Brain最新文献

{"title":"Reply: Critical considerations on neural mediators of dual-task gait and dementia risk in mild cognitive impairment.","authors":"Pauline Ali, Cédric Annweiler, Frederico Pieruccini-Faria, Robert Bartha, Manuel Montero-Odasso","doi":"10.1093/brain/awaf247","DOIUrl":"https://doi.org/10.1093/brain/awaf247","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559050","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":"Critical considerations on neural mediators of dual-task gait and dementia risk in mild cognitive impairment.","authors":"Zhouli Shao, Peng Sun","doi":"10.1093/brain/awaf246","DOIUrl":"https://doi.org/10.1093/brain/awaf246","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559128","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":"Brain health concerns in former rugby players: clinical and cognitive phenotypes","authors":"Thomas D Parker, Jessica A Hain, Erin J Rooney, Karl A Zimmerman, Ying Lee, Martina Del Giovane, Neil S N Graham, Maneesh Patel, Adam Hampshire, Mathew G Wilson, Daniel Friedland, David J Sharp, Richard J Sylvester","doi":"10.1093/brain/awae416","DOIUrl":"https://doi.org/10.1093/brain/awae416","url":null,"abstract":"Epidemiological studies have shown that elite rugby players are at greater risk of neurodegenerative disease in later life, with post-mortem studies conducted in ex-players demonstrating the presence of neuropathologies related to repetitive head impacts, such as chronic traumatic encephalopathy. However, detailed prospective data establishing the clinical presentation of former rugby players with brain health concerns are lacking. In particular, the rates of traumatic encephalopathy syndrome, the clinical correlate of chronic traumatic encephalopathy, and the relationship between clinical outcomes and repetitive head impacts are unknown. Two hundred former elite rugby players with brain health concerns and 33 matched healthy control subjects were assessed. Self-reported concussion history, career duration, player position, self-rated scales of depression, anxiety, sleep quality, post-concussion symptoms and quality of life, self and informant ratings of neuropsychiatric symptoms and executive function behaviours, were obtained. Formal cognitive testing, traumatic encephalopathy syndrome classification and 3 T MRI were performed. Former players had a median age of 44 years (90.5% male, median career length = 10.5 years, median self-reported career concussions = 7); 63% were forwards and 37% were backs. Ex-players had elevated scores compared to controls on all symptom scales except sleep quality. Despite frequent subjective memory complaints, performance on cognitive testing did not significantly differ from controls. No players fulfilled criteria for dementia. Twenty-four former players fulfilled research criteria for traumatic encephalopathy syndrome (seven with cognitive impairment, 12 with neurobehavioral dysregulation, five with both). Provisional levels of certainty for chronic traumatic encephalopathy were relatively low (21 ‘suggestive’, three ‘possible’, zero ‘probable/definite’). Forwards and those with higher self-reported concussions were more likely to be classified as having traumatic encephalopathy syndrome based on neurobehavioral disturbance. Symptom burden (depressive and anxiety symptoms, post-concussion symptoms, behaviour rating of executive dysfunction, and neuropsychiatric symptom severity) was higher in those with higher self-reported concussions but was unrelated to years of play or position played. Cavum septum pellucidum was visible on structural imaging in 24% of players (12% in controls) and was more common in the high compared to low concussion group (32% versus 16%). In summary, former elite rugby players in mid-life had significant symptom burden, especially those self-reporting more concussions. In contrast, objective cognitive impairments and traumatic encephalopathy syndrome were relatively uncommon and there was no evidence of dementia. These results provide insights into the clinical presentations of former elite rugby players with brain health concerns during mid-life and highlight the complex relationship be","PeriodicalId":9063,"journal":{"name":"Brain","volume":"13 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546937","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":"Exon skipping peptide-conjugated morpholinos downregulate dynamin 2 to rescue centronuclear myopathy.","authors":"Foteini Moschovaki-Filippidou, Juliana de Carvalho Neves, Nadège Diedhiou, Yahya Jad, Johann Böhm, Matthew J A Wood, Miguel A Varela, Jocelyn Laporte","doi":"10.1093/brain/awaf249","DOIUrl":"https://doi.org/10.1093/brain/awaf249","url":null,"abstract":"<p><p>Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and disorganization of myofibers. These conditions can result from dominant mutations in the DNM2 gene encoding the GTPase dynamin, making them potential targets for antisense therapy. Preclinical studies suggested decreasing DNM2 as a therapy but a recent clinical trial with antisense oligonucleotides did not effectively address the disease and showed some non-muscle toxicity. Here, to promote DNM2 