Journal of neurotrauma最新文献

Although blast-induced traumatic brain injury (bTBI) is considered as the signature injury of recent combat operations such as Operations Iraqi Freedom and Enduring Freedom, no precise biomechanical and biological mechanisms of injury have been identified. Consequently, to date, there are no FDA-approved countermeasures for the treatment of bTBI. Animal models that are highly translatable to humans are required for studying the injury mechanisms underlying bTBI. As a small animal with a gyrencephalic cerebral cortex, the ferret has been increasingly used for studying the mechanisms of neurological disorders in recent years, especially for mechanically induced brain injuries such as traumatic brain injury. In this study, we used a ferret model to understand both biochemical and neurobehavioral outcome measures following closely coupled blast exposure at ∼19 psi. The neurobehavioral battery was used to assess activity and thigmotaxis (open field test), short-term memory (novel object recognition test), motor and gait (CatWalk XT system), and sleep patterns (actigraphy) up to 1 month post-exposure. For biochemical outcome measures, enzyme-linked immunosorbent assays were performed for the estimation of levels of phosphorylated neurofilament heavy chain (pNFH) protein and corticosterone in the serum at 24 h and 1-month post-blast. Western blotting was performed to measure the differential expressions of known biomarkers of brain injury such as pNFH, neurofilament light chain (NFL) protein present in the neurons undergoing degeneration, phosphorylated Tau protein, and glial fibrillary acidic protein at 24-h and 1-month post-blast. The results revealed that blast exposure caused significant anxiety-like behaviors, short-term memory loss, disrupted front and hind limbs movements, and disturbed sleep pattern in a time-dependent manner. Levels of both pNFH and corticosterone increased in the plasma post-blast. Western blotting revealed that blast exposure increased the levels of the biomarker proteins evaluated in different brain regions. Overall, we observed changes in biochemical and neurobehavioral outcomes after blast exposure that together suggest that ferret is a potentially valuable animal model for understanding the mechanism of bTBI and developing effective countermeasures.

Traumatic brain injury (TBI) results from a primary injury that impacts the brain in a spatially dependent manner. In this study, we investigated the topographical relationship of early transcriptional responses to a single, focal TBI in mice by controlled cortical impact. Guided by the presence of the anterior commissure (AC) in coronal sections at the rostro-caudal point of impact, we compared gene expression changes in the neocortex (CTX) and corpus callosum-external capsule (CC-EC), striatum (STR), and AC. Injury-induced gene expression changes were detected in the CTX, CC-EC, and STR but not AC and were principally segregated based on cytoarchitecture and secondarily by proximity to the site of impact. In addition, unbiased spatial clustering revealed a positive relationship between proximity to the impact and the number of acutely differentially expressed genes within the laminar CTX. Gene pathways for interferon gamma response and for leukocyte-mediated migration and immunity were acutely enhanced across the injured CTX, CC-EC, and STR. Within 1 week post-injury, transcriptional responses to injury in the CTX and CC-EC included gene pathways for adaptive T- and B cell mediated immunity, whereas gene expression changes in the STR were largely resolved. Next, we examined the effects of systemic depletion of neutrophils and monocytes on spatial gene expression changes in the injured brain. The systemic depletion and attenuated infiltration of these immune cells into the damaged brain post-injury led to the upregulation of gene pathways functioning in synaptic transmission and an alternating down- and then upregulation of genes functioning in ribosomal messenger RNA translation and aerobic metabolism in mitochondria. These data suggest that infiltrating neutrophils and monocytes play an evolving, multifaceted role in modulating the metabolic, transcriptional, and synaptic activity of brain tissue post-injury.

