Ketamine is a dissociative anesthetic often used for airway management in trauma. While perceived to preserve hemodynamic stability, concerns exist regarding its effects on intracranial pressure and cardiac output in critically ill patients. There is a lack of studies evaluating outcomes after ketamine administration in the setting of traumatic brain injury (TBI). This study aimed to investigate the effects of ketamine on outcomes and physiological responses in a large cohort of TBI patients. We hypothesized that ketamine administration would not be associated with differences in survival, vital signs, or disposition outcomes compared with other induction medications when administered following TBI. This was a retrospective, observational study utilizing data from the Linking Investigations in Trauma and Emergency Services registry (2017–2021). Subjects were divided into two groups: those who received only ketamine ( n = 429) and those who received other induction medications (etomidate and/or propofol; n = 993). We compared 24-h mortality, initial in-hospital vital signs (systolic blood pressure [SBP], respiratory rate, heart rate, and Glasgow Coma Scale [GCS]), and hospital discharge disposition; a propensity score analysis adjusted for potential confounders including race, injury type, pre-hospital GCS, initial pre-hospital SBP and site location. Ketamine-exposed subjects were younger and presented with a worse clinical profile, including lower pre-hospital GCS (5 vs. 6, p < 0.01) and lower SBP (126.5 vs. 144.0 mmHg, p < 0.01) compared with the ketamine-unexposed group. Unadjusted analysis showed a significantly higher 24-h mortality rate in the ketamine-exposed group (3.5% vs. 1.4%, p = 0.02), as well as lower initial in-hospital vital signs. After propensity score adjustment, the odds of 24-h mortality remained significantly higher for the ketamine-exposed group (OR 2.358, p = 0.042). Hospital discharge disposition was not different between groups in any analysis. In this retrospective analysis, ketamine administration for pre-hospital airway management in TBI patients was associated with an increased 24-h mortality and lower in-hospital SBP, even after adjusting for baseline differences. However, injury severity and the length of time examined for mortality may explain the significant mortality association for ketamine in this study. Prospective studies are needed to examine the relationship between ketamine administration and mortality following TBI.

Traumatic brain injury (TBI) results from impact to the head that induces both primary and secondary injuries. Secondary injuries are characterized by downstream inflammation, metabolic dysfunction, and cell death manifest from the inflicting primary injury to the head. Secondary injury offers a window for therapeutic interventions, but the multifaceted nature of secondary injury is complicated, necessitating mechanistic tools to screen the efficacy of such interventions. As such, utilizing animal models to define the features of secondary injury mechanisms is critical for medications development. Various animal TBI models employ specialized equipment to recapitulate both primary and secondary injury aspects of human TBI. The organotypic hippocampal slice culture (OHSC) model offers a biological intermediate between live animal and dissociated cell culture models. In OHSC models, ex vivo tissue containing heterogenous hippocampal cell types is plated upon permeable culture membranes, which have the capacity to be manipulated. We, therefore, repurposed a commercially available impact device to mechanically distend the OHSC culture membrane, effectively inducing an indirect stretch injury to hippocampal tissue. This stretch injury technique causes characteristic secondary injury trauma, such as widespread cell death, loss of neuronal viability, and production of reactive oxygen species, following the initial insult. Importantly, both the impact force and dwell time of the membrane distention are scalable, a modular feature widely employed across other animal TBI models. This OHSC TBI model may lend itself to high-throughput preliminary assessment of therapeutic efficacy for treatment of secondary injury in animal TBI models.

A straightforward path to successful scientific translation remains uncharted, particularly in a complex progressive condition such as spinal cord injury (SCI), which affects multiple body functions simultaneously. Evolving regulatory requirements add to the complexity and expense of attaining a treatment that is both safe and efficacious. Although rare, there are examples of SCI scientists who have successfully navigated the "valley of death" from discovery science to completed clinical trials. This article reflects the translational journey of five SCI scientists who have encountered similar and different scenarios while striving to launch or complete a clinical trial. Learning from these experiences has identified lessons learned and gaps, particularly with respect to funding and support for SCI translation.

Heterogeneity associated with traumatic brain injury (TBI) outcomes necessitates validated controls to differentiate pathophysiological events from experimental methodology. While craniectomies are commonly used in TBI research, inadvertent dura disruption can result in structural deficits, impacting cellular function and neurobehavioral outcomes. Thus, there is a critical need to evaluate the effect of craniectomy on neurological outcomes to develop robust experimental controls and improve pre-clinical TBI research. In this study, craniectomy mice undergoing surgical and anesthetic intervention were assessed against naïve mice for neurological deficits and pathophysiological dysfunction. T2-weighted magnetic resonance imaging confirmed that no lesions or cavities were observed postcraniectomy. However, the cranial defect induced midline shifting over time, which might contribute to poorer behavioral outcomes in the novel object recognition assessment. Immunohistochemical analysis demonstrated an increase in GFAP and Iba1, indicating craniectomy elicited an inflammatory response. Indeed, neuroinflammation led to an increase in neuronal cell death, as measured by increases in α-II-spectrin breakdown products. However, craniectomy mice also presented with decreases in LC3BII and SQSTM1 expression, indicating an inhibition of autophagy. Last, craniectomy contributed to the altered expression of several tight junction proteins, including occludin and claudin-1/5, suggesting the blood–brain barrier was perturbed. Overall, the deficits associated with craniectomy preclude its use as an adequate sole control for TBI research, as craniectomy limits translational insights into the neurological changes observed in TBI. Additionally, these results support the need for the use of closed-head injury models where uninjured control mice do not show significant confounding minor injury patterns.

