CNS Neuroscience & Therapeutics最新文献

{"title":"Hyperglycemia-Induced Microglial CTSS Disrupts Blood-Retinal Barrier Integrity via PAR2-Dependent Downregulation of Endothelial MFSD2A","authors":"Chengye Xu,&nbsp;Hongxue Li,&nbsp;Qian Xu,&nbsp;Kangqi Zhao,&nbsp;Yangwen Chen,&nbsp;Yan Wang,&nbsp;Wei Zou,&nbsp;Binglin Kuang,&nbsp;Hongyu Kuang","doi":"10.1002/cns.71187","DOIUrl":"https://doi.org/10.1002/cns.71187","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Diabetic retinopathy (DR), a leading cause of blindness in diabetes, involves dysregulated neuroimmune crosstalk. While microglial activation and endothelial dysfunction are established in DR, the molecular mechanisms linking innate immunity to blood-retinal barrier (BRB) breakdown remain elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We combined single-cell RNA sequencing (scRNA-seq) of diabetic mouse retinas with in vivo models, retinal endothelial MFSD2A overexpression, and microglial Cathepsin S (CTSS) knockdown via adeno-associated virus (AAV). Human retinal microvascular endothelial cells (HRMECs) and human microglial cells (HMC3) were subjected to high-glucose conditions combined with in vitro systems (transwell co-cultures, holographic 3D tomography). Mechanistic studies employed siRNA knockdown, plasmid overexpression, exogenous CTSS supplementation, and transcytosis assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>scRNA-seq revealed diabetes-induced CTSS upregulation in retinal microglia (<i>p</i> = 0.0031) and MFSD2A downregulation in endothelial cells (<i>p</i> = 0.01). Microglial CTSS promoted M1 polarization (<i>p</i> &lt; 0.001) and pro-inflammatory cytokine secretion (IL-1β and TNF-α, <i>p</i> &lt; 0.05), while Ctss knockdown attenuated these effects (<i>p</i> &lt; 0.05). CTSS activated endothelial PAR2, suppressing endothelial MFSD2A and enhancing caveolin-1-mediated transcytosis. Endothelial MFSD2A overexpression reduced vascular permeability independently of tight junction modulation (ZO-1, Occludin, Claudin-5, <i>p</i> &gt; 0.05). Microglia-endothelial crosstalk was disrupted in diabetes, with ultrastructural alterations (cytoplasmic shrinkage, microglial amoeboid transformation) promoting cytotoxic interactions and exacerbate vascular endothelial damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Hyperglycemia induces retinal microglial activation and CTSS upregulation, disrupting microglia-endothelial crosstalk via the PAR2 pathway, suppressing endothelial MFSD2A expression, enhancing transcytosis, compromising iBRB integrity, and accelerating DR progression. Therapeutic strategies targeting microglial CTSS or endothelial MFSD2A represent promising avenues for preserving vision in diabetic patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Explore the Mechanism of Xiaoyaosan for Treatment of Bipolar Disorder Based on Network Pharmacology, Experimental Validation and Molecular Docking","authors":"Man Chen,&nbsp;Nana Ding,&nbsp;Xingmin Qiu,&nbsp;Lan Li,&nbsp;Yali Guo,&nbsp;Rongyanqi Wang,&nbsp;Xiaowei Mo,&nbsp;Tan Zou,&nbsp;Shangzhen Yu,&nbsp;Xiaojuan Li,&nbsp;Jiaxu Chen","doi":"10.1002/cns.71179","DOIUrl":"https://doi.org/10.1002/cns.71179","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim of the Study</h3>\u0000 \u0000 <p>Xiaoyaosan (XYS) has significant anti-inflammatory effects and is widely used for treating depression. However, the multitarget mechanism of XYS in the treatment of bipolar disorder (BD) remains unexplored. In this study, network pharmacology, molecular docking, and experimental validation were integrated to elucidate the mechanisms of XYS and its therapeutic efficacy in BD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>First, network pharmacology was employed to elucidate the anti-BD mechanism of XYS. Second, the therapeutic effects of XYS against BD were investigated in a BD mouse model induced by Ank3 gene knockdown combined with chronic social defeat stress (CSDS). Finally, the targets from these predictions were validated in a series of experiments and molecular docking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>First, on the basis of network pharmacology, 120 predicted intersection targets between the targets of XYS and BD-related targets were identified. The key core targets of the anti-BD activity of XYS were STAT3, AKT1, IL-6, and MAPK3. Thus, inflammation pathways might play a critical role in the anti-BD effects of XYS. Second, XYS clearly inhibited BD activity, which was manifested by a significant alleviation of manic hyperactivity behavior and a significant improvement in depressive hyperactivity behavior in BD model mice. Additionally, the up-regulation of STAT3, AKT1, IL-6, and MAPK3 was improved by XYS intervention in a BD mouse model. Moreover, molecular docking results also revealed that XYS showed strong stable binding to key core targets from network pharmacological predictions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>XYS can markedly improve BD through modulation of the expression of the key multitargets STAT3, AKT1, IL-6, and MAPK3 in inflammation pathways. These novel findings elucidate the anti-BD mechanism of XYS from the perspective of multiple targets and pathways.