Brain最新文献

{"title":"Correction to: Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.","authors":"","doi":"10.1093/brain/awae285","DOIUrl":"https://doi.org/10.1093/brain/awae285","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233418","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":"Decision cost hypersensitivity underlies Huntington’s disease apathy","authors":"Lee-Anne Morris, Kyla-Louise Horne, Sanjay Manohar, Laura Paermentier, Christina Buchanan, Michael MacAskill, Daniel Myall, Matthew Apps, Richard Roxburgh, Tim Anderson, Masud Husain, Campbell Le Heron","doi":"10.1093/brain/awae296","DOIUrl":"https://doi.org/10.1093/brain/awae296","url":null,"abstract":"The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington’s disease (HD). However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to utilise a theoretical framework of normal motivated behaviour, to determine where breakdown has occurred in people with this behavioural disruption. A fundamental computation underlying motivated, goal-directed behaviour across species is weighing up the costs and rewards associated with actions. Here, we asked whether people with apathy are more sensitive to costs of actions (physical effort and time delay), less sensitive to rewarding outcomes, or both. Based on the unique anatomical substrates associated with HD pathology, we hypothesised that a general hypersensitivity to costs would underpin HD apathy. Genetically confirmed carriers of the expanded Huntingtin gene (premanifest to mild motor manifest disease (n=53) were compared to healthy controls (n = 38). Participants performed a physical effort-based decision-making task (Apple Gathering Task) and a delay discounting task (Money Choice Questionnaire). Choice data was analysed using linear regression and drift diffusion models that also accounted for the time taken to make decisions. Apathetic people with HD accepted fewer offers overall on the Apple Gathering Task, specifically driven by increased sensitivity to physical effort costs, and not explained by motor severity, mood, cognition, or medication. Drift diffusion modelling provided further evidence of effort hypersensitivity, with apathy associated with a faster drift rate towards rejecting offers as a function of varying effort. Increased delay sensitivity was also associated with apathy, both when analysing raw choice and also drift rate, where there was moderate evidence of HD apathy drifting faster towards the immediately available (low cost) option. Furthermore, the effort and delay sensitivity parameters from these tasks were positively correlated. The results demonstrate a clear mechanism for apathy in HD, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that HD pathology may cause a domain-general disruption of cost processing, which is distinct to apathy occurrence in other brain disorders, and may require different therapeutic approaches.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231348","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":"Inside out: the neural basis of spontaneous and creative thinking","authors":"Alizée Lopez-Persem, Emmanuel Mandonnet, Emmanuelle Volle","doi":"10.1093/brain/awae294","DOIUrl":"https://doi.org/10.1093/brain/awae294","url":null,"abstract":"This scientific commentary refers to ‘Default mode network electrophysiological dynamics and causal role in creative thinking’ by Bartoli et al. (https://doi.org/10.1093/brain/awae199).","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233419","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":"Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer’s disease trials","authors":"Jesus Abanto, Alok K Dwivedi, Bruno P Imbimbo, Alberto J Espay","doi":"10.1093/brain/awae216","DOIUrl":"https://doi.org/10.1093/brain/awae216","url":null,"abstract":"Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer’s disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer’s Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: −0.55; 95% CI: −0.89, −0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: −0.16; 95% CI: −0.26, −0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ–PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170760","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":"Piezo2 channels and tactile pain: an intriguing voltage connection","authors":"Jorge Fernández-Trillo, Ana Gomis, Félix Viana","doi":"10.1093/brain/awae290","DOIUrl":"https://doi.org/10.1093/brain/awae290","url":null,"abstract":"This scientific commentary refers to ‘Piezo2 voltage-block regulates mechanical pain sensitivity’ by Sánchez-Carranza et al. (https://doi.org/10.1093/brain/awae227).","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170761","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":"Visual hallucinations in Parkinson's disease: spotlight on central cholinergic dysfunction.","authors":"Anna Ignatavicius,Elie Matar,Simon J G Lewis","doi":"10.1093/brain/awae289","DOIUrl":"https://doi.org/10.1093/brain/awae289","url":null,"abstract":"Visual hallucinations are a common non-motor feature of Parkinson's disease and have been associated with accelerated cognitive decline, increased mortality and early institutionalisation. Despite their prevalence and negative impact on patient outcomes, the repertoire of treatments aimed at addressing this troubling symptom is limited. Over the last two decades, significant contributions have been made in uncovering the pathological and functional mechanisms of visual hallucinations, bringing us closer to the development of a comprehensive neurobiological framework. Convergent evidence now suggests that degeneration within the central cholinergic system may play a significant role in the genesis and progression of visual hallucinations. Here, we outline how cholinergic dysfunction may serve as a potential unifying neurobiological substrate underlying the multifactorial and dynamic nature of visual hallucinations. Drawing upon previous theoretical models, we explore the impact that alterations in cholinergic neurotransmission has on the core cognitive processes pertinent to abnormal perceptual experiences. We conclude by highlighting that a deeper understanding of cholinergic neurobiology and individual pathophysiology may help to improve established and emerging treatment strategies for the management of visual hallucinations and psychotic symptoms in Parkinson's disease.