Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4-6 h and 24 h post-injury. Axonal injury was detected by amyloid beta precursor protein (APP) and neurofilament immunohistochemistry in pericontusional white matter tracts. The severity of axonal injury was quantified using stereological methods from APP stained histological sections. Two DTI parameters - axial diffusivity and relative anisotropy - were significantly reduced in the injured, pericontusional corpus callosum and external capsule, while no significant changes were seen with conventional MRI in these regions. The contusion was easily detectable on all MRI sequences. Significant correlations were found between changes in relative anisotropy and the density of APP stained axons across mice and across subregions spanning the spatial gradient of injury. The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose.     

Clinicoradiological and therapeutic considerations in severe diffuse traumatic brain injury in children

Forty-one children with severe head injuries and diffuse brain lesions were selected from a consecutive series of 62 children in traumatic coma (21 focal mass lesions) and studied. According to the CT pattern, two main types of intracranial lesions were considered: diffuse axonal injury (DAI) and diffuse brain swelling (DBS). High mortality, due to secondary increases of intracranial pressure (ICP), correlated well with the patterns of severe DBS, absence of perimesencephalic cisterns, and obliteration of the ventricles. However, children with normal CTs, and/or obvious shearing injuries indicative of DAI, had favorable outcomes; there was no mortality if increased ICP was not present. We conclude that although there does not seem to be any routine indications for ICP monitoring in children with pure DAI, early ICP monitoring and aggressive management of increasing ICP should be considered in comatose children with DBS, especially when associated with subarachnoid hemorrage and respiratory or circulatory failure.Presented at the 11th Meeting of the European Society for Paediatric Neurosurgery, Naples 1988     

Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma

Objective

Severe traumatic brain injury (TBI) has a major role in mortality rate among the other types of trauma. The aim of this clinical study was to assess the effect of progesterone on the improvement of neurologic outcome in patients with acute severe TBI.

Methods

A total of 76 patients who had arrived within 8 h of injury with a Glasgow Coma Score ≤8 were enrolled in the study. In a randomized style 38 received progesterone (1 mg/kg per 12 h for 5 days) and 38 did not.

Results

There was a better recovery rate and GOS score for the patients who were given progesterone than for those in the control group in a 3-months follow-up period (50% vs. 21%); subgroup analysis showed a significant difference in the percentage of favorable outcome between the two groups with GCS of 5–8 (p = 0.03).

Conclusion

The use of progesterone may significantly improve neurologic outcome of patients suffering severe TBI up to 3 months after injury, especially those with 5 ≤ GCS ≤ 8, providing a potential benefit to the treatment of acute severe TBI patients. Considering this drug had no significant side effects, so progesterone could be used in patients with severe TBI as a neuro-protective drug.     

Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.     

脑弥漫性轴索损伤的发生机制

弥漫性轴索损伤（diffuse axonal injury，DAI）是颅脑损伤中一种常见的原发性损伤，在平时和战时均常见，是颅脑损伤患者重残及植物生存的最常见原因之一，伤情重，治疗困难．预后差。文献报道其死亡率高达42％-62％。[第一段]     

The added prognostic value of magnetic resonance imaging in traumatic brain injury: The importance of traumatic axonal injury when performing ordinal logistic regression

Background and purposeThis study was performed to investigate the prognostic value of traumatic axonal injury (TAI) in severe head trauma.MethodsWe attempted to determine whether any MR imaging findings of TAI could be related to prognosis in 264 patients with severe head trauma. We performed an ordinal logistic regression, adjusted for the prognostic factors according to the IMPACT studies, adding each MR feature related to prognosis one at a time. A new prognostic model was described by adding these MR features to the classic prognostic factors. The model was externally validated in a prospective series. Harrel's c-statistic and ordinal c-index (ORC) were calculated to measure its predictive accuracy.ResultsWe found 178 patients with TAI lesions. Lesions in the basal ganglia/thalamus, corpus callosum (CC) and brain stem were associated with poor outcome (P < 0.01). The highest OR was for TAI lesions in the splenium (OR: 2.6) and brain stem dorsal lesions (OR: 3.1). We only found significant differences in outcome between haemorrhagic and non-haemorrhagic TAI lesions in the subgroup of patients with white matter and basal ganglia/thalamus lesions (P = 0.01). We obtained a superior discriminatory capacity by adding these MR findings to the previous prognostic model (Harrel's c-statistic 0.72 and ORC 0.7) in a prospective series of 93 patients.ConclusionsThe prognostic model including MR findings maintained a superior discriminatory capacity than that obtained for the model with the classic prognostic factors alone.     

