Search Results (11,899)

The brain–bone axis has garnered increasing attention over the years, leading to numerous studies that have unraveled the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This review explores this profound relationship, examining the complex mechanisms that regulate it, the key players involved, and the clinical implications of its dysfunction in various pathological situations affecting the CNS and skeletal system. Ultimately, it emphasizes the potential of ongoing research to develop diagnostic tools, therapeutic interventions, and preventive strategies aimed at enhancing skeletal and neurological health. Full article

Neurodegenerative diseases (NDDs) are a group of progressive diseases affecting neuronal cells in specific areas of the brain, causing cognitive decline and movement impairment. Nowadays, NDDs play a significant role in the global burden of disease, and their incidence is increasing, particularly due to population aging. NDD onset is multi-factorial; based on the current knowledge, genetic, environmental, and cellular factors are believed to contribute to their occurrence and progression. Taking into account that at an early stage, the symptoms are not clearly defined, and diagnosis may be delayed, the development of innovative and non-invasive methodological approaches for early diagnosis of NDDs is strategic for timely and tailored disease management, as well as for the overall improvement of patients’ quality of life. The present review aims to provide, in the first part, an overview based on the current level of knowledge on the environmental risk factors that can explicate a role in the onset of the most common NDDs and on the main pathogenic mechanisms involved in disease initiation and progression. The second part aims to define the current state of the art regarding the significance of Volatile Organic Compounds (VOCs) in the volatome of different human biological matrices (exhaled breath, feces, and skin sebum) as candidate biomarkers of specific NDDs, with the aim of developing non-invasive diagnostic approaches for the early diagnosis and personalized management of the patients. A critical synthesis and discussion on the applied methodological approaches and on the relevant outcomes obtained across the studies is reported. Full article

Brain MRI segmentation plays a crucial role in neuroimaging studies and clinical trials by enabling the precise localization and quantification of brain tissues and structures. The advent of deep learning has transformed the field, offering accurate and fast tools for MRI segmentation. Nevertheless, several challenges limit the widespread applicability of these methods in practice. In this systematic review, we provide a comprehensive analysis of developments in deep learning-based segmentation of brain MRI in adults, segmenting the brain into tissues, structures, and regions of interest. We explore the key model factors influencing segmentation performance, including architectural design, choice of input size and model dimensionality, and generalization strategies. Furthermore, we address validation practices, which are particularly important given the scarcity of manual annotations, and identify the limitations of current methodologies. We present an extensive compilation of existing segmentation works and highlight the emerging trends and key results. Finally, we discuss the challenges and potential future directions in the field. Full article

Background/Objectives: This article aims to investigate the multifaceted effects of alcohol on neurophysiopathological development from gestational stages through adult life and the consequent dynamic-relational challenges in individuals with Fetal Alcohol Spectrum Disorder (FASD). FASD, resulting from prenatal alcohol exposure (PAE), is characterized by a range of neurological, cognitive, behavioral, and sometimes physical impairments. This article explores how alcohol and its toxic metabolites cross the placenta, inducing direct cellular toxicity and epigenetic alterations that disrupt critical neurodevelopmental processes such as neurogenesis and brain circuit formation. Clinically, individuals with FASD exhibit diverse deficits in executive functioning, learning, memory, social skills, and sensory-motor abilities, leading to significant lifelong disabilities. A central focus is the application of the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) criteria to comprehensively frame these disabilities. The ICF’s biopsychosocial model allows for a multidimensional assessment of impairments in body functions and structures, limitations in activities, and restrictions in participation, while also considering the crucial role of environmental factors. Methods: PubMed and Semantic Scholar databases were searched for relevant papers published in English. Results: This article highlights the utility of the ICF in creating individualized functioning profiles to guide interventions and support services, addressing the limitations of traditional assessment methods. Conclusions: While the ICF framework offers a robust approach for understanding and managing FASD, further research is essential to develop and validate FASD-specific ICF-based assessment tools to enhance support and social participation for affected individuals. Full article

