black box in multiple sclerosis.

Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system that disturbs the flow of brain signals to other parts of the body. The actual cause of the disease is still not apparent. The intrinsically disordered proteins (IDP) play a crucial role in neurodegenerative diseases like Alzheimer's, Lewy bodies, Parkinson's, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, etc. In MS, it was known that the immune system attacks the proteins like Myelin Basic Protein (MBP), Myelin-associated Oligodendrocyte Basic protein (MOBP), Myelin-Associated Protein (MAG), and Myelin Proteolipid Protein (PLP) and this leads to demyelination causing MS. Here the proteins MBP and MOBP are both moonlighting intrinsically disordered proteins and exist between the myelin sheath, unlike MAG which is a transmembrane protein. The main focus of the article was to examine the significant role of proteins intrinsically disordered regions (IDR) in maintaining their function. Molecular dynamics simulation studies were performed to study the conformational dynamics of these protein IDRs both in water and near the myelin sheath. The results suggest that the IDR dominates the structural dynamics of these proteins and IDR in both proteins was responsible for their interaction with the myelin sheath. Interestingly, it was noted that the known epitopes MBP83-96 and MOBP65-87 in the IDR have no interaction with the myelin sheath. Thus when the protein remains intrinsically disordered it maintains the proper function and myelin integrity and if it adopts folds the region was identified as an epitope by the immune system leading to demyelination causing MS.

A step toward restoring hand functions in patients with multiple sclerosis-a study protocol.

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation, demyelination of axons, and oligodendrocyte loss in the central nervous system. This leads to neurological dysfunction, including hand impairment, which is prevalent among patients with MS. However, hand impairment is the least targeted area for neurorehabilitation studies. Therefore, this study proposes a novel approach to improve hand functions compared to current strategies. Studies have shown that learning new skills in the motor cortex (M1) can trigger the production of oligodendrocytes and myelin, which is a critical mechanism for neuroplasticity. Transcranial direct current stimulation (tDCS) has been used to enhance motor learning and function in human subjects. However, tDCS induces non-specific effects, and concurrent behavioral training has been found to optimize its benefits. Recent research indicates that applying tDCS during motor learning can have priming effects on the long-term potentiation mechanism and prolong the effects of motor training in health and disease. Therefore, this study aims to assess whether applying repeated tDCS during the learning of a new motor skill in M1 can be more effective in improving hand functions in patients with MS than current neurorehabilitation strategies. If this approach proves successful in improving hand functions in patients with MS, it could be adopted as a new approach to restore hand functions. Additionally, if the application of tDCS demonstrates an accumulative effect in improving hand functions in patients with MS, it could provide an adjunct intervention during rehabilitation for these patients. This study will contribute to the growing body of literature on the use of tDCS in neurorehabilitation and could have a significant impact on the quality of life of patients with MS.

A RhoA-mediated biomechanical response in Schwann cells modulates peripheral nerve myelination.

Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional mechanical and biochemical signaling to form the myelin sheath but the mechanism underlying this process is not understood. Rho GTPases are integrators of "outside-in" signaling that link cytoskeletal dynamics with cellular architecture to regulate morphology and adhesion. Using Schwann cell-specific gene inactivation in the mouse, we discovered that RhoA promotes the initiation of myelination, and is required to both drive and terminate myelin growth at different stages of peripheral myelination, suggesting developmentally-specific modes of action. In Schwann cells, RhoA targets actin filament turnover, via Cofilin 1, actomyosin contractility and cortical actin-membrane attachments. This mechanism couples actin cortex mechanics with the molecular organization of the cell boundary to target specific signaling networks that regulate axon-Schwann cell interaction/adhesion and myelin growth. This work shows that RhoA is a key component of a biomechanical response required to control Schwann cell state transitions for proper myelination of peripheral nerves.

Promoting the Differentiation of Neural Progenitor Cells into Oligodendrocytes through the Induction of Olig2 Expression: A Transcriptomic Study Using RNA-seq Analysis.

Oligodendrocytes are the myelinating cells of the central nervous system that facilitate efficient signal transduction. The loss of these cells and the associated myelin sheath can lead to profound functional deficits. Moreover, oligodendrocytes also play key roles in mediating glial-neuronal interactions, which further speaks to their importance in health and disease. Neural progenitor cells (NPCs) are a promising source of cells for the treatment of oligodendrocyte-related neurological diseases due to their ability to differentiate into a variety of cell types, including oligodendrocytes. However, the efficiency of oligodendrocyte differentiation is often low. In this study, we induced the expression of the Olig2 transcription factor in tripotent NPCs using a doxycycline-inducible promoter, such that the extent of oligodendrocyte differentiation could be carefully regulated. We characterized the differentiation profile and the transcriptome of these inducible oligodendrogenic NPCs (ioNPCs) using a combination of qRT-PCR, immunocytochemistry and RNA sequencing with gene ontology (GO) and gene set enrichment analysis (GSEA). Our results show that the ioNPCs differentiated into a significantly greater proportion of oligodendrocytes than the NPCs. The induction of Olig2 expression was also associated with the upregulation of genes involved in oligodendrocyte development and function, as well as the downregulation of genes involved in other cell lineages. The GO and GSEA analyses further corroborated the oligodendrocyte specification of the ioNPCs.

