Pub Date : 2023-11-03DOI: 10.1093/braincomms/fcad306
Mickael Audrain, Anne-Laure Egesipe, Noémie Tentillier, Laure Font, Monisha Ratnam, Lorene Mottier, Mathieu Clavel, Morgan Le Roux-Bourdieu, Alexis Fenyi, Romain Ollier, Elodie Chevalier, Florence Guilhot, Aline Fuchs, Kasia Piorkowska, Becky Carlyle, Steven E Arnold, James D Berry, Ruth Luthi-Carter, Oskar Adolfsson, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina, Tariq Afroz
Abstract In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of pharmacokinetics/pharmacodynamic effect for monoclonal antibody, ACI-5891.9 in vivo and in vitro confirmed that a CSF concentration of ≈ 1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.
{"title":"Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in cerebrospinal fluid","authors":"Mickael Audrain, Anne-Laure Egesipe, Noémie Tentillier, Laure Font, Monisha Ratnam, Lorene Mottier, Mathieu Clavel, Morgan Le Roux-Bourdieu, Alexis Fenyi, Romain Ollier, Elodie Chevalier, Florence Guilhot, Aline Fuchs, Kasia Piorkowska, Becky Carlyle, Steven E Arnold, James D Berry, Ruth Luthi-Carter, Oskar Adolfsson, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina, Tariq Afroz","doi":"10.1093/braincomms/fcad306","DOIUrl":"https://doi.org/10.1093/braincomms/fcad306","url":null,"abstract":"Abstract In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of pharmacokinetics/pharmacodynamic effect for monoclonal antibody, ACI-5891.9 in vivo and in vitro confirmed that a CSF concentration of ≈ 1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"39 5-6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135874838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-02DOI: 10.1093/braincomms/fcad304
Grace E Dessert, Brandon J Thio, Warren M Grill
Abstract Stereo-EEG is a minimally invasive technique used to localize the origin of epileptic activity (the epileptogenic zone) in patients with drug-resistant epilepsy. However, current stereo-EEG trajectory planning methods are agnostic to the spatial recording sensitivity of the implanted electrodes. We used image-based patient-specific computational models to design optimized stereo-EEG electrode configurations. Patient-specific optimized electrode configurations exhibited substantially higher recording sensitivity than clinically implanted configurations, and this may lead to more accurate delineation of the epileptogenic zone. The optimized configurations also achieved as good as or better recording sensitivity with fewer electrodes compared to clinically implanted configurations, and this may reduce the risk for complications including intracranial hemorrhage. This approach improves localization of the epileptogenic zone by transforming the clinical use of stereo-EEG from a discrete ad hoc sampling to an intelligent mapping of the regions of interest.
{"title":"Optimization of patient-specific stereo-EEG recording sensitivity","authors":"Grace E Dessert, Brandon J Thio, Warren M Grill","doi":"10.1093/braincomms/fcad304","DOIUrl":"https://doi.org/10.1093/braincomms/fcad304","url":null,"abstract":"Abstract Stereo-EEG is a minimally invasive technique used to localize the origin of epileptic activity (the epileptogenic zone) in patients with drug-resistant epilepsy. However, current stereo-EEG trajectory planning methods are agnostic to the spatial recording sensitivity of the implanted electrodes. We used image-based patient-specific computational models to design optimized stereo-EEG electrode configurations. Patient-specific optimized electrode configurations exhibited substantially higher recording sensitivity than clinically implanted configurations, and this may lead to more accurate delineation of the epileptogenic zone. The optimized configurations also achieved as good as or better recording sensitivity with fewer electrodes compared to clinically implanted configurations, and this may reduce the risk for complications including intracranial hemorrhage. This approach improves localization of the epileptogenic zone by transforming the clinical use of stereo-EEG from a discrete ad hoc sampling to an intelligent mapping of the regions of interest.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"9 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135975789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-31DOI: 10.1093/braincomms/fcad294
Christina Maher, Zihao Tang, Arkiev D’Souza, Mariano Cabezas, Weidong Cai, Michael Barnett, Omid Kavehei, Chenyu Wang, Armin Nikpour
Abstract The application of deep learning models to evaluate connectome data is gaining interest in epilepsy research. Deep learning may be a useful initial tool to partition connectome data into network subsets for further analysis. Few prior works have used deep learning to examine structural connectomes from patients with focal epilepsy. We evaluated whether a deep learning model applied to whole-brain connectomes could classify 28 participants with focal epilepsy from 20 controls and identify nodal importance for each group. Participants with epilepsy were further grouped based on whether they had focal seizures that evolved into bilateral tonic-clonic seizures (17 with, 11 without). The trained neural network classified patients from controls with an accuracy of 72.92%, while the seizure subtype groups achieved a classification accuracy of 67.86%. In the patient subgroups, the nodes and edges deemed important for accurate classification were also clinically relevant, indicating the model’s interpretability. The current work expands the evidence for the potential of deep learning to extract relevant markers from clinical datasets. Our findings offer a rationale for further research interrogating structural connectomes to obtain features that can be biomarkers and aid the diagnosis of seizure subtypes.
