ZL006 mitigates anxiety-like behaviors induced by closed head injury through modulation of the neural circuit from the medial prefrontal cortex to amygdala.

Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.

Non-Invasive Vagal Nerve Stimulation Pre-Treatment Reduces Neurological Dysfunction After Closed Head Injury in Mice.

Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1ß) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1ß activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.

Weight-Drop Method for Inducing Closed Head Diffuse Traumatic Brain Injury.

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

Altered DTI scalars in the hippocampus are associated with morphological and structural changes after traumatic brain injury.

Blunt and diffuse injury is a highly prevalent form of traumatic brain injury (TBI) which can result in microstructural alterations in the brain. The blunt impact on the brain can affect the immediate contact region but can also affect the vulnerable regions like hippocampus, leading to functional impairment and long-lasting cognitive deficits. The hippocampus of the moderate weight drop injured male rats was longitudinally assessed for microstructural changes using in vivo MR imaging from 4 h to Day 30 post-injury (PI). The DTI analysis found a prominent decline in the apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD) values after injury. The perturbed DTI scalars accompanied histological changes in the hippocampus, wherein both the microglia and astrocytes showed changes in the morphometric parameters at all timepoints. Along with this, the hippocampus showed presence of Aß positive fibrils and neurite plaques after injury. Therefore, this study concludes that TBI can lead to a complex morphological, cellular, and structural alteration in the hippocampus which can be diagnosed using in vivo MR imaging techniques to prevent long-term functional deficits.

Photobiomodulation therapy alleviates repeated closed head injury-induced anxiety-like behaviors.

Repeated closed head injury (rCHI) is one of the most common brain injuries. Although extensive studies have focused on how to treat rCHI-induced brain injury and reduce the possibility of developing memory deficits, the prevention of rCHI-induced anxiety has received little research attention. The current study was designed to assess the effects of photobiomodulation (PBM) therapy in preventing anxiety following rCHI. The rCHI disease model was constructed by administering three repeated closed-head injuries within an interval 5 days. 2-min daily PBM therapy using an 808 nm continuous wave laser at 350 mW/cm2 on the scalp was implemented for 20 days. We found that PBM significantly ameliorated rCHII-induced anxiety-like behaviors, neuronal apoptosis, neuronal injury, promotes astrocyte/microglial polarization to anti-inflammatory phenotype, preserves mitochondrial fusion-related protein MFN2, attenuates the elevated mitochondrial fission-related protein DRP1, and mitigates neuronal senescence. We concluded that PBM therapy possesses great potential in preventing anxiety following rCHI.

Model matters: Differential outcomes in traumatic optic neuropathy pathophysiology between blunt and blast-wave mediated head injuries.

Over 3 million people in the United States live with long-term disability because of a traumatic brain injury (TBI). The purpose of this study was to characterize and compare two different animal models of TBI (blunt head trauma and blast TBI) to determine common and divergent characteristics of these models. With recent literature reviews noting the prevalence of visual system injury in animal models of TBI, coupled with clinical estimates of 50-75% of all TBI cases, we decided to assess commonalities, if they existed, through visual system injury. A unilateral (left directed) blast and repeat blast model injury with coup-contra-coup injury patterns were compared to a midline blunt injury. Injuries were induced in adult male mice to observe and quantify visual deficits. Retinal ganglion cell loss and axonal degeneration in the optic tract, superior colliculus, and lateral geniculate nuclei were examined to trace injury outcomes throughout major vision-associated areas. Optokinetic response, immunohistochemistry, and western blots were analyzed. Where a single blunt injury produces significant visual deficits a single blast injury appears to have less severe visual consequences. Visual deficits after repeat blasts are similar to a single blast. Single blast injury induces contralateral damage to the right optic chiasm and tract whereas bilateral injury follows a single blunt TBI. Repeat blast injuries are required to see degeneration patterns in downstream regions similar to the damage seen in a single blunt injury. This finding is further supported by amyloid precursor protein (APP) staining in injured cohorts. Blunt injured groups present with staining 1.2 mm ahead of the optic nerve, indicating axonal breakage closer to the optic chiasm. In blast groups, APP was identifiable in a bilateral pattern only in the geniculate nucleus. Evidence for unilateral neuronal degeneration in brain tissue with bilateral axonal ruptures are pivotal discoveries in this model differentiation. Analysis of the two injury models suggests that there is a significant difference in the histological outcomes dependent on injury type, though visual system injury is likely present in more cases than are currently diagnosed clinically.