Enhancement of oligodendrocyte autophagy alleviates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion in rats.

Cognitive impairment caused by chronic cerebral hypoperfusion (CCH) is associated with white matter injury (WMI), possibly through the alteration of autophagy. Here, the autophagy-lysosomal pathway (ALP) dysfunction in white matter (WM) and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion (2VO). The results showed that cognitive impairment occurred by the 28th day after 2VO. Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day. By the 14th day, abnormal accumulation of autophagy substrate, lysosomal dysfunction, and the activation of mechanistic target of rapamycin (MTOR) pathway were observed in WM, paralleled with mature oligodendrocyte death. This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction. To target the ALP dysfunction, enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1 (BECN1) in oligodendrocytes reduced mature oligodendrocyte death, and subsequently alleviated the WMI and cognitive impairment after CCH. These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO, which was associated with the aggravation of WMI and cognitive impairment. This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.

Myelin sheath injury and repairment after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) can lead to damage to the myelin sheath in white matter. Through classification and analysis of relevant research results, the discussion in this paper provides a deeper understanding of the spatiotemporal change characteristics, pathophysiological mechanisms and treatment strategies of myelin sheath injury after SAH. The research progress for this condition was also systematically reviewed and compared related to myelin sheath in other fields. Serious deficiencies were identified in the research on myelin sheath injury and treatment after SAH. It is necessary to focus on the overall situation and actively explore different treatment methods based on the spatiotemporal changes in the characteristics of the myelin sheath, as well as the initiation, intersection and common action point of the pathophysiological mechanism, to finally achieve accurate treatment. We hope that this article can help researchers in this field to further clarify the challenges and opportunities in the current research on myelin sheath injury and treatment after SAH.

Peripheral Nerve Injury Induced by Japanese Encephalitis Virus in C57BL/6 Mouse.

Japanese encephalitis virus (JEV), with neurotoxic and neuroinvasive properties, is the major cause of human viral encephalitis in Asia. Although Guillain-Barré syndrome caused by JEV infections is not frequent, a few cases have been reported in recent years. To date, no existing animal model for JEV-induced peripheral nerve injury (PNI) has been established, and thus the pathogenic mechanism is not clarified. Therefore, an animal model is urgently required to clarify the correlation between JEV infection and PNI. In the present study, we used JEV GIb strain of NX1889 to establish a mouse model of JEV infection. The general neurological signs emerged on day 3 of modeling. The motor function continued to deteriorate, reaching a maximum at 8 to 13 days postinfection (dpi) and gradually recovered after 16 dpi. The injuries of 105 PFU and 106 PFU groups were the most severe. Transmission electron microscopy and immunofluorescence staining showed varying degrees of demyelination and axonal degeneration in the sciatic nerves. The electrophysiological recordings demonstrated the presence of demyelinating peripheral neuropathy with reduced nerve conduction velocity. The decreased amplitudes and the prolonged end latency revealed axonal-type motor neuropathy. Demyelination is predominant in the early stage, followed by axonal injury. The expression level of JEV-E protein and viral RNA was elevated in the injured sciatic nerves, suggesting that it may cause PNI at the early stage. Inflammatory cell infiltration and increased inflammatory cytokines indicated that neuroinflammation is involved in JEV-induced PNI. IMPORTANCE JEV is a neurotropic flavivirus belonging to the Flaviviridae family and causes high mortality and disability rates. It invades the central nervous system and induces acute inflammatory injury and neuronal death. Thus, JEV infection is a major global public health concern. Previously, motor dysfunction was mainly attributed to central nervous system damage. Our knowledge regarding JEV-induced PNI is vague and neglected. Therefore, a laboratory animal model is essential. Herein, we showed that C57BL/6 mice can be used to study JEV-induced PNI through multiple approaches. We also demonstrated that viral loads might be positively correlated with lesion severity. Therefore, inflammation and direct virus infection may be the putative mechanisms underlying JEV-induced PNI. The results of this study laid the foundation for further elucidation of the pathogenesis mechanisms of PNI caused by JEV.