Neurotherapeutics最新文献

{"title":"Personalizing neuromodulation for chronic pain: A connectivity-guided trial","authors":"Enrico De Martino,&nbsp;Margit Midtgaard Bach,&nbsp;Bruno Nascimento Couto,&nbsp;Anne Jakobsen,&nbsp;Pedro Nascimento Martins,&nbsp;Stian Ingemann-Molden,&nbsp;Adenauer G. Casali,&nbsp;Thomas Graven-Nielsen,&nbsp;Daniel Ciampi de Andrade","doi":"10.1016/j.neurot.2026.e00960","DOIUrl":"10.1016/j.neurot.2026.e00960","url":null,"abstract":"<div><div>In this randomized, double-blind, controlled trial, we evaluated 8 weeks of repetitive transcranial magnetic stimulation (rTMS) for chronic pain, comparing classic primary motor cortex (M1) stimulation with a novel target-selection strategy based on pre-therapy cortical connectivity. Guided by homeostatic plasticity, we hypothesized that stimulating the cortical site with the lowest pre-therapy global connectivity would produce more pain relief than stimulating the site with the highest connectivity or stimulating M1 independent of connectivity. Before treatment, TMS-evoked EEG potentials were recorded from four cortical targets: M1, dorsolateral prefrontal cortex, anterior cingulate cortex, and posterosuperior insular cortex. For each target, connectivity was quantified using a distance-weighted, phase-based measure (debiased weighted phase lag index, wPLI) that reflects the magnitude and spatial extent of TMS-induced oscillatory phase locking across cortical regions. Ninety patients with chronic pain were randomized to Low-Connectivity, High-Connectivity, or Classic-M1 groups and received 12 rTMS sessions over 8 weeks. The primary outcome was the proportion of patients achieving at least 30% reduction in pain intensity. Secondary outcomes included pain intensity, pain interference, sleep, fatigue, mood, quality of life, and patient global impression of change. No significant between-group differences were observed for primary or secondary outcomes (all p &gt; 0.05). In prespecified mechanistic exploratory analyses, lower pre-therapy local M1 connectivity was associated with greater pain reduction in the Classic-M1 group (r = 0.50, p = 0.005), but not in the Low- or High-Connectivity groups. These findings suggest that global connectivity-based target selection did not enhance analgesic efficacy and that the local M1 associations are hypothesis-generating and require prospective validation.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00960"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trajectory guide for minimally-invasive MRI-guided neurosurgery: Accelerating intraparenchymal therapeutic delivery through a simplified workflow with fewer scanning steps","authors":"Thomas Lilieholm PhD,&nbsp;Terrence R. Oakes PhD,&nbsp;Andrew L. Alexander PhD,&nbsp;Azam Ahmed MD,&nbsp;Walter F. Block PhD","doi":"10.1016/j.neurot.2026.e01014","DOIUrl":"10.1016/j.neurot.2026.e01014","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01014"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Disease Monitoring in Huntington’s Disease Using a Multi-Modal Digital Health Technology","authors":"Ashkan Vaziri PhD,&nbsp;Ram Kinker Mishra,&nbsp;Jamie L. Adam MD","doi":"10.1016/j.neurot.2026.e00995","DOIUrl":"10.1016/j.neurot.2026.e00995","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00995"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendrimer Conjugation Enhances the Anti-Neuroinflammatory Therapeutic Index of Propofol","authors":"Meixiang (Mei) Huang MD, PhD,&nbsp;Yu Su MD, PhD,&nbsp;Yuxin Zheng MD,&nbsp;Lukáš Tenora,&nbsp;Wathsala Liyanage PhD,&nbsp;Jesse Alt B.S.,&nbsp;Peter Pietri B.S.,&nbsp;Kaitlyn Huizar,&nbsp;Kannan Rangaramanujam PhD,&nbsp;Rana Rais PhamD,&nbsp;Barbara Slusher PhD, MAS","doi":"10.1016/j.neurot.2026.e01003","DOIUrl":"10.1016/j.neurot.2026.e01003","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01003"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Stress-Induced Microglial GLS1–Linked Endosomal–Genomic Signaling Axis Revealed by scRNA-seq","authors":"Naigang Li,&nbsp;Yannan Li,&nbsp;Jisu Ha,&nbsp;Tessa Schauermann,&nbsp;Giovanna Punzi,&nbsp;Gianluca Ursini,&nbsp;Xiaolei Zhu","doi":"10.1016/j.neurot.2026.e01005","DOIUrl":"10.1016/j.neurot.2026.e01005","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01005"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruptive impacts of developmental and epileptic encephalopathies on patient and family life: Interim results of a quality-of-life survey","authors":"Laurie D. Bailey BCPA,&nbsp;Tracy Dixon-Salazar PhD,&nbsp;Mary Anne Meskis,&nbsp;A. Michelle Manzo MPH,&nbsp;Mercedes Martin MSN, FNP-C,&nbsp;Amélie Lothe PhD,&nbsp;Andrea L. Wilkinson","doi":"10.1016/j.neurot.2026.e00993","DOIUrl":"10.1016/j.neurot.2026.e00993","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00993"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Black gas, bright future: H2S based therapeutics for neurodegenerative disorders” [Neurotherapeutics Volume 22, (Issue 6) (2025) e00755]","authors":"Jordan L. Morris,&nbsp;Jordan J. Lee,&nbsp;Russell E. Morris,&nbsp;Jan Lj. Miljkovic","doi":"10.1016/j.neurot.2026.e01052","DOIUrl":"10.1016/j.neurot.2026.e01052","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01052"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148770287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-neuron responses to neurostimulation: Insights for epilepsy","authors":"Rhiannon L. Cowan,&nbsp;Edward M. Merricks,&nbsp;Tyler S. Davis,&nbsp;John D. Rolston,&nbsp;Shervin Rahimpour,&nbsp;Ben Shofty,&nbsp;Catherine A. Schevon,&nbsp;Elliot