Protective effects of dl-3n-butylphthalide against diffuse brain injury

DI-3n-butyiphthalide can effectively treat cerebral ischemia; however, the mechanisms underlying the effects of dl-3n-butylphthalide on microcirculation disorders following diffuse brain injury remain unclear. In this study, models of diffuse brain injury were established in Sprague-Dawley rats with the vertical impact method. DI-3n-butylphthalide at 80 and 160 mg/kg was given via intraperitoneal injection immediately after diffuse brain injury. Ultrastructural changes in the cerebral cortex were observed using electron microscopy. Cerebral blood flow was measured by laser Doppler flowmetry, vascular density was marked by tannic acid-ferric chloride staining, vascular permeability was es- timated by the Evans blue method, brain water content was measured using the dry-wet method, and rat behavior was measured by motor function and sensory function tests. At 6, 24, 48, and 72 hours after administration of dl-3n-butylphthalide, reduced cerebral ultrastructure damage, in- creased vascular density and cerebral blood flow, and improved motor and sensory functions were observed. Our findings demonstrate that dl-3n-butylphthalide may have protective effects against diffuse brain injury by ameliorating microcirculation disorder and reducing blood-brain barrier dam- age and cerebral edema.

The occurrence of diffuse axonal injury in the brain:associated with the accumulation and clearance of myelin debris

The accumulation of myelin debris may be a major contributor to the inlfammatory response after diffuse axonal injury. In this study, we examined the accumulation and clearance of myelin debris in a rat model of diffuse axonal injury. Oil Red O staining was performed on sections from the cerebral cortex, hippocampus and brain stem to identify the myelin debris. Seven days after diffuse axonal injury, many Oil Red O-stained particles were observed in the cerebral cortex, hippocampus and brain stem. In the cerebral cortex and hippocampus, the amount of myelin debris peaked at 14 days after injury, and decreased signiifcantly at 28 days. In the brain stem, the amount of myelin debris peaked at 7 days after injury, and decreased signiifcantly at 14 and 28 days. In the cortex and hippocampus, some myelin debris could still be observed at 28 days after diffuse axonal injury. Our ifndings suggest that myelin debris may persist in the rat central ner-vous system after diffuse axonal injury, which would hinder recovery.

Apolipoprotein E mimetic peptide protects against diffuse brain injury

Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. Howev-er, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apo-lipoprotein E mimetic peptide signiifcantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental ifndings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mito-chondrial apoptotic pathway.

Brain-derived neurotrophic factor gene transfection promotes neuronal repair and neurite regeneration after diffuse axonal injury

This study sought to assess the potential of brain-derived neurotrophic factor （BDNF） to promote neuronal repair and regeneration in rats with diffuse axonal injury, and to examine the accompanying neurobiological changes. BDNF gene transfection reduced the severity of the pathological changes associated with diffuse axonal injury in cortical neurons of the frontal lobe and increased neurofilament protein expression. These findings demonstrate that BDNF can effectively promote neuronal repair and neurite regeneration after diffuse axonal injury.

The quantitative analysis of S100 in the brain tissue and serum following diffusebrain injury in rats

Objective To investigate the dynamics of the level of S100 in cerebrum,brainstem,and serum following the diffuse brain injury in rats and provide the experimental evidences for estimating injury time.Methods ELISA was used to determine whether S100 protein is changed after diffuse brain injury in rats.Forty rats were sacrificed at 0.5 hour, 2 hours,4 hours,12 hours,24 hours,3d and 7d after diffuse brain injury and normal rats as control.Results The level of S100 in cerebrum,brainstem,and serum increased,followed by a decrease,and then further increased.The level of S100 could be detected to increase at 30 minutes and reached the peak at 4 hours after DBI.The level decreased gradually to the normal at 1d and till 3d formed the second peak.The level returned to the normal at 7d following injury again.In the postmortem injury groups,there were no significant changes compared to the control group.Conclusion The present study showed that the time-dependent expression of S100 is obvious following diffuse brain injury in rats and suggested that S100 will be a suitable marker for diffuse brain injury age determination.

Altered expression of metabotropic glutamate receptor 1 alpha after acute diffuse brain injury Effect of the competitive antagonist 1-aminoindan-1, 5-dicarboxylic acid

The diffuse brain injury model was conducted in Sprague-Dawley rats, according to Marmarou＇s free-fall attack. The water content in brain tissue, expression of metabotropic glutamate receptor la mRNA and protein were significantly increased after injury, reached a peak at 24 hours, and then gradually decreased. After treatment with the competitive antagonist of metabotropic glutamate receptor la, （RS）-l-aminoindan-1,5-dicarboxylic acid, the water content of brain tissues decreased between 12-72 hours after injury, and neurological behaviors improved at 2 weeks. These experimental findings suggest that the 1-aminoindan-1, 5-dicarboxylic acid may result in marked neuroprotection against diffuse brain injury.

