Traumatic brain injury (TBI) results from physical or traumatic injuries to the brain\'s surrounding bony structures and associated tissues, which can lead to various sequelae, including simple concussion, acute epidural hematoma, parenchymal contusions, subarachnoid hemorrhage, diffuse axonal injury, and chronic traumatic encephalopathy. Susceptibility-weighted imaging (SWI) has enhanced the accuracy of neuroimaging for these injuries. SWI is based on 3D gradient echo magnetic resonance imaging (MRI) with long echo times and flow compensation. Owing to its sensitivity to deoxyhemoglobin, hemosiderin, iron, and calcium, SWI is extremely informative and superior to conventional MRI for the diagnosis and follow-up of patients with acute, subacute, and prolonged hemorrhage. This systematic review aimed to evaluate and summarize the published articles that report SWI results for the evaluation of TBI and to determine correlations between clinical status and SWI results. Consequently, our analysis also aimed to identify the appropriate MRI sequences to use in the assessment of patients with TBI. We searched the Medline and Embase online electronic databases for relevant papers published from 2012 onwards. We found that SWI had higher sensitivity than gradient echo MRI in detecting and characterizing microbleeds in TBIs and was able to differentiate diamagnetic calcifications from paramagnetic microhemorrhages. However, it is important that future research not only continues to evaluate the utility of SWI in TBIs but also attempts to overcome the limitations of the studies described in this review, which should help validate the conclusions and recommendations from our analysis.

Identification of Traumatic axonal injury (TAI) is critical in clinical practice, particularly in terms of long-term prognosis, but also for medico-legal issues, to verify whether the death or the after-effects were attributable to trauma. Multidisciplinary approaches are an undeniable asset when it comes to solving these problems. The aim of this work is therefore to list the different techniques needed to identify axonal lesions and to understand the lesion mechanisms involved in their formation. Imaging can be used to assess the consequences of trauma, to identify indirect signs of TAI, to explain the patient\'s initial symptoms and even to assess the patient\'s prognosis. Three-dimensional reconstructions of the skull can highlight fractures suggestive of trauma. Microscopic and immunohistochemical techniques are currently considered as the most reliable tools for the early identification of TAI following trauma. Finite element models use mechanical equations to predict biomechanical parameters, such as tissue stresses and strains in the brain, when subjected to external forces, such as violent impacts to the head. These parameters, which are difficult to measure experimentally, are then used to predict the risk of injury. The integration of imaging data with finite element models allows researchers to create realistic and personalized computational models by incorporating actual geometry and properties obtained from imaging techniques. The personalization of these models makes their forensic approach particularly interesting.

Contemporary biomechanical modeling of traumatic brain injury (TBI) focuses on either the global brain as an organ or a representative tiny section of a single axon. In addition, while it is common for a global brain model to employ real-world impacts as input, axonal injury models have largely been limited to inputs of either tension or compression with assumed peak strain and strain rate. These major gaps between global and microscale modeling preclude a systematic and mechanistic investigation of how tissue strain from impact leads to downstream axonal damage throughout the white matter. In this study, a unique subject-specific multimodality dataset from a male ice-hockey player sustaining a diagnosed concussion is used to establish an efficient and scalable computational pipeline. It is then employed to derive voxelized brain deformation, maximum principal strains and white matter fiber strains, and finally, to produce diverse fiber strain profiles of various shapes in temporal history necessary for the development and application of a deep learning axonal injury model in the future. The pipeline employs a structured, voxelized representation of brain deformation with adjustable spatial resolution independent of model mesh resolution. The method can be easily extended to other head impacts or individuals. The framework established in this work is critical for enabling large-scale (i.e., across the entire white matter region, head impacts, and individuals) and multiscale (i.e., from organ to cell length scales) modeling for the investigation of traumatic axonal injury (TAI) triggering mechanisms. Ultimately, these efforts could enhance the assessment of concussion risks and design of protective headgear. Therefore, this work contributes to improved strategies for concussion detection, mitigation, and prevention.