{"title":"Deep learning distinguishes connectomes from focal epilepsy patients and controls: feasibility and clinical implications","authors":"Christina Maher, Zihao Tang, Arkiev D’Souza, Mariano Cabezas, Weidong Cai, Michael Barnett, Omid Kavehei, Chenyu Wang, Armin Nikpour","doi":"10.1093/braincomms/fcad294","DOIUrl":"https://doi.org/10.1093/braincomms/fcad294","url":null,"abstract":"Abstract The application of deep learning models to evaluate connectome data is gaining interest in epilepsy research. Deep learning may be a useful initial tool to partition connectome data into network subsets for further analysis. Few prior works have used deep learning to examine structural connectomes from patients with focal epilepsy. We evaluated whether a deep learning model applied to whole-brain connectomes could classify 28 participants with focal epilepsy from 20 controls and identify nodal importance for each group. Participants with epilepsy were further grouped based on whether they had focal seizures that evolved into bilateral tonic-clonic seizures (17 with, 11 without). The trained neural network classified patients from controls with an accuracy of 72.92%, while the seizure subtype groups achieved a classification accuracy of 67.86%. In the patient subgroups, the nodes and edges deemed important for accurate classification were also clinically relevant, indicating the model’s interpretability. The current work expands the evidence for the potential of deep learning to extract relevant markers from clinical datasets. Our findings offer a rationale for further research interrogating structural connectomes to obtain features that can be biomarkers and aid the diagnosis of seizure subtypes.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135976611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-31DOI: 10.1093/braincomms/fcad300
Wen Zhu, Chenyi Chen, Lili Zhang, Tammy Hoyt, Elizabeth Walker, Shruthi Venkatesh, Fujun Zhang, Ferhan Qureshi, John F Foley, Zongqi Xia
Abstract Few studies examined blood biomarkers informative of patient-reported outcome (PRO) of disability in people with multiple sclerosis (MS). We examined the associations between serum multi-protein biomarker profiles and patient-reported disability. In this cross-sectional study (2017-2020), adults with diagnosis of MS (or precursors) from two independent clinic-based cohorts were divided into a training and test set. For predictors, we examined 7 clinical factors (age at sample collection, sex, race/ethnicity, disease subtype, disease duration, disease-modifying therapy [DMT], and time interval between sample collection and closest PRO assessment) and 19 serum protein biomarkers potentially associated with MS disease activity endpoints identified from prior studies. We trained machine learning (ML) models (Least Absolute Shrinkage and Selection Operator [LASSO] regression, Random Forest, Extreme Gradient Boosting, Support-Vector Machines, stacking ensemble learning, and stacking classification) for predicting Patient Determined Disease Steps (PDDS) score as the primary endpoint and reported model performance using the held-out testing set. The study included 431 participants (mean age 49 years, 81% women, 94% non-Hispanic White). For binary PDDS score, combined feature input of routine clinical factors and the 19 proteins consistently outperformed base models (comprising clinical features alone or clinical features plus one single protein at a time) in predicting severe (PDDS ≥ 4) versus mild/moderate (PDDS < 4) disability across multiple ML approaches, with LASSO achieving the best area under the curve (AUCPDDS = 0.91) and other metrics. For ordinal PDDS score, LASSO models comprising combined clinical factors and 19 proteins as feature input (R2PDDS = 0.31) again outperformed base models. The two best-performing LASSO models (i.e., binary and ordinal PDDS) shared 6 clinical features (age, sex, race/ethnicity, disease subtype, disease duration, DMT efficacy) and 9 proteins (cluster of differentiation 6, CUB-domain-containing protein 1, contactin-2, interleukin-12 subunit-beta, neurofilament light chain [NfL], protogenin, serpin family A member 9, tumor necrosis factor superfamily member 13B, versican). By comparison, LASSO models with clinical features plus one single protein at a time as feature input did not select either NfL or glial fibrillary acidic protein (GFAP) as a final feature. Forcing either NfL or GFAP as a single protein feature into models did not improve performance beyond clinical features alone. Stacking classification model using 5 functional pathways to represent multiple proteins as meta-features implicated those involved in neuroaxonal integrity as significant contributors to predictive performance. Thus, serum multi-protein biomarker profiles improve the prediction of real-world MS disability status beyond clinical profile alone or clinical profile plus single protein biomarker, reaching clinically actionable
