Sleep fragmentation after traumatic brain injury impairs behavior and conveys long-lasting impacts on neuroinflammation.

Traumatic brain injury (TBI) causes a prolonged inflammatory response in the central nervous system (CNS) driven by microglia. Microglial reactivity is exacerbated by stress, which often provokes sleep disturbances. We have previously shown that sleep fragmentation (SF) stress after experimental TBI increases microglial reactivity and impairs hippocampal function 30 days post-injury (DPI). The neuroimmune response is highly dynamic the first few weeks after TBI, which is also when injury induced sleep-wake deficits are detected. Therefore, we hypothesized that even a few weeks of TBI SF stress would synergize with injury induced sleep-wake deficits to promote neuroinflammation and impair outcome. Here, we investigated the effects of environmental SF in a lateral fluid percussion model of mouse TBI. Half of the mice were undisturbed, and half were exposed to 5 h of SF around the onset of the light cycle, daily, for 14 days. All mice were then undisturbed 15-30 DPI, providing a period for SF stress recovery (SF-R). Mice exposed to SF stress slept more than those in control housing 7-14 DPI and engaged in more total daily sleep bouts during the dark period. However, SF stress did not exacerbate post-TBI sleep deficits. Testing in the Morris water maze revealed sex dependent differences in spatial reference memory 9-14 DPI with males performing worse than females. Post-TBI SF stress suppressed neurogenesis-related gene expression and increased inflammatory signaling in the cortex at 14 DPI. No differences in sleep behavior were detected between groups during the SF stress recovery period 15-30 DPI. Microscopy revealed cortical and hippocampal IBA1 and CD68 percent-area increased in TBI SF-R mice 30 DPI. Additionally, neuroinflammatory gene expression was increased, and synaptogenesis-related gene expression was suppressed in TBI-SF mice 30 DPI. Finally, IPA canonical pathway analysis showed post-TBI SF impaired and delayed activation of synapse-related pathways between 14 and 30 DPI. These data show that transient SF stress after TBI impairs recovery and conveys long-lasting impacts on neuroimmune function independent of continuous sleep deficits. Together, these finding support that even limited exposure to post-TBI SF stress can have lasting impacts on cognitive recovery and regulation of the immune response to trauma.

Partially divided caging reduces overall aggression and anxiety which may indicate improved welfare in group housed male C57BL/6J mice.

Deciding which environmental enrichment is used in mouse caging is often subjective, with cost frequently prevailing over welfare benefits, including aggression and anxiety. While many devices introduced to encourage natural behaviors and reduce aggression show mixed results, we have previously demonstrated significant reductions in aggressive behavior between group-housed male mice housed in partially divided caging. To further assess behavior, we have raised male C57BL/6J mice in either partially divided caging or in standard caging with no divider. Animal behavior was tested on rotarod, open field, novel object recognition, elevated plus maze, and Y maze. Body weights were taken weekly beginning at weaning and bite wounds were counted weekly beginning at 133 days old. Aggressive behavior was recorded weekly beginning at 133 days old. Results indicated significantly less anxiety in the elevated-plus maze, statistically fewer bite wounds, and a statistically significant decrease in aggressive behaviors of mice in partially divided caging compared to mice in standard cages. We conclude that reductions in anxiety, aggressive behavior, and bite wounds may indicate improved overall welfare for non-sibling, group housed male mice.

Traumatic Brain Injury in Mice Generates Early-Stage Alzheimer's Disease Related Protein Pathology that Correlates with Neurobehavioral Deficits.

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 during early stages of AD, and that subacute accumulation of AD associated variants of amyloid beta (Aß) 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 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 Aß, 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 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 Aß or tau. Correlations at 28 DPI were all between a single Aß 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.

