Search Results (543)

Background: Although fentanyl significantly contributes to opioid-related morbidity and mortality, little is known about the epigenetic changes that may influence long-term neuronal adaptations. Objective: The effects of repeated fentanyl administration on class IIa histone deacetylase (HDAC) expression-activity were studied using the radiotracer [¹⁸F]TFAHA and positron emission tomography (PET) imaging in a model of fentanyl-induced behavioral sensitization. Methods: Female and male Wistar rats received 14 days of fentanyl (20 μg/kg) or saline injections and a 14-day drug-free period followed by a single fentanyl or saline challenge dose on day 28. Locomotor activity (LMA) was measured on days 0, 1, 14, and 28 with PET imaging being performed at baseline and again on day 28 following the fentanyl/saline challenge and LMA. The percent change in standard uptake value (body weight corrected) between pre- and post-administration was calculated as a measure of class IIa HDAC expression-activity. Results: Repeated fentanyl exposure resulted in significantly increased LMA in both sexes compared to controls. Females displayed an earlier onset (day 1) and a greater magnitude of behavioral sensitization on days 14 and 28 compared to males. Fentanyl significantly decreased class IIa HDAC expression-activity across time in the whole brain and in reward-related brain regions without sex differences. Conclusions: Prolonged fentanyl exposure induces robust sex-specific locomotor sensitization with varying magnitude over time, suggesting differential neuroadaptive processes. Fentanyl also appears to induce epigenetic changes in the brain independent of sex and region. The effect of fentanyl on class II HDACs may not directly impact the expression of behavioral sensitization. Full article

Radiotherapy-associated pain is among the most common and debilitating complications in head and neck cancer. Although historically viewed primarily as a treatment-related adverse effect, growing evidence suggests that pain is deeply intertwined with tumor biology, immune remodeling, and therapeutic outcomes. At the same time, recent advances in cancer neuroscience have identified sensory nerves as active components of the tumor microenvironment (TME), capable of influencing antitumor immunity through complex neuroimmune crosstalk. These observations raise the possibility that radiotherapy-associated pain is not merely a clinical symptom but also a biological indicator of dynamic changes within the tumor immune microenvironment (TIME). In this review, we outline the major clinical manifestations of radiotherapy-associated pain in head and neck cancer, including inflammatory or mucositis-related pain, neuropathic pain, and long-term chronic pain, with emphasis on their underlying biological features and potential therapeutic relevance. Given that oral mucositis is the dominant source of acute radiotherapy-associated pain in head and neck cancer, we further summarize evidence-based preventive and supportive strategies, including photobiomodulation, mucosal barrier-forming agents, anti-inflammatory mouthwashes, nutritional interventions, pain control, and multidisciplinary oral care. We further discuss how radiotherapy reshapes the TIME through mechanisms such as immunogenic cell death, activation of the cGAS-STING pathway, vascular and stromal remodeling, and regulation of lymphoid compartments, while also triggering compensatory immunosuppressive responses. Preclinical and translational studies suggest that nociceptive signaling pathways may modulate T-cell function, myeloid-cell activity, and immune-evasive programs. Through these neuroimmune interactions, radiotherapy-induced neural injury and persistent pain may contribute to the establishment of an immunosuppressive, wound-like microenvironment that ultimately affects treatment response and tumor progression. Finally, we discuss the translational significance of incorporating pain phenotyping into combined radiotherapy and immunotherapy strategies for head and neck cancer. Opioid-sparing multimodal analgesia, neuromodulation, and neuroimmune-targeted interventions may represent promising approaches to simultaneously improve symptom control and antitumor immunity. We propose that radiotherapy-associated pain may be considered a candidate neuroimmune phenotype rather than a passive adverse event, providing a new conceptual framework for precision management and translational research in head and neck cancer. Full article

Quantum dots (QDs) are semiconductor nanocrystals with unique photophysical properties, rendering them promising for applications in biomedical imaging, neuroscience, and various industrial sectors. However, the rapid expansion of their production and application inevitably leads to the release of QDs into the environment throughout their life cycle, classifying them as an emerging class of contaminants of concern. Their potential neurotoxicity not only represents a major bottleneck obstructing their clinical translation but also poses environmental and health risks that warrant serious attention. This review summarizes recent advances in the neurotoxicity of QDs, with a focus on their adverse effects on the central and peripheral nervous systems. It indicates that the mechanisms of QD neurotoxicity involve a complex network comprising oxidative stress, metabolic reprogramming, neuroinflammation, and multiple cell death pathways. Notably, the peripheral nervous system is highlighted as an early-warning target, and the significant risks associated with long-term, low-dose environmental exposure are emphasized. Full article