Traumatic axonal injury (TAI) may result in the disruption of brain functional networks and is strongly associated with cognitive impairment. However, the neural mechanisms affecting the neurocognitive function after TAI remain to be elucidated. We collected the resting-state functional magnetic resonance imaging data from 28 patients with TAI and 28 matched healthy controls. An automated anatomical labeling atlas was used to construct a functional brain connectome. We utilized a graph theoretical approach to investigate the alterations in global and regional network topologies, and network-based statistics analysis was utilized to localize the connected networks more precisely. The current study revealed that patients with TAI and healthy controls both showed a typical small-world topology of the functional brain networks. However, patients with TAI exhibited a significantly lower local efficiency compared to healthy controls, whereas no significant difference emerged in other small-world properties (Cp, Lp, γ, λ, and σ) and global efficiency. Moreover, patients with TAI exhibited aberrant nodal centralities in some regions, including the frontal lobes, parietal lobes, caudate nucleus, and cerebellum bilaterally, and right olfactory cortex. The network-based statistics results showed alterations in the long-distance functional connections in the subnetwork in patients with TAI, involving these brain regions with significantly altered nodal centralities. These alterations suggest that brain networks of individuals with TAI present aberrant topological attributes that are associated with cognitive impairment, which could be potential biomarkers for predicting cognitive dysfunction and help understanding the neuropathological mechanisms in patients with TAI.

Severe intracranial trauma during torture or assault is reportedly caused by shaken adult syndrome. However, intracranial traumas caused by natural forces, excluding human factors and collision impact, are extremely rare. We report an autopsy case of shaken adult syndrome caused by ocean wave forces. A man in his 40s without any medical history was washed away by a wave during recreational fishing. He was found approximately 500 m away from the fishing point drifting on the ocean in a state of cardiopulmonary arrest and was confirmed dead, with no response to cardiopulmonary resuscitation, 3 h after the accident. The autopsy revealed no mechanical trauma to the entire body surface, including the head. Both lungs were inflated, and pleural effusion was observed. The brain was swollen and congested, and subarachnoid hemorrhage was observed in the interhemispheric fissure and the convexity of the parietal occipital lobe. Macroscopic and microscopic hemorrhage spots were found in the brain, and the results of the blood alcohol test and urinary toxicological screening were negative. The cause of death was determined as drowning. This case demonstrates a rare but notable mechanism of injury observed in immersed bodies.

Traumatic axonal injury (TAI) is one of the most common pathological features of severe traumatic brain injury (TBI). Our previous study using proteomics suggested that peripherin (PRPH) should be a potential candidate as a biomarker for TAI diagnosis. This study is to further elucidate the role and association of PRPH with TAI. In the animal study, we performed immunohistochemistry, ELISA and morphological analysis to evaluate PRPH level and distribution following a severe impact. PRPH-positive regions were widely distributed in the axonal tract throughout the whole brain. Axonal injuries with PRPH inclusion were observed post-TBI. Besides, PRPH was significantly increased in both cerebral spinal fluid and plasma at the early phase post-TBI. Colocalization analysis based on microscopy revealed that PRPH represents an immunohistological biomarker in the neuropathological diagnosis of TAI. Brain samples from patients with TBI were included to further test whether PRPH is feasible in the real practice of neuropathology. Immunohistochemistry of PRPH, NFH, APP and NFL on human brain tissues further confirmed PRPH as an immunohistological biomarker that could be applied in practice. Collectively, we conclude that PRPH mirrors the cytoskeleton injury of axons and could represent a neuropathological biomarker for TAI.

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months-to-years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI-related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized for detecting longitudinal changes, we analyzed a sample consisting of 37 individuals with moderate-severe TBI who had primarily high-velocity and high-impact injury mechanisms. They were scanned up to three times during the first year after injury (3 months, 6 months, and 12 months post-injury) and compared with 33 demographically matched controls who were scanned once. Individuals with TBI already showed cortical thinning in frontal and temporal regions and reduced volume in the bilateral thalami at 3 months post-injury. Longitudinally, only a subset of cortical regions in the parietal and occipital lobes showed continued atrophy from 3 to 12 months post-injury. Additionally, cortical white matter volume and nearly all deep gray matter structures exhibited progressive atrophy over this period. Finally, we found that disproportionate atrophy of cortex along sulci relative to gyri, an emerging morphometric marker of chronic TBI, was present as early as 3 month post-injury. In parallel, neurocognitive functioning largely recovered during this period despite this pervasive atrophy. Our findings demonstrate msTBI results in characteristic progressive neurodegeneration patterns that are divergent across regions and scale with the severity of injury. Future clinical research using atrophy during the first year of TBI as a biomarker of neurodegeneration should consider the spatiotemporal profile of atrophy described in this study.

