Cell metabolism and epigenetic regulation play crucial roles in modulating cerebral ischemia/reperfusion (I/R) injury. How cell metabolism regulates cerebral I/R injury by regulating epigenetic modifications remains unclear. In this study, we utilized an in vivo injury model of transient middle cerebral artery occlusion (tMCAO) in C57BL/6 mice. The middle cerebral artery was occluded for 90 min, followed by reperfusion at different time points. We observed that the expression of ATP-citrate lyase (ACLY), an important enzyme involved in lipid synthesis, was significantly upregulated under cerebral I/R conditions. Inhibition of ACLY markedly exacerbated cerebral I/R injury in vivo. ACLY inhibition and knockdown in vitro also reduced cell viability in cultured neurons following oxygen-glucose deprivation/reoxygenation (OGD/R). Mechanistic studies revealed that ACLY enhances histone acetylation at the promoter regions of mitochondrial respiratory chain complexes by facilitating the accumulation of acetyl-CoA, thereby improving mitochondrial function and attenuating oxidative stress. Our findings reveal a novel metabolic-epigenetic axis mediated by ACLY in the regulation of cerebral I/R injury which may serve as a potential target for therapeutic intervention in ischemic stroke.
Subsequent to an intracerebral hemorrhage (ICH), a cascade of neuroinflammatory response drives the process of secondary brain injury. At present, no anti-inflammatory nor neuroprotective pharmacological interventions have been demonstrated to improve functional outcome after ICH. This Phase 2b study was designed to establish the safety and feasibility of CN-105, a neuroprotective and anti-inflammatory pentapeptide designed from the receptor binding region of apolipoprotein E, in patients with acute primary supratentorial ICH. The Singapore CN-105 in Participants with Acute Supratentorial ICH Trial (S-CATCH, NCT03711903) was a randomized, double-blind, placebo-controlled trial involving 60 patients (30 CN-105, 30 placebo) treated within 12 h of symptom onset. Safety was assessed through adverse events (AEs) and serious AEs (SAEs), while efficacy was evaluated using functional outcome measures, including the modified Rankin Scale (mRS) at 90 days. CN-105 was safe and well tolerated in patients with acute ICH, with no significant differences in incidence of SAEs between groups (30% SAEs in placebo vs. 26.7% in CN-105). Notably, fewer patients treated with CN-105 group experienced in-hospital neurological deterioration (0 vs. 10% in placebo). While treatment was not associated with a statistically significant improvement in 90-day mRS, higher proportion of patients treated with CN-105 achieved favorable mRS scores (≤ 3) compared with those in the placebo group (77.8 vs. 66.7%; p = 0.35). This Phase 2b trial confirmed the safety and feasibility of CN-105 administration in the acute setting of ICH. Although no statistically significant improvements in neurological outcomes were found, the observed trends warrant further investigation. Future Phase 3 trials should focus on refining patient selection and assessing the therapeutic efficacy of CN-105 in more targeted subgroups such as those with medium-sized subcortical ICH. Trial registration NCT03711903, https://clinicaltrials.gov/ https://clinicaltrials.gov/study/NCT03711903?term=NCT03711903&rank=1 . Registered 16 October 2018.
Mobility impairments caused by cerebral palsy (CP) negatively impact the daily lives of those with this neurodevelopmental disorder. The primary treatment method is physical therapy, which requires an understanding of the musculoskeletal system. While previous studies focus on muscles, tendons are also critical to movement and ambulatory activities. Therefore, this study aims to understand and quantitatively compare the patellar tendons of children with CP and their typically developing (TD) peers to guide physical therapy treatment. The right patellar tendon of 20 children, 8 with CP and 12 TD, was imaged using a Clarius L7HD3 wireless ultrasound probe (Clarius Mobile Health, Vancouver, BC, Canada) in both the transverse and sagittal planes. The raw radiofrequency ultrasound data were analyzed to quantify differences in image quality, ultrasonic spectral parameters and envelope statistics between children with CP and their TD peers, both as a group and across age- and sex-matched pairings. Significant and consistent differences were observed in 6 of the 10 investigated metrics, including contrast, contrast-to-noise ratio, signal-to-noise ratio, mid-band fit, spectral slope and Nakagami-m. One notable difference was observed in contrast, where the mean ± standard deviation in the transverse plane for children with CP was lower than that of their TD peers (1.66±4.43 vs. 5.14±5.37, respectively), indicating a statistically significant difference in echogenicity between the two groups. The observed trends in children with CP correlate with previous studies in injured tendons. These results demonstrate the potential for point-of-care quantitative ultrasound-derived parameters to characterize patellar tendon microstructure and support personalized physical therapy assessment and treatment planning for children with CP.
