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Mouse models are used to better understand brain injury mechanisms in humans, yet there is a limited understanding of biomechanical relevance, beginning with how the murine brain deforms when the head undergoes rapid rotation from blunt impact. This problem makes it difficult to translate some aspects of diffuse axonal injury from mouse to human. To address this gap, we present the two-dimensional strain field of the mouse brain undergoing dynamic rotation in the sagittal plane. Using a high-speed camera with digital image correlation measurements of the exposed mid-sagittal brain surface, we found that pure rotations (no direct impact to the skull) of 100-200 rad/s are capable of producing complex strain fields that evolve over time with respect to rotational acceleration and deceleration. At the highest rotational velocity tested, the largest tensile strains (≥ 21% elongation) in selected regions of the mouse brain approach strain thresholds previously associated with axonal injury in prior work. These findings provide a benchmark to validate the mechanical response in biomechanical computational models predicting diffuse axonal injury, but much work remains in correlating tissue deformation patterns from computational models with underlying neuropathology., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Traumatic brain injury (TBI) is one of the foremost causes of disability and death globally. Prerequisites for successful therapy of disabilities associated with TBI involved improved knowledge of the neurobiology of TBI, measurement of quantitative changes in recovery dynamics brought about by therapy, and the translation of quantitative methodologies and techniques that were successful in tracking recovery in preclinical models to human TBI. Frequently used animal models of TBI in research and development include controlled cortical impact, fluid percussion injury, blast injury, penetrating blast brain injury, and weight-drop impact acceleration models. Preclinical models of TBI benefit from controlled injury settings and the best prospects for biometric quantification of injury and therapy-induced gradual recovery from disabilities. Impact acceleration closed head TBI paradigm causes diffuse TBI (DTBI) without substantial focal brain lesions in rats. DTBI is linked to a significant rate of death, morbidity, and long-term disability. DTBI is difficult to diagnose at the time of hospitalization with imaging techniques making it challenging to take prompt therapeutic action. The weight-drop method without craniotomy is an impact acceleration closed head DTBI model that is used to induce mild/moderate diffuse brain injuries in rodents. Additionally, we have characterized neuropathological and neurobehavioral outcomes of the weight-drop model without craniotomy for inducing closed head DTBI of graded severity with a range of mass of weights (50-450 gm). This chapter also discusses techniques and protocols for measuring numerous functional disabilities and pathological changes in the brain brought on by DTBI., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Drug development in traumatic brain injury (TBI) has been impeded by the complexity and heterogeneity of the disease pathology, as well as limited understanding of the secondary injury cascade that follows the initial trauma. As a result, patients with TBI have an unmet need for effective pharmacological therapies. One promising drug candidate is cyclosporine, a polypeptide traditionally used to achieve immunosuppression in transplant recipients. Cyclosporine inhibits mitochondrial permeability transition, thereby reducing secondary brain injury, and has shown neuroprotective effects in multiple preclinical models of TBI. Moreover, the cyclosporine formulation NeuroSTAT ® displayed positive effects on injury biomarker levels in patients with severe TBI enrolled in the Phase Ib/IIa Copenhagen Head Injury Ciclosporin trial (NCT01825044). Future research on neuroprotective compounds such as cyclosporine should take advantage of recent advances in fluid-based biomarkers and neuroimaging to select patients with similar disease pathologies for clinical trials. This would increase statistical power and allow for more accurate assessment of long-term outcomes., (© 2023. The Author(s).)

Diffuse axonal injury (DAI) caused by acceleration is one of the most prominent forms of blast-induced Traumatic Brain Injury. However, the mechanical mechanism and indicator of axonal deformation-induced injury under blast-type acceleration with high peak and short duration are unclear. This study constructed a multilayer head model that can reflect the response characteristics of translational and rotational acceleration (the peak time of which is within 0.5 ms). Based on von Mises stress, axonal strain and axonal strain rate indicators, the physical process of axonal injury is studied, and the vulnerable area under blast-type acceleration load is given. In the short term (within 1.75 ms), dominated by sagittal rotational acceleration peaks, the constraint of falx and tentorium rapidly imposes the inertial load on the brain tissue, resulting in a high-rate deformation of axons (axonal strain rate of which exceed 100 s -1 ). For a long term (after 1.75 ms), fixed-point rotation of the brain following the head causes excessive distortion of brain tissue (von Mises stress of which exceeds 15 kPa), resulting in a large axonal stretch strain where the main axonal orientation coincides with the principal strain direction. It is found that the axonal strain rate can better indicate the pathological axonal injury area and coincides with external inertial loading in the risk areas, which suggests that DAI under blast-type acceleration overload is mainly caused by the rapid axonal deformation instead of by the excessive axonal strain. The research in this paper helps understand and diagnose blast-induced DAI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

More than two decades ago, Marmarou published a valid model for producing diffuse axonal injury (DAI) in rats. Since then, both mild and severe injuries have been obtained by researchers using the original method and a weight of 450 g. However, the diffuse brain injuries produced in rats were only similar to those seen in humans when the rats sustained severe brain injuries. In these cases, rat mortality in the original article was around 50%, and the cause of death was prolonged apnea post-impact. Rat survival after impact is critical for studying the progression of DAI. In order to explain the cause of death in human victims with cranial trauma who do not show gross brain injury, testing for the presence of DAI is essential. Thus, in order to minimize local and cervical injuries to increase rat survival, attention should be paid to the following aspects: a wider head protector disc should be used, the head of the rat should be elevated at the time of impact, and the foam bed should be soft enough to allow the movement caused by acceleration. With our modified method, rat survival increased by 30% compared to the original model (80% versus 50%). Moreover, 85.7% of rats demonstrated DAI after 24 h of survival. With these modifications, injuries appear in the same locations as in humans; thus, the method is suitable for the study of traumatic DAI in humans., (© 2023 American Academy of Forensic Sciences.)

