Focal Contusion Research Articles

Pediatric cervical spine clearance after blunt trauma and negative CT: What is the role of MRI?

Background and purposeThe cervical spine in children has marked anatomical and biomechanical differences compared to adults, leading to significantly different patterns and incidence of spinal injury, and consequently to different X-ray and computed tomography (CT) imaging recommendations. Magnetic resonance imaging (MRI) has been validated to clear cervical spine trauma in adults, but not in pediatric patients. We hypothesized that MRI findings have a low probability to change management in children with spine trauma and negative CT findings. Materials and methodsWe reviewed records for admitted pediatric patients due to blunt trauma from January 2011 to May 2021, and identified 212 patients who underwent MRI within 3 days of a negative CT. Two neuroradiologists independently reviewed all CT and MRI images for the following categories: fracture, subluxation, spinal canal compromise, ligamentous injury, spinal canal hemorrhage, cord contusion and soft tissue hemorrhage. We identified follow-up MRI examinations as negative or positive for the above categories, and calculated the prevalence of each category as a percentage of cases with negative CT. We also evaluated whether negative and positive MRI groups differed significantly with respect to age and sex of the patients. Results and conclusionsIn our study of 212 children with cervical spine trauma and a negative CT, most follow-up MRI scans were found to be negative (79.9 %). Positive MRI findings consisted mainly of ligamentous sprain without disruption (15.1 %). Ligamentous disruption and epidural or soft tissue hemorrhage were found in 4.5 %, and focal cord contusion in 0.5 %. There was no statically significant difference between negative and positive MRI groups with respect to age (P = 0.45) and sex (P = 0.52). ConclusionIn our patient group with a negative CT, MRI did not significantly impact management nor contribute to cervical spine clearance in children.

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion.

Pioglitazone interacts through the mitochondrial protein mitoNEET to improve brain bioenergetics following traumatic brain injury. To provide broader evidence regarding the therapeutic effects of pioglitazone after traumatic brain injury, the current study is focused on immediate and delayed therapy in a model of mild brain contusion. To assess pioglitazone therapy on mitochondrial bioenergetics in cortex and hippocampus, we use a technique to isolate subpopulations of total, glia-enriched and synaptic mitochondria. Pioglitazone treatment was initially administered at either 0.25, 3, 12 or 24 h following mild controlled cortical impact. At 48 h post-injury, ipsilateral cortex and hippocampus were dissected and mitochondrial fractions were isolated. Maximal mitochondrial respiration injury-induced deficits were observed in total and synaptic fractions, and 0.25 h pioglitazone treatment following mild controlled cortical impact was able to restore respiration to sham levels. While there are no injury-induced deficits in hippocampal fractions, we do find that 3 h pioglitazone treatment after mild controlled cortical impact can significantly increase maximal mitochondrial bioenergetics compared to vehicle-treated mild controlled cortical impact group. However, delayed pioglitazone treatment initiated at either 3 or 24 h after mild brain contusion does not improve spared cortical tissue. We demonstrate that synaptic mitochondrial deficits following mild focal brain contusion can be restored with early initiation of pioglitazone treatment. Further investigation is needed to determine functional improvements with pioglitazone beyond that of overt cortical tissue sparing following mild contusion traumatic brain injury.

Cellular and molecular mechanisms in vascular repair after traumatic brain injury: a narrative review.

Traumatic brain injury (TBI) disrupts normal brain function and is associated with high morbidity and fatality rates. TBI is characterized as mild, moderate or severe depending on its severity. The damage may be transient and limited to the dura matter, with only subtle changes in cerebral parenchyma, or life-threatening with obvious focal contusions, hematomas and edema. Blood vessels are often injured in TBI. Even in mild TBI, dysfunctional cerebral vascular repair may result in prolonged symptoms and poor outcomes. Various distinct types of cells participate in vascular repair after TBI. A better understanding of the cellular response and function in vascular repair can facilitate the development of new therapeutic strategies. In this review, we analyzed the mechanism of cerebrovascular impairment and the repercussions following various forms of TBI. We then discussed the role of distinct cell types in the repair of meningeal and parenchyma vasculature following TBI, including endothelial cells, endothelial progenitor cells, pericytes, glial cells (astrocytes and microglia), neurons, myeloid cells (macrophages and monocytes) and meningeal lymphatic endothelial cells. Finally, possible treatment techniques targeting these unique cell types for vascular repair after TBI are discussed.

