Journal of neurotrauma最新文献

{"title":"Attenuation of Blood-Brain Barrier Disruption in Traumatic Brain Injury via Inhibition of NKCC1 Cotransporter: Insights into the NF-κB/NLRP3 Signaling Pathway.","authors":"Zehan Zhang, Hui Wang, Bingyan Tao, Xudong Shi, Guilin Chen, Hengchao Ma, Ruiyun Peng, Jun Zhang","doi":"10.1089/neu.2023.0580","DOIUrl":"10.1089/neu.2023.0580","url":null,"abstract":"<p><p>Following traumatic brain injury (TBI), inhibition of the Na⁺-K⁺-Cl^- cotransporter1 (NKCC1) has been observed to alleviate damage to the blood-brain barrier (BBB). However, the underlying mechanism for this effect remains unclear. This study aimed to investigate the mechanisms by which inhibiting the NKCC1 attenuates disruption of BBB integrity in TBI. The TBI model was induced in C57BL/6 mice through a controlled cortical impact device, and an <i>in vitro</i> BBB model was established using Transwell chambers. Western blot (WB) analysis was used to evaluate NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and nuclear factor-kappaB (NF-κB) pathway proteins. Flow cytometry and transendothelial electrical resistance (TEER) were employed to assess endothelial cell apoptosis levels and BBB integrity. ELISA was utilized to measure cytokines interleukin-1β (IL-1β) and matrix metalloproteinase-9 (MMP-9). Immunofluorescence techniques were used to evaluate protein levels and the nuclear translocation of the rela (p65) subunit. The Evans blue dye leakage assay and the brain wet-dry weight method were utilized to assess BBB integrity and brain swelling. Inhibition of NKCC1 reduced the level of NLRP3 inflammasome and the secretion of IL-1β and MMP-9 in microglia. Additionally, NKCC1 inhibition suppressed the activation of the NF-κB signaling pathway, which in turn decreased the level of NLRP3 inflammasome. The presence of NLRP3 inflammasome in BV2 cells led to compromised BBB integrity within an inflammatory milieu. Following TBI, an upregulation of NLRP3 inflammasome was observed in microglia, astrocytes, vascular endothelial cells, and neurons. Furthermore, inhibiting NKCC1 resulted in a decrease in the positive rate of NLRP3 inflammasome in microglia and the levels of inflammatory cytokines IL-1β and MMP-9 after TBI, which correlated with BBB damage and the development of cerebral edema. These findings demonstrate that the suppression of the NKCC1 cotransporter protein alleviates BBB disruption through the NF-κB/NLRP3 signaling pathway following TBI.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"814-831"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of the GCS-Pupil Scale in Traumatic Brain Injury: Incremental Prognostic Value of Pupillary Reactivity with GCS in the Prospective Observational Cohorts CENTER-TBI and TRACK-TBI.","authors":"Rick J G Vreeburg, Florian D van Leeuwen, Geoffrey T Manley, John K Yue, Paul M Brennan, Xiaoying Sun, Sonia Jain, Thomas A van Essen, Wilco C Peul, Andrew I R Maas, David K Menon, Ewout W Steyerberg","doi":"10.1089/neu.2024.0458","DOIUrl":"10.1089/neu.2024.0458","url":null,"abstract":"<p><p>To compare the incremental prognostic value of pupillary reactivity captured as part of the Glasgow Coma Scale-Pupils (GCS-P) score or added as separate variable to the GCS+P, in traumatic brain injury (TBI). We analyzed patients enrolled between 2014 and 2018 in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI, <i>n</i> = 3521) and the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI, <i>n</i> = 1439) cohorts. Logistic regression was utilized to quantify the prognostic performances of GCS-P (GCS minus number of unreactive pupils) and GCS+P versus GCS alone according to Nagelkerke's <i>R</i>². End-points were mortality and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-4) at 6 month post-injury. We estimated 95% confidence intervals (CIs) with bootstrap resampling to summarize the improvement in prognostic capability. In a meta-analysis of CENTER-TBI and TRACK-TBI, GCS as a linear score had a <i>R</i>² of 25% (95% CI 19-31%) for mortality and 33% (4-41%) for unfavorable outcome. Pupillary reactivity as a separate variable improved the <i>R</i>² by an absolute value of 6% (4.0-7.7%) and 2% (1.2-3.0%) for mortality and unfavorable outcome, respectively, while comparatively half of this improvement was captured by the GCS-P score (3% [2.1-3.3%], 1% [1-1.7%], respectively). GCS-P showed a stronger association with 6-month outcome after TBI than GCS alone and provides a single integrated score. However, this comes at a loss of clinical and prognostic information compared with GCS+P. For prognostic models, inclusion of GCS and pupillary reactivity as separate factors may be preferable to using a GCS-P summary score.