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Severe traumatic brain injury (TBI) results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (in =/i 20) or sham (in =/i 21). Cognitive function was assessed (3- and 6-month novel object recognition [NOR], novel object location [NOL], and temporal order object recognition [TOR]). Six-month cerebral blood flow (CBF) and cerebral blood volume (CBV) using contrast magnetic resonance imaging (MRI) andiex vivo/icircle of Willis artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed significantly impaired NOR, with similar trends (non-significant) in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus, and primary somatosensory barrel cortex, whereas it inversely correlated with arterial smooth muscle-dependent dilation. Six-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin 2 stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin 2-stimulated smooth muscle-dependent vasoreactivity. The findings of persistent pathophysiological consequences of mTBI in this animal model add to the broader understanding of chronic pathophysiological sequelae in human mild TBI.

Traumatic brain injury (TBI) increases the long-term risk of neurodegenerative diseases, including Alzheimer’s disease (AD). Here, we demonstrate that protein variant pathology generated in brain tissue of an experimental TBI mouse model is similar to protein variant pathology observed in human ADbrains, and that subacute accumulation of two AD associated variants of amyloid beta (Aβ) and tau in the TBI mouse model correlated with behavioral deficits. Male C57BL/6 mice were subjected to midline fluid percussion injury or to sham injury, after which sensorimotor function (rotarod, neurological severity score), cognitive deficit (novel object recognition), and affective deficits (elevated plus maze, forced swim task) were assessed at different days post-injury (DPI). Protein pathology at 7, 14, and 28 DPI was measured in multiple brain regions using an immunostain panel of reagents selectively targeting different neurodegenerative disease-related variants of Aβ, tau, TDP-43, and alpha-synuclein. Overall, TBI resulted in sensorimotor deficits and accumulation of AD-related protein variant pathology near the impact site, both of which returned to sham levels by 14 DPI. Individual mice, however, showed persistent behavioral deficits and/or accumulation of selected toxic protein variants at 28 DPI. Behavioral outcomes of each mouse were correlated with levels of seven different protein variants in ten brain regions at specific DPI. Out of 21 significant correlations between protein variant levels and behavioral deficits, 18 were with variants of Aβ or tau. Correlations at 28 DPI were all between a single Aβ or tau variant, both of which are strongly associated with human AD cases. These data provide a direct mechanistic link between protein pathology resulting from TBI and the hallmarks of AD.

Traumatic brain injury (TBI) can affect different regions throughout the brain. Regions near the site of impact are the most vulnerable to injury. However, damage to distal regions occurs. We investigated progressive neuropathology in the dorsal hippocampus (near the impact) and cerebellum (distal to the impact) after diffuse TBI. Adult male rats were subjected to midline fluid percussion injury or sham injury. Brain tissue was stained by the amino cupric silver stain. Neuropathology was quantified in sub-regions of the dorsal hippocampus at 1, 7, and 28 days post-injury (DPI) and coronal cerebellar sections at 1, 2, and 7 DPI. The highest observed neuropathology in the dentate gyrus occurred at 7 DPI which attenuated by 28 DPI, whereas the highest observed neuropathology was at 1 DPI in the CA3 region. There was no significant neuropathology in the CA1 region at any time point. Neuropathology was increased at 7 DPI in the cerebellum compared to shams and stripes of pathology were observed in the molecular layer perpendicular to the cerebellar cortical surface. Together these data show that diffuse TBI can result in neuropathology across the brain. By describing the time course of pathology in response to TBI, it is possible to build the temporal profile of disease progression.

Intimate partner violence (IPV) increases risk of traumatic brain injury (TBI). Physical assaults increase in frequency and intensity during pregnancy. The consequences of TBI during pregnancy (gravida TBI; gTBI) on offspring development is unknown, for which stress and inflammation during pregnancy worsen fetal developmental outcomes. We hypothesized that gTBI would lead to increased anxiety- and depression-related behavior, altered inflammatory responses and gut pathology, and distorted brain circuitry in mixed-sex offspring compared to mice born to control mothers. Pregnant dams received either diffuse TBI or sham injury (control) 12 days post-coitum. We found that male gTBI offspring were principal drivers of the gTBI effects on health, physiology, and behavior. For example, male, but not female, gTBI offspring weighed significantly less at weaning compared to male control offspring. At post-natal day (PND) 28, gTBI offspring had significantly weaker intralaminar connectivity onto layer 5 pre-frontal pyramidal neurons compared to control offspring. Neurological performance on anxiety-like behaviors was decreased, with only marginal differences in depressive-like behaviors, for gTBI offspring compared to control offspring. At PND42 and PND58, circulating neutrophil and monocyte populations were significantly smaller in gTBI male offspring than control male offspring. In response to a subsequent inflammatory challenge at PND75, gTBI offspring had significantly smaller circulating neutrophil populations than control offspring. Anxiety-like behaviors persisted during the immune challenge in gTBI offspring. However, spleen immune response and gut histology showed no significant differences between groups. The results compel further studies to determine the full extent of gTBI on fetal and maternal outcomes.

