Search Results (7,985)

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, and can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in the serum and cerebrospinal fluid (CSF). Initially considered a variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), it is now widely recognized as a separate entity, supported by converging evidence from serological, pathological, and clinical studies. Patients with MOGAD often exhibit better recovery from acute attacks; however, their clinical and pathological features vary based on the immunological role of MOG-IgG via antibody- or complement-mediated perivenous demyelinating pathology, in addition to MOG-specific cellular immunity, resulting in heterogeneous demyelinated lesions from vanishing benign forms to tissue necrosis, even though MOGAD is not a mild disease. The key is the immunological mechanism of devastating lesion coalescence and long-term degenerating mechanisms, which may still accrue, particularly in the relapsing, progressing, and aggressive clinical course of encephalomyelitis. The warning features of the severe clinical forms are: (1) fulminant acute multifocal lesions or multiphasic ADEM transitioning to diffuse (Schilder-type) or tumefactive lesions; (2) cortical or subcortical lesions related to brain atrophy and/or refractory epilepsy (Rasmussen-type); (3) longitudinally extended spinal cord lesions severely affected with residual symptoms. In addition, it is cautious for patients refractory to acute stage early 1st treatment including intravenous methylprednisolone treatment and apheresis with residual symptoms and relapse activity with immunoglobulin and other 2nd line treatments including B cell depletion therapy. Persistent MOG-IgG high titration, intrathecal production of MOG-IgG, and suggestive markers of higher disease activity, such as cerebrospinal fluid interleukin-6 and complement C5b-9, could be identified as promising markers of higher disease activity, worsening of disability, and poor prognosis, and used to identify signs of escalating treatment strategies. It is promising of currently ongoing investigational antibodies against anti-interleukin-6 receptor and the neonatal Fc receptor. Moreover, due to possible refractory issues such as the intrathecal production of autoantibody and the involvement of complement in the worsening of the lesion, further developments of other mechanisms of action such as chimeric antigen receptor T-cell (CAR-T) and anti-complement therapies are warranted in the future. Full article

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition marked by persistent inattention, hyperactivity, and impulsivity. Despite its considerable global prevalence, key gaps remain in our understanding of the structural and molecular changes underlying ADHD which complicate adult diagnosis, as symptoms present differently from those observed during childhood ADHD. On the other hand, while psychostimulants effectively mitigate some symptoms, significant controversy surrounds their long-term effects on cognition, learning, and memory, and day-to-day living. Moreover, our understanding of how various medications given to alleviate ADHD symptoms during pregnancy impact the developing fetal brain also remains largely unexplored. Here, we discuss the subtle differences between ADHD in children and adults and how these symptoms alter brain development and maturation. We further examine changes in monoamine signaling in ADHD and how psychostimulant and non-pharmacological treatments modulate these neural networks. We evaluate and discuss findings as they pertain to the long-term use of ADHD medications, including in utero exposure, on cognitive outcomes, and contextualize these findings with mechanistic insights from animal models. Full article

Central nervous system (CNS) disorders such as neurodegenerative diseases, multiple sclerosis, or even brain ischemia represent major therapeutic challenges with limited effective treatments. The sigma-1 receptor (S1R), a unique ligand-operated molecular chaperone enriched at mitochondria-associated membranes, has emerged as a promising drug target due to its role in neuroprotection and neuroinflammation. Building upon our previously identified S1R ligand (compound 1), we designed and synthesized six novel benzamide derivatives through pharmacomodulation to optimize affinity, selectivity, and safety profiles. Among these, compound 2 demonstrated superior S1R affinity, improved selectivity over the sigma-2 receptor (S2R), and favorable ADME properties, including enhanced permeability and markedly reduced in vitro cardiac toxicity compared to the lead compound. Functional assays confirmed the agonist activity of key derivatives, while safety evaluations revealed low cytotoxicity and minimal off-target receptor interactions. Collectively, these findings support compound 2 as a promising candidate for further preclinical development in S1R-related CNS disorders. Full article

