BrainPub Date : 2025-10-01DOI: 10.1093/brain/awaf364
Selma Lugtmeijer, Edward H F de Haan, H Steven Scholte
{"title":"Reply: Lack of statistical significance is not evidence against modularity in visual feature processing.","authors":"Selma Lugtmeijer, Edward H F de Haan, H Steven Scholte","doi":"10.1093/brain/awaf364","DOIUrl":"https://doi.org/10.1093/brain/awaf364","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-10-01DOI: 10.1093/brain/awaf370
Asta Arendt-Tranholm, Ishwarya Sankaranarayanan, Cathryn Payne, Marisol Mancilla Moreno, Khadijah Mazhar, Natalie Yap, Abby P Chiu, Allison Barry, Pooja J Patel, Nikhil N Inturi, Diana Tavares-Ferreira, Anubhav Amin, Mahesh Karandikar, Jeffrey G Jarvik, Judith A Turner, Christoph P Hofstetter, Michele Curatolo, Theodore J Price
{"title":"Transcriptome of the human C2 dorsal root ganglia in C1-2 arthrodesis surgery: insight for neck pain","authors":"Asta Arendt-Tranholm, Ishwarya Sankaranarayanan, Cathryn Payne, Marisol Mancilla Moreno, Khadijah Mazhar, Natalie Yap, Abby P Chiu, Allison Barry, Pooja J Patel, Nikhil N Inturi, Diana Tavares-Ferreira, Anubhav Amin, Mahesh Karandikar, Jeffrey G Jarvik, Judith A Turner, Christoph P Hofstetter, Michele Curatolo, Theodore J Price","doi":"10.1093/brain/awaf370","DOIUrl":"https://doi.org/10.1093/brain/awaf370","url":null,"abstract":"Neurons in the dorsal root ganglion (DRG) receive and transmit sensory information from the tissues they innervate and from the external environment. Upper cervical (C1-C2) DRGs are functionally unique as they receive input from the neck, head, and occipital cranial dura, the latter two of which are also innervated by the trigeminal ganglion (TG). The C2 DRG also plays an important role in neck pain, a common and disabling disorder that is poorly understood. Advanced transcriptomic approaches have significantly improved our ability to characterize RNA expression patterns at single-cell resolution in the DRG and TG, but no previous studies have characterized the C2 DRG. Our aim was to use single-nucleus and spatial transcriptomic approaches to create a molecular map of C2 DRGs from patients undergoing arthrodesis surgery with ganglionectomy. Patients with acute (<3 months) or chronic (≥3 months) neck pain were enrolled and completed patient-reported outcome and somatosensory measures prior to surgery. C2 DRGs were characterized with bulk, single nucleus, and spatial RNA sequencing technologies from 22 patients. Through a comparative analysis to published datasets of the lumbar DRG and TG, neuronal clusters identified in both TG and DRG were identified in the C2 DRG. Therefore, our study characterizes the molecular composition of human C2 neurons and establishes their similarity with unique characteristics of subsets of TG neurons. We identified differentially expressed genes in endothelial, fibroblast and myelinating Schwann cells associated with chronic pain, including FGFBP2, C8orf34 and EFNA1, which have been identified in previous genome and transcriptome wide association studies (GWAS/TWAS). Our work provides the first characterization of the human C2 DRG and identifies altered gene expression patterns associated with chronic neck pain. This work establishes a foundation for the exploration of painful disorders in humans affecting the cervical spine.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"1 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-10-01DOI: 10.1093/brain/awaf369
Elena Barbieri, Allegra S Kawles, Michelle Los, Jordan Behn, Changiz Geula, Tamar Gefen, Sandra Weintraub, M Marsel Mesulam
{"title":"Atrophy progression in frontotemporal lobar degeneration-TDP-C with primary progressive aphasia","authors":"Elena Barbieri, Allegra S Kawles, Michelle Los, Jordan Behn, Changiz Geula, Tamar Gefen, Sandra Weintraub, M Marsel Mesulam","doi":"10.1093/brain/awaf369","DOIUrl":"https://doi.org/10.1093/brain/awaf369","url":null,"abstract":"Clinicopathologic correlations in neurodegenerative diseases have led to novel insights on the neurobiology of selective vulnerability and the anatomy of cognitive networks. The neuropathologic entity of frontotemporal lobar degeneration with abnormal precipitates of the transactive response DNA binding protein TDP-43 (FTLD-TDP) of type C (TDP-C) is one of the most distinctive examples. TDP-C invariably starts with neurodegeneration (atrophy) confined to the temporopolar regions (TPR). The process is usually asymmetric, causing behavioral abnormalities and associative agnosia when predominantly right-sided, semantic Primary Progressive Aphasia (PPA) when left-sided, and semantic dementia when bilateral. In this study, we investigated the relationship between atrophy progression and the progressive dissolution of word comprehension in TDP-C patients with asymmetric left TPR degeneration. For the sake of homogeneity, and in order to use a common yardstick of functional progression, we focused on patients with leftward asymmetry and initially isolated verbal impairment. Using data from 24 visits with structural MRI scans and specialized tests of naming, word definition, and word-to-picture