Search Results (1,583)

Background: We recently reported sex-dependent impairment in cognitive functions in male and female mice exposed for 24 h, 48 h or 15 days to 2G hypergravity (HG). Methods: In the present study, we investigated brain functional correlates by analyzing synaptic activity and plasticity in the CA1 area of the hippocampus in both genders of mice previously exposed to 2G for the same duration. This was assessed by electrophysiological extracellular recordings in ex vivo slice preparations. Results: Basal synaptic transmission and glutamate release were unchanged regardless of HG duration. However, plasticity was altered in a sex- and time-specific manner. In males, long-term potentiation (LTP) induced by strong high-frequency stimulation and NMDA receptor (NMDAr) activation was reduced by 26% after 24 h of exposure but recovered at later timepoints. This deficit was reversed by D-serine or glycine, suggesting decreased activation at the NMDAr co-agonist site. In females, LTP deficits (23%) were found only after 15 days following mild theta burst stimulation and were not reversed by D-serine. Long-term depression (LTD) was unaffected in both sexes. Conclusions: This study highlights, for the first time, sex-dependent divergence in the CA1 hippocampal plasticity timeline following 2G exposure. The synaptic changes depend on exposure duration and the stimulation protocol and could underlie the previously observed cognitive deficits. Full article

The Notch signaling pathway is a critical regulator of embryonic brain development. Among its four mammalian receptors, Notch1 and Notch2 are particularly significant in the developing cortex, yet their roles in human neurodevelopment are not well understood. In murine cortex development, Notch1 primarily regulates early progenitor identity and neurogenesis, while Notch2 is required for maintaining radial glial cells at later stages. However, it is unclear whether these functions are conserved in the human developing brain. In this study, we used cerebral organoids as an in vitro model of early human corticogenesis and conducted lentiviral shRNA-mediated knockdowns of NOTCH1 and NOTCH2. Our findings indicate that NOTCH1 is essential for organoid growth, lumen morphogenesis, radial glial identity, and progenitor proliferation. In contrast, depleting NOTCH2 did not significantly affect these early developmental processes. These results demonstrate that NOTCH1 and NOTCH2 have potentially non-redundant and temporally distinct roles in early human corticogenesis, reflecting receptor-specific specialization within the Notch signaling pathway. Full article

The current opinion paper puts into perspective how altered microbiota transplanted from Alzheimer’s patients initiates the impairment of the microbiota–gut–brain axis of a healthy recipient, leading to impaired cognition primarily arising from the hippocampus, dysfunctional adult hippocampal neurogenesis, dysregulated systemic inflammation, long-term spatial memory impairment, or chronic pain with hippocampal involvement. This altered microbiota may induce acquired Piezo2 channelopathy on enterochromaffin cells, which, in turn, impairs the ultrafast long-range proton-based oscillatory synchronization to the hippocampus. Therefore, an intact microbiota–gut–brain axis could be responsible for the synchronization of ultradian and circadian rhythms, with the assistance of rhythmic bacteria within microbiota, to circadian regulation, and hippocampal learning and memory formation. Hippocampal ultradian clock encoding is proposed to be through a Piezo2-initiated proton-signaled manner via VGLUT3 allosteric transmission at a distance. Furthermore, this paper posits that these unaccounted-for ultrafast proton-based long-range oscillatory synchronizing ultradian axes may exist not only within the brain but also between the periphery and the brain in an analogous way, like in the case of this depicted microbiota–gut–brain axis. Accordingly, the irreversible Piezo2 channelopathy-induced loss of the Piezo2-initiated ultradian prefrontal–hippocampal axis leads to Alzheimer’s disease pathophysiology onset. Moreover, the same irreversible microdamage-induced loss of the Piezo2-initiated ultradian muscle spindle–hippocampal and cerebellum–hippocampal axes may lead to amyotrophic lateral sclerosis and Parkinson’s disease initiation, respectively. Full article

Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances may in turn stimulate these brain systems to produce an overconsumption of these substances along with co-occurring emotional disturbances. To understand this positive feedback loop, this review focuses on a specific population of hypothalamic peptide neurons expressing melanin-concentrating hormone (MCH), which are positively related to dopamine reward and project to forebrain areas that mediate this behavior. It also examines neurons expressing the peptide hypocretin/orexin (HCRT) that are anatomically and functionally linked to MCH neurons and the molecular systems within these peptide neurons that stimulate their development and ultimately affect behavior. This report first describes evidence in animals that exposure in adults and during adolescence to rewarding substances, such as the drugs alcohol, nicotine and cocaine and palatable fat-rich food, stimulates the expression of MCH as well as HCRT and their intracellular molecular systems. It also increases reward-seeking and emotional behavior, leading to excess consumption and abuse of these substances and neurological conditions, completing this positive feedback loop. Next, this review focuses on the model involving embryonic exposure to these rewarding substances. In addition to revealing a similar positive feedback circuit, this model greatly advances our understanding of the diverse changes that occur in these neuropeptide/molecular systems in the embryo and how they relate, perhaps causally, to the disturbances in behavior early in life that predict a later increased risk of developing substance use disorders. Studies using this model demonstrate in animals that embryonic exposure to these rewarding substances, in addition to stimulating the expression of peptide neurons, increases the intracellular molecular systems in neuroprogenitor cells that promote their development. It also alters the morphology, migration, location and neurochemical profile of the peptide neurons and causes them to develop aberrant neuronal projections to forebrain structures. Moreover, it produces disturbances in behavior at a young age, which are sex-dependent and occur in females more than in males, that can be directly linked to the neuropeptide/molecular changes in the embryo and predict the development of behavioral disorders later in life. These results supporting the close relationship between the brain and behavior are consistent with clinical studies, showing females to be more vulnerable than males to developing substance use disorders with co-occurring emotional conditions and female offspring to respond more adversely than male offspring to prenatal exposure to rewarding substances. It is concluded that the continued consumption of or exposure to rewarding substances at any stage of life can, through such peptide brain systems, significantly increase an individual’s vulnerability to developing neurological disorders such as substance use disorders, anxiety, depression, or cognitive impairments. Full article

Background: Acute necrotising encephalopathy (ANE) is a rare and severe type of encephalopathy with bilateral symmetrical brain lesions, often following a viral prodrome. ANE type 1 (ANE1) is a disease subtype with a predisposing mutation in the gene encoding RAN binding protein 2 (RANBP2). Methods: We report a case of a 3-year-old girl with clinical symptoms of ANE and brain MRI findings suggesting ANE1, which was subsequently confirmed by genetic analysis. Results: MRI of the brain demonstrated symmetrical high T2/FLAIR signal changes in the lateral geniculate bodies, claustrum, ventromedial thalami, subthalamic nuclei, mamillary bodies, and brainstem, with partly corresponding diffusion restriction, as well as additional haemorrhagic changes in the lateral geniculate bodies on susceptibility weighted imaging. Genetic analysis revealed a heterozygous pathogenic variant of the RANBP2 gene. With immunosuppressive and supportive treatment, the patient fully recovered and was discharged after 10 days in the hospital with no residual symptoms. Conclusions: Recognition of the characteristic MRI findings in ANE1 can facilitate a timely diagnosis and enhance the clinical management of the patient and their relatives, especially given the high risk of disease recurrence. Full article

The quality of life (QoL) perception has been studied in neurological diseases; however, there is limited information linking brain morphological characteristics, QoL, and cognition. Human behavior and perception are associated with specific brain areas that interact through diffuse electrochemical networking. We used magnetic resonance imaging (MRI) to analyze the brain region volume (BRV) correlation with the scores of Rand’s 36-item Short Form Survey (SF-36) and cognitive domains (memory and dementia status). We analyzed data from 420 adult participants in the Maracaibo Aging Study (MAS). Principal component analysis with oblimin axis rotation was used to gather redundant information from brain parcels and SF-36 domains. Canonical correlation was used to analyze the relationships between SF-36 domains and BRV (adjusted for intracranial cavity), as well as sex, age, education, obesity, and hypertension. The average age (±SD) of subjects was 56 ± 11.5 years; 71% were female; 39% were obese; 12% had diabetes, 52% hypertension, and 7% dementia. No sex-related differences were found in memory and orientation scores, but women had lower QoL scores. The 1st and 2nd canonical correlation roots support the association of SF-36 domains (except social functioning and role emotional) and total brain volume, frontal lobe volume, frontal pole, lateral orbital lobe, cerebellar, and entorhinal areas. Other variables, including age, dementia, memory score, and systolic blood pressure, had a significant influence. The results of this study demonstrate significant correlations between BRV and SF-36 components, adjusted for covariates. The frontal lobe and insula were associated with the mental health component; the lateral-orbital frontal lobe and entorhinal area were correlated with the physical component. Full article