downregulation in muscle versus other tissues, we used an exon skipping peptide-conjugated phosphorodiamidate morpholino (PPMO) targeting Dnm2 exon 6 splicing in the Dnm2R369W/+ mouse model for the moderate CNM form. PPMOs intravenous administration at early age (4 weeks) significantly downregulated intact (i.e. normally spliced) Dnm2 mRNA (∼50%) and DNM2 protein levels in muscle. This intervention led to a rescue of muscle force, thereby preventing disease progression. PPMO administration at a later age (8 weeks), when mice demonstrated established phenotypes, efficiently decreased intact Dnm2 mRNA and protein levels in muscle, resulting in reversal of the disease phenotype and significant improvement in muscle force (from 11 mN/mg to nearly 16 mN/mg). Overall, our results indicate that PPMOs targeting Dnm2 splicing effectively decrease intact Dnm2 mRNA and protein levels in muscle and rescue muscle force in Dnm2R369W/+ mice, suggesting a promising translational approach for patients with DNM2 mutations and potentially other forms of CNM. More generally, it provides the concept of using the exon skipping strategy to decrease the protein expression of a target gene, rather than producing a shorter functional protein as is generally done.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559048","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":"Beyond resistance: early surgery for focal epilepsy","authors":"Felix Benninger, Ilan Goldberg","doi":"10.1093/brain/awaf250","DOIUrl":"https://doi.org/10.1093/brain/awaf250","url":null,"abstract":"Benninger and Goldberg argue that early surgery for lesional focal epilepsy should be considered even before the emergence of drug resistance. They note that despite seizure control, long-term use of anti-seizure medications carries health and social burdens, while modern surgery is safe, effective, and often curative.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"6 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547184","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":"Biomarker evidence of neurodegeneration in mid-life former rugby players","authors":"Neil S N Graham, Karl A Zimmerman, Jessica Hain, Erin Rooney, Ying Lee, Martina Del Giovane, Thomas Parker, Mathew G Wilson, Paresh Malhotra, Michael C B David, Magdalena Kolanko, Maneesh Patel, Elena Veleva, Owen Swann, Amanda Heslegrave, Henrik Zetterberg, Daniel Friedland, Richard Sylvester, David J Sharp","doi":"10.1093/brain/awaf152","DOIUrl":"https://doi.org/10.1093/brain/awaf152","url":null,"abstract":"Repetitive head impacts and traumatic brain injuries in contact sports, such as rugby union, are associated with increased risk of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. Advances in fluid and imaging biomarkers are transforming dementia diagnosis but have not been systematically applied to individuals previously exposed to head impacts during rugby participation. We used biomarkers, including those with sensitivity and specificity for early Alzheimer's pathology to explore neurodegenerative risk in mid-life elite retired rugby players with significant repetitive head impact exposure. Plasma neurofilament light, glial fibrillary acid protein, amyloid-β (Aβ)42, Aβ40 and phospho-tau217 were quantified using ultrasensitive single molecule array digital enzyme-linked immunosorbent assay (SiMoA) in former elite rugby players as well as age/sex-matched unexposed controls. 3 T MRI and neuropsychology assessments were performed, with National Institute for Neurological Disorders and Stroke criteria used to ascertain the presence of traumatic encephalopathy syndrome. Regression models were used to relate plasma/imaging biomarkers to clinical phenotype. Individual-levels analyses were performed for fluid and imaging metrics, based on control biomarker distributions. Biomarker data from two aligned un-exposed Alzheimer's cohorts were included to contextualize our findings. Two hundred ex-rugby players (median age 44 years, 90% males) and 33 unexposed controls were assessed. Twenty-four (12%) ex-players fulfilled criteria for traumatic encephalopathy syndrome but none had dementia. Plasma phospho-tau217 concentrations were 17.6% higher in ex-rugby players than controls (95% confidence interval 3.7–33.3, P = 0.047). A total of 46 (23.1%) ex-players had elevated phospho-tau217 at the individual level; as did 18 (9.0%) players in relation to raised plasma neurofilament light. Ex-players’ concentrations were lower than in unexposed adults with late onset Alzheimer's disease (n = 69). Ex-players also showed significantly reduced volumes in the frontal/cingulate cortex on voxel-based morphometry at the group level; with reduced white matter and lower hippocampal volume associated with longer career durations within ex-players. Trauma-associated white matter changes measured with diffusion tensor imaging were uncommon in ex-players (4.6%). Traumatic encephalopathy syndrome was significantly more common in ex-players with elevated phospho-tau217, while those with raised plasma neurofilament light had significantly more anxiety and depressive symptoms. Frontal brain volumes correlated negatively with