The prevalence of brain tissue hypoxia (BTH; PbtO2 < 20 mm Hg) in patients with spontaneous ICH is not well established. In this study, we aimed to quantify the prevalence of BTH and to assess determinants of brain tissue normoxia (BTN; PbtO2 ≥ 20 mm Hg) and BTH resolution. This retrospective cohort study included 58 patients with ICH admitted to a neurological intensive care unit (ICU) between 2010 and 2020 with multimodal invasive neuromonitoring. BTN was sought by avoiding low cerebral perfusion pressure (CPP) and low blood hemoglobin levels, and by maintaining normocapnia, normoxemia, normothermia, and metabolic homeostasis. Hourly PbtO2, CPP, and temperature data were matched with intermittent variables (blood gases, hemoglobin, glucose, sodium, and microdialysis) over 10 days. Regression analyses were performed using generalized estimating equations to account for repeated measurements. Patients were 61 [interquartile range (IQR), 55-69] years old and presented with an ICH score of 2 (1-3). Of the patients, 52 (90%) underwent surgical evacuation via hemicraniectomy and/or craniotomy, while 6 (10%) received invasive neuromonitoring only. The median initial ICH volume was 40.2 (IQR 29.5-55.8) mL. Surgical evacuation achieved a median reduction of 86.6% (IQR 69.0-94.2), leaving a median residual volume of 5.5 (IQR 3.0-14.1) mL. The overall prevalence of BTH was 31%. In multivariable analysis, the following factors led to the highest percentage of BTN: CPP 80-89 mm Hg [odds ratio (OR) 1.88, 95% confidence interval (CI) 1.32-2.68, p < 0.001; reference: < 60 mm Hg], partial pressure of oxygen (PaO2) 90-99 mm Hg (OR 1.64, 95% CI 1.15-2.14, p = 0.001; reference: < 80 mm Hg), core body temperature 36.0-37.4 °C (OR 2.10, 95% CI 1.34-3.28, p = 0.001; reference: < 36.0 °C), PaO2/fraction of inspired oxygen (FIO2) 100-199 (OR 3.52, 95% CI 1.60-7.75, p = 0.002; reference: < 100) in a model corrected for probe position. Only CPP [74.6 (66.8-82.7) vs. 72.5 (64.9-80.2) mm Hg, p < 0.001)] was significantly higher after BTH resolution as compared with the time when PbtO2 was lowest during 229 BTH episodes. BTH was observed during 31% of the monitored time in patients with a large hematoma volume despite the use of a PbtO2-targeted therapy. These findings generate the hypothesis that physiological determinants, such as CPP, are significantly associated with the achievement of BTN in regions near to the ICH.
Intracerebral hemorrhage (ICH) remains associated with high mortality and treatment variability. Current workflows rely on fragmented imaging interpretation and operator-dependent surgical planning. The objective was to develop and validate an agentic artificial intelligence (AI) framework integrating automated imaging analysis, guideline-based reasoning, and trajectory optimization for ICH treatment. Fifty consecutive computed tomography (CT) and computed tomography angiography (CTA) datasets from patients with spontaneous ICH were retrospectively analyzed. The system performed multi-class anatomical segmentation of skin, skull, brain, ventricles, and hematoma, followed by volumetric quantification and JavaScript Object Notation (JSON) based structured encoding of imaging biomarkers. A knowledge-based module incorporating international ICH guidelines generated risk stratification and treatment recommendations. When evacuation was indicated, an automated trajectory modeling module proposed a patient-specific minimally invasive surgical corridor. Overall agreement between AI-generated and expert treatment recommendations was 82% (41/50 cases), with substantial agreement beyond chance (Cohen's κ = 0.71). Discrepancies occurred primarily in borderline surgical indication scenarios. In evacuation candidates, the automated planner generated feasible trajectories in all 50 cases. Median angular deviation between AI-generated and expert-defined trajectories was 7.6°, interquartile range (IQR) 5.1-9.8°. AI-generated trajectories demonstrated equal or greater safety margins relative to expert planning in the majority of cases. End-to-end processing has a potential to substantially reduce simulated decision-support time compared with manual workflow. The proposed agentic AI framework enables structured, explainable, and workflow-integrated decision support for ICH management. This system may reduce operator variability and enhance precision in minimally invasive evacuation planning.
