Combined Traumatic Brain Injury Research Articles

Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). Detailed analyses of transcriptomic changes in the brain and adipose tissue were performed to elucidate the interactive effects between high-fat diet-induced obesity (DIO) and TBI. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. High-throughput transcriptomic analysis using Nanostring panels of the total visceral adipose tissue (VAT) and cellular components in the brain, followed by unsupervised clustering, principal component analysis, and IPA pathway analysis were used to determine shifts in gene expression patterns and molecular pathway activity. Cellular populations in the cortex and hippocampus, as well as in VAT, during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in selected gene expression signatures and pathways. Furthermore, combined TBI and HFD caused additive dysfunction in Y-Maze, Novel Object Recognition (NOR), and Morris water maze (MWM) cognitive function tests. These novel data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and VAT, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Thus, targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue immune cell populations, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.

Interorgan communication in neurogenic heterotopic ossification: the role of brain-derived extracellular vesicles

Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury. Inflammasome-related proteins encapsulated in brain-derived extracellular vesicles can cross the blood‒brain barrier to reach distal tissues. These proteins initiate inflammatory dysfunction, such as neurogenic heterotopic ossification. This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies. Accordingly, a rat model of neurogenic heterotopic ossification induced by combined traumatic brain injury and achillotenotomy was developed to address these two issues. Histological examination of the injured tendon revealed the coexistence of ectopic calcification and fibroblast pyroptosis. The relationships among brain-derived extracellular vesicles, fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo. The present work highlights the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offers a potential strategy for preventing neurogenic heterotopic ossification after traumatic brain injury.Brain-derived extracellular vesicles (BEVs) are released after traumatic brain injury. These BEVs contain pathogens and participate in interorgan communication to initiate secondary injury in distal tissues. After achillotenotomy, the phagocytosis of BEVs by fibroblasts induces pyroptosis, which is a highly inflammatory form of lytic programmed cell death, in the injured tendon. Fibroblast pyroptosis leads to an increase in calcium and phosphorus concentrations and creates a microenvironment that promotes osteogenesis. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk suppressed fibroblast pyroptosis and effectively prevented the onset of heterotopic ossification after neuronal injury. The use of a pyroptosis inhibitor represents a potential strategy for the treatment of neurogenic heterotopic ossification.

Use of navigation technologies in the installation of external ventricular drainage in patients with severe combined traumatic brain injury

The study investigated the possibilities and effectiveness of surgical navigation in the installation of external ventricular drainage in patients with severe combined traumatic brain injury. In total, 41 patients were examined, and in those with urgent indications during the first period of traumatic illness, external ventricular drainage was installed (up to 2 days). All patients were divided into the main group (n = 14) and control group (n = 27). In the main group, external ventricular drainage was installed using surgical navigation. The control group underwent surgery without surgical navigation. According to the treatment results of the main group, the use of surgical navigation during the introduction of ventricular drainage significantly increased the accuracy of its installation and reduced the number of complications and rechecks. The accuracy of ventricular drainage installation was improved by 35%. Thus, out of 13 drainage installations, 12 (92.3%) had an optimal position, and 1 had a satisfactory position because its tip had a deviation of 2 mm; however, this drainage did not require re-examination, performing its function. Moreover, in the control group using the classical free hand technique, out of 21 cases with drainage installed, only 12 (57.1%) had an optimal position, 9 (42.9%) drains were rechecked because of deviation from the specified trajectory over 3 mm, and 4 (19%) required repeated rechecking (p = 0.039). The main causes of errors and complications of the surgical treatment of patients with craniocerebral injuries are related to the difficulties in installing ventricular drainage, namely, inaccurate positioning of the drainage tip, placement of the drainage in the brain substance at a distance from the planned point (28.6%), the drainage is going beyond the ventricular system of the brain (14.3%), re-drainage during the operation (44.4%), which often (42.9%) leads to incorrect introduction of the drainage into the ventricular system of the brain. Thus, the application of the navigation technology technique when installing drains into the ventricular system of the brain is very effective in the treatment of patients with severe combined traumatic brain injury. This innovative technique for ventricular drainage in severe combined traumatic brain injury will reduce the frequency of errors and complications associated with repeated drains, which is fundamentally important in unstable patients with multiple traumas. The navigation system allows for accurate installation of the drainage to the planned location from the first attempt.