The prognostic factors related to traumatic brain stem injury

Objective

This study was conducted to assess the clinical significance of traumatic brain stem injury (TBSI) reflected on Glasgow Coma Score (GCS) and Glasgow Outcome Score (GOS) by various clinical variables.

Methods

A total of 136 TBSI patients were selected out of 2695 head-injured patients. All initial computerized tomography and/or magnetic resonance imaging studies were retrospectively analyzed according to demographic- and injury variables which result in GCS and GOS.

Results

In univariate analysis, mode of injury showed a significant effect on combined injury (p<0.001), as were the cases with skull fracture on radiologic finding (p<0.000). The GCS showed a various correlation with radiologic finding (p<0.000), mode of injury (p<0.002), but less favorably with impact site (p<0.052), age (p<0.054) and skull fracture (p<0.057), in order of statistical significances. However, only GOS showed a definite correlation to radiologic finding (p<0.000). In multivariate analysis, the individual variables to enhance an unfavorable effect on GCS were radiologic finding [odds ratio (OR) 7.327, 95% confidence interval (CI)], mode of injury (OR; 4.499, 95% CI) and age (OR; 3.141, 95% CI). Those which influence an unfavorable effect on GOS were radiologic finding (OR; 25.420, 95% CI) and age (OR; 2.674, 95% CI).

Conclusion

In evaluation of TBSI on outcome, the variables such as radiological finding, mode of injury, and age were revealed as three important ones to have an unfavorable effect on early stage outcome expressed as GCS. However, mode of injury was shown not to have an unfavorable effect on late stage outcome as GOS. Among all unfavorable variables, radiological finding was confirmed as the only powerful prognostic variable both on GCS and GOS.     

Divided attention and mental effort after severe traumatic brain injury

The aim of this study was to assess dual-task performance in TBI patients, under different experimental conditions, with or without explicit emphasis on one of two tasks. Results were compared with measurement of the subjective mental effort required to perform each task. Forty-three severe TBI patients at the subacute or chronic phase performed two tasks under single- and dual-task conditions: (a) random generation; (b) visual go-no go reaction time task. Three dual-task conditions were given, requiring either to consider both tasks as equally important or to focus preferentially on one of them. Patients were compared to matched controls. Subjective mental effort was rated on a visual analogic scale. TBI patients showed a disproportionate increase in reaction time in the go-no go task under the dual-task condition. However, they were just as able as controls to adapt performance to the specific instructions about the task to be emphasised. Patients reported significantly higher subjective mental effort, but the variation of mental effort according to task condition was similar to that of controls. These results suggest that the divided attention deficit of TBI patients is related to a reduction in available processing resources rather than an impairment of strategic processes responsible for attentional allocation and switching. The higher level of subjective mental effort may explain why TBI patients frequently complain of mental fatigue, although this subjective complaint seems to be relatively independent of cognitive impairment.     

64例弥漫性轴索损伤的临床特点与预后分析

目的 分析脑弥漫性轴索损伤(diffuse axonal injury,DAI)的临床特征及其预后因素。方法 按Levi分级法依据入院时GCS和瞳孔情况,将我科1997年1月至2000年7月收治的64例DAI病人分为Ⅰ～Ⅳ级,分析各级临床特点、入院时GCS和瞳孔变化与预后(GOS)的关系。结果 Ⅰ级2例(1/64),Ⅱ级8例(2/64),Ⅲ级18例(18/64),Ⅳ级36例(36/64)。Ⅲ、Ⅳ级的入院时GCS均明显低于Ⅱ级(P<0.05),其昏迷时间明显长于Ⅱ级(P<0.01)。预后按GOS分5级:恢复良好组、中残组、重残组、植物状态组及死亡组。死亡组年龄分别大于中、重残组(P<0.05)。死亡组GCS分别低于中、重残组(P<0.05),植物状态组GCS低于中残组(P<0.05)。死亡组瞳孔改变发生率分别高于中、重残组(P<0.05)。结论 入院时GCS和瞳孔情况有助于对DAI病情判断及预后估计。     