Prolonged course of brain edema and neurological recovery in a translational model of decompressive craniectomy after closed head injury in mice.

Background: The use of decompressive craniectomy in traumatic brain injury (TBI) remains a matter of debate. According to the DECRA trial, craniectomy may have a negative impact on functional outcome, while the RescueICP trial revealed a positive effect of surgical decompression, which is evolving over time. This ambivalence of craniectomy has not been studied extensively in controlled laboratory experiments. Objective: The goal of the current study was to investigate the prolonged effects of decompressive craniectomy (both positive and negative) in an animal model. Methods: Male mice were assigned to the following groups: sham, decompressive craniectomy, TBI and TBI followed by craniectomy. The analysis of functional outcome was performed at time points 3d, 7d, 14d and 28d post trauma according to the Neurological Severity Score and Beam Balance Score. At the same time points, magnetic resonance imaging was performed, and brain edema was analyzed. Results: Animals subjected to both trauma and craniectomy presented the exacerbation of the neurological impairment that was apparent mostly in the early course (up to 7d) after injury. Decompressive craniectomy also caused a significant increase in brain edema volume (initially cytotoxic with a secondary shift to vasogenic edema and gliosis). Notably, delayed edema plus gliosis appeared also after decompression even without preceding trauma. Conclusion: In prolonged outcomes, craniectomy applied after closed head injury in mice aggravates posttraumatic brain edema, leading to additional functional impairment. This effect is, however, transient. Treatment options that reduce brain swelling after decompression may accelerate neurological recovery and should be explored in future experiments.

Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats.

Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awake closed head injury (ACHI) model, that uses rapid head acceleration to induce a mTBI, we investigated the acute effects of repeated-mTBI (r-mTBI) on neurological function and cellular proliferation in juvenile male and female Long-Evans rats. We found that r-mTBI did not lead to cumulative neurological deficits with the model. R-mTBI animals exhibited an increase in BrdU + (bromodeoxyuridine positive) cells in the dentate gyrus (DG), and that this increase was more robust in male animals. This increase was not sustained, and cell proliferation returning to normal by PID3. A greater increase in BrdU + cells was observed in the dorsal DG in both male and female r-mTBI animals at PID1. Using Ki-67 expression as an endogenous marker of cellular proliferation, a robust proliferative response following r-mTBI was observed in male animals at PID1 that persisted until PID3, and was not constrained to the DG alone. Triple labeling experiments (Iba1+, GFAP+, Brdu+) revealed that a high proportion of these proliferating cells were microglia/macrophages, indicating there was a heightened inflammatory response. Overall, these findings suggest that rapid head acceleration with the ACHI model produces an mTBI, but that the acute neurological deficits do not increase in severity with repeated administration. R-mTBI transiently increases cellular proliferation in the hippocampus, particularly in male animals, and the pattern of cell proliferation suggests that this represents a neuroinflammatory response that is focused around the mid-brain rather than peripheral cortical regions. These results add to growing literature indicating sex differences in proliferative and inflammatory responses between females and males. Targeting proliferation as a therapeutic avenue may help reduce the short term impact of r-mTBI, but there may be sex-specific considerations.

Clinical Outcomes in Neurologically Intact Children With Small Intracranial Bleeds and Simple Skull Fractures.