Endoscopic Removal of Acute Traumatic Intracerebral Hemorrhage

ABSTRACT Nowadays surgical treatment of patients with traumatic intracranial hematoma (TICH) and injuries of the brain is a very actual problem in neurosurgery.The purpose of this work was to assess of the feasibility and safety of minimally invasive endoscopic removal of TICH.MATERIAL AND METHODS In the period of 2010–2019, 2734 operations were performed on patients with traumatic brain injury in the Sklifosovsky Research Institute. There were 334 patients with TICH and the CC/BC foci, that made 12.2% of all patients. The median of hematoma volume, that did not cause a loss of consciousness was 48 cm2, and in most of the patients the hematoma volume ranged 30–35 cm2. Local fibrinolysis of TICH was performed in 14 patients with the hematoma volume of 30–50 cm2 without brain dislocation and not causing the consciousness depression more severe than sopor.Endoscopic removal of TICH was performed in 4 men at mean age of 54.8 years within 18–36 hours after trauma. Three patients had depression of consciousness to obtundation (14 by Glasgow Outcome Scale (GCS)), and one patient was in clear consciousness. The volume of the dense part of the contusion foci in the pole-basal regions of the frontal and temporal lobes was 24–40 cm3.RESULTS Among patients with TICH operated on by using the traditional technique, postoperative lethality was 13%, good outcomes were seen in 41%, and 46% had neurological disorders of varying severity. While treating the patients with TICH by using the local fibrinolysis method, 1 patient died after surgery, a good outcome was seen in 8 of 14 patients, and neurological disorders persisted in 3 patients in the postoperative period.Radicality of surgery in patients operated on by using endoscopic technique averaged 76% ranging from 41% to 91%. There were no complications during surgery nor in post-operative period. Patients were discharged from hospital after 8-21 days.

Застосування препарату Гліатилін при консервативній фармакотерапії тяжкої черепно-мозкової травми з контузійним ураженням речовини головного мозку

Наведені дані дослідження ефективності препарату Гліатилін (холіну альфосцерат) у терапії гострого періоду черепно-­мозкової травми (ЧМТ), забою головного мозку тяжкого ступеня з порушенням свідомості у випадку, коли оперативне втручання не показано, але є верифіковані контузійні вогнища з порушенням свідомості. У дослідження були включені 40 пацієнтів (28 чоловіків і 12 жінок) віком від 21 до 63 років (середній вік — 42 роки) із ЧМТ тяжкого ступеня. Пацієнти були розділені на 2 групи по 20 осіб (по 14 чоловіків та 6 жінок) за призначеною терапією. I група отримувала стандартизовану метаболічну, протинабрякову, антибіотикотерапію та ноотропну терапію. II група — таку ж терапію, доповнену Гліатиліном у дозі 1000 мг/добу внутрішньовенно краплинно. На тлі проведеної фармакотерапії в динаміці відстежувалася її ефективність протягом усього курсу (14 діб) за шкалою коми Глазго, за даними епідурального сенсора внутрішньочерепного тиску та за даними спіральної комп’ютерної томограми головного мозку.

The Influence of Traumatic Injuries Early Diagnosis on the Development of Pulmonary Complications in Patients With Multisystem Chest Trauma