轻度颅脑损伤患者执行功能障碍研究

目的探讨轻度颅脑损伤(mild traumatic brain injury,m TBI)患者伤后执行功能(executive function,EF)的动态变化特点。方法对63例m TBI患者(研究组)在伤后1周、1个月、3个月和6个月进行执行功能测查,并与60例健康受试者(对照组)比较。测查工具采用连线测验(trail making test,TMTA)、霍普金斯词语学习测验修订版(Hopkins verbal learning test-revised,HVLT-R)、简易视觉记忆测验—修订版(brief visuospatial memory test-revised,BVMT-R)、Stroop色词测验、持续操作测验(continuous performance test,CPT)。结果伤后1周与对照组比较,TMTA、HVLT-R、BVMT-R、Stroop和CPT-IP分值差异有统计学意义(P0.05);与伤后1周相比,伤后1个月、3个月和6个月时的TMTA分值下降,HVLT-R、BVMT-R、Stroop和CPT-IP分值增加(P0.05)。组内两两比较,伤后1个月与伤后1周比较,TMTA分值下降,BVMT-R、Stroop分值增加(P0.05);伤后3个月与伤后1个月比较,Stroop、BVMT-R和CPT-IP分值增加(P0.05);伤后6个月与伤后3个月比较,Stroop和CPTIP分值增加(P0.05)。结论m TBI患者在注意能力/警觉性、学习与工作记忆、信息处理速度及执行功能上都可能存在一定的损害,伤后不同时间点恢复速度并不一致。     

轻度颅脑损伤患者的执行功能研究

背景 颅脑损伤常遗留神经精神的损害,包括认知功能损害、精神病性障碍和行为问题等.认知功能损害是颅脑损伤后常见的后遗问题,其中执行功能是一个十分重要的维度.轻度颅脑损伤一直被认为是脑遭受外力打击后出现的暂时的脑功能障碍,无肉眼可见的器质性损害.近年来这一传统的观点受到质疑,目前国内外一些学者认为轻度颅脑损伤是一种弥漫性的脑损伤.关于轻度颅脑损伤患者的神经心理学研究是众多研究者争论的焦点,观点不一致.本研究对恢复期的颅脑损伤患者进行执行功能评定,目的是探讨轻度颅脑损伤患者的执行功能状况.方法 对159例因交通事故造成颅脑外伤的幸存者于损伤后3～6个月医疗终结后进行执行功能评定,并与68例正常人对照.病例组的入组标准为①年龄16～65岁;②文化程度小学及以上文化,能理解执行功能测验的内容;③右利手;④有明确的脑损伤史;⑤检查前4周内未使用抗精神病药物或其他影响中枢神经系统功能的药物;⑥资料齐全;⑦自愿参加本研究.正常对照组的入组标准为①年龄16～65岁;②文化程度小学及以上文化,能理解认知功能测验的内容;③右利手;④自愿参加本研究.排除标准为①以往有脑损伤史、脑部疾患史、精神疾病史者;②精神发育迟滞者;③严重的躯体疾患者;④有药物、酒精或其他影响中枢神经系统功能的物质滥用史者;⑤色盲、色弱者;⑥对测验不合作或不能有效完成测验者.病例组分组根据颅脑损伤伤情评定的国际标准格拉斯哥昏迷计分法将病例组分成三组轻度脑损伤组78例(49.1%)GCS评分15～13分,伤后昏迷时间＜20 min;中度脑损伤组52例(32.7%)GCS评分12～9分,伤后昏迷时间20 min至6 h;重度脑损伤组29例(18.2%)GCS评分8～6分,伤后昏迷时间＞6 h.测验包括韦氏智力测验中的木块拼图测验、STROOP测验、威斯康辛卡片分类测验-改良版(M-WCST)和词汇的流畅性测验,比较轻度颅脑损伤与中、重度颅脑损伤患者的测验成绩,以及CT/MRI有无阳性发现患者的测验成绩,分析与执行功能有关的因素.结果 轻度颅脑损伤患者所有的测验成绩均低于正常对照组,其差异达到显著性水平(P＜0.01).而与中度损伤组的成绩比较则没有显著性差异(P＞0.05).在轻度组与重度组的比较中,除STROOP测验和WCST的分类个数外,其余测验成绩均存在显著性差异(P＜0.05).CT/MRI结果为阳性的病例中,不同脑损伤程度组间的执行功能检测成绩除木块拼图测验外均不具有显著性差异;CT/MRI结果为阴性的病例中,结果显示不同脑损伤程度组间的执行功能测验成绩没有显著性差异(P＞0.05).相关分析显示木块拼图和词汇流畅性两个测验成绩与脑损伤程度呈负相关(P＜0.05).年龄和执行功能呈负相关,受教育程度与执行功能呈正相关.结论 轻度颅脑损伤患者在医疗终结时仍然存在执行功能损害.我们在伤残评定中应对轻度颅脑损伤患者予以重视,同时要注意综合多方面的检测结果考虑.     

