Because of their involvement in outbreaks, hantaviruses as emerging zoonotic diseases have been regarded a public health issue. Recent reports have identified CNS symptoms of hantavirus infection, although the data are still relatively sparse and inconsistent, especially for Andes orthohantavirus (ANDV) and to a lesser extent Puumala virus (PUUV). Reported neurological features include headache, dizziness, altered mental state, seizures, focal deficits, and peripheral neuropathy, possibly accompanied by ocular symptoms such as impaired vision and photophobia. The results of neuroimaging have been inconsistent and nonspecific, ranging from hemorrhagic or edematous changes to thalamic or brainstem abnormalities and splenial lesions. Evidence could suggest that endothelial dysfunction, capillary leak, inflammatory damage, and, in certain situations, potential intrathecal immunological responses or direct viral presence may all contribute to CNS involvement. However, most evidence stems from case reports or case series, and causative neuroinvasion may not have been fully demonstrated. Recent studies, especially the recent ANDV-associated outbreak, may emphasize the necessity for rigorous neurological examination. A better understanding of the neurological range of hantavirus infection may enhance detection, risk stratification, and supportive therapy.
Periodic complexes occur in the electroencephalogram (EEG) during a number of pathological conditions, often having a poor prognosis (Kuroiwa and Celesia 1980). The contexts in which periodic EEGs occur generally fall into three major categories: infections, sequelae to hypoxic/ischemic events, and metabolic disorders. In this review, we examine morphological and electrophysiological data from in vitro preparations. These data suggest several cellular mechanisms, which may underlie periodic EEGs, including altered excitation-inhibition relations, tonic activation of metabotropic glutamate receptors, altered neuromodulation, and electrical coupling of neurons by cell fusion or gap junctions. Some of the proposed mechanisms are empirically testable: for example, the occurrence of very fast oscillations (>∼70 Hz) superimposed on periodic complexes, and the occurrence of gamma oscillations (∼30 Hz-∼70 Hz) between complexes. The in vitro data further suggest an hypothesis concerning why some patients with periodic EEGs respond to anticonvulsant drugs (ACDs), while other patients do not: if the main cellular mechanism for neuronal synchrony involves excitatory chemical synapses, then a response to ACDs is possible; however, if a major factor in neuronal synchrony involves electrical coupling - as can occur with viral infections - then a response to ACDs would not be expected.
Aneurysmal subarachnoid hemorrhage (aSAH) confers substantial mortality and morbidity driven not only by primary brain injury but also by systemic remote organ complications across the pulmonary, cardiac, renal and gastrointestinal systems. Despite growing recognition of neuroimmune crosstalk in this process, a cohesive, systems-level model connecting intracranial hemorrhage to multi-organ dysfunction remains absent from the literature. Here, we propose a unified neuroimmune framework centered on a long-underappreciated mechanism: glymphatic and meningeal lymphatic drainage dysfunction is hypothesized to act as the upstream initiating event that forces brain-derived damage-associated molecular patterns, inflammatory cytokines and activated immune cells to spill into the systemic circulation. We systematically map three mechanistically distinct, mutually amplifying transmission pathways: the classical neuroendocrine-immune axis, the recently identified meningeal lymphatic-deep cervical lymph node immune drainage axis, and circulating humoral effectors exemplified by neutrophil extracellular traps. Most notably, we integrate these pathways with a temporally stratified immune continuum spanning early hyperinflammatory SIRS, stroke-induced immunodepression, and chronic low-grade inflammation - an integrative temporal architecture that has eluded prior single-organ or single-pathway studies. Grounded in this framework, we put forward a tiered, phase-specific neuroimmunomodulatory strategy that simultaneously addresses central inflammatory origins, systemic signal propagation, and end-organ tissue damage. By reframing remote organ injury as a time-dependent immune process rather than a collection of isolated organ complications, this work provides a mechanistic and translational roadmap for time-stratified clinical trials and redefines the investigative direction for multi-organ management in aSAH.
