Diffuse axonal injury in early infancy.

Diffuse axonal injury typified by retraction balls and axonal swellings was identified in the brains of a series of infants, 5 months old and younger, who had suffered closed head injuries. These axonal discontinuities were shown by using Nauomenko and Feigin's silver method, which is particularly useful for showing fine axons such as those found in the developing brain. Diffuse axonal injury in early infancy may occur in the same way as that described in adults. The low incidence of intracerebral haematomata suggests that recurrent trauma to the head from a combination of direct contact and shaking results in axonal damage to the poorly myelinated axons and that blood vessels are rarely damaged.     

The effect of varying impact energy on diffuse axonal injury in the rat brain: a preliminary study

Diffuse axonal injury (DAI) is seen as widespread damage in the white matter of brain characterized by morphological changes to axons throughout the brain and brain stem. The current study attempted to investigate the effect of increasing impact energy on the presence and severity of DAI in corpus callosum (CC). DAI was induced in adult male Sprague-Dawley rats using an injury model adapted from Marmarou et al. in 1994. A 450-g cylindrical brass weight was dropped from three different heights (2.0 m, 1.5 m and 1.0 m) on to a metal helmet affixed to the skull of the rats. In the sham group, rats underwent a surgical procedure with no impact. After a 24-h survival period the animals were transcardially perfused. The brain was removed and the cerebral hemispheres were sectioned with a vibrotome and stained by silver impregnation technique. The CC of all the impacted rats showed DAI in the form of beaded axons, retraction balls and vacuole-like enlargements. The axonal injury was most severe in the 2-m group, while mildest in the 1-m group. In the sham group, axons appeared to be normal. This study demonstrates evidence of graded DAI depending on the impact energy. Such data is useful for mathematical modeling of axonal injury in rat brain using the same impact parameters and potential determination of injury thresholds for neural trauma. Electronic Publication     

Intracranial diffuse axonal injury at autopsy

An illustrative case of diffuse axonal injury (DAI) emphasizes features that help to separate focal outer head trauma owing to blows and/or falls from angular acceleration head injuries associated with diffuse inner brain lesions. In the past, explaining significant neurological deficits and death as the result of diffuse closed head trauma received from high-speed automobile accidents has been difficult as well as confusing. The long-term consequences from such diffuse inner cerebral trauma are still poorly defined. Head injuries sustained in automobile accidents have been associated with diffuse brain damage characterized by axonal injury at the moment of impact. The reported victim of a motor vehicle accident showed post-mortem findings for both inner cerebral trauma and focal outer cerebral damage. The diffuse degeneration of cerebral white matter is associated with sagittal and lateral acceleration with centroaxial trauma and has a different pathogenesis from outer focal head trauma, typified by subdural hematomas and coup injuries. Unlike outer cerebral injury, over 50 percent of victims with diffuse axonal injury die within two weeks. These individuals characteristically have no lucid interval and remain unconscious, vegetative, or severely disabled until death. Compared to head trauma victims without diffuse axonal injury, there is a lower incidence of skull fractures, subdural hemorrhages, or other intracranial mass effect as well as outer brain contusions. Primary brainstem injuries often demonstrated at autopsy are seen in the reported victim. Diffuse axonal injury is produced by various angles of acceleration with prolonged acceleration/deceleration usually accompanying traffic accidents. Less severe diffuse axonal injury causes concussion.     

基于体素的健康中国成人概率性弥散张量成像脑图谱的建立

目的 使用计算机医学图像处理技术在标准人脑空间建立基于体素的健康中国成人概率性弥散张量成像（DTI）脑图谱,以期为脑白质的功能研究和相关疾病的诊治提供基础信息。 方法 选择50例健康成年志愿者进行常规MRI扫描,确认未发现异常后,再行DTI扫描,获取相应图像数据。首先使用MRIcron软件包中的相关程序,将原始的DICOM数据格式转换为图像处理所需要的格式,然后运用DtiStudio和DiffeoMap软件,结合自动图像配准算法对DTI数据进行数据预处理、张量计算和图像归一化,最后在MATLAB中对图像进行平均计算,构建图谱。结果 成功构建出基于50例健康中国成人的概率性DTI脑图谱,图谱清晰。各向异性（FA）图和彩色编码图上均可见脑白质结构和纤维束走向,在彩色编码图上以特定颜色代表了不同纤维束的走行方向。结论 运用图像处理技术可以构建国人概率性DTI脑图谱。该图谱以通用数据格式保存,可被大部分医学图像处理软件及分析软件识别读取,能为研究脑白质正常结构功能及相关疾病服务。     