Threat activation or deactivation in the brain–body is associated with learned nocebo or placebo somatic effects induced by fake invasive medical–surgical procedures. Some functional somatic disorders (FSDs) originate as acute nocebo somatic effects and can become 30–50% of chronic somatic presentations to primary care physicians. Patients with FSD overutilize medical–surgical services, despite the lack of identified pathophysiology, and are at risk for morbidity from unintentional iatrogenic injury. The Conditioned Response Model (CRM) of learning postulates three innate mechanisms, modulated by trait hypnotizability, which drive placebo and nocebo somatic effects and FSD. The High Risk Model of Threat Perception (HRMTP) postulates 10 psychosocial risk factors that modulate threat perception, driving placebo and nocebo somatic effectsandbiologically embedded FSD. Psychosocial factors and the trait of high and low hypnotizability modulate threat and are postulated to reduce heart rate variability(HRV), inducing autonomic nervous system(ANS)dysregulation. Reduced HRV was found in a large (N = 6,891) sample of patients with FSD. A total of 50% of patients with FSD with chronic pain (n = 224) without identified pathophysiology had a Paradoxical Increase in hand Temperature (PTI) during experimental threat induction. The HRMTP predicts that PTI associated with ANS dysregulation is associated with the risk factor Adverse Childhood Experiences (ACEs). This ACE prediction was independently confirmed. Learning predicts that threat activation by unconscious neutral stimuli (CS) can amplify nocebo and FSD and can negate placebo effects in clinician–patient relationships. Identifying psychosocial risk factors that modulate threat perception enables the diagnosis of FSD by inclusion and not simply by excluding pathophysiology. Full article

Background: Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by compulsive alcohol seeking, loss of control over drinking, and negative emotional states when not using. It has significant psychological, physiological, and social consequences, often co-occurring with mental health disorders such as depression and anxiety. Psychological resilience is gaining more recognition. Sense of coherence (SOC) could be treated as a health factor, and individual predispositions play a crucial role in fighting disease and addiction. Our study examines whether SOC and its components—comprehensibility, manageability, and meaningfulness—predict life satisfaction in patients with AUD and whether perceived stress and health behaviors mediate these relationships. Methods: The study was conducted on a sample of 100 adult patients diagnosed with alcohol use disorder. Results: We found that the higher the manageability and meaningfulness, the lower the level of perceived stress and the higher the level of preventive behavior. Notably, perceived stress emerged as a significant mediator between SOC and satisfaction with life, while health behaviors did not show a mediating effect. Conclusions: The findings emphasize the protective role of SOC in enhancing psychological well-being among individuals with AUD and suggest that interventions aimed at strengthening SOC may reduce stress and improve overall life satisfaction in this population. Full article

Alcohol use disorder (AUD) is a widespread, multifaceted disorder involving overproduction of pro-inflammatory cytokines, oxidative liver injury, and dysfunction of the brain’s dopaminergic reward circuits. Korean red ginseng (KRG), an herbal supplement derived from Panax ginseng, has demonstrated qualities potentially useful to the treatment of AUD, including antioxidative, anti-inflammatory, neuroprotective, and anxiolytic effects. This review examines active constituents of KRG, their pharmacological actions, and evidence supporting KRG’s therapeutic potential in the context of AUD, while also assessing its safety profile, adverse effects, and potential drug interactions. KRG’s main bioactive constituents, ginsenosides, appear to have roles in modulating alcohol-metabolizing enzymes, ethanol-activated inflammatory cytokine cascades, and neurological systems disrupted by AUD, including GABAergic and dopaminergic pathways. Evidence from animal models and limited small-scale human trials suggests KRG may alleviate symptoms of alcohol withdrawal, enhance cognitive performance, and attenuate anxiety through these pathways. While generally safe for consumption, several case reports and animal studies have indicated KRG’s potential to pose a variety of risks in vulnerable populations at high, prolonged doses, including hepatotoxicity, cardiovascular changes, mood disturbances, and hormonal effects. Furthermore, KRG’s neuromodulating role and influence on cytochrome P450 enzymes make it liable to interact with several medications, including warfarin, midazolam, selegiline, and serotonergic agents. Overall, KRG shows promise as a complementary supplement in managing aspects of AUD, though current evidence is limited by low sample sizes, inconsistent reports regarding nuances of ginsenosides’ mechanisms, and a low number of human trials. Further human-focused research is needed to elucidate its safety, efficacy, and mechanism. Full article