The interaction between microorganisms in the dental microfilm (plaque) at the gingival margin, the immune system, and the brain is vital for gingival health. The brain constantly receives information regarding microbial composition and inflammation status through afferent nerves and the bloodstream. It modulates immune responses via efferent nerves and hormonal systems to maintain homeostasis. This relationship determines whether the gingiva remains healthy or develops into gingivitis (non-destructive inflammation) or periodontitis (a destructive condition), collectively referred to as periodontal disease. Factors associated with severe periodontitis heighten the responsiveness of this homeostatic system, diminishing the adaptive immune system’s defence against symbiotic microorganisms with pathogenic properties, known as pathobionts. This leads to excessive innate immune system activation, effectively preventing infection but damaging the periodontium. Consequently, investigating the microbiota–brain axis is vital for understanding its impact on periodontal health and disease. Herein, we examine recent advancements in how the defence against pathobionts is organised within the brain, and how it regulates and adapts the pro-inflammatory and anti-inflammatory immune balance, controlling microbiota composition. It also discussed how pathobionts and emotional stress can trigger neurodegenerative diseases, and how inadequate coping strategies for managing daily stress and shift work can disrupt brain circuits linked to immune regulation, weakening the adaptive immune response against pathobionts. Full article

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders. Full article

Background: Combined cognitive and physical training develops resilience to mental fatigue, reduces perceived effort, and improves endurance exercise performance when compared to physical training and no training. The isolated contribution of cognitive training toward endurance performance has yet to be determined. Accordingly, we examined the effects of separate cognitive training on endurance exercise performance. Method: Two studies employed a pre-test/training/post-test design, with participants randomly assigned to cognitive training or control groups. At pre-test and post-test, participants completed a rhythmic handgrip task (Study 1) or a graded exercise test on a cycle ergometer (Study 2). In Study 1, the cognitive training group completed 20 sessions (four 20 min sessions per week for five weeks) of cognitive training (incongruent Stroop and 2-back tasks), whereas the control group completed no training. In Study 2, the cognitive training group completed nine sessions (three 10 min sessions per week for three weeks) of cognitive training (incongruent Stroop, stop-signal and typing inhibition tasks), whereas the control group completed nine sessions of sham training (congruent Stroop, sham stop-signal and sham typing inhibition tasks). Endurance exercise performance was measured as force production (Study 1) and time to exhaustion (Study 2). Heart rate, exertion and fatigue were also measured. Results: Endurance performance, indexed by force production (Study 1) and time to exhaustion (Study 2), did not change from pre-test to post-test and did not differ between cognitive training and control groups. Similarly, ratings of perceived exertion and heart rate during the exercise tasks did not differ between cognitive training and control groups (Studies 1 and 2). Conclusions: Since separate cognitive training did not improve exercise endurance performance, combined training should be used to create a synergistic training stimulus for brain adaptation and performance enhancement. Full article

Background/Objectives: Despite the intent of most mothers to breastfeed their children, breast or nipple pain can be the reason for early cessation of breastfeeding. Current understanding about lactation-related pain revolves around mechanical or pathological causes, discounting the role of psychosocial factors which can influence management of pain. The Breastfeeding Pain Reasoning Model is a clinical reasoning tool developed to support those evaluating women’s lactation-related pain. We aimed to explore perspectives of breastfeeding women on lactation-associated pain and determine how they align with the Breastfeeding Pain Reasoning Model (BPRM). Methods: We conducted a qualitative descriptive study using phenomenological approach in Singapore. Eighteen women with recent breast and/or nipple pain during lactation underwent individual semi-structured interviews in 2022. Thematic analysis was performed. Results: Deductive analysis showed that lactation-associated pain was aligned with BPRM’s domains (i.e., local stimulation, external influences, and central modulation). Psychosocial factors likely influencing central processing of pain were not recognised by most of the participants. Participants described severe breastfeeding pain often accompanied by feelings of vulnerability, injustice, and uncertainty. Inductive analysis identified two additional themes of motivation and expectations. Conclusions: Greater awareness of the interplay between the broad influences on pain is needed. Using an interoceptive lens could help to illustrate how signals from the breast inform the brain, and how social, emotional, and cognitive factors influence the individuals’ perception of painful experiences. Educating breastfeeding women and healthcare personnel about the biopsychosocial nature of pain may empower women to better navigate the challenges of breastfeeding and improve breastfeeding outcomes. Full article