Diffuse axonal injury induced by simultaneous moderate linear and angular head accelerations in rats

Diffuse axonal injury (DAI) is one of the most common and important pathologic features of human traumatic brain injury (TBI), accounting for high mortality and development of persistent post-traumatic neurologic sequelae. Although a relatively high number of therapies have been shown to be effective in experimental models, there are currently few treatments that are effective for improving the prognosis of clinical DAI. A major reason is the failure of current models to validly reproduce the pathophysiological characteristics observed after clinical DAI. In the present study, we employed a specially designed, highly controllable model to induce a sudden rotation in the coronal plane (75 degrees rotation at 1.6×10⁴ degrees/s) combined with lateral translation (1.57 cm displacement at 3.4×10² cm/s) to the rat's head. We were interested in discovering whether the combined accelerations could reproduce the pathophysiological changes analogous to those seen in human DAI. The axonal injury as assessed with amyloid protein precursor (APP) as a marker was consistently present in all injured rats. The commonly injured brain regions included the subcortical regions, deep white matter, corpus callosum and brain stem. The evolution of APP accumulations in brain sections depicted the detailed progression of axonal pathology. Ultrastructural studies gave further insights into the presence and progression of axonal injury. All injured rats exhibited transient physiological dysfunction, as well as immediate and dramatic neurological impairment that still persisted at 14 days after injury. These results suggest that this model reproduced the major pathophysiological changes analogous to those observed after severe clinical TBI and provides an attractive vehicle for experimental brain injury research.     

A tissue-level anisotropic criterion for brain injury based on microstructural axonal deformation

Different length scales from micrometers to several decimeters play an important role in diffuse axonal injury. The kinematics at the head level result in local impairments at the cellular level. Finite element methods can be used for predicting brain injury caused by a mechanical loading of the head. Because of its oriented microstructure, the sensitivity of brain tissue to a mechanical load can be expected to be orientation dependent. However, the criteria for injury that are currently used at the tissue level in finite element head models are isotropic and therefore do not consider this orientation dependence, which might inhibit a reliable assessment of injury. In this study, an anisotropic brain injury criterion is developed that is able to describe the effects of the oriented microstructure based on micromechanical simulations. The effects of both the main axonal direction and of local deviations from this direction are accounted for. With the anisotropic criterion for brain injury, computational head models will be able to account for aspects of diffuse axonal injury at the cellular level and can therefore more reliably predict injury.     

CLARITY reveals a more protracted temporal course of axon swelling and disconnection than previously described following traumatic brain injury

Diffuse axonal injury (DAI) is an important consequence of traumatic brain injury (TBI). At the moment of trauma, axons rarely disconnect, but undergo cytoskeletal disruption and transport interruption leading to protein accumulation within swellings. The amyloid precursor protein (APP) accumulates rapidly and the standard histological evaluation of axonal pathology relies upon its detection. APP+ swellings first appear as varicosities along intact axons, which can ultimately undergo secondary disconnection to leave a terminal “axon bulb” at the disconnected, proximal end. However, sites of disconnection are difficult to determine with certainty using standard, thin tissue sections, thus limiting the comprehensive evaluation of axon degeneration. The tissue‐clearing technique, CLARITY, permits three‐dimensional visualization of axons that would otherwise be out of plane in standard tissue sections. Here, we examined the morphology and connection status of APP+ swellings using CLARITY at 6 h, 24 h, 1 week and 1 month following the controlled cortical impact (CCI) model of TBI in mice. Remarkably, many APP+ swellings that appeared as terminal bulbs when viewed in standard 8‐µm‐thick regions of tissue were instead revealed to be varicose swellings along intact axons when three dimensions were fully visible. Moreover, the percentage of these potentially viable axon swellings differed with survival from injury and may represent the delayed onset of distinct mechanisms of degeneration. Even at 1‐month post‐CCI, ~10% of apparently terminal bulbs were revealed as connected by CLARITY and are thus potentially salvageable. Intriguingly, the diameter of swellings decreased with survival, including varicosities along intact axons, and may reflect reversal of, or reduced, axonal transport interruption in the chronic setting. These data indicate that APP immunohistochemistry on standard thickness tissue sections overestimates axon disconnection, particularly acutely post‐injury. Evaluating cleared tissue demonstrates a surprisingly delayed process of axon disconnection and thus longer window of therapeutic opportunity than previously appreciated. Intriguingly, a subset of axon swellings may also be capable of recovery.     

