Although microvascular decompression (MVD) is a reliable treatment for hemifacial spasm (HFS), postoperative delayed relief is one of its main issues. We previously evaluated the morphology of the lateral spread response (LSR) and reported correlation between delayed relief after MVD and polyphasic morphology of the LSR. This study aimed to investigate the morphology of LSR and the course of recovery of the compound motor action potential (CMAP), to better understand the pathophysiology of delayed healing of HFS. Based on the pattern of the initial LSR morphology on temporal and marginal mandibular branches stimulation, patients were divided into two groups: the monophasic and polyphasic groups. The results of MVD surgery and sequential changes in the CMAP were evaluated 1 week, 1 month, 1 year, and final follow-up after the surgery. Significantly higher rates of persistent postoperative HFS were observed in patients with the polyphasic type of initial LSR at 1 week and 1 month after the surgery (P < 0.05, respectively). In the polyphasic group, the amplitude of the CMAP tended to gradually improve with time, while in the monophasic group, the amplitude of the CMAP decreased on the seventh postoperative day, followed by its gradual improvement. There is a significant correlation between delayed relief after MVD and polyphasic morphology of the initial LSR in patients with HFS. In the polyphasic group, CMAP recovered earlier and showed less reduction in amplitude, suggesting segmental demyelination, with less damage to peripheral nerves.

BACKGROUND: Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice.
METHODS: We examined whether arketamine can improve both depression-like behaviors and demyelination in the brains of CRS-exposed mice. Additionally, we investigated the role of transforming growth factor β1 (TGF-β1) in the beneficial effects of arketamine.
RESULTS: A single dose of arketamine (10 mg/kg) improved both depression-like behavior and demyelination in the corpus callosum of CRS-exposed mice. Correlations were found between depression-like behaviors and demyelination in this region. Furthermore, pretreatment with RepSox, an inhibitor of TGF-β1 receptor, significantly blocked the beneficial effects of arketamine on depression-like behaviors and demyelination in CRS-exposed mice. Finally, a single intranasal administration of TGF-β1 ameliorated both depression-like behaviors and demyelination in CRS-exposed mice.
CONCLUSIONS: The precise mechanisms by which TGF-β1 contributes to the effects of arketamine remain unclear.
CONCLUSIONS: These data suggest that CRS-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and that arketamine can mitigate these changes through a TGF-β1-dependent mechanism.

BACKGROUND: In sepsis-associated encephalopathy (SAE), the activation of microglial cells and ensuing neuroinflammation are important in the underlying pathological mechanisms. Increasing evidence suggests that the protein Piezo1 functions as a significant regulator of neuroinflammation. However, the influence of Piezo1 on microglial cells in the context of SAE has not yet been determined. This study aims to investigate the role of Piezo1 in microglial cells in the context of SAE.
METHODS: By inducing cecal ligation and puncture (CLP), a mouse model of SAE was established, while the control group underwent a sham surgery in which the cecum was exposed without ligation and puncture. Piezo1 knockout mice were employed in this study. Morris water maze tests were conducted between Days 14 and 18 postop to assess both the motor activity and cognitive function. A proteomic analysis was conducted to assess the SAE-related pathways, whereas a Mendelian randomization analysis was conducted to identify the pathways associated with cognitive impairment. Dual-label immunofluorescence and flow cytometry were used to assess the secretion of inflammatory factors, microglial status, and oligodendrocyte development. Electron microscopy was used to evaluate axonal myelination. A western blot analysis was conducted to evaluate the influence of Piezo1 on oligodendrocyte ferroptosis.
RESULTS: The results of the bioinformatics analysis have revealed the significant involvement of CCL25 in the onset and progression of SAE-induced cognitive impairment. SAE leads to cognitive dysfunction by activating the microglial cells. The release of CCL25 by the activated microglia initiates the demyelination of oligodendrocytes in the hippocampus, resulting in ferroptosis and the disruption of hippocampal functional connectivity. Of note, the genetic knockout of the Piezo1 gene mitigates these changes. The treatment with siRNA targeting Piezo1 effectively reduces the secretion of inflammatory mediators CCL25 and IL-18 by inhibiting the p38 pathway, thus preventing the ferroptosis of oligodendrocytes through the modulation of the CCL25/GPR78 axis.
CONCLUSIONS: Piezo1 is involved in the activation of microglia and demyelinating oligodendrocytes in the animal models of SAE, resulting in cognitive impairment. Consequently, targeting Piezo1 suppression can be a promising approach for therapeutic interventions aimed at addressing cognitive dysfunction associated with SAE.

Multiple sclerosis, neuromyelitis optica, Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy are representative demyelinating diseases of the central and peripheral nervous system. Remyelination by myelin forming cells is important for functional recovery from the neurological deficits caused in the demyelinating diseases. Lysophosphatidylcholine-induced demyelination in mice is commonly used to identify and study the molecular pathways of demyelination and remyelination. However, detection of focally demyelinated lesions is difficult and usually requires sectioning of demyelinated lesions in tissues for microscopic analysis. In this review, we describe the development and application of a novel vital staining method for labeling demyelinated lesions using intraperitoneal injection of neutral red (NR) dye. NR labeling reduces the time and effort required to search for demyelinated lesions in tissues, and facilitates electron microscopic analysis of myelin structures. NR labeling also has the potential to contribute to the elucidation of pathologies in the central and peripheral nervous system and assist with identification of drug candidates that promote remyelination.