Abstract A defining feature of electroencephalography (EEG) data is its 1/ f -like spectral structure, whereby power decreases as frequency increases. The nonoscillatory, aperiodic activity underlying this structure has regained attention as an index of cortical excitation–inhibition balance or neural noise, though its precise link to cognition remains unclear. Accordingly, this PRISMA-compliant systematic review examined 45 studies on aperiodic EEG features and cognition in healthy adults (∼18–65 years), organized across cognitive domains, which included processing speed, attention, perception, memory, working memory, executive functions, learning, language, and complex/naturalistic tasks. The aperiodic exponent showed consistent associations: steeper spectra correlated with inhibitory control, conflict resolution, and encoding; flatter spectra with sensory engagement, cognitive flexibility, and recall. Evidence from resting-state and task-based EEG indicates that aperiodic activity reflects both stable, trait-like neural efficiency and flexible, state-dependent adaptability. These findings support the functional relevance of aperiodic parameters and call for methodological standardization to guide future research.
The blood-brain barrier (BBB) is recognized as a protective interface that maintains neural homeostasis. Specifically, it blocks the entrance of potentially harmful agents and controls the molecular traffic between the circulatory system and the central nervous system. Emerging evidence from preclinical models and clinical studies indicates that alterations in the BBB's permeability and transport processes contribute to the pathophysiology of several mental illnesses, including depression, anxiety, bipolar disorder, and schizophrenia. Specifically, we examine whether BBB disruption contributes to the onset and progression of psychiatric conditions, whether psychiatric pathology itself promotes barrier dysfunction, or whether these processes interact in a self-perpetuating cycle. By providing a translational perspective that bridges experimental models and clinical observations, this review provides a comprehensive and dynamic perspective on its role in mental health. Understanding these mechanisms may open new avenues for therapeutic strategies focused on preserving or restoring barrier integrity as a means of preventing or mitigating psychiatric disorders.
The lateral prefrontal cortex (LPFC) receives visual, auditory, and somatosensory information and has extensive local neural connections across different sensory regions. Therefore, this cortical area is likely an ideal site for investigating the neural mechanisms of multisensory integration and for understanding how such integration contributes to various cognitive functions. However, it has been shown that the LPFC is functionally heterogeneous and compartmentalized with respect to different sensory modalities and that each sensory area exhibits topographic representation of sensory information. Human neuroimaging studies indicate that although multiple sensory modalities are integrated in domain-general regions of the prefrontal cortex, each sensory modality is primarily processed within functionally segregated networks. These domain-general regions largely correspond to visual areas, whereas modality-specific regions are located adjacent to them. This organization suggests that each sensory modality is mainly processed by distinct functional networks in the prefrontal cortex. Despite the importance of multisensory integration for understanding prefrontal functions, relatively few studies have been conducted, with most focusing audio-visual integration in vocal communication. This limitation is partly due to the difficulty of activating prefrontal neurons using simple sensory stimuli and behavioral tasks, as well as the limitation of experimental data for computational approach and experimental techniques for investigating activities under multimodal conditions. Recently, several novel multisensory technologies have been developed, enabling the investigation of multisensory integration under conditions close to natural environments. These approaches are expected to advance our understanding of the neural mechanisms underlying multisensory integration in the prefrontal cortex.
Although some drugs have been approved for clinical treatment, early diagnosis and intervention remain the most effective strategies for managing Alzheimer's disease (AD) at present. With advances in deep learning and multimodal fusion, an increasing number of complex frameworks have been proposed. This paper systematically reviews multimodal deep learning-based models for AD diagnosis between 2020 and 2026. Beyond the technical survey, we explore how to deal with the heterogeneous modality integration and missing modality processing. From these experimental results, many models show impressive performance on public datasets. However, we have noticed a troubling problem that these "lab-perfect" results often falter when they face the chaos of the real-world. Because of the persistent black-box problem and the hidden traps of data leakage, the path to clinical use is still uphill. This work suggests that it is time to move beyond chasing tiny gains in accuracy and focus on building models that doctors can truly trust, understand, and use in real clinical settings.
