Search Results (941)

Recently, cognitive training programs using digital content with visuoperceptual stimulation have been developed and commercialized. In particular, digital intervention content for children with attention deficit hyperactivity disorder (ADHD) has been developed as games, enhancing motivation and accessibility for the target population. Active stimulation is required to elicit positive effects on self-regulation training, including attention control and impulse inhibition, through task-based content. Common forms of stimulation include emotional stimuli, such as praise and encouragement, and economic stimuli based on a self-directed token economy system. Economic stimulation can serve as active reinforcement because the child directly engages as the primary agent within the task content. This study applied and validated a token economy intervention using digital therapeutic content in children with ADHD. Behavioral assessments were conducted using the Comprehensive Attention Test (CAT) and the Korean version of the Child Behavior Checklist (K-CBCL). The developed digital intervention content implemented a user-centered token economy based on points within the program. In the CAT Flanker Task, the experimental group (0.84 ± 0.40) showed significantly higher sensitivity factor scores than the control group (0.72 ± 0.59) after 4 weeks, with a large effect size (F = 4.76, p = 0.038, partial η² = 0.150). Additionally, the rate of change in externalizing behavior scores on the K-CBCL showed a significant difference between the two groups (t = 2.35, p = 0.026, Cohen’s d = 0.860), demonstrating greater improvement in externalizing symptoms in the experimental group than in the control group. Therefore, this study suggests that the participant-centered implementation model using token economy mechanisms in digital intervention content may serve as a novel and effective therapeutic approach for children with ADHD. Full article

Erectile dysfunction (ED) and cognitive decline share overlapping vascular, metabolic, and neurodegenerative mechanisms, particularly in aging populations. Phosphodiesterase type 5 inhibitors (PDE5-Is), such as sildenafil and vardenafil, are widely used to treat ED by elevating cyclic guanosine monophosphate (cGMP) levels and enhancing vascular function. Emerging evidence suggests that PDE5-Is may also benefit cognitive function by promoting neurovascular coupling, synaptic plasticity, and neuroprotection. This review synthesizes clinical, preclinical, and mechanistic studies on PDE5-Is in the context of learning, memory, and Alzheimer’s disease, highlighting their potential as therapeutic agents for cognitive impairment. Full article

Protein kinases are important molecules of Alzheimer’s Disease (AD), driving neuronal demise and the emergence of the disease’s destructive hallmarks. Cdk5 has recently been highlighted as a key therapeutic target for AD. This study evaluated the expression levels of Cdk5 and Mcl1 (Cdk5’s substrate) in blood samples of 61 AD, 55 Mild Cognitive Impairment (MCI), and 57 Geriatric Controls (GC), and explored the in vitro inhibition of Cdk5. The serum levels of Cdk5 and Mcl1 were measured by Surface Plasmon Resonance (SPR) and verified by Western blot and RT-PCR. Molecular modeling and simulation studies were used to identify a potent hit targeting Cdk5 and validated by binding studies using SPR. The peptide rescue effect was analyzed by MTT assay in the AD cellular model. SPR analysis revealed a significant change in Cdk5 and Mcl1 levels in the serum samples of AD and MCI compared to GC. Results were validated by Western blot and RT-PCR. Binary logistic regression analysis revealed that the concentration of both Cdk5 and Mcl1 was independently associated with disease after adjusting for certain parameters. ROC analysis established an optimum diagnostic cutoff value for Cdk5 [24.97 ng/µL (AUC-0.90)] and Mcl1 [23.08 ng/µL (AUC-0.94)] with high sensitivity and specificity. The peptide YCWS strongly binds to Cdk5′s ATP binding site, confirmed by molecular modeling and SPR. In the AD cellular model, peptide YCWS rescued neurotoxicity, increased Mcl1 levels, and reduced destructive hallmarks by inhibiting Cdk5. It can be concluded that Cdk5 is a promising molecule as a circulatory biomarker for the diagnosis of the early stages of AD, and its peptide inhibitor YCWS is a potential therapeutic agent. Full article