Globins are a class of globular proteins that function in the transportation or storage of oxygen. They are critical for cellular metabolism. Notable examples include hemoglobin, which is found in red blood cells, and myoglobin, which is present in muscle cells. Approximately two decades ago, a third globin, designated as neuroglobin, was identified, expressed predominantly in neuronal cells. This was followed two years later by the fourth, cytoglobin, found in cells of the fibroblast lineage, as well as in neuronal cell populations of the central and nervous systems. Both neuroglobin and cytoglobin have been found in the sensory and endocrine systems, albeit inconsistently, and it is thought that they are engaged in functions such as oxygen transport and storage, scavenging of free radicals, NO metabolism, peroxidase activity, and signaling functions. Neuroglobin is also expressed in astrocytes under challenging conditions. Common neuroscience methods were utilized to study the distribution and regulation of globin tissues and of single brain cells. Despite considerable overlap in the findings of various studies, some results deviate significantly from other studies. The potential causes of these discrepancies may include variations in detection methods, animal age and sex, time of day and year, and differing cell culture conditions. This review will explore factors that may influence functional aspects of globins and their detection in the mammalian brain. Full article

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms. Full article

Glaucoma is a trans-synaptic neurodegenerative disease, and the pathological increase in intraocular pressure (IOP) is a major risk factor of glaucoma. High IOP alters microstructure and morphologies of the brain tissue. Since mechanical properties of the brain are sensitive to the alteration of the tissue microstructure, we investigate how varying durations of chronic elevated IOP alter brain mechanical properties. A chronic high IOP rat model was induced by episcleral vein cauterization with subconjunctival injection of 5-Fluorouracil. At 2, 4 and 8 weeks after induction, indentation tests were performed on the brain slices to measure mechanical properties in the hippocampus, lateral geniculate nucleus and occipital lobe of both hemispheres. Meanwhile, the brain’s microstructure was assessed via F-actin and myelin staining. Compared to the blank control group, the Young’s modulus decreased in all three brain regions in the highIOP experimental groups. F-actin fluorescence intensity and myelin area fraction were reduced in the hippocampus, while β-amyloid levels and tau phosphorylation were elevated in the experimental groups. Our study provides insight into Alzheimer’s disease pathogenesis by demonstrating how chronic high IOP alters the brain’s mechanical properties. Full article

The gut–brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management. Full article

Researchers are increasingly focusing on understanding the microbiota’s influence on disease susceptibility and overall health. The vast number of microorganisms in our gastrointestinal tract and their extensive surface area underscore their undeniable impact on well-being. Viewing the gut microbiome as a distinct pool of microbial genetic information that interacts with the human genome highlights its pivotal role in genetically predisposed diseases. Investigating this complex crosstalk may lead to the development of novel therapeutic strategies—such as targeting dysbiosis—to complement conventional treatments and improve patient care. Parkinson’s disease (PD) is a multifactorial condition originating from a combination of genetic and environmental risk factors. Compelling evidence points to the enteric nervous system as an initial site of pathological processes that later extend to the brain—a pattern known as the ‘body-first’ model. Furthermore, most patients with PD exhibit both qualitative and quantitative alterations in the composition of the gut microbiota, including dysbiosis and small intestinal overgrowth. Nonetheless, the existing literature predominantly addresses fecal microbiota, while knowledge of upper intestinal sections, like the duodenum, remains scarce. Given the potential for microbiota modulation to impact both motor and gastrointestinal symptoms, further research exploring the therapeutic roles of balanced diets, probiotics, and fecal transplants in PD is warranted. Full article

Emotion recognition by wearable devices is essential for advancing emotion-aware human–computer interaction in real life. Earphones have the potential to naturally capture brain activity and its lateralization, which is associated with emotion. In this study, we newly introduced tympanic membrane temperature (TMT), previously used as an index of lateralized brain activation, for earphone-based emotion recognition. We developed custom earphones to measure bilateral TMT and conducted two experiments consisting of emotion induction by autobiographical recall and scenario imagination. Using features derived from the right–left TMT difference, we trained classifiers for both four-class discrete emotion and valence (positive vs. negative) classification tasks. The classifiers achieved 36.2% and 42.5% accuracy for four-class classification and 72.5% and 68.8% accuracy for binary classification, respectively, in the two experiments, confirmed by leave-one-participant-out cross-validation. Notably, consistent improvement in accuracy was specific to models utilizing right–left TMT and not observed in models utilizing the right–left wrist skin temperature. These findings suggest that lateralization in TMT provides unique information about emotional state, making it valuable for emotion recognition. With the ease of measurement by earphones, TMT has significant potential for real-world application of emotion recognition. Full article