Background: Managing neuropathic pain (NP) is particularly challenging in the context of opioid use, and the mechanisms behind chronic pain remain unclear. Objective: This study evaluated the impact of turmeric bioactive compounds on brain regions including frontal cortex (FC), hippocampus (HPC), and hypothalamus (HPT) in the spinal nerve ligation (SNL) in a rat model of NP. Methods: Twenty-four SD rats were assigned to four groups (N = 6 per group), namely sham+vehicle (Sham-V), SNL+vehicle (SNL-V), SNL + 100 mg/kg curcumin (SNL+100CUR), and SNL + 50 mg/kg bisdemethoxycurcumin (SNL+50BDMC), treated daily for four weeks via oral gavage. Gene expression levels related to neuroinflammation, oxidative stress, and mitochondrial homeostasis were measured using qRT-PCR. Protein-level or functional mitochondrial assays were not performed due to limited sample availability. Results: In the FC, SNL decreased the expression level of NRF1 and OPA1, but only OPA1 was increased by BDMC. In the HPC, SNL increased CD11b, NRF2, and MFN1; BDMC decreased CD11b and increased IBA1, NRF1, TFAM, PGC1α and Complex I; and CUR increased NRF1, TFAM, DRP1 and Complex I levels. In the HPT, SNL decreased GFAP and MFN1, with CUR and BDMC further decreasing GFAP but not affecting MFN1. Additionally, CUR and BDMC decreased the expression of several key markers of neuroimmune signaling and mitochondrial homeostasis, including IBA1, CD11b, NFkB, NRF1/2, DRP1, OPA1, PGC1α, TFAM, and PINK1. Conclusions: CUR and BDMC induced region-specific transcriptional remodeling of mitochondrial homeostasis across FC, HPC, and HPT in SNL rats, with somewhat limited effects in the FC, mixed effects in the HPC, and broader downregulation in the HPT. Full article

Education systems face increasing pressure to adopt evidence-informed innovations that respond to learner diversity. In early childhood, understanding neuroplasticity is foundational for developing inclusive pedagogies, yet translating basic neuroscience into teacher professional development remains complex. This study presents a descriptive and exploratory bibliometric analysis characterizing the intersection of neuroplasticity, neuropedagogy, and early childhood to map how research evidence is organized. A corpus of 2937 documents spanning from 1975 to early 2026 was analyzed to identify publication trends, global collaboration networks, and thematic structures. Results indicate exponential growth in the field, with the United States leading in volume but European and South American nations demonstrating higher international collaboration rates. Thematic mapping reveals a structural separation between applied human studies and mechanistic basic science. This translational distance, combined with the documented prevalence of neuromyths among educators, presents a significant barrier to evidence-informed inclusive education. These findings provide researchers and policymakers with a diagnostic map of the field, outlining specific implications for the content, design, implementation, and evaluation of future teacher professional development to responsibly advance educational equity and inclusion. Full article

Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases—including Parkinson’s disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes—gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson’s disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a “sixth vital sign” reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology. Full article

Human digital twins (HDTs) are patient-specific computational models that combine medical imaging, physiological measurements and predictive algorithms. They are moving from an exciting concept to a realistic clinical opportunity. The key question is no longer whether HDTs can be built. The key question is which methods are mature enough to support clinical decisions and what is still missing for routine use. This systematic review maps the methodological landscape of HDTs and highlights practical bottlenecks that limit clinical translation. A PRISMA 2020 guided search of PubMed, Scopus, IEEE Xplore, and the Cochrane Library, covering publications from 2016 to 2026, identified 151 eligible studies. Bibliometric mapping and thematic synthesis were used to characterize research clusters, computational paradigms, and collaboration patterns. Three dominant application streams were identified: cardiovascular HDTs for hemodynamic simulation and procedural planning, musculoskeletal HDTs for biomechanics-driven orthopedic innovation, and neurological HDTs integrating neuroimaging with computational neuroscience. Across domains, the strongest technical trend is the rise in hybrid pipelines that combine physics-based simulation, including finite element and computational fluid dynamics models, with machine learning for segmentation, parameter identification, reduced-order modeling, and faster inference. However, reporting of verification, validation, uncertainty quantification, and explicit context of use remains uneven and prospective clinical evidence is still limited. Overall, the literature shows rapid progress toward clinically credible HDTs, while highlighting the need for scalable computation, standardized credibility pipelines, and workflow-integrated platforms to support safe and reproducible clinical adoption. Full article