Background: The pathophysiology of Alzheimer’s disease (AD) is strongly linked to damage to the cholinergic systems of the central nervous system (CNS), mainly due to the formation of β-amyloid peptide plaques, which trigger intense inflammatory responses and are currently the main cause of the symptoms of the disease. Among the therapeutic strategies under investigation, classes of natural products with immunomodulatory properties, action on the CNS, and potent antioxidant activity, which contribute to neuroprotection, stand out. Methods: We aimed to evaluate the flavonoid quercetin using in silico, in vitro, and in vivo methods for the treatment of AD. Initially, the compounds were selected, and molecular dynamics simulations were performed. The in vitro assays included tests of antioxidant activity (DPPH), enzymatic inhibition of acetylcholinesterase (AChE), and prediction of oral toxicity. The in vivo studies investigated the effects on scopolamine-induced learning deficits and conducted histopathological analysis of the brain. Results: Quercetin showed structural stability in the complex with (AChE), with no significant alterations in the Root Mean Square Deviation (RMSD), SASA and radius of gyration (Rg) parameters. Through the same method it was possible to predict stability between the quercetin and inducible nitric oxide synthase (iNOS) complex, a possible mechanism for quercetin immunomodulation in the CNS. In the AChE inhibition test, the IC₅₀ obtained for quercetin was 59.15 μg mL⁻¹, while in the antioxidant test with DPPH, the concentration of 33.1 µM exhibited 50% of the scavenging of reactive oxygen species. This corroborates the perspective of quercetin having neuroprotective activity. This activity was also corroborated in vivo, in a zebrafish model, in which quercetin reduced the cognitive deficit induced by scopolamine. Histopathological analysis revealed its ability to prevent atrophy, caused by scopolamine, in the nervous tissue of animals, reinforcing the potential of quercetin as a neuroprotective agent. Conclusions: The results of the tests carried out with quercetin suggest that this molecule has antioxidant, AChE inhibitory, and neuroprotective activities, making it a good candidate for use in future clinical trials to ensure its efficacy and safety. Full article

Parkinson’s disease (PD) is a progressive, irreversible neurodegenerative disorder characterized by motor impairments and a wide spectrum of non-motor symptoms, including gastrointestinal dysfunction, sleep disturbances, depression, and cognitive decline. These manifestations arise from disturbances across multiple systems—gastrointestinal, neuroendocrine, immune, enteric, and central nervous systems. Alterations in the gut microbiota may play a causal role in PD onset and frequently accompany disease progression. The gut–brain axis, particularly the vagus nerve, is increasingly recognized as a key communication pathway whose dysregulation contributes to systemic dysfunction and the breakdown of homeostasis, ultimately driving PD pathology. Currently, there is no cure for PD, and existing treatments primarily target symptom relief. Effective management of PD requires a comprehensive approach that integrates multiple pharmacologically active agents aimed at restoring impaired organ functions and, when possible, neutralizing toxic factors that accelerate disease progression. One promising therapeutic avenue lies in functional gut bacteria, which form the basis for developing live biotherapeutic products, postbiotics, and bacterial vesicles. In this review, we summarize current data on the effects of probiotics in PD, drawing on both animal models and clinical studies. We highlight the role of probiotics in modulating PD pathophysiology and discuss their potential as adjunctive therapeutic agents. To provide a broader perspective, we also include sections describing the clinical manifestations of PD, gut microbiota alterations associated with the disease, and the role of artificial intelligence, particularly machine learning, in constructing functional models of PD. Full article