Neuropathological outcomes of traumatic brain injury and alcohol use in males and females: studies using preclinical rodent and clinical human specimens.

Traumatic brain injury (TBI) and alcohol misuse are inextricably linked and can increase the risk for developing neurodegenerative diseases, particularly in military veterans and contact sport athletes. Proteinopathy (defects in protein degradation) is considered an underlying factor in neurodegenerative diseases. However, whether it contributes to TBI/alcohol-mediated neurodegeneration is unexplored. Our recent studies have identified ISGylation, a conjugated form of ISG15 (Interferon-Stimulated Gene 15) and inducer of proteinopathy, as a potential mechanistic link underlying TBI-mediated neurodegeneration and proteinopathy in veterans. In the current study, a rat model of combined TBI and alcohol use was utilized to investigate the same relationship. Here, we report sustained induction of Interferon β (IFNβ), changes in TAR DNA Binding 43 (TDP-43) ISGylation levels, TDP-43 proteinopathy (C-terminal fragmentation (CTF)), and neurodegeneration in the ventral horns of the lumbar spinal cords (LSCs) and/or motor cortices (MCs) of female rats post-TBI in a time-dependent manner. In males, these findings mostly remained non-significant, though moderate alcohol use appears to decrease neurodegeneration in males (but not females) post-TBI. We, however, do not claim that moderate alcohol consumption is beneficial for preventing TBI-mediated neurodegeneration. We have previously demonstrated that ISGylation is increased in the LSCs of veterans with TBI/ALS (Amyotrophic Lateral Sclerosis). Here, we show increased ISGylation of TDP-43 in the LSCs of TBI/ALS-afflicted female veterans compared to male veterans. Knowing that ISGylation induces proteinopathy, we suggest targeting ISGylation may prevent proteinopathy-mediated neurodegeneration post-TBI, particularly in women, however, causal studies are required to confirm this claim.

МОРФОФУНКЦИОНАЛЬНАЯ ХАРАКТЕРИСТИКА КОРНЯ ЛЕВОГО ЛЕГКОГО ПРИ ЭКСПЕРИМЕНТАЛЬНОМ СИСТЕМНОМ ВОСПАЛЕНИИ И ЧЕРЕПНО-МОЗГОВОЙ ТРАВМЕ

Systemic inflammation is a complex syndrome in terms of its significance for the body. Systemic inflammation may be part of the pathogenesis of traumatic brain injury. Purpose of the study: Purpose of the study: Structural and functional characteristics of the experimental root of the left lung in systemic inflammation and traumatic brain injury. Materials and methods. To reproduce traumatic brain injury, a modified weight-drop model was used. Albino rats were studied experimental animals. To inflict injury, a device with a load (weight 200 g) was used, which falls from a height of 1 m onto the parietal region of the animal's head. For the study of experimental fever, the animals were injected intramuscularly with the pharmacopoeial form of LPS pyrogenal solution. Results. A morphological and histochemical study of the caudal lobar bronchus of the left lung of rats was carried out. The average height of the bronchial epithelium of the caudal lobar bronchus of the left lung most significantly and significantly decreases with a combination of traumatic brain injury and systemic inflammation. The bronchial epithelium retains its cilia. With the combination of SI and traumatic brain injury on the 6th day, argentophilia and an increase in the size of the nucleoli of the bronchial epithelium significantly increase. Argyrophilia of connective tissue fibers is revealed. Conclusion. With a combination of traumatic brain injury and systemic inflammation, the most informative changes in the content of mast cells are at the point of contact of the adventitial membrane of the caudal lobar bronchus of the left lung of the rat with the adventitial membrane of the caudal lobar vein of the left lung. Mastocytes localized at the site of contact between the adventitial membranes of lobe bronchus and lobe vien remain an insufficiently studied cell population of this differ on in both humans an rat. Thus, it is revealed that the pathogenesis of systemic inflammation combined with craniocerebral injury may involve dystrophically altered bronchial epithelium of the lobar bronchi, and mast cells of the adventitia of the lobar pulmonary veins.