Neurosteroid Receptor Modulators for Treating Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers wide-ranging pathology that impacts multiple biochemical and physiological systems, both inside and outside the brain. Functional recovery in patients is impeded by early onset brain edema, acute and chronic inflammation, delayed cell death, and neurovascular disruption. Drug treatments that target these deficits are under active development, but it seems likely that fully effective therapy may require interruption of the multiplicity of TBI-induced pathological processes either by a cocktail of drug treatments or a single pleiotropic drug. The complex and highly interconnected biochemical network embodied by the neurosteroid system offers multiple options for the research and development of pleiotropic drug treatments that may provide benefit for those who have suffered a TBI. This narrative review examines the neurosteroids and their signaling systems and proposes directions for their utility in the next stage of TBI drug research and development.

Colony-Stimulating Factor-1 Receptor Inhibition Transiently Attenuated the Peripheral Immune Response to Experimental Traumatic Brain Injury.

To investigate microglial mechanisms in central and peripheral inflammation after experimental traumatic brain injury (TBI), we inhibited the colony-stimulating factor-1 receptor (CSF-1R) with PLX5622 (PLX). We hypothesized that microglia depletion would attenuate central inflammation acutely with no effect on peripheral inflammation. After randomization, male mice (n = 105) were fed PLX or control diets (21 days) and then received midline fluid percussion injury or sham injury. Brain and blood were collected at 1, 3, or 7 days post-injury (DPI). Immune cell populations were quantified in the brain and blood by flow cytometry. Cytokines (interleukin [IL]-6, IL-1ß, tumor necrosis factor-α, interferon-γ, IL-17A, and IL-10) were quantified in the blood using a multi-plex enzyme-linked immunosorbent assay. Data were analyzed using Bayesian multi-variate, multi-level models. PLX depleted microglia at all time points and reduced neutrophils in the brain at 7 DPI. PLX also depleted CD115+ monocytes, reduced myeloid cells, neutrophils, and Ly6Clow monocytes in blood, and elevated IL-6. TBI induced a central and peripheral immune response. TBI elevated leukocytes, microglia, and macrophages in the brain and elevated peripheral myeloid cells, neutrophils, Ly6Cint monocytes, and IL-1ß in the blood. TBI lowered peripheral CD115+ and Ly6Clow monocytes in the blood. TBI PLX mice had fewer leukocytes and microglia in the brain at 1 DPI, with elevated neutrophils at 7 DPI compared to TBI mice on a control diet. TBI PLX mice also had fewer peripheral myeloid cells, CD115+, and Ly6Clow monocytes in the blood at 3 DPI, but elevated Ly6Chigh, Ly6Cint, and CD115+ monocyte populations at 7 DPI, compared to TBI mice on a control diet. TBI PLX mice had elevated proinflammatory cytokines and lower anti-inflammatory cytokines in the blood at 7 DPI compared to TBI mice on a control diet. CSF-1R inhibition reduced the immune response to TBI at 1 and 3 DPI, but elevated peripheral inflammation at 7 DPI.

Traumatic brain injury in mice generates early-stage Alzheimer's disease related protein pathology that correlates with neurobehavioral deficits.

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 (Aß) 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 Aß, 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 Aß or tau. Correlations at 28 DPI were all between a single Aß 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.

Public Awareness of the Fencing Response as an Indicator of Traumatic Brain Injury: Quantitative Study of Twitter and Wikipedia Data.

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.

Peg Forest Rehabilitation - A novel spatial navigation based cognitive rehabilitation paradigm for experimental neurotrauma.

Traumatic brain injury (TBI) results from mechanical forces applied to the head. Ensuing cascades of complex pathophysiology transition the injury event into a disease process. The enduring constellation of emotional, somatic, and cognitive impairments degrade quality of life for the millions of TBI survivors suffering from long-term neurological symptoms. Rehabilitation strategies have reported mixed results, as most have not focused on specific symptomatology or explored cellular processes. The current experiments evaluated a novel cognitive rehabilitation paradigm for brain-injured and uninjured rats. The arena is a plastic floor with a cartesian grid of holes for plastic dowels to create new environments with the rearrangement of threaded pegs. Rats received either two weeks of Peg Forest rehabilitation (PFR) or open field exposure starting at 7 days post-injury; or one week starting at either day 7 or 14 post-injury; or served as caged controls. Cognitive performance was assessed on a battery of novel object tasks at 28 days post-injury. The results revealed that two weeks of PFR was required to prevent the onset of cognitive impairments, while one week of PFR was insufficient regardless of when rehabilitation was initiated after injury. Further assessment of the task showed that novel daily arrangements of the environment were required to impart the cognitive performance benefits, as exposure to a static arrangement of pegs for PFR each day did not improve cognitive performance. The results indicate that PFR prevents the onset of cognitive disorders following acquired a mild to moderate brain injury, and potentially other neurological conditions.