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165966","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":"An algorithm for drug-resistant epilepsy in Danish national registers","authors":"Eva Bølling-Ladegaard, Julie W Dreier, Jakob Christensen","doi":"10.1093/brain/awae286","DOIUrl":"https://doi.org/10.1093/brain/awae286","url":null,"abstract":"Patients with drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. Identification of persons with DRE in administrative data can allow for effective large-scale research, and we therefore aimed to construct an algorithm for identification of DRE in Danish nation-wide health registers. We used a previously generated sample of 525 persons with medical record-validated incident epilepsy between 2010-2019, of which 80 (15%) fulfilled International League Against Epilepsy (ILAE) criteria of DRE at the time of the latest contact – this cohort was considered the gold standard. We linked information in the validated cohort to Danish national health registers and constructed register-based algorithms for identification of DRE-cases. The accuracy of each algorithm was validated against the medical record-validated gold standard. We applied the best performing algorithm according to test accuracy (F1 score) to a large cohort with incident epilepsy identified in the Danish National Patient Registry between 1995 and 2013 and performed descriptive and logistic regression analyses to characterize the cohort with DRE as identified by the algorithm. The best performing algorithm in terms of F1 score was defined as ‘fillings of prescriptions for ≥ 3 distinct antiseizure medications (ASMs) within 3 years or acute hospital visit with epilepsy/convulsions following fillings of prescriptions for two distinct ASMs’ (sensitivity 0.59, specificity 0.93, positive predictive value 0.59, negative predictive value 0.92, area under the receiver operating characteristic curve 0.77, and F1 score 0.595). Applying the algorithm to a register-based cohort of 83,682 individuals with incident epilepsy yielded 8,650 cases (10.3 %) with DRE. In multivariable logistic regression analysis, early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse, were independently associated with risk of being classified with DRE. We developed an algorithm for the identification of DRE in Danish national registers, which can be applied for a variety of research questions. We identified early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse as risk factors for DRE.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166647","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":"Intracerebral delivery of antiseizure medications by microinvasive neural implants.","authors":"Hannah D Jackson, Max J Cotler, Gerald W Saunders, Carena A Cornelssen, Peter J West, Cameron S Metcalf, Karen S Wilcox, Michael J Cima","doi":"10.1093/brain/awae282","DOIUrl":"https://doi.org/10.1093/brain/awae282","url":null,"abstract":"<p><p>Focal epilepsy is a difficult disease to treat as two-thirds of patients will not respond to oral antiseizure medications (ASMs) or have severe off-target effects that lead to drug discontinuation. Current non-pharmaceutical treatment methods (resection or ablation) are underutilized due to the associated morbidities, invasive nature, and inaccessibility of seizure foci. Less invasive non-ablative modalities may potentially offer an alternative. Targeting the seizure focus in this way may avoid unassociated critical brain structures to preserve function and alleviate seizure burden. Here we report use of an implantable, miniaturized neural drug delivery system [Microinvasive neural implant infusion platform (MINI)] to administer antiseizure medications (ASMs) directly to the seizure focus in a mouse model of temporal lobe epilepsy. We examined the effect local delivery of phenobarbital (PB) and valproate (VPA) had on focal seizures, as well as adverse effects, and compared this to systemic delivery. We show that local delivery of PB and VPA using our chronic implants significantly reduced focal seizures at all doses given. Furthermore, we show that local delivery of these compounds resulted in no adverse effects to motor function, whereas systemic delivery resulted in significant motor impairment. The results of this study demonstrate the potential of ASM micro dosing to the epileptic focus as a treatment option for people with drug resistant epilepsy. This technology could also be applied to a variety of disease states, enabling a deeper understanding of focal drug delivery in the treatment of neurological disorders.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143023","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":"Iatrogenic harm in functional neurological disorder.","authors":"Caoimhe Mcloughlin, Wei Hao Lee, Alan Carson, Jon Stone","doi":"10.1093/brain/awae283","DOIUrl":"https://doi.org/10.1093/brain/awae283","url":null,"abstract":"<p><p>Functional Neurological Disorder (FND) is continuing to gain increasing recognition globally as a valid and potentially treatable disorder. Iatrogenic harm towards patients with FND is significant however, and has been around for centuries. Despite advances in our understanding around the aetiology, pathophysiology, and treatment of FND, many aspects of such harm continue to persist. Avoidance of iatrogenic harm has been highlighted by clinicians as one of the most important therapeutic considerations in FND, however, the sources and range of potential harms, or indeed ways to mitigate them, have not been previously summarised. Using a combination of clinical and research experience and scoping review methodology, this review aims to describe the main sources of iatrogenic harm towards patients with FND, including harm from misdiagnosis, delayed diagnosis and treatment, direct harm from professional interactions, other stigma-related harms, harm related to diagnostic overshadowing and over-diagnosis of FND. We also describe some potential ways to address and prevent such harms, such as ways to reduce misdiagnosis with a focus on rule in signs, optimising teaching and communication, ensuring parity of FND with other medical conditions, and continued integration of patient and professional organisations.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143022","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":"Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis.","authors":"Rachel J Sharkey, Filomeno Cortese, Bradley G Goodyear, Lawrence W Korngut, Sarah M Jacob, Keith A Sharkey, Sanjay Kalra, Minh Dang Nguyen, Richard Frayne, Gerald Pfeffer","doi":"10.1093/brain/awae288","DOIUrl":"https://doi.org/10.1093/brain/awae288","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central in the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we perform a longitudinal analysis of glymphatic function in ALS and compare it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analyzed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate), and white matter hyperintensity (WMH) burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared to PLS and control participants across all three time points. There was no association with clinical factors, however the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143024","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}