Neuroscience最新文献

Loss of language function (aphasia) is a common complication after stroke, and post-stroke recovery remains highly unpredictable due to the absence of reliable neurobiomarkers. Growing evidence points to involvement of the cerebellum in language processing; however, it is unclear if abnormal cerebellar activity and altered functional connectivity (FC) to language-related regions of cerebral cortex are underlying neural mechanisms for subcortical aphasia. In this longitudinal observational study, we used resting-state functional magnetic resonance imaging to examine potential abnormalities in spontaneous cerebellar activity and resting-state (rs)FC with language networks among post-stroke patients with subacute subcortical aphasia (n = 19) compared to healthy controls (HCs, n = 18). In addition, correlations between rsFC variables and language performance metrics were examined at post-stroke baseline and at follow-up. Compared to HCs, patients with subacute subcortical aphasia exhibited significantly reduced fractional amplitude of low frequency fluctuations, a measure of spontaneous activity, in the right cerebellar Crus II (rCrus II) region and reduced rsFC between rCrus II and left inferior frontal gyrus (LIFG), left angular gyrus (LAG), and left middle temporal gyrus (LMTG). Both rCrus II-LAG and rCrus II-LMTG rsFC values were positively correlated with Aphasia Battery of Chinese scores at baseline. Baseline rCrus II-LIFG rsFC was also positively correlated with spontaneous speech and naming scores at follow-up. A stronger baseline rCrus II-LIFG rsFC predicted superior recovery of language function post-stroke. We conclude that the right cerebellum may be an effective therapeutic target for subcortical aphasia.

Vagus nerve stimulation (VNS) has garnered significant attention as a promising bioelectronic therapy. In recent years, respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel non-invasive vagus nerve stimulation technique, has emerged. RAVANS integrates respiration with transcutaneous auricular vagus nerve stimulation (taVNS) and shares a similar mechanism of action to traditional VNS. Similar to conventional Vagus Nerve Stimulation (VNS), RAVANS may mitigate brain injury through three primary pathways: reducing neuronal apoptosis, modulating neurotransmitter release, and influencing inflammatory factor pathways. In this paper, we emphasize how RAVANS enhances the activation of nucleus of the solitary tract （NTS）and the locus coeruleus by regulating the monoaminergic and GABA systems through respiratory control. Additionally, it leverages the beneficial effects of respiration on the central nervous system. In this review, we delineate the potential mechanisms of action of RAVANS, provide a comprehensive overview of its clinical applications in chronic low back pain, migraine, depression, hypertension, and cognitive disorders. Furthermore, we offer future perspectives on optimizing the parameters of RAVANS and its application in post-stroke dysphagia. This will pave the way for new avenues in RAVANS research.

Increasing evidence indicates that neuropeptide FF (NPFF) produces analgesic effects and augments opioid-induced analgesia at the spinal level. However, our recent research demonstrated that NPFF exerted complex opioid-modulating effects in an inflammatory pain model after intrathecal (i.t.) injection. Consistent with previous findings, we found that i.t. NPFF dose-dependently attenuated complete Freund's adjuvant-induced pain hypersensitivity. Interestingly, pharmacological results illustrated that NPFF exhibited opposite opioid-modulating effects at the spinal level depending on its administration dosage, wherein i.t. NPFF potentiated morphine-induced anti-allodynia at the dose of 10 nmol, while attenuated morphine analgesia at an ultra-low-dose of 10 pmol. Behavioral results obtained from neuropeptide FF receptor 2 (NPFFR2) knockout animals suggested that both pro- and anti-opioid effects of NPFF were mediated by NPFFR2. Moreover, these modulating effects of spinal NPFFR2 were selectively targeting mu-opioid receptor, had no effect on delta- and kappa-opioid receptor agonist-induced analgesia. Finally, the opioid-modulating effects of NPFF were further verified using in vitro calcium imaging assay, demonstrating that pretreated with NPFF in primary-cultured spinal neurons significantly attenuated the inhibitory effects of morphine on high-K⁺-induced neuronal excitability. Taken together, our results suggested that NPFF exhibited dual modulating effects on morphine-induced analgesia after i.t. administration, which provides a possible mechanism to explain the complex opioid-modulating effects of endogenous NPFF systems.

Background: The conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD) is related to various factors. The causal relationships among these factors remain unclear. This study aims to investigate pathways of the progression by using causal analysis and build a predictive model with high accuracy.

Methods: 162 MCI patients were recruited from the Alzheimer's Disease Neuroimaging Initiative database. 68 patients progressed to AD. 94 patients did not convert to AD. We captured standard T1-weighted images, processed them for feature extraction, and selected relevant features using mRMR and LASSO to calculate cortical and nuclear scores. The computational causal structure discovery and regression analyses were adopted to analyze the intricate relationships among APOE ε4 alleles, P-tau, Aβ1-42, cortical and nuclear scores. The individualized prediction nomogram was constructed.