matching, we stratified the anatomy of peak degeneration sites according to three increasingly more advanced stages of impaired noun representations. According to this pattern of progression, an initial stage of relatively isolated anomia is followed by additional intra-category blurring of word meaning and, at still more advanced stages, inter-category blurring. Voxel Based Morphometry (VBM) maps of gray matter volume were binarized to identify regions most frequently atrophied at each of these stages. Results illustrate that the progressive dissolution of word meaning is associated with caudal progression of atrophy from the left temporopolar cortex at initial stages to more posterior fusiform, lateral temporal and temporooccipital regions in later stages. The stratification of progressive atrophy by precisely characterized stages of word comprehension impairment, rather than by estimated time of symptom onset, offers a functional rather than just chronological anatomy of progression for TDP-C and a clearer view of the relationship between TPR components and the cognitive mapping of word representations.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"115 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-10-01DOI: 10.1093/brain/awaf366
Inge M W Verberk, Argonde C van Harten, Wiesje M van der Flier
{"title":"Opposing views or like-minded? International Working Group and Alzheimer’s Association criteria","authors":"Inge M W Verberk, Argonde C van Harten, Wiesje M van der Flier","doi":"10.1093/brain/awaf366","DOIUrl":"https://doi.org/10.1093/brain/awaf366","url":null,"abstract":"The 2024 AA and IWG diagnostic criteria for Alzheimer’s disease differ in their classification of asymptomatic individuals. Verberk et al. argue, however, that their shared requirement for biomarker use in diagnosis means they are now largely aligned, marking a pivotal step towards precision medicine in dementia care.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"72 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis.","authors":"Paolo Vincenzo Fioretti,Anna Barbieri,Alice Migazzi,Davide Bressan,Maurizio Grassano,Luisa Donini,Michela Roccuzzo,Maria Claudia Torrieri,Francesca Conci,Elisa Ferracci,Sabrina Invernizzi,Katie M Bowden,Francesca Bacchetti,Sara Cappelli,Daniele Peroni,Romina Belli,Michael Pancher,Vera Mugoni,Giorgina Scarduelli,Matteo Gianesello,Laura Pasetto,Giulia Canarutto,Serena Carra,Alessia Soldano,Alessandra Bisio,Sergio Robbiati,Chiara Valentini,Caterina Nardella,Silvano Piazza,Vito Giuseppe D'Agostino,Alessandro Quattrone,Sama Sleiman,Jonathan R Whitfield,Laura Soucek,Beatrice Vignoli,Gabriella Viero,Luca Tiberi,Alessio Zippo,Francesca Demichelis,Valentina Bonetto,Marco Milanese,Emanuele Buratti,Federico Verde,Nicola Ticozzi,Andrea Calvo,Antonia Ratti,Pamela J Shaw,Marco Terenzio,Fulvio Chiacchiera,Maria Pennuto,Manuela Basso","doi":"10.1093/brain/awaf360","DOIUrl":"https://doi.org/10.1093/brain/awaf360","url":null,"abstract":"Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice, and patient-derived cells modeling TDP-43, SOD1, and C9orf72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioral abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived EVs that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"320 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-09-25DOI: 10.1093/brain/awaf355
Tue G Banke,Michael C Regan,Riley E Perszyk,Lu Zhang,Hao Xing,Jiahui Chen,Sehoon Won,Noriko Simorowski,Eva S Diaz,Sukhan Kim,Rui Song,Jian Rong,Xin Zhou,Ahmad F Chaudhary,Jing Zhang,John F Traynelis,Ellington D McDaniels,Karolina Nitsche,Steve Roache,Christopher S Raymond,Chian-Ming Low,Scott J Myers,Katherine W Roche,Steven H Liang,Stephen F Traynelis,Hiro Furukawa,Hongjie Yuan
{"title":"Inhibition of GluN2B-containing N-methyl-d-aspartate receptors by radiprodil.","authors":"Tue G Banke,Michael C Regan,Riley E Perszyk,Lu Zhang,Hao Xing,Jiahui Chen,Sehoon Won,Noriko Simorowski,Eva S Diaz,Sukhan Kim,Rui Song,Jian Rong,Xin Zhou,Ahmad F Chaudhary,Jing Zhang,John F Traynelis,Ellington D McDaniels,Karolina Nitsche,Steve Roache,Christopher S Raymond,Chian-Ming Low,Scott J Myers,Katherine W Roche,Steven H Liang,Stephen F Traynelis,Hiro Furukawa,Hongjie Yuan","doi":"10.1093/brain/awaf355","DOIUrl":"https://doi.org/10.1093/brain/awaf355","url":null,"abstract":"N-methyl-D-aspartate receptors mediate a slow, Ca2+ permeable component of excitatory synaptic transmission in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetrameric assemblies of two GluN1 and two GluN2 subunits encoded by five genes (GRIN1, GRIN2A-D), which produce GluN1 and GluN2A-D subunits. NMDA receptors that contain the GluN2B subunit have unique pharmacological properties, being inhibited by multiple structurally distinct series of biaryl compounds with high potency and selectivity. These agents are of considerable therapeutic interest, given the numerous roles that GluN2B-containing NMDA receptors play in normal brain function and pathological situations. Among GluN2B-selective negative allosteric modulators, radiprodil inhibits NMDA receptors that contain GluN2B with high potency and