Traumatic brain injury (TBI) has high morbidity and poor prognosis and imposes a serious socioeconomic burden. Traumatic axonal injury (TAI), which is one of the common pathological changes in the primary injury of TBI, is often caused by the external force to the head that causes the white matter bundles to generate shear stress and tension; resulting in tissue damage and leading to the cytoskeletal disorder. At present, the forensic pathological diagnosis of TAI-caused death is still a difficult problem. Most of the TAI biomarkers studied are used for the prediction, evaluation, and prognosis of TAI in the living state. The research subjects are mainly humans in the living state or model animals, which are not suitable for the postmortem diagnosis of TAI. In addition, there is still a lack of recognized indicators for the autopsy pathological diagnosis of TAI. Different diagnostic methods and markers have their limitations, and there is a lack of systematic research and summary of autopsy diagnostic markers of TAI. Therefore, this study mainly summarizes the pathological mechanism, common methods, techniques of postmortem diagnosis, and corresponding biomarkers of TAI, and puts forward the strategies for postmortem diagnosis of TAI for forensic cases with different survival times, which is of great significance to forensic pathological diagnosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite being a major health concern, little is known about the pathophysiological changes that underly concussion. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage-gated sodium channels (NaChs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain's network signaling machinery, changes in their integrity have not been studied in context with DAI. Here, we utilized a clinically relevant swine model of concussion that induces evolving axonal pathology, demonstrated by accumulation of amyloid precursor protein (APP) across the white matter. Over a two-week follow-up post-concussion with this model, we found widespread loss of NaCh isoform 1.6 (Nav1.6), progressive increases in NOR length, the appearance of void and heminodes and loss of βIV-spectrin, ankyrin G, and neurofascin 186 or their collective diffusion into the paranode. Notably, these changes were in close proximity, yet distinct from APP-immunoreactive swollen axonal profiles, potentially representing a unique, newfound phenotype of axonal pathology in DAI. Since concussion in humans is non-fatal, the clinical relevance of these findings was determined through examination of post-mortem brain tissue from humans with higher levels of acute traumatic brain injury. Here, a similar loss of Nav1.6 and changes in NOR structures in brain white matter were observed as found in the swine model of concussion. Collectively, this widespread and progressive disruption of NaChs and NOR appears to be a form of sodium channelopathy, which may represent an important substrate underlying brain network dysfunction after concussion., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Paroxysmal sympathetic hyperactivity (PSH) is a syndrome of excessive sympathetic activity, mainly occurring in severe traumatic brain injury. However, few studies have reported the frequency of PSH and its related risk factors in adult patients with brain injury., Methods: We performed this systematic review and meta-analysis to estimate the combined incidence of PSH and the associated risk factors in adult patients with brain injury. This study was registered with the PROSPERO international prospective register of systematic reviews (https://www.crd.york. ac.uk/PROSPERO/Identifier: CRD 42021260493), and a systematic search was conducted of the scientific databases Embase, PubMed, Web of Science, Cochrane Library, and Google Scholar. All identified observational studies regarding the incidence and risk factors of PSH in adult patients with brain injury were included. Two authors extracted data independently; data were analyzed by STATA version 16., Results: The search yielded 9 studies involving 1643 adult patients. PSH was detected in 438 patients. The combined incidence of PSH in adult patients with brain injury was 27.4% (95% confidence interval [CI], 0.190-0.358). The risk factors include patients' age (SMD = -0.592; I 2  = 77.5%; 95% CI, -1.027 to -0.156; P = 0.008), traffic accident (odds ratio [OR], 1.783; I 2  =18.0%; 95% CI, 1.128-2.820; P = 0.013), admission Glasgow Coma Scale score (SMD = -1.097; I 2  =28.3%; 95% CI, -1.500 to -0.693; P = 0.000), hydrocephalus (OR, 3.936; I 2  =67.9%; 95% CI, 1.144-13.540; P = 0.030), and diffuse axonal injury (OR, 4.747; I 2  =71.1%; 95% CI, 1.221-18.463; P = 0.025) and were significantly associated with the presence of PSH after brain injury., Conclusions: PSH occurs in nearly a quarter of adult patients with brain injury. Patient's age, traffic accident, admission Glasgow Coma Scale score, hydrocephalus, and diffuse axonal injury were risk factors for PSH in adult patients with brain injury. These findings may contribute to novel strategies for early diagnosis and interventions that aid in the rehabilitation of patients with brain injury., (Copyright © 2022. Published by Elsevier Inc.)

Traumatic brain injury (TBI) contributes to a significant portion of the injuries resulting from motor vehicle crashes, falls, and sports collisions. The development of advanced countermeasures to mitigate these injuries requires a complete understanding of the tolerance of the human brain to injury. In this study, we developed a new method to establish human injury tolerance levels using an integrated database of reconstructed football impacts, subinjurious human volunteer data, and nonhuman primate data. The human tolerance levels were analyzed using tissue-level metrics determined using harmonized species-specific finite element (FE) brain models. Kinematics-based metrics involving complete characterization of angular motion (e.g., diffuse axonal multi-axial general evaluation (DAMAGE)) showed better power of predicting tissue-level deformation in a variety of impact conditions and were subsequently used to characterize injury tolerance. The proposed human brain tolerances for mild and severe TBI were estimated and presented in the form of injury risk curves based on selected tissue-level and kinematics-based injury metrics. The application of the estimated injury tolerances was finally demonstrated using real-world automotive crash data., (Copyright © 2022 by ASME.)

The article refers to actual problems of forensic diagnostics of diffuse axonal brain injury in the acute post-traumatic period, that is of particular importance in the case of head trauma in conditions of non-evidence. To solve the existing problems, it is necessary to conduct a comprehensive study aimed at improving the diffuse axonal brain injury examination by developing a unified methodological approach to running the forensic medical diagnostics of this form of traumatic brain injury and determining the duration of the acute (up to three days) post-traumatic period.

Based on the study results it were identified and systematized the most common deficiencies and mistakes that negatively affect the diagnosis of diffuse axonal brain injury and its genesis detection in the early post-traumatic period. It makes possible to organize correctly the diagnostic process and prevent an erroneous assessment of morphological changes in the brain during the examination of traumatic brain injury.

The article offers an original method for human corpus callosum autopsy examination in the case of diffuse axonal injury (DAI) and a rational scheme for sampling its zones for microscopic examination, aimed at determining the morphological characteristics of injuries, taking into account their anatomical and topographic localization. The results of the comparative study prove the objectivity and high efficiency of the proposed approach to post-mortem diagnosis of DAI.

Objective: Establishing the diagnostic criteria for diagnosing of brain diffuse axonal injury duration as a separate form of traumatic brain injury. The dynamics of structural and functional changes in the neuron-gliovascular module and neuroinflammatory response revealed at the light-optical level and their diagnostically significant morphological signs established as a result of a comprehensive study that can be considered as evidence-based criteria for the diffuse axonal brain damage duration.

