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.

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.

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.

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.

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.

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 pig as a preclinical traumatic brain injury model:current models,functional outcome measures,and translational detection strategies

Traumatic brain injury(TBI) is a major contributor of long-term disability and a leading cause of death worldwide. A series of secondary injury cascades can contribute to cell death, tissue loss, and ultimately to the development of functional impairments. However, there are currently no effective therapeutic interventions that improve brain outcomes following TBI. As a result, a number of experimental TBI models have been developed to recapitulate TBI injury mechanisms and to test the efficacy of potential therapeutics. The pig model has recently come to the forefront as the pig brain is closer in size, structure, and composition to the human brain compared to traditional rodent models, making it an ideal large animal model to study TBI pathophysiology and functional outcomes. This review will focus on the shared characteristics between humans and pigs that make them ideal for modeling TBI and will review the three most common pig TBI models–the diffuse axonal injury, the controlled cortical impact, and the fluid percussion models. It will also review current advances in functional outcome assessment measures and other non-invasive, translational TBI detection and measurement tools like biomarker analysis and magnetic resonance imaging. The use of pigs as TBI models and the continued development and improvement of translational assessment modalities have made significant contributions to unraveling the complex cascade of TBI sequela and provide an important means to study potential clinically relevant therapeutic interventions.

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.

Differences in pathological changes between two rat models of severe traumatic brain injury

The rat high-impact free weight drop model mimics the diffuse axonal injury caused by severe traumatic brain injury in humans,while severe controlled cortical impact can produce a severe traumatic brain injury model using precise strike parameters.In this study,we compare the pathological mechanisms and pathological changes between two rat severe brain injury models to identify the similarities and differences.The severe controlled cortical impact model was produced by an electronic controlled cortical impact device,while the severe free weight drop model was produced by dropping a 500 g free weight from a height of 1.8 m through a plastic tube.Body temperature and mortality were recorded,and neurological deficits were assessed with the modified neurological severity score.Brain edema and bloodbrain barrier damage were evaluated by assessing brain water content and Evans blue extravasation.In addition,a cytokine array kit was used to detect inflammatory cytokines.Neuronal apoptosis in the brain and brainstem was quantified by immunofluorescence staining.Both the severe controlled cortical impact and severe free weight drop models exhibited significant neurological impairments and body temperature fluctuations.More severe motor dysfunction was observed in the severe controlled cortical impact model,while more severe cognitive dysfunction was observed in the severe free weight drop model.Brain edema,inflammatory cytokine changes and cortical neuronal apoptosis were more substantial and blood-brain barrier damage was more focal in the severe controlled cortical impact group compared with the severe free weight drop group.The severe free weight drop model presented with more significant apoptosis in the brainstem and diffused blood-brain barrier damage,with higher mortality and lower repeatability compared with the severe controlled cortical impact group.Severe brainstem damage was not found in the severe controlled cortical impact model.These results indicate that the severe controlled cortical impact model is relatively more stable,more reproducible,and shows obvious cerebral pathological changes at an earlier stage.Therefore,the severe controlled cortical impact model is likely more suitable for studies on severe focal traumatic brain injury,while the severe free weight drop model may be more apt for studies on diffuse axonal injury.All experimental procedures were approved by the Ethics Committee of Animal Experiments of Tianjin Medical University,China(approval No.IRB2012-028-02)in Febru ary 2012.

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).

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.

Structural and functional connectivity in traumatic brain injury

Traumatic brain injury survivors often experience cognitive deficits and neuropsychiatric symptoms.However,the neurobiological mechanisms underlying specific impairments are not fully understood.Advances in neuroimaging techniques（such as diffusion tensor imaging and functional MRI）have given us new insights on structural and functional connectivity patterns of the human brain in both health and disease.The connectome derived from connectivity maps reflects the entire constellation of distributed brain networks.Using these powerful neuroimaging approaches,changes at the microstructural level can be detected through regional and global properties of neuronal networks.Here we will review recent developments in the study of brain network abnormalities in traumatic brain injury,mainly focusing on structural and functional connectivity.Some connectomic studies have provided interesting insights into the neurological dysfunction that occurs following traumatic brain injury.These techniques could eventually be helpful in developing imaging biomarkers of cognitive and neurobehavioral sequelae,as well as predicting outcome and prognosis.

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.

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.

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.

Photosensitivity detection using diffusion tensor imaging in a traumatic brain injury patient

The present study examined a patient with traumatic brain injury who exhibited visual photosensitivity and axonal iniury of the left optic radiation, which was detected by diftusion tensor imaging. The patient was a 41-year-old man. He began to complain of photosensitivity at 4 months after head trauma. Ophthalmic evaluation, including visual-evoked potential and conventional brain magnetic resonance imaging, did not reveal a pathologic basis for photosensitivity. Axonal injury in the left optic radiation was detected via diffusion tensor imaging at 36 months after head trauma. The lesion was almost recovered at 76 months. However, photosensitivity continued. Therefore, the photosensitivity was considered to be a result of axonal injury to the left optic radiation, which could be a symptom of maladaptive plasticity that occurs during recovery of axonal injury of the left optic radiation.

Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury

Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury,substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell-based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic.

Numerical study on dynamic mechanism of brain volume and shear deformation under blast loading

Blast-induced traumatic brain injury(b-TBI)is a kind of significant injury to soldiers in the current military conflicts.However,the mechanism of b-TBI has not been well understood,and even there are some contradictory conclusions.It is crucial to reveal the dynamic mechanism of brain volume and shear deformations under blast loading for better understanding of b-TBI.In this paper,the numerical simulation method is adopted to carry out comprehensive and in-depth researches on this issue for the first time.Based on the coupled Eulerian-Lagrangian method,the fluid-structure coupling model of the blast wave and human head is developed to simulate two situations,namely the head subjected to the frontal and lateral impacts.The simulation results are analyzed to obtain the underlying dynamic mechanisms of brain deformation.The brain volume deformation is dominated by the local bending vibration of the skull,and the corresponding frequency for the forehead skull under the frontal impact and the lateral skull faced to the lateral impact is as high as 8 kHz and 5 kHz,respectively.This leads to the high-frequency fluctuation of brain pressure and the large pressure gradient along the skull,totally different from the dynamic response of brain under head collisions.While the brain shear deformation mainly depends on the relative tangential displacement between the skull and brain and the anatomical structure of inner skull,being not related to the brain pressure and its gradient.By further comparing the medical statistics,it is inferred that diffuse axonal injury and brain contusion,the two most common types of b-TBI,are mainly attributed to brain shear deformations.And the von Mises stress can be adopted as the indicator for these two brain injuries.This study can provide theoretical guidance for the diagnosis of b-TBI and the development of protective equipment.