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"798-813"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Pathway Changes Associated with Different Post-Conditioning Exercise Interventions After Experimental TBI.","authors":"James P Barrett, Taryn G Aubrecht, Aidan Smith, Maria Vaida, Rebecca J Henry, Sarah J Doran, Alan I Faden, Bogdan A Stoica","doi":"10.1089/neu.2024.0120","DOIUrl":"10.1089/neu.2024.0120","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Traumatic brain injury (TBI) causes complex, time-dependent molecular and cellular responses, which include adaptive changes that promote repair and recovery, as well as maladaptive processes such as chronic inflammation that contribute to chronic neurodegeneration and neurological dysfunction. Hormesis is a well-established biological phenomenon in which exposure to low-dose toxins or stressors results in protective responses to subsequent higher-level stressors or insults. Hormetic stimuli show a characteristic U-shaped or inverted J-shaped dose-response curve, as well as being time and exposure-frequency dependent, similar to pre-conditioning and post-conditioning actions. Voluntary exercise interventions, before or after injury, appear to follow these general hormetic principles. But the molecular alterations associated with exercise interventions or more general hormetic responses have received only limited attention. In this study, we used a well-characterized mouse TBI model to assess the effects of different post-conditioning exercise-intervention paradigms on diverse molecular pathways, including neuroinflammation regulators, and post-traumatic neurological deficits. We generated high-throughput gene expression data and associated molecular pathway analyses to assess the potential molecular mechanisms associated with time- and duration-dependent voluntary exercise intervention, as well as time after treatment. Importantly, we also used newer analytical methods to more broadly assess the impact of exercise on diverse molecular pathways. TBI caused long-term changes in multiple neuroinflammation markers and chronic cognitive dysfunction. Notably, all delayed, post-conditioning exercise interventions reduced post-traumatic neuroinflammation and/or attenuated the related cognitive changes, albeit with different pathway specificity and effects magnitude. Exercise comprehensively reversed injury-associated effects in the hippocampus across both activated inflammatory and inhibited neuronal pathways, consistent with a return toward the noninjured, homeostatic state. In contrast, the cortex showed a less consistent pattern with more limited attenuation of inflammatory pathway activation and an amplification in the injury-dependent inhibition of select noninflammatory pathways, indicating less effective and potentially detrimental responses to exercise. Exercise intervention beginning 2 weeks after injury and lasting 2 weeks was less effective than exercise continuing for 4 weeks. Exercise initiated at a more delayed timepoint of 6 weeks after injury and continuing for 4 weeks was more effective than that during the acute phase. The delayed paradigm was also more effective than exercise initiated at 10 weeks after injury and continuing for 8 weeks, consistent with hormetic responses in other models and species. Overall, our study delineates regional and interventional parameters, as well as related molecular pathway changes, associated with","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"851-876"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-Based Protein Biomarkers in the Chronic Phase of Traumatic Brain Injury: A Systematic Review.","authors":"Amelia J Hicks, Holly Carrington, Lisa Bura, Alicia Yang, Rico Pesce, Belinda Yew, Kristen Dams-O'Connor","doi":"10.1089/neu.2024.0294","DOIUrl":"10.1089/neu.2024.0294","url":null,"abstract":"<p><p>There