Objective: To review the historical, clinical, radiographic, and outcome characteristics of individuals diagnosed with an acquired brain injury (ABI) due to cerebral fat embolism syndrome (CFES) with and without features of traumatic brain injury (TBI)., Methods: A retrospective chart review of individuals with the diagnosis of CFES admitted to an ABI rehabilitation program. Cases were divided into two cohorts 1) individuals with evidence of classic features of CFES alone, and 2) individuals with evidence of CFES in conjunction with features of TBI., Results: 14 individuals were identified, seven individuals with diagnosis of CFES alone, and seven with CFES and TBI. Median initial GCS was 15 for the isolated CFES cohort and 8 for the dual diagnosis cohort (p =.006). There were clear qualitative differences in MRI findings with characteristic patterns between the two groups., Conclusion: The diagnosis of CFES is an important consideration for individuals who have new neurologic impairment following a trauma, especially in cases where initial GCS was high. MRI has an important role in differentiating lesions of CFES from TBI and should be utilized for prognostication and management decisions. Individuals with neurologic injury secondary to CFES had good functional recovery outcomes as measured by Glasgow Outcome Scale.

Aim of this study is to establish a possibility of finding morphologic signs of diffuse axonal injury early after the injury. Use of immunohistochemical examination of the brain to detect protein β-APP made it possible not only to diagnose this condition correctly, but also to reasonably and categorically answer the question of a causal relationship between causing damage and the onset of death.

An anatomically detailed rhesus monkey brain FE model was developed to simulate in vivo responses of the brain of sub-human primates subjected to rotational accelerations resulting in diffuse axonal injury (DAI). The material properties used in the monkey model are those in the GHBMC 50th percentile male head model (Global Human Body Model Consortium). The angular loading simulations consisted of coronal, oblique and sagittal plane rotations with the center of rotation in neck to duplicate experimental conditions. Maximum principal strain (MPS) and Cumulative strain damage measure (CSDM) were analyzed for various white matter structures such as the cerebrum subcortical white matter, corpus callosum and brainstem. The MPS in coronal rotation were 45% to 54% higher in the brainstem, 8% to 48% higher in the corpus callosum, 13% to 22% higher in the white matter when compared to those in oblique and sagittal rotations, suggesting that more severe DAI was expected from coronal and oblique rotations as compared to that from sagittal rotation. The level 1+ DAI was associated with 1.3 to 1.42 MPS and 50% CSDM (0.5) responses in the brainstem, corpus callosum and cerebral white matter. The mass scaling method, sometimes referred to as Holbourn's inverse 2/3 power law, used for development of human brain injury criterion was evaluated to understand the effect of geometrical and anatomical differences between human and animal head. Based on simulations conducted with the animal and human models in three different planes - sagittal, coronal and horizontal - the scaling from animal to human models are not supported due to lack of geometrical similitude between the animal and human brains. Thus, the scaling method used in the development of brain injury criterion for rotational acceleration/velocity is unreliable.

Impairments of executive brain function after traumatic brain injury (TBI) due to head impacts in traffic accidents need to be obviated. Finite element (FE) analyses with a human brain model facilitate understanding of the TBI mechanisms. However, conventional brain FE models do not suitably describe the anatomical structure in the deep brain, which is a critical region for executive brain function, and the material properties of brain parenchyma. In this study, for better TBI prediction, a novel brain FE model with anatomical structure in the deep brain was developed. The developed model comprises a constitutive model of brain parenchyma considering anisotropy and strain rate dependency. Validation was performed against postmortem human subject test data associated with brain deformation during head impact. Brain injury analyses were performed using head acceleration curves obtained from reconstruction analysis of rear-end collision with a human whole-body FE model. The difference in structure was found to affect the regions of strain concentration, while the difference in material model contributed to the peak strain value. The injury prediction result by the proposed model was consistent with the characteristics in the neuroimaging data of TBI patients due to traffic accidents.

Autoregulation of cerebral blood flow (ACBF) is a system of mechanisms for maintaining stable adequate perfusion of the brain despite changes in systemic arterial pressure. In recent years, new data on the numerous metabolic and systemic mechanisms of cerebral blood flow regulation have been obtained, but the role of neurogenic regulation has not yet been fully understood and, therefore, not considered in clinical practice., Aim: The study aim was to assess the effect of anatomical injuries to deep brain structures on the extent and duration of ACBF abnormalities in a model of severe diffuse axonal injury (DAI)., Results: The study demonstrated that brain injury in the projection of a dopaminergic structure (substantia nigra) and a cholinergic structure (nucleus basalis of Meynert region) was more common in patients with impaired ACBF and was associated with a longer duration of the impairment., Conclusion: The obtained data may indicate the presence of central (neurogenic) pathways of cerebral vessel tone regulation; traumatic injury of the pathways leads to a more severe and prolonged period of impaired ACBF. Probably, injury to these regulatory structures in some patients has an indirect effect on the course of intracranial hypertension. Further experimental and clinical studies in this direction are needed to elucidate all elements of neurogenic regulation of cerebral vessel tone and ACBF mechanisms.

Traumatic brain injury (TBI) is a serious public health problem and the leading cause of death in children and young adults. It also contributes to a substantial number of cases of permanent disability. As lipids make up over 50% of the brain mass and play a key role in both membrane structure and cell signaling, their profile is of particular interest. In this study, we show that advanced mass spectrometry imaging (MSI) has sufficient technical accuracy and reproducibility to demonstrate the anatomical distribution of 50 μm diameter microdomains that show changes in brain ceramide levels in a rat model of controlled cortical impact (CCI) 3 days post injury with and without treatment. Adult male Sprague-Dawley rats received one strike and were euthanized 3 days post trauma. Brain MS images showed increase in ceramides in CCI animals compared to control as well as significant reduction in ceramides in CCI treated animals, demonstrating therapeutic effect of a peptide agonist. The data also suggests the presence of diffuse changes outside of the injured area. These results shed light on the extent of biochemical and structural changes in the brain after traumatic brain injury and could help to evaluate the efficacy of treatments.

Traumatic brain injury (TBI) is a major public health issue around the world and can be especially devastating in children as TBI can derail cognitive and social development. White matter (WM) is particularly vulnerable to disruption post-TBI, as myelination is ongoing during this period. Diffusion magnetic resonance imaging (dMRI) is a versatile modality for identifying and quantifying WM disruption and can detect diffuse axonal injury (DAI or TAI (traumatic axonal injury)). This review covers dMRI studies of pediatric TBI, including mild to severe injuries, and covering all periods post-injury. While there have been considerable advances in our understanding of pediatric TBI through the use of dMRI, there are still large gaps in our knowledge, which will be filled in by larger studies and more longitudinal studies. Heterogeneity post-injury is an obstacle in all TBI studies, but we expect that larger better-characterized samples will aid in identifying clinically meaningful subgroups within the pediatric TBI patient population.

