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.

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.

Susceptibility weighted imaging in the evaluation of hemorrhagic diffuse axonal injury

Diffuse axonal injury（DAI）is axonal and small vessel injury produced by a sudden acceleration of the head by an external force,and is a major cause of death and severe disability（Paterakis et al.,2000）.Prognosis is poorer in patients with apparent hemorrhage than in those without（Paterakis et al.,2000）.Therefore,it is important to identify the presence and precise position of hemorrhagic foci for a more accurate diagnosis.CT and magnetic resonance imaging（MRI）have long been applied in the diagnosis of DAI, but they are not sensitive enough for the detection of small hemorrhagic foci, and cannot meet the requirements for early diagnosis. A major advance in MRI has been the development of susceptibility weighted imaging （SWI）, which has greatly increased the ability to detect small hemorrhagic foci after DAI （Ashwal et al., 2006）.

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.

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.

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.

Diagnostic value of fluid attenuated inversion recovery versus T_2-weighted image in diffuse axonal injury

BACKGROUND：At present, the most common examination modality for diffuse axonal injury （DAI） is CT or MRI. However, both methods exhibit low sensitivity in the diagnosis of DAI lesions. OBJECTIVE： To investigate the value of fluid attenuated inversion recovery （FLAIR） in the clinical diagnosis of DAI, and to compare with T2-weighted images. DESIGN, TIME AND SETTING： This prospective study was based on imaging analysis, and was performed in the First Affiliated Hospital of Chongqing Medical University （Chongqing, China） between October 2002 and April 2004. PARTICIPANTS： Sixty-three patients with craniocerebral injury were admitted to the Department of Neurosurgery at the First Affiliated Hospital of Chongqing Medical University, including 50 males and 13 females. The patients were included in the experiment and were divided into DAI （n=24） and non-DAI （n=39） groups, according to the emergent CT findings and clinical manifestations. METHODS： Both groups underwent MR examinations, including axial and sagittal T1 weighted images （TR = 450 ms, TE = 8-9 ms）, T2-weighted images （TR = 3 600 ms, TE = 100 ms）, and FLAIR （TR = 10 000 ms, TI = 2 500 ms, TE = 40 ms）, 8-mm thick and 2-mm wide, using a GE Sigma MRI device. MAIN OUTCOME MEASURES： The DAI diagnostic rate and lesion-detecting rate of T2-weighted images and FLAIR were determined. RESULTS： All 63 patients were included in the final analysis. The DAI diagnosis rates of FLAIR and T2-weighted images were 88% （21/24） and 62% （15/24）, respectively, of which the difference was statistically significant （P 〈 0.05）. T2-weighted images and FLAIR detected lesions located in the gray matter-white matter junction in parasagittal areas, the corpus callosum, deep periventricular white matter, basal ganglia, internal capsule, hippocampus, cerebellum, and brain stem, with a detailed amount of 123 and 256, respectively. FLAIR was significantly greater than T2-weighted images （P 〈 0.01）. CONCLUSION： FLAIR is superior to T2-weighted images for improving the DAI diagnostic rate and lesion-detecting rate, as well as revealing the extent and severity of DAI.

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 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.

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.

Hippocampal expression of apoptotic protease activating factor-1 following diffuse axonal injury under mild hypothermia

The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury （DAI） at 33℃. Morris water maze results demonstrated significantly better learning and memory functions in DAI rats with hypothermia compared with DAI rats with normothermia. Expression of apoptotic protease activating factor-1 in the hippocampal CA1 region was significantly lower in the DAI hypothermia group compared with the DAI normothermia group. Expression of apoptotic protease activating factor-1 positively correlated with latency, but negatively correlated with platform location times and time of swimming in the quadrant area. Results suggested that post-traumatic mild hypothermia in a rat model of DAI could provide cerebral protection by attenuating expression of apoptotic protease activating factor-1.

Present status of studies on diffuse axonal injury

OBJECTIVE: To explain the present status of study on diffuse axonal injury, investigate its pathogenesis and pathophysiological changes, and suggest principles for the diagnosis and treatment. DATA SOURCES: Articles about diffuse axonal injury published in English from January 1994 to October 2006 were searched in Pubmed database using the of 'diffuse axonal injury, pathogenesis, therapy'. STUDY SELECTION: The collected articles were primarily screened to select those associated with diffuse axonal injury, the obviously irrelated articles were excluded, and the rest ones were retrieved manually, and the full-texts were searched. DATA EXTRACTION: Totally 98 articles were collected, 41 of them were involved, and the other 57 were excluded. DATA SYNTHESIS: Diffuse axonal injury is mainly caused by acceleratory or deceleratory injury, and its pathophysiological change is a progressive duration, local axonal injury finally develops to axonal breakage, mainly includes inactivation of natrium channel, intracellular Ca2+ overloading, activation of calcium protease, caspase, etc., and mitochondrial injury. At present, there is still lack of effective therapeutic methods for diffuse axonal injury, so we should actively explore more effective methods to relieve the pain of patients and improve their prognosis. CONCLUSION: At present, diffuse axonal injury has not attracted enough attentions in China, the mechanisms for its diagnosis and attack are still unclear, and the treatments are mainly aiming at the symptoms.