Diffuse axonal injury after traumatic cerebral microbleeds: an evaluation of imaging techniques

Previous neuropathological studies regarding traumatic brain injury have primarily focused on changes in large structures, for example, the clinical prognosis after cerebral contusion, intrace- rebral hematoma, and epidural and subdural hematoma. In fact, many smaller injuries can also lead to severe neurological disorders. For example, cerebral microbleeds result in the dysfunc- tion of adjacent neurons and the disassociation between cortex and subcortical structures. These tiny changes cannot be adequately visualized on CT or conventional MRI. In contrast, gradient echo sequence-based susceptibility-weighted imaging is very sensitive to blood metabolites and microbleeds, and can be used to evaluate traumatic cerebral microbleeds with high sensitivity and accuracy. Cerebral microbleed can be considered as an important imaging marker for dif- fuse axonal injury with potential relevance for prognosis. For this reason, based on experimental and clinical studies, this study reviews the role of imaging data showing traumatic cerebral microbleeds in the evaluation of cerebral neuronal injury and neurofunctional loss.

Mild hypothermia for treatment of diffuse axonal injury: a quantitative analysis of diffusion tensor imaging

Fractional anisotropy values in diffusion tensor imaging can quantitatively reflect the consistency of nerve fibers after brain damage, where higher values generally indicate less damage to nerve fibers. Therefore, we hypothesized that diffusion tensor imaging could be used to evaluate the effect of mild hypothermia on diffuse axona[ injury. A total of 102 patients with diffuse axonal injury were randomly divided into two groups： normothermic and mild hypothermic treatment groups. Patient＇s modified Rankin scale scores 2 months after mild hypothermia were significant- ly lower than those for the normothermia group. The difference in average fractional anisotropy value for each region of interest before and after mild hypothermia was 1.32-1.36 times higher than the value in the normothermia group. Quantitative assessment of diffusion tensor imaging indicates that mild hypothermia therapy may be beneficial for patients with diffuse axonal injury.

Traumatic axonal injury of the cingulum in patients with mild traumatic brain injury: a diffusion tensor tractography study

The cingulum,connecting the orbitofrontal cortex to the medial temporal lobe,involves in diverse cognition functions including attention,memory,and motivation.To investigate the relationship between the cingulum injury and cognitive impairment in patients with chronic mild traumatic brain injury,we evaluated the integrity between the anterior cingulum and the basal forebrain using diffusion tensor tractography in 73 patients with chronic mild traumatic brain injury(39 males,34 females,age 43.29±11.42 years)and 40 healthy controls(22 males,18 females,age 40.11±16.81 years).The patients were divided into three subgroups based on the integrity between the anterior cingulum and the basal forebrain on diffusion tensor tractography:subgroup A(n=19 patients)– both sides of the anterior cingulum were intact;subgroup B(n=36 patients)– either side of the anterior cingulum was intact;and subgroup C(18 patients)– both sides of the anterior cingulum were discontinued.There were significant differences in total Memory Assessment Scale score between subgroups A and B and between subgroups A and C.There were no significant differences in diffusion tensor tractography parameters(fractional anisotropy,apparent diffusion coefficient,and fiber volume)between patients and controls.These findings suggest that the integrity between the anterior cingulum and the basal forebrain,but not diffusion tensor tractography parameter,can be used to predict the cognitive function of patients with chronic mild traumatic brain injury.This study was approved by Yeungnam University Hospital Institutional Review Board(approval No.YUMC-2014-01-425-010)on August 16,2017.

Prognosis in prolonged coma patients with diffuse axonal injury assessed by somatosensory evoked potential

A total of 43 prolonged coma patients with diffuse axonal injury received the somatosensory evoked potential examination one month after injury in the First Affiliated Hospital, School of Medicine, Zhejiang University in China. Somatosensory evoked potentials were graded as normal, abnormal or absent （grades I-III） according to N20 amplitude and central conduction time. The outcome in patients with grade III somatosensory evoked potential was in each case unfavorable. The prognostic accuracy of grade III somatosensory evoked potential for unfavorable and non-awakening outcome was 100% and 80%, respectively. The prognostic accuracy of grade I somatosensory evoked potential for favorable and wakening outcome was 86% and 100%, respectively. These results suggest that somatosensory evoked potential grade is closely correlated with coma severity and degree of recovery. Somatosensory evoked potential is a valuable diagnostic tool to assess prognosis in prolonged coma patients with diffuse axonal injury.