Traumatic brain injury (TBI) is common, disabling, and a growing public health concern. There are limited large-scale studies providing insight into factors associated with recovery in the general TBI population. Our aim was to identify factors associated with concussion/TBI symptom severity and return-to-work. We performed a prospective cohort study of concussion/TBI (predominantly mild to moderate) patients with data collected over a 20-year period (1998-2018). This is the first study presenting data from the Sunnybrook TBI (SUNTBI) cohort. Primary outcome at approximately 3-month postinjury was the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), and secondary outcome was return-to-work. Outcomes were analyzed using multivariable linear regression and logistic regression models, respectively. There were 2924 TBI patients included in the study. General Health Questionnaire (GHQ), a screening measure of current psychiatric symptoms, and all its subscales (depression, anxiety, somatic, and social) (p < 0.0001), and active litigation (p < 0.001) were significantly associated with higher RPQ scores. Notably, factors related to injury characteristics and severity were not (e.g., injury mechanism, TBI severity, and neuroimaging abnormalities). For return-to-work, having a professional occupation (p < 0.001) was significantly positively associated with return, while abnormal CT scan (p = 0.001), admission to hospital (p < 0.001), and higher GHQ score (p < 0.001) were negatively associated. In one of the largest observational studies of general population concussion/TBI patients to date, we found that psychiatric symptoms and litigation status were significantly associated with symptoms at 3 months, while factors related to the injury severity were not. We also observed a decoupling of factors that impact symptom score outcomes from return-to-work outcomes. These results have important implications for the management of at-risk TBI subpopulations and wider public policy considerations.

Traumatic brain injury (TBI) is a major health problem worldwide. Approximately 2.8 million people in the United States sustain a TBI each year, the majority of which can be classified as mild TBI (mTBI) or concussive injuries. Although mTBI may not cause overt brain damage, it triggers many cellular and molecular changes in brain cells, resulting in neurological, cognitive, and behavioral impairments. Metabolites are released in response to mTBI and can serve as diagnostic markers, as well as potentially contributing to ongoing pathophysiological changes. N-formylmethionine (fMet) is used as the first amino acid for protein synthesis in mitochondria, bacteria, and chloroplasts. Both formylated peptides and free fMet have been detected in human plasma. While a number of studies have demonstrated that formylated peptides can activate the innate immune response, less is known about the role of free fMet in health and disease. In this study, we quantified the free fMet concentration in plasma samples obtained from persons who have sustained an mTBI and compared it with the plasma concentrations detected in healthy volunteers. Our results show that the plasma levels of fMet increased within 24 h of a documented mTBI in both males and females. Receiver operator characteristic (ROC) analysis indicated that the acute change in plasma fMet (<48 h after an injury) has an area under ROC (AUROC) of 0.82 in identifying an mTBI. Interestingly, when fMet was measured in plasma samples collected from these patients 3 months later, it remained elevated and had an AUROC of 0.88. The systemic administration of fMet to mTBI mice impaired brain mitochondrial function, suggesting that it may affect ongoing mTBI pathophysiology.

The family environment plays an important role in children's recovery from traumatic brain injury (TBI); however, parental and family factors have not been examined in-depth in pediatric mild TBI (mTBI). Existing research on postconcussive symptoms (PCS) typically employs conventional statistical analyses that assume that children with mTBI are a homogenous group. However, children may display distinct trajectories of PCS across time after mTBI. Group-based multitrajectory modeling can identify latent clusters of individuals following similar trajectories across multiple indicators of an outcome. This study sought to: (1) identify trajectories of PCS after mTBI in children, and (2) examine their association with parental and family functioning. Participants were 506 children and adolescents aged 8- to 16-years-old who were recruited during emergency department (ED) visits within 48 h of injury at five Pediatric Emergency Research Canada hospitals. Injury information was collected in the ED, and parental and family functioning was measured at approximately 7 days postinjury. Child and parent PCS ratings were obtained weekly to 3 months and biweekly to 6 months postinjury using the Health and Behavior Inventory. Parental and family functioning were assessed using validated measures of family functioning, parental adjustment, perceived social support from parents, and parental responses to children's symptom complaints. Group-based multitrajectory modeling was used to classify individual children into distinct trajectories of child- and parent-reported cognitive and somatic PCS over time and to examine predictors of those trajectories. Six distinct trajectories were identified: "low acute/resolved PCS" (n = 98), "low acute/declining PCS" (n = 64), "moderate acute/elevated cognitive PCS" (n = 106), "moderate acute/declining PCS" (n = 118), "high acute/declining PCS" (n = 88), and "high acute/persisting PCS" (n = 32). Parental adjustment, protectiveness, and social support were independent predictors of trajectory membership after adjusting for demographic and injury characteristics. The identification of different symptom trajectories and specific aspects of parental and family functioning as predictors of these trajectories provides guidance for developing family-based treatments and targeting treatments to children at risk for poor recovery.