neurofilament light (r = −0.21, P = 0.010), and hippocampal volumes correlated negatively with phospho-tau217 (r = −0.19, P = 0.024). Elite rugby participation is associated with abnormal fluid and neuroimaging neurodegeneration biomarkers in mid-life. These include elevated phospho-tau217, which may indicate amyloid-d","PeriodicalId":9063,"journal":{"name":"Brain","volume":"46 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546938","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":"Males but not females report genital sensations evoked by fixed-parameter stimulation of somatosensory cortex.","authors":"Sandra Proelss, Mehmed Tuncer, Christine Heim, John-Dylan Haynes, Peter Vaikoczy, Michael Brecht, Katharina Faust","doi":"10.1093/brain/awaf240","DOIUrl":"https://doi.org/10.1093/brain/awaf240","url":null,"abstract":"<p><p>The localisation of the human genital cortex has been debated since its unusual placement in Penfield's somatosensory homunculus. While male and female genitalia are different, it remains unclear how these external differences are mapped onto the male and female brain. We investigated genital representation in the human somatosensory cortex by patient-report of sensations evoked by fixed parameter electrical stimulation during awake craniotomies. We find a reproducible genital representation in male subjects (n = 3) at the somatotopically appropriate location between the legs situated in the dorsal postcentral gyrus and sulcus. Our findings contradict early stimulation-maps derived by Penfield and colleagues, which indicated an absence of genital responses in this brain region, but align with more recent imaging data from males and females that described blood-flow responses to genital stimulation at these coordinates. Surprisingly, however, we find no evidence for stimulation-evoked genital sensations in the postcentral gyrus and sulcus of females (n = 5) in line with Penfield's earlier conclusions. Specifically, females reported no genital sensations, but often leg sensations, when stimulated at the putative coordinates of female genital cortex. We conclude that reports of genital sensations differ between male and female somatosensory cortex upon stimulation. Our observations add to the growing evidence that genital representations differ between males and females.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559049","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":"Endosomal 2Cl-/H+ exchangers regulate neuronal excitability by tuning Kv7/KCNQ channel density.","authors":"Guanxiao Qi,Alberto Diaz-Castillo,Christoph Aretzweiler,Lilly Steinmetz,Stefanie Bungert-Plümke,Frank Müller,Dirk Feldmeyer,Raul E Guzman","doi":"10.1093/brain/awaf243","DOIUrl":"https://doi.org/10.1093/brain/awaf243","url":null,"abstract":"CLCN3 and CLCN4 encode the endosomal 2Cl-/H+ exchangers ClC-3 and ClC-4, which are highly expressed within the central nervous system, including hippocampal formation. Pathogenic variants recently found in these genes have given rise to the rare CLCN3- and CLCN4-neurodevelopmental conditions, characterised by a range of neurological and neuropsychiatric complications, such as global developmental delay, intellectual disability as a core feature, seizures, behavioural issues, and brain abnormalities. The mechanisms by which ClC-3 and ClC-4 regulate neuronal function and viability, as well as the molecular pathways affected in CLCN3- and CLCN4-related neurodevelopmental conditions, remain unknown. In neurodegenerative diseases, neuronal dendrites undergo pathological changes often associated with aberrant electrical activity. To investigate how ClC-3 or ClC-4 deficit alters neuronal excitability and morphology, we combined patch-clamp recordings in acute hippocampal slice preparations with simultaneous intracellular biocytin filling. We analysed the functional and structural properties of Clcn3-/- and Clcn4-/- neurons. Two firing patterns are found in the hippocampus's Cornu Ammonis 2 (CA2) region: regular and burst firing. At post-natal day 13 (P13), 62% of the assessed CA2 wild-type neurons showed a rhythmic bursting behaviour; this was reduced to 19% in Clcn4-/- and completely absent in the Clcn3-/- condition. Changes in the firing patterns were accompanied by a depolarising shift in the action potential threshold and an increase in the afterhyperpolarizing phase of the action potentials. Blockade of Kv7/KCNQ, and to a lesser extent Kv1, but not BK, SK or Kv2 channels, recapitulates the wild-type firing pattern phenotype in the Clcn3-/- condition. Moreover, we detected abnormalities in the complexity of the dendritic arborisation. Branching and lengths of apical and basal domains were significantly reduced in the Clcn3-/- and moderately altered in the Clcn4-/- neurons. At P3, we found 25% of bursting neurons in Clcn3-/- with no significant morphological abnormalities in the dendritic arborisation compared to the wild-type, suggesting that functional defects precede structural changes in Cl-/H+ exchangers-deficient neurons. Similarly, dentate granule cells exhibited defective action potential properties and reduced burst-firing activity, which was substantially, but not fully rescued by Kv7/KCNQ blockage. We conclude that Cl-/H+ exchangers regulate neurons' electrical excitability and firing patterns primarily by fine-tuning Kv7/KCNQ channel density, and that functional defects might contribute to alterations in dendritic morphology. Our findings provide new insights into the underlying molecular mechanisms of Cl-/H+ exchangers in neurons and pave the way toward potential therapeutic interventions for CLCN3- and CLCN4-related patients associated with disruption of Cl-/H+ exchange function.