Despite the existing progress in providing care to patients with severe multisystem chest injury using advanced diagnostic methods, a high mortality rate still reaches 20–30%.Aim of study.To assess the impact of early diagnosis and correction of chest injuries on the development of complications in patients with multisystem trauma.Material and methods.The results of diagnosis and treatment of 89 patients with severe multisystem closed chest injury were studied. According to the time of admission to the Institute, the patients were divided into two groups: Group I, who were admitted to the Institute within the first hours after the injury (51 patients), and Group II, who were transferred from other medical institutions on the 3rd–7th day (38). CT was performed as a standard method of diagnosis and monitoring the dynamics of the process. With the development of purulent-inflammatory pulmonary complications, the bacteriological test of bronchoalveolar lavage was performed. Treatment included complex intensive therapy, drainage of the pleural cavity and emergency surgical interventions, if necessary.Results.In Group I, lung contusion occurred in 43 (84%) patients, and after 7-10 days, the contusion foci partially regressed in 20 (46.5%) patients. In 8 (16%) patients with lung rupture, infiltrative changes in the lung were resolved on the 18th-30th day, while 4 (50%) of them had pneumonia outside the contusion zones. In Group II, patients were put on a ventilator and inflammatory changes in the lungs were revealed in 30 patients (79%). Lung rupture associated with the contusion was revealed in 2 (5.2%). When comparing the groups by the composition of the isolated microflora, it was found that in patients of group II, Acinetobacter spp was more often found (46.7% vs. 17.1% in group I patients, p=0.021) and Enterococcus spp. (30.0% and 8.6%, respectively, p=0.058), as well as Klebsiella pneumoniae (46.7% and 37.1%, p=0.6). At the same time, Staphylococcus aureus was not found in these patients, while it was detected in 14.3% of patients from Group I (p=0.09). Medical care in Group I was carried out according to the principles of the “golden hour”: within the first hour from the moment of admission to the patients with the presence of pneumothorax and hemothorax, the pleural cavity was drained. In Group II, this procedure was performed in other medical institutions and in 5 additional patients at the Institute.Conclusions.Early computed tomography diagnosis of multisystem trauma makes it possible to assess the severity of injuries to the chest organs and other areas of the body and determine the treatment tactics. A comprehensive approach to the management of patients, including early diagnosis of trauma, drainage of the pleural cavity, determination of management tactics, bacterial test of the lower respiratory tract discharge, helps reduce infectious complications by an average of 45.46%.

Порушення натрієвого балансу у хворих з ураженням гіпоталамо-гіпофізарної ділянки при черепно-мозковій травмі

Актуальність. Черепно-мозкова травма (ЧМТ) до цього часу залишається провідною причиною смерті людей працездатного віку. В Україні частота ЧМТ щорічно становить у різних регіонах від 2,3 до 6 випадків (у середньому 4–4,2) на 1000 населення. Пацієнти з первинним ураженням головного мозку і гіпоталамо-гіпофізарної системи становлять групу ризику з розвитку набряку головного мозку через виникнення у них порушення водно-електролітної рівноваги та відповідно порушення рівноваги осмолярності між клітинним та позаклітинним простором. Порушення водно-електролітного балансу як наслідок ураження гіпоталамо-гіпофізарної системи при ЧМТ в літературі висвітлено недостатньо. Мало вивчені особливості функціонування центральних та периферичних ланцюжків ендокринної системи залежно від локалізації, характеру і тяжкості травми. Недостатньо вивчене питання про діагностичні та прогностичні цінності різних показників волемічного статусу у хворих із ЧМТ. Мета: вивчити види дизнатріємії у хворих з ізольованою ЧМТ і ураженням гіпоталамо-гіпофізарної ділянки головного мозку; вияснити вплив виду порушення натрієвого балансу на летальність у хворих із ЧМТ та ураженням гіпоталамо-гіпофізарної ділянки головного мозку. Матеріали та методи. Нами було обстежено 74 пацієнтів (чоловіків/жінок = 60/14) із вогнищевим забоєм головного мозку й ураженням гіпоталамічної ділянки. Серед 74 хворих з ізольованою ЧМТ і ураженням гіпоталамо-гіпофізарної ділянки головного мозку в 47 хворих було діагностовано гіповолемію, що поєднувалась з гіпонатріємією. У 15 хворих було виявлено гіпернатріємію з гіперволемією. Моніторинг внутрішньочерепного тиску здійснювали за допомогою поліфункціонального монітора (Monitor Model BSM-3562 (Nihon Konden Corporation, Японія, 2018)) із лінією для інвазивного вимірювання тиску. Постійне неінвазивне вимірювання оксигенації тканин органів (rSO2) проводили на моніторі Somanetics Invos Oximeter Cerebral/Somatik (Covidien, Mansfield, MA, США, 2020). В усіх хворих визначали рівень електролітів плазми крові. Висновки. У хворих із ЧМТ і ураженням гіпоталамо-гіпофізарної системи виникають різнонаправлені зміни водно-натрієвого балансу, що вимагають диференційованого підходу до їх лікування. Зважаючи на невелику кількість спостережень, ми не наважуємося пов’язувати вид дизнатріємії у хворих із ЧМТ і ураженням гіпоталамо-гіпофізарної ділянки головного мозку з летальністю. Вважаємо за доцільне продовжувати дослідження в цьому напрямку.