Background/Objectives: Generalized anxiety disorder (GAD) is one of the most commonly diagnosed anxiety disorders in primary care. The global lifetime prevalence of GAD is estimated at 3.7%, ranging from 1.6% in low-income countries to 5.0% in high-income countries, underscoring its widespread impact. Given the frequent co-occurrence of GAD with obesity, this association has important clinical implications, particularly for screening, prevention, and treatment strategies. The aim of this review is to identify potential biological mechanisms linking obesity and GAD, summarize the current state of knowledge in this area, and highlight existing research gaps, as well as directions for future research. Methods: This narrative review is based on the literature published between 2015 and 2025 concerning the co-occurrence of GAD and obesity, with a focus on potential shared mechanisms including HPA axis dysregulation, chronic inflammation, oxidative stress, insulin resistance, gut–brain axis and microbiota dysbiosis, sleep disturbance, and maladaptive eating behaviors. Results/Conclusions: A growing body of evidence suggests an important, albeit still ambiguously defined, relationship between obesity and GAD. GAD and obesity may reinforce each other, leading to a mutually reinforcing relationship. Despite growing interest, high-quality prospective and interventional studies focusing specifically on GAD are lacking. A potentially effective therapeutic approach should be integrated and multidisciplinary, combining psychological, pharmacological, and lifestyle interventions. It may also be beneficial for clinicians to consider routine assessment of anxiety in patients with obesity and, conversely, to monitor metabolic risk in individuals with GAD. Such an approach, targeting both mental and metabolic domains, holds promise for improving outcomes. Full article

The repeated head impacts experienced by athletes have attracted significant interest from both the public and the scientific community; however, the neurobiological effects following the games are not well understood. For example, a single football match carries the risk of repeated concussive and subconcussive head impacts, which can increase the risk of developing neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is one of the neurodegenerative conditions athletes often face or are unaware of. However, addressing the disease progression in CTE is difficult to determine due to several reasons, such as the failure to identify risk factors, difficulty in differentiating CTE from other neurodegenerative diseases, and the lack of a specific mechanism by which CTE leads to tau protein accumulation. In addition, CTE symptoms overlap with other neurodegenerative conditions, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), which poses a challenge to producing specific targeted therapy. In this case, ultrasound represents a promising non-invasive technique that enables clear visualization of brain structures and may modulate neuronal activity. The term ultrasound encompasses various modalities; for example, high-intensity focused ultrasound (HIFU) employs thermal energy to ablate cells, whereas low-intensity pulsed ultrasound (LIPUS) delivers mechanical energy that activates molecular signaling pathways to impede the progression of CTE. Therefore, the LIPUS application could potentially minimize the risk of damage in the surrounding tissues of the brain and reduce the disease progression in individuals with CTE. Nevertheless, limited studies have been reported in the literature, with a poor mechanistic approach. Hence, this review aims to highlight the molecular signaling pathways, such as AKT, MAPK, and ERK, affected by LIPUS and emphasize the need for additional research to clarify its mechanistic effects in CTE management. Ultimately, this review aims to contribute to a nuanced understanding of LIPUS as a therapeutic strategy in addressing the complexities of CTE and its associated neurodegenerative disorders. Full article

Background/Objectives: Radiotherapy can cause severe and irreversible brain damage, including cognitive impairment, increased dementia risk, debilitating depression, and other neuropsychiatric disorders. Current radioprotective drugs face limitations, such as single-target inefficacy or manufacturing hurdles. Isoliquiritigenin (ISL), a natural flavonoid derived from licorice root, exhibits broad bioactivities. It exhibits anti-inflammatory, anti-cancer, immunoregulatory, hepatoprotective, and cardioprotective activities. This study aimed to elucidate ISL’s neuronal radiation mitigation effects and key targets. Methods: In vitro and in vivo models of radiation-induced neuronal injury were established. ISL’s bioactivities were evaluated through cellular cytotoxicity assays, LDH release, ROS, ATP, glutamate, and GSH levels. In vivo, ISL’s radiation mitigation effect was evaluated with sucrose preference test, IL-β level, histopathological analysis, and Golgi-Cox staining analysis. Proteomics, pathway enrichment, and ensemble models (four machine learning models, weighted gene co-expression network, protein–protein interaction) identified core targets. Molecular docking and dynamic simulations validated ISL’s binding stability with key targets. Results: ISL attenuated radiation-induced cellular cytotoxicity, reduced LDH/ROS, restored ATP, elevated GSH, and mitigated glutamate accumulation. In rats, ISL alleviated anhedonia-like phenotypes and hippocampal synaptic loss. ISL also significantly suppressed radiation-induced neuroinflammation, as evidenced by reduced levels of the pro-inflammatory cytokine IL-1β. Proteomic analysis revealed that ISL’s main protective pathways included the synaptic vesicle cycle, glutamatergic synapse, MAPK signaling pathway, SNARE interactions in vesicular transport, insulin signaling pathway, and insulin secretion. Grm8, Grik3, and Grin3a were identified as key targets using the integrated models. The expression of these targets was upregulated post-radiation and restored by ISL. Molecular docking and dynamic simulations indicated that ISL showed stable binding to these receptors compared to native ligands. Conclusions: ISL demonstrates multi-scale radiation mitigation activities in vitro and in vivo by modulating synaptic and inflammatory pathways, with glutamate receptors as core targets. This work nominates ISL as an important natural product for mitigating radiotherapy-induced neural damage. Full article