Domestic violence (DV) is a chronic societal epidemic that often involves physical assault to the head, neck, and face, which increases the risk of traumatic brain injuries (TBIs) in DV victims. However, epidemiological data on the extent of TBI-DV at the population scale remain sparse. We performed a statewide, multi-institution, retrospective review of all medical records for patients diagnosed with a concussion, the most common type of TBI, at health care facilities in Arizona, USA, that were licensed by Arizona Department of Health Services (ADHS) during 2016-2018. De-identified records were extracted from discharge data reported to ADHS, which we decoded and transformed to spatiotemporal demographic data of patients who were diagnosed with concussion concurrent with DV. Among 72,307 concussion diagnoses, 940 were concurrent with DV. Sixteen patients died as a result of TBI-DV injuries, where TBI is defined as concussion. Although females were most of the TBI-DV diagnoses, median ages for males and females were 1 and 32 years, respectively, demonstrating that males were predominantly child abuse victims. Whites and Hispanics were victims most diagnosed with concussion and DV, but Native Americans and Blacks comprised a much greater proportion of diagnoses compared with the representative state demographics. Although likely underreported, approximately half of the cases were inflicted by intimate partners, which corresponded closely to marital status. Surprisingly, 61% of victims sought medical treatment for non-concussion injuries and then concussion was entered as a primary diagnosis. The demographic and health care facility disparities demand TBI/concussion screening in suspected DV patients, education and training of care providers, and potential redistribution of resources to select health care facilities.

Traumatic brain injury (TBI) is an extremely complex condition due to heterogeneity in injury mechanism, underlying conditions, and secondary injury. Pre-clinical and clinical researchers face challenges with reproducibility that negatively impact translation and therapeutic development for improved TBI patient outcomes. To address this challenge, TBI Pre-clinical Working Groups expanded upon previous efforts and developed common data elements (CDEs) to describe the most frequently used experimental parameters. The working groups created 913 CDEs to describe study metadata, animal characteristics, animal history, injury models, and behavioral tests. Use cases applied a set of commonly used CDEs to address and evaluate the degree of missing data resulting from combining legacy data from different laboratories for two different outcome measures (Morris water maze [MWM]; RotorRod/Rotarod). Data were cleaned and harmonized to Form Structures containing the relevant CDEs and subjected to missing value analysis. For the MWM dataset (358 animals from five studies, 44 CDEs), 50% of the CDEs contained at least one missing value, while for the Rotarod dataset (97 animals from three studies, 48 CDEs), over 60% of CDEs contained at least one missing value. Overall, 35% of values were missing across the MWM dataset, and 33% of values were missing for the Rotarod dataset, demonstrating both the feasibility and the challenge of combining legacy datasets using CDEs. The CDEs and the associated forms created here are available to the broader pre-clinical research community to promote consistent and comprehensive data acquisition, as well as to facilitate data sharing and formation of data repositories. In addition to addressing the challenge of standardization in TBI pre-clinical studies, this effort is intended to bring attention to the discrepancies in assessment and outcome metrics among pre-clinical laboratories and ultimately accelerate translation to clinical research.