A cortical injury model in a non-human primate to assess execution of reach and grasp actions: implications for recovery after traumatic brain injury

BackgroundTechnological advances in developing experimentally controlled models of traumatic brain injury (TBI) are prevalent in rodent models and these models have proven invaluable in characterizing temporal changes in brain and behavior after trauma. To date no long-term studies in non-human primates (NHPs) have been published using an experimentally controlled impact device to follow behavioral performance over time. New methodWe have employed a controlled cortical impact (CCI) device to create a focal contusion to the hand area in primary motor cortex (M1) of three New World monkeys to characterize changes in reach and grasp function assessed for 3 months after the injury. ResultsThe CCI destroyed most of M1 hand representation reducing grey matter by 9.6 mm3, 12.9 mm3, and 15.5 mm3 and underlying corona radiata by 7.4 mm3, 6.9 mm3, and 5.6 mm3 respectively. Impaired motor function was confined to the hand contralateral to the injury. Gross hand-use was only mildly affected during the first few days of observation after injury while activity requiring skilled use of the hand was impaired over three months. Comparison with existing method(s)This study is unique in establishing a CCI model of TBI in an NHP resulting in persistent impairments in motor function evident in volitional use of the hand. ConclusionsEstablishing an NHP model of TBI is essential to extend current rodent models to the complex neural architecture of the primate brain. Moving forward this model can be used to investigate novel therapeutic interventions to improve or restore impaired motor function after trauma.

The factors of the outcome of neurosurgical treatment in traumatic brain injury

The purpose of the research: to improve the results of neurosurgical treatment in patients with traumatic brain injury by detecting an optimal way of craniotomy. Material and methods. The study includes the analysis of 127 patients operated on in the Department of Neurosurgery. The examination sample consisted of 109 (85.8%) male and 18 (14.2%) female patients. Patients’ ages varied from 16 to 85 years. The average age of the patients was 43.8 ± 4.2 years. Results. Not depending on craniotomy method, there was not a statistically significant difference in outcome in patients with traumatic brain injury. Using of trephination, craniectomy and osteoplastic craniotomy revealed no significant differences in outcomes in patients with traumatic brain injury. Patients’ age over 60 years, consciousness degree 4-6 scores according to Glasgow Coma Scale, and dislocation syndrome are unfavorable prognostic factors. Resection craniotomy in traumatic brain injury may be effective even in deep coma consciousness level and dislocation syndrome, but in absence of intraoperative brain edema. Conclusion. During the planning of craniotomy method in traumatic brain injury, 4-9 score consciousness degree according to Glasgow Coma Scale, brain contusion foci, acute subdural and intracerebral hematomas, brain compression volume of 30-150 cm³, patient’ age and dislocation syndrome should be considered, which, in total, predicts an outcome.