has been limited exploration of blood-based biomarkers in the chronic period following traumatic brain injury (TBI). Our objective was to conduct a systematic review of studies examining blood-based protein biomarkers with at least one sample collected 12 months post-TBI in adults (≥16 years). Database searches were conducted in Embase, MEDLINE, and Science Citation Index-Expanded on July 24, 2023. Risk of bias was assessed using modified Joanna Briggs Institute critical appraisal tools. Only 30 of 12,523 articles met inclusion criteria, with samples drawn from 12 months to 48 years. Higher quality evidence (low risk of bias; large samples) identified promising inflammatory biomarkers at 12 months post-injury in both moderate-severe TBI (GFAP) and mild TBI (eotaxin-1, IFN-y, IL-8, IL-9, IL-17A, MCP-1, MIP-1β, FGF-basic, and TNF-α). Studies with low risk of bias but smaller samples also suggest NSE, MME, and CRP may be informative, alongside protein variants for α-syn (10H, D5), amyloid-β (A4, C6T), TDP-43 (AD-TDP 1;2;3;9;11), and tau (D11C). Findings for NfL were inconclusive. Longitudinal data were mostly available for acute samples followed until 12 months post-injury, with limited evaluation of changes beyond 12 months. Associations of some blood-based biomarkers with cognitive, sleep, and functional outcomes were reported. The overall strength of the evidence in this review was limited by the risk of bias and small sample sizes. Replication is required within prospective longitudinal studies that move beyond 12 months post-injury. Novel efforts should be guided by promising neurodegenerative-disease markers and use panels to model polypathology.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"759-797"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational Outcomes Project in Neurotrauma (TOP-NT) Pre-Clinical Consortium Study: A Synopsis.","authors":"Hannah L Radabaugh, Neil G Harris, Ina B Wanner, Mark P Burns, Joseph T McCabe, Alexandru V Korotcov, Bernard J Dardzinski, Jinyuan Zhou, Raymond C Koehler, Jieru Wan, Javier Allende Labastida, Babak Moghadas, Adnan Bibic, Marcelo Febo, Firas H Kobeissy, Jiepei Zhu, Richard Rubenstein, Jiamei Hou, Prodip K Bose, Seza Apiliogullari, Michael S Beattie, Jacqueline C Bresnahan, Susanna Rosi, J Russell Huie, Adam R Ferguson, Kevin K W Wang","doi":"10.1089/neu.2023.0654","DOIUrl":"10.1089/neu.2023.0654","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) has long been a leading cause of death and disability, yet research has failed to successfully translate findings from the pre-clinical, animal setting into the clinic. One factor that contributes significantly to this struggle is the heterogeneity observed in the clinical setting where patients present with injuries of varying types, severities, and comorbidities. Modeling this highly varied population in the laboratory remains challenging. Given feasibility constraints, individual laboratories often focus on single injury types and are limited to an abridged set of outcome measures. Furthermore, laboratories tend to use different injury or outcome methodologies from one another, making it difficult to compare studies and identify which pre-clinical findings may be best suited for clinical translation. The NINDS-funded Translational Outcomes Project in Neurotrauma (TOP-NT) is a multi-site consortium designed to address the reproducibility, rigor, and transparency of pre-clinical development and validation of clinically relevant biomarkers for TBI. The current overview article provides a detailed description of the infrastructure and strategic approach undertaken by the consortium. We outline the TOP-NT strategy to address three goals: (1) selection and cross-center validation of biomarker tools, (2) development and population of a data infrastructure to allow for the sharing and reuse of pre-clinical, animal research following findable, accessible, interoperable, and reusable data guidelines, and (3) demonstration of feasibility, reproducibility, and transparency in conducting a multi-center, pre-clinical research trial for TBI biomarker development. The synthesized scientific analysis and results of the TOP-NT efforts will be the topic of future articles.