Traumatic brain injury (TBI) is the leading cause of death and disability in the industrialized world. This pilot study investigated demographic, clinical and environmental factors associated with return to work (RTW) among workers who sustained a mild to moderate work-related TBI (WrTBI). Using a retrospective cohort design, participants were recruited through an outpatient clinic dedicated to evaluating injured workers after a WrTBI. A mailed survey and medical record abstraction tool were used for data collection. Of the 40 injured workers who participated in this study, 19 reported working at time of follow-up. Those who were unable to RTW scored significantly lower on measures of emotional well-being; there were no significant between-group differences in cognitive or physical impairments. Gradual RTW and workplace accommodations were reported as key factors facilitating RTW. Our findings provide information that addresses improved rehabilitation and management of WrTBI as well as better education and support for employers.

Traumatic brain injury (TBI) is the leading cause of death and disability in the industrialized world. This pilot study investigated demographic, clinical and environmental factors associated with return to work (RTW) among workers who sustained a mild to moderate work-related TBI (WrTBI). Using a retrospective cohort design, participants were recruited through an outpatient clinic dedicated to evaluating injured workers after a WrTBI. A mailed survey and medical record abstraction tool were used for data collection. Of the 40 injured workers who participated in this study, 19 reported working at time of follow-up. Those who were unable to RTW scored significantly lower on measures of emotional well-being; there were no significant between-group differences in cognitive or physical impairments. Gradual RTW and workplace accommodations were reported as key factors facilitating RTW. Our findings provide information that addresses improved rehabilitation and management of WrTBI as well as better education and support for employers.

Traumatic brain injury (TBI) effects a large number of individuals, both civilians and military personnel, every year. The neuroinflammatory response mounted in the brain following a head injury continues long after the effects of initial subside. While it was initially thought to only occur in moderate or severe TBI, the deleterious effects of this cascade have recently been identified in patients with mild TBI (mTBI). Hypopituitarism is an often underreported condition and can result from TBI of all severity. The long-term sequelae of TBI can manifest in or exacerbate many other comorbidities of brain injury, such as neuroendocrine dysfunction or mental health conditions. Both TBI and hypopituitarism can present with symptoms similar to some psychiatric disorders, or exacerbation comorbid conditions. Veteran patients presenting to their primary care providers with symptoms of irritability, depression, anxiety, or cognitive and behavioral changes may meet criteria to receive diagnoses of psychiatric illnesses prevalent in the military population, while not being evaluated for pituitary dysfunction, and thus receive inadequate treatment. The proposed study aims to identify the prevalence of patients that are receiving psychiatric treatment that have both a history of mTBI and reduced levels of pituitary hormones on serum assays. By identifying a significant portion of this population, future studies can assess the impact that hormonal replacement has on success of psychotherapy, resolution of symptoms, and impact on functional status, among other factors.

This quantitative research is on the efficacy of Minnesota Statute 144.574 enacted in 2005 in response to the growing awareness of behavior leading to inflicted Traumatic Brain Injuries (iTBI) in infants and children. The model for this research is grounded in the Theory of Reasoned Action wherein the education of new parents which graphically explains the physiologic changes to the structural architecture of the brain post-trauma, paired with their signature on a social contract (SC), demonstrated a reduction in incidence. Because the enacted statute does not include the signing of a SC, nor does it require face-to-face education as in the model, Statute 144.574 cannot claim to be completely grounded in medical science. The result is that neither legislators nor the medical and public health community know whether the statute is effective in lowering incidence. This research was designed to explore the difference in the incidence pre-and post-enactment, in rural vs. urban communities, the proportion of incidence and ethnicity, and an ordinal shift in the distribution of severity. All births in Minnesota from 1998 through 2017 were included. Cases defined using International Classification of Disease were extracted from secondary data from the brain and spinal cord injury, hospital discharge, and vital statistics databases. A Z-test was employed to compare the incidence in a control cohort of infants and children born prior to enactment to the incidence of same in an interventional cohort born post-enactment. Results suggest the statute has not resulted in lowering incidence, have uncovered an unanticipated statistically significant increase in rural vs. urban incidence, yet point to a trend in favor of less severe iTBI. These results represent a positive social change which is grounded in the society's imperative and social justice of protecting children by informing public health officials, caregivers, and legislators of the need for meaningful reform and strengthening of programs leading to lowering the incidence of iTBI in children in Minnesota.