Diffusion tensor imaging studies in children suggest a link between abnormal white matter in limbic-prefrontal circuitry and behavioral problems. However, in children with traumatic injury, links between atypical limbic-prefrontal circuitry and new behavioral problems remain largely unexamined. In a prospective longitudinal study of children ages 8-15 years, we examined white matter microstructure 7 weeks following a traumatic brain injury (TBI) or extracranial injury (EI) relative to typically developing children (TDC). Internalizing and externalizing behavioral problems were assessed via the Child Behavior Checklist; ratings estimated preinjury and 7-month postinjury status. Limbic-prefrontal white matter fiber tracts were estimated using seed-to-seed analysis originating in each amygdala and hippocampus; fractional anisotropy (FA) was calculated along with the tracts. Controlling for preinjury behavior problems, general linear models examined the effect of injury type on behavioral outcomes and pathway FA, including group (TBI+EI vs. TDC; TBI vs. EI), age, sex, and their interactions. Injured children had higher postinjury internalizing problem scores than TDC, and FA was lower in several pathways connecting hippocampi with nucleus accumbens and parahippocampal cingulate. Internalizing and/or externalizing problems were associated with FA of pathways connecting hippocampi to amygdalae, medial orbitalfrontal cortex, and parahippocampal cingulate, as well as pathways connecting amygdale to thalami. The relation between FA and behavioral problems was negative for the TBI group but neutral to positive for the EI and TDC groups. Together, these findings suggest disrupted microstructural organization of the limbic-prefrontal circuitry as a neurobiological predictor of behavioral problems following TBI.

Federal agencies including the National Institutes of Health (NIH), the Department of Defense (DoD) Congressionally Directed Medical Research Program (CDMRP) Spinal Cord Injury Research Program (SCIRP), and the Department of Veterans Affairs (VA) provide the majority of funding for spinal cord injury (SCI) research in the United States. However, systematic evaluation of how funding is distributed across research areas, therapeutic approaches, and translational stages has been limited. To understand the distribution of funds, we curated and classified 1,589 federally funded SCI research awards from the NIH (2008-2023), the CDMRP SCIRP (2009-2023), and the VA (2017-2025). Each award was annotated based on the biological system or problem studied, the therapeutic intervention or approach utilized, and its placement along the translational continuum. Our analysis revealed that the NIH predominantly supports basic and early-stage translational research, especially in areas of SCI pathology, regeneration, and motor functional recovery. In contrast, the CDMRP funding is more concentrated on applied and clinical research, particularly in the areas of pain, bladder function, and neuromodulatory device development. The VA predominantly invests in rehabilitation-focused studies and interventions aimed at improving musculoskeletal and functional health outcomes. While the complementary missions of these agencies collectively support a diverse SCI research ecosystem, we identified critical gaps in funding for high-priority areas such as bowel/gastrointestinal health, cardiovascular function, and mental health. Furthermore, the recent discontinuation of the CDMRP SCIRP and proposed NIH budget reductions are projected to lead to an approximate 50% decline in federal SCI research funding by 2026-posing a substantial risk to the field's progress and threatening the stability of this ecosystem. These findings underscore the urgent need for coordinated, data-driven funding strategies that align more closely with the needs and priorities of the SCI community. To that end, we propose the development of a publicly accessible "living dashboard" to enhance transparency, foster interdisciplinary collaboration, and guide strategic investment in SCI research moving forward.

The objective of the Australian Traumatic Brain Injury (AUS-TBI) Initiative is to develop a data dictionary to inform data collection and facilitate prediction of outcomes of people who experience moderate-severe TBI in Australia. The aim of this systematic review was to summarize the evidence of the association between demographic, injury event, and social characteristics with outcomes, in people with moderate-severe TBI, to identify potentially predictive indicators. Standardized searches were implemented across bibliographic databases to March 31, 2022. English-language reports, excluding case series, which evaluated the association between demographic, injury event, and social characteristics, and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Abstracts and full text records were independently screened by at least two reviewers in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association. The review findings were discussed with an expert panel to determine the feasibility of incorporation of routine measurement into standard care. The search strategy retrieved 16,685 records; 867 full-length records were screened, and 111 studies included. Twenty-two predictors of 32 different outcomes were identified; 7 were classified as high-level (age, sex, ethnicity, employment, insurance, education, and living situation at the time of injury). After discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous predictors capable of enabling early identification of those at risk for poor outcomes and improved personalization of care through inclusion in routine data collection.