Traumatic brain injury in forensic psychiatry

IntroductionAssessment of neuropsychiatric sequelae of traumatic brain injury (TBI) brings about challenges in the forensic setting, comprising analysis of neurobiological variables, preinjury variables (personality/psychiatric disturbances), postinjury psychosocial, allowing the expert witness to provide clear and appropriate explanations, so the court can decide with justice, particularly in civil law cases.ObjectivesDiscuss the main clinical and neuroimagiologic aspects to consider in civil litigation of TBI cases.MethodsComprehensive literature review.ResultsAlthough accurate predictions are difficult, some generalizations can be made. Recovery from hypoxic and diffuse axonal injury (DAI) takes longer and is less complete than focal contusions. Posttraumatic amnesia is the main predictor of long-term cognitive outcome. In moderate/severe TBI (m/sTBI) occurs chronic lesion expansion (axonal degeneration) and brain atrophy. DAI topography determinates the cognitive disfunction pattern yet underestimated in conventional neuroimaging. Diffusion-Tension-Imaging (DTI) may be valuable to outcome predictions in m/sTBI: structural disconnection within the Default Mode and the Salience Networks are linked to attention and executive impairments; hippocampus and fornix damage correlates with memory/learning impairments. Conversely, DTI findings can be misleading in mild TBI (mTBI), and case-by-case analysis seldomly prove its scientific validity.ConclusionsTo elaborate formulations within reasonable medical certainty, outcome predictions should not be made until at least six months following the TBI, considering that most mTBI symptoms resolve in few months, and up to 1-½ years, when m/sTBI neuropathologic changes stabilize. The neurobiological underpinnings are fundamental for causality formulations, however atypical outcomes in mTBI are frequently predicated upon non–brain-injury psychiatric conditions and psychosocial factors.DisclosureNo significant relationships.

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.

Suppression of Aquaporin-4 By Antisense Oligonucleotides Reduces Brain Edema In Experimental Traumatic Brain Injury.

In this study, suppression of Aquaporin-4 (AQP4) synthesis via intracerebroventricular (i.c.v.) injection of antisense oligonucleotide after focal cortical contusion injury in mice was investigated. 12-week female Swiss albino mice of 20-25 g were used to create a focal cortical contusion model by the weight drop method (35 grams blunt weight, 70 cm height) onto the parietal cortex after craniectomy. The sham group underwent craniectomy without trauma. In the control group, weight was dropped onto the parietal cortex immediately after Dulbecco\'s Modified Eagle Medium (DMEM) i.c.v. injection following craniectomy. In addition, 1 nM of aquaporin-4 (AQP4) antisense oligonucleotide (ASO) was injected via i.c.v route immediately after trauma (0 hours) and 4 hours after trauma. All animals underwent magnetic resonance (MR) imaging and were sacrificed at 24 h. Brain water content was determined using the wet/dry weight method. In the sham group, the average percentage of brain water content was 77.75% compared to the control group with 79.87%. The difference was statistically significant (*p=0.017). In the therapy group, the average was 78.81% and significantly reduced compared to the control group (*p=0.026) at 0 hours. In the 4-hour treatment group, the average of 79.11% was not statistically significant (p=0.39). MR imaging findings also showed a substantial reduction in brain edema in the 0-hour treatment group. However, the 4-hour treatment results, when compared with the control trauma group, did not show a significant difference. This study demonstrated that AQP4 antisense oligonucleotide therapy, when administered early after diffuse traumatic brain injury, leads to a significant reduction in brain edema.

Comparative analysis of craniotomy methods in severe traumatic brain injury

The goal of research: to improve the results of neurosurgical management in patients with traumatic brain compression by detecting an optimal way of craniotomy.Material and methods. The study includes data of 127 patients with traumatic brain compression. The series consisted of 109 (85.8 %) males and 18 (14.2 %) females out of examined. The patients’ age ranged from 16 to 85 years. The neurosurgical interventions were performed in all patients with traumatic brain compression.Results. The patients with traumatic brain compression regardless of craniotomy method (burr hole surgery, craniectomy, osteoplastic craniotomy) did not experience a statistically significant difference in the outcome. When planning a method of craniotomy in traumatic brain compressio, the grade of consciousness impairment on the Glasgow coma scale, brain contusion foci, acute subdural and intracerebral hematomas, brain compression, patients’ age and brain dislocation syndrome should be considered that predicts an outcome.Conclusion. The results of a burr hole, resection, and osteoplastic craniotomy revealed no significant differences in outcome in patients with traumatic brain injury. Resection craniotomy in traumatic brain injury may be effective enough even in deep coma and dislocation syndrome but in absence of intraoperative brain edema. The absence of brain edema, the moderate coma level are indications for osteoplastic craniotomy.