Purpose: Interdisciplinary research in epidemiology, neurology, neuroscience, and sports medicine commonly highlight the dangerous short- and long-term sequelae of sport-related concussions (SRC). Despite advancements in clinical evaluation and recognition, many SRCs are not properly diagnosed and managed, leaving many athletes in danger of acute and chronic neurological deficits. Epidemiological studies suggest the prevalence of chronic traumatic encephalopathy (CTE) is three times, and Alzheimer's disease is four times greater in former athletes with a history of SRC than non-athletes. The underlying mechanisms linking SRC and contact-sport participation to neurodegeneration are not fully understood. Herein, I hypothesized that transient insufficiency of the lymphatic and glymphatic clearance systems in the central nervous system (CNS) could play a crucial role in the SRC-mediated neurological conditions. Therefore, this study aimed to examine the differences in plasma levels of extracellular vesicles (EV) that are associated with the lymphatic and glymphatic clearance systems of the CNS among athletes following sport-related head impacts. Participants: Plasma EV concentrations were analyzed in collegiate athletes (controls n=29, SRC n=19) with and without SRC. In a parallel study, fourteen college-aged soccer players participated in a laboratory-based, repetitive subconcussion paradigm. All participants provided written informed consent, and the study was approved by institutional review board at Temple University. Methods: We evaluated EVs containing markers associated with the CNS lymphatic and glymphatic systems, including lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), astrocyte-specific glial fibrillary acidic protein (GFAP), aquaporin 4 (AQP4), and the platelet and endothelial cell adhesion molecule 1(PECAM-1 or CD31). Tetraspanin-28 (CD81) was used as an EV-specific marker. Blood samples from athlete controls were collected once during preseason baseline assessments. Samples from athletes with SRC were collected within 72 hours of injury. Whole blood was double-centrifuged to obtain platelet-poor plasma, snap-frozen in liquid nitrogen, and stored at -80°C until analyzed. Quantification of plasma EVs was performed using spectral flow cytometry. Mann-Whitney U tests were used for group comparisons of single and double-positive EV concentrations, and receiver-operating characteristic curve (ROC) and area under the curve (AUC) analyses assessed diagnostic efficacy. Within-group changes in plasma EVs following repetitive, subconcussive head impacts were assessed with Friedman's test using Dunn's correction for multiple comparisons. Results: Among athletes with SRC, plasma concentrations of LYVE1+EVs and CD31+EVs were significantly elevated within 72 hours of injury compared to controls (LYVE1+EVs, p < 0.0001; CD31+EVs, p = 0.005). ROC analysis revealed plasma concentrations of LYVE1+EVs demonstrated significant diagnostic accuracy to differentiate athletes with SRC from athlete controls (AUC: 0.971, 95% C.I. = 0.933-1.000, p < 0.0001). Notably, concentrations of LYVE1+/CD81+ double-positive EVs, CD31+/CD81+ double-positive EVs, and GFAP+/CD81+ double-positive EVs were significantly higher among athletes with SRC within 72 hours of injury compared to control athletes (p < 0.0001; p = 0.0002; p < 0.0001, respectively). Plasma AQP4+/GFAP+ double-positive EVs and AQP4+/CD81+ double-positive EVs were not. However, plasma concentrations of GFAP+/CD81+ double-positive EVs and AQP4+/GFAP+ double-positive EVs were significantly elevated after repetitive, subconcussive head impacts (p < 0.0001 and p = 0.004, respectively). Conclusion: Plasma concentrations of double-positive EVs, including LYVE1+/CD81+EVs, CD31+/CD81+EVs, and GFAP+/CD81+EVs, may be promising biomarkers for acute SRC. EVs associated with the glymphatic system, GFAP+/CD81+EVs and AQP4+/GFAP+EVs, were significantly elevated after repetitive subconcussive head impacts. The differences observed in EV responses to SRC and subconcussion may provide novel mechanistic insights about sport-associated neurodegeneration for current and future athletes. / Kinesiology

ABSTRACT: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. METHODS: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.