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"898-912"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.","authors":"William J Flerlage, Sarah C Simmons, Emily H Thomas, Shawn Gouty, Mumeko C Tsuda, T John Wu, Regina C Armstrong, Brian M Cox, Fereshteh S Nugent","doi":"10.1089/neu.2024.0184","DOIUrl":"10.1089/neu.2024.0184","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI during late adolescence (at ∼8 weeks old). In this study, we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice, as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Because persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we tested whether the LHb CRF subsystem becomes engaged following mTBI. We found that &lt;i&gt;in vitro&lt;/i&gt; inhibition of CRF receptor type 1 (CRFR1) within the LHb reverses mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors toward more passive action locking rather than escape behaviors in response to an aerial threat in both male and female mice, as well as prolonging the latency to escape responses in female mice. While this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this pre-clinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially ","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"832-850"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prospective Harmonization, Common Data Elements, and Sharing Strategies for Multicenter Pre-Clinical Traumatic Brain Injury Research in the Translational Outcomes Project in Neurotrauma Consortium.","authors":"Ina-Beate Wanner, Joseph T McCabe, J Russell Huie, Neil G Harris, Afshin Paydar, Chloe McMann-Chapman, Anthony Tobar, Alexandru Korotcov, Mark P Burns, Raymond C Koehler, Jieru Wan, Javier Allende Labastida, Jonathan Tong, Jinyuan Zhou, Lex Maliga Davis, Hannah L Radabaugh, Adam R Ferguson, Timothy E Van Meter, Marcelo Febo, Prodip Bose, Kevin K Wang, Firas Kobeissy, Seza Apiliogullari, Jiepei Zhu, Richard Rubenstein, Hibah O Awwad","doi":"10.1089/neu.2023.0653","DOIUrl":"10.1089/neu.2023.0653","url":null,"abstract":"<p><p>Effective team science requires procedural harmonization for rigor and reproducibility. Multicenter studies across experimental modalities (domains) can help accelerate translation. The Translational Outcomes Project in NeuroTrauma (TOP-NT) is a pre-clinical traumatic brain injury (TBI) consortium charged with establishing and validating noninvasive TBI assessment tools through team science. Here, we present practical approaches for harmonization of TBI research across five centers providing needed vocabulary and structure to achieve centralized data organization and use. This includes data sharing as an essential step that enables validating data between domains, evaluating reproducibility between sites, and performing multimodal analyses. As part of this process, TOP-NT (1) produced a library of TBI-relevant standard operating procedures to coordinate workflow, (2) aligned 481 pre-clinical and clinical common data elements (CDEs), and (3) generated 272 new pre-clinical TBI CDEs. This consortium then (4) connected diverse data types to validate assessments across domains and to allow multivariable TBI phenotyping. Lastly, TOP-NT (5) specified technical quality controls for pre-clinical studies. These harmonization tools can facilitate reproducibility in team science, help distinguish a wide injury spectrum from technical variability, apply quality-controls, and ease higher level data analyses. TOP-NT uses three rat TBI models across four sites. Each site collects primary outcome measures, including magnetic resonance imaging (MRI) protocols and blood biomarkers of neuronal and glial injury, validated by histopathology and behavioral outcomes. Collected data are organized using the 481 TOP-NT pre-clinical CDEs, covering surgical, behavioral, biomarker, MRI, and quantitative histopathological methods. We report data curation steps suited for data storage using the Open Data Commons for TBI as a centralized data repository, allowing unbiased cross-site analysis. This approach leads to introducing a higher level, syndromic understanding of TBI signatures. TOP-NT authors outline a semantic and structural framework suggesting strategies for robust pre-clinical research in multicenter trials to improve translatability for TBI assessments. [Figure: see text].