{"title":"Association between serum multi-protein biomarker profile and real-world disability in multiple sclerosis","authors":"Wen Zhu, Chenyi Chen, Lili Zhang, Tammy Hoyt, Elizabeth Walker, Shruthi Venkatesh, Fujun Zhang, Ferhan Qureshi, John F Foley, Zongqi Xia","doi":"10.1093/braincomms/fcad300","DOIUrl":"https://doi.org/10.1093/braincomms/fcad300","url":null,"abstract":"Abstract Few studies examined blood biomarkers informative of patient-reported outcome (PRO) of disability in people with multiple sclerosis (MS). We examined the associations between serum multi-protein biomarker profiles and patient-reported disability. In this cross-sectional study (2017-2020), adults with diagnosis of MS (or precursors) from two independent clinic-based cohorts were divided into a training and test set. For predictors, we examined 7 clinical factors (age at sample collection, sex, race/ethnicity, disease subtype, disease duration, disease-modifying therapy [DMT], and time interval between sample collection and closest PRO assessment) and 19 serum protein biomarkers potentially associated with MS disease activity endpoints identified from prior studies. We trained machine learning (ML) models (Least Absolute Shrinkage and Selection Operator [LASSO] regression, Random Forest, Extreme Gradient Boosting, Support-Vector Machines, stacking ensemble learning, and stacking classification) for predicting Patient Determined Disease Steps (PDDS) score as the primary endpoint and reported model performance using the held-out testing set. The study included 431 participants (mean age 49 years, 81% women, 94% non-Hispanic White). For binary PDDS score, combined feature input of routine clinical factors and the 19 proteins consistently outperformed base models (comprising clinical features alone or clinical features plus one single protein at a time) in predicting severe (PDDS ≥ 4) versus mild/moderate (PDDS &lt; 4) disability across multiple ML approaches, with LASSO achieving the best area under the curve (AUCPDDS = 0.91) and other metrics. For ordinal PDDS score, LASSO models comprising combined clinical factors and 19 proteins as feature input (R2PDDS = 0.31) again outperformed base models. The two best-performing LASSO models (i.e., binary and ordinal PDDS) shared 6 clinical features (age, sex, race/ethnicity, disease subtype, disease duration, DMT efficacy) and 9 proteins (cluster of differentiation 6, CUB-domain-containing protein 1, contactin-2, interleukin-12 subunit-beta, neurofilament light chain [NfL], protogenin, serpin family A member 9, tumor necrosis factor superfamily member 13B, versican). By comparison, LASSO models with clinical features plus one single protein at a time as feature input did not select either NfL or glial fibrillary acidic protein (GFAP) as a final feature. Forcing either NfL or GFAP as a single protein feature into models did not improve performance beyond clinical features alone. Stacking classification model using 5 functional pathways to represent multiple proteins as meta-features implicated those involved in neuroaxonal integrity as significant contributors to predictive performance. Thus, serum multi-protein biomarker profiles improve the prediction of real-world MS disability status beyond clinical profile alone or clinical profile plus single protein biomarker, reaching clinically actionable","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"164 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135976452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Glioblastoma multiforme represents the most prevalent primary malignant brain tumor, while long non-coding RNA assumes a pivotal role in the pathogenesis and progression of glioblastoma multiforme. Nonetheless, the successful delivery of long non-coding RNA-based therapeutics to the tumor site has encountered significant obstacles attributable to inadequate biocompatibility and inefficient drug delivery systems. In this context, using a biofunctional surface modification of graphene oxide has emerged as a promising strategy to surmount these challenges. Through the change of the graphene oxide surface, enhanced biocompatibility can be achieved, facilitating efficient transport of long non-coding RNA-based therapeutics specifically to the tumor site. This innovative approach presents the opportunity to exploit the therapeutic potential inherent in long non-coding RNA biology for treating glioblastoma multiforme patients. This study aimed to extract relevant genes from The Cancer Genome Atlas database and associate them with long non-coding RNAs to identify Graphene Therapy-related