BACKGROUND Traumatic brain injury (TBI) is a disruption in normal brain function caused by an impact of external forces on the head. TBI affects millions of individuals per year, many potentially experiencing chronic symptoms and long-term disability, creating a public health crisis and an economic burden on society. The public discourse around sport-related TBIs has increased in recent decades; however, recognition of a possible TBI remains a challenge. The fencing response is an immediate posturing of the limbs, which can occur in individuals who sustain a TBI and can be used as an overt indicator of TBI. Typically, an individual demonstrating the fencing response exhibits extension in 1 arm and flexion in the contralateral arm immediately upon impact to the head; variations of forearm posturing among each limb have been observed. The tonic posturing is retained for several seconds, sufficient for observation and recognition of a TBI. Since the publication of the original peer-reviewed article on the fencing response, there have been efforts to raise awareness of the fencing response as a visible sign of TBI through publicly available web-based platforms, such as Twitter and Wikipedia. OBJECTIVE We aimed to quantify trends that demonstrate levels of public discussion and awareness of the fencing response over time using data from Twitter and Wikipedia. METHODS Raw Twitter data from January 1, 2010, to December 31, 2019, were accessed using the RStudio package academictwitteR and queried for the text “fencing response.” Data for page views of the Fencing Response Wikipedia article from January 1, 2010, to December 31, 2019, were accessed using the RStudio packages wikipediatrend and pageviews. Data were clustered by weekday, month, half-year (to represent the American football season vs off-season), and year to identify trends over time. Seasonal regression analysis was used to analyze the relationship between the number of fencing response tweets and page views and month of the year. RESULTS Twitter mentions of the fencing response and Wikipedia page views increased overall from 2010 to 2019, with hundreds of tweets and hundreds of thousands of Wikipedia page views per year. Twitter mentions peaked during the American football season, especially on and following game days. Wikipedia page views did not demonstrate a clear weekday or seasonal pattern, but instead had multiple peaks across various months and years, with January having more page views than May. CONCLUSIONS Here, we demonstrated increased awareness of the fencing response over time using public data from Twitter and Wikipedia. Effective scientific communication through free public platforms can help spread awareness of clinical indicators of TBI, such as the fencing response. Greater awareness of the fencing response as a “red-flag” sign of TBI among coaches, athletic trainers, and sports organizations can help with medical care and return-to-play decisions. CLINICALTRIAL

Diffuse brain injury is better described as multi-focal, where pathology can be found adjacent to seemingly uninjured neural tissue. In experimental diffuse brain injury, pathology and pathophysiology have been reported far more lateral than predicted by the impact site. Finite element biomechanical models of diffuse brain injury predict regions of maximum stress and strain. However, the application of a skull with uniform thickness may mask the pathophysiology due to varying thickness of human and animal skulls. Force applied to the intact skull would diffuse the forces, whereas forces applied through an open skull are distributed along paths of least resistance within and then exiting the skull. We hypothesized that the local thickening of the rodent skull at the temporal ridges serves to focus the intracranial mechanical forces experienced during brain injury and generate predictable pathology in underlying cortical tissue. We demonstrated local thickening of the skull at the temporal ridges using contour analysis of coronal skull sections and oblique sectioning on MRI. After diffuse brain injury induced by midline fluid percussion injury (mFPI), pathological foci along the anterior-posterior length of cortex under the temporal ridges were evident acutely (1, 2, 7 days) and chronically (28 days) post-injury by deposition of argyophilic reaction product. Area CA3 of the hippocampus and lateral nuclei of the thalamus showed pathological change, suggesting that mechanical forces to or from the temporal ridges shear subcortical regions. A proposed model of mFPI biomechanics suggests that injury force vectors reflect off the skull base and radiate toward the temporal ridge due to the material properties of the skull based on thickness, thereby injuring ventral thalamus, dorsolateral hippocampus, and sensorimotor cortex. Surgically thinning the temporal ridge prior to injury reduced the injury-induced inflammation in sensorimotor cortex. These data build evidence for the temporal ridges of the rodent skull to contribute to the observed pathology, whether by focusing extracranial forces to enter the cranium or intracranial forces to escape the cranium. Pre-clinical investigations can take advantage of the predicted pathology to explore injury mechanisms and treatment efficacy.HighlightsThe temporal ridge is 75% thicker than the adjacent skull of the rodentExperimental diffuse TBI neuropathology occurs beneath the length of the temporal ridgeNeuropathology encompasses sensorimotor cortex, somatosensory thalamus, and dorsolateral hippocampusProposed mechanism of biomechanical injury forces include the temporal ridge

Traumatic brain injury (TBI) affects millions of individuals each year and is a leading cause of death and disability worldwide. TBI is heterogeneous and outcome is influenced by a combination of factors that include injury location, severity, genetics, and environmental factors. More recently, sex as a biological variable has been incorporated into TBI research, although there is conflicting literature regarding clinical outcomes in males versus females after TBI. We review the current clinical literature investigating sex differences after TBI. We focus our discussion on differences within contemporary gender categories to suggest that binary categories of male and female are not sufficient to guide clinical decisions for neurotrauma. Some studies have considered physiological variables that influence sex such as hormone cycles and stages in males and females pre- and post-TBI. These data suggest that there are phasic differences within male populations and within female populations that influence an individual's outcome after TBI. Finally, we discuss the impact of gender identity and expression on outcome after TBI and highlight the lack of neurotrauma research that includes non-binary individuals. Social constructs regarding gender impact an individual's vulnerability to violence and consequent TBI, including the successful reintegration to society after TBI. We call for incorporation of gender beyond the binary in TBI education, research, and clinical care. Precision medicine necessarily must progress beyond the binary to treat individuals after TBI.