Background/Objectives: COVID-19, caused by the SARS-CoV-2 virus, can lead to widespread neurological and cognitive complications, even in the absence of significant structural brain abnormalities. Understanding the evolving health concerns in the context of viral infections is critical to service member readiness, fitness, and mission completion. The potential neuroprotective effects of SARS-CoV-2 vaccination remain underexplored. Methods: Using a cross-sectional, non-human primate model (female cynomolgus macaques), we employed magnetoencephalography (MEG) to assess resting-state brain activity following vaccination with escalating doses of a novel psoralen-inactivated SARS-CoV-2 vaccine (PsIV) or a combination of PsIV and a DNA vaccine (prime boost), and subsequent challenge with the Delta variant (SARS-CoV-2 B.1.617.2). MEG scans were acquired 41 days after inoculation. Source series were constructed for 42 regions of interest for each subject, and band power was computed. Results: Band power demonstrated substantial preservation of neural activity across multiple brain regions in vaccinated subjects compared to unvaccinated controls following viral challenge. Significantly lower power was observed across the brain at all bandwidths in the unvaccinated group relative to the prime boost group. As PsIV concentration increased, spectral power increased, with the prime boost group having the greatest power. Conclusions: This approach not only underscores the role of vaccination in mitigating neuropathology but also highlights the capability of MEG to detect subtle yet significant changes in brain function that may be overlooked by other imaging modalities. These findings advance our understanding of vaccine-induced neuroprotection and establish MEG as a powerful tool for monitoring brain function in the context of viral infections. Full article

Not all sleep loss is equal, and overlooking this limits progress in sleep and neurological disease research. We compared nine rodent sleep deprivation paradigms, gentle handling, multiple platform variants, disk-over-water, the Unpredictable Chronic Sleep Deprivation (UCSD) paradigm, novel object introduction, curling prevention by water, automated systems, and head-lifting, evaluating stress confounds, sleep stage specificity, chronicity, and neurobiological outcomes. Effects included hippocampal plasticity, prefrontal chemistry, glymphatic clearance, neuroinflammation, oxidative stress, neurogenesis, and circadian regulation, linked to Alzheimer’s, Parkinson’s, and psychiatric comorbidities. UCSD with caffeine produced antioxidant depletion, serotonin reduction, acetylcholinesterase upregulation, and synaptophysin loss, early neurodegeneration markers. We propose a disease-targeted framework with six translational priorities and reporting standards. Full article

Stress alters hemodynamic regulation through intricate brain–body pathways, translating psychological phenomena into systemic cardiovascular changes. This review explores these complex neurobiological mechanisms, focusing on how the autonomic nervous system and hypothalamic–pituitary–adrenal axis orchestrate pathological fluctuations in heart rate, vascular resistance, and blood pressure. The neurophysiological data link limbic system hyperactivation to endothelial dysfunction and altered cerebral blood flow. Furthermore, we investigate the bidirectional nature of this relationship wherein stress-induced hemodynamic instability can exacerbate psychiatric conditions. Bridging affective neuroscience with cardiovascular physiology, this integrative framework underscores the critical need for multidisciplinary clinical approaches in managing stress-related psychosomatic and cardiovascular pathologies. Full article