Background: Juvenile fibromyalgia (JFM) is a chronic pain disorder characterised by widespread musculoskeletal pain, functional impairment, fatigue, and mood disturbances. Treatment remains challenging, considering the multifactorial nature of the condition and the limited high-quality evidence supporting pharmacological or non-pharmacological interventions. Objectives: This review aimed to critically appraise level I evidence from randomised controlled trials assessing the efficacy and safety of pharmacological and non-pharmacological treatments for adolescents with JFM. Methods: Seven published peer-reviewed clinical trials were examined, including studies investigating duloxetine, milnacipran, pregabalin, cognitive-behavioural therapy (CBT), and the integrated Fibromyalgia Integrative Training Teens (FIT) program, which combines CBT with neuromuscular training. Outcomes of interest included pain intensity, functional disability, depression symptoms, physical activity, and adverse events. Results: Pharmacological agents such as duloxetine, milnacipran, and pregabalin demonstrated modest improvements in pain, but failed to produce consistent benefits in function or mood, and were associated with a high incidence of adverse effects. CBT significantly improved functional disability and depression symptoms, yet it had a limited impact on pain reduction or objectively measured activity levels. The FIT Teens program showed superior outcomes in pain intensity and biomechanical function compared to CBT alone, suggesting a synergistic effect of combining psychological and physical reconditioning strategies. Conclusions: Current evidence supports the use of multimodal treatment approaches in JFM. Non-pharmacological interventions, particularly when integrated with structured exercise, offer meaningful benefits with minimal safety concerns. Larger, methodologically rigorous trials are needed to establish optimal treatment pathways and long-term outcomes for this complex and underserved paediatric population. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder that significantly impacts the lives of patients and their families. The pathological features of AD include the accumulation of amyloid-β (Aβ) and Tau, which disrupt neuronal function and communication, ultimately leading to neuronal loss and brain atrophy. Efforts to understand the molecular mechanisms underlying these pathological changes have led to advancements in diagnostic techniques and potential therapeutic interventions. However, the complexity of AD necessitates further research to develop more effective treatments and, ideally, preventive measures. Extensive research suggests that diminishing mTOR signaling increases lifespan and health span across various species. Increased PI3K/mTOR signaling has been linked to the progression of AD pathology, leading to neuronal degeneration and impairments in cognitive function. In this study, we explored the therapeutic potential of PF-04691502, a dual PI3K/mTOR inhibitor, in Alzheimer’s disease (AD)-like pathology using male and female B6.Cg-Tg(APPswe, PSEN1dE9)85Dbo/Mmjax mice (APP/PS1), a well-established transgenic model of AD. Eighteen-month-old APP/PS1 and wild-type mice received oral administration of PF-04691502 at a dose of 1 mg/kg for 12 weeks. Following the treatment period, spatial learning and memory were evaluated using the Morris water maze. Subsequently, the mice brains were collected for neuropathological and biochemical assessments. Our findings showed that PF-04691502 enhanced cognitive performance in APP/PS1 mice and significantly reduced insoluble Aβ accumulation in the brain. Mechanistically, these effects were associated with enhanced autophagy induction. Treatment with PF-04691502 increased the LC3-II/LC3-I ratio, upregulated Beclin-1, and elevated LAMP-2 levels, indicative of stimulated autophagosome formation and lysosomal activity. Overall, these preclinical results suggest that PF-04691502 holds promise as a potential therapeutic agent for AD and other aging-related neurodegenerative diseases involving mTOR pathway dysregulation. Full article

Emerging evidence highlights the role of chronic low-grade inflammation and dysregulated cytokines in both obesity and schizophrenia, suggesting overlapping immune system pathways that contribute to cognition and nervous system inflammation. Excess adipose tissue functions as an active endocrine organ, releasing pro-inflammatory mediators that may serve as potential biomarkers, while the use of antipsychotic agents in schizophrenia further modifies cytokine profiles and immune responses. A key knowledge gap lies in understanding how adipose-related inflammation modifies the severity of psychotic symptoms, cognitive deficits, and the efficacy of antipsychotic medications. This review aims to present excess adipose tissue as a potential contributor to the development of SCZ or a modifier of treatment efficacy, emphasizing the role of immune imbalance, inflammatory pathways, and metabolic dysfunction. By synthesizing current findings, we aim to present obesity not only as a frequent comorbidity in schizophrenia but also as a potential driver of neuroinflammation and disease progression. Here, we demonstrate that excess adiposity may perpetuate a vicious cycle linking metabolic dysfunction, immune activation, and psychiatric symptomatology. Situating these findings within a broader context, the review underscores the clinical need for inflammation-informed, individualized management strategies that integrate psychiatric care with metabolic monitoring. Ultimately, clarifying the shared inflammatory pathways of obesity and schizophrenia may open new avenues for biomarker development and targeted interventions. Full article