Dynamic changes in cerebral microcirculation and hypoxia in the early stages of diffuse axonal injury

This study demonstrated that damage to the cerebral microvasculature, the formation of microthrombi and swelling of vascular endothelial cells occur early and peak 12 hours after injury in a rat model of diffuse axonal injury. Moreover, these pathological changes were most evident in the cerebral cortex. Cerebral microcirculatory dysfunction peaked later and had a shorter duration than axonal injury. In addition, the radioactive imaging agent, 99Tcm-4, 9-diaza-2, 3, 10, 10- tetramethyldodecan-2, 11 -dione dioxime, was used to visualize the dynamic changes that occur in tissue with cerebral hypoxia. The results demonstrated that cerebral hypoxia occurs at an early stage in diffuse axonal injury. Cerebral hypoxia was evident 12 hours after injury and declined slightly 24 hours after injury, but was significantly higher than in the control group. The pathological changes that underpin microcirculatory dysfunction did not occur at the same time as axonal injury, but did occur simultaneously with neuronal injury. Cerebral hypoxia plays a key role in promoting the secondary brain injury that occurs after diffuse axonal injury.

Evaluation of non-typical diffuse axonal injury by magnetic resonance techniques

Because diffuse axonal injury（DAI）lacks specific clinical manifestations,it is difficult to evaluate DAI using computer tomography or conventional magnetic resonance imaging（MRI）.This study investigated the value of magnetic resonance techniques using fluid-attenuated inversion recovery（FLAIR）and proton magnetic resonance spectroscopy（1HMRS）for diagnosing DAI.The corpus callosum and basal nuclei were analyzed using morphological and functional imaging.Similar to the DAI group,the non-typical DAI group exhibited similar lesion characteristics on FLAIR,as well as post-injury neurochemical and molecular changes in the corpus callosum,as detected by 1HMRS.However,there were differences in degree and severity of injury.Compared to conventional MRI,FLAIR significantly increased lesion detection.1HMRS determined biochemical metabolism changes in midline structures following DAI,which resulted in increased diagnosis of non-typical DAI,which displayed similar lesion distribution,morphology,and function as DAI.Thus,the experiment proved the value of FLAIR and 1HMRS in non-typical DAI.

Diffusion tensor tractography characteristics of axonal injury in concussion/mild traumatic brain injury

The main advantage of diffusion tensor tractography is that it allows the entire neural tract to be evaluated.In addition,configurational analysis of reconstructed neural tracts can indicate abnormalities such as tearing,narrowing,or discontinuations,which have been used to identify axonal injury of neural tracts in concussion patients.This review focuses on the characteristic features of axonal injury in concussion or mild traumatic brain injury(m TBI)patients through the use of diffusion tensor tractography.Axonal injury in concussion(m TBI)patients is characterized by their occurrence in long neural tracts and multiple injuries,and these characteristics are common in patients with diffuse axonal injury and in concussion(m TBI)patients with axonal injury.However,the discontinuation of the corticospinal tract is mostly observed in diffuse axonal injury,and partial tearing and narrowing in the subcortical white matter are frequently observed in concussion(m TBI)patients with axonal injury.This difference appears to be attributed to the observation that axonal injury in concussion(m TBI)patients is the result of weaker forces than those producing diffuse axonal injuries.In addition,regarding the fornix,in diffuse axonal injury,discontinuation of the fornical crus has been frequently reported,but in concussion(m TBI)patients,many collateral branches form in the fornix in addition to these findings in many case studies.It is presumed that the impact on the brain in TBI is relatively weaker than that in diffuse axonal injury,and that the formation of collateral branches occurs during the fornix recovery process.Although the occurrence of axonal injury in multiple areas of the brain is an important feature of diffuse axonal injury,case studies in concussion(m TBI)have shown that axonal injury occurs in multiple neural tracts.Because axonal injury lesions in m TBI patients may persist for approximately 10 years after injury onset,the characteristics of axonal injury in concussion(m TBI)patients,which are reviewed and categorized in this review,are expected to serve as useful supplementary information in the diagnosis of axonal injury in concussion(m TBI)patients.