Objective: Facial emotion recognition impairment has been well documented in patients with traumatic brain injury. Studies exploring the neural substrates involved in such deficits have implicated specific grey matter structures (e.g. orbitofrontal regions), as well as diffuse white matter damage. Our study aims to clarify whether different types of injuries (i.e. focal vs. diffuse) will lead to different types of impairments on facial emotion recognition tasks, as no study has directly compared these patients., Methods: The present study examined performance and response patterns on a facial emotion recognition task in 14 participants with diffuse axonal injury (DAI), 14 with focal injury (FI) and 22 healthy controls., Results: We found that, overall, participants with FI and DAI performed more poorly than controls on the facial emotion recognition task. Further, we observed comparable emotion recognition performance in participants with FI and DAI, despite differences in the nature and distribution of their lesions. However, the rating response pattern between the patient groups was different., Conclusion: This is the first study to show that pure DAI, without gross focal lesions, can independently lead to facial emotion recognition deficits and that rating patterns differ depending on the type and location of trauma.

The physical structure of neurons - dendrites converging on the soma, with an axon conveying activity to distant locations - is uniquely tied to their function. To perform their role, axons need to maintain structural precision in the soft, gelatinous environment of the central nervous system and the dynamic, flexible paths of nerves in the periphery. This requires close mechanical coupling between axons and the surrounding tissue, as well as an elastic, robust axoplasm resistant to pinching and flattening, and capable of sustaining transport despite physical distortion. These mechanical properties arise primarily from the properties of the internal cytoskeleton, coupled to the axonal membrane and the extracellular matrix. In particular, the two large constituents of the internal cytoskeleton, microtubules and neurofilaments, are braced against each other and flexibly interlinked by specialised proteins. Recent evidence suggests that the primary function of neurofilament sidearms is to structure the axoplasm into a linearly organised, elastic gel. This provides support and structure to the contents of axons in peripheral nerves subject to bending, protecting the relatively brittle microtubule bundles and maintaining them as transport conduits. Furthermore, a substantial proportion of axons are myelinated, and this thick jacket of membrane wrappings alters the form, function and internal composition of the axons to which it is applied. Together these structures determine the physical properties and integrity of neural tissue, both under conditions of normal movement, and in response to physical trauma. The effects of traumatic injury are directly dependent on the physical properties of neural tissue, especially axons, and because of axons' extreme structural specialisation, post-traumatic effects are usually characterised by particular modes of axonal damage. The physical realities of axons in neural tissue are integral to both normal function and their response to injury, and require specific consideration in evaluating research models of neurotrauma., (Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.)

MR imaging is an extremely useful tool in the evaluation of traumatic brain injury in the emergency department. Although CT still plays the dominant role in urgent patient triage, MR imaging's impact on traumatic brain injury imaging continues to expand. MR imaging has shown superiority to CT for certain traumatic processes, such as diffuse axonal injury, cerebral contusion, and infarction. Magnetic resonance angiography and magnetic resonance venography allow emergent vascular imaging for patients that should avoid ionizing radiation or intravenous contrast., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Reporting the outcome of two patients who underwent unilateral ablative stereotactic surgery to treat pharmacologic resistant posttraumatic tremor (PTT)., Methods: We present two patients (31 and 47 years old) with refractory PTT severely affecting their quality of life. Under stereotactic guidance, refined by T2-weighted magnetic resonance imaging and double-channel multiunit microelectrode recording (MER), three sequential radiofrequency lesions were performed in the caudal zona incerta (cZi) up to the base of thalamus (VOP). Effects of cZi/VOP lesion were prospectively rated with a tremor rating scale., Results: Both patients demonstrated intraoperative tremor suppression with sustained results up to 18 months follow-up, with improvement of 92% and 84%, respectively, on the tremor rating scale. Tremor improvement was associated with enhancement functionality and quality of life for the patients. The patients returned to their work after the procedure. No adverse effects were observed up to the last follow-up., Conclusion: Radiofrequency lesion of the cZi/VOP target was effective for posttraumatic tremor in both cases. The use of T2-weighted images and MER was found helpful in increasing the precision and safety of the procedure, because it leads the RF probe by relying on neighbor structures based on thalamus and subthalamic nucleus., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or "concussion". The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, "SNTF", was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI.

Repetitive mild traumatic brain injury (mTBI) is implicated in chronic neurological illness. The development of animal models of repetitive mTBI in mice is essential for exploring mechanisms of these chronic diseases, including genetic vulnerability by using transgenic backgrounds. In this study, the rat model of impact acceleration (IA) was redesigned for the mouse cranium and used in two clinically relevant repetitive mTBI paradigms. We first determined, by using increments of weight dropped from 1m that the 40g weight was most representative of mTBI and was not associated with fractures, brain contusions, anoxic-ischemic injury, mortality, or significant neurological impairments. Quantitative evaluation of traumatic axonal injury (TAI) in the optic nerve/tract, cerebellum and corpus callosum confirmed that weight increase produced a graded injury. We next evaluated two novel repetitive mTBI paradigms (1 time per day or 3 times per day at days 0, 1, 3, and 7) and compared the resulting TAI, neuronal cell death, and neuroinflammation to single hit mTBI at sub-acute (7days) and chronic time points (10weeks) post-injury. Both single and repetitive mTBI caused TAI in the optic nerve/tract, cerebellum, corticospinal tract, lateral lemniscus and corpus callosum. Reactive microglia with phagocytic phenotypes were present at injury sites. Severity of axonal injury corresponded to impact load and frequency in the optic nerve/tract and cerebellum. Both single and repeat injury protocols were associated with retinal ganglion cell loss and optic nerve degeneration; these outcomes correlated with impact load and number/frequency. No phosphorylated tau immunoreactivity was detected in the brains of animals subjected to repetitive mTBI. Our findings establish a new model of repetitive mTBI model featured by TAI in discrete CNS tracts, especially the visual system and cerebellum. Injury in retina and optic nerve provides a sensitive measure of severity of mTBI, thus enabling further studies on mechanisms and experimental therapeutics. Our model can also be useful in exploring mechanisms of chronic neurological disease caused by repetitive mTBI in wild-type and transgenic mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Impact-acceleration forces to the head cause traumatic brain injury (TBI) with damage in white matter tracts comprised of long axons traversing the brain. White matter injury after TBI involves both traumatic axonal injury (TAI) and myelin pathology that evolves throughout the post-injury time course. The axon response to initial mechanical forces and secondary insults follows the process of Wallerian degeneration, which initiates as a potentially reversible phase of intra-axonal damage and proceeds to an irreversible phase of axon fragmentation. Distal to sites of axon disconnection, myelin sheaths remain for prolonged periods, which may activate neuroinflammation and inhibit axon regeneration. In addition to TAI, TBI can cause demyelination of intact axons. These evolving features of axon and myelin pathology also represent opportunities for repair. In experimental TBI, demyelinated axons exhibit remyelination, which can serve to both protect axons and facilitate recovery of function. Myelin remodeling may also contribute to neuroplasticity. Efficient clearance of myelin debris is a potential target to attenuate the progression of chronic pathology. During the early phase of Wallerian degeneration, interventions that prevent the transition from reversible damage to axon disconnection warrant the highest priority, based on the poor regenerative capacity of axons in the CNS. Clinical evaluation of TBI will need to address the challenge of accurately detecting the extent and stage of axon damage. Distinguishing the complex white matter changes associated with axons and myelin is necessary for interpreting advanced neuroimaging approaches and for identifying a broader range of therapeutic opportunities to improve outcome after TBI., (Published by Elsevier Inc.)