Observation on the Clinical Effect of Different Pressures in Hyperbaric Oxygen Therapy on Patients with Diffuse Axonal Injury

Objective:To observe the efficacy and significance of hyperbaric oxygen at different pressures in the treatment of diffuse axonal injury(DAI).Methods:Sixty patients with DAI were randomly divided into 1.8 ATA group(30 cases)and 2.2 ATA group(30 cases).The routine treatment for each group was the same.The 1.8 ATA.group received hyperbaric oxygen therapy under 1.8 ATA on the basis of routine treatment,whereas the 2.2 ATA group received hyperbaric oxygen therapy under 2.2 ATA.on the basis of routine treatment.The therapy was given once a day over 3 consecutive courses,with each course having 10 sessions.The Glasgow Coma Scale(GCS)on day 10,day 20,and day 30 after treatment,as well as the Glasgow Outcome Scale(GOS)after 6 months were compared between the two groups.Results:The mean GCS on day 10,day 20,and day 30 after treatment,as well as the mean GOS after 6 months of treatment in the 2.2 ATA group were significantly higher than those in the 1.8 ATA group(p<0.05).Conclusion:For patients with dififtise axonal injury,hyperbaric oxygen therapy is more effective with 2.2 ATA.compared with 1.8 ATA.

The Effects of Ultra-early Hyperbaric Oxygen Intervention in the Treatment of Diffuse Axonal Injury

Objective:To investigate the efficacy and mechanism of ultra-early hyperbaric oxygen intervention in the treatment of diffuse axonal injury(DAI).Methods:Eighty-six patients with diffuse axonal injury were selected and then divided into an ultra-early hyperbaric oxygen treatment group and a conventional treatment group with 43 patients in each group.The Glasgow Coma Scale(GCS)on the 10h day(10d),20h day(20d),and 30h day(30d)after treatment and the Glasgow Outcome Score(GOS)6 months later were observed and compared between both the groups.Results:The average score of the GCS at 10d,20d,and 30d as welll as the GOS 6 months later in the ultra-early hyperbaric oxygen treatment group were higher than those in the conventional treatment group(P<0.05).Conclusion:Hyperbaric oxygen therapy is one of the unique and effective methods in clinical treatment especially for the treatment of DAI patients and it is worthy of promotion.

Risk factors for corticosteroid insufficiency during the sub-acute phase of acute traumatic brain injury

Hypothalamic-pituitary-adrenal axis dysfunction may lead to the occurrence of critical illness-related corticosteroid insufficiency.Critical illness-related corticosteroid insufficiency can easily occur after traumatic brain injury,but few studies have examined this occurrence.A multicenter,prospective,cohort study was performed to evaluate the function of the hypothalamic-pituitary-adrenal axis and the incidence of critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury.One hundred and forty patients with acute traumatic brain injury were enrolled from the neurosurgical departments of three tertiary-level hospitals in China,and the critical illness-related corticosteroid insufficiency incidence,critical-illness-related corticosteroid insufficiency-related risk factors,complications,and 28-day mortality among these patients was recorded.Critical illness-related corticosteroid insufficiency was diagnosed in patients with plasma total cortisol levels less than 10μg/dL(275.9 nM)on post-injury day 4 or when serum cortisol was insufficiently suppressed(less than 50%)during a dexamethasone suppression test on post-injury day 5.The results demonstrated that critical illness-related corticosteroid insufficiency occurred during the sub-acute phase of traumatic brain injury in 5.6%of patients with mild injury,22.5%of patients with moderate injury,and 52.2%of patients with severe injury.Traumatic brain injury-induced critical illness-related corticosteroid insufficiency was strongly correlated to injury severity during the sub-acute stage of traumatic brain injury.Traumatic brain injury patients with critical illness-related corticosteroid insufficiency frequently presented with hemorrhagic cerebral contusions,diffuse axonal injury,brain herniation,and hypotension.Differences in the incidence of hospital-acquired pneumonia,gastrointestinal bleeding,and 28-day mortality were observed between patients with and without critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury.Hypotension,brain-injury severity,and the types of traumatic brain injury were independent risk factors for traumatic brain injury-induced critical illness-related corticosteroid insufficiency.These findings indicate that critical illness-related corticosteroid insufficiency is common during the sub-acute phase of traumatic brain injury and is strongly associated with poor prognosis.The dexamethasone suppression test is a practical assay for the evaluation of hypothalamic-pituitary-adrenal axis function and for the diagnosis of critical illness-related corticosteroid insufficiency in patients with traumatic brain injury,especially those with hypotension,hemorrhagic cerebral contusions,diffuse axonal injury,and brain herniation.Sub-acute infection of acute traumatic brain injury may be an important factor associated with the occurrence and development of critical illness-related corticosteroid insufficiency.This study protocol was approved by the Ethics Committee of General Hospital of Tianjin Medical University,China in December 2011(approval No.201189).