Background and Purpose: Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phosphatidylcholine, cholesterol, and monosialogangliosides (nanoliposomes) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that nanoliposomes will preserve human neuroblastoma (SH-SY5Y) and human brain microvascular endothelial cells viability following oxygen-glucose deprivation (OGD)–reoxygenation and will reduce injury in mice following middle cerebral artery occlusion. Methods: SH-SY5Y and human brain microvascular endothelial cells were exposed to oxygen-glucose deprivation–reoxygenation (3 hours 0.5%–1% oxygen and glucose-free media followed by 20-hour ambient air/regular media) without or with nanoliposomes (300 µg/mL). Viability was measured (calcein-acetoxymethyl fluorescence) and protein expression of antioxidant proteins HO-1 (heme oxygenase-1), NQO1 (NAD[P]H quinone dehydrogenase 1), and SOD1 (superoxide dismutase 1) were measured by Western blot. C57BL/6J mice were treated with saline (n=8) or nanoliposomes (10 mg/mL lipid, 200 µL, n=7) while undergoing 60-minute middle cerebral artery occlusion followed by reperfusion. Day 2 postinjury neurological impairment score and infarction size were compared. Results: SH-SY5Y and human brain microvascular endothelial cells showed reduced viability post–oxygen-glucose deprivation–reoxygenation that was reversed by nanoliposomes. Nanoliposomes increased protein expressions of HO-1, NQO1 in both cell types and SOD1 in human brain microvascular endothelial cells. Nanoliposomes-treated mice showed reduced neurological impairment and brain infarct size (18.8±2% versus 27.3±2.3%, P =0.017) versus controls. Conclusions: Nanoliposomes reduced stroke injury in mice subjected to middle cerebral artery occlusion likely through induction of an antioxidant protective response. Nanoliposome is a candidate novel agent for stroke.

Severe traumatic brain injury results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (N=20) or sham (N=21). Cognitive function was assessed (3- and 6-month novel object recognition (NOR), novel object location (NOL) and temporal order object recognition (TOR)). 6-month cerebral blood flow (CBF) and blood volume (CBV) using contrast MRI and ex vivo pial artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed impaired NOR, with similar (non-significant) trends in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus and primary somatosensory barrel cortex while inversely correlating with arterial smooth muscle-dependent dilation. 6-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin II stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin II-stimulated smooth muscle-dependent vasoreactivity, a paradigm that could advance understanding of the long-term sequelae of human mild TBI.

Traumatic brain injury (TBI) can induce acute lung injury (ALI). The exact pathomechanism of TBI-induced ALI is poorly understood, limiting treatment options. Remote ischemic conditioning (RIC) can mitigate detrimental outcomes following transplants, cardiac arrests, and neurological injuries. In this study, we hypothesized that RIC would reduce TBI-induced ALI by regulating the sphingosine-1-phosphate (S1P)-dependent pathway, a central regulator of endothelial barrier integrity, lymphocyte, and myokine trafficking. Male mice were subjected to either diffuse TBI by midline fluid percussion or control sham injury and randomly assigned among four groups: sham, TBI, sham RIC, or TBI RIC; RIC was performed 1 h prior to TBI. Mice were euthanized at 1-h postinjury or 7 days post-injury (DPI) and lung tissue, bronchoalveolar lavage (BAL) fluid, and blood were collected. Lung tissue was analyzed for histopathology, irisin myokine levels, and S1P receptor levels. BAL fluid and blood were analyzed for cellularity and myokine/S1P levels, respectively. One-hour postinjury, TBI damaged lung alveoli and increased neutrophil infiltration; RIC preserved alveoli. BAL from TBI mice had more neutrophils and higher neutrophil/monocyte ratios compared with sham, where TBI RIC mice showed no injury-induced change. Further, S1P receptor 3 and irisin-associated protein levels were significantly increased in the lungs of TBI mice compared with sham, which was prevented by RIC. However, there was no RIC-associated change in plasma irisin or S1P. At 7 DPI, ALI in TBI mice was largely resolved, with evidence for residual lung pathology. Thus, RIC may be a viable intervention for TBI-induced ALI to preserve lung function and facilitate clinical management.