Introduction Children with minor intracranial hemorrhage (ICH) and/or simple skull fractures are often hospitalized for monitoring; however, the majority do not require any medical, surgical, or critical care interventions. Our purpose was to determine the rate of significant clinical sequela (SCS) and identify associated risk factors in neurologically intact children with close head trauma. Methods This is a retrospective observational study. Children (≤ 3 years of age) admitted with closed head trauma, documented head injuries (ICH ≤ 5mm and/or simple skull fracture), and a Glasgow Coma Scale (GCS) score of ≥14, between January 2015 and January 2020, were included. We collected demographics, resource utilization, and patient outcomes variables. SCS was defined as any radiologic progression, and/or clinically important medical or neurological deterioration. Results A total of 205 patients were enrolled in the study (65.4% male, mean age 7.7 months). Repeat neuroimaging was obtained in 41/205 patients (20%) with radiologic progression noted in 5/205 (2.4%). Thirteen out of 205 patients (6.3%) experienced SCS. Patients with SCS were more likely to be males (92.3% vs 63.5% in females, P=0.035) to have had a report filed with child protective services due to a concern for abuse/neglect (92.3% vs 61.5% in females, P=0.025), and to have had a non-linear skull fracture (P<0.001). No other factors were shown to be predictive of SCS with enough statistical significance. Conclusion Neurologically intact children with traumatic closed head injury are at low risk for developing SCS. This study suggests that most of these children may not need ICU monitoring. This study also showed that a certain subset might be at an increased risk of developing SCS.

Neuroprotective Effect of Sub-lethal Hyperthermia Preconditioning in a Rat Model of Repeated Closed Head Injury.

Repeated mild traumatic brain injury (rTBI), one of the most common forms of traumatic brain injury, is a worldwide severe public health concern. rTBI induces cumulative neuronal injury, neurological dysfunction, and cognitive deficits. Although there are clinical treatment methods, there is still an urgent need to develop preventive approaches for susceptible populations. Using a repeated closed head injury (rCHI) rat model, we interrogate the effect of sub-lethal hyperthermia preconditioning (SHP) on rCHI-induced neuronal injury and behavioral changes. Our study applied the repeated weight-drop model to induce the rCHI. According to the changes of heat shock protein 70 (HSP 70) in the cortex and hippocampus following a single SHP treatment in normal rats, the SHP was delivered to the rats 18 h before rCHI. We found that HSP significantly alleviated rCHI-induced anxiety-like behaviors and impairments in motor abilities and spatial memory. SHP exerts significant neuroprotection against rCHI-induced neuronal damage, apoptosis, and neuroinflammation. Our findings support the potential use of SHP as a preventative approach for alleviating rCHI-induced brain damage.

Regional variances depict a unique glial-specific inflammatory response following closed-head injury.

Mild traumatic brain injuries (mTBI) constitute a significant health concern with clinical symptoms ranging from headaches to cognitive deficits. Despite the myriad of symptoms commonly reported following this injury, there is still a lack of knowledge on the various pathophysiological changes that occur. Preclinical studies are at the forefront of discovery delineating the changes that occur within this heterogeneous injury, with the emergence of translational models such as closed-head impact models allowing for further exploration of this injury mechanism. In the current study, male rats were subjected to a closed-head controlled cortical impact (cCCI), producing a concussion (mTBI). The pathological effects of this injury were then evaluated using immunoflourescence seven days following. The results exhibited a unique glial-specific inflammatory response, with both the ipsilateral and contralateral sides of the cortex and hippocampus showing pathological changes following impact. Overall these findings are consistent with glial changes reported following concussions and may contribute to subsequent symptoms.

Traumatic brain injury detection performance of the infant scalp score in children younger than 2 years in the pediatric emergency department.