Paroxysmal sympathetic hyperactivity (PSH) is a condition in which there is extreme autonomic dysregulation leading to multiple episodes of sympathetic hyperactivity. Its occurrence after traumatic brain injury (TBI) in pediatric population is a neglected scenario. In our series, all pediatric patients with moderate and severe head injuries were studied and those patients who developed PSH were monitored for the PSH episodes. Four children out of 36 cases of pediatric severe traumatic brain injury developed features of PSH. Admission GCS of 3 children were 4/15 and 1 child was 6/15 and each of them had an ICU stay of more than 2 weeks and a poor DRS score at discharge. The presence of PSH is known to produce poorer outcome in terms of overall mortality, time needed for recovery, chances of developing infections, etc. which was also seen in these cases presented here. Though some studies have provided guidelines for the management of PSH like symptomatic management and use of drugs like clonidine, bromocriptine, benzodiazepines, and gabapentin, strict management guidelines are not established and exact incidence in pediatric population is not determined., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) in the context of contact and collision sports, but not all exposed individuals develop this condition. In addition, experiments in animal models in several laboratories have shown that non-transgenic mice do not develop tauopathy after exposure to repetitive mTBI schedules. It is thus reasonable to assume that genetic factors may play an etiological role in the development of CTE. More than 40 mutations in the tau gene are known to confer proneness to aggregation and are thought to cause neurodegenerative diseases including frontotemporal degeneration (FTD). Transgenic mice harboring these mutations can be used to ask the question whether repetitive mTBI can accelerate onset and course of tauopathy or worsen the outcomes of transgenic disease. In this study, we exposed mice harboring the tau P301S transgene associated with FTD to repetitive mTBI schedules by impact acceleration (IA) that we have previously characterized. We explored the progression of tauopathy in the retina and neocortex based on density of neuronal profiles loaded with tau pS422, a marker of advanced tau hyperphosphorylation. We found that the density of tau pS422 (+) retinal ganglion cells (RGCs) increased twenty fold with one mTBI hit, a little over fifty fold with four mTBI hits and sixty fold with 12 mTBI hits. The severity of mTBI burden (number of hits) was a significant factor in tauopathy outcome. On the other hand, we found no association between repetitive mTBI and density of pS422 (+) neuronal profiles in neocortex, a region that is not featured by significant TAI in our repetitive mTBI model. We observed similar, but less prominent, trends in tauopathy-prone transgenic mice harboring all 6 isoforms of wild-type human tau without mouse tau. Our findings indicate that repetitive mTBI accelerates tauopathy under diverse genetic conditions predisposing to tau aggregation and suggest a vulnerability-stress model in understanding some cases of acquired neurodegenerative disease after repetitive mTBI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a prevalent condition and there is limited visual perception research with this population. Here, we investigated perceptual organization changes in a rather homogeneous sample of closed head TBI outpatients with diffuse axonal injury only and no other known comorbidities. Patients had normal or corrected visual acuity. Perceptual organization was measured with the Leuven Perceptual Organization Screening Test (L-POST), a coherent motion task (CM) and the Leuven Embedded Figures Test (L-EFT). These tests were chosen to screen for deficits in different aspects of perceptual organization (L-POST), to evaluate local and global processing (L-EFT) and grouping in a dynamic set of stimuli (CM). TBI patients were significantly impaired compared to controls in all measures for both response time and accuracy, except for CM thresholds and object recognition subtests. The TBI group was similarly affected in all aspects of the L-EFT. TBI was also similarly affected in all perceptual factors of the L-POST. No significant correlations were found between scores and time post-injury, except for CM thresholds (rs=-0.74), which might explain the lack of group-level differences. The only score significantly correlated to IQ was L-EFT response time (rs=-0.67). These findings demonstrate that perceptual organization is diffusely affected in TBI and this effect has no substantial correlations with IQ. As many of the neuropsychological tests used to measure different cognitive functions involve some level of visual discrimination and perceptual organization demands, these results must be taken into account in the general neuropsychological evaluation of TBI patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Traumatic brain injury (TBI) is associated with long-term changes in daily life functioning, yet the neuroanatomical correlates of these changes are poorly understood. This study related outcome assessed across several domains to brain structure derived from quantitative magnetic resonance imaging (MRI). Sixty individuals spanning a wide range of TBI severity participated 1-year post-injury as part of the Toronto TBI study. Volumetric data over 38 brain regions were derived from high resolution T1-weighted MRI scans. Functioning was assessed with a battery of self- and significant-other rated measures. Multivariate analysis (partial least squares) was used to identify shared variance between the neuroimaging and outcome measures. TBI was associated with item endorsement on outcome questionnaires without strong evidence for severity or focal lesion effects. Prefrontal midline, cingulate, medial temporal, right inferior parietal and basal ganglia/thalamic volumes were associated with measures of initiative, energization, and physical complaints. In the chronic stage of TBI, self-initiation, energization, and physical complaints related to a specific pattern of volume loss in midline and lateral regions known to be involved in motivation, apathy, and attention. These results suggest that crucial functional changes in chronic TBI may be associated with volume loss in established midline-frontal and attentional circuits.

Vertigo, dizziness, and disequilibrium are common symptoms following concussion or mild traumatic brain injury (mTBI). Dizziness and vertigo may be the result of trauma to the peripheral vestibular system or the central nervous system, or, in some cases, may be due to anxiety, depression, or posttraumatic stress disorder; these mechanisms are not mutually exclusive. While most peripheral vestibular disorders can be identified by testing and examination, those without inner-ear causes that have persisting complaints of dizziness and motion sickness are more difficult to understand and to manage. Some of these patients exhibit features compatible with vestibular migraine and may be treated successfully with migraine-preventative medications. This paper reviews the nonotogenic causes of persisting dizziness, the possible mechanisms, and the pathophysiology, as a framework for patient management and for future research., (© 2015 New York Academy of Sciences.)