8-hydroxy-2-(di-n-propylamino)tetralin intervenes with neural cell apoptosis following diffuse axonal injury

Previous studies have reported a neuroprotective effect of 8-hydroxy-2-（di-n-propylamino）tetralin （8-OH-DPAT） against traumatic brain injury. In accordance with the Marmarou method, rat models of diffuse axonal injury were established. 8-OH-DPAT was intraperitoneally injected into model rats. 8-OH-DPAT treated rats maintained at constant temperature served as normal temperature controls TUNEL results revealed that neural cell swelling, brain tissue necrosis and cell apoptosis occurred around the injured tissue. Moreover, the number of Bax-, Bcl-2- and caspase-3-positive cells increased at 6 hours after diffuse axonal injury, and peaked at 24 hours. However, brain injury was attenuated, the number of apoptotic cells reduced, Bax and caspase-3 expression decreased, and Bcl-2 expression increased at 6, 12, 24, 72 and 168 hours after diffuse axonal injury in normal temperature control and in 8-OH-DPAT-intervention rats. The difference was most significant at 24 hours. All indices in 8-OH-DPAT-intervention rats were better than those in the constant temperature group. These results suggest that 8-OH-DPAT inhibits Bax and caspase-3 expression, increases Bcl-2 expression, and reduces neural cell apoptosis, resulting in neuroprotection against diffuse axonal injury. This effect is associated with a decrease in brain temperature.

Protective effects of edaravone on diffuse brain njury in rats

BACKGROUND：Edaravone can alleviate brain injury and improve neurological functions and symptoms. This study aimed to investigate the effect of edaravone on the p38Mitogen-activated protein kinases/Caspase-3 （p38MAPK/Caspase-3） pathway after diffuse brain injury （DBI） in rats. METHODS： DBI models were established according to the description of Marmarou＇s method. A total of 250 rats were divided （random number） into four groups： control group （CG, n=45）, model group （MG, n=77）, low-dose edaravone group （n=67, dosage 5 mg/kg） and high-dose edaravone group （n=61, dosage 10 mg/kg）. After 1,6, 24, 48, and 72 hours after injury, brain tissues were collected. The changes of neuron morphous in the hippocampal region were observed through Nissl staining. The expression levels of phosphorylated p38MAPK and caspase-3 were detected by immunohistochemistry and Western blotting respectively. Learning and memory function were tested with Morris water maze from the 3rd to 7th day after injury. RESULTS： Some neurons had histopathologic changes of necrosis and apoptosis in the model group compared with the control group. The phosphorylated p38MAPK expressions increased at 1,6, 4, and 48 hours （P〈0.05）, but no significant difference was observed at 72 hours （0.54±0.19 vs. 0.40±0.14, P〉0.05）. Caspase-3 expressions increased at 6, 24, 48, and 72 hours respectively （P〈0.05）, but there was no significant difference at 1 hour （0.59±0.29 vs. 0.40±0.17, P〉0.05）. From the 3rd to 6th day during the Morris water maze test, the latency to find the platform was significantly prolonged （P〈0.05） and times of rats crossing the platform was decreased on the 7th day （2.28±1.18 vs. 8.20±1.52, P〈0.05）. The phosphorylated p38MAPK expressions decreased at 6, 24 and 48 hours respectively in the low dose edaravone group compared with the model group （P〈0.05）, whereas no significant difference was seen at 1 hour （1.66±0.80 vs. 1.85±0.86, P〉0.05）. Caspase-3 expression decreased at 6, 24, 48, and 72 hours （P〈0.05）. The latency to find the platform was significantly shortened （P〈0.05）, and times of rats crossing the platform increased （4.17±1.15 vs. 2.28±1.18, P〈0.05）. The above mentioned parameters changed more significantly in the high-dose edaravone group than in the low-dose edaravone group. CONCLUSION：Edaravone can alleviate brain tissue damage after DBI, inhibit p38MAP signal activation after early injury, reduce the expression of caspase-3, and promote the recovery of neurological function in the late period.

The usefulness of diffusion tensor imaging in detection of diffuse axonal injury in a patient with head trauma

Diffuse axonal injury is the predominant mechanism of injuries in patients with traumatic brain injury. Neither conventional brain computed tomography nor magnetic resonance imaging has shown sufficient sensitivity in the diagnosis of diffuse axonal injury. In the current study, we attempted to demonstrate the usefulness of diffusion tensor imaging in the detection of lesion sites of diffuse axonal injury in a patient with head trauma who had been misdiagnosed as having a stroke. A 44-year-old man fell from a height of about 2 m. Brain magnetic resonance imaging （32 months after onset） showed leukomalactic lesions in the isthmus of the corpus callosum and the left temporal lobe. He presented with mild quadriparesis, intentional tremor of both hands, and trunkal ataxia. From diffusion tensor imaging results of 33 months after traumatic brain injury onset, we found diffuse axonal injury in the right corticospinal tract （centrum semiovale, pons）, both fomices （columns and crus）, and both inferior cerebellar peduncles （cerebellar portions）. We think that diffusion tensor imaging could be a useful tool in the detection of lesion sites of diffuse axonal injury in patients with head trauma.