long non-coding RNA. We conducted a series of analyses to achieve this goal, including univariate Cox regression, Least Absolute Shrinkage and Selection Operator regression, and multivariate Cox regression. The resulting Graphene Therapy-related long non-coding RNAs were utilized to develop a risk score model. Subsequently, we conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses on the identified Graphene Therapy-related long non-coding RNAs. Additionally, we employed the risk model to construct the Tumor Microenvironment model and analyze drug sensitivity. To validate our findings, we referenced the IMvigor 210 immunotherapy model. Finally, we investigated differences in the tumor stemness index. Through our investigation, we identified four promising Graphene Therapy-related long non-coding RNAs (AC011405.1, HOXC13-AS, LINC01127, and LINC01574) that could be utilized for the treatment of glioblastoma multiforme patients. Furthermore, we identified 16 compounds that could be utilized in graphene therapy. Our study offers novel insights into treating glioblastoma multiforme, and the identified Graphene Therapy-related long non-coding RNAs and compounds hold promise for further research in this field. Furthermore, conducting additional biological experiments will be essential to validate the clinical significance of our model. These experiments can help confirm the potential therapeutic value and efficacy of the identified Graphene Therapy-related long non-coding RNAs and compounds in treating glioblastoma multiforme.
{"title":"Computational identification of lncRNAs associated with graphene therapy in glioblastoma multiforme","authors":"Zhuoheng Zou, Ming Zhang, Shang Xu, Youzhong Zhang, Junzheng Zhang, Zesong Li, Xiao Zhu","doi":"10.1093/braincomms/fcad293","DOIUrl":"https://doi.org/10.1093/braincomms/fcad293","url":null,"abstract":"Abstract Glioblastoma multiforme represents the most prevalent primary malignant brain tumor, while long non-coding RNA assumes a pivotal role in the pathogenesis and progression of glioblastoma multiforme. Nonetheless, the successful delivery of long non-coding RNA-based therapeutics to the tumor site has encountered significant obstacles attributable to inadequate biocompatibility and inefficient drug delivery systems. In this context, using a biofunctional surface modification of graphene oxide has emerged as a promising strategy to surmount these challenges. Through the change of the graphene oxide surface, enhanced biocompatibility can be achieved, facilitating efficient transport of long non-coding RNA-based therapeutics specifically to the tumor site. This innovative approach presents the opportunity to exploit the therapeutic potential inherent in long non-coding RNA biology for treating glioblastoma multiforme patients. This study aimed to extract relevant genes from The Cancer Genome Atlas database and associate them with long non-coding RNAs to identify Graphene Therapy-related long non-coding RNA. We conducted a series of analyses to achieve this goal, including univariate Cox regression, Least Absolute Shrinkage and Selection Operator regression, and multivariate Cox regression. The resulting Graphene Therapy-related long non-coding RNAs were utilized to develop a risk score model. Subsequently, we conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses on the identified Graphene Therapy-related long non-coding RNAs. Additionally, we employed the risk model to construct the Tumor Microenvironment model and analyze drug sensitivity. To validate our findings, we referenced the IMvigor 210 immunotherapy model. Finally, we investigated differences in the tumor stemness index. Through our investigation, we identified four promising Graphene Therapy-related long non-coding RNAs (AC011405.1, HOXC13-AS, LINC01127, and LINC01574) that could be utilized for the treatment of glioblastoma multiforme patients. Furthermore, we identified 16 compounds that could be utilized in graphene therapy. Our study offers novel insights into treating glioblastoma multiforme, and the identified Graphene Therapy-related long non-coding RNAs and compounds hold promise for further research in this field. Furthermore, conducting additional biological experiments will be essential to validate the clinical significance of our model. These experiments can help confirm the potential therapeutic value and efficacy of the identified Graphene Therapy-related long non-coding RNAs and compounds in treating glioblastoma multiforme.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"29 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134973591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-20DOI: 10.1093/braincomms/fcad283