Unilateral acute foot drop due to diffuse axonal injury after head trauma

Acute foot drop due to diffuse axonal injury (DAI) has not been previously described in the literature. In this report, we present a patient with unilateral acute foot drop caused by a DAI lesion after head trauma.     

直线加速度所致的猫弥漫性轴突损伤

目的：为了解直线加速度在颅脑损伤特别是在弥漫性轴突损伤（ＤＡＩ）中的作用。方法：用一套撞击装置对２６只猫进行实验。结果：直线加速度可以导致几乎所有类型的颅脑损伤，包括颅骨骨折、蛛网膜下腔出血、硬膜下血肿、硬膜外血肿、脑挫伤、脑干损伤，特别是ＤＡＩ。ＤＡＩ的特征性改变－轴突回缩球在２４小时内死亡的动物脑标本中看不到，２４小时后可见到，７２小时则多而典型，７天时仍然存在。结论：凡能使脑的神经纤维受到广泛剪力和（或）张力的任何形式的外部作用均可产生ＤＡＩ。     

Exploring the roles of the executive and short-term feature-binding functions in retrieval of retrograde autobiographical memories in severe traumatic brain injury

Conway’s autobiographical memory (AM) model postulates that memories are not stored in a crystallised form in long-term memory but are reconstructed at time of retrieval via executive and binding processes, to create a temporary multimodal representation from different AM knowledge. Traumatic brain injury (TBI) impairs AM recollection. However, no study has yet considered the distinct roles of executive and short-term feature-binding functions in the retrieval deficits of retrograde AMs after TBI. Examining a group of 33 TBI patients and 33 controls, our study addresses these roles through a first-ever exploration of the links between performance on an AM verbal fluency evaluation that distinguishes four levels of representation, from semantic to episodic (lifetime periods, general events, specific events, specific details of a specific event), and three executive functions (shifting, inhibition and updating) and two short-term feature-binding functions (short-term formation and maintenance of multimodal representations). The results showed that TBI patients were impaired compared to controls in the retrieval of both semantic and episodic retrograde AM representations, but especially for the most episodic level of AM, in the three executive functions and the short-term maintenance of multimodal representations. Regression analyses indicated that the executive predictors (mainly updating) mediated a large proportion (over 70%) of TBI-related deficit on the retrieval of lifetime periods, general events and specific events, in contrast with the main impairment on generation of specific details which were only mildly (just 12%) predicted by the short-term maintenance of multimodal representations. Additional analyses in a subgroup of patients point to episodic memory abilities and time since injury in predicting the retrieval of specific events and details. In summary, the present study mainly emphasizes that the executive deficits in TBI are involved in the disruption of the first levels of AM generative processes that give access to the multiple episodic details recollection.     

华东地区颅脑交通伤临床及流行病学特点

目的调查与研究华东地区的颅脑交通伤流行病学,为颅脑交通伤的预防与治疗提供科学依据。方法从2004年华东六省一市颅脑创伤住院患者数据库中整群抽取颅脑交通伤患者,用SPSS 13.0统计软件包分析。结果 7 369例颅脑交通伤患者中男女之比为2.72:1。平均年龄(39.28±16.51)岁。25～44岁年龄组所占比例最大,为43.7%。受伤人员中行人所占比例最大,为33.3%。以每年1月份发生颅脑交通伤最多,占13.90%。一天中有一半以上的颅脑交通伤发生在上午7～10时及下午5～9时,分别占23.7%和31.5%。所有住院患者中死亡858例(11.6%),存活6511例(88.4%)。Logistic回归分析显示年龄、颅脑损伤严重度、首送医院、省份、交通伤发生的季度和医院等级等都是影响患者住院期间死亡的重要因素。结论我国应加大颅脑交通伤高发时间段,也就是一天中的早晚上下班高峰以及一年中的第一季度尤其是1月份的道路交通管理,加强中青年男性的道路安全教育,加大对高龄人群的道路交通保护。     