Background: Borderline personality disorder (BPD) is a severe psychiatric condition characterised by emotional instability, impulsivity, interpersonal dysfunction, and self-injurious behaviours. Despite growing clinical interest, the neuropsychological mechanisms underlying these symptoms are still not fully understood. This review aims to summarise findings from neuroimaging, psychophysiological, and neurodevelopmental studies in order to clarify the neurobiological and physiological basis of BPD, with a particular focus on emotional dysregulation and implications for the treatment of adolescents. Methods: A narrative review was conducted, integrating results from longitudinal neurodevelopmental studies, functional and structural neuroimaging research (e.g. FMRI and PET), and psychophysiological assessments (e.g., heart rate variability and cortisol reactivity). Studies were selected based on their contribution to understanding the neural correlates of BPD symptom dimensions, particularly emotion dysregulation, impulsivity, interpersonal dysfunction, and self-harm. Results: Findings suggest that early reductions in amygdala volume, as early as age 13 predict later BPD symptoms. Hyperactivity of the amygdala, combined with hypoactivity in the prefrontal cortex, underlies deficits in emotion regulation. Orbitofrontal abnormalities correlate with impulsivity, while disruptions in the default mode network and oxytocin signaling are related to interpersonal dysfunction. Self-injurious behaviour appears to serve a neuropsychological function in regulating emotional pain and trauma-related arousal. This is linked to disruption of the hypothalamic-pituitary-adrenal (HPA) axis and structural brain alterations. The Unified Protocol for Adolescents (UP-A) was more effective to Mentalization-Based Therapy for Adolescents (MBT-A) at reducing emotional dysregulation compared, though challenges in treating identity disturbance and relational difficulties remain. Discussion: The reviewed evidence suggests that BPD has its in early neurodevelopmental vulnerability and is sustained by maladaptive neurophysiological processes. Emotional dysregulation emerges as a central transdiagnostic mechanism. Self-harm may serve as a strategy for regulating emotions in response to trauma-related neural dysregulation. These findings advocate for the integration of neuroscience into psychotherapeutic practice, including the application of neuromodulation techniques and psychophysiological monitoring. Conclusions: A comprehensive understanding of BPD requires a neuropsychologically informed framework. Personalised treatment approaches combining pharmacotherapy, brain-based interventions, and developmentally adapted psychotherapies—particularly DBT, psychodynamic therapy, and trauma-informed care—are essential. Future research should prioritise interdisciplinary, longitudinal studies to further bridge the gap between neurobiological findings and clinical innovation. Full article

Background: CIC-rearranged sarcoma is a rare and aggressive type of undifferentiated round cell tumor characterized by CIC gene fusion, most commonly CIC::DUX4. This study presents a series of eleven cases, highlighting their clinicopathological features. Methods: Pathology records (2019 to 2024) were searched using “sarcoma with CIC”, identifying eleven cases, of which seven referred cases were initially misdiagnosed. Pathological and clinical analysis was conducted. Treatment was dictated upon multidisciplinary panel discussion based on tumor stage. Follow-up data (1–25 months) was available for all patients. Results: The cohort included six males and five females, with a median age of 43 years (range;14–53), with nine in soft tissue and two in bone. Tumor size ranged from 3.5 cm to 20.0 cm (mean: 9.8 cm). Most cases showed sheets of undifferentiated round- to oval-shaped cells. Two cases showed an Ewing-like pattern, and one case showed spindle cells in a fibrotic stroma transitioning to epithelioid cells. Necrosis was present in nine cases, and mitotic count ranged from 2 to 38/ 10HPFs (mean = 14.2). CD99 was positive in (10/11) cases and WT-1 in (6/9). NKX2.2, S100, and MDM2 were positive in rare cases. CIC::DUX4 fusion was detected in four cases. FISH for CIC gene rearrangement was positive in seven cases, two of them confirmed by methylation analysis. Metastasis at diagnosis was common (n = 8), primarily in the lungs, with later metastasis to the brain and bone. At time of final analysis, eight patients died within a median of 10 months (range: 1–19 months), while three were alive, two with stable disease (for a period of 6 and 25 months) and one with progression after 10 months. Significant correlation was seen between overall survival and the presence of metastasis at diagnosis (p value = 0.03). Conclusions: CIC-rearranged sarcomas are rare, high-grade tumors with predilection for soft tissue. Misdiagnosis is frequent, necessitating molecular confirmation. These tumors are treatment-resistant, often present with lung metastasis, and carry a poor prognosis, especially with initial metastasis. Full article

Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut–brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF’s capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience. Full article