Chunling Chen, Julie Ziobro, Larissa Robinson-Cooper, Samantha L Hodges, Yan Chen, Nnamdi Edokobi, Luis Lopez-Santiago, Karl Habig, Chloe Moore, Joe Minton, Sabrina Bramson, Caroline Scheuing, Noor Daddo, Katalin Štěrbová, Sarah Weckhuysen, Jack M Parent, Lori L Isom
Abstract Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules, and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C > T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C > T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b-/- mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C > T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared to severely reduced body weight and 100% mortality in Scn1b-/- mice. β1-p.R89C polypeptides are expressed in brain at comparable levels to wildtype. In heterologous cells, β1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wildtype. Heterologous expression of β1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a, and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b-/- mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at postnatal day 15 compared to Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at postnatal day 15 vs. a subset that were not hyperthermia-exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C > T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared to Scn1b-/- mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.
{"title":"Epilepsy and sudden unexpected death in epilepsy in a mouse model of human <i>SCN1B</i>-linked developmental and epileptic encephalopathy","authors":"Chunling Chen, Julie Ziobro, Larissa Robinson-Cooper, Samantha L Hodges, Yan Chen, Nnamdi Edokobi, Luis Lopez-Santiago, Karl Habig, Chloe Moore, Joe Minton, Sabrina Bramson, Caroline Scheuing, Noor Daddo, Katalin Štěrbová, Sarah Weckhuysen, Jack M Parent, Lori L Isom","doi":"10.1093/braincomms/fcad283","DOIUrl":"https://doi.org/10.1093/braincomms/fcad283","url":null,"abstract":"Abstract Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules, and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C &gt; T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C &gt; T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b-/- mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C &gt; T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared to severely reduced body weight and 100% mortality in Scn1b-/- mice. β1-p.R89C polypeptides are expressed in brain at comparable levels to wildtype. In heterologous cells, β1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wildtype. Heterologous expression of β1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a, and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b-/- mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at postnatal day 15 compared to Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at postnatal day 15 vs. a subset that were not hyperthermia-exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C &gt; T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared to Scn1b-/- mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"67 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135566608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-18DOI: 10.1093/braincomms/fcad268
Mikael Levy, Mika Zurawel, Vincent d’Hardemare, Anan Moran, Fani Andelman, Yael Manor, Jacob Cohen, Moshe Meshulam, Yacov Balash, Tanya Gurevich, Itzhak Fried, Hagai Bergman
Abstract Subthalamic nucleus (STN) deep brain stimulation (DBS) is commonly indicated for symptomatic relief of idiopathic Parkinson’s disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intra-operative microelectrode recordings (MER). However, there are no MER-based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson’s disease who had STN-DBS at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015-2016. Forty-eight patients (19 women, 29 men; mean age, 58±8 years) who were implanted with a STN-DBS device underwent pre- and post-surgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant vs the rigidity-bradykinesia-dominant motor-symptoms, frontal vs posterior neuropsychological deficits and acoustic characteristics vs speech intelligibility abnormalities. MER of STN spiking activity were analysed off-line and correlated with the original scores, and with the principal component results. Based on 198 MER trajectories we suggest an intraoperative STN-DBS score which is a simple sum of three MER properties: normalized neuronal activity, the STN width and the relative proportion of the STN dorsolateral oscillatory region. A threshold STN-DBS score >2.5 (preferentially composed of normalized root mean square >1.5, STN width >3 mm and a dorsolateral oscillatory region/STN width ratio >1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of DBS contact localization based on MER with the aim of improving long-term (>1 year) motor, neuropsychological and voice symptoms.
