Multiple sclerosis is a chronic immune-mediated neurodegenerative disorder characterized by inflammation, demyelination, axonal injury, and progressive neurological disability. Although current disease-modifying therapies effectively reduce relapse frequency and peripheral immune activation, they provide limited protection against long-term neurodegeneration and remyelination failure. Emerging evidence suggests that neurotransmitter receptor-linked intracellular signaling pathways play crucial roles in regulating neuroinflammation, glial function, and neuronal survival. This review comprehensively examines the interconnected roles of the CHRM1, H1R, and the PI3K/Akt/mTOR signaling pathway in MS pathophysiology. CHRM1 and H1R both G protein-coupled receptors widely expressed in neurons, glial cells, and immune cells, modulate intracellular calcium signaling, cytokine production, blood-brain barrier integrity, and oligodendrocyte precursor cell dynamics. Dysregulated activation of these receptors contributes to persistent neuroinflammation, impaired remyelination, and synaptic dysfunction. Downstream, the PI3K/Akt/mTOR axis functions as a critical integrative hub controlling cell survival, metabolism, autophagy, and myelin protein synthesis. Balanced activation of this pathway promotes neuronal protection and oligodendrocyte maturation, whereas its chronic dysregulation exacerbates mitochondrial dysfunction, oxidative stress, and axonal degeneration. By synthesizing current experimental and mechanistic evidence, this review highlights the functional cross-talk between cholinergic and histaminergic signaling and their convergence on PI3K/Akt/mTOR-mediated cellular responses. Understanding these interconnected molecular networks provides a foundation for developing multi-target therapeutic strategies aimed at simultaneously reducing neuroinflammation, enhancing neuroprotection, and promoting remyelination in progressive MS.

People with multiple sclerosis (PwMS) face an uncertain future as the nature of the disease can be progressive and unpredictable, leading to chronic serious symptomatology impacting quality of life. Serious illness discussions and symptom management should be part of routine care in all outpatient neurology clinics. Yet few standard clinical approaches to palliative care exist for this population. Providers frequently lack understanding about when to incorporate specialist palliative care. The MS-Support project established a specialized nurse practitioner (NP)-led palliative care clinic embedded in an MS center. A feasibility project evaluated clinician perceptions and referral patterns, as well as the impact on symptom identification and advance care planning/serious illness discussions. Twenty-six patients were referred over 3 months, 77% were seen once; 29% were seen more than twice. The average number of symptoms identified per patient increased from 1.8 to 6.7 postintervention. Seventeen (85%) had serious illness discussions documented compared with zero preintervention. NP productivity increased by 67%. Results indicate that NP provision of embedded palliative care can increase acceptance of palliative care, increase the frequency of serious illness discussions, and improve identification of multidimensional symptoms in patients with progressive MS. An NP-embedded clinic can improve palliative care provided to this vulnerable population.

In the central nervous system, myelin formed around nerve axons by oligodendrocyte enables efficient conduction of action potentials and maintains axonal homeostasis. Therefore, in demyelinating diseases, such as multiple sclerosis (MS), axonal degeneration and loss, particularly in small-diameter axons, are observed. Teneurin-4 deficient (Ten-4 -/-) mice exhibit severe dysmyelination of small-diameter axons, but survive for over a year. Here, we aimed to elucidate the mechanism of the survival of small-diameter axons without myelin using Ten-4 -/- mice. An immunohistochemical analysis showed abnormally diffused and intense staining of neurofilament. Further, the immunohistochemical signal of nonphosphorylated neurofilament and amyloid precursor protein was higher in Ten-4 -/- mice. An electron microscopy analysis unexpectedly revealed that small-diameter axons in Ten-4 -/- mice survived at the age of 1 year, despite the absence of compact myelin. To elucidate the molecular mechanism, we performed a proteomics analysis in the Ten-4 -/- tissue by mass spectrometry. The result indicated that four of the seven 14-3-3 isoforms were highly expressed in Ten-4 -/- small-diameter axons. Finally, when the function of 14-3-3s in Ten-4 -/- mice was inhibited by 14-3-3 inhibitors, BV02 and difopein, the progression of small-diameter axon damage was observed. Altogether, 14-3-3s are among the pro-survival factors in dysmyelinated small-diameter axons. Our findings may be useful for better understanding the pathogenesis of demyelinating diseases, such as MS, as well as for the development of new treatments.

B cell depleting therapies in multiple sclerosis (MS) have transformed disease management, yet the immunological mechanisms linking B cells to chronic compartmentalised CNS inflammation, the key pathological driver of disability accrual, remain poorly defined. Here, we leverage anti-CD20 therapy as an in vivo perturbational probe to disentangle MS immunobiology. We combine longitudinal, high-dimensional multimodal immune profiling in patients initiating ocrelizumab with a novel machine learning pipeline to resolve treatment-induced shifts in continuous immune cell states, revealing treatment-associated modulation of shared biological processes that act across the boundaries of discretely partitioned cell types. We identify a distinct chronically activated, proinflammatory-cytotoxic T cell state with CNS-homing properties that is selectively depleted following B cell ablation. Importantly, across independent datasets, the same T cell state is enriched in the circulation of patients with clinically aggressive relapsing disease, in CSF-enriched expanded clonotypes, including a subset with proven Epstein-Barr virus-specificity, and in chronically inflamed lesion rims in end-stage MS. Finally, we demonstrate that blockade of lymphocyte trafficking across the blood-brain barrier with the anti-integrin α4 therapy natalizumab leads to enrichment of this cell state in the circulation, demonstrating a mechanistically concordant effect across distinct high-efficacy MS therapies. Together, our findings support a B cell-dependent, pathogenic T cell state which links peripheral immune activation to CNS-compartmentalised smouldering neuroinflammation across disease stages. Direct therapeutic manipulation of this T cell state may represent a key opportunity for targeting chronic neuroinflammation and facilitate a strategic shift away from broad immune cell ablation.

Trauma Releasing Exercises (TRE®) is a mind-body technique predominantly used to address stress and anxiety. Occupational therapists use such techniques to enhance occupational performance but require evidence-based support. This scoping review, following the JBI framework, synthesized 22 studies on TRE (24 records). The JBI is an organization aimed at guiding how health research is generated and evaluated. The study objectives were to describe the characteristics of TRE intervention studies (including population characteristics, measurement tools used to measure treatment outcomes and outcomes of treatment), in order to provide evidence for occupational therapy practice related to anxiety management, as well as to indicate the gaps in the literature. TRE was mainly applied to stress- and trauma-exposed populations, with potential benefits for mood, anxiety-related sleep difficulties, and cognitive functions. Preliminary evidence also suggests benefit for conditions such as Parkinson's disease and multiple sclerosis. While study designs were not consistently rigorous, findings highlight TRE's promise and the need for more research to inform evidence-based practice.

Gadolinium-based contrast agents (GBCAs) are essential for improving the diagnostic accuracy of magnetic resonance imaging (MRI) studies. Although traditionally regarded as highly safe, in recent years the marketing authorisation for certain linear GBCAs has been withdrawn, and the use of macrocyclic GBCAs has become subject to regulatory oversight. Current recommendations advocate the use of the lowest effective dose at all times. Central nervous system (CNS) pathology is the most common indication for MRI with GBCAs. However, clinical recommendations and best practices in this setting often lack a comprehensive approach. This document presents recommendations for the use of GBCAs in the main categories of CNS disease-namely neuro-oncological, inflammatory, infectious and vascular conditions-as well as in CNS angiographic studies. These recommendations have been developed by a nationally convened expert committee. It also highlights the importance of ensuring clinical and environmental safety in the use of these contrast media.