BACKGROUND: Astrocytes respond to injury and disease through a process known as reactive astrogliosis, of which inflammatory signaling is one subset. This inflammatory response is heterogeneous with respect to the inductive stimuli and the afflicted central nervous system region. This is of plausible importance in e.g. traumatic axonal injury (TAI), where lesions in the brainstem carries a particularly poor prognosis. In fact, astrogliotic forebrain astrocytes were recently suggested to cause neuronal death following axotomy. We therefore sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro.
METHODS: We derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of mouse embryonic stem cells (ES). We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α and clinically relevant inflammatory mediators. In co-cultures with reactive ES-astrocytes and motor neurons, we assessed neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions.
RESULTS: We confirmed the brainstem/rostroventral ES-astrocyte identity using RNA-sequencing, immunocytochemistry, and by comparison with primary subventricular zone-astrocytes. Following cytokine stimulation, the c-Jun N-terminal kinase pathway down-stream product phosphorylated c-Jun was increased, thus demonstrating ES-astrocyte reactivity. These reactive ES-astrocytes conferred a contact-dependent neurotoxic effect upon co-culture with motor neurons. When exposed to IL-1β and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following human severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. Activation of ES-astrocytes by these cytokines was associated with pathways relating to endoplasmic reticulum stress and altered regulation of MYC.
CONCLUSIONS: Ventral brainstem and rostroventral spinal cord astrocytes differentiated from mouse ES can exert neurotoxic effects in vitro. This highlights how neuroinflammation following CNS lesions can exert region- and cell-specific effects. Our in vitro model system, which uniquely portrays astrocytes and neurons from one niche, allows for a detailed and translationally relevant model system for future studies on how to improve neuronal survival in particularly vulnerable CNS regions following e.g. TAI.

OBJECTIVE: Application of Tandem Mass Tags (TMT)-based LC-MS/MS analysis to screen for differentially expressed proteins (DEPs) in traumatic axonal injury (TAI) of the brainstem and to predict potential biomarkers and key molecular mechanisms of brainstem TAI.
METHODS: A modified impact acceleration injury model was used to establish a brainstem TAI model in Sprague-Dawley rats, and the model was evaluated in terms of both functional changes (vital sign measurements) andstructural changes (HE staining, silver-plating staining and β-APP immunohistochemical staining). TMT combined with LC-MS/MS was used to analyse the DEPs in brainstem tissues from TAI and Sham groups. The biological functions of DEPs and potential molecular mechanisms in the hyperacute phase of TAI were analysed by bioinformatics techniques, and candidate biomarkers were validated using western blotting and immunohistochemistry on brainstem tissues from animal models and humans.
RESULTS: Based on the successful establishment of the brainstem TAI model in rats, TMT-based proteomics identified 65 DEPs, and bioinformatics analysis indicated that the hyperacute phase of TAI involves multiple stages of biological processes including inflammation, oxidative stress, energy metabolism, neuronal excitotoxicity and apoptosis. Three DEPs, CBR1, EPHX2 and CYP2U1, were selected as candidate biomarkers and all three proteins were found to be significantly expressed in brainstem tissue 30 min-7 days after TAI in both animal models and humans.
CONCLUSIONS: Using TMT combined with LC-MS/MS analysis for proteomic study of early TAI in rat brainstem, we report for the first time that CBR1, EPHX2 and CYP2U1 can be used as biomarkers of early TAI in brainstem by means of western blotting and immunohistochemical staining, compensating for the limitations of silver-plating staining and β-APP immunohistochemical staining, especially in the case of very short survival time after TAI (shorter than 30 min). A number of other proteins that also have a potential marker role are also presented, providing new insights into the molecular mechanisms, therapeutic targets and forensic identification of early TAI in brainstem.

Leukemia inhibitory factor (LIF) is a neuroprotective cytokine that is essential for appropriate glial responses, remyelination, and preservation of neuronal conductance after injury. The intranasal route for delivery of therapeutics to the central nervous system is of particular interest given that it bypasses the blood-brain barrier and peripheral clearance systems. We explored the possibility that LIF might improve neurological function when administered intranasally during the acute phase in a pediatric model of mild traumatic brain injury (mTBI). We tested two doses of LIF and evaluated behavioral outcomes. Here, we show that acute 40-ng intranasal LIF treatment twice a day for 3 days attenuates astrogliosis and microgliosis, protects against axonal damage, significantly improves sensorimotor function, and is well tolerated without detrimental effects on growth. Altogether, our studies provide pre-clinical evidence for the use of acute intranasal LIF treatment as a viable therapeutic for pediatric cases of mTBIs.