</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"877-897"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trajectory of Post-Traumatic Stress During the First Year after Pediatric Traumatic Brain or Orthopedic Injury.","authors":"Linda Ewing-Cobbs, Charles S Cox, Amy Clark, Heather T Keenan","doi":"10.1089/neu.2024.0578","DOIUrl":"https://doi.org/10.1089/neu.2024.0578","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Up to 50% of children sustaining physical injury develop post-traumatic stress symptoms (PTSS). Most studies of PTSS have not included patients with traumatic brain injury (TBI); consequently, the influence of injury type and severity on the longitudinal course of PTSS is unclear. To address this gap, we completed a longitudinal prospective cohort study examining the trajectory of self-reported PTSS severity during the first year after TBI or orthopedic injury (OI). Within a biopsychosocial framework, we examined PTSS in relation to injury variables, demographic characteristics, and pre-injury child and family functioning. Patients ages 9-15 years with TBI or OI were recruited from two level I pediatric trauma centers. Online surveys were completed as soon as possible following injury (mdn = 8 days). Caregivers rated pre-injury family, sociodemographic, and child characteristics. Follow-up surveys assessing children's self-reported PTSS using the Children's PTSD Symptom Scale (CPSS) were scheduled 3,6, and 12 months after injury. English-speaking families completed surveys either online or by telephone interview; Spanish-speaking families were interviewed. Baseline surveys were completed by 303 families; 265 (87%) completed at least 1 follow-up and comprised the cohort. General linear mixed models examined the influence of injury group and severity, age, sex, and time of assessment on CPSS scores. Pre-injury estimates of child and family functioning were examined as predictors in supplemental models. Participants (72% boys, mean [SD] age 12.7 [1.9] years) included 204 with TBI (76 mild, 82 complicated-mild/moderate, 46 severe) and 61 with OI. Relative to OI, patients with TBI had significantly elevated mean CPSS scores at 3 (3.7 points, 95% confidence intervals [CI]: 1.1, 6.3); 6 (3.2, 95% CI: 0.7, 5.7) and 12 months (2.3, 95% CI: 0.1, 4.5). The primary model indicated that TBI severity had a nonlinear relation with CPSS. Mild TBI (mTBI) had the highest mean scores; with significant differences relative to OI at 3 (4.6 points, 95% CI: 1.6, 7.6); 6 (5.7, 95% CI: 2.7, 8.6) and 12 months (3.2, 95% CI: 0.6, 5.8). This model also revealed that adolescent females had higher CPSS scores than children or adolescent males. Differences relative to younger males at 6 and 12 months were 4.9 (95% CI: 1.6, 8.3) and 5.0 points (95% CI: 2.1, 8.0). In supplemental models, higher symptom burden was associated with poorer baseline family functioning and with higher levels of children's pre-injury anxiety, affective problems, and conduct problems. PTSS persisted for a significant minority of patients with TBI across the first year of recovery, particularly those with mTBI. Screening should emphasize risk factors to target patients with the greatest need for trauma-focused intervention. Cost-effective, scalable, evidence-based trauma-focused interventions are essential to meet American College of Surgeons standards to provide psychological screening and treatme","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigation of Acute Seizures and Neuropathology after Traumatic Brain Injury by Structure-Based Discovery-Identified Drugs.","authors":"Natallie Kajevu, Ivette Banuelos, Pedro Andrade, Elina Hämäläinen, Laureano Sabatier, Manuel Couyoupetrou, María Luisa Villalba, Luciana Gavernet, Anssi Lipponen, Teemu Natunen, Noora Puhakka, Mikko Hiltunen, Alan Talevi, Asla Pitkänen","doi":"10.1089/neu.2024.0070","DOIUrl":"https://doi.org/10.1089/neu.2024.0070","url":null,"abstract":"<p><p>Our objective was to test the hypothesis that structure-based identified or designed compounds exhibiting neuroprotective, antioxidant, and anti-inflammatory properties <i>in vitro</i> will mitigate early seizures and neuropathology after traumatic brain injury (TBI) <i>in vivo</i>. The neuroprotective