Mathematical modelling of axonal microtubule bundles under dynamic torsion

Owing to its viscoelastic nature, axon exhibits a stress rate-dependent me- chanical behavior. An extended tension-shear chain model with Kelvin-Voigt viscoelas- ticity is developed to illustrate the micromechanical behavior of the axon under dynamic torsional conditions. Theoretical closed-form expressions are derived to predict the de- formation, stress transfer, and failure mechanism between microtubule （MT） and tau protein while the axon is sheared dynamically. The results obtained from the present an- alytical solutions demonstrate how the MT-tau interface length, spacing between the tau proteins, and loading rate affect the mechanical properties of axon. Moreover, it is found that the MTs are more prone to rupture due to the contributions from the viscoelastic effects. Under the torsional force, the MTs are so long that the stress concentrates at the loaded end where axonal MTs will break. This MT-tau protein dynamics model can help to understand the underlying pathology and molecular mechanisms of axonal injury. Additionally, the emphasis of this paper is on the micromechanical behavior of axon, whereas this theoretical model can be equally applicable to other soft or hard tissues, owning the similar fibrous structure.

Diffusion tensor imaging in the courtroom:Distinction between scientific specificity and legally admissible evidence

Interest and uptake of science and medicine peer-reviewed literature by readers outside of a paper’s topical subject,field or even discipline is ever-expanding.While the application of knowledge from one field or discipline to others can stimulate innovative solutions to problems facing modern society,it is also fraught with danger for misuse.In the practice of law in the United States,academic papers are submitted to the courts as evidence in personal injury litigation from both the plaintiff(complainant)and defendant.Such transcendence of an academic publication over disciplinary boundaries is immediately met with the challenge of application by a group that inherently lacks in-depth knowledge on the scientific method,the practice of evidence-based medicine,or the publication process as a structured and internationally synthesized process involving peer review and guided by ethical standards and norms.A modern-day example of this is the ongoing conflict between the sensitivity of diffusion tensor imaging(DTI)and the legal standards for admissibility of evidence in litigation cases of mild traumatic brain injury(mTBI).In this review,we amalgamate the peer-reviewed research on DTI in mTBI with the court’s rationale underlying decisions to admit or exclude evidence of DTI abnormalities to support claims of brain injury.We found that the papers which are critical of the use of DTI in the courtroom reflect a primary misunderstanding about how diagnostic biomarkers differ legally from relevant and admissible evidence.The clinical use of DTI to identify white matter abnormalities in the brain at the chronic stage is a valid methodology both clinically as well as forensically,contributes data that may or may not corroborate the existence of white matter damage,and should be admitted into evidence in personal injury trials if supported by a clinician.We also delve into an aspect of science publication and peer review that can be manipulated by scientists and clinicians to publish an opinion piece and misrepresent it as an unbiased,evidencebased,systematic research article in court cases,the decisions of which establish precedence for future cases and have implications on future legislation that will impact the lives of every citizen and erode the integrity of science and medicine practitioners.

Single low-dose lipopolysaccharide preconditioning:neuroprotective against axonal injury and modulates glial cells

Aim:Over 7 million traumatic brain injuries (TBI) are reported each year in the United States.However,treatments and neuroprotection following TBI are limited because secondary injury cascades are poorly understood.Lipopolysaccharide (LPS) administration before controlled cortical impact can contribute to neuroprotection.However,the underlying mechanisms and whether LPS preconditioning confers neuroprotection against closed-head injuries remains unclear.Methods:The authors hypothesized that preconditioning with a low dose of LPS (0.2 mg/kg) would regulate glial reactivity and protect against diffuse axonal injury induced by weight drop.LPS was administered 7 days prior to TBI.LPS administration reduced locomotion,which recovered completely by time of injury.Results:LPS preconditioning significantly reduced the post-injury gliosis response near the corpus callosum,possibly by downregulating the oncostatin M receptor.These novel findings demonstrate a protective role of LPS preconditioning against diffuse axonal injury.LPS preconditioning successfully prevented neurodegeneration near the corpus callosum,as measured by fluorojade B.Conclusion:Further work is required to elucidate whether LPS preconditioning confers long-term protection against behavioral deficits and to elucidate the biochemical mechanisms responsible for LPS-induced neuroprotective effects.