Results: Our results indicated that APOE ε4 alleles was the promoter that caused MCI to transform into AD. Three independent pathways were identified, including P-tau, Aβ1-42, and cortical atrophy. P-tau was the cause of nuclear atrophy. The APOE ε4 alleles, P-tau, Aβ1-42, cortical and nuclear scores all had good predictive value for the MCI conversion. The predictive accuracy of the combined model was the highest, with an AUC of 0.918 in the training cohort and 0.908 in the testing cohort. A multi-predictor nomogram was established.

Conclusion: Our study elucidated the initiating factors and three independent pathways involved in the conversion of MCI to AD. The predictive value of each factor was clarified and a multi-predictor nomogram was established with high accuracy.

The analytical and experimental investigation of several targets and biomarkers that help in explaining significant cognitive deficits, covering drug development and precision medicine aimed at different chronic neurodegenerative conditions such as Alzheimer's disease (AD), Parkinson's disease, synaptic dysfunction, brain damage from neuronal apoptosis, and other disease pathologies; this served as the foundation for all phase studies. The focus of current therapeutic approaches is on developing humanized antibodies, agonist and antagonist drugs, receptors, signaling molecules, major targeted drug-metabolizing enzymes, and other metabolites to treat neurodegeneration in the AD brain brought on by tau hyperphosphorylation, amyloid plagues, or other cholinergic effects. The five A's-amnesia, agnosia, aphasia, apraxia, and anomia-are the typical symptoms associated with AD. While the main goal of drug therapeutics studies is modified amino acids acting as pro-drugs, pharmacokinetics studies and trends in evaluating drug-drug interactions focus on interactions between drugs and antibodies, drugs and therapeutic biologics like metabolites, herbs, interleukin-based, and gene silencing mechanism-based. Studies on the biotransformation of xenobiotic compounds and the metabolism of exogenous and endogenous substances are conducted under Phase I, Phase II, and Phase III trials because the pivotal pharmacokinetic properties of drugs, such as absorption, distribution, metabolism, and excretion (ADME), aid in understanding variations in the crucial improvement of various target drugs. This review also highlights the developments in soon-to-be genetically created targeted medications that may serve as ground-breaking treatments for cholinergic illnesses in the brains of AD patients and other neurodegenerative conditions.

Clinical and preclinical studies suggest that early life stress can increase the risk of developing ethanol use disorder later in life. Although the endocannabinoid (eCB) system plays a role in stress-related behaviors and ethanol consumption, it remains unclear whether the eCB system is affected in response to a combination of both factors. By using male and female adolescent C57BL/6J mice subjected to a maternal separation (MS) stress paradigm from postnatal day (PND) 1 to 14, we explored (1) the consequences of early life stress experiences on ethanol consumption in adolescent mice and (2) how these events affect the eCB system and neuronal activation in brain regions associated with the reward system. In Experiment 1, we found that MS increased involuntary ethanol consumption specifically during the first exposure to the drug (during a 24 h-long trial on PND 28) and decreased the active/inactive nose poke ratio (discrimination index) specifically when mice were subjected to 1 h-sessions (PND 82-86) in an operant ethanol self-administration paradigm. In Experiment 2, during a two-bottle free choice paradigm, we found that MS increased mice preference for high ethanol concentrations (15 % and 20 %) but not lower ethanol concentrations (5 % and 10 %). Except for Mgll gene expression in the dorsal striatum (DS) in Experiment 2, no statistically significant effects of MS were observed regarding neuronal activation on the prefrontal cortex, DS, globus pallidus, and substantia nigra following a binge operant ethanol self-administration session (Experiment 1) or the eCB system molecules (Cnr1 and Faah gene expression) in the DS (Experiment 2).

Stroke is a serious condition often resulting in mortality or long-term disability, causing cognitive, memory, and motor impairments. A reduction in cerebral blood flow below critical levels defines the ischemic core and penumbra: the core undergoes irreversible damage, while the penumbra remains viable but functionally impaired. This functional impairment activates complex cell signaling pathways that determine cell survival or death, making the penumbra a key target for therapeutic interventions to prevent further damage. The Wnt/β-catenin (WβC) signaling pathway has emerged as a potential neuroprotective mechanism, promoting neurogenesis, angiogenesis, neuronal connectivity, and maintaining blood-brain barrier integrity after stroke. Activation of the WβC pathway also mitigates oxidative stress, inflammation, and apoptosis in ischemic regions, enhancing its neuroprotective effects. However, the overexpression of GSK3β and DKK1, or the presence of their agonists, can counteract these benefits. This review explores the therapeutic potential of WβC signaling, highlighting the effects of pharmacological modulation through antagonists, agonists, synthetic chemicals, natural products, stem cells, and macromolecules in preclinical models of ischemic stroke. While preclinical evidence supports the benefits of WβC activation, its role in human stroke requires further investigation. Additionally, the review discusses the potential adverse effects of prolonged WβC activation and suggests strategies to mitigate them. Overall, WβC signaling holds promise as a therapeutic target, offering insights into stroke pathophysiology and informing the development of novel treatment strategies.