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"41 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547905","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":"The cognitive neuroscience of ketamine in major depression","authors":"Sara Costi, Chloe Wigg, Erdem Pulcu, Susannah E Murphy, Catherine J Harmer","doi":"10.1093/brain/awaf242","DOIUrl":"https://doi.org/10.1093/brain/awaf242","url":null,"abstract":"Ketamine's potential as a rapid-acting antidepressant was first identified in 2000, despite its long-standing use as an anesthetic agent. Clinically, ketamine alleviates depressive symptoms, including the difficult to treat symptom of anhedonia, within hours, with the effects of a single dose lasting for days. Since then, research has focused on uncovering the mechanisms underlying its rapid antidepressant effects in both humans and animal models. While its molecular and cellular effects have been extensively characterized, its impact on cognitive and neuropsychological mechanisms - potential mediators of its clinical efficacy - remains an area of ongoing investigation. Preclinical studies suggest that ketamine rapidly influences the lateral habenula (involved in punishment processing) and fronto-striatal (reward) systems, reverses negative affective biases in established memories, and promotes long-term stress resilience. Translating these findings to human models is crucial, and emerging evidence suggests that ketamine engages similar mechanisms in healthy volunteer and patient groups. However, its clinical application is constrained by acute side effects and an unknown long-term safety profile. Further research into ketamine’s mechanisms of action will be essential to inform the development of novel, safer, and more accessible rapid-acting antidepressants.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"15 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516020","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":"Intronic VNTRs downregulate expression of HSF1 and confer genetic risk of essential tremor","authors":"Hongyan Bi, Yalan Wan, Rongrong Zhao, Shirang Pan, Mingyue Luan, Wei Wu, Yusen Qiu, Jiaxi Yu, Yunchuang Sun, Luhua Wei, Jing Chen, Fan Li, Wei Sun, Lin Wang, Xue Wang, Wenlu Zhao, Depeng Wang, Houzhen Tuo, Yongbo Zhang, Wei Zhang, Yining Huang, Yun Yuan, Daojun Hong, Zhaoxia Wang, Jianwen Deng","doi":"10.1093/brain/awaf241","DOIUrl":"https://doi.org/10.1093/brain/awaf241","url":null,"abstract":"Essential tremor (ET) is a highly prevalent movement disorder characterized by high heritability. However, the genetic basis of this disease remains largely unknown. Understanding the genetic causes of ET is crucial for unraveling its pathogenesis and developing targeted therapies. In this study, we aimed to investigate tandem repeats in a Chinese cohort of ET pedigrees. To explore the genetic causes of ET, we enrolled 165 Chinese ET pedigrees and performed whole-exome sequencing (WES) as well as long-read sequencing (LRS) within this cohort. Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analyses were employed to assess HSF1 expression levels. Transgenic Drosophila model and induced pluripotent stem cells (iPSCs) were constructed to investigate the pathogenic role of HSF1 in ET. Our study identified the expanded variable number of tandem repeats (VNTRs) in intron 10 of HSF1. LRS revealed two repeat configurations consisting of CCCCGCNCCGCCT and CCNCGCCT in this VNTR loci. Expanded VNTRs alleles were highly enriched in ET affected individuals, and VNTRs length was positively correlated with disease severity. We found the intronic repeat expansions downregulated HSF1 expression in affected individuals, indicating its loss-of-function in ET. Consistently, RNAi knockdown of HSF1 homolog in Drosophila led to leg and head shaking and age-dependent movement deficits, recapitulating the ET phenotype in fly model. iPSCs derived from the ET affected individual carrying expanded VNTRs in the HSF1 gene exhibited significantly reduced expression of HSF1 compared to control iPSCs. Bulk RNA-sequencing analysis of these iPSCs revealed that diminished HSF1 expression resulted in the downregulation of genes associated with GABAergic synapse function. In conclusion, our study suggests that impaired GABAergic signaling may play a critical role in the pathogenesis of HSF1-related ET. These findings provide new information on the etiology of ET and highlight the role of HSF1 in human genetic disorder.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"195 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513173","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}