Introduction: Neuroprotective strategies for stroke are lacking leading to significant disability and death. Liposomes (phospholipid particles) are commonly used as molecular carriers of therapeutic agent cargos. We previously showed that cargo-less nanoliposomes (NL, Hypothesis: NL will preserve neuroblastoma cell viability in the setting of hypoxic injury and will reduce functional and histologic injury in mice following middle cerebral artery occlusion (MCAO). Methods: SH-SY5Y neuroblastoma cells were exposed to 20-hour physoxic (5% oxygen) condition or hypoxic (1% oxygen) condition without or with NL (100 or 300 μg/mL). Viability was measured using calcein-AM fluorescence and SH-SY5Y gene expression of antioxidant proteins heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and superoxide dismutase 1 (SOD1) were measured by quantitative polymerase chain reaction. C57BL/6J mice were treated with saline (N=8) or NL (10000 ug/mL, N=7) while undergoing 60-minute MCAO followed by reperfusion. Day 2 post-injury neurologic impairment scoring was compared as well as post-mortem brain infarction size. Results: Neuroblastoma cells showed reduced viability following hypoxia that was reversed by treatment with NL. NL increased gene expression of HO-1, NQO1 and SOD1 compared to untreated controls. NL-treated mice showed reduced neurologic function impairment and reduced brain infarct size compared to controls (18.8±2% versus 27.3±2.3%, p=0.017, see Figure). Conclusions: Cargo-less NL reduced functional and structural stroke injury in mice subjected to MCAO likely mediated in part through induction of an antioxidant stress response. NL is a candidate novel agent to mitigate stroke injury.

Traumatic brain injury (TBI) can occur at any age, from youth to the elderly, and its contribution to age-related neuropathology remains unknown. Few studies have investigated the relationship between age-at-injury and pathophysiology at a discrete biological age. In this study, we report the immunohistochemical analysis of naïve rat brains compared to those subjected to diffuse TBI by midline fluid percussion injury (mFPI) at post-natal day (PND) 17, PND35, 2-, 4-, or 6-months of age. All brains were collected when rats were 10-months of age (n = 6–7/group). Generalized linear mixed models were fitted to analyze binomial proportion and count data with R Studio. Amyloid precursor protein (APP) and neurofilament (SMI34, SMI32) neuronal pathology were counted in the corpus callosum (CC) and primary sensory barrel field (S1BF). Phosphorylated TAR DNA-binding protein 43 (pTDP-43) neuropathology was counted in the S1BF and hippocampus. There was a significantly greater extent of APP and SMI34 axonal pathology and pTDP-43 neuropathology following a TBI compared with naïves regardless of brain region or age-at-injury. However, age-at-injury did determine the extent of dendritic neurofilament (SMI32) pathology in the CC and S1BF where all brain-injured rats exhibited a greater extent of pathology compared with naïve. No significant differences were detected in the extent of astrocyte activation between brain-injured and naïve rats. Microglia counts were conducted in the S1BF, hippocampus, ventral posteromedial (VPM) nucleus, zona incerta, and posterior hypothalamic nucleus. There was a significantly greater proportion of deramified microglia, regardless of whether the TBI was recent or remote, but this only occurred in the S1BF and hippocampus. The proportion of microglia with colocalized CD68 and TREM2 in the S1BF was greater in all brain-injured rats compared with naïve, regardless of whether the TBI was recent or remote. Only rats with recent TBI exhibited a greater proportion of CD68-positive microglia compared with naive in the hippocampus and posterior hypothalamic nucleus. Whilst, only rats with a remote brain-injury displayed a greater proportion of microglia colocalized with TREM2 in the hippocampus. Thus, chronic alterations in neuronal and microglial characteristics are evident in the injured brain despite the recency of a diffuse brain injury.

Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phos-phatidylcholine, cholesterol and monosialogangliosides (NL) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that NL will preserve SH-SY5Y neuroblastoma cell viability following hypoxic injury and will reduce injury in mice following middle cerebral artery occlusion (MCAO). Neuroblastoma were exposed to 20-hour physoxic (5% oxygen) or hypoxic (1% oxygen) condition without or with NL (100 or 300 µg/mL). Viability was measured using calcein-AM fluorescence and SH-SY5Y gene expression of antioxidant proteins heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and superoxide dismutase 1 (SOD1) were measured by quantitative polymerase chain reaction. C57BL/6J mice were treated with saline (N=8) or NL (10000 ug/mL, N=7) while undergoing 60-minute MCAO followed by reperfusion. Day 2 post-injury neurologic impairment score and infarction size were compared. Neuroblastoma showed reduced viability following hypoxia that was reversed by NL. NL increased gene expression of HO-1, NQO1 and SOD1 versus controls. NL-treated mice showed reduced neurologic impairment and brain infarct size (18.8±2% versus 27.3±2.3%, p=0.017) versus controls. NL reduced stroke injury in mice subjected to MCAO likely through induction of an antioxidant stress response. NL is a candidate novel agent for stroke.