Traumatic brain injury (TBI) and its consequences represent one of the leading causes of death in young adults. This lesion mediates glial activation and the release of harmful molecules and causes brain edema, axonal injury, and functional impairment. Since glial activation plays a key role in the development of this damage, it seems that controlling it could be beneficial and could lead to neuroprotective effects. Recent studies show that minocycline suppresses microglial activation, reduces the lesion volume, and decreases TBI-induced locomotor hyperactivity up to 3 months. The endocannabinoid system (ECS) plays an important role in reparative mechanisms and inflammation under pathological situations by controlling some mechanisms that are shared with minocycline pathways. We hypothesized that the ECS could be involved in the neuroprotective effects of minocycline. To address this hypothesis, we used a murine TBI model in combination with selective CB1 and CB2 receptor antagonists (AM251 and AM630, respectively). The results provided the first evidence for the involvement of ECS in the neuroprotective action of minocycline on brain edema, neurological impairment, diffuse axonal injury, and microglial activation, since all these effects were prevented by the CB1 and CB2 receptor antagonists., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Primary Objective: Paediatric traumatic brain injury (TBI) has been associated with acute and long-term mathematical difficulties. Little is known about the recovery of these impairments in children with mild TBI (mTBI) and their underlying pathophysiology, such as white matter abnormalities., Research Design: A prospective longitudinal study followed the recovery of mathematical abilities and white matter in children with mTBI from the sub-acute (1 month post-injury) to chronic stage (6-8 months post-injury) of recovery., Methods and Procedures: Twenty children with mTBI and 20 matched controls completed mathematics tests. Diffusion Tensor Imaging (DTI) metrics of white matter pathways corpus callosum (CC), superior and longitudinal fasciculi were examined with DTI-tractography., Main Outcomes and Results: Mathematical difficulties and white matter abnormalities in the CC observed shortly after the injury resolved after 6-8 months of recovery. Children with mTBI continued to show working memory deficits. Longitudinal DTI data suggest continued maturation of the CC in controls, but little maturation of the damaged CC in children with mTBI., Conclusions: Children with mTBI recovered in terms of mathematical abilities and white matter. These children continued to show working memory deficits, which might interfere with learning at school.

The aim of this study is to explore the white matter structure integrity in patients with mild traumatic brain injury (mTBI) using diffusion tensor imaging (DTI), and to analyze the relationship between the white matter structure integrity and cognitive impairment of patients with mTBI. Twenty-five patients with mTBI and 25 healthy control subjects were studied with conventional MR imaging and diffusion tensor imaging. Fractional anisotropy (FA) and mean diffusivity (MD) maps of patients with mTBI were calculated and compared, with these control maps using tract-based spatial statistics (TBSS). Significantly lower fractional anisotropy was found in patients in the uncinate fasciculus, superior longitudinal fasciculus, inferior longitudinal fasciculus, and internal capsule. Mean diffusivity was significantly elevated in the body of corpus callosum, uncinate fasciculus, superior longitudinal fasciculus, and internal capsule in the mTBI group compared with the control group (P<0.05). The mTBI group showed a significant negative correlation between the elevated mean diffusivity of the uncinate fasciculus and the working memory index (WMI) (R(2)=0.51, P<0.05), and the internal capsule of MD values was significantly negatively related to processing speed index (PSI) (R(2)=0.45, P<0.05). There was a positive correlation between the FA value of the uncinate fasciculus and Mini Mental State Examination (MMSE) in the mTBI patient group (R(2)=0.36, P<0.05). TBSS analysis of DTI suggests that patients with mTBI have focal axonal injury, and the pathophysiology is significantly related to the MMSE and IQ of mTBI patients. Diffusion tensor imaging can be a powerful technique for in vivo detection of mTBI, and can help in the diagnosis of patients with mTBI., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Establish rate of disorders of consciousness (DOC) and course of recovery in adults who have sustained severe traumatic brain injury (sTBI)., Setting: Four Norwegian neurosurgical departments., Participants: Vegetative or minimally conscious patients., Design: Prospective, longitudinal population-based study of adults with sTBI with follow-ups at 3, 12, and 24-36 months postinjury., Main Measures: Coma Recovery Scale-Revised, Glasgow Coma Scale, Extended Glasgow Outcome Scale, and Disability Rating Scale., Results: Three months postinjury, 2% of the sTBI population remained in a vegetative or minimally conscious state, reduced by the half after 1 year, corresponding to average annual age-adjusted incidence rates of DOC of 0.09 per 100 000 3 months post-sTBI. At 3 and 12 months, the incidence was 0.06 and 0.01 per 100 000 for the vegetative state and 0.03 and 0.04 per 100 000 for the minimally conscious state. Diagnostic categorization was stable between 12 and 24-36 months, although clinically relevant improvements were observed in minimally conscious patients., Conclusion: The data suggest that prolonged DOC is rare following sTBI in Norway, contrary to the commonly held belief that improvements in intensive care treatment have resulted in an increased incidence of DOC. Prolonged DOC was associated with severity of injury, subcortical lesions, and diffuse axonal injury.

The objectives of this prospective study in 62 moderate-severe TBI patients were to investigate volume change in cortical gray matter (GM), hippocampus, lenticular nucleus, lobar white matter (WM), brainstem and ventricles using a within subject design and repeated MRI in the early phase (1-26 days) and 3 and 12 months postinjury and to assess changes in GM apparent diffusion coefficient (ADC) in normal appearing tissue in the cortex, hippocampus and brainstem. The impact of Glasgow Coma Scale (GCS) score at admission, duration of post-traumatic amnesia (PTA), and diffusion axonal injury (DAI) grade on brain volumes and ADC values over time was assessed. Lastly, we determined if MRI-derived brain volumes from the 3-month scans provided additional, significant predictive value to 12-month outcome classified with the Glasgow Outcome Scale-Extended after adjusting for GCS, PTA and age. Cortical GM loss was rapid, largely finished by 3 months, but the volume reduction was unrelated to GCS score, PTA, or presence of DAI. However, cortical GM volume at 3 months was a significant independent predictor of 12-month outcome. Volume loss in the hippocampus and lenticular nucleus was protracted and statistically significant first at 12 months. Slopes of volume reduction over time for the cortical and subcortical GGM were significantly different. Hippocampal volume loss was most pronounced and rapid in individuals with PTA > 2 weeks. The 3-month volumes of the hippocampus and lentiform nucleus were the best independent predictors of 12-month outcome after adjusting for GCS, PTA and age. In the brainstem, volume loss was significant at both 3 and 12 months. Brainstem volume reduction was associated with lower GCS score and the presence of DAI. Lobar WM volume was significantly decreased first after 12 months. Surprisingly DAI grade had no impact on lobar WM volume. Ventricular dilation developed predominantly during the first 3 months, and was strongly associated with volume changes in the brainstem and cortical GM, but not lobar WM volume. Higher ADC values were detected in the cortex in individuals with severe TBI, DAI and PTA > 2 weeks, from 3 months. There were no associations between ADC values and brain volumes, and ADC values did not predict outcome.