{"title":"Subthalamic nucleus physiology is correlated with deep brain stimulation motor and non-motor outcomes","authors":"Mikael Levy, Mika Zurawel, Vincent d’Hardemare, Anan Moran, Fani Andelman, Yael Manor, Jacob Cohen, Moshe Meshulam, Yacov Balash, Tanya Gurevich, Itzhak Fried, Hagai Bergman","doi":"10.1093/braincomms/fcad268","DOIUrl":"https://doi.org/10.1093/braincomms/fcad268","url":null,"abstract":"Abstract Subthalamic nucleus (STN) deep brain stimulation (DBS) is commonly indicated for symptomatic relief of idiopathic Parkinson’s disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intra-operative microelectrode recordings (MER). However, there are no MER-based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson’s disease who had STN-DBS at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015-2016. Forty-eight patients (19 women, 29 men; mean age, 58±8 years) who were implanted with a STN-DBS device underwent pre- and post-surgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant vs the rigidity-bradykinesia-dominant motor-symptoms, frontal vs posterior neuropsychological deficits and acoustic characteristics vs speech intelligibility abnormalities. MER of STN spiking activity were analysed off-line and correlated with the original scores, and with the principal component results. Based on 198 MER trajectories we suggest an intraoperative STN-DBS score which is a simple sum of three MER properties: normalized neuronal activity, the STN width and the relative proportion of the STN dorsolateral oscillatory region. A threshold STN-DBS score &gt;2.5 (preferentially composed of normalized root mean square &gt;1.5, STN width &gt;3 mm and a dorsolateral oscillatory region/STN width ratio &gt;1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of DBS contact localization based on MER with the aim of improving long-term (&gt;1 year) motor, neuropsychological and voice symptoms.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"12 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135823396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-17DOI: 10.1093/braincomms/fcad273
Paulo R Nóbrega, Anderson R B de Paiva, Katiane S Souza, Jorge Luiz B de Souza, Pedro Lucas G S B Lima, Delson José da Silva, Milena Sales Pitombeira, Viviennee K Borges, Daniel A Dias, Luciana M Bispo, Carolina F Santos, Fernando Freua, Paulo Diego S Silva, Isabela S Alves, Leonardo B Portella, Paulina R Cunha, Rubens Paulo A Salomao, José Luis Pedroso, Veridiana P Miyajima, Fábio Miyajima, Elisa Cali, Charles Wade, Annapurna Sudarsanam, Mary O’Driscoll, Tom Hayton, Orlando G P Barsottini, Stephan Klebe, Fernando Kok, Leandro Tavares Lucato, Henry Houlden, Christel Depienne, David S Lynch, Pedro Braga-Neto
Abstract Mutations in CLCN2 are a rare cause of autosomal recessive leukoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder.Informed consent was obtained for all patients. Patients underwent either whole exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical magnetic resonance imaging (MRI) changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2 related leukoencephalopathy and reinforces the finding that although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leukoencephalopathy by adding prominent seizures, severe spastic paraplegia, and developmental delay.