Impact of a Femoral Fracture on Outcome after Traumatic Brain Injury-A Matched-Pair Analysis of the TraumaRegister DGU®.

Traumatic brain injury (TBI) is the leading cause of death and disability in polytrauma and is often accompanied by concomitant injuries. We conducted a retrospective matched-pair analysis of data from a 10-year period from the multicenter database TraumaRegister DGU® to analyze the impact of a concomitant femoral fracture on the outcome of TBI patients. A total of 4508 patients with moderate to critical TBI were included and matched by severity of TBI, American Society of Anesthesiologists (ASA) risk classification, initial Glasgow Coma Scale (GCS), age, and sex. Patients who suffered combined TBI and femoral fracture showed increased mortality and worse outcome at the time of discharge, a higher chance of multi-organ failure, and a rate of neurosurgical intervention. Especially those with moderate TBI showed enhanced in-hospital mortality when presenting with a concomitant femoral fracture (p = 0.037). The choice of fracture treatment (damage control orthopedics vs. early total care) did not impact mortality. In summary, patients with combined TBI and femoral fracture have higher mortality, more in-hospital complications, an increased need for neurosurgical intervention, and inferior outcome compared to patients with TBI solely. More investigations are needed to decipher the pathophysiological consequences of a long-bone fracture on the outcome after TBI.

Cognitive and Cellular Effects of Combined Organophosphate Toxicity and Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) is considered the most common neurological disorder among people under the age of 50. In modern combat zones, a combination of TBI and organophosphates (OP) can cause both fatal and long-term effects on the brain. We utilized a mouse closed-head TBI model induced by a weight drop device, along with OP exposure to paraoxon. Spatial and visual memory as well as neuron loss and reactive astrocytosis were measured 30 days after exposure to mild TBI (mTBI) and/or paraoxon. Molecular and cellular changes were assessed in the temporal cortex and hippocampus. Cognitive and behavioral deficits were most pronounced in animals that received a combination of paraoxon exposure and mTBI, suggesting an additive effect of the insults. Neuron survival was reduced in proximity to the injury site after exposure to paraoxon with or without mTBI, whereas in the dentate gyrus hilus, cell survival was only reduced in mice exposed to paraoxon prior to sustaining a mTBI. Neuroinflammation was increased in the dentate gyrus in all groups exposed to mTBI and/or to paraoxon. Astrocyte morphology was significantly changed in mice exposed to paraoxon prior to sustaining an mTBI. These results provide further support for assumptions concerning the effects of OP exposure following the Gulf War. This study reveals additional insights into the potentially additive effects of OP exposure and mTBI, which may result in more severe brain damage on the modern battlefield.

Altered early immune response after fracture and traumatic brain injury.

Clinical and preclinical data suggest accelerated bone fracture healing in subjects with an additional traumatic brain injury (TBI). Mechanistically, altered metabolism and neuro-endocrine regulations have been shown to influence bone formation after combined fracture and TBI, thereby increasing the bone content in the fracture callus. However, the early inflammatory response towards fracture and TBI has not been investigated in detail so far. This is of great importance, since the early inflammatory phase of fracture healing is known to be essential for the initiation of downstream regenerative processes for adequate fracture repair. Therefore, we analyzed systemic and local inflammatory mediators and immune cells in mice which were exposed to fracture only or fracture + TBI 6h and 24h after injury. We found a dysregulated systemic immune response and significantly fewer neutrophils and mast cells locally in the fracture hematoma. Further, local CXCL10 expression was significantly decreased in the animals with combined trauma, which correlated significantly with the reduced mast cell numbers. Since mast cells and mast cell-derived CXCL10 have been shown to increase osteoclastogenesis, the reduced mast cell numbers might contribute to higher bone content in the fracture callus of fracture + TBI mice due to decreased callus remodeling.

ANALYSIS OF DEFECTS IN THE DIAGNOSIS OF TRAUMATIC BRAIN INJURY FOR THE DECEASED WITHIN 24 HOURS FOLLOWING ADMISSION.