Repeated blast exposures commonly induce traumatic brain injury (TBI) characterized by diffuse axonal injury (DAI). We hypothesized that degradation of cytoskeletal proteins in the brain can lead to DAI, and evaluated α-II spectrin degradation in the pathophysiology of blast-induced TBI using the tightly-coupled three repetitive blast exposure mice model with a 1-30 min window in between exposures. Degradation of α-II spectrin and the expression profiles of caspase-3 and calpain-2, the major enzymes involved in the degradation were analyzed in the frontal cortex and cerebellum using Western blotting with specific antibodies. DAI at different brain regions was evaluated by neuropathology with silver staining. Repeated blast exposures resulted in significant increases in the α-II spectrin degradation products in the frontal cortex and cerebellum compared to sham controls. Expression of active caspase-3, which degrades α-II spectrin, showed significant increase in the frontal cortex after blast exposure at all the time points studied, while cerebellum showed an acute increase which was normalized over time. The expression of another α-II spectrin degrading enzyme, calpain-2, showed a rapid increase in the frontal cortex after blast exposure and it was significantly higher in the cerebellum at later time points. Neuropathological analysis showed significant levels of DAI at the frontal cortex and cerebellum at multiple time points after repeated blast injury. In summary, repeated blast exposure results in specific degradation of α-II spectrin in the brain along with differential expression of caspase-3/calpain-2 suggesting cytoskeletal breakdown as a possible contributor of DAI after repeated blast exposure., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This article focuses on advancements in neuroimaging techniques, compares the advantages of each of the modalities in the evaluation of mild traumatic brain injury, and discusses their contribution to our understanding of the pathophysiology as it relates to prognosis. Advanced neuroimaging techniques discussed include anatomic/structural imaging techniques, such as diffusion tensor imaging and susceptibility-weighted imaging, and functional imaging techniques, such as functional magnetic resonance imaging, perfusion-weighted imaging, magnetic resonance spectroscopy, and positron emission tomography., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The principal aim in the management of patients with cerebral contusion (CC) following severe traumatic brain injury (TBI) is the prevention, amelioration, and treatment of secondary neuronal dysfunction and pathology. Distinguishing between irreversibly damaged and surviving tissue could have considerable therapeutic and prognostic implications for patients. To characterize structurally the neuronal compartment of the contused region in samples derived from patients who suffered severe TBI and were subjected to decompressive craniectomy, we used NeuN, a neuronal marker. We determined that NeuN "patches", sectors with loss of NeuN immunoreactivity (NeuN-IR), represented 25% of the area among the analyzed cases. We also found a 67% decrease in NeuN levels via Western blot. Tissue adjoining patches of NeuN-IR were considered "preserved" due to the apparent normal density of neurons and conservation of the six cortical layers. Nevertheless, these sectors retained only 39% of their neurons with the classical pattern described for normal NeuN-IR. Using Fluorojade we identified a 16-fold increase in density of moribund neurons in "preserved" sectors when compared to controls. Additionally these abnormalities were enhanced 5-fold in "patches" of NeuN-IR when compared to preserved regions. Therefore, NeuN/Fluorojade abnormalities are indicative of different cell fates characteristic of CC tissue. This analysis addressed exclusively the neuronal compartment and provides new insights into the degenerative state of neurons in the contused region that is likely to contribute to clinical outcome and differentiate TBI from ischemia., (© 2013 Elsevier B.V. All rights reserved.)

Over the past 70years, diffuse axonal injury (DAI) has emerged as one of the most common and important pathological features of traumatic brain injury (TBI). Axons in the white matter appear to be especially vulnerable to injury due to the mechanical loading of the brain during TBI. As such, DAI has been found in all severities of TBI and may represent a key pathologic substrate of mild TBI (concussion). Pathologically, DAI encompasses a spectrum of abnormalities from primary mechanical breaking of the axonal cytoskeleton, to transport interruption, swelling and proteolysis, through secondary physiological changes. Depending on the severity and extent of injury, these changes can manifest acutely as immediate loss of consciousness or confusion and persist as coma and/or cognitive dysfunction. In addition, recent evidence suggests that TBI may induce long-term neurodegenerative processes, such as insidiously progressive axonal pathology. Indeed, axonal degeneration has been found to continue even years after injury in humans, and appears to play a role in the development of Alzheimer's disease-like pathological changes. Here we review the current understanding of DAI as a uniquely mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Little is known about neural recovery of an injured cingulum following brain injury. We report on a patient with brain injury who showed apparent neural recovery of an injured cingulum on follow up diffusion tensor tractography (DTT)., Methods: A 53-year-old female patient had suffered hypoxic ischemic brain injury for a period of approximately nine hours following spontaneous subarachnoid hemorrhage and intraventricular hemorrhage, and underwent coiling of a left ruptured aneurysm of the posterior communicating artery. She showed severe cognitive impairment, so that she could not be evaluated on the Mini-Mental State Examination, however, her cognition showed improvement to 21 at five months after onset and 24 at 14 months after onset on the Mini-Mental State Examination., Results: On seven-day DTT for the fornix in the patient, we observed a discontinuation in the left crus and thinning of the right crus. However, on 14-month DTT, the thinned right fornical crus had disappeared. Regarding the cingulum, on seven-day DTTs, discontinuations of both cingulums anterior to the genu of the corpus callosum were observed. However, on 14-month follow up DTT, the right cingulum was elongated to the right basal forebrain and no change in the discontinuation of the left cingulum was observed., Conclusions: These changes observed on DTT in both cingulums appeared to indicate recovery of the injured cingulum in this patient. The results of this study may suggest a mechanism for recovery of injured cingulum following brain injury.

Quantitative neuroimaging has now become a well-established method for analyzing magnetic resonance imaging in traumatic brain injury (TBI). A general review of studies that have examined quantitative changes following TBI is presented. The consensus of quantitative neuroimaging studies is that most brain structures demonstrate changes in volume or surface area after injury. The patterns of atrophy are consistent with the generalized nature of brain injury and diffuse axonal injury. Various clinical caveats are provided including how quantitative neuroimaging findings can be used clinically and in predicting rehabilitation outcome. The future of quantitative neuroimaging also is discussed.