猫头半约束非撞击致伤DAI动物模型的有限元分析

对猫头半约束非撞击致伤弥漫性轴索损伤（Diffuse axonal injury,DAI)动物模型进行生物力学分析，探讨DAI发生机理。这一锚头颅CT断层确定各层节面点并数字化，在有限元专用vizi CAD系统建立猫头颅三维有限元网格体模型，用SuperSAP有限元软件（93版）分析15只猫头半约束非撞击致伤时颅脑最大主应力、最小主应力、von Mises应力值及其在各层面的分布。结果表明；颅骨纵轴各层面应力在施载点同侧前后最高，并向颅底延伸，在颅脑内，脑表浅应力分布最高，但由于小脑幕、大脑镰及隆起的岩滩，鞍床突等结构，应力并非均匀向脑深部递减，而在邻近这些结构的脑组织，大小脑脚、脑干、胼胝体、基底节区有很高的应力分布， 这种应力分布特征与前期动物实验的病理损害分布一致。据此得出结论，脑内质点应力差值致脑组织剪应变 损伤，猫颅骨不规则的几何形状、小脑幕、大脑镰结构是导致旋转暴力向脑内传递广泛而不均一的主要原因。     

弥漫性轴索损伤患者血清和脑脊液中NSE变化及临床意义

目的:观察弥漫性轴索损伤(DAI)患者早期血清和脑脊液中神经元特异性烯醇化酶(NSE)的变化,探讨两者损伤程度与预后的关系。方法:分别采用放射免疫分析检测79例DAI病人(实验组)和30例无神经系统疾病者(对照组)血清和脑脊液NSE的含量。根据入院时GCS评分实验组分为轻型组23例、中型组27例和重型组29例。分别于颅脑损伤后24h内、2d～3d、7d、14d采集脑脊液、血清标本。分析NSE水平与颅脑损伤严重程度及预后的关系。结果:DAI患者伤后24h内NSE水平明显高于对照组(P<0.01)。NSE平均水平在伤后2d～3d达高峰,7d～14d逐渐下降。重型组NSE明显高于轻中型组(P<0.01);预后不良组则明显高于预后良好组(P<0.01或P<0.05);死亡组NSE值持续增高。结论:DAI血清和脑脊液NSE水平变化不仅能反映脑组织损伤的严重程度,还可作为病情监测和预后评估的一项重要指标。     

寰椎骨折的生物力学分析

目的采用有限元方法,预测寰椎在不同位置条件下寰椎应力的分布,并以此推断可能出现的寰椎骨折类型。方法构建寰椎三维骨性结构,分析寰椎在中立、屈曲、后伸三种位置下应力分布状况。结果寰椎高应力在中立位时,出现在寰椎前部和双侧椎弓根;屈曲位时,分布在寰椎前部;后伸位时,存在寰椎前弓和双侧椎弓根。结论寰椎前弓和前结节交界处、前弓和侧块交界处、后弓和侧块交界处、后弓和后结节交界处是应力较为集中的部位,也是寰椎骨折容易发生的部位。骨折部位和骨折类型与寰椎损伤时所处的位置、寰椎几何形状、外力的方向以及寰椎的力学特征密切相关。     

Mild Traumatic Brain Injury Predictors Based on Angular Accelerations During Impacts