Spinal cord injury (SCI) triggers an inflammatory response that is partially mediated by the inflammasome and the production of pro-inflammatory cytokines. We have previously shown that pannexin-1 is involved in the activation of the inflammasome, and that probenecid inhibits this caspase-1-mediated inflammatory process. In this study, we employed an invivo model of contusive SCI to investigate the therapeutic effect of acute probenecid administration on histopathological and functional outcomes following SCI. Adult female Fischer rats (n = 46) underwent moderate thoracic SCI produced by dropping a 10 g weight from a height of 12.5 mm onto the exposed cord at T9, assigned three different groups, PBS administration group, and 1, 10, 100 mg/kg probenecid group, those were injected subcutaneously 15 min and 12 h after SCI. The sham group (n = 11) was the group that only had a laminectomy and did not have SCI. Histopathological analysis by Luxol Fast Blue/hematoxylin and eosin staining revealed that the penumbra volume was significantly reduced in the probenecid 100 mg/kg group compared with the PBS group. CatWalk gait analysis was performed at 7 weeks after SCI, which showed significant differences in coordination between the PBS and the probenecid 100 mg/kg-treated groups. Acute administration of probenecid after SCI resulted in the preservation of penumbra formation and coordination function in a thoracic SCI rat model. This report suggests that probenecid, an inhibitor of pannexin-1, has the potential to prevent secondary injury after SCI and improve outcomes following SCI.

Traumatic brain injury is a world-leading cause of disability. Current treatments are not sufficient to promote neurological recovery. Intracerebral transplantation of allogeneic mesenchymal stem cells, specifically SB623, has shown promise in achieving better neurological recovery compared with a sham surgery group in the STEMTRA trial. However, the optimal location for cell transplantation remains unclear, as transplanted lesions vary between patients. This study aimed to explore the relationship between functional recovery and the location of transplanted lesions. This study included all Japanese subjects from the STEMTRA trial who were assigned to the cell transplantation group. Functional recovery was assessed by the difference in Fugl–Meyer Motor Scale (FMMS) scores between the screening period and 24 or 48 weeks post-transplantation. An FMMS score improvement of >8 was defined as an improved group. Lesions responsible for motor deficits were categorized into three groups: motor cortex (Cortex), deep white matter (DWM), or both (Cortex and DWM). Data on the 15 transplanted sites per patient were obtained from surgical navigation software, and the distance from the damaged area to the transplanted sites was calculated. Twelve patients were included in this post-hoc analysis. No patients in the 2.5 × 106 cells group showed improvement and were therefore excluded from further analysis. Five patients were categorized into the Cortex group and four into the DWM group. The distance between the transplanted site and the injury point ranged from 0 to 39 mm. A moderate to strong trend of correlations was observed, suggesting that a shorter distance is preferable for the motor cortex group, while a greater distance is preferable for the DWM group. The optimal site for stem cell transplantation may be different from the damaged site of the patient; however, a further large number cohort is necessary to elucidate this hypothesis.

Insomnia and depression are common co-morbidities associated with mild traumatic brain injury (mTBI). Data from Transforming Research and Clinical Knowledge in TBI, a longitudinal cohort study of TBI and orthopedic controls (OTC), were used to examine insomnia trajectories and the temporal relationship between insomnia and depressive symptoms during recovery. mTBI (n = 1,557) and OTC (n = 226) adult patients with no psychiatric or sleep disorder history were assessed at 2 weeks and 3, 6, and 12 months post-injury, and at three long-term assessments between 2 and 10 years post-injury. Latent class growth analysis identified five insomnia trajectory classes during the first year post-injury, revealing 25% with persistent insomnia, 4% improving, and 71% below the clinical cutoff. A random intercept cross-lagged panel model tested the lagged effects between insomnia and depression. In addition to being longitudinally correlated (φ = 0.74, p < 0.001), depressive symptomatology operated as a leading indicator of worsening insomnia from 3 to 6 months post-injury (β = 0.20, p = 0.001) across the whole sample. The multigroup model revealed less insomnia (α = -0.31, p = 0.006) and depressive symptoms (α = -0.52, p < 0.001) in OTC relative to mTBI. From 1 to 5-10 years post-injury, mTBI low insomnia classes remained stable, while the highest class improved moderately (-5.50, 95% confidence interval: -7.84, -3.16, p < 0.001). Our findings suggest depressive symptoms may lead to worsening insomnia during the subacute recovery period and that a subset of patients with mTBI may suffer from new-onset insomnia that persists for more than 5 years.