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Banxia Shumi Decoction Alleviates PCPA-Induced Insomnia and Regulates ADAM10 Expression via Melatonin Signaling in Rats","authors":"Baojun Guo,&nbsp;Yuqin Tang,&nbsp;Yongqiang Zhang,&nbsp;Yeke Wu,&nbsp;Ranran Gao","doi":"10.1002/cns.70988","DOIUrl":"10.1002/cns.70988","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Insomnia is a pathological sleep disorder marked by persistent sleep-onset difficulties. This study explored the therapeutic effects and underlying mechanism of Banxia Shumi Decoction (BXSMD) in treating insomnia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study used network pharmacology to predict the core targets and signaling pathways of BXSMD in insomnia intervention. A rat insomnia model was constructed via 4-Chloro-DL-phenylalanine (PCPA) to assess BXSMD's behavioral impacts. ELISA, qRT-PCR, Western blot, and IHC were applied to detect the expression of 5-hydroxytryptamine (5-HT), melatonin (MT), MT1/MT2 receptors, and related factors (CLOCK, PER1, CaMKII, p-CREB/CREB, GABARAP, mGLuR1, ADAM10) in the rat suprachiasmatic nucleus (SCN), hippocampus, and serum. The non-selective melatonin receptor antagonist luzindole was administered to explore its influence on BXSMD-regulated expression of the above molecules.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with the model group, the BXSMD group showed shortened sleep latency and prolonged sleep duration. BXSMD significantly elevated 5-HT, MT, and MT1/MT2 levels. BXSMD upregulated the mRNA and protein expression of downstream effector molecules including CLOCK, PER1, CaMKII, and GABARAP, downregulated mGLuR1 expression, and increased the expression of ADAM10. Notably, CREB mRNA expression remained unchanged, while BXSMD significantly increased the p-CREB/CREB protein ratio. The regulatory effects of BXSMD on all altered molecules were significantly reversed by luzindole.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>BXSMD effectively alleviates PCPA-induced insomnia in rats. The mechanism relies on MT1/MT2 as core targets, which mediate the regulation of sleep-related molecules (CLOCK, PER1, CaMKII, p-CREB/CREB, GABARAP, and mGluR1), as well as the membrane protein shedding-related molecule ADAM10.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactoferrin and Nanotechnology: New Insights Into Glioblastoma Therapy","authors":"Atena Abed,&nbsp;Javad Amini Mahabadi","doi":"10.1002/cns.71070","DOIUrl":"10.1002/cns.71070","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This review aimed to explore emerging therapeutic strategies for glioblastoma multiforme (GBM) through the integration of lactoferrin (LF) and nanotechnology, emphasizing mechanisms that improve drug delivery across the blood–brain barrier (BBB).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Published studies on LF-based nanocarriers and their biological mechanisms were systematically reviewed, focusing on LF's molecular interactions, tumor-targeting capacity, and the design of nanoscale delivery systems capable of enhancing drug bioavailability and selectivity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LF, an iron-binding glycoprotein with antimicrobial, antioxidant, and antitumor properties, can interact with low-density lipoprotein receptor-related protein-1 (LRP1), enabling its transport across the BBB and preferential uptake by glioblastoma cells. Nanocarrier systems incorporating LF improved the solubility, circulation half-life (typically 2- to 5-fold enhancement compared with free drug), and therapeutic performance of chemotherapeutic agents while minimizing systemic toxicity. Studies demonstrated that LF-based nanoparticles could induce apoptosis, inhibit tumor growth (with tumor volume reductions ranging from approximately 40% to 70% in orthotopic GBM models), and enhance radiosensitivity in GBM models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>LF provides a promising molecular platform for targeted glioblastoma therapy. When integrated with nanocarrier technologies, it enhances therapeutic efficacy, stability, and safety of anticancer agents. The combined LF–nanocarrier approach represents a rational and innovative strategy for improving treatment outcomes in glioblastoma multiforme.