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are marked by progressive network dysfunction that challenges conventional, protocol-based neurorehabilitation. In parallel, neuromodulation, encompassing deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and artificial intelligence (AI), has matured rapidly, offering complementary levers to tailor therapy in real time. This narrative review synthesizes current evidence at the intersection of AI and neuromodulation in neurorehabilitation, focusing on how data-driven models can personalize stimulation and improve functional outcomes. We conducted a targeted literature synthesis of peer-reviewed studies identified via PubMed, Embase, Scopus, and reference chaining, prioritizing recent clinical and translational reports on adaptive/closed-loop systems, predictive modeling, and biomarker-guided protocols. Across indications, convergent findings show that AI can optimize device programming, enable state-dependent stimulation, and support clinician decision-making through multimodal biomarkers derived from neural, kinematic, and behavioral signals. Key barriers include data quality and interoperability, model interpretability and safety, and ethical and regulatory oversight. Here we argue that AI-enhanced neuromodulation reframes neurorehabilitation from static dosing to adaptive, patient-specific care. Advancing this paradigm will require rigorous external validation, standardized reporting of control policies and artifacts, clinician-in-the-loop governance, and privacy-preserving analytics. Full article

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate channels that play a pivotal role in brain development and the regulation of learning and memory processes. De novo pathogenic variants in four genes encoding NMDA receptor subunits (GRIN1, GRIN2A, GRIN2B, and GRIN2D) have been implicated in a broad spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorders, epilepsy, and movement disorders. Mutations in the GRIN1 and GRIN2B genes, which encode the GluN1 and GluN2B subunits, respectively, are strongly associated with malformations of cortical development, including diffuse dysgyria, bilateral polymicrogyria, hippocampal dysplasia, corpus callosum hypoplasia, and other findings such as ventricular enlargement and basal ganglia abnormalities. Conversely, GRIN2A mutations are associated with heterogeneous and less specific neuroimaging patterns. We reviewed the existing literature on the neuroradiological features associated with GRIN gene mutations, also providing pictorial representations from our patient cohort. The analysis revealed a more consistent association of malformations of cortical development with GRIN1 and GRIN2B variants, likely reflecting the critical role of these genes in neuronal migration and proper development of cortical structures. In comparison, GRIN2A mutations are associated with milder brain abnormalities. An integrated assessment of neuroimaging patterns and GRIN gene variants provides valuable insights for differential diagnosis and supports targeted genetic screening in patients presenting with epileptic encephalopathy, global developmental delay, and autism spectrum disorders. Full article

Ketamine, a widely used anesthetic with emerging evidence suggesting neuroprotective and anti-inflammatory properties across various neurological disorders, is recognized for its NMDA receptor antagonism. It has been postulated to play a role in neuroprotection, due to its anti-inflammatory properties, and decrease microglial activation, as well as cytokines TNF and IL-6. Despite its established role, the extent of ketamine’s effects on neuroinflammation and neuroprotection remains to be fully elucidated. Here, we conducted a narrative review synthesizing current knowledge on ketamine’s operating mechanisms, including its modulation of synaptic plasticity, excitotoxicity, and cytokine release, alongside its therapeutic applications in traumatic brain injury, neurodegenerative diseases, psychiatric disorders, and pain management. For this narrative review, we searched the Medline, Embase, Scopus, Web of Science, and PubMed databases. Our findings indicate that ketamine reduces excitotoxicity and inflammation, which may contribute to neuroprotection in acute neurological injuries. These insights underscore ketamine’s potential as an adjunctive neuroprotective agent, warranting further clinical investigation to optimize its therapeutic utility across neurological and psychiatric contexts. Full article