Objectives: There is evidence that childhood traumatic brain injury (TBI) is associated with increased risk of offending and violent crime. This study aimed to explore associations between TBI in a group of delinquent and vulnerable young people (VYP) at risk of offending, and facial emotion recognition (FER) abilities, inhibition control (Stop-IT) and self-reported reactive-proactive aggression (RPQ). Methods: There were two studies. The first study used a cross sectional between group design to compare 45 VYP (with and without TBI) and a control group of 59 students on FER task measuring emotion recognition accuracy of six basic emotions. The second study examined differences between TBI and non-TBI groups in the VYP sample (N=21) on a Stop-IT task, FER accuracy and self-reported reactive-proactive aggression. Results: A history of TBI was reported by 60% of the VYP group (48.9% with loss of consciousness [LoC]), whereas 30% of the control group reported a history of TBI (25.4% with LoC). The VYP group (with and without TBI) demonstrated a similar pattern of reduced overall FER accuracy that was significantly different to the control group. Compared to the control group, The VYP groups (with and without TBI) were less accurate on recognising anger, disgust, sadness and surprise, but not happy and fear. There were no significant differences between the TBI- and non-TBI groups. The second study did not find any significant differences between the TBI and non-TBI groups on overall FER accuracy, Stop-IT performance, and RPQ scores. There were also no significant associations between these measures. Conclusions: Future research requires larger samples that enable investigating the association between different severity of TBI, FER and inhibition control ability. Better and more youth-friendly measures are also needed.

Traumatic brain injury (TBI) remains an important cause of morbidity and mortality within society. TBI may result in both focal and diffuse brain injury. Diffuse traumatic axonal injury (TAI) is an important pathological substrate of TBI, and can be associated with a range of clinical states, ranging from concussion through to death, the clinical severity being associated with a number of factors related to the injury. A retrospective study was conducted using 406 cases with TBI, from the archive of the Academic Department of Pathology (Neuropathology) University of Edinburgh, during the period from1982 and 2005. This cohort was sequential and provided a unique description of the range of pathologies associated with fatal TBI within the Edinburgh catchment area. All the data was collected on a proforma and analysed to provide a description of the incidence in the injury patterns among the Edinburgh cohort. This cohort was then used to provide cases to try and critically assess the mechanisms of axonal injury in TBI. A study was undertaken to investigate TAI in an experimental model of non-impact head injury in a gyrencephalic mammalian model (piglet model) and in human autopsy materials using immunohistochemical analysis of a range of antibodies, and to define the distribution of axonal injury with flow and neurofilament markers in TAI. A further objective was to examine the expression of β-APP as an indicator of impaired axonal transport, three neurofilament markers targeting NF-160, NF-200, and the phosphorylated form of the neurofilament heavy chain (NFH), in different anatomical regions of piglet and human brains. The double immunofluorescence labelling method was then employed to investigate the hypothesis of co-localisation between β-APP and each one of the previous neurofilament markers. The animal studies showed significant differences in NF-160 between sham and injured 3-5 days old piglet cases (6 hour survival) and between 3-5 days sham and injured, when stained with SMI-34 antibody. In 4 weeks old piglet cases (6 hour survival), immunoreactivity of β-APP was significantly higher in injured than control. No other significant differences for any of the antibodies were noted, based on age, velocity, and survival time. Human results suggested that the brainstem had a higher level of β-APP and NF-160 than the corpus callosum and internal capsule. Co-localisation of β-APP with NFs was not a consistent feature of TAI in piglet and human brains, suggesting that markers of impaired axonal transport and neurofilament accumulation are sensitive to TAI, but may highlight different populations involved in the evolution of TAI.