Pre-injury assessment of everyday executive function in moderate to severe traumatic brain injury

Executive dysfunction is frequently observed in moderate to severe traumatic brain injury (TBI) and is commonly assessed with objective measures or subjective rating scales. Given the variability in executive function in the normal population, a reliable measure of pre-injury executive function would be of considerable value. In this study we examined pre-injury self and collateral (relative or friend) ratings on the Frontal Systems Behavior Rating Scale (FrSBe). Fifty-one persons with moderate to severe TBI and their collaterals provided before- and after-TBI ratings at 3 months post injury. A subset of 36 dyads were retested at 6 and 12 months; 26 neurologically intact controls and their collaterals also provided FrSBe ratings. At 3 months post injury, the difference between patient and collateral ratings of current status was larger than the difference relating to premorbid status, suggesting that patients were able to rate themselves from a pre-injury perspective. However, pre-injury ratings from collaterals were more reliable over time compared with patients’ self-ratings. For all sets of ratings – before injury, after injury, and status of healthy controls – collateral ratings indicated more abnormality, overall, than comparable self-ratings. Evaluating one’s own executive behaviour may be a difficult task even without TBI, with the difficulty exacerbated by the effects of injury.     

大鼠弥漫性轴索损伤后神经元超微结构的观察研究

目的 探讨大鼠弥漫性轴索损伤(DAI)后神经轴索与神经元胞体超微结构特征与动态变化规律.方法 选用32只SD成年大鼠,其中对照组4只,损伤组28只.采用自制头颅旋转致伤装置,将损伤组大鼠头颅在冠状面绕脑组织中心逆时针旋转90°造成剪力伤,于伤后30 min、2 h、6 h、12 h、24 h、36 h、72 h分批处死大鼠并取脑组织制作成电镜样品,于透射电镜下观察.结果 损伤组大鼠伤后可见轴索肿胀、断裂等形态学改变;各组轴索受损程度计分分别与对照组比较,结果显示损伤组受损程度显著重于后者(P<0.05).神经元胞体的形态学改变在伤后2 h开始出现,伤后各组受损程度计分分别与对照组比较,30 min组和72 h组与对照组无显著性差异(P＞0.05),其余各组受损程度显著重于对照组(P<0.05).结论 DAI是原发损伤与继发损伤共同作用的病理生理过程,继发损伤加重轴索损伤,引起相应的临床症状;轴索损伤与神经元胞体的受损机制不同,病理过程不同步.     

Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs

Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 microg/kg rFVIIa (n=5) or vehicle control (n=5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI.     

Regional and temporal characterization of neuronal, glial, and axonal response after traumatic brain injury in the mouse

Fluid percussion injury (FPI) is a commonly used and clinically relevant model of traumatic brain injury (TBI) in the rat. Recently, our lab successfully adapted FPI to mice. To account for differences in response to injury between mice and rats and provide a foundation for further use of FPI in gene-targeting studies, we sought to characterize the temporal and regional response to FPI in male C57BL/6 mice. Animals were killed at 10 min, 24 h, and 4, 7, 14, and 35 days (n = 3 for each group) after a very severe parasagittal FPI (> 4.0 atm) or sham injury (n = 3). Extensive numbers of damaged neurons were consistently found in the ipsilateral cortex, thalamus, and hippocampus by 10 min. This damage was nearly identical at 24 h, but quickly declined at subsequent time points. Activated microglia were found only in regions of neuronal injury at the earliest time points. Glial fibrillary acidic protein immunoreactivity reached significantly higher levels compared with controls at 7 days (P < 0.05) in the cortex, thalamus, and hippocampus and remained elevated for 35 days. White matter degeneration was present in all regions examined. This damage did not appear until at least day 4, but progressed up to day 35. The spatial pattern of damage we observed in mice after FPI is similar to that seen in rats. However, the temporal progression of neuronal injury in mice is comparatively abbreviated in the hippocampus and thalamus. In conclusion, these results suggest that FPI in mice may be a particularly useful tool for studying mechanisms of TBI in gene-targeting studies. Received: 13 October 1998 / Revised: 22 February 1999 / Accepted: 24 March 1999