A Preclinical Controlled Cortical Impact Model for Traumatic Hemorrhage Contusion and Neuroinflammation.

Cerebral contusion is a severe medical problem affecting millions of people worldwide each year. There is an urgent need to understand the pathophysiological mechanism and to develop effective therapeutic strategy for this devastating neurological disorder. Intraparenchymal hemorrhage and post-traumatic inflammatory response induced by initial physical impact can aggravate microglia/macrophage activation and neuroinflammation which subsequently worsen brain pathology. We provide here a controlled cortical impact (CCI) protocol that can reproduce experimental cortical contusion in mice by using a pneumatic impactor system to deliver mechanical force with controllable magnitude and velocity onto the dural surface. This preclinical model allows researchers to induce moderately severe focal cerebral contusion in mice and to investigate a wide range of post-traumatic pathological progressions including hemorrhage contusion, microglia/macrophage activation, iron toxicity, axonal injury, as well as short-term and long-term neurobehavioral deficits. The present protocol can be useful for exploring the long-term effects of and potential interventions for cerebral contusion.

Time-dependent hemeoxygenase-1, lipocalin-2 and ferritin induction after non-contusion traumatic brain injury

Traumatic brain injury (TBI) often presents with focal contusion and parenchymal bleeds, activating heme oxygenase (HO) to degrade released hemoglobin. Here we show that diffuse, midline fluid percussion injury causes time-dependent induction of HO-1 and iron binding proteins within both hemorrhagic neocortex and non-hemorrhagic hippocampus. Rats subjected to midline fluid percussion injury (FPI) survived 1-15d postinjury and tissue was collected for Western blot and immunohistochemical assays. HO-1 was elevated 1d after FPI, peaked at 3d, and returned to control baseline 7-15d. Iron management proteins lipocalin 2 (LCN2) and ferritin (FTL) exhibited distinct postinjury time courses, where peak LCN2 response preceded, and FTL followed that of HO-1. LCN2 elevation supported not only its role in iron transport, but also mediation of matrix metalloproteinase 9 (MMP9) activity. Upregulation of FTL for intracellular iron sequestration was delayed relative to both HO-1 and LCN2 induction. In the neocortex IBA-1+ microglia around the injury core expressed HO-1, but astrocytes co-localized with HO-1 in perilesional parenchyma. Non-hemorrhagic dentate gyrus showed predominant HO-1 labeling in hilar microglia and in molecular layer astrocytes. At 1d postinjury, LCN2 and HO-1 co-localized in a subpopulation of reactive glia within both brain regions. Notably, FTL was distributed within cells around injured vessels, damaged subcortical white matter, and along vessels of the hippocampal fissure. Together these results confirm that even the moderate, non-contusional insult of diffuse midline FPI can significantly activate postinjury HO-1 heme processing pathways and iron management proteins. Moreover, this activation is time-dependent and occurs in the absence of overt hemorrhage.

Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury.

The neuroinflammatory response to traumatic brain injury (TBI) is critical to both neurotoxicity and neuroprotection, and has been proposed as a potentially modifiable driver of secondary injury in animal and human studies. Attempts to broadly target immune activation have been unsuccessful in improving outcomes, in part because the precise cellular and molecular mechanisms driving injury and outcome at acute, subacute, and chronic time points after TBI remain poorly defined. Microglia play a critical role in neuroinflammation and their persistent activation may contribute to long-term functional deficits. Activated microglia are characterized by morphological transformation and transcriptomic changes associated with specific inflammatory states. We analyzed the temporal course of changes in inflammatory genes of microglia isolated from injured brains at 2, 14, and 60 days after controlled cortical impact (CCI) in mice, a well-established model of focal cerebral contusion. We identified a time dependent, injury-associated change in the microglial gene expression profile toward a reduced ability to sense tissue damage, perform housekeeping, and maintain homeostasis in the early stages following CCI, with recovery and transition to a specialized inflammatory state over time. This later state starts at 14 days post-injury and is characterized by a biphasic pattern of IFNγ, IL-4, and IL-10 gene expression changes, with concurrent proinflammatory and anti-inflammatory gene changes. Our transcriptomic data sets are an important step to understand microglial role in TBI pathogenesis at the molecular level and identify common pathways that affect outcome. More studies to evaluate gene expression at the single cell level and focusing on subacute and chronic timepoint are warranted.