Traumatic brain injury (TBI) is associated with diffuse axonal injury (DAI), a primary pathology linked to progressive neurodegeneration and neuroinflammation, including chronic astrogliosis, which influences long-term post-TBI recovery and morbidity. Sex-based differences in blood-brain barrier (BBB) permeability increases the risk of accelerated brain aging and early-onset neurodegeneration. However, few studies have evaluated chronic time course of astrocytic responses around cerebrovascular in the context of aging after TBI and sex dependence. We observed increased glial fibrillary acidic protein (GFAP)-labeled accessory processes branching near and connecting with GFAP-ensheathed cortical vessels, suggesting a critical nuance in astrocyte-vessel interactions after TBI. To quantify this observation, male and female Sprague Dawley rats (∼3 months old, n = 5–6/group) underwent either sham surgery or midline fluid percussion injury. Using immunohistochemical analysis, we quantified GFAP-labeled astrocyte primary and accessory processes that contacted GFAP-ensheathed vessels in the somatosensory barrel cortex at 7, 56, and 168 days post-injury (DPI). TBI significantly increased GFAP-positive primary processes at 7 DPI (P < 0.01) in both sexes. At 56 DPI, these vessel-process interactions remained significantly increased exclusively in males (P < 0.05). At 168 DPI, both sexes showed a significant reduction in vessel-process interactions compared to 7 DPI (P < 0.05); however, a modest but significant injury effect reemerged in females (P < 0.05). A similar sex-dependent pattern in the number of accessory processes provides novel evidence of long-term temporal changes in astrocyte-vessel interactions. TBI-induced changes in astrocyte-vessel interactions may indicate chronic BBB vulnerability and processes responsible for early onset vascular and neurodegenerative pathology. [ABSTRACT FROM AUTHOR]

Background Between 3 and 15% of winter sports–related injuries are related to head injuries, which are the primary cause of mortality and disability among skiers. Despite the widespread adoption of helmets in winter sports, which has reduced the incidence of direct head injury, there is a paradoxical trend of an increasing number of individuals wearing helmets sustaining diffuse axonal injuries (DAI), which can result in severe neurologic sequelae. Methods We retrospectively reviewed 100 cases collected by the senior author of this work from 13 full winter seasons during the period from 1981 to 1993 and compared them with 17 patients admitted during the more shortened 2019 to 2020 ski season due to COVID-19. All data analyzed come from a single institution. Population characteristics, mechanism of injury, helmet use, need for surgical treatment, diagnosis, and outcome were collected. Descriptive statistics were used to compare the two databases. Results From February 1981 to January 2020, most skiers with head injuries were men (76% for the 1981–1993 and 85% for 2020). The proportion of patients aged over 50 increased from <20% in 1981 to 65% in 2020 (p < 0.01), with a median age of 60 years (range: 22–83 years). Low- to medium-velocity injuries were identified in 76% (13) of cases during the 2019 to 2020 season against 38% (28/74) during the 1981 to 1993 seasons (p < 0.01). All injured patients during the 2020 season wore a helmet, whereas none of the patients between 1981 and 1993 wore one (p < 0.01). DAI was observed in six cases (35%) for the 2019 to 2020 season against nine cases (9%) for the 1981 to 1993 season (p < 0.01). Thirty-four percent (34) of patients during the 1981 to 1993 seasons and 18% (3) of patients during the 2019 to 2020 season suffered skeletal fractures (p = 0.02). Among the 100 patients of the 1981 to 1993 seasons, 13 (13%) died against 1 (6%) from the recent season during care at the hospital (p = 0.15). Neurosurgical intervention was performed in 30 (30%) and 2 (12%) patients for the 1981 to 1993 and 2019 to 2020 seasons, respectively (p = 0.003). Neuropsychological sequelae were reported in 17% (7/42) of patients from the 1981 to 1993 seasons and cognitive evaluation before discharge detected significant impairments in 24% (4/17) of the patients from the 2019 to 2020 season (p = 0.29). Conclusion Helmet use among skiers sustaining head trauma has increased from none in the period from 1981 to 1993 to 100% during the 2019 to 2020 season, resulting in a reduction in the number of skull fractures and deaths. However, our observations suggest a marked shift in the type of intracranial injuries sustained, including a rise in the number of skiers experiencing DAI, sometimes with severe neurologic outcomes. The reasons for this paradoxical trend can only be speculated upon, leading to the question of whether the perceived benefits of helmet use in winter sports are actually misinterpreted. [ABSTRACT FROM AUTHOR]

Traumatic axonal injury (TAI) is a common finding on magnetic resonance imaging (MRI) in patients with moderate–severe traumatic brain injury (TBI), and the burden of TAI is associated with outcome in this patient group. Lesion mapping offers a way to combine imaging findings from numerous individual patients into common lesion maps where the findings from a whole patient cohort can be assessed. The aim of this study was to evaluate the spatial distribution of TAI lesions on different MRI sequences and its associations to outcome with use of lesion mapping. Included prospectively were 269 patients (8–70 years) with moderate or severe TBI and MRI within six weeks after injury. The TAI lesions were evaluated and manually segmented on fluid-attenuated inversed recovery (FLAIR), diffusion weighted imaging (DWI), and either T2* gradient echo (T2*GRE) or susceptibility weighted imaging (SWI). The segmentations were registered to the Montreal Neurological Institute space and combined to lesion frequency distribution maps. Outcome was assessed with Glasgow Outcome Scale Extended (GOSE) score at 12 months. The frequency and distribution of TAI was assessed qualitatively by visual reading. Univariable associations to outcome were assessed qualitatively by visual reading and also quantitatively with use of voxel-based lesion-symptom mapping (VLSM). The highest frequency of TAI was found in the posterior half of corpus callosum. The frequency of TAI was higher in the frontal and temporal lobes than in the parietal and occipital lobes, and in the upper parts of the brainstem than in the lower. At the group level, all voxels in mesencephalon had TAI on FLAIR. The patients with poorest outcome (GOSE scores ≤4) had higher frequencies of TAI. On VLSM, poor outcome was associated with TAI lesions bilaterally in the splenium, the right side of tectum, tegmental mesencephalon, and pons. In conclusion, we found higher frequency of TAI in posterior corpus callosum, and TAI in splenium, mesencephalon, and pons were associated with poor outcome. If lesion frequency distribution maps containing outcome information based on imaging findings from numerous patients in the future can be compared with the imaging findings from individual patients, it would offer a new tool in the clinical workup and outcome prediction of the patient with TBI. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function. [ABSTRACT FROM AUTHOR]