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148965758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advancements in Drug Delivery Across the Blood–Brain Barrier in Amyotrophic Lateral Sclerosis (ALS)","authors":"Nitesh Sanghai,&nbsp;Kaitlyn Pierce,&nbsp;Nidhi Sharma,&nbsp;Sasha Leggett,&nbsp;Tara Chand Yadav,&nbsp;Pegah Masrori,&nbsp;Devi Atukorallaya,&nbsp;Senthilnathan Palaniyandi,&nbsp;Paul C. Marcogliese,&nbsp;Geoffrey K. Tranmer","doi":"10.1002/cns.71078","DOIUrl":"https://doi.org/10.1002/cns.71078","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neurodegenerative disease with limited therapeutic options. The blood–brain barrier (BBB) and blood-spinal cord barrier (BSCB) present major obstacles to central nervous system (CNS) drug delivery, restricting the effectiveness of many potential therapies. Increasing evidence suggests that BBB and BSCB dysfunction are not only barriers to treatment but also important contributors to ALS pathophysiology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To examine current evidence regarding BBB and BSCB dysfunction in ALS and evaluate the implications of stage-dependent barrier alterations for CNS drug delivery and therapeutic outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Recent mechanistic, pathological, preclinical, and clinical studies examining BBB and BSCB alterations in ALS were reviewed. Evidence on tight junction disorganization, endothelial dysfunction, vascular leakage, altered transporter activity, and emerging therapeutic and drug delivery strategies was analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Converging evidence indicates that BBB and BSCB dysfunction are intrinsic and progressive features of ALS pathophysiology rather than passive consequences of neurodegeneration. Barrier impairment emerges early in the disease course and evolves across clinical stages. Disruption of barrier integrity may increase motor neuron vulnerability while modulating CNS drug exposure. Emerging strategies that bypass, exploit, or restore barrier function hold promise for enhancing CNS bioavailability and improving therapeutic outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Improved understanding of barrier alterations may facilitate development of more effective CNS-targeted therapies and improve therapeutic outcomes in ALS patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mediators of the Association Between Stroke and Blood Cells: A Two-Step Multivariable Mendelian Randomization Study","authors":"Tao Chen,&nbsp;Yan Li,&nbsp;Long Cai,&nbsp;Yijun Liu,&nbsp;Pengchen Kuang,&nbsp;Liuyi Zou,&nbsp;Ping Li","doi":"10.1002/cns.70903","DOIUrl":"https://doi.org/10.1002/cns.70903","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background and Purpose&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Stroke remains one of the leading causes of death and disability worldwide, posing a serious global health burden. Identifying reliable and easily accessible biomarkers for stroke risk is therefore of great clinical importance. The complete blood count (CBC) is a routine and widely available hematological test that provides key information about blood cell components, including red blood cells, white blood cells, and platelets. These parameters collectively reflect systemic conditions such as inflammation, infection, and coagulation, which are known to play critical roles in stroke pathogenesis. Recent evidence suggests that certain CBC parameters may be associated with an increased risk of stroke; however, the nature and direction of these associations remain unclear. This study aims to comprehensively evaluate the relationship and potential causal links between individual CBC parameters and the risk of stroke.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our analysis encompassed 6736 participants from the NHANES dataset (2011–2016). We utilized a suite of statistical techniques: multivariable logistic regression, Weighted Quantile Sum (WQS) regression, restricted cubic spline analysis, and Mendelian randomization. These methods were applied to assess the link between blood cell metrics (CBC) and stroke, considering a broad spectrum of covariates such as age, race, socioeconomic status, BMI, lifestyle factors (smoking, alcohol consumption, physical activity), serum calcium levels, hypertension, and diabetes. Stroke cases were ascertained using a dedicated questionnaire, and an extensive array of CBC parameters was examined. This study aims to systematically assess the association between CBC parameters and stroke risk, and explore their potential causal relationship using multivariate statistical analysis and genetic epidemiological methods.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Initial analysis revealed significant disparities in age, education, income, hypertension, and diabetes between the stroke and nonstroke cohorts. CBC, notably LBXRDW, LBXHCT, LBXHGB, and LBXMCHSI, emerged as independent predictors of stroke. WQS regression underscored a positive association between these indices and stroke risk, which was attenuated after adjusting for confounders. Restricted cubic spline analysis uncovered significant nonlinear correlations for LBXRDW and LBXMCHSI with stroke events. Mendelian randomization further suggested potential causal links between specific CBC (e.g., mean erythrocyte hemoglobin concentration, red blood cell distribution width) and stroke, albeit with variable correlation","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.70903","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking Abstinence Elicits