The aim: To conduct the analysis of medical records with the diagnosis of traumatic brain injury for the deceased within 24 hours following admission to Clinical Emergency Hospital. Materials and methods: The study was aimed at a retrospective analysis of 102 cases of the lethality of the deceased within 24 hours following admission to Clinical Emergency Hospital for 2012-2019 in cases of traumatic brain injury. Medical histories of the deceased and data from the forensic autopsy had been analyzed. Results: There were 62 cases (60.8%) of isolated traumatic brain injury, and 40 cases (39.2%) of combined traumatic brain injury. The following defects were identified in the diagnosis: absence of a complete description of the local status with external injuries on the head, absence of a complete and qualitative assess¬ment and objectification of hemodynamics and the function of external breathing using laboratory indicators and electrocardiography, absence of neuroimaging. Conclusions: The percentage of diagnostic defects prevailed among traumatic brain injury patients who died from acute blood loss. The maximum number of diagnostic defects for the patients with traumatic brain injury was observed in the polytrauma department, and the minimum - in the neurological department. The maximum number of defects of a diagnostic nature as a whole fall on those patients who were admitted to the hospital in the interval I - 6:00 a.m. - 9:59 a.m. and in the interval IV - 6:00 p.m. - 9:59 p.m.

MULTIMODAL TREATMENT APPROACHES TO COMBINED TRAUMATIC BRAIN INJURY AND HEMORRHAGIC SHOCK ALTER POSTINJURY INFLAMMATORY RESPONSE.

Introduction: The optimal management strategies for patients with polytraumatic injuries that include traumatic brain injury (TBI) are not well defined. Specific interventions including tranexamic acid (TXA), propranolol, and hypertonic saline (HTS) have each demonstrated benefits in patient mortality after TBI, but have not been applied to TBI patients with concomitant hemorrhage. The goals of our study were to determine the inflammatory effects of resuscitation strategy using HTS or shed whole blood (WB) and evaluate the cerebral and systemic inflammatory effects of adjunct treatment with TXA and propranolol after combined TBI + hemorrhagic shock. Methods: Mice underwent TBI via weight drop and were subsequently randomized into six experimental groups: three with HTS resuscitation and three with WB resuscitation. Mice were then subjected to controlled hemorrhagic shock for 1 h to a goal MAP of 25 mmHg. Mice were then treated with an i.p. dose of 4 mg/kg propranolol, 100 mg/kg TXA, or normal saline (NS) as a control. Mice were killed at 1, 6, or 24 h for serum and cerebral biomarker evaluation by multiplex ELISA and serum neuron-specific enolase, a biomarker of cerebral cellular injury. Results: Mice resuscitated with HTS had elevated serum proinflammatory cytokines compared with WB resuscitated groups at 6 and 24 h after injury, with no significant difference in cerebral cytokine levels. Within the TBI/shock + HTS groups, the addition of propranolol or TXA did not significantly alter serum cytokine concentration, but cerebral IL-2, IL-12, and macrophage inflammatory protein-1α (MIP-1α) decreased after propranolol administration. In the TBI/shock + WB cohorts, the addition of both propranolol and TXA increased systemic proinflammatory cytokine levels at 6 and 24 h after injury as demonstrated by serum IL-2, IL-12, MIP-1α, and IL-1β compared with NS control. By contrast, TBI/shock + WB mice demonstrated a significant reduction in cerebral IL-2, IL-12, and MIP-1α in propranolol treated mice 6 h after injury compared with NS group. While serum neuron-specific enolase was significantly increased 1 and 24 h after injury in TBI/shock + HTS + TXA cohorts compared with NS control, it was significantly reduced in the TBI/shock + WB + propranolol mice compared with NS control 24 h after injury. Conclusions: Whole blood resuscitation can reduce the acute postinjury neuroinflammatory response after combined TBI/shock compared with HTS. The addition of either propranolol or TXA may modulate the postinjury systemic and cerebral inflammatory response with more improvements noted after propranolol administration. Multimodal treatment with resuscitation and pharmacologic therapy after TBI and hemorrhagic shock may mitigate the inflammatory response to these injuries to improve recovery.