Introduction: Annually, an estimated 2.5 million traumatic brain injuries (TBI) occur in the United States, of which, over 50,000 result in deaths. Currently, 5.3 million Americans are living with neurological dysfunction secondary to TBIs leading to a $60 billion dollar cost in medical expenses and productivity losses. To date, there are limited treatments available to cure or ease the morbidity of TBI. Despite preventative efforts, traumatic brain injuries (TBI) occur at a staggering rate and it is estimated that 15-20% of survivors develop persistent post-traumatic neurological impairment. The purposed source of neurological dysfunction is a result of circuit reorganization when the brain rebuilds itself. After diffuse TBI, rodents have been shown to develop a late-onset, gain-of-function sensory sensitivity to whisker stimulation; similar to phonophobia and photophobia experienced by human TBI survivors. This morbidity coincides with evidence of post-TBI circuit reorganization, however the etiology of post-traumatic neurological impairment remains largely unknown. Thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) are heavily expressed during pediatric neuronal synapse development. Expression of TSPs, however declines with age. Mechanistically during development, TSP mediates synaptogenesis via bindingα2δ-1 subunit of the voltage-gated calcium channel receptor (α2δ-1). After neurological insult, re-expression of TSPs has been demonstrated and experimental modulation of the TSP/α2δ-1 interaction has led to changes in morbidity. We therefore hypothesize that experimental diffuse TBI will result in re-expression of TSPs, which will be synchronous with increases in synaptic markers in the thalamocortical whisker circuit. Methods: Adult male Sprague-Dawley rats underwent sham or moderate midline fluid percussion brain injury. At multiple time points over 2-months post-injury, expression of TSPs and synaptic markers were quantified from thalamocortical circuit (ventroposterior medial thalamus (VPM), primary somatosensory barrel fields (S1BF)) biopsies using qPCR and automated capillary westerns, respectively. Results: TSP-1 gene expression and protein levels increase in the VPM during the first week after injury. Gene expression of TSP-1 did not significantly change over time in the S1BF, however, there was a significant increase in protein levels in the first and second weeks after injury. No significant changes were demonstrated in synaptic markers in the VPM over the time course. TSP-1 protein levels demonstrated a similar multimodal response to synaptic markers in the S1BF.Conclusion: Re-expression of TSP-1 and synchronous changes in synaptic marker supports a role for TSP-1 mediated synaptogenesis after experimental diffuse TBI in the S1BF. These data positions us for future investigation of pharmacological inhibition of TSP-mediated synaptogenesis after TBI; which may represent a prophylactic strategy against circuit reorganization and neurological dysfunction after TBI.

Traumatic brain injury (TBI) is a devastating health problem based on its high incidence, economic burden, and lack of effective pharmacological treatment. Individuals who suffer an injury often experience lifelong disability. TBI results in abrupt, initial cell damage leading to delayed neuronal death. The calcium-activated proteases, calpains, are known to contribute to this secondary neurodegenerative cascade. Prolonged activation of calpains results in proteolysis of numerous cellular substrates including cytoskeletal components, membrane receptors, and cytosolic proteins, contributing to cell demise despite coincident expression of calpastatin, the specific inhibitor of calpains. A comprehensive analysis using two separate calpastatin transgenic mouse lines was performed to test the hypothesis that calpastatin overexpression will reduce posttraumatic calpain activity affording neuroprotection and behavioral efficacy. Increased calpastatin expression was achieved using transgenic mice that overexpress the human calpastatin (hCAST) construct under control of a neuron-specific calcium-calmodulin dependent kinase II alpha or a ubiquitous prion protein promoter. Both transgenic lines exhibited enhanced calpastatin expression within the brain, extending into peripheral tissues under the prion protein promoter. hCAST overexpression significantly reduced protease activity confirmed by reductions in acute calpain-mediated substrate proteolysis in the cortex and hippocampus following controlled cortical impact brain injury. Aspects of posttraumatic motor and cognitive behavioral deficits were also lessened in hCAST transgenic mice compared to their wildtype littermates. However, volumetric analyses of neocortical contusion revealed no histological neuroprotection at either acute or long-term time points in either transgenic line. Partial hippocampal neuroprotection observed at a moderate injury severity in neuron-specific calpastatin overexpressing transgenic mice was lost after severe TBI. Greater levels of calpastatin under the prion protein promoter line failed to protect against hippocampal cell loss after severe brain injury. This study underscores the effectiveness of calpastatin overexpression in reducing calpain-mediated proteolysis and behavioral impairment after TBI, supporting the therapeutic potential for calpain inhibition. However, the reduction in proteolysis without accompanied neocortical neuroprotection suggests the involvement of other factors that are critical for neuronal survival after contusion brain injury. Augmenting calpastatin levels may be an effective method for calpain inhibition and may have efficacy in reducing behavioral morbidity after TBI and neurodegenerative disorders.