BACKGROUND: Our study sought to externally validate the Infant Scalp Score (ISS) within an international pediatric emergency department (PED) setting. The ISS for pediatric Closed Head Injury (CHI), includes age, hematoma localization, and size, and has the potential to predict the presence of Traumatic Brain Injury (TBI) on computed tomography. We aimed to describe a potentially low risk cohort of children younger than 24 months with CHI and scalp hematomas, where clinicians may limit diagnostic radiation exposure to this vulnerable patient population. METHODS: This single-center retrospective study was conducted in Gazi University. Faculty of Medicine, Pediatric Emergency Department, a tertiary trauma care hospital. We reviewed patients (< 24 months) with CHI and scalp hematoma who visited the PED of our institution between January 1, 2019, and June 30, 2021 for rates of TBI and clinically important TBI (ciTBI). RESULTS: 380 cases met inclusion criteria for this study. The median age was 11 months and 58.7% were male children. 121 (31.8%) patients underwent CT, and 57% (n:69) of these studies were normal. TBI on CT was found in 26 (21.5%) patients with ciTBI was detected in 5 (1.3%) patients. All children with TBI were noted to have ISS scores of ≥ 5. Hematoma location OR 18.9 (95% CI, 3.4-105.1) and hematoma size OR 3.0 (95% CI, 1.2-7.3) were positively associated with presence of TBI. CONCLUSIONS: Children with ISS scores of ≥ 5 were noted to have increased rates of both TBI and ciTBI. CHI related scalp hematomas located in the temporal/parietal region or with a size greater than 3 cm were associated with increased rates of TBI. Within the context of this study, ISS scores of 4 or less represented a lower risk for TBI and ciTBI. Future research on this potentially low risk pediatric CHI cohort is needed.

Progressive lifespan modifications in the corpus callosum following a single juvenile concussion in male mice monitored by diffusion MRI.

Introduction: The sensitivity of white matter (WM) in acute and chronic moderate-severe traumatic brain injury (TBI) has been established. In concussion syndromes, particularly in preclinical rodent models, there is lacking a comprehensive longitudinal study spanning the lifespan of the mouse. We previously reported early modifications to WM using clinically relevant neuroimaging and histological measures in a model of juvenile concussion at one month post injury (mpi) who then exhibited cognitive deficits at 12mpi. For the first time, we assess corpus callosum (CC) integrity across the lifespan after a single juvenile concussion utilizing diffusion MRI (dMRI). Methods: C57Bl/6 mice were exposed to sham or two severities of closed-head concussion (Grade 1, G1, speed 2 m/sec, depth 1mm; Grade 2, G2, 3m/sec, 3mm) using an electromagnetic impactor at postnatal day 17. In vivo diffusion tensor imaging was conducted at 1, 3, 6, 12 and 18 mpi (21 directions, b=2000 mm2/sec) and processed for dMRI parametric maps: fractional anisotropy (FA), axial (AxD), radial (RD) and mean diffusivity (MD). Whole CC and regional CC data were extracted. To identify the biological basis of altered dMRI metrics, astrocyte and microglia in the CC were characterized at 1 and 12 mpi by immunohistochemistry. Results: Whole CC analysis revealed altered FA and RD trajectories following juvenile concussion. Shams exhibited a temporally linear increase in FA with age while G1/G2 mice had plateaued FA values. G2 concussed mice exhibited high variance of dMRI metrics at 12mpi, which was attributed to the heterogeneity of TBI on the anterior CC. Regional analysis of dMRI metrics at the impact site unveiled significant differences between G2 and sham mice. The dMRI findings appear to be driven, in part, by loss of astrocyte process lengths and increased circularity and decreased cell span ratios in microglia. Conclusion: For the first time, we demonstrate progressive perturbations to WM of male mice after a single juvenile concussion across the mouse lifespan. The CC alterations were dependent on concussion severity with elevated sensitivity in the anterior CC that was related to astrocyte and microglial morphology. Our findings suggest that long-term monitoring of children with juvenile concussive episodes using dMRI is warranted, focusing on vulnerable WM tracts.

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a greater than twofold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long-lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, and inhibition of the ISR-even weeks after injury-can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here, we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach to the clinical treatment of chronic cognitive deficits after TBI.

Attaining the recesses of the cognitive space.