Although Head Injury Criterion (HIC) is an effective criterion for head injuries caused by linear acceleration such as skull fractures, no criteria for head injuries caused by rotational kinematics has been accepted as effective so far. This study proposed two criteria based on angular accelerations for Traumatic Brain Injury (TBI), which we call Rotational Injury Criterion (RIC) and Power Rotational Head Injury Criterion (PRHIC). Concussive and non-concussive head acceleration data obtained from football head impacts were utilized to develop new injury criteria. A well-validated human brain Finite Element (FE) model was employed to find out effective injury criteria for TBI. Correlation analyses were performed between the proposed criteria and FE-based brain injury predictors such as Cumulative Strain Damage Measure (CSDM), which is defined as the percent volume of the brain that exceeds a specified first principal strain threshold, proposed to predict Diffuse Axonal Injury (DAI) which is one of TBI. The RIC was significantly correlated with the CSDMs with the strain thresholds of less than 15% (R > 0.89), which might predict mild TBI. In addition, PRHIC was also strongly correlated with the CSDMs with the strain thresholds equal to or greater than 20% (R > 0.90), which might predict more severe TBI.     

Diffuse axonal injury in infants with nonaccidental craniocerebral trauma: enhanced detection by beta-amyloid precursor protein immunohistochemical staining

OBJECTIVE: Accurate identification of diffuse axonal injury is important in the forensic investigation of infants who have died from traumatic brain injury. beta-Amyloid precursor protein (beta-APP) immunohistochemical staining is highly sensitive in identifying diffuse axonal injury. However, the effectiveness of this method in brain-injured infants has not been well established. The present study was undertaken to assess the utility of beta-APP immunohistochemistry in detecting diffuse axonal injury in infants with either shaken baby syndrome or blunt head trauma. MATERIALS AND METHODS: Archival formalin-fixed, paraffin-embedded blocks from infants (<1 year old) with shaken baby syndrome (7 cases) and blunt head trauma (3) and blocks from 7 control cases that included nontraumatic cerebral edema (1), acute hypoxic-ischemic encephalopathy (1), and normal brain (5) were immunostained for beta-APP. A semiquantitative assessment of the severity of axonal staining was made. Corresponding hematoxylin-eosin-stained sections were examined for the presence of axonal swellings. RESULTS: Immunostaining for beta-APP identified diffuse axonal injury in 5 of 7 infants with shaken baby syndrome and 2 of 3 infants with blunt head trauma. Immunoreactive axons were easily identified and were present in the majority of the sections examined. By contrast, hematoxylineosin staining revealed axonal swellings in only 3 of 7 infants with shaken baby syndrome and 1 of 3 infants with blunt head trauma. Most of these sections had few if any visible axonal swellings, which were often overlooked on initial review of the slides. No beta-APP immunoreactivity was observed in any of the 7 control cases. CONCLUSIONS: Immunostaining for beta-APP can easily and reliably identify diffuse axonal injury in infants younger than 1 year and is considerably more sensitive than routine hematoxylin-eosin staining. We recommend its use in the forensic evaluation of infants with fatal craniocerebral trauma.     

用有限元法计算媒质各向异性真实头模型脑电正问题

神经元所产生的脑内电活动通常可用电流源偶极子来模拟。讨论用有限元法计算电流源偶极子产生的电流与电位分布，推导出计算偶极子源在各向异性导电媒质中的有限元方程，并对其进行变形，使得在各向异性导电媒质中生成的有限元刚度阵对称。这一算法已应用于媒质各向异性的真实头模型脑电计算，得到了较为满意的结果。     

Calcium signaling is implicated in the diffuse axonal injury of brain stem

Evaluating diffuse axonal injury (DAI) remains challenging in clinical sciences since the physiopathologic mechanism of DAI is still unclear. The calcium overload in the axoplasm is considered to be crucial for secondary axonal injury. The present study use calcium channel blocker, nimodipine, to explore the influence of Ca²⁺ in the pathogenesis of rat DAI. In the DAI group, the expressions of β-APP and NF-L in axons were increased from 12 to 72 h. The ultrastructural observation indicated the axon and vessel injury appeared at 12 h post-injury and severely aggravated from 24 to 72 h. The expression of vWF and brain water content was increased at 12 h after injury and further increased at 24 h. Nimodipine decreased the expression of β-APP, NF-L and vWF, and also attenuated the ultrastructural damage of vascular wall and axons. Furthermore, Ca-dependent enzyme, the calcineurin activity were increased in DAI and nimodipine suppressed the activity of calcineurins (CaN). However, the amount of CaN expression was not changed. Our results showed that disturbances of axonal calcium homeostasis play an important role in the secondary damage of the axon, neuron and capillary vessel which may be related with activating CaN during the acute phase of DAI. Nimodipine can alleviate the secondary damage by suppressing the calcineurin activity.     