Police officers around the world respond to and investigate calls regarding domestic violence (DV) daily. Police departments operate with standard protocols, particularly when engaging in i...

The article serves as the introduction to a special issue of the journal focused on traumatic brain injury in the context of domestic and intimate partner violence. The scope of the problem...

Intimate partner violence (IPV) causes harm to an estimated 42 million victims each year. Routine forensic examination excludes specific evaluation of traumatic brain injury (TBI), thereby ...

While much of the focus on brain injury has centered on athletes and military veterans, victims of domestic violence (DV) comprise an under-represented cohort. Epidemiological studies show ...

Microglia undergo dynamic structural and transcriptional changes during the immune response to traumatic brain injury (TBI). For example, TBI causes microglia to form rod-shaped trains in the cerebral cortex, but their contribution to inflammation and pathophysiology is unclear. The purpose of this study was to determine the origin and alignment of rod microglia and to determine the role of microglia in propagating persistent cortical inflammation. Here, diffuse TBI in mice was modeled by midline fluid percussion injury (FPI). Bone marrow chimerism and BrdU pulse-chase experiments revealed that rod microglia derived from resident microglia with limited proliferation. Novel data also show that TBI-induced rod microglia were proximal to axotomized neurons, spatially overlapped with dense astrogliosis, and aligned with apical pyramidal dendrites. Furthermore, rod microglia formed adjacent to hypertrophied microglia, which clustered among layer V pyramidal neurons. To better understand the contribution of microglia to cortical inflammation and injury, microglia were eliminated prior to TBI by CSF1R antagonism (PLX5622). Microglial elimination did not affect cortical neuron axotomy induced by TBI, but attenuated rod microglial formation and astrogliosis. Analysis of 262 immune genes revealed that TBI caused profound cortical inflammation acutely (8 hr) that progressed in nature and complexity by 7 dpi. For instance, gene expression related to complement, phagocytosis, toll-like receptor signaling, and interferon response were increased 7 dpi. Critically, these acute and chronic inflammatory responses were prevented by microglial elimination. Taken together, TBI-induced neuronal injury causes microglia to structurally associate with neurons, augment astrogliosis, and propagate diverse and persistent inflammatory/immune signaling pathways.

Clinically, traumatic brain injury (TBI) results in complex heterogeneous pathology that cannot be recapitulated in single pre-clinical animal model. Therefore, we focused on evaluating utility of nanoparticle (NP)-based therapeutics following three diffuse-TBI models: mildclosed-head injury (mCHI), repetitive-mCHI and midline-fluid percussion injury (FPI). We hypothesized that NP accumulation after diffuse TBI correlates directly with blood–brainbarrier permeability. Mice received PEGylated-NP cocktail (20-500 nm) (intravenously) after single- or repetitive-(1 impact/day, 5 consecutive days) CHI (immediately) and midline-FPI (1 h, 3 h and 6 h). NPs circulated for 1 h before perfusion/brain extraction. NP accumulation was analyzed using fluorescent microscopy in brain regions vulnerable to neuropathology. Minimal/no NP accumulation after mCHI/RmCHI was observed. In contrast, midlineFPI resulted in significant peak accumulation of up to 500 nm NP at 3 h post-injury compared to sham, 1 h, and 6 h groups in the cortex. Therefore, our study provides the groundwork for feasibility of NP-delivery based on NPinjection time and NPsize after mCHI/RmCHI and midline-FPI.

Contemporary microglia morphologies include ramified, activated and amoeboid, with the morphology of microglia considered highly coupled to the cellular function. Rod microglia are an additional activated microglia variant observed in the ageing, injured and diseased brain. Rod microglia were reported frequently in the early 1900s by neuropathologists in post-mortem cases of general paresis, Alzheimer’s disease and encephalitis, and then remained largely ignored for almost 100 years. Recent reports have renewed interest in rod microglia, most notably after experimental traumatic brain injury. Rod microglia are formed by the narrowing of the soma and retraction of planar processes, which results in the appearance of an elongated, rod-shaped cell. Rod microglia are most commonly observed in the cortex, aligned perpendicular to the dural surface and adjacent to neuronal processes; in the hippocampus, they are aligned perpendicular to hippocampal layers. Furthermore, rod microglia form trains with one another, apical end to basal end. By replicating the process of sketching microscopic observation, rod microglia are re-defined by circumnutation around the long axis. In this update, we summarize the rod microglia variant in clinical and experimental literature and advocate for investigation into mechanisms of rod microglia origin and function., Rod microglia are a variant of activated microglia reported in the brain after neurological injury and disease. Despite their discovery over 100 years ago, little is known about their formation, expression, or function. Advanced molecular tools are required to elucidate the role of rod microglia., Graphical Abstract Graphical Abstract