Helicobacter pylori infects nearly half of the global population and has traditionally been viewed as a pathogen restricted to the gastric mucosa. Growing evidence, however, suggests that chronic infection may exert systemic effects extending to the central nervous system. This review critically examines the potential neurological implications of H. pylori infection within the emerging framework of the gut-brain axis. We performed a narrative, hypothesis-generating review of human observational and interventional studies complemented by mechanistic experimental research. The literature was evaluated with particular attention to study design, heterogeneity, and potential confounding in reported associations between H. pylori infection and neurological disorders. Across multiple studies, H. pylori infection has been linked to a modestly increased prevalence of Parkinson's disease and dementia, although findings remain heterogeneous. In Parkinson's disease, infection may exacerbate motor fluctuations and reduce levodopa bioavailability, with partial clinical improvement reported following eradication in selected patients. Experimental studies further demonstrate that bacterial outer membrane vesicles can access the brain and promote neuroinflammatory and amyloidogenic processes, supporting biological plausibility. By contrast, several epidemiological studies report an inverse association with multiple sclerosis, suggesting potential immunomodulatory effects. Evidence relating H. pylori to migraine and mood disorders remains inconsistent. Current data do not support H. pylori as a primary cause of neurological disease. Instead, the infection may act as a context-dependent modifier within the complex inflammatory and immunometabolic networks of the gut-brain axis. Clarifying this relationship will require prospective studies integrating microbial strain profiling, biomarker-defined neurological phenotypes, and adequately powered interventional trials.
The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.
Exercise training is a vital component of rehabilitation for individuals with spinal cord injury (SCI). However, its mechanisms of action remain unclear, which severely limits the development and implementation of precise exercise prescriptions for SCI. In this article, we propose a core hypothesis: mechanical stimulation generated by exercise is converted into key biological signals that regulate SCI repair through the activation of mechanosensitive channels (MSCs). To test this hypothesis, we adopt a narrative review approach to systematically integrate current evidence on MSCs including Piezo1, TRAAK/TREK-1, and TRPC1 in the contexts of neuroplasticity, bone and muscle homeostasis, and inflammatory responses. Based on this evidence, we construct a mechanistic framework linking specific MSCs to exercise-induced functional benefits, revealing the potential molecular logic by which exercise promotes spinal cord injury repair. As a hypothesis-driven narrative review, this article not only provides a theoretical foundation for developing quantifiable, personalized exercise prescriptions for SCI rehabilitation, but also outlines several testable research directions to facilitate experimental validation and clinical translation of the proposed hypothesis.
Effort-based decision-making refers to the process by which humans and animals choose between competing courses of action by weighing expected costs, in terms of effort, against anticipated benefits such as food reward. Although this topic has been the focus of extensive research, the behavioral, neural, and neurochemical mechanisms underlying effort-based decision-making are incompletely understood. In this review, I address these issues by focusing primarily on neurobiological studies in rodents. Using a broad range of behavioral tasks, the studies reviewed here point to a complex neural circuit underlying effort-based decision making. Key components of this circuit include the anterior cingulate cortex, the orbitofrontal cortex, the basolateral amygdala, the nucleus accumbens core and the ventral pallidum. Many of these studies do not allow for a clear dissociation of specialized roles for these regions, e.g., whether they encode effort, reward, or both. Instead, recent evidence suggests that effort-based decision making may depend on the coordinated activity across components of this neural circuit through which information from diverse neural sources is integrated in parallel. Multiple neurotransmitters and neuromodulators, as for instance, dopamine, noradrenaline, adenosine and ghrelin modulate the activity of this neural network. They likely act in concert to adapt the willingness to expend effort according to the organism's actual physiological state, the presence of environmental stimuli and the nature of available rewards, thereby supporting adaptive effort-related decision making. Implications of these findings are discussed with respect to the neural and neurochemical bases of motivational dysfunctions observed in disorders such as depression and apathy.