Time Course of Remote Neuropathology Following Diffuse Traumatic Brain Injury in the Male Rat.

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.

Chronic Cognitive and Cerebrovascular Function after Mild Traumatic Brain Injury in Rats.

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 (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]). Six-month cerebral blood flow (CBF) and cerebral blood volume (CBV) using contrast magnetic resonance imaging (MRI) and ex vivo circle 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.

The pentagram of concussion: an observational analysis that describes five overt indicators of head trauma.

BACKGROUND: Multifarious clinical presentations of traumatic brain injury (TBI) makes detection difficult. Acceptance of the Fencing Response as an indicator of moderate TBI with localization to the brainstem expanded interest towards other possible indicators. METHODS: We hypothesized that an individual experiencing traumatic forces to the head resulting in concussion could display additional brainstem-mediated responses. Using YouTube™, videos were systematically evaluated for mechanical forces imposed on the head with a subsequent, observable behavior. Searches identified 9.9 million non-unique videos in which 0.01% were viewed and 79 met inclusion criteria. Videos of head injuries occurred during athletic activity (57%), assaults (38%), automobile accidents (4%) and impact by an inanimate object (1%). RESULTS: Individuals with acute head injury were identified as adults (70%; n = 55), teens (29%; n = 23), and children (1.2%; n = 1). Those identified as males made up majority of injured persons (n = 77♂, 2♀). Individuals in the videos were observed to demonstrate the Fencing Response (47%; n = 37), seizing (44%; n = 35), snoring (24%; n = 19), crying (7.6%; n = 6), and vomiting (3.8%; n = 3). CONCLUSION: Each response, which together comprise the "Pentagram of Concussion", indicates the presence of traumatic forces to the head that present with one or more pentagram signs that would localize dysfunction to the brainstem. Clinical consideration of these responses helps to immediately identify patients at high risk for a brain injury with brainstem involvement that may have otherwise been mistaken for a different diagnosis.

Intimate Partner Violence, Clinical Indications, and Other Family Risk Factors Associated With Pediatric Abusive Head Trauma.

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 <12 months of age. IPV was associated with a twofold increase in the risk of AHT (Exp(ß) = 2.3 [p = .02]). This study confirmed IPV was an associated risk factor for AHT in a single institution cohort of pediatric patients with both fatal and nonfatal injuries. Identifying IPV along with other family factors may improve detection and surveillance of AHT in medical settings and help reduce injury, disability, and death.

Nanoliposomes Reduce Stroke Injury Following Middle Cerebral Artery Occlusion in Mice.

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.

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats.

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.

Spatial Distribution of Neuropathology and Neuroinflammation Elucidate the Biomechanics of Fluid Percussion Injury.

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. We hypothesized that 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. We demonstrated local thickening of the skull at the temporal ridges using contour analysis on magnetic resonance imaging. 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, and 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, thereby injuring ventral thalamus, dorsolateral hippocampus, and sensorimotor cortex. Surgically thinning the temporal ridge before injury reduced injury-induced inflammation in the sensorimotor cortex. These data build evidence for 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.

Mice Born to Mothers with Gravida Traumatic Brain Injury Have Distorted Brain Circuitry and Altered Immune Responses.

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.

Population-Level Epidemiology of Concussion Concurrent with Domestic Violence in Arizona, USA.

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.

An update on the rod microglia variant in experimental and clinical brain injury and disease.

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.

Remote Ischemic Conditioning Reduced Acute Lung Injury After Traumatic Brain Injury in the Mouse.

ABSTRACT: 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.