Emergency Traumatology at the N.V. Sklifosovsky Research Institute for Emergency Medicine: History and Modernity

The purpose of this work was to study the history of the development of traumatology-orthopedics at the N.V. Sklifosovsky Research Institute for Emergency Medicine.Traumatology as an independent discipline began to form at the N.V. Sklifosovsky Research Institute for Emergency Medicine during the reign of Professor S.S. Yudin (chief surgeon since 1928), who invited the famous Argentinean traumatologist-orthopedist Professor Lelio Zeno to work at the institute.In 1932, the trauma department of the N.V. Sklifosovsky Research Institute for Emergency Medicine was headed by Professor V.V. Gorinevskaya. She organized a 100-bed trauma clinic for the treatment of injuries to the head, spine, limbs, chest and abdominal cavity. She is rightfully considered one of the founders of trauma science in the USSR.With the development of traumatology and orthopedics as an independent specialty in 1961, two clinics were formed at the institute. The first trauma clinic was run by Dr. med. sciences professor I.I. Sokolov. The second clinic was headed by Dr. med. Sci. P.N. Petrov.In 1971, Dr. med. Professor, Honored Scientist of the Russian Federation, Academician of the Russian Academy of Medical and Technical Sciences of the Russian Federation V.P. Okhotsky was appointed the head of the traumatological service of the institute and the chief traumatologist of Moscow (from 1971 to 2001). With his active participation in Moscow, the reorganization of outpatient care was completed, work was widely launched on the medical aspects of the prevention of road traffic injuries and the introduction into practice of the most rational methods of diagnosis and treatment of patients with injuries of the musculoskeletal system. In the N.V. Sklifosovsky Research Institute for Emergency Medicine A.G. Suvalyan introduced the method of intramedullary osteosynthesis of long tubular bones (humerus, femur and tibia). Under the guidance of prof. V.P. Okhotsky the dissertation researches of A.G. Suvalyan, M.A. Suvalyan and S.S. Myakota were carried out. The expediency of early surgical intervention on the extremities in case of combined traumatic brain injury and multiple trauma of the extremities has also been proven, new functional methods of treatment of diaphyseal fractures of the shoulder, lower leg, spine and intra-articular injuries have been developed.In close scientific cooperation with scientists from other clinics of the institute, a comprehensive method of treating open injuries of the limbs has been developed (dissertation researches of I.F. Byalik, I.Yu. Klyukvin, O.P. Filippov, M.V. Zvezdina, R.S. Titov). Much scientific work has been carried out to improve the diagnosis and treatment of intra-articular injuries of the knee joint (dissertation researches by M.A. Malygina, O.P. Filippov, A.Yu. Vasa).From 2001 to 2016 the head of the department of emergency traumatology of the musculoskeletal system was a student of prof. V.P. Okhotsky – Dr. med. sciences, Professor, Academician of the Academy of Medical and Technical Sciences of the Russian Federation I.Yu. Klyukvin. Since 2016 the department is headed by Dr. med. sciences Alexey M. Fine.The scientific developments of the employees of the Department of Emergency Traumatology have a practical orientation. Every year, the department’s employees successfully perform more than 2500 surgical interventions using advanced low-traumatic techniques, making extensive use of the achievements of biotechnology.

Influence of age on acute traumatic spinal cord injury in Saint Petersburg, Russia.

Retrospective cohort study. To evaluate influence of age after traumatic spinal cord injury (TSCI). 13 specialized hospitals with neurosurgical departments of Saint Petersburg, Russia. Charts of all patients admitted with TSCI to the city hospitals 2012-2016. Demographic and clinical characteristics, surgical interventions, complications, mortality rate, and hospital stays were recorded. 311 patients with TSCI were included. TSCI was more common in younger age. Mean age (SD) was 42.4 (16.8) years. Patients were divided into four age groups: 18-29, 30-44, 45-59 and ≥60 years. The group ≥60 years had the lowest percentage of concomitant traumatic brain injury (TBI), 25%, versus 43% in TSCI < 60 years, p < 0.05. Low falls were the most frequent cause in patients aged 60 years and older, and led to less severe neurological deficits (p < 0.05). Complications were most frequent in motor complete TSCI (AIS A and AIS B) and in persons with combined TSCI and TBI at older age. Total complication rate was 67% at the age of ≥60 years versus 38% <60 years in TSCI with TBI (p < 0.05). Respiratory complications occurred in 67% ≥45 years versus 45% <45 years, p < 0.05. In-hospital mortality rate after TSCI was higher in the oldest age group. Respiratory complications are common and the in-hospital mortality is higher among elderly people. Older patients with TSCI and TBI are at high risk for complications.