Diffusion tensor imaging of neural tract injury in a patient with hypoxic-ischemic brain injury

Hypoxic-ischemic brain injury （HI-BI） is one of the most common causes of severe neurological disability, Some studies have reported diffusion tensor imaging （DTI） findings of neonatal patients with HI-BI. However, very little is known about DTI in the adult brain. The present study reports on a 15-year-old male patient with HI-BI, who exhibited no specific focal lesions on conventional brain MRI at 5 weeks. However, neural tract injuries were revealed by DTI. Seven control subjects were also evaluated. The patient suffered from cardiac arrest due to ventricular fibrillation for a period of 10 15 minutes. At 4 weeks after onset of cardiac arrest, although he was conscious and alert, he exhibited mild quadriparesis and severe cognitive dysfunction. DTI was acquired at 5 weeks after HI-BI onset. Decreased fractional anisotropy or voxel number of neural tracts suggested partial injury of the corticospinal tract, fornix, and cingulum. Disruptions of the fornix and cingulum on DTI confirmed neural tract injury. DTI could serve as a useful tool for evaluating the state of neural tracts in patients with HI-BI.

The apparent diffusion coefficient does not reflect cytotoxic edema on the uninjured side after traumatic brain injury

After traumatic brain injury, vasogenic and cytotoxic edema appear sequentially on the involved side. Neuroimaging investigations of edema on the injured side have employed apparent diffusion coefficient measurements in diffusion tensor imaging. We investigated the changes occurring on the injured and uninjured sides using diffusion tensor imaging/apparent diffusion coefficient and histological samples in rats. We found that, on the injured side, that vasogenic edema appeared at 1 hour and intracellular edema appeared at 3 hours. Mixed edema was observed at 6 hours, worsening until 12–24 hours post-injury. Simultaneously, microglial cells proliferated at the trauma site. Apparent diffusion coefficient values increased at 1 hour, decreased at 6 hours, and increased at 12 hours. The uninjured side showed no significant pathological change at 1 hour after injury. Cytotoxic edema appeared at 3 hours, and vasogenic edema was visible at 6 hours. Cytotoxic edema persisted, but vasogenic edema tended to decrease after 12–24 hours. Despite this complex edema pattern on the uninjured side with associated pathologic changes, no significant change in apparent diffusion coefficient values was detected over the first 24 hours. Apparent diffusion coefficient values accurately detected the changes on the injured side, but did not detect the changes on the uninjured side, giving a false-negative result.

Motor recovery via aberrant pyramidal tract in a patient with traumatic brain injury A diffusion tensor tractography study

The aberrant pyramidal tract is the collateral pathway of the pyramidal tract through the medial lemniscus in the brainstem. A 21-year-old man presented with right hemiparesis due to a traumatic intracerebral hemorrhage in the left corona radiata. His motor function recovered almost to the normal state at 10 months after onset. Through diffusion tensor tractography, the pyramidal tract in the affected （left） hemisphere showed discontinuation at the pontine level at 13 months after onset. An aberrant pyramidal tract was observed, which originated from the primary motor cortex and the supplementary motor area and descended through the corona radiata, then through the posterior limb of the internal capsule and the medial lemniscus pathway from the midbrain to the pons, finally entered into the pyramidal tract area at the pontomedullary junction, it suggests that the motor functions of the right extremities in this patient had recovered by this aberrant pyramidal tract.

Diffusion Tensor Imaging and Its Application to Traumatic Brain Injury: Basic Principles and Recent Advances

Traumatic axonal injury is a progressive process evoked by shear forces on the brain, gradually evolving from focal axonal alteration and cumulating in neural disconnection. Clinical classifiers and conventional neuroimaging are limited in traumatic axonal injury detection, outcome prediction, and treatment guidance. Diffusion weighted imaging is an advanced magnetic resonance imaging (MRI) technique that is sensitive to the movement of water molecules, providing additional information on the micro-structural arrangement of tissue. Quantitative analysis of diffusion metrics can aid in the localization of axonal injury and/or de(dys)myelination caused by trauma. Diffusion MRI tractography is an extension of diffusion weighted imaging, and can provide additional information about white matter pathways and the integrity of brain neural networks. Both techniques are able to detect the early micro-structural changes caused by Traumatic Brain Injury (TBI), and can be used to increase understanding of the mechanisms of brain plasticity in recovery after brain injury and possibly optimize treatment planning of patients with Traumatic Brain Injury. This review focuses on the theoretical basis and applied advanced techniques of diffusion weighted imaging, their limitations and applications, and future directions in the application to TBI.