Diffusion tensor imaging of diffuse axonal injury in a rat brain trauma model

Diffusion tensor imaging (DTI) was used to study traumatic brain injury. The impact-acceleration trauma model was used in rats. Here, in addition to diffusivities (mean, axial and radial), fractional anisotropy (FA) was used, in particular, as a parameter to characterize the cerebral tissue early after trauma. DTI was implemented at 7 T using fast spiral k-space sampling and the twice-refocused spin echo radiofrequency sequence for eddy current minimization. The method was carefully validated on different phantom measurements. DTI of a trauma group (n = 5), as well as a sham group (n = 5), was performed at different time points during 6 h following traumatic brain injury. Two cerebral regions, the cortex and corpus callosum, were analyzed carefully. A significant decrease in diffusivity in the trauma group versus the sham group was observed, suggesting the predominance of cellular edema in both cerebral regions. No significant FA change was detected in the cortex. In the corpus callosum of the trauma group, the FA indices were significantly lower. A net discontinuity in fiber reconstructions in the corpus callosum was observed by fiber tracking using DTI. Histological analysis using Hoechst, myelin basic protein and Bielschowsky staining showed fiber disorganization in the corpus callosum in the brains of the trauma group. On the basis of our histology results and the characteristics of the impact-acceleration model responsible for the presence of diffuse axonal injury, the detection of low FA caused by a drastic reduction in axial diffusivity and the presence of fiber disconnections of the DTI track in the corpus callosum were considered to be related to the presence of diffuse axonal injury.     

Contribution of axonal orientation to pathway-dependent modulation of excitatory transmission by direct current stimulation in isolated rat hippocampus

Transcranial direct current stimulation (tDCS) is a method for modulating cortical excitability by weak constant electrical current that is applied through scalp electrodes. Although often described in terms of anodal or cathodal stimulation, depending on which scalp electrode pole is proximal to the cortical region of interest, it is the orientation of neuronal structures relative to the direct current (DC) vector that determines the effect of tDCS. To investigate the contribution of neural pathway orientation, we studied DCS-mediated neuromodulation in an in vitro rat hippocampal slice preparation. We examined the contribution of dendritic orientation to the direct current stimulation (DCS) neuromodulatory effect by recording field excitatory postsynaptic potentials (fEPSPs) in apical and basal dendrites of CA1 neurons within a constant DC field. In addition, we assessed the contribution of axonal orientation by recording CA1 and CA3 apical fEPSPs generated by stimulation of oppositely oriented Schaffer collateral and mossy fiber axons, respectively, during DCS. Finally, nonsynaptic excitatory signal propagation was measured along antidromically stimulated CA1 axons at different DCS amplitudes and polarity. We find that modulation of both the fEPSP and population spike depends on axonal orientation relative to the electric field vector. Axonal orientation determines whether the DC field is excitatory or inhibitory and dendritic orientation affects the magnitude, but not the overall direction, of the DC effect. These data suggest that tDCS may oppositely affect neurons in a stimulated cortical volume if these neurons are excited by oppositely orientated axons in a constant electrical field.     