and anti-inflammatory effects of 11 compounds identified by computer-assisted approximations were tested <i>in vitro</i> in neuronal microglial co-cultures. Among these, compound FBA exhibited the best neuroprotective (MAP-2, microtubule-associated-protein 2, a neuronal damage biomarker), antioxidative (nitrite production), and anti-inflammatory effects <i>in vitro</i> (all <i>p</i> < 0.01). Consequently, its neuroprotective and antiseizure effects were assessed <i>in vivo</i> in adult male Sprague-Dawley rats exposed to severe lateral fluid-percussion-induced TBI. Rats under continuous video-electroencephalogram monitoring received prophylactic treatment with an intraperitoneal (i.p.) injection of FBA (FBApro, 30 mg/kg) or vehicle (VEH, 48% PEG in 0.9% saline, 3 mL/kg) at 2 and 24 h post-TBI. Rats that developed status epilepticus received 1-2 additional on-demand FBA doses (FBApro+, 100 mg/kg, i.p.) to stop epileptiform activity. FBApro treatment reduced the cortical lesion area (18.9 ± 4.1 mm², <i>n</i> = 7) compared with VEH treatment (24.8 ± 5.7 mm², <i>n</i> = 10, <i>p</i> < 0.05). FBApro treatment also showed a favorable effect on the white matter by reducing plasma levels of pNF-H, a biomarker of axonal injury, compared with VEH treatment (Cohen's delta 0.657). Both FBApro (368 ± 407 s) and FBApro+ (256 ± 327 s) treatments reduced the average cumulative seizure duration compared with VEH (896 ± 703 s, both <i>p</i> < 0.05). The FBApro+ treatment regimen also reduced the mean relative theta and alpha power and increased the mean relative gamma power in the electroencephalogram (<i>p</i> < 0.05). Our data identified FBA as a novel structure-based discovered compound with promising favorable effects on structural and functional recovery after TBI.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Participation after Mild Traumatic Brain Injury in Comparison to Orthopedic Trauma Controls: Results from a Longitudinal Multicenter Observational Cohort Study.","authors":"Jolein Manders, Melloney Wijenberg, Skye King, Sven Stapert, Jeanine Verbunt, Caroline van Heugten","doi":"10.1089/neu.2024.0413","DOIUrl":"https://doi.org/10.1089/neu.2024.0413","url":null,"abstract":"<p><p>A subgroup of patients shows incomplete recovery after mild traumatic brain injury (mTBI). Outcomes are commonly measured on the level of symptoms or functional recovery. An alternative way to study outcome after mTBI is to measure the level of participation. The objectives of this study were to examine (1) the level of participation in patients with mTBI at 12 months post-injury in comparison to a non-head injury orthopedic trauma control group; (2) the relationship between the outcome domains participation, functional outcome, and post-concussion symptoms. A prospective, longitudinal, multicenter cohort study was conducted. Participants were 140 adults with mTBI and 144 adults with minor (non-head) orthopedic injury. The following outcomes were measured: participation (Utrecht Scale for Evaluation and Rehabilitation-Participation: USER-P), functional outcome (Glasgow Outcome Scale Extended: (GOS-E), and post-concussion symptoms (Rivermead Post-Concussion Symptoms Questionnaire: RPQ). Adults with mTBI have a significantly lower objective participation level (USER-P Frequency scale) than controls. No differences were found between the groups on subjective participation (USER-P Restrictions and Satisfaction scales) nor on functional outcome (GOS-E). Fifty-three people with mTBI (38%) had a score of ≥2 on ≥3 items, while 26 (19%) had an unfavorable USER-P outcome (≥2 restrictions) and only 9 (6.5%) had an unfavorable GOS-E score (<7). In both groups, the presence of persistent symptoms led to a significantly unfavorable outcome on both the USER-P and GOS-E. Participation frequency is lower in mTBI than in orthopedic controls, mainly determined by a significantly lower number of hours of (un)paid work, education, and/or household activities. People with mTBI more often report post-concussion symptoms, but functional recovery is not different between the groups. Participation seems to better represent incomplete recovery than functional outcome, but future research should confirm these findings.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}