Neurogenesis in adult mammalian brain persists in restricted areas, especially the subgranular zone (SGZ) of the hippocampus and the ventricular-subventricular zone (V-SVz), where neural stem cells (NSCs) occupy neurogenic niches. These NSC niches provide signals that regulate stem cell behavior. Among extrinsic modulators, Growth Differentiation Factor 11 (GDF11 or BMP11) which is a transforming growth factor-β (TGF-β) superfamily member, was shown to play key role in the NSC biology and brain aging. In this review, the most recent molecular mechanisms of GDF11 signaling in the regulation of NSC will be addressed. GDF11 plays mainly through activin type II receptors (ActRIIA/B) and ALK4/ALK5, activating classical Smad2/3 pathways that impact transcriptional networks controlling neural cell behavior. Moreover, GDF11 stimulates non-Smad signaling pathways - including ERK, p38, JNK, and PI3K/AKT - providing context-dependent integration of proliferative and anti-proliferative signals. Furthermore, GDF11 functions as a feedback regulator limiting the number of progenitor cells and organizing neurogenic timing. In the adult brain, GDF11 plays important role in neurovascular remodeling, glial inflammatory states, and extracellular matrix interactions. Despite its recognized roles, the effect of GDF11 on aging remains a subject of intense debate, characterized by conflicting reports regarding its circulating levels, tissue-specific dynamics, and dose-dependent effects. Recent evidence suggests that GDF11 acts as a context-dependent modulator, integrating systemic, vascular, and cellular cues to maintain NSC homeostasis and neurogenic potential. Therefore, elucidating the exact cellular and molecular mechanisms by which GDF11 controls NSC behavior is vital to advancing novel therapeutic strategies for neurodegenerative disorders and age-related cognitive decline.
Epilepsy is a brain disease caused by transient changes in the patients' clinical status due to excessive neuronal discharge or depolarization. Despite the increasing understanding of potential risk factors for epileptic seizures, there is still no method to prevent the onset of epilepsy in high-risk populations, and clear diagnostic criteria remain lacking. Currently, the clinical diagnosis of epilepsy primarily depends on the patient's detailed seizure history and reliable witness accounts. Correct diagnosis facilitates the selection of optimal therapy and the evaluation of the epilepsy outcome. Mounting evidence indicates that protein glycosylation exerts specific modulatory effects on neural transmission and neural circuit excitability. Glycosylation defects often lead to central nervous system structural abnormalities, developmental delay, and seizures. With advancements in glycosylation research methods and techniques, nervous system diseases associated with glycosylation changes have garnered growing attention. This paper reviews recent studies on glycosylation changes related to epilepsy, aiming to elucidate the mechanisms of epilepsy development from a glycosylation perspective and provide a theoretical basis for epilepsy diagnosis and targeted therapy. Notably, our recently published study on kainic acid-induced epileptic rats provides direct experimental evidence for the association between abnormal glycosylation and epilepsy, further supporting the clinical relevance of glycosylation research in this field.
The zebrafish (Danio rerio) is a widely used model organism for studying neurobehavioral processes and neuropsychiatric disorders. Numerous protocols in adult zebrafish assess anxiety-like, locomotor, social and cognitive responses. The increasing experimental complexity and experimentation throughput has led many studies to combine multiple assays into behavioral test batteries. However, the methodological implications of such multi-test designs remain insufficiently understood. Here, we examined current practices in zebrafish behavioral batteries through an initial laboratory survey followed by a systematic literature analysis. Responses from 24 active zebrafish behavioral neuroscience laboratories were used to characterize experimental workflows and guide a targeted PubMed literature search. We further analyzed 357 studies employing the novel tank test (NTT) to assess the prevalence of multi-assay designs, identify commonly co-reported behavioral paradigms, and evaluate methodological variability. Our analyses confirm the central role of the NTT, frequently combined with the light-dark, open field, social interaction, and Y-maze tasks, and indicate that multi-assay experimental designs are common in the literature. However, methodological descriptions also often lacked sufficient clarity on whether assays were conducted sequentially in the same animals (as test batteries) or performed in independent cohorts. These findings highlight an important methodological gap in the field, and emphasize the need for greater clarity and consistency in the design and reporting of zebrafish behavioral batteries to improve the interpretability and comparability of multi-domain behavioral phenotyping.