弥漫性轴索损伤后胶质细胞的反应性变化

目的 探讨大鼠弥漫性轴索损伤（DAI）后胶质细胞的反应性变化规律及与轴索继发损伤的相互关系。 方法 SD 成年大鼠随机分为对照组及DAI损伤1d、2d、3d、7d组,每组8只。参照Marmarou方法制做 DAI 模型,并对大鼠的脑干部位进行胶质纤维酸性蛋白（GFAP）、离子钙结合适配器分子1（Iba1）、少突胶质细胞系转录因子2（Olig 2）、CC-1、NG2免疫组织化学染色及TUNEL染色,并且通过透射电子显微镜进一步观察脑干超微结构变化。 结果 DAI大鼠损伤后3d脑干Iba1标记的小胶质细胞细胞数目显著增多,一直持续至伤后7d,且激活的小胶质细胞呈肥大样形态学改变;DAI大鼠伤后1周内脑干GFAP标记的星形胶质细胞数目虽有所增多,但并没有统计学意义;CC-1标记的成熟少突胶质细胞在DAI后1d即开始明显降低,且随损伤时间的延长而进一步降低。DAI大鼠脑干TUNEL标记的凋亡细胞随损伤时间延长持续增多,与成熟少突胶质细胞的丢失成正相关。Olig2标记的少突胶质细胞系表达在DAI损伤后1周内各时间点均明显增高,于损伤后3d达峰值。NG2标记的少突胶质细胞前体细胞数量于损伤后3d和7d显著增多。透射电子显微镜结果示,DAI大鼠损伤呈现由髓鞘到轴索的特点,最早表现为髓鞘松解,轴索完整;且脱髓鞘会进一步促进轴索骨架崩解,最终导致轴索变性。 结论 成熟少突胶质细胞对DAI损伤具有选择易感性,髓鞘脱失是轴索继发损伤的重要因素。少突胶质细胞前体细胞增殖,并伴随小胶质细胞的激活。探索胶质细胞的动态变化将为进一步解释轴索继发损伤的病理生理学机制奠定基础。     

Diffuse axonal injury in head injury: definition, diagnosis and grading

Diffuse axonal injury is one of the most important types of brain damage that can occur as a result of non-missile head injury, and it may be very difficult to diagnose post mortem unless the pathologist knows precisely what he is looking for. Increasing experience with fatal non-missile head injury in man has allowed the identification of three grades of diffuse axonal injury. In grade 1 there is histological evidence of axonal injury in the white matter of the cerebral hemispheres, the corpus callosum, the brain stem and, less commonly, the cerebellum; in grade 2 there is also a focal lesion in the corpus callosum; and in grade 3 there is in addition a focal lesion in the dorsolateral quadrant or quadrants of the rostral brain stem. The focal lesions can often only be identified microscopically. Diffuse axonal injury was identified in 122 of a series of 434 fatal non-missile head injuries--10 grade 1, 29 grade 2 and 83 grade 3. In 24 of these cases the diagnosis could not have been made without microscopical examination, while in a further 31 microscopical examination was required to establish its severity.     

From myelin debris to inflammatory responses: a vicious circle in diffuse axonal injury

Based on current knowledge and our preliminary study, in this paper we hypothesized a novel mechanism in secondary injury of diffuse axonal injury (DAI): (1) myelin debris from injured axons triggers undesirable inflammation and up-regulates the expression of cytokines such as TNF-α, IL-1 and IL-2; (2) inflammatory response is involved in DAI and (3) will lead to further axonal injury. That just forms a vicious circle in DAI. The key mission to prove this theory is to investigate the downstream effects of inflammatory process on the secondary injury in DAI. Appropriate methods are also discussed, as well as the significance in future treatment of DAI.     

The possible role of hypoxia in the formation of axonal bulbs.

AIMS: To assess the possible role of hypoxia in the formation of axonal bulbs. METHODS: Study material comprised sections from 28 brains showing evidence of cerebral hypoxia with no history of head injury, four with a history of head trauma but no evidence of hypoxic change, eight with a history of head trauma and hypoxic change, and four from control brains originally described as "diffuse axonal injury." These were subjected to microwave antigen retrieval and immunohistochemistry using monoclonal antibodies to beta amyloid precursor protein (beta APP), glial fibrillary acid protein (GFAP), and CD68-PGM1. RESULTS: Positive staining for beta APP was seen in all four controls, all four cases of head injury only, seven of eight cases of head injury and hypoxic changes, and 12 of 28 cases of hypoxia without history of head injury; 22 of 25 cases who had been ventilated showed positive staining. The majority of cases showed evidence of cerebral swelling. CONCLUSIONS: Axonal bulbs staining positively for beta APP may occur in the presence of hypoxia and in the absence of head injury. The role of hypoxia, raised intracranial pressure, oedema, shift effects, and ventilatory support in the formation of axonal bulbs is discussed. The presence of axonal bulbs cannot necessarily be attributed to shearing forces alone.