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Miniaturized microscopes or 'miniscopes' for neuroimaging in freely behaving animals mostly operate over short durations (<2 h) and image either neuronal activity or cerebral hemodynamics. In contrast, central nervous system (CNS) disease models involving seizures, brain tumors etc. necessitate long-term (>24 h) imaging, remote operation and simultaneous characterization of multiple neurophysiological variables such as neuronal activity, blood flow, blood volume, oxygenation and cellular dynamics (a capability that we call 'neurosurveillance'). Thus, we developed the 'CloudScope', a cloud-based multicontrast miniscope for autonomous neurosurveillance in freely behaving animals. Its cloud-based architecture enables global remote operation and continuous acquisition of multicontrast images over CNS disease model life cycles. We demonstrate CloudScope's neurosurveillance capabilities in predicting behavior from 24-h neuroimaging data with deep learning (DL), characterizing neurovascular changes during natural behavior, seizure-induced neurovascular disruptions, and in vivo cellular and microvascular phenotyping of brain tumor microenvironments. Finally, CloudScope's architecture enables 'time-shared' imaging, which potentially reduces animal use. Collectively, CloudScope's neurosurveillance capabilities in conjunction with CNS disease models establish a new paradigm for characterizing their etiology and evolution.
Cells release heterogeneous extracellular vesicles and particles (EVPs) into circulation, carrying RNA and proteins that reflect their origin. Recently, brain-derived EVs have gained significant attention as non-invasive biomarkers for Alzheimer's disease (AD). Here, we identified sub-50nm extracellular nanoparticles in human brain and blood that lack the hallmarks of small EVs, exosomes, exomeres, and supermeres but are enriched for brain-specific markers, hereafter termed small EPs or 'SECmeres'. We discovered that RNAs associated with SECmeres discriminated AD cases from controls with higher significance than small EVs, large EVs showed no differences. Discriminating RNAs were enriched in small EVs (Synaptotagmin, Alpha-synuclein, MAPT) or SECmeres (L1CAM, Syntaxin, Neurogranin), indicating distinct brain-derived signatures. Single-cell RNAseq deconvolution shows small EVs contain RNAs from diverse brain cells, whereas SECmeres enrich brain endothelial transcripts, lining cerebral blood vessels and forming the blood-brain barrier (BBB). These findings challenge the prevailing view that small EVs are the primary carriers of biomarkers. Collectively, our study shows that blood EVPs carry brain-specific information for liquid biopsy, pending validation in larger blinded clinical trials.
Peganum harmala L. is a plant rich in β-carboline alkaloids, especially harmine, which is widely used in folk medicine and has therapeutic and toxic effects depending on the dose. In order to determine the toxic properties of harmine, the experiment was carried out by perorally treating this substance to the animals at a dose of 20 mg/kg every day for 14 days. As a result, although the absolute liver weight was significantly increased in the harmine-treated group compared to the control rats (4.65 g vs. 4.25 g, p = 0.04), the relative liver weight was significantly decreased (2.96% vs. 3.55%, p = 0.0045), likely reflecting the disproportionate increase in total body mass observed in the harmine group (157.25 g vs. 119.5 g, p = 0.0002). Additionally, the relative weight of the cerebral hemispheres was significantly reduced, and a statistically significant increase in ALT levels was observed. In the rats treated with harmine, blood was observed in the urine in 85.72% on the first day, and nitrites and proteins were observed in 71.3%. Examination of the amounts of alkaloids in organs and samples, very high amounts of harmine were found, especially in the liver. The 97.78% decrease in harmine content when passing from the stomach to the small intestine indicates its absorption from the stomach. As the result of light and transmission electron microscopy pathological changes were detected due to harmine such as damage to the wall of the central venous vessels and sinusoids, increase in the amount of edema fluid as a result of increased vascular permeability, indistinguishability of boundaries between hepatocytes and steatosis in their cytoplasm, vacuolization, increase in the amount of lysosomes, dystrophy of some nuclei, destruction of the microvilles of bile capillaries.
Sudden infant death syndrome (SIDS) occurs predominantly during sleep between 2 and 6 months of age, suggesting impaired maturation of arousal pathways. The neurobiological mechanisms involved remain unclear. We investigated the role of wake-promoting Orexin (Ox) and Histamine (HA) neurons in SIDS. Cerebrospinal fluid (CSF) Ox levels were measured in 61 living controls and 70 Sudden Unexpected Death Infants (SUDI: 38 SIDS, 32 explained deaths (ED)). HA and tele-methylhistamine (t-MeHA) were analyzed in an additional 46 SUDI (34 SIDS, 12 ED) and 42 controls. Immunohistochemistry was performed on hypothalamic tissue from 11 SIDS and 8 ED cases to quantify Ox and HA neuron numbers. CSF Ox levels did not differ overall between groups but were higher in SUDI infants aged 2-6 months. HA and t-MeHA levels were elevated in SUDI, likely reflecting postmortem release. Ox neuron numbers were increased in rostral hypothalamic region in SIDS compared with EDs, whereas HA neuron numbers were unchanged. SIDS is associated with increased Ox neuronal activity during the peak risk period, possibly reflecting a homeostatic upregulation in response to arousal deficit or repeated stress or hypoxia, while the role of HA system remains to be clarified with more sensitive biomarkers. First study evaluating orexin and histamine systems in SIDS using CSF and postmortem brain tissue. Identifies elevated orexin activity in SIDS infants, particularly in the 2-6 month risk window. No evidence to date for direct histamine involvement; need for more sensitive biomarkers. Suggests orexin system as a potential biomarker for SIDS risk stratification. Highlights the importance of combined neurobiological approaches for prevention.