Existing neuropsychological tests of executive function often manifest a difficulty pinpointing cognitive deficits when these are intermittent and come in the form of omissions. We discuss the hypothesis that two partially interrelated reasons for this failure stem from relative inability of neuropsychological tests to explore the cognitive space and to explicitly take into account strategic and opportunistic resource allocation decisions, and to address the temporal aspects of both behaviour and task-related brain function in data analysis. Criteria for tasks suitable for neuropsychological assessment of executive function, as well as appropriate ways to analyse and interpret observed behavioural data are suggested. It is proposed that experimental tasks should be devised which emphasize typical rather than optimal performance, and that analyses should quantify path-dependent fluctuations in performance levels rather than averaged behaviour. Some implications for experimental neuropsychology are illustrated for the case of planning and problem-solving abilities and with particular reference to cognitive impairment in closed-head injury.

Advocacy for Change: An Osteopathic Review of Traumatic Brain Injury Among Combat Veterans.

As a "signature injury" of the Iraq and Afghanistan wars, traumatic brain injury (TBI) remains a major health concern among military service members. Traumatic brain injury is associated with a wide range of symptoms which may be cognitive, emotional, psychological, biochemical, and social in nature. Mild TBI (mTBI) ranks as the most common traumatic brain injury among veterans. Due to the absence of specific symptoms, mTBI diagnosis may be challenging in acute settings. Repetitive traumatic brain injury during combat deployments can lead to devastating chronic neurodegenerative diseases and other major life disruptions. Many cases of TBI remain undetected in veterans and may lead to long-term adverse comorbidities such as post-traumatic stress disorder (PTSD), suicide, alcohol disorders, psychiatric diagnoses, and service-related somatic dysfunctions. Veterans with TBI are almost twice as likely to die from suicide in comparison to veterans without a history of TBI. Veterans diagnosed with TBI experience significant comorbid conditions and thus advocacy for improved care is justified and necessary. Given the complexity and variation in the symptomatology of TBI, a personalized, multimodal approach is warranted in the evaluation and treatment of veterans with TBI and other associated conditions. As such, this review provides a broad overview of treatment options, with an emphasis on advocacy and osteopathic integration in the standard of care for veterans.

TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury.

Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer's disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aß formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.

Cortical Spreading Depolarization, Blood Flow, and Cognitive Outcomes in a Closed Head Injury Mouse Model of Traumatic Brain Injury.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI. METHODS: Adult male C57Bl/6J mice (8-14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests. RESULTS: CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10-7 CHI without CSD [CSD-] vs. 1.17 ± 0.04 × 10-7 CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD- (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1-2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD- mice (n = 11 CHI CSD-). CONCLUSIONS: The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.

Cerebral Venous Sinus Thrombosis in Closed Head Injury: Systematic Review and Meta-analysis.

BACKGROUND: Cerebral venous sinus thrombosis (CSVT) is a rare condition, causing 0.5% of all strokes only, several mechanisms might be involved in forming the thrombosis, including closed head injury. METHODS: Systematic review was done by using the following databases: PubMed, Google Scholar, Microsoft Academic, Clinical Trials, Cochrane Library, and Web of Science. RESULTS: 25 articles met our criteria out of 152 articles, average and standard deviation of the age was 38.2 ± 16.8 years with an age range of 18-82. The majority of cases presented with loss of consciousness or decreased GCS (41%), followed by headache (26%), scalp abrasions/lacerations (21%), paralysis (18%), visual disturbance (18%), nystagmus (15%), and agitation (15%). The most commonly used diagnostic method was angiography. Thrombosis was the most frequently reported radiological finding among all the cases (26/34, 76%). Comparisons of outcomes between patients who underwent surgical intervention and those who did not undergo surgery revealed a significant difference in outcome favoring non-surgical treatment (p < 0.005, odds ratio (OR) 0.04, (95% CI) 0.003 - 0.30). CONCLUSION: Non-surgical outcomes were better than the surgical outcomes. However, no significant difference was seen comparing anti-coagulation versus conservative management (supportive without anticoagulation), single versus multi-sinuses (≥2 sinuses) involvement, and between any of the sinuses involved.