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke, disproportionately affecting older adults and is associated with high rates of mortality, functional dependence, and long-term cognitive decline. Aging profoundly alters the structure and function of the cerebral vasculature, predisposing the brain to both covert hemorrhage and the development of cerebral microbleeds (CMBs), small, often subclinical lesions that share common pathophysiological mechanisms with ICH. These mechanisms include endothelial dysfunction, impaired cerebral autoregulation, blood–brain barrier breakdown, vascular senescence, and chronic inflammation. Systemic factors such as age-related insulin-like growth factor 1 (IGF-1) deficiency further exacerbate microvascular vulnerability. CMBs and ICH represent distinct yet interconnected manifestations along a continuum of hemorrhagic small vessel disease, with growing recognition of their contribution to vascular cognitive impairment and dementia (VCID). Despite their increasing burden, older adults remain underrepresented in clinical trials, and few therapeutic approaches specifically target aging-related mechanisms. This review synthesizes current knowledge on the cellular, molecular, and systemic drivers of ICH and CMBs in aging, highlights diagnostic and therapeutic challenges, and outlines opportunities for age-sensitive prevention and individualized care strategies. Full article

Drug delivery to the brain faces a critical obstacle in the form of the blood–brain barrier (BBB), which severely limits therapeutic options for Alzheimer’s disease (AD). Transferrin receptor 1 (TfR1) is abundantly expressed in brain capillary endothelial cells, offering a potential pathway for circumventing this barrier. Physiologically, TfR1 binds to iron-laden transferrin, leading to cellular uptake through clathrin-mediated endocytosis. Within acidic endosomes, the iron is released, and the receptor–apotransferrin complex recycles to the cell surface for further rounds of transport. Furthermore, studies in AD mouse models have demonstrated that TfR1 expression in brain microvessels remains stable, highlighting its suitability as a delivery target even in disease conditions. Based on this, various drug delivery strategies targeting TfR1 have been developed, including bispecific antibodies, antibody fragments, ligand conjugates, and nanoparticle-based carriers. While these approaches hold great promise, they face practical limitations such as competition with endogenous transferrin, receptor saturation, and inefficient intracellular trafficking. This review details the current understanding of TfR1-mediated BBB transport mechanisms, evaluates emerging delivery platforms, and argues that TfR1 represents an accessible gateway for brain-targeted therapeutics in AD. The insights presented will be of interest to researchers in molecular biology, pharmacology, and drug development. Full article

Objective: Hexafluoropropylene oxide dimer acid (HFPO-DA), also known as GenX, is widely used globally, raising concerns about its safety and public health implications. However, its toxicity mechanism remains unclear. The purpose of this study was to develop a reliable method for detecting HFPO-DA in mice and to investigate its absorption, distribution, and impact on hepatic lipid metabolism. Method: HFPO-DA levels were measured in the serum and eight tissues of C57BL/6J mice after oral administration using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Lipid metabolites in the liver were also detected and analyzed. Results: HFPO-DA was rapidly absorbed into the bloodstream and widely distributed throughout all tested tissues. It penetrated the blood–brain barrier, with the highest concentration in the liver; however, long-term effects on the lungs also warrant attention. HFPO-DA disrupted liver lipid metabolism, leading to acylcarnitine accumulation while lowering triglycerides and cholesterol. Conclusion: This study on the pharmacokinetics and tissue distribution of HFPO-DA in mice following oral exposure revealed that HFPO-DA exacerbates liver injury by altering hepatic lipid metabolism. These findings provide theoretical support for toxicological studies on the emerging environmental pollutant HFPO-DA. Full article

Caffeine is one of the most widely consumed psychoactive substances globally and is a common component of daily diets, particularly among women of reproductive age. Numerous in vitro and in vivo studies have indicated potential adverse effects of prenatal caffeine exposure, including disturbances in fetal growth, metabolic dysregulation, organ malformations, and neurodevelopmental alterations. These findings suggest that caffeine may influence multiple physiological pathways during gestation, including epigenetic modifications and metabolic programming. However, evidence from human studies remains heterogeneous and often inconclusive. Recent cohort studies and meta-analyses have reported that moderate maternal caffeine intake is not significantly associated with increased risks of gestational diabetes mellitus, gestational hypertension, or preeclampsia, although higher intake levels have been linked to anemia, preterm birth, and low birth weight in some populations. Furthermore, emerging data suggest potential associations between prenatal caffeine exposure and early neurodevelopmental outcomes, including behavioral changes, subtle structural brain differences, and alterations in offspring metabolic health and obesity risk. Despite these findings, the magnitude and clinical relevance of these effects remain uncertain, partly due to variability in caffeine sources, dosages, study designs, and reliance on self-reported intake. This review aims to synthesize current evidence on maternal caffeine consumption, its impact on pregnancy complications, fetal development, and long-term child health outcomes. By integrating experimental and clinical data, the study provides a comprehensive overview that may assist clinicians and healthcare professionals in counseling pregnant women regarding caffeine intake and potential risks. Full article