{"title":"Expanding the phenotypic spectrum of <i>CLCN2</i>-related leukoencephalopathy and ataxia","authors":"Paulo R Nóbrega, Anderson R B de Paiva, Katiane S Souza, Jorge Luiz B de Souza, Pedro Lucas G S B Lima, Delson José da Silva, Milena Sales Pitombeira, Viviennee K Borges, Daniel A Dias, Luciana M Bispo, Carolina F Santos, Fernando Freua, Paulo Diego S Silva, Isabela S Alves, Leonardo B Portella, Paulina R Cunha, Rubens Paulo A Salomao, José Luis Pedroso, Veridiana P Miyajima, Fábio Miyajima, Elisa Cali, Charles Wade, Annapurna Sudarsanam, Mary O’Driscoll, Tom Hayton, Orlando G P Barsottini, Stephan Klebe, Fernando Kok, Leandro Tavares Lucato, Henry Houlden, Christel Depienne, David S Lynch, Pedro Braga-Neto","doi":"10.1093/braincomms/fcad273","DOIUrl":"https://doi.org/10.1093/braincomms/fcad273","url":null,"abstract":"Abstract Mutations in CLCN2 are a rare cause of autosomal recessive leukoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder.Informed consent was obtained for all patients. Patients underwent either whole exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical magnetic resonance imaging (MRI) changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2 related leukoencephalopathy and reinforces the finding that although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leukoencephalopathy by adding prominent seizures, severe spastic paraplegia, and developmental delay.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"32 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135993810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-11DOI: 10.1093/braincomms/fcad265
Guillaume Dannhoff, Phanindra P Poudel, Chacchu Bhattarai, Sneha Guruprasad Kalthur, Igor L Maldonado
Abstract A cerebral gyrus is made up of an external layer of folded cortex and an inner core of white matter. The architecture of the core has specific features that make it distinct from the white matter of the deep brain regions. Limited externally by the gray matter that covers the top of the gyrus and the neighboring sulci, this gyral white matter is made up of a mix of fiber populations with multiple directions and destinations. The presence of densely packed fibers with multiple crossings, the proximity to the cortex, and the existence of inter-regional and inter-individual variations make the task of depicting this microanatomy extremely challenging. The topic is, however, of paramount relevance for both fundamental and applied neurosciences. This fiber colocalization is crucial for the functional role of each cerebral region and is key to clinical manifestations in cases of parenchymal damage. As track tracing, imaging, and dissection are based on different biological or physical principles, it is natural for their results to sometimes be different, but they are often complementary. As the amount of available information increases, it becomes fragmented due to the multiplicity of methods, target phenomena, and studied species. In this scoping review, we present the key concepts and map the primary sources of evidence regarding identifying the fiber pathways that compose the gyral white matter, enabling the discussion of avenues for future research. The general pattern in which these pathways are distributed in the gyral white matter was detailed, and the main variations as a function of brain topography were explained and illustrated with typical examples.
{"title":"Depicting the anatomy of the gyral white matter: <i>ubi sumus? quo vadimus?</i>","authors":"Guillaume Dannhoff, Phanindra P Poudel, Chacchu Bhattarai, Sneha Guruprasad Kalthur, Igor L Maldonado","doi":"10.1093/braincomms/fcad265","DOIUrl":"https://doi.org/10.1093/braincomms/fcad265","url":null,"abstract":"Abstract A cerebral gyrus is made up of an external layer of folded cortex and an inner core of white matter. The architecture of the core has specific features that make it distinct from the white matter of the deep brain regions. Limited externally by the gray matter that covers the top of the gyrus and the neighboring sulci, this gyral white matter is made up of a mix of fiber populations with multiple directions and destinations. The presence of densely packed fibers with multiple crossings, the proximity to the cortex, and the existence of inter-regional and inter-individual variations make the task of depicting this microanatomy extremely challenging. The topic is, however, of paramount relevance for both fundamental and applied neurosciences. This fiber colocalization is crucial for the functional role of each cerebral region and is key to clinical manifestations in cases of parenchymal damage. As track tracing, imaging, and dissection are based on different biological or physical principles, it is natural for their results to sometimes be different, but they are often complementary. As the amount of available information increases, it becomes fragmented due to the multiplicity of methods, target phenomena, and studied species. In this scoping review, we present the key concepts and map the primary sources of evidence regarding identifying the fiber pathways that compose the gyral white matter, enabling the discussion of avenues for future research. The general pattern in which these pathways are distributed in the gyral white matter was detailed, and the main variations as a function of brain topography were explained and illustrated with typical examples.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136062559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-06DOI: 10.1093/braincomms/fcad257