17\u03b1-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial

BackgroundTraumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS.MethodsAll methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation).ResultsA comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood–brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration.ConclusionsEE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

Psychobiological Treatment Response to a Two-Week Posttraumatic Stress Disorder and Mild Traumatic Brain Injury Integrated Treatment Program: A Case Report

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) demonstrate high prevalence and comorbidity among post-9/11 veterans. Veterans with this comorbidity often present with multiple co-occurring healthcare needs and increased clinical complexity. The current case report describes the clinical presentation of a veteran with mild TBI and PTSD, both before, during, and after treatment within a multidisciplinary 2-week intensive outpatient program involving prolonged exposure, evidence-based PTSD treatment, and Cognitive Symptom Management and Rehabilitation Therapy, evidence-based treatment for postconcussive symptoms. Mr. A was a 25-year-old White, transgender male who presented with a complex mental health history. At intake, presenting complaints included anxiety, panic attacks, nightmares, and depression secondary to military sexual trauma, as well as reported cognitive difficulties secondary to a concussion. He met current criteria for PTSD as well as panic disorder with agoraphobia. Head injury history consisted of a motor vehicle collision with less than 30 seconds loss of consciousness, brief posttraumatic amnesia, and alterations of consciousness. Mr. A demonstrated habituation during individual exposure sessions as assessed via skin conductance during imaginal exposures and decreased subjective ratings during in vivo exposures, as well as a decrease in trauma-potentiated startle response to trauma cues. Posttreatment data indicates significant reduction in neurobehavioral, posttraumatic stress, and depression symptoms and significant improvement in subjective cognitive functioning. The current findings support the feasibility and efficacy of short-term integrated treatment for complex clinical presentations and the need for larger scale research investigating combined PTSD and TBI intervention.

Sleep disturbances following traumatic brain injury are associated with poor neurobehavioral outcomes in US military service members and veterans.

This study examined whether sleep disturbances were associated with neurobehavioral outcome following a traumatic brain injury (TBI) in a well characterized group of service members and veterans. Six hundred and six participants were enrolled into the Defense and Veterans Brain Injury Center, 15-Year Longitudinal TBI study. All participants completed a battery of tests measuring self-reported sleep disturbances, neurobehavioral symptoms, and posttraumatic stress disorder symptoms. Data were analyzed using analysis of variance with post hoc comparisons. Four groups were analyzed separately: uncomplicated mild TBI; complicated mild, moderate, severe, or penetrating combined TBI; injured controls (ie, orthopedic or soft-tissue injury without TBI); and noninjured controls. A higher proportion of the mild TBI group reported moderate-severe sleep disturbances (66.5%) compared to the injured control group (54.9%), combined TBI (47.5%), and noninjured control groups (34.3%). Participants classified as having Poor Sleep had significantly worse scores on the majority of TBI-Quality of Life scales compared to those classified as having Good Sleep, regardless of TBI severity or the presence of TBI. There was a significant interaction between sleep disturbances and posttraumatic stress disorder. While sleep disturbances and posttraumatic stress disorder by themselves were significant factors associated with worse outcome, both factors combined resulted in worse outcome than either singularly. Regardless of group (injured or noninjured control), sleep disturbances were common and were associated with significantly worse neurobehavioral functioning. When experienced concurrently with posttraumatic stress disorder, sleep disturbances pose significant burden to service members and veterans. Pattinson CL, Brickell TA, Bailie J, etal. Sleep disturbances following traumatic brain injury are associated with poor neurobehavioral outcomes in US military service members and veterans. J Clin Sleep Med. 2021;17(12):2425-2438.