Mindfulness meditation has received growing interest in research over the past decades. Mindfulness meditation training (MMT) can be employed as a mental practice to improve cognitive skills such as attention and emotion regulation and may promote well-being. Neuroimaging studies have emerged to understand the effects of MMT on brain functioning. However, no review exists on the effects of MMT on resting-state brain functional connectivity (rsFC) in healthy meditation-naïve adults specifically. We, therefore, aimed to provide an overview of studies that investigated the effects of MMT on rsFC in healthy meditation-naïve adults, as well as their link to cognitive and clinical measures. Several studies reported changes in MMT-induced rsFC within and between regions of the default mode (DMN), salience (SN), and central executive (CEN) networks. Both increases and decreases in rsFC have been observed for brain regions associated with these networks after MMT, each with differential roles in emotion regulation, stress, and cognitive functions. Some studies highlighted associations between changes in rsFC after MMT and modifications in cognitive performance and psycho-affective measures, which may be influenced by MMT-specific characteristics such as practice duration or delivery methods. MMT may induce a reorganization in the brain's functional architecture by altering rsFC within and between these networks and seems to modify processes related to attention, executive memory, emotional regulation, stress, and resilience. Investigating functional connectivity during rest in key brain networks seems a promising approach to understand the effects of mindfulness meditation on overall well-being.
Multiple sclerosis (MS) is classically understood through pathogenic T and B cell responses, while increasing evidence indicates that altered myelopoiesis and bone marrow-derived myeloid programs also contribute to disease initiation and progression. This review summarizes the dynamic evolution of hematopoietic dysregulation in MS, proposing a pathological mechanism spanning from transient emergency myelopoiesis to persistent chronic myeloid reprogramming. Driven by sustained inflammatory stress, hematopoietic stem and progenitor cells (HSPCs) undergo epigenetic remodeling to acquire a stable myeloid differentiation bias. Regulatory crosstalk between the inflamed central nervous system (CNS) and the bone marrow may occur through a neuro bone marrow axis involving anatomical fluid drainage, neuroendocrine and circadian regulation, and immune cell feedback loops. This bone marrow-derived reprogramming modulates the downstream effector functions of myeloid cells following their infiltration into the CNS. This framework may refine stage-matched therapeutic thinking in MS by highlighting maladaptive myelopoiesis and immune-homeostatic modulation as potential intervention targets.
Neuroinflammation underlies many neurodegenerative disorders and is orchestrated by interactions between microglia, astrocytes, and neurons. While cytokines, chemokines, and damage-associated molecular patterns (DAMPs) are established neuroimmune mediators, extracellular matrix (ECM)-derived protein fragments, collectively termed matrikines, have received little attention in the central nervous system (CNS). Emerging evidence suggests that matrikines constitute a distinct and functionally important class of neuroimmune modulators. This review focuses on six CNS-relevant matrikines: type I collagen-derived acetylated Pro-Gly-Pro (Ac-PGP) and Gly-His-Lys (GHK); laminin-derived Ile-Lys-Val-Ala-Val (IKVAV) and Tyr-Ile-Gly-Ser-Arg (YIGSR); elastin-derived Val-Gly-Val-Ala-Pro-Gly (VGVAPG); and endorepellin, corresponding to domain V of perlecan. We describe their generation, receptor interactions, and signaling properties, and summarize their established effects in peripheral tissues and the limited evidence for CNS-specific roles. Current findings indicate that CNS matrikines may arise by peripheral entry through a compromised blood-brain barrier (BBB), proteolysis of the BBB basement membrane, or local degradation of CNS interstitial matrix and perineuronal nets during injury or disease. Their CNS effects are highly context- and cell-specific, ranging from neuroprotection and enhanced neuronal survival to modulation of microglial and astrocytic functions, cell migration, autophagy, and direct neurotoxicity. Collectively, evidence supports matrikines as CNS signaling molecules that complement classical immune mediators. Of note, studies using human CNS cells and tissues remain largely absent and should be prioritized to assess translational relevance. Systematic profiling of CNS matrikines, combined with mechanistic studies of their cell-specific signaling, especially in human cells, may reveal novel biomarkers and therapeutic targets, offering new avenues for intervention in neurodegenerative and other neurological disorders.