Hyperalgesia: Neural Mechanism, Clinical Implications, and Pharmacological Managements","authors":"Shan-shan Hu,&nbsp;Chao-feng Zhang,&nbsp;Battuvshin Lkhagvasuren,&nbsp;Di Wang","doi":"10.1002/cns.71132","DOIUrl":"10.1002/cns.71132","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Purpose&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Nicotine exerts acute analgesic effects and serves as the major addictive component of tobacco. Nicotine withdrawal contributes to altered pain perception and hyperalgesia, further exacerbating postoperative pain and increasing opioid consumption in abstinent smokers during the perioperative period. This review aimed to systematically summarize the alterations in pain sensitivity induced by nicotine abstinence, elaborate the underlying neurochemical mechanisms, and clarify clinical intervention strategies as well as existing research limitations, so as to provide theoretical evidence for perioperative pain management in smoking cessation populations.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This was a narrative review based on published animal and human studies. We comprehensively summarized changes in somatic sensitivity to cold, heat, and mechanical pain stimuli following nicotine abstinence. The clinical relevance of perioperative nicotine/tobacco abstinence for postoperative pain control was outlined. Moreover, we analyzed the regulatory roles of central neurotransmitters (serotonin, norepinephrine, endogenous opioids, and dopamine) and receptor activation remodeling in abstinence-related pain sensitization. Additionally, the application value of nicotine replacement therapy in improving withdrawal-induced hyperalgesia was summarized.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Nicotine abstinence significantly reduces pain threshold and enhances nociceptive sensitivity, leading to aggravated postoperative pain and elevated demand for opioid analgesics in perioperative smokers. Neurotransmitter dysfunction and abnormal receptor activation in the brain are core neural mechanisms mediating nicotine withdrawal-induced hyperalgesia. Nicotine replacement therapy can effectively alleviate withdrawal-evoked pain hypersensitivity and relieve its adverse impacts on postoperative pain outcomes. Current studies are limited by insufficient clinical data, especially studies focusing on chronic pain patients, while neuroimaging techniques exhibit great potential for exploring the neural mechanisms of abstinence-related pain perception changes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Nicotine abstinence induces prominent pain sensitization via central neurochemical maladjustment. Nicotine replacement therapy is an effective pharmacological intervention for withdrawal-induced hyperalgesia. This review deepens the systematic understanding of the mechanism underlying nicotine withdrawal-altered pain sensitivi","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Choroid Plexus Microstructural Alterations Link Glymphatic Dysfunction and White Matter Degeneration in Parkinson's Disease","authors":"Suyi Zhou,&nbsp;Zhiming Zhen,&nbsp;Cheng Lai,&nbsp;Peiyu Huang,&nbsp;Zhe Sun,&nbsp;Taotao Yang,&nbsp;Fengwei Yu,&nbsp;Wei Chen,&nbsp;Zhentao Zuo,&nbsp;Wei Chen","doi":"10.1002/cns.71039","DOIUrl":"10.1002/cns.71039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Glymphatic dysfunction is increasingly recognized as a key contributor to the progression of Parkinson's disease (PD). In PD, both choroid plexus (CP) alterations and white matter abnormalities have been linked to glymphatic dysfunction. However, how CP microstructural abnormalities relate to glymphatic function, corpus callosum (CC) degeneration, and clinical impairment remains unclear. This study aimed to investigate these associations in PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Eighty-one patients with idiopathic PD and eighty age- and sex-matched healthy controls (HC) underwent MRI scanning. CP microstructural metrics (free water [FW], FW-corrected fractional anisotropy [FA_FWcorr] and FW-corrected mean diffusivity [MD_FWcorr]) were extracted, along with the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and CC subregional volumes. Group comparisons, partial correlation, multiple linear regression, and mediation analyses were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients with PD showed significantly higher CP FW and MD_FWcorr values and a lower DTI-ALPS index than HC. Higher CP MD_FWcorr was associated with worse motor symptoms and poorer cognitive performance after covariate adjustment. Mediation analysis suggested that the ALPS index mediated the associations between CP microstructural alterations and CC subregional volumes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CP microstructural abnormalities were associated with DTI-ALPS alterations, CC degeneration, and clinical impairment in PD. FW-DTI metrics of the CP may provide useful imaging markers for characterizing CP-related changes in PD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural Circuit Mechanisms of Disorders of Consciousness and Potential Therapeutic Targets of Brain Stimulation","authors":"Yichen Zhou,&nbsp;Tianqing Cao,&nbsp;Sipeng Zhu,&nbsp;Qiheng He,&nbsp;Yitong Jia,&nbsp;Xiaoke Chai,&nbsp;Nan Wang,&nbsp;Yi Yang","doi":"10.1002/cns.71037","DOIUrl":"10.1002/cns.71037","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Disorders of consciousness (DoC) lack an integrated framework to guide neuromodulation. This review updates three hierarchical frameworks—ARAS, mesocircuit, and ICNs—and maps therapeutic targets within each.