Early identification of autism spectrum disorder (ASD) remains a critical challenge, particularly in utero when non-genetic factors such as maternal obesity (MO) are implicated. Here, we report results of whole-genome bisulfite sequencing of cell-free DNA (cfDNA) from third-trimester maternal plasma in a high-likelihood ASD pregnancy cohort associated with child (3 y) ASD diagnosis and/or MO. Differentially methylated regions (DMRs) between ASD and control cfDNA are strongly enriched for synaptic functions and genes previously implicated in ASD. These cfDNA ASD DMRs recapitulate those observed in ASD placenta and postmortem cortex and significantly overlap with MO DMRs. Our findings establish cfDNA methylation derived from maternal blood as a minimally invasive window into fetal brain ASD etiology, providing a framework for future mechanistic and early intervention studies. Future studies could investigate additional prenatal environmental exposures interacting with genetics during neurodevelopment.
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Shaken Baby Syndrome and Abusive Head Trauma are significant traumatic brain injuries observed in infants and represent a critical public health issue. Although there is a vast literature on this subject, conducting a descriptive bibliometric analysis is essential to map the topic's quantitative development over time and to reveal its current geographical and conceptual distribution objectively. This study systematically analyzes 3,571 articles published between 1977 and 2025 in the Web of Science Core Collection database, examining the distribution of publications by year and country, leading journals, citation rates, and keyword networks. Our findings indicate a linear increase in the volume of SBS/AHT research publications since the 2000s. The analysis highlights two significant strengths and shifts in the literature. First, the emergence of countries from diverse regions-such as Romania, the United Arab Emirates, Malaysia, and Russia-in the literature network, alongside traditional research hubs, objectively confirms the subject's expanding global scope. Second, the fact that the highest citation rates and publication density are not limited to clinical medicine journals (e.g., Pediatrics) but are simultaneously concentrated in pioneering journals with social and legal content (e.g., Child Abuse & Neglect) highlights the field's multidimensional and interdisciplinary nature. In conclusion, this study provides an objective resource for all stakeholders-including physicians, forensic scientists, and legal professionals-by visualizing the current geographic diversity of scientific output, key terms, and journal dynamics.
Temporal visual processing deficits are well-documented in psychosis spectrum disorders and linked to core symptoms including hallucinations and cognitive disorganization. However, studying these mechanisms in isolation may overlook the influence of co-occurring autistic traits, which are increasingly recognized within psychosis populations. We hypothesized that psychosis-proneness and autistic traits would interactively affect temporal crowding. We investigated temporal crowding using an orientation-estimation task in neurotypical participants across two experiments (N1 = 81, N2 = 93). Participants viewed sequences of three randomly oriented stimuli at varying stimulus onset asynchronies (SOA: 200-400ms) and reported the middle item's orientation. Mixture models examined performance in terms of encoding precision, guessing rates, and substitution errors. The Community Assessment of Psychic Experiences (CAPE) and Autism-Spectrum Quotient (AQ) measured trait expression. Response surface analysis (RSA) mapped trait interactions. RSA revealed that balanced expressions of both traits (particularly when both were elevated) were associated with significantly reduced temporal order errors. These findings align with the diametric model, which suggests compensatory interactions between psychosis-proneness and autistic traits. Our findings extend this model to mid-to-high level perceptual mechanisms, suggesting that opposing cognitive tendencies can create mutual compensation at the perceptual level, with implications for understanding symptom heterogeneity across both conditions.
Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.
Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are severe psychiatric disorders with distinct and overlapping clinical and neurobiological features. Despite extensive evidence of brain structural abnormalities, the transdiagnostic neuropathological mechanisms remain poorly understood. A comprehensive literature search was performed for voxel-based morphometry (VBM) studies reporting altered gray matter volume (GMV) in MDD, BD or SZ. A transdiagnostic meta-analysis was conducted to identify common and disorder-specific GMV alterations using the Seed-based d Mapping toolbox. Disease epicenter and buffering mapping were further investigated using a normative functional connectome to understand the network-constrained GM atrophy patterns. A total of 221 studies (MDD: n = 66; BD: n = 59; SZ: n = 96) encompassing 10,485 patients and 12,128 healthy controls were included. Transdiagnostic GMV reductions were identified in the medial prefrontal cortex and superior temporal gyrus. Less atrophy in the limbic/paralimbic regions and temporoparietal junction were observed for MDD, whereas SZ patients exhibited more pronounced GMV reductions in these areas. The ventrolateral prefrontal cortex emerged as a shared disease epicenter and the precuneus as a common buffer across these affective and psychotic disorders. The visual and dorsal attention networks exhibited the most pronounced buffering effects, while epicenter effects were primarily concentrated within the limbic, frontoparietal, subcortical and default mode networks. These findings suggested that affective and psychotic disorders are characterized by both shared and unique network-constrained GM atrophy patterns, which might advance precision diagnostics and inform targeted therapeutic strategies in the future.
Nightmare disorder is historically conceptualised as a rapid eye movement (REM) sleep parasomnia, but evidence also points to altered non-rapid eye movement (NREM) sleep physiology. Here, in a retrospective case-control study, we analysed overnight polysomnography from 26 adults with nightmare disorder and 32 controls using a harmonised event-based EEG pipeline. Nightmare disorder showed reduced frontal slow-oscillation-spindle coupling, whereas delta-spindle coupling was preserved, yielding lower coupling dominance than in controls (0.137 ± 0.083 versus 0.238 ± 0.096; p = 6.8 × 10-5). Stage-adjusted K-complex density across the first 6 h from sleep onset was also lower in nightmare disorder (0.463 ± 0.345 versus 0.723 ± 0.475 events per minute of available N2/N3 sleep; p = 0.019), whereas peak-timing differences were not robust. These findings suggest altered NREM sleep microarchitecture in nightmare disorder rather than a phenotype confined to REM sleep, and warrant prospective confirmation in harmonised, clinically phenotyped cohorts.
Children with severe self-injurious behaviour (SIB) are at risk of permanent injury and lack effective treatment options. Neuromodulation of the nucleus accumbens (NAc), a key node in reward and behavioural regulation circuits, may directly modulate the drivers of SIB. We report long-term outcomes from a first-in-human, single-centre trial of deep brain stimulation (DBS) targeting the NAc in children and adolescents with profound autism and treatment-refractory SIB (NCT03982888). Six participants (ages 7-14 years; mean 11.7) underwent bilateral implantation and were followed prospectively for at least 24 months (mean 32.5 months, range 25.8-56.0). One serious adverse event occurred: a device-related infection requiring hardware explantation, followed by relapse to baseline levels of self-injury. Subsequent re-implantation in this participant yielded rapid improvement in SIB, providing single-subject, causal withdrawal-rechallenge evidence of treatment-specific benefit. Across the cohort, NAc-DBS produced sustained reductions in SIB frequency and severity, repetitive and obsessive-compulsive behaviours, and clinically meaningful improvements in quality of life. The durability of these effects over multi-year follow-up suggests that circuit-targeted neuromodulation may modify the developmental course of severe behavioural pathology. These findings provide the first long-term evidence that modulation of reward circuitry can durably alter maladaptive behaviour in childhood neurodevelopmental disorders.
Introduction: A vast body of cognitive research in psychosis has focused on auditory hallucinations, though more recent studies are turning towards other sensory modalities. This study aimed to compare the cognitive profile of persons experiencing uni- or multisensory versus multimodal hallucinations. Methods: Participants with primary diagnosis of a psychotic disorder were subdivided into those experiencing uni- or multisensory (UMS; n = 31) versus multimodal (MM; n = 28) hallucinations relative to non-clinical controls (NC; n = 32). Cognitive assessment comprised the MATRICS Consensus Cognitive Battery, supplemented by a Colour Word Interference Test. Analyses of variance (ANOVAs) and correlation analyses were performed. Results: The UMS and MM groups performed significantly worse than the NC group on some cognitive domains (i.e. speed of processing, attention/vigilance, working memory, verbal learning), but not others (i.e. reasoning and problem-solving, social cognition). For visual learning, the MM group performed significantly worse than the NC group only, whereas for inhibition, the UMS group performed significantly worse than the NC group only. Conclusion: A novel cognitive profile associated with multimodal hallucinations was documented. Dissociation between performance of the two clinical groups on visual learning and inhibition suggests these cognitive domains may be of relevance to hallucinations, pending further investigations.