In this study, we develop an in silico model of a neuron\'s behaviour under demyelination caused by a cytokine storm to investigate the effects of viral infections in the brain. We use a comprehensive model to measure how cytokine-induced demyelination affects the propagation of action potential (AP) signals within a neuron. We analysed the effects of neuron-neuron communications by applying information and communication theory at different levels of demyelination. Our simulations demonstrate that virus-induced degeneration can play a role in the signal power and spiking rate, which compromise the propagation and processing of information between neurons. We propose a transfer function to model the weakening effects on the AP. Our results show that demyelination induced by a cytokine storm not only degrades the signal but also impairs its propagation within the axon. Our proposed in silico model can analyse virus-induced neurodegeneration and enhance our understanding of virus-induced demyelination.

The precise neurophysiological changes prompted by meningeal lymphatic dysfunction remain unclear. Here, we showed that inducing meningeal lymphatic vessel ablation in adult mice led to gene expression changes in glial cells, followed by reductions in mature oligodendrocyte numbers and specific lipid species in the brain. These phenomena were accompanied by altered meningeal adaptive immunity and brain myeloid cell activation. During brain remyelination, meningeal lymphatic dysfunction provoked a state of immunosuppression in the brain that contributed to delayed spontaneous oligodendrocyte replenishment and axonal loss. The deficiencies in mature oligodendrocytes and neuroinflammation due to impaired meningeal lymphatic function were solely recapitulated in immunocompetent mice. Patients diagnosed with multiple sclerosis presented reduced vascular endothelial growth factor C in the cerebrospinal fluid, particularly shortly after clinical relapses, possibly indicative of poor meningeal lymphatic function. These data demonstrate that meningeal lymphatics regulate oligodendrocyte function and brain myelination, which might have implications for human demyelinating diseases.

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

Multiple sclerosis (MS) is a devastating autoimmune disease that leads to profound disability. This disability arises from the stochastic, regional loss of myelin-the insulating sheath surrounding neurons-in the central nervous system (CNS). The demyelinated regions are dominated by the brain\'s resident macrophages: microglia. Microglia perform a variety of functions in MS and are thought to initiate and perpetuate demyelination through their interactions with peripheral immune cells that traffic into the brain. However, microglia are also likely essential for recruiting and promoting the differentiation of cells that can restore lost myelin in a process known as remyelination. Given these seemingly opposing functions, an overarching beneficial or detrimental role is yet to be ascribed to these immune cells. In this chapter, we will discuss microglia dynamics throughout the MS disease course and probe the apparent dichotomy of microglia as the drivers of both demyelination and remyelination.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuroprotective and anti-inflammatory molecules of the central nervous system (CNS). Both bind to three G protein-coupled receptors, namely PAC1, VPAC1 and VPAC2, to elicit their beneficial effects in various CNS diseases, including multiple sclerosis (MS). In this study, we assessed the expression and distribution of PACAP/VIP receptors in the normal-appearing white matter (NAWM) of MS donors with a clinical history of either relapsing-remitting MS (RRMS), primary MS (PPMS), secondary progressive MS (SPMS) or in aged-matched non-MS controls. Gene expression studies revealed MS-subtype specific changes in PACAP and VIP and in the receptors\' levels in the NAWM, which were partly corroborated by immunohistochemical analyses. Most PAC1 immunoreactivity was restricted to myelin-producing cells, whereas VPAC1 reactivity was diffused within the neuropil and in axonal bundles, and VPAC2 in small vessel walls. Within and around lesioned areas, glial cells were the predominant populations showing reactivity for the different PACAP/VIP receptors, with distinctive patterns across MS subtypes. Together, these data identify the differential expression patterns of PACAP/VIP receptors among the different MS clinical entities. These results may offer opportunities for the development of personalized therapeutic approaches to treating MS and/or other demyelinating disorders.

Background: Depression is one of the most severe sequelae of COVID-19, with major depressive disorder often characterized by disruption in white matter (WM) connectivity stemming from changes in brain myelination. This study aimed to quantitatively assess brain myelination in clinically diagnosed post-COVID depression (PCD) using the recently proposed MRI method, macromolecular proton fraction (MPF) mapping. Methods: The study involved 63 recovered COVID-19 patients (52 mild, 11 moderate, and 2 severe) at 13.5 ± 10.0 months post-recovery, with matched controls without prior COVID-19 history (n = 19). A post-COVID depression group (PCD, n = 25) was identified based on psychiatric diagnosis, while a comparison group (noPCD, n = 38) included participants with neurological COVID-19 complications, excluding clinical depression. Results: Fast MPF mapping revealed extensive demyelination in PCD patients, particularly in juxtacortical WM (predominantly occipital lobe and medial surface), WM tracts (inferior fronto-occipital fasciculus (IFOF), posterior thalamic radiation, external capsule, sagittal stratum, tapetum), and grey matter (GM) structures (hippocampus, putamen, globus pallidus, and amygdala). The noPCD group also displayed notable demyelination, but with less magnitude and propagation. Multiple regression analysis highlighted IFOF demyelination as the primary predictor of Hamilton scores, PCD presence, and severity. The number of post-COVID symptoms was a significant predictor of PCD presence, while the number of acute symptoms was a significant predictor of PCD severity. Conclusions: This study, for the first time, reveals extensive demyelination in numerous WM and GM structures in PCD, outlining IFOF demyelination as a key biomarker.