Insomnia is a common and complex disorder, rooted in the dysregulation of circadian rhythms, impaired neurotransmitter function, and disturbances in sleep–wake homeostasis. While conventional hypnotics such as benzodiazepines and Z-drugs are effective in the short term, their use is limited by a high potential for dependence, cognitive side effects, and withdrawal symptoms. In contrast, melatonergic receptor agonists—melatonin, ramelteon, tasimelteon, and agomelatine—represent a pharmacologically targeted alternative that modulates MT1 and MT2 receptors, which are pivotal to the regulation of circadian timing and sleep initiation. Clinical evidence supports the efficacy of these agents in reducing sleep onset latency, extending total sleep duration, and re-aligning disrupted circadian rhythms, particularly among older individuals and patients with non-24 h sleep–wake disorders. Notably, agomelatine offers additional antidepressant properties through selective antagonism of the 5-HT_2C receptor in micromolar concentrations. In contrast, its agonistic activity at melatonergic receptors is observed in the low sub-nanomolar range, which illustrates the complexity of this drug’s interactions with the human body. All compounds reviewed demonstrate a generally favorable safety and tolerability profile. Accumulating evidence highlights that selected medicinal plants, such as chamomilla, lemon balm, black cumin, valeriana, passionflower and lavender, may exert relevant hypnotic or anxiolytic effects, thus complementing melatonergic strategies in the management of insomnia. This structured narrative review presents a comprehensive analysis of the molecular pharmacology, receptor affinity, signaling pathways, and clinical outcomes associated with melatonergic agents. It also examines their functional interplay with serotonergic, GABAergic, dopaminergic, and orexinergic systems involved in arousal and sleep regulation. Through comparative synthesis of pharmacokinetics and neurochemical mechanisms, this work aims to inform the development of evidence-based strategies for the treatment of insomnia and circadian rhythm sleep–wake disorders. Full article

Despite increased interest in embodied learning, the role of sensorimotor activity in shaping students’ probabilistic reasoning remains underexplored. This design-based study examines how high school students develop key probabilistic concepts, including sample space, certainty, and event probability, through whole-body movement activities situated in an authentic classroom setting. Grounded in embodied cognition theory, we introduce a two-axis interpretive framework. One axis spans sensorimotor exploration and formal reasoning, drawing from established continuums in the literature. The second axis, derived inductively from our analysis, contrasts engagement with distraction, foregrounding the affective and attentional dimensions of embodied participation. Students engaged in structured yet open-ended movement sequences that elicited intuitive insights. This approach, epitomized by one student’s spontaneous question, “Can I use my leg too?”, captures the agentive and improvisational character of the embodied learning environment. Through five analyzed classroom episodes, we trace how students shifted between bodily exploration and formalization, often through nonlinear trajectories shaped by play, uncertainty, and emotionally driven reflection. While moments of insight emerged organically, they were also fragile, as they were affected by ambiguity and the difficulty in translating physical actions into mathematical language. Our findings underscore the pedagogical potential of embodied design for probabilistic learning while also highlighting the need for responsive teaching that balances structure with improvisation and supports affective integration throughout the learning process. Full article

Background/Objectives: Neurotransmitters such as dopamine and serotonin are critical regulators of mood, cognition, and neuronal homeostasis. This study aimed to evaluate the neuropharmacological potential of Hawaiian plants by investigating their ability to modulate the expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), key enzymes in neurotransmitter biosynthesis. Methods: A total of 108 aqueous and methanolic extracts of Hawaiian plants were screened for cytotoxicity against PC-12 and Neuro-2A cells using the MTT assay. Fifty-six non-toxic extracts were selected and further analyzed for TH and TPH expression via quantitative real-time PCR (qPCR). Results: Several extracts significantly upregulated TH and TPH expression without inducing cytotoxicity. Extracts derived from Morinda citrifolia, Pipturus albidus, and Hedychium coronarium showed the most notable activity, suggesting their potential to enhance dopaminergic and serotonergic pathways. Conclusions: The findings highlight the promise of native Hawaiian flora as sources of neuroactive compounds that may support neuroprotection and regeneration. These results provide a foundation for in vivo studies and further exploration of novel neurotherapeutic agents. Full article

Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer’s disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases. Full article

Can human–machine hybrid systems (HMHs) constitute genuine collective agents? This paper defends an affirmative answer. I argue that HMHs achieve collective intentionality without shared consciousness by satisfying the following three functional criteria: goal alignment, functional complementarity, and stable interactivity. Against this functionalist account, the following two objections arise: (1) the cognitive bloat problem, that functional criteria cannot distinguish genuine cognitive integration from mere tool use; and (2) the phenomenological challenge, that AI’s lack of practical reason reduces human–AI interaction to subject–tool relations. I respond by distinguishing constitutive from instrumental functional contributions and showing that collective agency requires stable functional integration, not phenomenological fusion. The result is what I call Functional Hybrid Collective Agents (FHCAs), which are systems exhibiting irreducible collective intentionality through deep human–AI coupling. Full article

Alzheimer’s disease (AD) is the most common cause of dementia, pathologically defined by extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Recent U.S. Food and Drug Administration (FDA) approvals of anti-amyloid monoclonal antibodies (mAbs) aducanumab, lecanemab, and donanemab represent the first disease-modifying therapies for early AD. These therapies have generated both optimism and controversy due to modest efficacy and safety concerns, particularly amyloid-related imaging abnormalities (ARIAs). This review synthesizes current evidence on the efficacy, safety, and biomarker-guided use of anti-Aβ mAbs in AD. Methods: We searched PubMed, Scopus, Web of Science, and Google Scholar to 31 July 2025 for studies on anti-amyloid mAbs in AD. Sources included peer-reviewed articles and regulatory reports. The extracted data covered study design, population, amyloid confirmation, dosing, outcomes, biomarkers, ARIA incidence, and management. Results: Anti-amyloid mAbs consistently demonstrated robust amyloid clearance and modest slowing of clinical decline in early symptomatic AD. Differences emerged across agents in efficacy signals, safety profiles, and regulatory outcomes. Lecanemab and donanemab showed more consistent cognitive benefits, while aducanumab yielded mixed findings, leading to its withdrawal. ARIAs were the most frequent adverse events, occurring more often in APOE ε4 carriers and typically during early treatment. Biomarker analyses also revealed favorable downstream effects, including reductions in phosphorylated tau and markers of astroglial injury, supporting engagement of disease biology. Conclusions: Anti-amyloid mAbs provide proof of concept for AD modification, with the greatest benefit in early disease stages and moderate tau burden. Optimal use requires biomarker confirmation of the amyloid, careful tau staging, and genetic risk assessment. While limitations remain, these therapies represent a pivotal step toward precision neurology and may serve as a foundation for multimodal strategies targeting tau, neuroinflammation, and vascular pathology. Full article

Urban mobility systems face escalating challenges associated with sustainability, equity, and resilience, further compounded by environmental pressures. Traditional agent-based models (ABMs) often fail to capture cognitively rich, adaptive behaviors, limiting their ability to simulate realistic user responses to disruptions. In this work, we propose a cognitive agent architecture based on Large Language Models (LLMs), featuring multi-horizon memory-driven planning, reflection, and adaptation. Integrated into the SimFleet agent-based simulator with realistic sociodemographic profiles, the agents dynamically generate, adjust, and reflect upon travel plans across a 20-day simulation involving over 320 individuals. Experimental results reveal emergent adaptation patterns under both stable and disrupted transport conditions, and an ablation study under severe service disruption quantifies the contributions of short-term and long-term memory modules to memory-driven reasoning, demonstrating the potential of LLM-driven agents to enhance the realism, flexibility, and interpretability of urban mobility simulations. Full article