H. Smith","doi":"10.1016/j.neurot.2026.e01031","DOIUrl":"10.1016/j.neurot.2026.e01031","url":null,"abstract":"<div><div>Invasive neurostimulation has been used in humans to treat and diagnose epilepsy for decades. Despite such ubiquitous probing and recording from the human brain, the efficacy of surgical outcomes has remained stable. One potential reason for the gradual improvement in outcome efficacy is the continued reliance on passive recordings of meso-scale field potentials for diagnosis. Yet, recordings from individual neurons have enriched our understanding of seizure physiology. Here, we review evidence that cellular recording, especially in response to stimulation, is a potentially valuable tool in diagnosing, treating, and advancing therapeutics for epilepsy. Building on recent evidence, we propose a shift toward expanded investigation in neuromodulation research and treatment, toward approaches that leverage the potential of single-neuron recordings as a therapeutic strategy to enhance diagnosis, surgical precision, and treatment efficacy.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01031"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small proline-rich repeat protein 1A-mediated ephrin-A5 downregulation drives neuropathic pain via brain-derived neurotrophic factor/Tropomyosin receptor kinase B signaling","authors":"Meiling Deng,&nbsp;Ting Zhang,&nbsp;Jie Yang,&nbsp;Qiqi Yan,&nbsp;Jun Yang,&nbsp;Wangyuan Zou,&nbsp;Jun Cao,&nbsp;Li Ren","doi":"10.1016/j.neurot.2026.e00964","DOIUrl":"10.1016/j.neurot.2026.e00964","url":null,"abstract":"<div><div>Neuropathic pain is a common chronic pain condition that severely impacts patients’ quality of life. While Small proline-rich protein 1A (SPRR1A) is a well-known marker for axonal regeneration, its specific role and the underlying molecular mechanisms in neuropathic pain remain elusive. The present study demonstrates that SPRR1A is significantly increased in the spinal dorsal horn of spared nerve injury (SNI) mice, accompanied by ephrin-A5 downregulation, activation of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway, and enhanced neuronal excitability. SPRR1A overexpression induces allodynia in naïve mice, whereas knockdown of SPRR1A alleviates hyperalgesia and reduces neuronal hyperactivity. Silencing SPRR1A restores ephrin-A5 expression and suppresses BDNF/TrkB activation. Co-immunoprecipitation confirms that SPRR1A interacts with ephrin-A5, while ephrin-A5 competitively binds TrkB to block BDNF-mediated signaling. Conversely, SPRR1A overexpression decreases ephrin-A5 level and facilitates BDNF/TrkB activation. Ephrin-A5 siRNA reverses the inhibitory effects of SPRR1A knockdown on TrkB signaling. Furthermore, intrathecal administration of recombinant ephrin-A5 significantly attenuates hyperalgesia in SNI mice. Together, these findings identify SPRR1A as a key mediator of neuropathic pain that promotes central sensitization by suppressing ephrin-A5, thereby enhancing BDNF/TrkB signaling in the spinal dorsal horn. Targeting the SPRR1A-ephrin-A5-BDNF/TrkB axis may represent a promising therapeutic strategy for neuropathic pain management.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00964"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FRRS1L gene replacement ameliorates disease phenotypes in the mouse model of developmental and epileptic encephalopathy 37","authors":"Mehrnaz Sheibani,&nbsp;Esther O. Alao,&nbsp;Ummay Mariam,&nbsp;Jun Wu,&nbsp;Sahba Kasiri,&nbsp;Afsaneh Talai,&nbsp;Jochen Schwenk,&nbsp;Bernd Fakler,&nbsp;Steven J. Gray,&nbsp;Berge A. Minassian","doi":"10.1016/j.neurot.2026.e00961","DOIUrl":"10.1016/j.neurot.2026.e00961","url":null,"abstract":"<div><div>Gene therapy offers unique therapeutic potential for treating rare genetic disorders such as DEE37, a severe Developmental and Epileptic Encephalopathy caused by biallelic loss-of-function mutations in the Ferric Chelate Reductase 1 Like (<em>FRRS1L</em>) gene, presenting with seizures, developmental delay, dyskinesia, ataxia and progressive, eventually debilitating cognitive and motor impairments. There is currently no treatment for DEE37. <em>FRRS1L</em> encodes an auxiliary subunit essential for the tetrameric assembly of α-amino-3 hydroxy-5-methyl-4 isoxazolepropionic acid receptors (AMPARs) and their recruitment to synaptic membranes. FRRS1L is expressed brain-wide, with high levels in the cerebellum. Here, we developed an adeno-associated virus 9 (AAV9) gene replacement vector expressing human <em>FRRS1L</em> driven by the JeT promoter. Administering the virus intrathecally in two doses (5 × 10¹⁰ and 3 × 10¹¹ vg) to <em>Frrs1l</em>-knockout mice, we evaluated safety and efficacy in multiple phenotypic traits shared with affected patients. We obtained robust, near-normal, FRRS1L expression in the cerebellum and low levels of expression elsewhere in the brain, which were associated with corresponding levels of increased synaptic AMPAR abundance. Importantly, our phenotypic assessments revealed dose-dependent improvement trends, or rescue, across multiple brain structural, electrocorticographic, and behavioral domains. Our results indicate that cerebrospinal fluid-directed virally mediated <em>FRRS1L</em> gene replacement partially restores synaptic AMPAR and ameliorates disease-relevant phenotypes, supporting gene therapy as a promising therapeutic strategy for children suffering from this catastrophic, FRRS1L-related, 37th form of DEE.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00961"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}