Background: The gut microbiota and the gut epithelium play a central role in maintaining systemic and brain homeostasis from early life. Stressful experiences during sensitive developmental windows can disrupt this balance, increasing long-term susceptibility to psychiatric disorders. However, the mechanisms through which early-life alterations in the microbiota influence brain development and function remain poorly understood. Here, the sex-specific impact of prenatal stress (PNS) on gut integrity and microbial composition in adult offspring was explored. Methods: Thirty dams were mated and randomly assigned to PNS or control. Offspring microbiota was analysed through 16S rRNA sequencing, intestinal morphology with morphometric analyses, and tight junctions using qPCR and immunofluorescence. Results: Exposure to PNS was associated with reduced intestinal surface area in males and shortened crypts in females. In both sexes, PNS caused a decrease in the expression of ZO-1, suggesting impaired gut barrier integrity. 16S rRNA sequencing revealed, furthermore, that PNS exposure was associated with a decrease in beneficial genera, including Akkermansia in males and Clostridia vadinBB60 in females, along with an increase in the pro-inflammatory genus Anaerotruncus, regardless of sex. Notably, some of these alterations were more pronounced in PNS-exposed animals that showed impaired sociability, highlighting gut microbiota inter-individual variability in the response to early-life adversity. Moreover, selected microbial changes show significant correlations with the behavioural outcomes, as well as with intestinal morphology or brain inflammatory markers. Conclusions: Together, these findings pinpoint the gut as a central player in stress vulnerability and highlight specific microbial signatures as promising biomarkers and therapeutic targets for stress-related disorders. Full article

Background: Major depression is a significant source of suffering and economic loss. Despite efforts to understand this condition and find better treatments, the burden imposed by this disease continues to rise. Most approved pharmacological treatments for depression focus on controlling the availability of monoamines in synapses. However, accumulating evidence suggests that neuroinflammation, oxidative stress, and reduced hippocampal neurogenesis play key roles as causal factors in the development of major depression symptoms. Therefore, preclinical testing of pharmacological approaches targeting these factors is essential. Mesenchymal stem cells (MSCs) are known for their potential as powerful antioxidants and anti-inflammatory agents, exerting neuroprotective actions in the brain. They produce various therapeutic molecules in a paracrine manner, collectively known as secretome. Methods: In this work, we evaluated the antidepressant potential of repeated intranasal administration of MSC-derived secretome in an animal model of major depressive disorder induced by chronic mild unpredictable stress. Results: We observed that intranasal administration of MSC-derived secretome reduced the appearance of some of the behavioral parameters commonly associated with major depression, including anhedonic, apathetic, and anxious behaviors, inducing a strong reduction in the overall depression score compared to vehicle-treated animals. At the structural level, secretome administration prevented increased astrocyte density and the atrophy of astrocyte processes observed in vehicle-treated stressed animals. Additionally, secretome administration induced an increase in myelin levels and oligodendroglia in the cortex. Conclusions: Our data suggests that intranasal administration of MSC-derived secretome may represent a potential therapeutic alternative to current treatments for this devastating pathology. Full article

Acquired Brain injury (ABI) is now widely regarded as a chronic condition but this change in conceptualization has not yet been realized in the way rehabilitation and care are offered and funded in the United States. Similarly, it is widely accepted that an optimized ABI system includes integration across the phases of care and recovery that considers the bio-psycho-socio-ecological (BPSE) dimensions beyond the injury itself. Despite the importance of BPSE factors informing care, typical post-injury care and management remain focused on acute presentation and the biological nature of the injury and there still exists relevant inter-country differences for disorders of consciousness (DoC) neurorehabilitation after severe ABI. This collaboration with Italian colleagues explores and compares the types and locations of rehabilitative services offered in a Post-Coma Unit of neurorehabilitation center in Italy (namely, Santa Lucia Foundation IRCCS in Rome) and in the United States following a “severe” ABI (sABI). This narrative seeks to describe the degree to which both systems utilize a BPSE informed approach to care. Full article