Traumatic brain injury (TBI) is initiated by mechanical forces to the head that disrupt neurological function. Pathophysiology may begin immediately with the mechanical forces or evolve as an indirect response in an attempt to alleviate damage. In both instances, pathophysiology can develop into transient and/or persistent clinical symptoms after TBI. The magnitude and duration of pathophysiology and resultant symptoms may differ with injury severity, but hallmark pathophysiological processes are similar across the diversity of TBI. In this chapter, we introduce the common pathophysiology after diffuse TBI as a means to appreciate the complexity of injury, damage, repair, and recovery of injured tissue. Understanding the pathophysiology underlying clinical symptoms can guide therapeutic targets and treatment pathways to mitigate negative outcomes after TBI.

Elderly populations (≥65 years old) have the highest risk of developing Alzheimer's disease (AD) and/or obtaining a traumatic brain injury (TBI). Using translational mouse models, we investigated sleep disturbances and inflammation associated with normal aging, TBI and aging, and AD. We hypothesized that aging results in marked changes in sleep compared with adult mice, and that TBI and aging would result in sleep and inflammation levels similar to AD mice. We used female 16-month-old wild-type (WT Aged) and 3xTg-AD mice, as well as a 2-month-old reference group (WT Adult), to evaluate sleep changes. WT Aged mice received diffuse TBI by midline fluid percussion, and blood was collected from both WT Aged (pre- and post-TBI) and 3xTg-AD mice to evaluate inflammation. Cognitive behavior was tested, and tissue was collected for histology. Bayesian generalized additive and mixed-effects models were used for analyses. Both normal aging and AD led to increases in sleep compared with adult mice. WT Aged mice with TBI slept substantially more, with fragmented shorter bouts, than they did pre-TBI and compared with AD mice. However, differences between WT Aged and 3xTg-AD mice in immune cell populations and plasma cytokine levels were incongruous, cognitive deficits were similar, and cumulative sleep was not predictive of inflammation or behavior for either group. Our results suggest that in similarly aged individuals, TBI immediately induces more profound sleep alterations than in AD, although both diseases likely include cognitive impairments. Unique pathological sleep pathways may exist in elderly individuals who incur TBI compared with similarly aged individuals who have AD, which may warrant disease-specific treatments in clinical settings.

Over half of fatal pediatric traumatic brain injuries are estimated to be the result of physical abuse, i.e., abusive head trauma (AHT). Although intimate partner violence (IPV) is a well-established risk for child maltreatment, little is known about IPV as an associated risk factor specifically for AHT. We performed a single-institution, retrospective review of all patients (0–17 years) diagnosed at a Level 1 pediatric trauma center with head trauma who had been referred to an in-hospital child protection team for suspicion of AHT between 2010 and 2016. Data on patient demographics, hospitalization, injury, family characteristics, sociobehavioral characteristics, physical examination, laboratory findings, imaging, discharge, and forensic determination of AHT were extracted from the institution’s forensic registry. Descriptive statistics (mean, median), chi-square and Mann–Whitney U tests were used to compare patients with fatal head injuries to patients with nonfatal head injuries by clinical characteristics, family characteristics, and forensic determination. Multiple logistic regression was used to estimate adjusted odds ratios for the presence of IPV as an associated risk of AHT while controlling for other clinical and family factors. Of 804 patients with suspicion for AHT in the forensic registry, there were 240 patients with a forensic determination of AHT; 42 injuries were fatal. There were 101 families with a reported history of IPV; 64.4% of patients in families with reported IPV were