Thomas D Parker, Karl A Zimmerman, Etienne Laverse, Niall J Bourke, Neil S N Graham, Emma-Jane Mallas, Amanda Heslegrave, Henrik Zetterberg, Simon Kemp, Huw R Morris, David J Sharp
Abstract There is growing concern that elite rugby participation may negatively influence brain health, but the underlying mechanisms are unclear. Cortical thickness is a widely applied biomarker of grey matter structure, but there is limited research into how it may be altered in active professional rugby players. Cross-sectional MRI data from 44 active elite rugby players, including 21 assessed within one week of head injury, and 47 healthy controls were analysed. We investigated how active elite rugby participation with and without subacute traumatic brain injury influenced grey matter structure using whole cortex and region of interest cortical thickness analyses. Relationships between cortical thickness and biomarkers of traumatic brain injury, including fractional anisotropy, plasma neurofilament light and glial fibrillary acidic protein, were also examined. In whole cortex analyses, precentral cortical thickness in the right hemisphere was lower in rugby players compared with controls, which was due to reductions in non-injured players. Post-hoc region of interest analyses showed non-injured rugby players had reduced cortical thickness in the inferior precentral sulcal thickness bilaterally (p = 0.005) and the left central sulcus (p = 0.037) relative to controls. In contrast, players in the subacute phase of mild traumatic brain injury had higher inferior precentral sulcal cortical thickness in the right hemisphere (p = 0.015). Plasma glial fibrillary acidic protein, a marker of astrocyte activation, was positively associated with right inferior precentral sulcal cortical thickness in injured rugby players (p = 0.0012). Elite rugby participation is associated with localised alterations in cortical thickness, specifically in sulcal motor regions. Subacute changes after mild TBI are associated with evidence of astrocytic activation. The combination of cortical thickness and glial fibrillary acidic protein may be useful in understanding the pathophysiological relationship between sporting head injury and brain health.
{"title":"Active elite rugby participation is associated with altered precentral cortical thickness","authors":"Thomas D Parker, Karl A Zimmerman, Etienne Laverse, Niall J Bourke, Neil S N Graham, Emma-Jane Mallas, Amanda Heslegrave, Henrik Zetterberg, Simon Kemp, Huw R Morris, David J Sharp","doi":"10.1093/braincomms/fcad257","DOIUrl":"https://doi.org/10.1093/braincomms/fcad257","url":null,"abstract":"Abstract There is growing concern that elite rugby participation may negatively influence brain health, but the underlying mechanisms are unclear. Cortical thickness is a widely applied biomarker of grey matter structure, but there is limited research into how it may be altered in active professional rugby players. Cross-sectional MRI data from 44 active elite rugby players, including 21 assessed within one week of head injury, and 47 healthy controls were analysed. We investigated how active elite rugby participation with and without subacute traumatic brain injury influenced grey matter structure using whole cortex and region of interest cortical thickness analyses. Relationships between cortical thickness and biomarkers of traumatic brain injury, including fractional anisotropy, plasma neurofilament light and glial fibrillary acidic protein, were also examined. In whole cortex analyses, precentral cortical thickness in the right hemisphere was lower in rugby players compared with controls, which was due to reductions in non-injured players. Post-hoc region of interest analyses showed non-injured rugby players had reduced cortical thickness in the inferior precentral sulcal thickness bilaterally (p = 0.005) and the left central sulcus (p = 0.037) relative to controls. In contrast, players in the subacute phase of mild traumatic brain injury had higher inferior precentral sulcal cortical thickness in the right hemisphere (p = 0.015). Plasma glial fibrillary acidic protein, a marker of astrocyte activation, was positively associated with right inferior precentral sulcal cortical thickness in injured rugby players (p = 0.0012). Elite rugby participation is associated with localised alterations in cortical thickness, specifically in sulcal motor regions. Subacute changes after mild TBI are associated with evidence of astrocytic activation. The combination of cortical thickness and glial fibrillary acidic protein may be useful in understanding the pathophysiological relationship between sporting head injury and brain health.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"71 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134944042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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