Pathogenetic mechanisms of mild traumatic brain injury in patients of different ages

This study was carried out to reveal the influence of mechanical energy, which triggers a whole cascade of pathological and compensatory processes of different depth and duration in the brain in traumatic brain injury (TBI). One of the most common consequences of TBI is impaired working memory – the ability to temporarily hold small pieces of information necessary for current mental activity. The aim of the work is to study the relationship between the TBI mechanism and the types of brain damage, as well as the consequences of trauma in patients of different ages. 95 case histories of patients with closed TBI were studied. All patients were treated in the Neurosurgical department of the Emergency hospital, Chernivtsi. Among them were 76 men and 19 women. The study found that TBI of patients in most cases was obtained as a result of traffic and others accidents. All patients had closed TBI. Contusion foci in all age groups were equally identified in the frontal, temporal and occipital lobes, less in the parietal lobe. The incidence of contusion increased slightly with increasing age of patients. In the presence of hemorrhages in patients, hemiparesis and liquor-hypertensive syndrome occurred. In men, TBI was more common than in women, and was expressed as moderate brain contusion, subacute and chronic compression of the brain. This TBI development was more common in young patients. It is promising to further study the nature of combined TBI in people of all ages and analyze the results of specialized neurosurgical care. Keywords: traumatic brain injury, neurosurgical care, liquor-hypertensive syndrome.

Systemic and local cardiac inflammation after experimental long bone fracture, traumatic brain injury and combined trauma in mice

BackgroundTrauma is the leading cause of death and disability worldwide, especially in the young population. Cardiac injuries are an independent predictor for a poor overall outcome after trauma. The aim of the present study was to analyze systemic inflammation as well as local cardiac inflammation after experimental limb-, neuro- and combined trauma in mice.MethodsMale C57BL/6 mice received either a closed tibia fracture (Fx), isolated traumatic brain injury (TBI) or a combination of both (Fx ​+ ​TBI). Control animals underwent sham procedure. After 6 and 24 ​h, systemic levels of inflammatory mediators were analyzed, respectively. Locally, cardiac inflammation and cardiac structural alterations were investigated in left ventricular tissue of mice 6 and 24 ​h after trauma.ResultsMice showed enhanced systemic inflammation after combined trauma, which was manifested by increased levels of KC, MCP-1 and G-CSF. Locally, mice exhibited increased expression of inflammatory cytokines (IL-1β, TNF) in heart tissue, which was probably mediated via toll-like receptor (TLR) signaling. Furthermore, mice demonstrated a redistribution of connexin 43 in cardiac tissue, which appeared predominantly after combined trauma. Besides inflammation and structural cardiac alterations, expression of glucose transporter 4 (GLUT4) mRNA was increased in the heart early after TBI and after combination of TBI and limb fracture, indicating a modification of energy metabolism. Early after combination of TBI and tibia fracture, nitrosative stress was increased, manifested by elevation of nitrotyrosine in cardiac tissue. Finally, mice showed a trend of increased systemic levels of cardiac troponin I and heart-fatty acid binding protein (HFABP) after combined trauma, which was associated with a significant decrease of troponin I and HFABP mRNA expression in cardiac tissue after TBI and combination of TBI and limb fracture.ConclusionMice exhibited early cardiac alterations as well as alterations in cardiac glucose transporter expression, indicating a modification of energy metabolism, which might be linked to increased systemic- and local cardiac inflammation after limb-, neuro- and combined trauma. These cardiac alterations might predispose individuals for secondary cardiac damage after trauma that might compromise cardiac function after TBI and long bone fracture.Translational potential statementInjuries to the head and extremities frequently occur after severe trauma. In our study, we analyzed the effects of closed tibia fracture, isolated TBI, and the combination of both injuries with regard to the development of post-traumatic secondary cardiac injuries.

The effects of different fluid resuscitations in the acute phase of combined traumatic brain injury and hemorrhagic shock in an experimental rat model

The effects of different fluid resuscitations in the acute phase of combined traumatic brain injury and hemorrhagic shock in an experimental rat model

Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment.

Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment. We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography-mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada). In untargeted reversed-phase liquid chromatography-mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001). Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.

Valproic acid treatment rescues injured tissues after traumatic brain injury.

No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways. Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis. Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm) compared with the controls (1,900 ± 614 mm). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery. Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.