Schizophrenia (SCZ) is a complex, polygenic neurodevelopmental disorder influenced by interactions between genetic vulnerability and environmental exposures. While research has historically prioritized genetic factors, air pollution has emerged as a potentially modifiable environmental factor associated with the onset, progression, and relapse of the disorder. This review synthesizes current clinical, epidemiological, and preclinical evidence to clarify the relationship between various air pollutants and SCZ. Epidemiological data, including large-scale cohort studies such as the UK Biobank, demonstrate dose-dependent associations between long-term exposure to particulate matter (PM2.5, PM10) and gaseous pollutants (NO2, SO2, CO) and increased SCZ risk. Notably, individuals with high polygenic risk scores (PRS) may exhibit heightened vulnerability, with hazard ratios reaching up to 7.38 when combined with high pollution exposure. Mechanistically, air pollutants may influence SCZ-related biology through direct neurotoxicity via olfactory translocation, neuroinflammatory signaling, oxidative stress, disruption of neuroplasticity (including brain-derived neurotrophic factor (BDNF) suppression), and dysregulation of the gut-brain axis. However, most mechanistic evidence is preclinical, and the translational gap to human disease remains substantial. Despite these insights, challenges remain regarding causal inference, biomarker validation, and geographical representation in research. Moving forward, large-scale longitudinal cohorts and the integration of exposomics with genomics are essential to refine risk stratification. At present, the evidence supports cautious consideration of air pollution as an environmental factor associated with schizophrenia, rather than as a proven causal determinant.
Traditional cardiovascular pathophysiology often relies on heart-centric models, yet the maintenance of neurocardiac homeostasis fundamentally depends on higher-order central regulation. While the bidirectional brain-heart axis is widely recognized, the spatiotemporal principles governing its network dynamics remain incompletely understood. This review presents an integrative theoretical framework to conceptualize brain-heart communication not merely as a linear reflex, but as a hierarchical, multidimensional process. We highlight the critical role of asymmetric neural regulation - where lateralized central control dictates efferent autonomic outflow - and map how this central asymmetry progressively cascades into a systemic neuro-immune-endocrine interactive network. By adopting this multiscale perspective, we delineate the mechanistic pathways through which psychological stress acts as an upstream driver to precipitate cardiovascular vulnerabilities, such as arrhythmias and heart failure. Furthermore, we discuss the translational potential of this framework, emphasizing how spatiotemporal features can be leveraged to develop dynamic biomarkers and guide precision neuromodulation therapies, ultimately providing new avenues for restoring neurocardiac homeostasis.
Drug-resistant epilepsy (DRE) is a prominent concern in the management of recurrent seizures. Anti-seizure medications (ASM), surgical intervention, and neurostimulation are a few classical remedial measures of epilepsy. Nevertheless, DRE requires immense investigation, a comprehensive understanding of holistic management, and additional therapeutic effects. Dysbiosis, an imbalance of the gut microbiome, is the foremost concern associated with various neurological disorders. In epilepsy, the gut microbiome plays a pivotal role in its pathophysiology, unveiling new avenues for microbiome-mediated strategies to treat epileptic patients. Furthermore, the differential gut microbial composition in epileptic patients serves as a cornerstone for advanced research to delineate the influence of each bacterial species on epilepsy. Drosophila melanogaster, a simple model organism with an evolutionarily conserved gut microbiome composition, can be efficiently deployed to scrutinize the role of discrete microbes and their influence on the gut-brain axis, impacting neurological disorders. In this review, the role of distinct bacterial species in influencing epileptic conditions and how model organisms like Drosophila can be employed to explore this realm are deliberated as a comprehensive overview.