Abusive head trauma (AHT) is the leading cause traumatic death in children ≤5 years of age. AHT remains seriously under-surveilled, increasing the risk of subsequent injury and death. This study assesses the clinical and social risks associated with fatal and non-fatal AHT.A single-institution, retrospective review of suspected AHT patients ≤5 years of age between 2010 and 2016 using a prospective hospital forensic registry data yielded demographic, clinical, family, psycho-social and other follow-up information. Descriptive statistics were used to look for differences between patients with AHT and accidental head trauma. Logistic regression estimated the adjusted odds ratios (AOR) for AHT. A receiver operating characteristic (ROC) curve was created to calculate model sensitivity and specificity.Forensic evaluations of 783 children age ≤5 years with head trauma met the inclusion criteria; 25 were fatal with median[IQR] age 23[4.5-39.0] months. Of 758 non-fatal patients, age was 7[3.0-11.0] months; 59.5% male; 435 patients (57.4%) presented with a skull fracture, 403 (53.2%) with intracranial hemorrhage. Ultimately 242 (31.9%) were adjudicated AHT, 335(44.2%) were accidental, 181 (23.9%) were undetermined. Clinical factors increasing the risk of AHT included multiple fractures (Exp(β) = 9.9[p = 0.001]), bruising (Expβ = 5.7[p 0.001]), subdural blood (Exp(β) = 5.3[p = 0.001]), seizures (Exp(β) = 4.9[p = 0.02]), lethargy/unresponsiveness (Exp(β) = 2.24[p = 0.02]), loss of consciousness (Exp(β) = 4.69[p = 0.001]), and unknown mechanism of injury (Exp(β) = 3.9[p = 0.001]); skull fracture reduced the risk of AHT by half (Exp(β) = 0.5[p = 0.011]). Social risks factors included prior police involvement (Exp(β) = 5.9[p = 0.001]), substance abuse (Exp(β) = 5.7[p = .001]), unknown number of adults in the home (Exp(β) = 4.1[p = 0.001]) and intimate partner violence (Exp(β) = 2.3[p = 0.02]). ROC area under the curve (AUC) = 0.90([95% CI = 0.86-0.93] p = .001) provides 73% sensitivity; 91% specificity.To improve surveillance of AHT, interviews should include and consider social factors including caregiver/household substance abuse, intimate partner violence, prior police involvement and household size. An unknown number of adults in home is associated with an increased risk of AHT.Prognostic, Level III.

Remote ischemic conditioning (RIC), transient restriction and recirculation of blood flow to a limb after traumatic brain injury (TBI), can modify levels of pathology-associated circulating protein. This study sought to identify TBI-induced molecular alterations in plasma and whether RIC would modulate protein and metabolite levels at 24 h after diffuse TBI. Adult male C57BL/6 mice received diffuse TBI by midline fluid percussion or were sham-injured. Mice were assigned to treatment groups 1 h after recovery of righting reflex: sham, TBI, sham RIC, TBI RIC. Nine plasma metabolites were significantly lower post-TBI (six amino acids, two acylcarnitines, one carnosine). RIC intervention returned metabolites to sham levels. Using proteomics analysis, twenty-four putative protein markers for TBI and RIC were identified. After application of Benjamini–Hochberg correction, actin, alpha 1, skeletal muscle (ACTA1) was found to be significantly increased in TBI compared to both sham groups and TBI RIC. Thus, identified metabolites and proteins provide potential biomarkers for TBI and therapeutic RIC in order to monitor disease progression and therapeutic efficacy.

Introduction The extracellular matrix (ECM) provides structural support for neuronal, glial, and vascular components of the brain, and regulates intercellular signaling required for cellular morphogenesis, differentiation and homeostasis. We hypothesize that the pathophysiology of diffuse brain injury impacts the ECM in a multi‐dimensional way across brain regions and over time, which could facilitate damage and repair processes. Methods Experimental diffuse TBI was induced in male Sprague‐Dawley rats (325–375 g) by midline fluid percussion injury (FPI); uninjured sham rats serve as controls. Tissue from the cortex, thalamus, and hippocampus was collected at 15 min, 1, 2, 6, and 18 hr postinjury as well as 1, 3, 7, and 14 days postinjury. All samples were quantified by Western blot for glycoproteins: fibronectin, laminin, reelin, and tenascin‐C. Band intensities were normalized to sham and relative to β‐actin. Results In the cortex, fibronectin decreased significantly at 15 min, 1 hr, and 2 hr postinjury, while tenascin‐C decreased significantly at 7 and 14 days postinjury. In the thalamus, reelin decreased significantly at 2 hr, 3 and 14 days postinjury. In the hippocampus, tenascin‐C increased significantly at 15 min and 7 days postinjury. Conclusion Acute changes in the levels of these glycoproteins suggest involvement in circuit dismantling, whereas postacute levels may indicate a restorative or regenerative response associated with recovery from TBI., The extracellular matrix (ECM) provides structural support for neuronal, glial, and vascular components of the brain, and regulates intercellular signaling required for cellular morphogenesis, differentiation, and homeostasis. We hypothesize that the ECM is susceptible to degradation and accumulation of glycoproteins, which can serve as spatial–temporal biomarkers of diffuse traumatic brain injury (TBI).