Background: The nationally advertised mass media campaign Act-FAST UK, delivered in multiple waves since its launch in 2009, has increased public awareness of stroke symptoms. However, many stroke patients still delay in calling for help and reach the hospital too late to receive emergency treatments. The reasons for this cognitive dissonance between recognition of symptoms and urgent seeking of emergency medical services (EMS) are unclear. Aims: This study aimed to quantify cognitive, psychological, and knowledge-based barriers to help-seeking in patients with acute stroke or transient ischaemic attack (TIA), as well as in intervening witnesses, and to examine their association with the use of EMS as the initial point of contact. Methods: We interviewed patients admitted to a hyperacute stroke unit with a stroke or transient ischaemic attack (TIA) from 2013 to 2016. People who contacted emergency services on the patient’s behalf (intervening witnesses (IWs)) were also interviewed when available. Reasons given for delays in calling for help were related to correct symptom recognition, and whether/at what time, emergency services were contacted after symptoms onset. Results: A total of 602 patients (429 with stroke, 173 with TIA) along with 128 witnesses who intervened in calling for help in those cases (IWs) were interviewed. In the subset of patients with both measures available, there was a strong positive correlation between NIHSS score and number of FAST symptoms (Spearman’s rho = 0.645, p < 0.001), providing supportive evidence for the use of FAST symptom count as a proxy measure of stroke severity. A total of 469 (77.9%) of the patients were aware of a media education campaign about stroke, but only 145 (24.1%) had attributed their own symptoms to stroke at onset. However, correct self-diagnosis of stroke was not associated with direct calls to the EMS (OR 1.43, 95% CI 0.84–2.45). Cognitive, psychological or emotional barriers to help-seeking, as reported by prior published studies, were reported by 463 (81.2%) of the patients we interviewed but in only 63 (53.3%) of the IWs (p < 0.001). Amongst the patient cohort, “not thinking symptoms were serious” (275, 45.7%) and “waiting to see if symptoms would go away” (285, 47.3%) were most strongly negatively associated with EMS use (OR 0.52, 95% CI 0.32–0.84 and OR 0.34, 95% CI 0.21–0.55, respectively). Only 55 (9.1%) of the patients interviewed had been aware of any time-critical stroke treatment prior to their stroke. Eighteen stroke patients (4.2%) reached hospital in time to receive thrombolysis, but an additional 170 (39%) could have been considered for this treatment (i.e., had no apparent other contraindications from a notes review) had they arrived within 4 h of symptom onset. Conclusions: Future public education campaigns may be more effective if they specifically address factors associated with delays in calling for help after stroke symptoms and emphasise the existence of emergency treatments, which are also time-critical. More effective public education may have the potential to increase the proportion of patients arriving in time to benefit from such treatments. Full article

Visual discomfort or visual stress is an uncomfortable subjective experience that occurs in response to specific visual stimuli. It affects a large proportion of the population to various degrees, disproportionately impacting those with heightened sensory sensitivities, particularly neurodivergent individuals. We argue that this might stem from a mismatch between the statistical properties of visual stimuli in human-made environments and those in natural environments that the visual system can process efficiently. We discuss the inefficiency with which images with certain spatial, chromatic and temporal characteristics are processed by the visual system and propose a cerebral mechanism to account for the discomfort they induce. The mechanism offers a potential explanation for the large individual differences in susceptibility to discomfort. We highlight two avenues for intervention: (1) environmental modifications aimed at reducing the prevalence of visually stressing stimuli in urban settings, and (2) individual-level strategies, such as personalised optical treatments. Addressing these challenges requires an interdisciplinary effort bridging neuroscience, vision science, interior and urban design and typography to create visually accessible and inclusive environments. Full article

Background: Plasma biomarkers are promoted as scalable tools for the staging of Alzheimer’s disease (AD), yet head-to-head comparisons against the clinical scales used to define diagnostic labels remain scarce. Reported gains from machine learning fusion of clinical and biomarker features may reflect label circularity rather than biological signals, and quantifying this circularity is a central aim of the present work. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we assembled 655 participants (CN = 296, MCI = 168, and AD = 191) with concurrent plasma biomarkers (pT217, A$\beta$42/40, NfL, and GFAP), clinical scales (MMSE, CDR-SB, and FAQ), APOE genotype, and demographics. Three pre-specified feature sets (clinical-only, biomarker plus demographic–genetic, and full fusion) were compared across four classifiers (Logistic Regression, SVM, Random Forest, and XGBoost) using repeated, nested cross-validation (5-fold × 3 outer, 5-fold inner) with balanced class weighting. Because the external Center for Neurodegeneration and Translational Neuroscience (CNTN) cohort ($n=130$) measures pT181 rather than pT217 and lacks A$\beta$42/40, external evaluation used a separate reduced feature panel (NfL, GFAP, APOE, age, sex, and education), not the proposed pT217-inclusive panel. Results: Clinical scales alone reached a three-class AUC-OVR of $0.9539\pm 0.0041$, and fusion reached $0.9559\pm 0.0046$, an indistinguishable gain. Because MMSE, CDR-SB, and FAQ partly determine ADNI diagnostic labels, both estimates are circularity-inflated upper bounds and do not reflect independent classification power. Independent of this circularity, the internal plasma plus demographic–genetic model still achieved AUC-OVR $=0.7455\pm 0.0150$, with pT217 as the dominant contributor. Pairwise discrimination was excellent for CN vs. AD ($1.0000$) and MCI vs. AD ($0.9739$) but markedly weaker for CN vs. MCI ($0.9302$ for fused and $0.6972$ for plasma only). The separate reduced-feature model, which contains neither pT217 nor A$\beta$42/40, transferred to CNTN with AUC-OVR $=0.702$ (95% CI $0.635$–$0.764$). Conclusions: Apparent fusion gains in ADNI are largely a consequence of label circularity. After removing the circular clinical features, the internal pT217-inclusive plasma model supports three-class CN/MCI/AD screening at AUC $\approx 0.74$ and a reduced panel without pT217 transfers to an independent cohort at AUC $\approx 0.70$. These values provide a realistic performance estimate for blood-based AD staging under the current feature set, diagnostic label structure, and cohort design, and richer feature sets or pathology-anchored labels may shift this estimate. MCI detection remains the principal bottleneck. Full article