Effect of Early Sacral Neuromodulation on Bladder Function in a Rat Model of Incomplete Spinal Cord Injury Due to Focal Contusion

Incomplete spinal cord injury (SCI) accounts for two-thirds of all SCIs in clinical practice. Preclinical research on the effect of sacral neuromodulation (SNM) on bladder function, however, has been focused only on animal models of complete SCI. We aimed to evaluate the effect of early SNM on bladder responses in a rat model of incomplete SCI. Altogether, 21 female Sprague-Dawley rats were equally assigned to control (CTR), SCI + sham stimulation (SHAM), and SCI + SNM (SNM) groups. In the SHAM and SNM groups, incomplete SCI was created by producing a moderate contusion with an NYU-MASCIS impactor at the T9-T10 level of the spine, with needle electrodes implanted bilaterally into the S2 or S3 sacral foramen. Only SNM group underwent electrical stimulation for 28 days, beginning on day 7 after SCI. Cystometry was performed 35 days after SCI. Although the interval between voiding contractions was significantly longer in the SHAM group than the CTR group (25.5 ± 1.4 vs. 12.5 ± 1.7 min; p < 0.05), there were no significant differences between the SNM group (16.5 ± 1.5 min) and the CTR group. Maximum voiding contraction pressure did not differ among the groups. The SNM group had a significantly lower frequency (3.5 ± 0.5 vs. 14.6 ± 2.0; p < 0.05) and maximum pressure (11.4 ± 6.2 vs. 21.3 ± 1.8 cmH2 O; p < 0.05) of nonvoiding contractions than the SHAM group. Our results provide experimental evidence that early SNM treatment may prevent or diminish bladder dysfunctions (e.g., detrusor overactivity, abnormal micturition reflex) in a clinical condition of incomplete SCI.

Behavioral and Structural Effects of Single and Repeat Closed-Head Injury.

The effects of multiple head impacts, even without detectable primary injury, on subsequent behavioral impairment and structural abnormality is yet well explored. Our aim was to uncover the dynamic changes and long-term effects of single and repetitive head injury without focal contusion on tissue microstructure and macrostructure. We introduced a repetitive closed-head injury rodent model (n = 70) without parenchymal lesions. We performed a longitudinal MR imaging study during a 50-day study period (T2-weighted imaging, susceptibility-weighted imaging, and diffusion tensor imaging) as well as sequential behavioral assessment. Immunohistochemical staining for astrogliosis was examined in a subgroup of animals. Paired and independent t tests were used to evaluate the outcome change after injury and the cumulative effects of impact load, respectively. There was no gross morphologic evidence for head injury such as skull fracture, contusion, or hemorrhage on micro-CT and MR imaging. A significant decrease of white matter fractional anisotropy from day 21 on and an increase of gray matter fractional anisotropy from day 35 on were observed. Smaller mean cortical volume in the double-injury group was shown at day 50 compared with sham and single injury (P < .05). Behavioral deficits (P < .05) in neurologic outcome, balance, and locomotor activity were also aggravated after double injury. Histologic analysis showed astrogliosis 24 hours after injury, which persisted throughout the study period. There are measurable and dynamic changes in microstructure, cortical volume, behavior, and histopathology after both single and double injury, with more severe effects seen after double injury. This work bridges cross-sectional evidence from human subject and pathologic studies using animal models with a multi-time point, longitudinal research paradigm.

1 - Effect of early sacral neuromodulation on bladder function in a rat model of incomplete spinal cord injury due to focal contusion

1 - Effect of early sacral neuromodulation on bladder function in a rat model of incomplete spinal cord injury due to focal contusion

Abstract # 2056 Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2-alpha. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampal dependent cognitive deficits induced by TBI in two different injury mouse models—focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head trauma induced chronic cognitive deficits.