selectivity and appears to be safe in human. Here, we evaluate the structural determinants of radiprodil binding to the heterodimeric GluN1-GluN2B amino terminal domain by X-ray crystallography and explore the molecular mechanism of inhibition. A large number of de novo variants have been identified in the GRIN gene family in patients with various neurological and neuropsychiatric conditions, including autism, intellectual disability, epilepsy, language disorders, and movement disorders. We show that radiprodil is an effective antagonist at over 80% of human disease-associated GRIN1 and GRIN2B missense variants tested in vitro (22/27, equally or more effective as WT receptors), including variants in the pore-forming region, linker regions, and elsewhere that uniformly increase NMDA receptor-mediated charge transfer. We show radiprodil blocks synaptic GluN2B receptors in brain slices acutely isolated from a knock-in mouse line harboring the gain-of-function variant GluN2B-Ser810Arg associated with early-onset epileptic encephalopathy and intractable seizures in patients. In addition, radiprodil delays the onset of seizures (458 ± 90 sec vs 207 ± 23 sec of vehicle group) in response to the in vivo administration of the chemoconvulsant pentylenetetrazole. These data support the potential utility of GluN2B-selective antagonists like radiprodil for clinical treatments of neurological conditions, where clinical etiologies may involve increased current mediated by GluN2B-containing NMDA receptors.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"11 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BrainPub Date : 2025-09-25DOI: 10.1093/brain/awaf361
Linda Kollenburg,Erkan Kurt,Wim Mulleners,Hisse Arnts,Cristopher Louis Robinson,Janneke Poelen,Kaare Meier,Moises Dominguez,Sait Ashina,Kris Vissers
{"title":"Bridging the gap: molecular mechanisms, regional activity, and connectivity in headache disorders.","authors":"Linda Kollenburg,Erkan Kurt,Wim Mulleners,Hisse Arnts,Cristopher Louis Robinson,Janneke Poelen,Kaare Meier,Moises Dominguez,Sait Ashina,Kris Vissers","doi":"10.1093/brain/awaf361","DOIUrl":"https://doi.org/10.1093/brain/awaf361","url":null,"abstract":"Chronic headache disorders have a tremendous impact on psychosocial functioning. Despite the availability of various treatment options, suboptimal management remains present in a subset of patients, leading to persistent suffering. Molecular mechanisms, regional activity patterns, and connectivity pathways are crucial for understanding the pathophysiology, serving as a foundation for developing novel treatments, refining existing therapies, and ultimately optimizing the management of headache disorders. Nevertheless, articles combining fundamental and clinical aspects of the pathophysiology and treatment of headache disorders remain limited. The current literature review provides a thorough overview of the molecular mechanisms, regional activity patterns and connectivity pathways involved in migraine, cluster headache (CH), paroxysmal hemicrania (PH), hemicrania continua (HC) and occipital neuralgia (ON), thereby bridging the gap between different fields of expertise. In this scoping review, literature on molecular mechanisms, regional activity and connectivity pathways for migraine, CH, PH, HC and ON has been collected from the PubMed, MEDLINE and EMBASE databases. Reports were also manually searched using the search function in Google Scholar, as well as reviews or references cited within the articles. In total, 130 and 97 articles, published between 1976-2024, are included in the analysis of the molecular mechanism and regional activity patterns/connectivity pathways respectively. Molecular data show that the trigeminal nucleus caudalis (TNC) is a central structure in headache pathology, comprising various neuropeptides and neurochemicals including VIP, glutamate, substance P and serotonin, and connecting the pathophysiology of these headache disorders. Sensitization of higher cortical brain areas, neuroinflammation within the trigeminal system and vasodilatation of cranial vessels seem to contribute to headache pain. Headache disorders are also associated with atypical regional activity patterns and connectivity pathways in pain processing areas, as well as the default mode network, salience network, and sensorimotor network. These abnormalities help explain the mechanisms underlying overall headache-related symptoms and additional manifestations unique to each headache disorder, including cortical spreading depression in migraine, rhythmicity of attacks in CH, and autonomic symptoms in CH, PH and HC. The current article fosters a deeper understanding of the molecular mechanisms, neuronal pathways and clinical symptoms involved in headache pathology across different fields of expertise. By bridging these perspectives, it provides essential insights for developing innovative treatment strategies and enhancing existing therapeutic options.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"41 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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