Background: Auditory oddball paradigms are widely used to investigate neural responses to deviant stimuli and attentional processing. However, different paradigms involve deviant stimuli with varying levels of stimulus relevance, and the corresponding neural responses have rarely been directly compared within a unified experimental framework. The aim of this study was to compare neural responses elicited by three variants of the auditory oddball paradigm that differ in the type of deviant stimuli: tone, reversed speech, and self-name deviants. Methods: Electroencephalography (EEG) data were recorded from 38 healthy participants while they performed three paradigm variants. Event-related potentials (ERPs) were analyzed to examine neural responses to deviant stimuli. In addition, cortical activation patterns were identified via source reconstruction, and classification analyses were conducted to assess the discriminability of neural responses across the three variants. Results: ERP results revealed that the self-name paradigm elicited the largest ERP responses, characterized by a significant P300 amplitude (3.95 μV) and prominent MMN (−6.39 μV). Crucially, source-space analysis revealed a graded expansion of cortical recruitment: acoustic deviance (tone) and structural reanalysis (reversed speech) were associated with 7 and 6 significant clusters, respectively, primarily in the auditory and fronto-cingulate cortices, whereas the self-name paradigm engaged 12 significant clusters spanning a distributed network encompassing salience-processing regions and cortical midline structures associated with self-referential processing (including the insula and posterior cingulate cortex). Classification analyses mirrored these findings, with the self-name paradigm consistently yielding the highest neural separability (~80% accuracy) and greater robustness to interindividual variability, demonstrating the superior discriminability of self-referential neural patterns. Conclusions: These findings demonstrate that self-referential auditory stimuli elicit stronger and more discriminable neural responses than other auditory deviant stimuli in the oddball paradigm. These results provide a comparative perspective on how different dimensions of auditory relevance modulate neural processing and may inform the design of effective auditory paradigms for cognitive neuroscience and related translational applications. Full article

Background/Objectives: Caffeine consumption has been reported to have beneficial effects in metabolic disorders; however, its effects on food intake are not fully elucidated. This study evaluated the impact of chronic caffeine consumption on weight gain, food intake, and metabolic parameters in C57BL/6 male mice. Methods: Eight-week-old male mice (28 animals) were divided into four groups: control (chow diet), caffeine (chow diet + 1 g/L caffeine in drinking water), high-fat diet (HFD), and HFD + caffeine (HFD + 1 g/L caffeine in drinking water). Diets and caffeine were provided ad libitum for 8 weeks. Food and water intake were recorded weekly, and blood glucose was measured every 4 weeks. After 8 weeks of diet and caffeine exposure, metabolic tests were conducted, and tissues were collected for biochemical analysis. Results: HFD consumption for 8 weeks induced an increase in body weight and adiposity compared to the chow diet, without changes in food intake. Caffeine consumption prevented body weight gain and adiposity, although it increased food intake. Caffeine also improved glucose tolerance in the HFD mouse model, without changes in random blood glucose, triglyceride, or cholesterol levels. Analysis of hypothalamic neuropeptide (Agrp, NPY, Pomc, Cart), involved in the control of food intake, showed no differences in expression. There were also no changes observed in locomotion nor in anxiety-like behavior. Conclusions: In conclusion, chronic high-fat diet (HFD) exposure induced obesity characterized by increased body weight and adiposity without altering food intake. Chronic caffeine consumption counteracted HFD-induced weight gain and fat accumulation and improved glucose tolerance, despite increasing food intake. Importantly, caffeine consumption in the HFD group did not affect locomotor activity or anxiety-like behavior, suggesting that its metabolic effects are not driven by changes in general activity or emotional state. Overall, these findings indicate that chronic caffeine consumption improves metabolic homeostasis in HFD-fed mice. Full article