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We synthesized recent neuroanatomical, optogenetic, neuroimaging, and clinical trial evidence, reevaluating classic frameworks and proposing a hierarchical integration to inform multi-target strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Three major updates are identified. In ARAS, glutamatergic neurons in PPN/LDT and parabrachial nucleus, rather than cholinergic neurons, are the primary arousal drivers; clinical translation relies on peripheral nerve stimulations with variable efficacy. The mesocircuit is expanded from a unidirectional GPi-mediated pathway to a bidirectional GPi–GPe balance modulated by dopamine and adenosine; DBS targeting CM-Pf/CL shows ~44.7% response rate (38/85) but lacks RCTs, whereas amantadine remains the sole Level 1 evidence. Within ICNs, the executive control network has the strongest RCT support, though efficacy depends on etiology and consciousness level; salience network stimulation is untested. These frameworks are hierarchically integrated: ARAS sustains wakefulness, mesocircuit enables cortical activation, and ICNs support conscious content.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Future strategies should adopt multi-target, multi-level approaches grounded in individualized network profiling. Priorities include large-scale RCTs for DBS and stratified protocols based on etiology and consciousness level.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual Transcranial Direct Current Stimulation Modulates Hierarchical Functional Network Organization in Post-Stroke Cognitive Impairment: A Randomized Controlled Trial","authors":"Yao Wang,&nbsp;Wan Liu,&nbsp;Wenjie Yang,&nbsp;Jun Hu,&nbsp;Xinxin Cheng,&nbsp;Hao Yu,&nbsp;Yin Shi,&nbsp;Li Liu,&nbsp;Jiang Rao,&nbsp;Guangxu Xu","doi":"10.1002/cns.71111","DOIUrl":"10.1002/cns.71111","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate the clinical efficacy of dual transcranial direct current stimulation (tDCS) in patients with post-stroke cognitive impairment (PSCI) and to explore the effects on the hierarchical organization of functional brain networks, ranging from regional synchronization to inter-regional connectivity and global network topology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this randomized, double-blind, sham-controlled trial, 74 PSCI patients received conventional therapy alongside either active dual-tDCS (<i>n</i> = 38) or sham stimulation (<i>n</i> = 36). Active tDCS targeted the dorsolateral prefrontal cortex (DLPFC) via anodal-left/cathodal-right nodes (2.0 mA, 20 min/day, 20 sessions). The primary outcome was the Montreal Cognitive Assessment (MoCA). Secondary outcomes included the Mini-Mental Status Examination (MMSE), Stroop Test (ST), Trail Making Test (TMT), Wechsler Memory Scale (WMS), and Barthel Index (BI). A subgroup of 36 participants (18 per group) underwent resting-state functional magnetic resonance imaging (rs-fMRI) to analyze regional homogeneity (ReHo), functional connectivity (FC), and network topology. Partial correlations assessed the association between neuroimaging alterations and clinical improvements.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The tDCS group showed significantly greater improvements in MoCA scores (tDCS: 5.74 ± 2.76 vs. sham: 2.69 ± 2.69; <i>t</i> = 4.799, <i>p</i> &lt; 0.001) as well as in attention and memory domains compared to the sham group. The rs-fMRI changes included increased ReHo in the right middle temporal gyrus (MTG) and the left inferior frontal gyrus (IFG), and reduced FC between the right MTG-left superior frontal gyrus and left IFG-cerebellum (<i>p</i> &lt; 0.05, FWE-corrected). Additionally, small-worldness and global efficiency increased (<i>p</i> &lt; 0.05) with these alterations correlating with clinical recovery. Adverse events were rare and self-limiting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Dual-tDCS over bilateral DLPFC safely improves cognitive recovery in PSCI. These clinical gains are associated with rs-fMRI alterations, specifically in regional synchronization, inter-regional connectivity, and global topology, which suggest a potential biomarker for monitoring tDCS efficacy, offering a rationale for precision neuromodulation in stroke rehabilitation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 9","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13538461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}