Mild traumatic brain injury (mTBI) can produce persistent cognitive and behavioral deficits. These impairments result in a reduced quality of life and difficulty returning to work, school, or other activities. Individuals with repeated injuries show increased risk for greater cognitive impairment and persistence of symptoms. A variety of pharmacological approaches have been tried to limit cognitive symptoms and other aspects of secondary injury following mTBI. However, their efficacy and ability to treat the sequela of mTBI remains disputed and no FDA-approved drug exists for mTBI. However, neurotrophins have considerable promise as regenerative therapies for mTBI by exhibiting procognitive, neuroprotective, and anti-inflammatory actions. One neurotrophin, hepatocyte growth factor, and its receptor MET (HGF/MET) are upregulated in response to CNS injury within the prefrontal cortex and other regions supporting memory and higher cognitive function impaired by TBI. HGF/MET activation can be anti-inflammatory and neuroprotective, yet an understanding of its actions on cognitive function after mTBI is limited. Using a closed-head midline impact model of mild TBI, we characterized the actions of the HGF/MET system on working memory performance after repeated injury. Following repeated mild TBI, the HGF/MET-positive modulator dose-dependently rescued the working memory deficits following injury. These actions indicate that neuroptrophic transmitter systems, including HGF/MET, may hold critical pharmacological targets for treating the neurosequela of TBI.

Clinically relevant models of concussion are critical in understanding the pathophysiology of concussion and its long-term outcomes. To bridge the gap between preclinical and clinical research, animal models of concussion should be produced by mild traumatic brain injuries (mTBIs) that possess the same physical and biomechanical properties found in the mTBIs that cause concussion in humans. Specifically, to have good construct validity the mTBIs used in animal models of concussion should feature closed-head impacts with unrestrained head and body motion, resulting in peak angular velocities that approximate the human experience. We describe a mouse model of concussion using a cortical impactor to deliver closed-head mTBIs. Mice are placed on a break-away platform that allows free head and body movement during and after impact resulting in rapid head rotation. We assessed this model of concussion in over 100 mice carrying humanized versions of the genes encoding the amyloid precursor protein and tau. We found that this method consistently produced injuries with peak angular velocities in mice that, when scaled, approximated the average peak angular velocities reported in concussive football impacts. Face validity of this model of concussion was evaluated by histopathology and revealed that three impacts delivered 24 hours apart led to diffuse axonal injury, astrogliosis, and microglial activation one week after injury, particularly in white matter tracts aligned orthogonally to the axis of rotation. Persistent axonal degeneration was observed up to 6 months postinjury. This mouse model of concussion captures key biomechanical and pathological features of human concussions.

The central nervous system (CNS) evokes a complex inflammatory response to injury. Inflammatory cascades are present in traumatic, infectious, and noninfectious disorders affecting the brain. It contains a mixture of pro- and anti-inflammatory reactions involving well-known proteins, but also numerous proteins less explored in these processes. The aim of this study was to explore the distinct inflammatory response in traumatic brain injury (TBI) compared with other CNS injuries by utilization of mass-spectrometry. In total, 56 patients had their cerebrospinal fluid (CSF) analyzed with the use of mass-spectrometry. Among these, CSF was collected via an external ventricular drain (EVD) from n = 21 patients with acute TBI. The resulting protein findings were then compared with CSF obtained by lumbar puncture from n = 14 patients with noninfectious CNS disorders comprising relapsing-remitting multiple sclerosis, anti-N-methyl-d-aspartate-receptor encephalitis, acute disseminated encephalomyelitis, and n = 14 patients with progressive multifocal leukoencephalopathy, herpes simplex encephalitis, and other types of viral meningitis. We also utilized n = 7 healthy controls (HCs). In the comparison between TBI and noninfectious inflammatory CNS disorders, concentrations of 55 proteins significantly differed between the groups. Among them, 23 and 32 proteins were up- and downregulated, respectively, in the TBI group. No proteins were uniquely identified in either group. In the comparison of TBI and HC, 51 proteins were significantly different, with 24 and 27 proteins being up- and downregulated, respectively, in TBI. Two proteins (fibrinogen gamma chain and transketolase) were uniquely identified in all samples of the TBI group. Also in the last comparison, TBI versus infectious inflammatory CNS disorders, 51 proteins differed between the two groups, with 19 and 32 proteins being up- and downregulated, respectively, in TBI, and no unique proteins being identified. Due to large discrepancies between the groups compared, the following proteins were selected for further deeper analysis among those being differentially regulated: APOE, CFB, CHGA, CHI3L1, C3, FCGBP, FGA, GSN, IGFBP7, LRG1, SERPINA3, SOD3, and TTR. We found distinct proteomic profiles in the CSF of TBI patients compared with HC and different disease controls, indicating a specific interplay between inflammatory factors, metabolic response, and cell integrity. In relation to primarily infectious or inflammatory disorders, unique inflammatory pathways seem to be engaged, and could potentially serve as future treatment targets.