Aims: This study was aimed to investigate frequency-specific LFO changes and their correlation with gene pathways in PACG using transcriptome-neuroimaging analysis.

Methods: Resting-state fMRI (Rs-fMRI) data were acquired from individuals with PACG and healthy controls for evaluating the amplitude of low-frequency oscillations (ALFF) across different frequency bands such as the full band, slow-4 band, and slow-5 band. Transcriptome analysis integrated information from the Allen Human Brain Atlas (AHBA) through gene set enrichment analysis, protein-protein interaction network construction, and specific expression analysis, aiming to clarify the link between ALFF patterns and gene expression profiles in PACG. Statistical analyses, including one-sample t-tests and two-sample t-tests, were used to assess ALFF differences between groups, while partial least squares (PLS) regression was applied to explore the associations between ALFF and transcriptome data.

Results: This study identifies significant variations in ALFF values in PACG patients, observed consistently across multiple frequency bands, including slow-4 and slow-5. Enrichment analysis indicates that these genes are primarily involved in cellular components such as the cytosol and cytoplasm, molecular functions like protein binding, and key pathways, including metabolic and circadian rhythms, epithelial signaling in Helicobacter pylori infection, and glutathione metabolism. Protein-protein interaction (PPI) analysis further underscores the role of PACG-related genes in forming a functional network, highlighting hub genes critical for various biological processes.

Conclusion: This study establishes a connection between the molecular mechanisms of PACG and alterations in brain function and gene expression, providing valuable perspectives on the fundamental processes impacting low-frequency oscillations in PACG.

The most characteristic feature of the human electroencephalogram is the peak alpha frequency (PAF). While PAF has been proposed as a biomarker in several diseases and disorders, the disease mechanisms modulating PAF, as well as its physiological substrates, remain elusive. This has partly been due to challenges related to experimental manipulation and invasive procedures in human neuroscience, as well as the scarcity of animal models where PAF is consistently present in resting-state. With the potential inclusion of PAF in clinical screening and decision-making, advancing the mechanistic understanding of PAF is warranted. In this paper, we propose the female Danish Landrace pig as a suitable animal model to probe the mechanisms of PAF and its feature as a biomarker. We show that somatosensory alpha oscillations are present in anesthetized pigs using electrocorticography and intracortical electrodes located at the sensorimotor cortex. This was evident when looking at the time-domain as well as the spectral morphology of spontaneous recordings. We applied the FOOOF-algorithm to extract the spectral characteristics and implemented a robustness threshold for any periodic component. Using this conservative threshold, PAF was present in 18/20 pigs with a normal distribution of the peak frequency between 8-12 Hz, producing similar findings to human recordings. We show that PAF was present in 69.6 % of epochs of approximately six-minute-long resting-state recordings. In sum, we propose that the pig is a suitable candidate for investigating the neural mechanisms of PAF as a biomarker for disease and disorders such as pain, neuropsychiatric disorders, and response to pharmacotherapy.

Sleep deprivation is a prevalent issue in contemporary society, with significant ramifications for both physical and mental well-being. Emerging scientific evidence illuminates its intricate interplay with the gut-brain axis, a vital determinant of neurological function. Disruptions in sleep patterns disturb the delicate equilibrium of the gut microbiota, resulting in dysbiosis characterized by alterations in microbial composition and function. This dysbiosis contributes to the exacerbation of neurological disorders such as depression, anxiety, and cognitive decline through multifaceted mechanisms, including heightened neuroinflammation, disturbances in neurotransmitter signalling, and compromised integrity of the gut barrier. In response to these challenges, there is a burgeoning interest in therapeutic interventions aimed at restoring gut microbial balance and alleviating neurological symptoms precipitated by sleep deprivation. Probiotics, dietary modifications, and behavioural strategies represent promising avenues for modulating the gut microbiota and mitigating the adverse effects of sleep disturbances on neurological health. Moreover, the advent of personalized interventions guided by advanced omics technologies holds considerable potential for tailoring treatments to individualized needs and optimizing therapeutic outcomes. Interdisciplinary collaboration and concerted research efforts are imperative for elucidating the underlying mechanisms linking sleep, gut microbiota, and neurological function. Longitudinal studies, translational research endeavours, and advancements in technology are pivotal for unravelling the complex interplay between these intricate systems.