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant neurological plasticity in early childhood, where timely interventions like behavioral therapy, language training, and social skills development can mitigate symptoms. Contributions: We introduce a novel Multi-Atlas Guided Multi-View Contrast Learning (MAMVCL) framework for ASD classification, leveraging functional connectivity (FC) matrices from multiple brain atlases to enhance diagnostic accuracy. Methodology: The MAMVCL framework integrates imaging and phenotypic data through a population graph, where node features derive from imaging data, edge indices are based on similarity scoring matrices, and edge weights reflect phenotypic similarities. Graph convolution extracts global field-of-view features. Concurrently, a Target-aware attention aggregator processes FC matrices to capture high-order brain region dependencies, yielding local field-of-view features. To ensure consistency in subject characteristics, we employ a graph contrastive learning strategy that aligns global and local feature representations. Results: Experimental results on the ABIDE-I dataset demonstrate that our model achieves an accuracy of 85.71%, outperforming most existing methods and confirming its effectiveness. Implications: The proposed model demonstrates superior performance in ASD classification, highlighting the potential of multi-atlas and multi-view learning for improving diagnostic precision and supporting early intervention strategies. Full article

Both basic and preclinical research, as well as the development of new therapies, require tools that allow for the selective labelling of specific cell types and the targeted delivery of drugs. The developed tools must then be validated in biological systems. In view of the lack of effective therapies for many neurodevelopmental disorders, including neonatal brain injuries, we decided to use the newly described, innovative SPAchips^® (a4cell, Pozuelo de Alarcón, Spain) tool and test it in labelling neonatal rat neural cells. In our studies, rat primary cultures of neurons and glial cells (astrocytes, oligodendrocytes, and microglia) were incubated with different concentrations of SPAchips^®. At selected time points, uptake of the tested microchips by particular cell types was assessed using lineage-specific antibodies and visualized using a confocal microscope. Additionally, the potential cytotoxicity of added microparticles was verified, as was the possibility of microglia activation. The study indicates that the tested microdevices selectively label neonatal rat microglia and can be a useful tool for visualizing this cell type, as well as a non-toxic tool for developing innovative strategies based on the functionalization of microparticles aimed at modulating neuroinflammatory processes. Full article

We here delve into the intricate and evolving concepts of brain death and consciousness, particularly at the end of life. We examine the historical and technological advancements that have influenced our understanding of death, such as mechanical ventilation and resuscitation techniques. These developments have challenged traditional definitions of death, leading to the concept of brain death, defined as the irreversible loss of all brain functions, including the brainstem. We emphasize that consciousness exists on a continuum, ranging from full alertness to deep coma and complete cessation of brain activity. It explores various disorders of consciousness, including coma, vegetative state, minimally conscious state, and locked-in syndrome, each with distinct characteristics and levels of awareness. Neuroimaging techniques, such as EEG, fMRI, and DTI, are highlighted for their crucial role in diagnosing and understanding disorders of consciousness. These techniques help to detect covert consciousness, assess brain activity, and predict recovery potential. The phenomenon of the “wave of death,” which includes a paradoxical surge in brain activity at the point of death, is also discussed. We address the challenges in defining and understanding both death and consciousness, calling for biologically grounded, ethically defensible, and culturally sensitive definitions. We advocate for standardized neuroimaging protocols, longitudinal studies, and the integration of artificial intelligence to improve diagnosis and treatment. In conclusion, the document underscores the importance of an integrated, evidence-based approach to understanding the gray zones between life and death, recognizing that consciousness and death are dynamic processes with both biological and experiential dimensions. Full article